TW201206448A - Methods of treating platinum-sensitive recurrent ovarian cancer with 4-iodo-3-nitrobenzamide in combination with an anti-metabolite and a platinum compound - Google Patents

Abstract

The present invention provides a method of treating platinum-sensitive recurrent ovarian cancer in a patient, comprising administering to the patient an effective amount of 4-iodo-3-nitrobenzamide or a metabolite or a pharmaceutically acceptable salt thereof; gemcitabine; and carboplatin.

Description

201206448 六、發明說明： 相關申請案 本申請案主張2010年6月4曰提交之美國臨時申請案第 US 61/351，785號及2011年5月2日提交之美國臨時申請案第 US 61/481，634號的優先權權益，該等文獻均以全文引用的 方式併入本文中。 【先前技術】 癌症為一個複雜的疾病家族，其影響著身體中的幾乎每 一個組織且特徵在於對細胞生長之控制異常。所有癌症類 型之每年發病率估計僅在美國就超過130萬例。雖然已經 運用了多種一線療法來治療不同類型之癌症並獲得了不同 程度的成功，包括手術切除、放射療法、化學療法及激素 療法’但是其仍然為美國位居第二位的死亡原因，估計每 年有56萬美國人死於癌症。 卵巢癌為全世界女性中第8位最常見的癌症，估計每年 有225,500個新診斷病例且估計每年有14〇,2〇〇例死亡。卵 巢癌一線化學療法之目前的醫護標準為鉑化合物（例如順 在白（cisplatin)、卡#及奥沙利翻（oxaiipiatin))與紫杉院 (taxane)之組合。大多數新近診斷之印巢癌患者會對一線 基於鉑的及太平洋紫杉醇（paclitaxel)之化學療法有反應。 然而，在對此種組合療法有反應之患者中50-80%會最終復 發。參見例如 Herzog, 「Update on the role of topotecan in the treatment of recurrent ovarian cancer」，77ze 7(增刊5): 3-10 (2002)。患有晚期卵巢癌之女性因疾病復發 156510.doc 201206448 而具有較差的長期存活率且大多在5年内死亡。顯然需要 改進復發性卵巢癌的當前治療選項。 【發明内容】 本文中提供一種治療患者之鉑敏感性復發性印巢癌的方 法，包括投與該卵巢癌患者有效量之（i) 4-碘-3-硝基苯曱 醯胺（4-iodo-3-nitrobenzamide)、其代謝產物或其醫藥學上 可接受之鹽，（ii)吉西他濱；及（iii)卡翻。在一些實施例 中，該始敏感性復發性卵巢癌為上皮卵巢癌。在一些實施 例中，該鉑敏感性復發性卵巢癌為法婁皮歐氏管（faU〇pian tube，即輸卵管）癌。在一些實施例中，該鉑敏感性復發性 卵巢癌為原發性腹膜癌。在一些實施例中，該治療包括至 少約1個治療週期（例如約2個週期、3個週期、4個週期、5 個週期、6個週期、7個週期、8個週期、9個週期、1〇個週 期、11個週期、12個週期、13個週期、14個週期、Η個週 期、16個週期、17個週期或18個週期中之任一者），其中 每一個週期（或該等週期中之每一者）包括投與有效量2⑴ 4-碘-3-硝基苯甲醯胺、其代謝產物或其醫藥學上可接受之 鹽；⑼吉©⑽’·及㈣卡始。在—些實施例中，該治療 。括至夕、力4個至約12個治療週期，其中該等週期中之每 一者包括投與有效量之⑴4_蛾〜肖基苯甲酿胺、其代謝 產物或其㉝藥學上可接受之鹽；⑴）吉西他濱；及（出)卡 翻°在一些實施例中’該患者在復發背景下先前未曾接受 過:胞母性化學療法。在—些實施例中，該有效量在^天 之《療週期内投與’其中⑴卡翻在治療週期之第1天以4 156510.doc 201206448 mg/m卜min (AUC 4)投與該患者；（ii)吉西他濱在治療週期 之第1天及第8天以looo mg/m2之劑量投與該患者；且（iii) 4-碘-3-硝基苯曱醯胺或其代謝產物或醫藥學上可接受之鹽 在治療週期之第1天、第4天、第8天及第11天每週兩次以 5.6 mg/kg之劑量投與該患者。在一些實施例中，該有效量 產生至少一種選自由以下組成之群的治療效果：卵巢腫瘤 大小縮小，轉移減少，完全緩解，部分緩解，疾病穩定， 總反應率升高，或病理完全反應（path〇1〇gi(； complete response)。在一些實施例中’該方法進一步包括手術、放 射療法、化學療法、基因療法、DNA療法、病毒療法、 RNA療法、輔助療法、新辅助療法、免疫療法、奈米療法 或其組合。在一些實施例中，該方法進一步包括投與該患 者γ輻射。在一些實施例中’該患者患有鉑敏感性復發性 印巢癌。在一些實施例中，該鉑敏感性復發性卵巢癌係選 自由以下組成之群：上皮腫瘤、生殖細胞腫瘤及基質細胞 腫瘤。在一些實施例中，該鉑敏感性復發性卵巢癌為轉移 性的《在一些實施例中，該患者患有鉑敏感性復發性卵巢 癌。在一些實施例中，4_碘_3_硝基苯甲醯胺、其代謝產物 或其醫藥學上可接受之鹽經靜脈内投與。在一些實施例 中’吉西他濱經靜脈内投與。在一些實施例中，卡銘經靜 脈内投與。在一些實施例中，該患者患有可測得的疾病。 在一些實施例中’該治療提供與投與吉西他濱及卡鉑但 不投與4-碰-3-硝基苯曱醯胺之治療相比提高的臨床效益 率。在一些實施例中，獲得了與投與吉西他濱及卡鉑但不 156510.doc 201206448 投與4-碘-3-硝基苯曱醯胺之治療相比提高的臨床效益率 (CBR=CR(完全緩解）+PR(部分緩解）+SD(疾病穩定公6個 月）。在一些實施例中，使臨床效益率提高約20%或更高。 在一些實施例中，該治療效果為總反應率升高。在一些實 施例中，總反應率大於40%。在一些實施例中，總反應率 大於5 0%。在一些實施例中，總反應率大於60%。 在一些實施例中，患者患有鉑敏感性復發性卵巢癌。在 一些實施例中，該鉑敏感性復發性卵巢癌在同源重組DNA 修復上有缺陷。在一些實施例中，同源重組DNA修復缺陷 型鉑敏感性復發性卵巢癌為BRCA缺陷型。在一些實施例 中’ BRCA缺陷型鉑敏感性復發性卵巢癌為BRCA1缺陷 型。在一些實施例中，BRCA缺陷型鉑敏感性復發性即巢 癌為BRCA2缺陷型。在一些實施例中，BRCA缺陷型鉑敏 感性復發性卵巢癌既為BRCA1缺陷型又為BRCa2缺陷型。 本文中亦提供本文所述之任何醫藥組合物用於製造用以 治療鉑敏感性復發性卵巢癌之藥物的用途。例如，本文中 提供之用途與本文所述之任何方法有關或一致。 本文中亦提供⑴4-碘-3-硝基苯甲醯胺、其代謝產物或 其醫藥學上可接受之鹽或溶劑合物合併(Η)抗代謝產物、 其醫藥學上可接受之鹽或溶劑合物中之任一者及㈣本文 所述之翻化合物、其f藥學上可接受之鹽或溶劑合物令之 任一者用於製造用以治療或肋本文所述之_感性復發 性即巢癌之藥物的用途。本文中亦提供4冬3“肖基苯甲酿 扣、其代謝產物或其醫藥學上可接受之鹽或溶劑合物用於 1565I0.doc 201206448 製造用以與抗代謝產物（例如吉西他濱）及鉑化合物（例如卡 鉑）組合來治療或預防本文所述之鉑敏感性復發性卵巢癌 之藥物的用途。本文中亦提供4·碘-3-硝基苯甲醯胺、其代 謝產物或其醫藥學上可接受之鹽或溶劑合物用於製造用以 治療或預防本文所述患者之鉑敏感性復發性卵巢癌之藥物 的用途，其中4-碘-3-硝基苯甲醯胺、其代謝產物或其醫藥 學上可接受之鹽或溶劑合物欲與抗代謝產物（例如吉西他 濱）及鉑化合物（例如卡鉑）組合來投與患者。 本文中亦提供用於治療患者之鉑敏感性復發性卵巢癌的 協同組合物，包括投與該患者a) 4-碘-3-硝基苯甲醯胺或其 代謝產物或其醫藥學上可接受之鹽或溶劑合物，b)抗代謝 產物，及c)鉑化合物，其中該抗代謝產物係選自由以下組 成之群：西他濱（citabine)、卡培他濱（capecitabine)、吉西 他濱（gemcitabine)或伐洛比西他濱（valopicitabine)，且其 中該鉑化合物係選自由以下組成之群：順鉑（cisplatin); 順-二胺二水合始（Π)-離子（cis-diamminediaquoplatinum (II)-i〇n)；氯（二伸乙基三胺）-鉑（II)氯化物（chloro (diethylenetriamine)-platinum (II) chloride);二氯（伸乙 基二胺）-韵（II) (dichloro(ethylenediamine)-platinum (II));二胺（1,1-環丁烧二緩根基）| 自（II) (diammine(l,l-cyclobutanedicarboxylato) platinum (11))(卡翻（carboplatin)); 螺翻（spiroplatin);異丙翻（iproplatin);二胺（2-乙基丙二 酸根基）翻（Π) (diammine(2-ethylmalonato)platinum (II)); 伸乙基二胺丙二酸翻（II) (ethylenediaminemalonatoplatinum 156510.doc 201206448 (II));水合（1，2-二胺基二環己院）硫酸鉑（II) (aqua(l，2-diaminodicyclohexane)sulfatoplatinum (II));水合（1，2-二胺 基二環己烧）丙二酸翻（Π) (aqua(l，2-diaminodicyclohexane) malonatoplatinum (II)) ; (1，2-二胺基環己烧）丙二酸始（II) ((l，2-diaminocycloliexane)malonatoplatinum (II)); (4-叛基 酿酸根基）（1，2-二胺基環己烧）鉑（II) ((4-carboxyphthalato) (l，2_diaminocyclohexane) platinum (II)); (1，2-二胺基環己 烧）-(異檸檬酸）I白（II) ((1,2-diaminocyclohexane)-(isocitrato)platinum (II)); (1，2-二胺基環己烧）草酸銘（II) ((1,2-diaminocyclohexane)oxalatoplatinum (II));奥馬始 (ormaplatin);四翻（tetraplatin);卡銘（carboplatin);奈達 舶（nedaplatin);及奥沙利翻（oxaliplatin)。 本文中亦提供用於治療患者之鉑敏感性復發性卵巢癌的 套組。在一些實施例中，該等套組包含（a) 4-碘-3-硝基苯 甲醯胺或其代謝產物或其醫藥學上可接受之鹽或溶劑合 物、（b)抗代謝產物及（c)鉑化合物。該等套組可進一步包 含產品或包裝插頁或標籤，其包含關於依照本文所述之任 何方法使用有效量之（a) 4-碘-3-硝基苯甲醯胺或其代謝產 物或其醫藥學上可接受之鹽或溶劑合物、（b)抗代謝產物及 (c)鉑化合物的用法說明及/或資訊。在一些實施例中，該 等套組包含4-碘-3-硝基苯甲醯胺或其代謝產物或其醫藥學 上可接受之鹽或溶劑合物及產品或包裝插頁或標籤，其包 含關於依照本文所述之任何方法使用有效量之4-碘-3-硝基 笨甲醯胺或其代謝產物或其醫藥學上可接受之鹽或溶劑合 156510.doc 201206448 物與抗代謝產物（例如吉西他濱）及麵化合物（例如卡始）組 合來治療患者之鉑敏感性復發性卵巢癌的用法說明及/或 資訊。在一些實施例中，抗代謝產物為吉西他濱，且鉑化 合物為卡鉑。在一些實施例中，該有效量在21天之治療週 期内投與’其中⑴卡鉑在治療週期之第i天以4 mg/mhmin (AUC 4)投與該患者，（ii)吉西他濱在治療週期之第1天及 第8天以1000 mg/m2之劑量投與該患者；且（iH) 4•碘_3硝 基本甲醯胺或其代謝產物或醫藥學上可接受之鹽在治療週 期之第1天、第4天、第8天及第11天每週兩次以5 6 mg/kg 之劑量投與該患者。在一些實施例中，該鉑敏感性復發性 卵巢癌為上皮卵巢癌、法婁皮歐氏管癌或原發性腹膜癌。 在些貫施例中’該患者在復發背景下先前未曾接受過細 胞毒性化學療法。在一些實施例令，該患者患有可測得的 疾病。 應瞭解，可組合本文所述之各個實施例的一個、一些或 所有特性以形成本發明之其他實施例。本發明之此等及其 他態樣對於熟習此項技術者會變得顯而易見。 以引用方式併入 本說明書中提及之所有公開案及專利申請案以引用方式 併入本文中，其引用程度就如同明確地且個別地指定將各 個別公開案或專利申請案以引用方式併入一般。 【實施方式】 本發明之新穎特徵精確地闡述於隨附申請專利範圍中。 藉由參照下面的[實施方式]及隨附圖式可更好地理解本發 156510.doc 201206448 明之特徵及優勢，該[實施方式]闡述利用本發明原理之說 明性實施例。如本文中使用之術語「鉑敏感性（platinum-sensitive) 」 指一類 卵巢癌 （例如 復發性 卵巢癌 ） 。 卵 巢癌一 線化學療法之目前的醫護標準（current standard of care)為 銘化合物（例如順翻、卡翻及奥沙利始）與紫杉烧之組合β 大多數新近診斷之卵巢癌患者會對一線基於鉑的及太平洋 紫杉醇之化學療法有反應。然而，在對此種組合療法有反 應之患者中50-80%會最終復發。參見例如Herz〇g， 「Update on the role of topotecan in the treatment of recurrent ovarian cancer，」 TTie Onco/ogi&quot; 7(增刊 5): 3_i〇 (2002)。在6個月内復發之患者不大可能對第二輪基於鉑之 療法有反應。因此’若復發發生於最後一劑基於始之療法 後超過6個月時’則復發的晚期卵巢癌腫瘤歸類為「鉑敏 感性」；若復發發生於最後一劑基於鉑之療法後不到或等 於6個月時，則歸類為「鉑抗性」；若在初始基於鉑之療法 期間k有發生反應或疾病消退’則歸類為「麵不應性 (platinum-refractory)」。 如本文中使用之「手術」指任何涉及手或手及器械對人 或其他哺乳動物之身體有方法的作用（meth〇dical acti〇n)以 產生治癒、補救或診斷效果的治療或診斷程序。 放射療法」彳a使患者暴露於高能輕射，包括但不限於 X-射線、γ射線及中子。此類療法包括但不限於外線束療 法、内部放射療法、植入性放射、近接療法、系統放射療 法及放射療法。 156510.doc •11· 201206448 「化學療法」指藉由各種方法對患有鉑敏感性卵巢癌 (例如復發性卵巢癌）之患者投與一種或多種抗癌藥物，諸 如抗贅生性化學治療劑、化學預防劑及/或其他藥劑，該 等方法包括靜脈内、口服、肌肉内、腹膜内、膀胱内、皮 下、經皮、經頰或吸入或以栓劑的形式。除非上下文另有 明確說明，否則如本文中使用之「化學療法」不意指如本 文所述投與4-碘-3-硝基苯甲醯胺、抗代謝產物（例如吉西 他濱）及鉑化合物（例如卡鉑）。化學療法可在手術前給予以 在切除大腫瘤之手術程序前使其縮小，在放射療法前給 予，或在手術及/或放射療法後給予以預防身體中任何殘 餘卵巢癌細胞的生長。化學療法亦可發生於放射療法過程 期間。 術語「有效量」或「醫藥學有效量」指某藥劑足以提供 所要之生物學、治療及/或預防效果的量。該效果可為某 疾病之一種或多種跡象、症狀或原因的減少及/或減輕， 或者生物學系統之任何其他所要的變化。例如，用於治療 用途之「有效量」為本文中提供的約4_碘_3_硝基苯甲醯胺 或其代謝產物或其醫藥學上可接受之鹽或溶劑合物、…抗 代謝產物（例如吉西他濱）或其醫藥學上可接受之鹽或溶劑 合物、及c)鉑化合物（例如卡鉑）或者包含本文中提供的昀 4-碘-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可接受之 鹽或溶劑合物、b)抗代謝產物（例如吉西他濱）或其醫藥學 上可接受之鹽或溶劑合物、及幻鉑化合物（例如卡鉑）之組 合物在臨床上顯著地減輕鉑敏感性卵巢癌（例如復發性卵 156510.doc 201206448 巢癌）或 &gt;咸緩翻敏感性印巢癌（例如復發性印巢癌）進展所需 要的量。 「代謝產物」指經由任何活體外或活體内代謝過程產生 之化。物’ β過程產生在結構上與起始化合物不同的產 物。換言之，術語「代謝產物」包括4-埃-3-石肖基苯甲酿胺 之代謝產物化合物。代謝產物相對於前體化合物可包括存 在於任何位置處之不同數目或類型的取代基。另外，術語 「代謝產物」及「代謝產物化合物」在本文中可互換使 用。 邊藥學上可接受之」意謂某材料在生物學或其他方面 皆無不良之處’亦即該材料可投與患者而不會引起任何不 想要的生物學效應或以.有害方式與包含其之組合物的任何 成分相互作用。 如本文中使用之術語「治療」及其語法同義詞包括實現 治療好處及/或預防好處。治療好處意指所治療之潛在病 症的根除或改善。例如，在具有鉑敏感性卵巢癌（例如復 發性卵巢癌）之患者中，治療好處包括潛在印巢癌之根除 或改善，例如減緩該卵巢癌之進展。此外，治療好處以一 種或多種與潛在病症（例如卵巢癌）有關之生理症狀的根除 或改善來實ί見’以冑得儘管存在患者可能仍受該潛在病症 (例如卵巢癌）折磨之實情，但仍在該患者中觀察到改善。 對於預防好處，可對有患上鉑敏感性卵巢癌（例如復發性 卵巢癌）之風險的患者或對報告有鉑敏感性卵巢癌（例如復 發性卵巢癌）之一種或多種生理症狀的患者執行本發明方 156510.doc •13· 201206448 法或投與本發明組合物，即使可能尚未作出鉑敏感性印巢 癌（例如復發性印巢癌）之診斷亦然。在一些實施例中，所 治療之患者已被診斷有本文所述之始敏感㈣巢癌（例如 復發性卵巢癌）。 本文中k到約」某數值或參數包括（並描述）針對該數 值或參數本身之變化。例如，提到「約X」之描述包括 「X」之描述。 除非上下文另有明確說明’否則如本文中及隨附申請專 利範圍中使用之單數形式「一(個/種)」、「或」&amp;「該」包 括複數所指物。應瞭解，本文中描述之本發明的各態樣及 各變體包括「由」及/或「基本上由」各態樣及各變體 「組成」。 卵巢癌之治療 印巢腫瘤有三種基本類型：上皮、生殖細胞及基質細胞 腫瘤。上皮腫瘤始自覆蓋印巢外表面之細胞；纟多數印巢 腫瘤為上皮細.胞腫瘤。生殖細胞腫瘤始自生成卵子之細 胞》基質腫瘤始自使印巢合在一起及生成***之2 胞。 卵巢癌之重要風險因子包括在同源重組DNA修復上有缺 陷，諸如BRCA1或BRCA2基因之突變。彼等基因最初在有 多例乳腺癌之家族中鑑定出，但是已經與大約5%至1〇%之 卵巢癌聯繫起來。 ° 可能的卵巢癌治療包括手術、免疫療法、化學療法、激 素療法、放射療法或其組合。用於治療卵巢癌之手術程^ 156510.doc •14- 201206448 包括大塊切除術（debulking)及單側或雙側卵巢切除術及/或 單側或雙側輸卵管切除術。亦已用於治療卵巢癌之抗癌藥 包括環碳酿胺、依託泊苦（etoposide)、六甲蜜胺 (altretamine)及異環磷醯胺。使用藥物他莫昔芬 (tamoxifen)之激素療法亦用於使卵巢腫瘤縮小。放射療法 視情況包括外線束放射療法及/或近接療法。 在一個態樣中’本文中提供治療患者之鉑敏感性復發性 卵巢癌的方法’包括投與該患者4-埃-3-硝基苯曱醯胺或其 代謝產物或其醫藥學上可接受之鹽、抗代謝產物及鉑化合 物。在一些實施例中’抗代謝產物係選自由以下組成之 群：西他濱、卡培他濱、吉西他濱或伐洛比西他濱。在一 些實施例中，抗代謝產物為吉西他濱。在一些實施例中， 翻化合物係選自由以下組成之群：順鉑；順-二胺二水合 始（11)_離子；氯（二伸乙基三胺）-鉑（II)氯化物；二氯（伸乙 基二胺）-翻（II);二胺（丨山環丁烷二羧根基）鉑（π)(卡鉑）； 螺鉑；異丙鉑；二胺（2-乙基丙二酸根基）鉑;伸乙基二 胺丙二酸銘（II);水合（1，2-二胺基二環己烷）硫酸鉑（π); 水合（1，2-二胺基二環己烷）丙二酸鉑（π) ; (i,2二胺基環己 烷）丙二酸鉑（Π) ; (4·羧基酞酸根基）（1，2-二胺基環己烷）鉑 (II)，（1’2-二胺基環己烷η異檸檬酸）始; (1，2_二胺基 環己烷）草酸鉑（H);奥馬鉑；四鉑；卡鉑；奈達鉑；及奥 利翻，且較佳為卡始或奥沙利始。在一些實施例中祐 化合物為卡鉑。例如，提供一種治療患者之鉑敏感性復發 性卵巢癌的方法，包括投與有效量之⑴4-碘-3-硝基苯曱 156510.doc 15· 201206448 醯胺或其代謝產物或其醫藥學上可接受之鹽；（⑴吉西他 濱；及㈣卡始。在-些實施财，該患者患有始敏感性 復發性卵巢癌。在一些實施例中，獲得了至少一種治療效 果，該至少一種治療效果為腫瘤大小縮小、轉移減少、完 全緩解、部分緩解、病理完全反應或疾病穩定。 在本文所述之任何方法的一些實施例中，該方法進一步 包括手術、放射療法、化學療法、基因療法、病毒療法、 RNA療法、DNA療法、輔助療法、新輔助療法、免疫療 法、奈米療法或其組合。在一些實施例中，該方法進一步 包括投與該患者γ輻射。在一些實施例中，鉑敏感性復發 性卵巢癌係選自由以下組成之群：上皮腫瘤、生殖細胞腫 瘤及基質細胞腫瘤。在一些實施例中，鉑敏感性復發性卵 巢癌為轉移性的。在一些實施例中，鉑敏感性復發性卵巢 癌不為轉移性的。在一些實施例中，鉑敏感性復發性卵巢 癌包含侵襲性惡，性腫瘤。在一些實施例中，鉑敏感性復發 性卵巢癌不包含侵襲性惡性腫瘤。 在一個態樣中’本發明提供一種治療患者之鉑敏感性卵 巢癌（例如鉑敏感性復發性卵巢癌）的方法，包括投與具有 卵巢癌（例如鉑抗性卵巢癌;)之患者有效量的：4-碘_3_硝 基笨甲醯胺或其代謝產物或醫藥學上可接受之鹽；（ii)吉 西他濱，及（ill)卡鉑。在—些實施例中，該有效量在21天 之治療週期内投與，其中⑴有效量之卡鉑在治療週期之第 1天以4 mg/m卜min (AUC 4)(或約AUC4)投與該患者；（ii)有 效量之吉西他濱在治療週期之第i天及第8天以丨〇〇〇 156510.doc • 16 - 201206448 mg/m2(或約1000 mg/m2)之劑量投與該患者；且（出）有效量 之4-碘-3-硝基苯曱醯胺或其代謝產物或醫藥學上可接受之 鹽在治療週期之第1天、第4天、第8天及第11天每週兩次 以5.6 mg/kg(或約5.6 mg/kg)之劑量投與該患者。在一些實 施例中’該有效量產生至少一種選自由以下組成之群的治 療效果：卵巢腫瘤大小縮小’轉移減少，完全緩解，部分 緩解’疾病穩定，總反應率升高，或病理完全反應。在一 些實施例中，獲得與投與吉西他濱及卡鉑但不投與4_攝_3_ 硝基苯曱醯胺之治療相比提高的臨床效益率（Cbr=cr(完 全緩解）+PR(部分緩解）+SD(疾病穩定沦6個月）。在—些實 施例中’使臨床效益率提高約20%或更高。在一些實施例 中，該治療效果為總反應率升高。在一些實施例中，總反 應率大於40°/。。在一些實施例中’總反應率大於5〇%。在 一些實施例中’總反應率大於60%。在一些實施例中，該 方法進一步包括手術、放射療法、化學療法、基因療法、 病毒療法、RNA療法、DNA療法、辅助療法、新辅助療 法、免疫療法、奈米療法或其組合。在一些實施例中，該 方法進一步包括投與該患者γ輻射。在一些實施例中，該 在白敏感性卵巢癌（例如鉑敏感性復發性卵巢癌）係選自由以 下組成之群：上皮腫瘤、生殖細胞腫瘤及基質細胞腫瘤。 在一些實施例中，該鉑敏感性卵巢癌為復發性卵巢癌。在 一些實施例中，該鉑敏感性卵巢癌（例如鉑敏感性復發性 印巢癌）為轉移性的。在一些實施例中，該鉑敏感性卵巢 癌（例如銷敏感性復發性卵巢癌）在同源重組DNA修復上有 156510.doc • 17· 201206448 缺陷。在一些實施例中，同源重組DNA修復缺陷型鉑敏感 性卵巢癌為BRCA缺陷型。在一些實施例中，BRCA缺陷型 鉑敏感性卵巢癌為BRCA1缺陷型。在一些實施例中’ BRCA缺陷型鉑敏感性卵巢癌為BRCA2缺陷型。在一些實 施例中，BRCA缺陷型鉑敏感性卵巢癌既為BRCA1缺陷型 又為BRCA2缺陷型。在一些實施例中，鉑敏感性復發性卵 巢癌包含BRCA1之突變。在一些實施例中’鉑敏感性復發 性卵巢癌包含BRCA2之突變。在一些實施例中，鉑敏感性 復發性卵巢癌包含BRCA1及BRCA2之突變。 在本文所述之任何方法的一些實施例中，鉑敏感性復發 性卵巢癌在同源重組DNA修復上有缺陷。在一些實施例 中》同源重組DNA修復缺陷型鉑敏感性復發性卵巢癌為 BRCA缺陷型。在一些實施例中，在卵巢癌患者中檢測到 BRCA基因之缺陷。在其他實施例中，該缺陷為BRCA基因 之遺傳缺陷&quot;在一些實施例中，該遺傳缺陷為BRCA基因 之突變、***、替代、複製或缺失。在一些實施例中，該 BRCA基因為BRCA-1。在其他實施例中，該BRCA基因為 BRCA-2 〇在一些實施例中，BRCA缺陷型鉑敏感性復發性 卵巢癌為BRCA1缺陷型。在一些實施例中，BRCA缺陷型 鉑敏感性復發性卵巢癌為BRCA2缺陷型。在一些實施例 中，BRCA缺陷型鉑敏感性復發性卵巢癌既為BRCA1缺陷 型又為BRCA2缺陷型。 在一些實施例中，提供一種治療鉑敏感性復發性卵巢癌 之方法，包括投與有效量之4-碘-3-硝基苯曱醢胺或其代謝 156510.doc • 18 - 201206448 產物或其醫藥學上可接受之鹽、抗代謝產物（例如吉西他 續）及翻化合物（例如卡錄）。在·一些實施例中’ s亥始敏感性 復發性卵巢癌為上皮卵巢癌。在一些實施例中’該鉑敏感 性復發性卵巢癌為法婁皮歐氏管癌。在一些實施例中’該 鉑敏感性復發性卵巢癌為原發性腹膜癌。例如’在一些實 施例中，提供一種治療患者之鉑敏感性復發性卵巢癌的方 法’包括投與具有鉑敏感性復發性卵巢癌之患者有效量 之：（i) 4-碘-3-硝基苯曱醯胺或其代謝產物或醫藥學上可 接受之鹽；（ii)吉西他濱；及（iii)卡鉑，其中該卵巢癌為上 皮卵巢癌、法婁皮歐氏管癌或原發性腹膜癌。在一些實施 例中’該鉑敏感性復發性卵巢癌為漿液卵巢癌（serous ovarian cancer)。在一些實施例中，該鉑敏感性復發性卵 巢癌為漿液腺癌印巢癌（serous adenocarcinoma ovarian cancer)。在一些實施例中’該鉑敏感性復發性卵巢癌為乳 頭狀聚液卵巢癌（papillary serous ovarian cancer)。在一此 實施例中，該銘敏感性復發性卵巢癌為子宮内膜樣卵巢癌 (endometrioid ovarian cancer)。在一些實施例中，該鉑敏 感性復發性卵巢癌為透明細胞卵巢癌（clear cell 〇vaHan cancer)。在一些實施例中，該患者患有可測得的疾病（諸 如依照RECIST 1.1可測得的疾病）^例如，該可測得的疾 病可用至少一個如下的病變定義，該病變之至少一個尺寸 (諸如最長尺寸）可被精確量測，且當藉由習知技術（例如觸 診、普通x_射線、電腦斷層攝影術或磁共振成像）量測時 mm或當藉由螺旋CT量測時mm。在一些實施例 156510.doc -19· 201206448 中’患者未曾接受2種或更多種的先前化學療法（例如細胞 毒性化予療法）。在一些實施例中，該鉑敏感性復發性卵 巢癌包含任何等級之卵巢腫瘤，例如等級1、2或3中之任 一者。卵巢腫瘤之分級可依照熟習此項技術者已知之任何 方法。例如，等級0可指非侵襲性腫瘤或交界性腫瘤。等 級1腫瘤可能具有充分分化之細胞（看上去與正常組織非常 相似）且可能為具有最佳預後之腫瘤。等級2腫瘤可為適度 充分分化的且可由類似正常組織之細胞構成。等級3腫瘤 可能具有最差的預後且其細胞可能異常，稱作分化不良。 在些貫施例中，患者在復發背景下先前未曾接受過化學 療法（例如細胞毒性化學療法）^在一些實施例中，患者未 曾用超過1線的細胞毒性化學療法及〗線生物製品（諸如抗 VEGF抗體，例如貝伐單抗）治療超過約6個月（激素不算作 一線治療）^在一些實施例中，患者未曾接受包含4_碘_3_ 硝基苯曱醯胺或其代謝產物或醫藥學上可接受之鹽的先前 化學療法。在一些實施例中，患者未曾接受包含以以抑 制劑（例如奥拉帕尼（Olaparib)、ABT-888(維利帕尼 (Veliparib))、AG014699、CEP 9722、MK 4827、KU-0059436 (AZD2281)或LT-673)之先前化學療法。在一些實施例中， 患者具有約或至少約6個月（例如約或至少約9個月、丨2個 月、15個月、18個月、24個月、30個月、36個月或42個月 中之任一者）的無舶化合物間隔期。例如，在開始任何本 文所述治療之前，在最後一劑鉑化合物之後有約或至少約 6個月（例如約或至少約9個月、12個月、15個月、18個 156510.doc _20- 201206448 月、24個月、30個月、36個月或42個月中之任一者）的時 段》.在本發明之實例1及2的合格標準令提供可用本文提供 之任-方法治療的患者之其他特徵。4，·3_硝基苯子醯胺 或其代謝產物或其醫藥學上可接受之鹽、抗代謝產物（例 如吉西他濱）及鉑化合物（例如卡鉑）的給藥方案可依照下文 所述之「調配物、投藥途徑及給藥方案」部分中描述的任 何給藥時間表或給藥方案。 在本文所述之任何方法的一些實施例中，術語「患者」 或「個體」指人類患者或個體。 鉑敏感性復發性卵巢癌可處於任何階段。在本文所述之 任何方法的一些實施例中，該鉑敏感性復發性卵巢癌不為 轉移I1 生的在些實施例中，該始敏感性復發性卵巢癌為 轉移性的。在一些實施例中，該鉑敏感性復發性卵巢癌處 於階段1、2、3或4中之任一者。在一些實施例中，該翻敏 感性復發性卵巢癌處於階段la、lb、lc、2a、孔、以、 3a、3b、3c或4中之任一者。分階段可依照熟習此項技術 者已知之任何方法。例如，分階段可依照 p //www.cancer.org/cancer/ovariancancer/detailedguide/ 〇varian-cancer_staging(2〇11 年 5 月 3〇 日最後一次訪問）上所 描述的分階段。 在本文提供之任何方法的一些實施例中，獲得了至少一 種治療效果，該至少一種治療效果為卵巢腫瘤大小縮小、 轉移減）、π全緩解、部分緩解、病理完全反應、總反應 率升高或疾病較。在―些實施例中，㈣療提供與未用 156510.doc -21- 201206448 4-峨-3-硝基苯曱醢胺或其代謝產物或其醫藥學上可接受之 鹽的治療相比提高的臨床效益率。在一些實施例中，與未 用4-碘-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可接受 之鹽的治療相比，獲得了臨床效益率之提高 (CBR=CR+PR+SD26個月）。在一些實施例中，使臨床效益 率提高至少約 20%、30%、40%、50%、60%、70%、80% 或更高中之任一者。在一些實施例中，該治療效果為總反 應率升高。在一些實施例中，總反應率升高約1〇%、 20〇/〇、30%、40%、50%、60%、70%、80%或更高中之任 一者。 本文所述之任何臨床功效參數可依照RECIST i ·丨版標準 來量測’該標準描述於Eisenhauer EA等人，2009，Eur J Cancer·，45(2):228-47，其揭示内容以全文引用方式併入本 文中。 在本文所述之任何方法的一些實施例中，用於治療鉑敏 感性復發性印巢癌之方法進一步包括與抗腫瘤藥（或至少 一種抗腫瘤藥）組合投與4-碘-3-硝基苯甲醯胺或其代謝產 物或其醫藥學上可接受之鹽。例如，提供一種治療患者之 始敏感性復發性卵巢癌的方法，包括與至少一種其他抗腫 瘤藥組合投與有效量之4-碘-3-硝基苯曱醯胺或其代謝 產物或其醫藥學上可接受之鹽、（b)抗代謝產物（例如吉西 他濱）及（c)鉑複合物（例如卡鉑）^在一些實施例中，抗腫 瘤藥為抗腫瘤烷化劑、抗腫瘤抗代謝產物、抗腫瘤抗生 素、植物源性抗腫瘤藥、抗腫瘤鉑複合物、抗腫瘤喜樹鹼 156510.doc -22- 201206448 (camptothecin)衍生物、抗腫瘤酪胺酸激酶抑制劑、單株抗 體、干擾素、生物反應調節劑、激素抗腫瘤藥、抗腫瘤病 f劑、血管生成抑制劑、分化劑或其他展現抗腫瘤活性之 藥劑，或其醫藥學上可接受之鹽。在一些實施例中，鉑複 合物為順鉑、卡鉑、草酸鉑（〇xaplatin)或奥沙利鉑。在一 些實施例中，抗代謝產物為西他濱、卡培他濱、吉西他濱 或伐洛比西他濱。在一些實施例中，該等方法進一步包括 投與該患者與超過一種之抗腫瘤藥組合的4_碘_3_硝基苯曱 醯胺或其代謝產物或其醫藥學上可接受之鹽。在一些實施 例中’提供一種治療患者之鉑敏感性復發性卵巢癌的方 法’包括投與該患者有效量的與至少超過一種之抗腫瘤藥 組合的4-碘-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可 接受之鹽、抗代謝產物（例如吉西他濱）及鉑化合物（例如卡 鉑）。在一些實施例中’抗腫瘤藥在投與4_碘_3_硝基苯甲 醯胺或其代謝產物或其醫藥學上可接受之鹽、抗代謝產物 (例如吉西他濱）及/或鉑複合物（例如卡鉑）之前、同時或之 後投與。在一些實施例中，抗腫瘤藥為抗血管生成劑，諸 如安維汀（Avastin);或受體酪胺酸激酶抑制劑，包括但不 限於索坦（Sutent) '蕾莎瓦（Nexavar)、雷森汀（Recentin)、 ABT-869及阿西替尼（Axitinib)。在一些實施例中，抗腫瘤 藥為拓撲異構酶抑制劑，包括但不限於伊立替康 (irinotecan)、托泊替康（t〇p〇tecan)或喜樹驗。在一些實施 例中’抗Μ瘤藥為紫杉烷，包括但不限於太平洋紫杉醇 」pachtaxel)、多西他赛（d〇cetaxei)及紫杉醇白蛋白微粒 156510.doc -23- 201206448 (Abraxane)。在一些實施例中，抗腫瘤藥為靶向Her_2之藥 劑赫赛汀（Herceptin)或拉帕替尼（Lapatinib)。在一些實施 例中’抗腫瘤藥為激素類似物，例如孕綱。在一也實施例 中’抗腫瘤藥為他莫昔芬、類固醇芳香酶抑制劑、非類固 醇芳香酶抑制劑或氟維司群（Fulvestrant)。在一些實施例 中，抗遁瘤藥為靶向生長因子受體之藥劑。在一些實施例 中’此藥劑為表皮生長因子受體（EGFR)抑制劑，包括但不 限於西妥昔單抗（Cetuximab)及帕尼單抗（panitumimab)。在 一些實施例中’靶向生長因子受體之藥劑為胰島素樣生長 因子1 (IGF-1)受體（IGF1R)抑制劑，諸如cp_751871。在其 他實施例中，該方法進一步包括手術、放射療法、化學療 法、基因療法、DNA療法、輔助療法、新輔助療法、病毒 療法、RNA療法、免疫療法、奈米療法或其組合。在一些 實施例中，獲得了至少一種治療效果，該至少一種治療效 果為腫瘤大小縮小、轉移減少、完全緩解、部分緩解、病 理完全反應或疾病穩定。 在本文所述之任何方法的一些實施例中，該治療包括持 續時間為至少11天（例如約11天至約30天）之治療週期，其 中在該週期的1至10個分開之日，患者接受約1 mg/kg至約 100 mg/kg 4-碘-3-硝基苯甲醯胺或莫耳當量的其代謝產 物。在一些實施例中，在該週期的1至10個分開之日，患 者接受約1 mg/kg至約50 mg/kg 4-碘-3-硝基苯甲醯胺或莫 耳當量的其代謝產物。在一些實施例中，在該週期的1至 10個分開之曰，患者接受約1、2、3、4、5、5.6、6、8、 156510.doc -24 - 201206448 10、11·2、12、14、16、18或2〇 mg/kg肛碘冬确基苯甲醯 胺。該治療進一步包括抗代謝產物（例如吉西他濱）及鉑化 合物（例如卡翻）。 本文中描述之一些實施例提供一種治療患者（例如具有 BRCA基因缺之患者）之始敏感性復發性卵巢癌的方法， 包括在21天之治療週期期間，在該週期之第1天、第4天、 第8天及第11天投與該患者約1〇 mg/kg至約1〇〇 4碘_ 3-硝基苯甲醯胺或莫耳當量的其代謝產物。在一些實施例 中，4-碘-3-硝基苯曱醯胺經口投與，或以非經腸注射或輸 注、或吸入方式投與。該治療進一步包括抗代謝產物（例 如吉西他濱）及鉑化合物（例如卡鉑）。 本文中描述之一些實施例提供一種治療患者（例如具有 BRCA基因缺陷之患者）之鉑敏感性復發性卵巢癌的方法， 包括.（a)建立持續時間為約1 〇天至約3 〇天之治療週期； (b)在該週期的1至1〇個分開之日，投與該患者約1爪^^至 約50 mg/kg 4-碘-3_硝基苯甲醯胺或莫耳當量的其代謝產 物。在一些實施例中，4-碘_3_硝基苯曱醯胺經口投與，或 以非經腸注射或輸注、或吸入方式投與。該治療進一步包 括抗代謝產物（例如吉西他濱）及翻化合物（例如卡始）。 本文中提供之一些實施例包括一種治療需要此類治療之 患者之卵巢癌的方法，包括：（a)自該患者獲得樣品；（b) 測試該樣品以測定BRC A基因中是否有缺陷；（c)若該測試 指示該患者具有BRCA基因之缺陷，則用4-碘-3-硝基笨甲 酿胺或其代謝產物或其醫藥學上可接受之鹽治療該患者； 156510.doc •25- 201206448 及（d)若該測試指示該患者無BRCA基因之缺陷，則選擇不 同的治療選項。在一些實施例中，獲得了至少一種治療效 果’該至少一種治療效果為卵巢腫瘤大小縮小、轉移減 少、完全緩解、部分緩解、病理完全反應、總反應率升高 或疾病穩定。在一些實施例中，與未用4-碘-3-硝基苯曱醯 胺或其代謝產物或其醫藥學上可接受之鹽的治療相比，獲 得了臨床效益率之提高（CBR=CR+PR+SD26個月）》在一些 實施例中’臨床效益率為至少約30%。在一些實施例中， 該樣品為組織或體液樣品。在一些實施例中，該樣品為腫 瘤樣品、血液樣品、血漿樣品、腹膜液樣品、滲出物或流 出物。在一些實施例中，該卵巢癌為轉移性卵巢癌。在一 些實施例中，該BRCA基因為BRCA-1。在其他實施例中， 該BRCA基因為BRCA-2。在一些實施例中，該BRCA基因 為BRCA-1及BRCA-2。在其他實施例中，該缺陷為該 BRCA基因之遺傳缺陷。在一些實施例中，該遺傳缺陷為 該BRCA基因之突變、***、替代、複製或缺失。 在本文所述之任何方法的一些實施例中，4蛾_3硝基苯 甲醯胺或其代謝產物或其醫藥學上可接受《鹽可能夠以多 種物理形式存在-例如游離鹼、鹽（尤其為醫藥學上可接受 之J»·)尺。物多日日型物（polymorph)、溶劑合物等。除 非本文另有限定’否則使用某化學名稱意欲涵蓋該指定化 學品之所有物理形式。例如，在無其他限定下述及4-碘_3_ 硝基苯曱醯胺意欲-般涵蓋游離驗以及所有醫藥學上可接 受之鹽、多晶^物、水合物等。在意欲使本發明或申請專 256510.doc •26- 201206448 利範圍限於某化合物之特定物理形式時，此根據提及該化 合物之段落或申請專利範圍的上下文將為清楚的。 在本文所述之任何方法的一些實施例中，鉑化合物（例 如卡鉑）以靜脈内輸注方式投與。在一些實施例中，4_填· 3-确基笨甲醯胺或其代謝產物或其醫藥學上可接受之鹽經 口才又與，或以非經腸注射或輸注、或吸入方式投與。在一 些實施例中，抗代謝產物（例如吉西他濱）以靜脈内輸注方 式投與。 在本文所述之任何方法的一些實施例中，所述方法包括 用至少三種在化學上不同之物質治療患者，其中之一為抗 代謝產物(例如吉西他濱），其中之一為含鉑複合物(例如卡 翻或順始）及4|3_确基苯甲醯胺或其代謝產物或其醫藥 學上可接受之鹽。在一些實施例中，此等物質中之一或多 者可肖b夠以多種物理形式存在_例如游離鹼、鹽（尤其為醫 藥學上可接受之鹽)、水合物、多晶型物、溶劑合物或代 謝產物等。除非本文另有限定，㈣❹某化學名稱意欲 涵蓋該指定化學品之所有物理形式。例如，在無其他限定 下述及4-碘-3_硝基苯甲酿胺意欲—般涵蓋游離鹼以及其所 有醫藥學上可接受之鹽、多晶型物、水合物及代謝產物。 在意欲使本發明或中請專利範圍限於某化合物之特定物理 形式時，此根據提及該化合物之段落或中請專利範圍的上 下文將為清楚的。 本：中亦提供⑴4-碘-3-硝基笨甲醯胺、其代謝產物或 其醫樂學上可接受之鹽或溶劑合物合併⑼抗代謝產物、 156510.doc -27- 201206448 其醫藥學上可接受之鹽或溶劑合物中之任一者及（Hi)本文 所述之鉑化合物、其醫藥學上可接受之鹽或溶劑合物中之 任一者用於製造用以治療或預防本文所述之鉑敏感性復發 性卵巢癌之藥物的用途。本文中亦提供4_碘_3_硝基苯甲醯 胺、其代謝產物或其醫藥學上可接受之鹽或溶劑合物用於 製造用以與抗代謝產物（例如吉西他濱）及鉑化合物（例如卡 鉑）組合來治療或預防本文所述之鉑敏感性復發性卵巢癌 之藥物的用途。本文中亦提供4•碘_3_硝基苯甲醯胺、其代 謝產物或其醫藥學上可接受之鹽或溶劑合物用於製造用以 治療或預防本文所述患者之鉑敏感性復發性卵巢癌之藥物 的用途，其中4-碘-3-硝基苯甲醯胺、其代謝產物或其醫藥 學上可接受之鹽或溶劑合物欲與抗代謝產物（例如吉西他 濱）及鉑化合物（例如卡銘）組合來投與該患者。 本文中亦提供本文所述之任何醫藥組合物用於製造用以 治療鉑敏感性復發性卵巢癌之藥物的用途。例如，本文中 提供之用途與本文所述之任何方法有關或一致。 抗腫瘤藥 在-些實施例中，提供一種治療患者之鉑敏感性復發性 卵巢癌的方法，包括投與該患者有效量的⑴4碘硝基 苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽；（ii)抗 代謝產物（諸如吉西他濱）；及㈣純合物（諸如卡翻）合併 另一抗腫瘤藥°可在本發明t使用之抗腫瘤藥包括但不限 於抗腫瘤貌化劑、抗腫瘤抗代謝產物 '抗腫瘤抗生素、植 物源性抗腫瘤藥、抗遁錢複合物化合物、抗腫瘤喜樹驗 156510.doc -28· 201206448 衍生物、抗腫㈣胺酸激酶抑制劑、抗腫瘤病毒劑、單株 ㈣、干擾素 '生物反應調節劑及其他展現抗腫瘤活性之 樂劑’或其醫藥學上可接受之鹽。在一些實施例中，⑴肛 碘冬硝基苯甲醯胺、其代謝產物或其醫藥學上可接受之 鹽、⑻抗代謝產物（諸如吉西他濱）、及㈣始化合物（諸如 卡鉑）與抗血管生成劑組合使用。在其他實施例中，⑴心 碘-3-硝基苯甲醯胺、其代謝產物或其醫藥學上可接受之 鹽、（π)抗代謝產物（諸如吉西他濱）、及（iii)鉑化合物（諸如 卡鉑）與拓撲異構酶抑制劑（諸如伊立替康）組合使用❶在其 他實施例中’ (!）4-碘-3-硝基苯甲醯胺、其代謝產物或其 醫藥學上可接受之鹽、（丨〇抗代謝產物（諸如吉西他濱）、及 (in)鉑化合物（諸如卡鉑）與激素療法組合使用。在其他實 施例中，（1) 4-碘-3-硝基苯曱醯胺、其代謝產物或其醫藥 千上可接党之鹽、（U)抗代謝產物（諸如吉西他濱）、及 翻化合物（諸如卡翻）與包括但不限於E(}FR!IGF1R抑制劑 之生長因子受體抑制劑組合使用。在一些實施例中，該卵 巢癌為轉移性癌症。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為烷 化齊I °術語「炫化劑」在本文中一般指在烷基化反應中給 出焼1基之藥劑’其中某有機化合物之某氫原子經烷基取 代°抗腫瘤院化劑之實例包括但不限於氮芥N_氧化物、環 填醯胺（cyclophosphamide)、異環磷醯胺（ifosfamide)、美 法侖（melphalan)、白消安（busulfan)、二溴甘露醇 (mitobronitol)、卡波酿（carb〇qUOne)、塞替派（thiotepa)、 156510.doc •29· 201206448 雷莫司汀（ranimustine)、尼莫司汀（nimustine)、替莫α坐胺 (temozolomide)或卡莫司 丁（carmustine)。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為抗 代謝產物。本文中使用之術語「抗代謝產物」以廣義包括 由於與對活生物體重要之代謝產物（諸如維生素、辅酶、 胺基酸及醣）具有結構或功能相似性而干擾正常代謝之物 質及抑制電子傳遞體系以阻止富含能量之中間體生成的物 質。具有抗腫瘤活性之抗代謝產物的實例包括但不限於甲 胺蝶吟（methotrexate)、6-疏基 D票吟核普（6-mercaptopurine riboside)、疏基嗓。令（mercaptopurine)、5-氣尿 °密 α定（5-fluorouracil)、 喃氟咬（tegafur)、 去氧氟尿苷 (doxifluridine)、卡莫氟（carmofur)、阿糖胞苦 (cytarabine)、阿糖胞_十八烧基構酸鹽（cytarabine ocfosfate)、依諾他濱（enocitabine)、S-1、吉西他濱 (gemcitabine)、氟達拉濱（fludarabine)或培美曲塞二納 (pemetrexed disodium)，且較佳為5-氟尿嘯°定、S-1、吉西 他濱及其類似物。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為抗 腫瘤抗生素。抗腫瘤抗生素之實例包括但不限於放線菌素 D (actinomycin D)、多柔比星（doxorubicin)、柔紅徽素 (daunorubicin)、新制癌菌素（neocarzinostatin)、博萊徽素 (bleomycin)、培洛黴素（peplomycin)、絲裂黴素 C (mitomycin C)、阿柔 I：匕星（aclarubicin)、D比柔比星 (pirarubicin)、表柔比星（epirubicin)、淨司他 丁斯醋 156510.doc -30- 201206448 (zinostatin stimalamer)、伊達比星（idarubicin)、西羅莫司 (sirolimus)或戊柔比星（vaimbicin)。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為植 物源性抗腫瘤藥。植物源性抗腫瘤藥之實例包括但不限於 長春新鹼（vincristine)、長春鹼（vinbiastine)、長春地辛 (vindesine)、依託泊苷（et〇p〇side)、索布佐生 (S〇bUZ〇xane)、多西他賽（d〇cetaxel)、太平洋紫杉醇 (paclitaxel)及長春瑞濱（vinorelbine)，且較佳為多西他赛 及太平洋紫杉醇。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為 現抗腫瘤活性之喜樹鹼衍生物。抗腫瘤喜樹鹼衍生物之實 例包括但不限於喜樹鹼（campt〇thecin)、1〇-羥基喜樹鹼、 托泊替康（t〇P〇tecan)、伊立替康（irin〇tecan)或9·胺基喜樹 鹼，較佳為喜樹鹼、托泊替康及伊立替康。另外伊立替 康在活體内代謝並作為购8展現抗腫瘤效果。認為喜樹 鹼何^物之作用機制及活性實際上與喜樹鹼的相同（例如201206448 VI. INSTRUCTIONS: RELATED APPLICATIONS This application claims US Provisional Application No. US 61/351,785, filed on June 4, 2010, and US Provisional Application No. 61/, filed on May 2, 2011. Priority rights to 481, 634, each of which is incorporated herein by reference in its entirety. [Prior Art] Cancer is a complex family of diseases that affect almost every tissue in the body and is characterized by abnormal control of cell growth. The annual incidence of all cancer types is estimated to be more than 1.3 million in the United States alone. Although a variety of first-line therapies have been used to treat different types of cancer and have achieved varying degrees of success, including surgical resection, radiation therapy, chemotherapy, and hormonal therapy, 'it is still the second leading cause of death in the United States, estimated annually. 560,000 Americans have died of cancer. Ovarian cancer is the 8th most common cancer among women worldwide, with an estimated 225,500 new diagnoses per year and an estimated 14 weeks per year, with 2 deaths. The current standard of care for first-line chemotherapy for ovarian cancer is the combination of platinum compounds (such as cisplatin, card # and oxaiipiatin) and taxane. Most newly diagnosed patients with nest-negative cancer respond to first-line platinum-based and paclitaxel chemotherapy. However, 50-80% of patients who respond to this combination therapy will eventually relapse. See, for example, Herzog, "Update on the role of topotecan in the treatment of recurrent ovarian cancer", 77ze 7 (Supp. 5): 3-10 (2002). Women with advanced ovarian cancer relapse due to disease 156,510. Doc 201206448 has poor long-term survival and mostly dies within 5 years. There is a clear need to improve current treatment options for recurrent ovarian cancer. SUMMARY OF THE INVENTION Provided herein is a method of treating platinum-sensitive recurrent nested cancer in a patient comprising administering an effective amount of (i) 4-iodo-3-nitrobenzamide to the ovarian cancer patient (4- Iodo-3-nitrobenzamide), a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine; and (iii) a card flip. In some embodiments, the initially sensitive recurrent ovarian cancer is epithelial ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is a faU〇pian tube (or fallopian tube) cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is primary peritoneal cancer. In some embodiments, the treatment comprises at least about 1 treatment cycle (eg, about 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 1 cycle, 11 cycles, 12 cycles, 13 cycles, 14 cycles, one cycle, 16 cycles, 17 cycles, or 18 cycles, each of which (or Each of the equal cycles includes the administration of an effective amount of 2(1) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (9) K. (10)' and (iv) card start . In some embodiments, the treatment. Including, until 4, to about 12 treatment cycles, wherein each of the cycles comprises administering an effective amount of (1) 4_ moth to Schottyl benzoate, a metabolite thereof, or 33 thereof, which is pharmaceutically acceptable Salt; (1) gemcitabine; and (out) card flipping. In some embodiments, the patient has not previously received a regimen of chemotherapeutic chemotherapy in the context of relapse. In some embodiments, the effective amount is administered within a "day of treatment" wherein (1) the card is turned over on the first day of the treatment cycle to 4,156,510. Doc 201206448 mg/m bmin (AUC 4) is administered to the patient; (ii) gemcitabine is administered to the patient at a dose of looo mg/m2 on days 1 and 8 of the treatment cycle; and (iii) 4-iodine -3-Nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered twice a week on days 1st, 4th, 8th and 11th of the treatment cycle. The patient was administered at a dose of 6 mg/kg. In some embodiments, the effective amount produces at least one therapeutic effect selected from the group consisting of ovarian tumor size reduction, reduced metastasis, complete remission, partial remission, stable disease, increased overall response rate, or pathological complete response ( Path〇1〇gi(; complete response). In some embodiments, the method further includes surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy The nanotherapy or a combination thereof. In some embodiments, the method further comprises administering the patient gamma radiation. In some embodiments, the patient has platinum-sensitive recurrent nested cancer. In some embodiments, The platinum-sensitive recurrent ovarian cancer line is selected from the group consisting of epithelial tumors, germ cell tumors, and stromal cell tumors. In some embodiments, the platinum-sensitive recurrent ovarian cancer is metastatic. In some embodiments The patient has platinum-sensitive recurrent ovarian cancer. In some embodiments, 4_iodo-3-nitrobenzamide, its metabolism The product or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, 'gemcitabine is administered intravenously. In some embodiments, the cardin is administered intravenously. In some embodiments, the The patient has a measurable disease. In some embodiments, the treatment provides an increased clinical benefit rate compared to treatment with gemcitabine and carboplatin but without 4-beta-3-nitrobenzamine. In some embodiments, gemcitabine and carboplatin are obtained and not 156510. Doc 201206448 Increased clinical benefit rate compared with treatment with 4-iodo-3-nitrobenzamine (CBR = CR (complete remission) + PR (partial remission) + SD (stable stable for 6 months). In some embodiments, the clinical benefit rate is increased by about 20% or higher. In some embodiments, the therapeutic effect is an increase in overall response rate. In some embodiments, the overall response rate is greater than 40%. In some implementations In one example, the overall response rate is greater than 50%. In some embodiments, the overall response rate is greater than 60%. In some embodiments, the patient has platinum-sensitive recurrent ovarian cancer. In some embodiments, the platinum is sensitive Recurrent ovarian cancer is defective in homologous recombinant DNA repair. In some embodiments, homologous recombinant DNA repair-deficient platinum-sensitive recurrent ovarian cancer is BRCA-deficient. In some embodiments, 'BRCA-deficient platinum Sensitive recurrent ovarian cancer is BRCA1-deficient. In some embodiments, BRCA-deficient platinum-sensitive recurrent, or nestal, is BRCA2-deficient. In some embodiments, BRCA-deficient platinum-sensitive recurrent ovarian cancer is It is BRCA2-deficient and BRCa2-deficient. Also provided herein is the use of any of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of platinum-sensitive recurrent ovarian cancer. For example, the uses provided herein are related or consistent with any of the methods described herein. Also provided is (1) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, in combination with an antimetabolite, a pharmaceutically acceptable salt or a solvent thereof. Any one of (4) a compound of the formula described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of a sensuous recurrent The use of cancer drugs. Also provided herein is 4 winter 3 "Schottky benzoquinone, its metabolite or its pharmaceutically acceptable salt or solvate for 1565I0. Doc 201206448 The use of a medicament for the treatment or prevention of platinum-sensitive recurrent ovarian cancer as described herein in combination with an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin). Also provided herein is 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of a platinum-sensitive relapse in a patient described herein. Use of a medicament for ovarian cancer, wherein 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof is intended to be combined with an antimetabolite (such as gemcitabine) and a platinum compound ( For example, carboplatin is combined to give to the patient. Also provided herein is a synergistic composition for treating platinum-sensitive recurrent ovarian cancer in a patient, comprising administering to the patient a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable drug thereof Accepted salts or solvates, b) antimetabolites, and c) platinum compounds, wherein the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine ( Gemcitabine) or valopicitabine, and wherein the platinum compound is selected from the group consisting of cisplatin; cis-diamminedia platinum (II) )-i〇n); chloro (diethylenetriamine)-platinum (II) chloride; dichloro(ethylenediamine)-rhythm (II) (dichloro(ethylenediamine)-platinum (II)); diamine (1,1-cyclobutanthene); from (II) (diammine(l,l-cyclobutanedicarboxylato) platinum (11)) (carboplatin) )); spiroplatin; iproplatin; diamine (2-ethylmalonate) turn (Π) (diam Mine(2-ethylmalonato)platinum (II)); Ethylene diamine malonate (II) (ethylenediaminemalonatoplatinum 156510. Doc 201206448 (II)); Hydrated (1,2-diaminobicyclohexyl) platinum (II) (aqua(l,2-diaminodicyclohexane)sulfatoplatinum (II)); hydrated (1,2-diamino) (2,2-diaminodicyclohexane) malonatoplatinum (II)); (1,2-diaminocyclohexane) malonate (II) ((l, 2-diaminocycloliexane)malonatoplatinum (II)); (4-reactyl oleate) (1,2-diaminocyclohexane) platinum (II) ((4-carboxyphthalato) (l,2_diaminocyclohexane) platinum (II) (1,2-diaminocyclohexane)-(isocitric acid) I white (II) ((1,2-diaminocyclohexane)-(isocitrato)platinum (II)); (1,2-diamine) Base ring hexahydrate) (1,2-diaminocyclohexane) oxalatoplatinum (II)); ormaplatin; tetraplatin; carboplatin; nedaplatin; And oxaliplatin. Kits for platinum-sensitive recurrent ovarian cancer for treating patients are also provided herein. In some embodiments, the kit comprises (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof, (b) an antimetabolite And (c) a platinum compound. The kits may further comprise a product or package insert or label comprising an effective amount of (a) 4-iodo-3-nitrobenzamide or a metabolite thereof or any of its metabolites or any of the methods described herein. Instructions and/or information on pharmaceutically acceptable salts or solvates, (b) antimetabolites, and (c) platinum compounds. In some embodiments, the kits comprise 4-iodo-3-nitrobenzamide or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, and a product or package insert or label, Included in an amount effective according to any of the methods described herein for the use of an effective amount of 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof 156510. Doc 201206448 Instructions and/or information for the treatment of platinum-sensitive recurrent ovarian cancer in patients with anti-metabolites (eg, gemcitabine) and facial compounds (eg, card). In some embodiments, the antimetabolite is gemcitabine and the platinum compound is carboplatin. In some embodiments, the effective amount is administered within 21 days of the treatment period wherein (1) carboplatin is administered to the patient at 4 mg/mhmin (AUC4) on the ith day of the treatment cycle, (ii) gemcitabine is treated The patient is administered at a dose of 1000 mg/m2 on days 1 and 8 of the cycle; and (iH)4•iodine-3 nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is in the treatment cycle The patient was administered twice a week at a dose of 5 6 mg/kg on Days 1, 4, 8, and 11 of the day. In some embodiments, the platinum-sensitive recurrent ovarian cancer is epithelial ovarian cancer, sputum epithelial carcinoma, or primary peritoneal cancer. In some embodiments, the patient has not previously received cytotoxic chemotherapy in the context of relapse. In some embodiments, the patient has a measurable disease. It will be appreciated that one, some or all of the features of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the invention will become apparent to those skilled in the art. All publications and patent applications mentioned in this specification are hereby incorporated by reference in their entirety herein in the the the the the the Into the general. [Embodiment] The novel features of the present invention are precisely set forth in the appended claims. The present invention can be better understood by referring to the following [embodiment] and the accompanying drawings. Doc 201206448 The features and advantages of the present invention are set forth in the accompanying drawings. The term "platinum-sensitive" as used herein refers to a type of ovarian cancer (eg, recurrent ovarian cancer). The current standard of care for first-line chemotherapy for ovarian cancer is the combination of Ming compounds (such as shun, Kap and Oxali) and yew fever. Most newly diagnosed ovarian cancer patients will be in the first line. Platinum-based and paclitaxel chemotherapy responds. However, 50-80% of patients who respond to this combination therapy will eventually relapse. See, for example, Herz〇g, "Update on the role of topotecan in the treatment of recurrent ovarian cancer," TTie Onco/ogi&quot; 7 (Supplement 5): 3_i〇 (2002). Patients who relapse within 6 months are unlikely to respond to a second round of platinum-based therapy. Therefore, if the recurrence occurs in more than 6 months after the last dose based on the initial therapy, the recurrent advanced ovarian cancer tumor is classified as "platinum sensitivity"; if the recurrence occurs after the last dose of platinum-based therapy Or equal to 6 months, it is classified as "platinum resistance"; if there is a reaction or disease regression during the initial platinum-based therapy, it is classified as "platinum-refractory". As used herein, "surgery" refers to any treatment or diagnostic procedure involving the action of a hand or hand and a device on the body of a human or other mammal to produce a healing, remedy or diagnostic effect. Radiation therapy 彳a exposes patients to high-energy light, including but not limited to X-rays, gamma rays, and neutrons. Such therapies include, but are not limited to, external beam therapy, internal radiation therapy, implantable radiation, brachytherapy, systemic radiation therapy, and radiation therapy. 156510. Doc •11· 201206448 “Chemotherapy” refers to the administration of one or more anticancer drugs, such as antineoplastic chemotherapeutics, chemoprevention, to patients with platinum-sensitive ovarian cancer (eg, recurrent ovarian cancer) by various methods. And/or other agents, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal or inhalation or in the form of a suppository. As used herein, "chemotherapy" is not meant to mean 4-iodo-3-nitrobenzamide, an antimetabolite (eg, gemcitabine), and a platinum compound (eg, as described herein). Carboplatin). Chemotherapy can be given prior to surgery to reduce the size of the large tumor before it is surgically removed, prior to radiation therapy, or after surgery and/or radiation therapy to prevent the growth of any residual ovarian cancer cells in the body. Chemotherapy can also occur during the radiation therapy process. The term "effective amount" or "pharmaceutically effective amount" means an amount of an agent sufficient to provide the desired biological, therapeutic and/or prophylactic effect. This effect may be a reduction and/or alleviation of one or more signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is about 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof, as shown herein. a product (eg, gemcitabine) or a pharmaceutically acceptable salt or solvate thereof, and c) a platinum compound (eg, carboplatin) or comprising the indole 4-iodo-3-nitrobenzamide provided herein or a combination of a metabolite or a pharmaceutically acceptable salt or solvate thereof, b) an antimetabolite (eg, gemcitabine) or a pharmaceutically acceptable salt or solvate thereof, and a palladium platinum compound (eg, carboplatin) The substance is clinically significantly reduced in platinum-sensitive ovarian cancer (eg, recurrent egg 156510. Doc 201206448 Nest cancer) or &gt; The amount required for the progression of salty stagnation sensitive nested cancer (eg, recurrent seminal cancer). "metabolite" refers to the production via any in vitro or in vivo metabolic process. The 'beta' process produces a product that is structurally different from the starting compound. In other words, the term "metabolite" includes a metabolite compound of 4-A-3-stone succinylbenzamide. Metabolites may include different numbers or types of substituents at any position relative to the precursor compound. In addition, the terms "metabolite" and "metabolite compound" are used interchangeably herein. "Pharmaceutically acceptable" means that a material is biologically or otherwise non-defective&apos; that is, the material can be administered to a patient without causing any undesirable biological effects or effects. Harmful ways interact with any component of the composition comprising it. The term "treatment" as used herein and its grammatical synonyms include the realization of therapeutic benefits and/or prophylactic benefits. The therapeutic benefit means the eradication or improvement of the underlying condition being treated. For example, in patients with platinum-sensitive ovarian cancer (e. g., recurrent ovarian cancer), therapeutic benefits include eradication or amelioration of potential Indian cancer, such as slowing the progression of the ovarian cancer. In addition, the therapeutic benefit is based on the eradication or amelioration of one or more of the physiological symptoms associated with a underlying condition, such as ovarian cancer, to see that in spite of the fact that the patient may still be afflicted with the underlying condition (eg, ovarian cancer), However, improvement was still observed in this patient. For prophylactic benefit, it can be performed on patients at risk for platinum-sensitive ovarian cancer (eg, recurrent ovarian cancer) or on patients with one or more physiological symptoms reporting platinum-sensitive ovarian cancer (eg, recurrent ovarian cancer) The invention is 156510. Doc •13·201206448 The method of the invention or the administration of the composition of the invention, even if a diagnosis of platinum-sensitive nested cancer (e.g., recurrent printed cancer) may not have been made. In some embodiments, the patient being treated has been diagnosed with the first sensitive (four) nest cancer (e.g., recurrent ovarian cancer) described herein. In this context, a value or parameter includes (and describes) a change to the value or the parameter itself. For example, the description of "about X" includes the description of "X". The singular forms "a", "the", and "the" are used in the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; It is to be understood that the various aspects and variations of the invention described herein include """ and/or "substantially" and "various". Treatment of ovarian cancer There are three basic types of nested tumors: epithelial, germ cell, and stromal cell tumors. The epithelial tumor begins with the cells that cover the outer surface of the nest; the majority of the tumors are fine. Cell tumor. Germ cell tumors originate from the cells that produce the egg. The stromal tumors begin with the nesting of the nest and the production of estrogen. Important risk factors for ovarian cancer include defects in homologous recombinant DNA repair, such as mutations in the BRCA1 or BRCA2 genes. These genes were originally identified in a family with multiple breast cancers, but have been linked to approximately 5% to 10,000% of ovarian cancer. ° Possible treatments for ovarian cancer include surgery, immunotherapy, chemotherapy, hormone therapy, radiation therapy, or a combination thereof. Surgical procedure for the treatment of ovarian cancer ^ 156510. Doc •14- 201206448 Includes debulking and unilateral or bilateral oophorectomy and/or unilateral or bilateral salpingectomy. Anticancer drugs that have also been used to treat ovarian cancer include cyclocarbanamine, etoposide, altretamine, and ifosfamide. Hormone therapy with the drug tamoxifen is also used to shrink ovarian tumors. Radiation therapy Depending on the situation, external beam radiation therapy and/or proximity therapy. In one aspect, 'a method of treating platinum-sensitive recurrent ovarian cancer in a patient' includes administering the patient 4-A-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable thereof Salt, antimetabolite and platinum compound. In some embodiments, the antimetabolite is selected from the group consisting of citabine, capecitabine, gemcitabine, or valprobine. In some embodiments, the antimetabolite is gemcitabine. In some embodiments, the compound is selected from the group consisting of: cisplatin; cis-diamine dihydrate starting (11)-ion; chlorine (diethylidene triamine)-platinum (II) chloride; Chlorine (extended ethyldiamine)-turned (II); diamine (alzanthocyclobutanedicarboxylate) platinum (π) (carboplatin); spiroplatinum; isopropaplatin; diamine (2-ethylpropane) Diacid) platinum; ethyl diamine malonate (II); hydrated (1,2-diaminodicyclohexane) platinum platinum (π); hydrated (1,2-diamino bicyclic Hexane) Platinum malonate (π); (i, 2 diaminocyclohexane) Platinum malonate (Π); (4·carboxydecanoate) (1,2-diaminocyclohexane) Platinum (II), (1'2-diaminocyclohexane η isocitric acid); (1,2-diaminocyclohexane) oxalic acid platinum (H); omalim; tetraplatin; carboplatin Nidaplatin; and Olivier, and preferably starting from the beginning of the card or Osali. In some embodiments the compound is carboplatin. For example, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering an effective amount of (1) 4-iodo-3-nitrophenylhydrazine 156510 is provided. Doc 15· 201206448 guanamine or its metabolites or pharmaceutically acceptable salts thereof; ((1) gemcitabine; and (iv) card. In some implementations, the patient has initial sensitivity recurrent ovarian cancer. In some implementations In one embodiment, at least one therapeutic effect is obtained, the at least one therapeutic effect being tumor size reduction, metastasis reduction, complete remission, partial remission, pathological complete response, or disease stabilization. In some embodiments of any of the methods described herein, The method further includes surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy, or a combination thereof. In some embodiments, the method further comprises The patient is administered gamma radiation. In some embodiments, the platinum-sensitive recurrent ovarian cancer is selected from the group consisting of epithelial tumors, germ cell tumors, and stromal cell tumors. In some embodiments, platinum-sensitive relapse Ovarian cancer is metastatic. In some embodiments, platinum-sensitive recurrent ovarian cancer is not metastatic. In some embodiments, the platinum-sensitive recurrent ovarian cancer comprises an aggressive malignant tumor. In some embodiments, the platinum-sensitive recurrent ovarian cancer does not comprise an invasive malignancy. In one aspect, the invention provides a A method of treating platinum-sensitive ovarian cancer (eg, platinum-sensitive recurrent ovarian cancer) in a patient, comprising administering an effective amount of a patient having ovarian cancer (eg, platinum-resistant ovarian cancer;): 4-iodo_3_nitro a compound or a metabolite or a pharmaceutically acceptable salt thereof; (ii) gemcitabine, and (ill) carboplatin. In some embodiments, the effective amount is administered over a 21 day treatment period, wherein (1) an effective amount of carboplatin administered to the patient at 4 mg/m b min (AUC 4) (or approximately AUC4) on the first day of the treatment cycle; (ii) an effective amount of gemcitabine on the ith day and the first of the treatment cycle 8 days later 丨〇〇〇 156510. Doc • 16 - 201206448 mg/m2 (or approximately 1000 mg/m2) dose administered to the patient; and (out) an effective amount of 4-iodo-3-nitrobenzamine or its metabolite or pharmaceutically The acceptable salt is administered twice a week on the first, fourth, eighth and eleventh days of the treatment cycle. 6 mg/kg (or about 5. A dose of 6 mg/kg) was administered to the patient. In some embodiments, the effective amount produces at least one therapeutic effect selected from the group consisting of: ovarian tumor size reduction&apos; reduced metastasis, complete remission, partial remission&apos; stable disease, increased overall response rate, or pathological complete response. In some embodiments, an improved clinical benefit rate (Cbr=cr (complete remission) + PR (partial) is obtained compared to treatment with gemcitabine and carboplatin but without administration of 4_photo_3_nitrobenzamide Relief) + SD (stable disease 沦 6 months). In some embodiments 'increasing the clinical benefit rate by about 20% or higher. In some embodiments, the therapeutic effect is an increase in the overall response rate. In some embodiments, the overall reaction rate is greater than 40°. In some embodiments, the total reaction rate is greater than 5%. In some embodiments, the total reaction rate is greater than 60%. In some embodiments, the method further includes Surgery, radiation therapy, chemotherapy, gene therapy, viral therapy, RNA therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, immunotherapy, nanotherapy, or a combination thereof. In some embodiments, the method further comprises administering the Patient gamma radiation. In some embodiments, the white-sensitive ovarian cancer (eg, platinum-sensitive recurrent ovarian cancer) is selected from the group consisting of epithelial tumors, germ cell tumors, and stromal cell tumors. In some embodiments The platinum-sensitive ovarian cancer is recurrent ovarian cancer. In some embodiments, the platinum-sensitive ovarian cancer (eg, platinum-sensitive recurrent nested cancer) is metastatic. In some embodiments, the platinum is sensitive Sexual ovarian cancer (such as pin-sensitive recurrent ovarian cancer) has 156,510 on homologous recombinant DNA repair. Doc • 17· 201206448 Defect. In some embodiments, the homologous recombinant DNA repair defective platinum-sensitive ovarian cancer is BRCA-deficient. In some embodiments, the BRCA-deficient platinum-sensitive ovarian cancer is BRCA1-deficient. In some embodiments, the &apos;BRCA-deficient platinum-sensitive ovarian cancer is BRCA2-deficient. In some embodiments, BRCA-deficient platinum-sensitive ovarian cancer is both BRCA1-deficient and BRCA2-deficient. In some embodiments, the platinum-sensitive recurrent ovarian cancer comprises a mutation in BRCA1. In some embodiments, the platinum-sensitive recurrent ovarian cancer comprises a mutation in BRCA2. In some embodiments, the platinum-sensitive recurrent ovarian cancer comprises mutations in BRCA1 and BRCA2. In some embodiments of any of the methods described herein, platinum-sensitive recurrent ovarian cancer is defective in homologous recombinant DNA repair. In some embodiments, "homologous recombinant DNA repair-deficient platinum-sensitive recurrent ovarian cancer is BRCA-deficient. In some embodiments, a defect in the BRCA gene is detected in an ovarian cancer patient. In other embodiments, the defect is a genetic defect in the BRCA gene &quot; In some embodiments, the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene. In some embodiments, the BRCA gene is BRCA-1. In other embodiments, the BRCA gene is BRCA-2. In some embodiments, the BRCA-deficient platinum-sensitive recurrent ovarian cancer is BRCA1-deficient. In some embodiments, the BRCA-deficient platinum-sensitive recurrent ovarian cancer is BRCA2-deficient. In some embodiments, the BRCA-deficient platinum-sensitive recurrent ovarian cancer is both a BRCA1 deficient and a BRCA2-deficient. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer comprising administering an effective amount of 4-iodo-3-nitrobenzamine or its metabolism 156510 is provided. Doc • 18 - 201206448 Product or its pharmaceutically acceptable salts, antimetabolites (eg, Gemcitab continuation), and compounds (eg, card). In some embodiments, the sensitivity of recurrent ovarian cancer is epithelial ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is Faye's parietal carcinoma. In some embodiments, the platinum-sensitive recurrent ovarian cancer is primary peritoneal cancer. For example, 'in some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient' includes administering an effective amount to a patient having platinum-sensitive recurrent ovarian cancer: (i) 4-iodo-3-nitrate Benzobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the ovarian cancer is epithelial ovarian cancer, esculent epithelial carcinoma or primary Peritoneal cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is serous ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is serous adenocarcinoma ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is a papillary serous ovarian cancer. In one embodiment, the sensitive ovarian cancer is endometrioid ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is clear cell 〇 va Han cancer. In some embodiments, the patient has a measurable disease (e.g., according to RECIST 1. 1 measurable disease) ^ For example, the measurable disease can be defined by at least one lesion whose at least one dimension, such as the longest dimension, can be accurately measured, and by conventional techniques (eg Palpation, general x-ray, computed tomography or magnetic resonance imaging) measured mm or when measured by spiral CT mm. In some embodiments 156510. Doc -19· 201206448 'The patient has not received 2 or more prior chemotherapy (eg cytotoxic chemotherapy). In some embodiments, the platinum-sensitive recurrent ovarian cancer comprises any grade of ovarian tumor, such as any of ranks 1, 2 or 3. The grading of ovarian tumors can be according to any method known to those skilled in the art. For example, level 0 can refer to a non-invasive tumor or a borderline tumor. A grade 1 tumor may have well differentiated cells (which appear to be very similar to normal tissue) and may be the tumor with the best prognosis. Grade 2 tumors may be moderately well differentiated and may be composed of cells resembling normal tissues. Grade 3 tumors may have the worst prognosis and their cells may be abnormal, called poor differentiation. In some embodiments, the patient has not previously received chemotherapy (eg, cytotoxic chemotherapy) in the context of relapse. In some embodiments, the patient has not used more than 1 line of cytotoxic chemotherapy and linear biologics (such as Anti-VEGF antibodies, such as bevacizumab, are treated for more than about 6 months (hormone is not considered first-line treatment). In some embodiments, the patient has not received 4_iodo_3_nitrobenzamide or its metabolites. Or prior chemotherapy of a pharmaceutically acceptable salt. In some embodiments, the patient has not received inclusion of an inhibitor (eg, Olaparib, ABT-888 (Veliparib), AG014699, CEP 9722, MK 4827, KU-0059436 (AZD2281) ) or LT-673) prior chemotherapy. In some embodiments, the patient has about or at least about 6 months (eg, about or at least about 9 months, 2 months, 15 months, 18 months, 24 months, 30 months, 36 months or The non-imported compound interval of any of 42 months. For example, prior to the initiation of any of the treatments described herein, there is about or at least about 6 months after the last dose of the platinum compound (e.g., about or at least about 9 months, 12 months, 15 months, 18 156,510. Doc _20- 201206448, 24 months, 30 months, 36 months or 42 months). Eligibility criteria in Examples 1 and 2 of the present invention provide additional features of a patient that can be treated by any of the methods provided herein. The dosage regimen of 4,3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine), and a platinum compound (such as carboplatin) can be as described below. Any dosing schedule or dosing schedule described in the "Formulations, routes of administration, and dosing regimen" section. In some embodiments of any of the methods described herein, the term "patient" or "individual" refers to a human patient or individual. Platinum-sensitive recurrent ovarian cancer can be at any stage. In some embodiments of any of the methods described herein, the platinum-sensitive recurrent ovarian cancer is not metastatic. In some embodiments, the primary-susceptible recurrent ovarian cancer is metastatic. In some embodiments, the platinum-sensitive recurrent ovarian cancer is in any of stages 1, 2, 3 or 4. In some embodiments, the desensitizing recurrent ovarian cancer is in any of the stages la, lb, lc, 2a, porcine, ima, 3a, 3b, 3c or 4. The stages may be in accordance with any method known to those skilled in the art. For example, in stages, you can follow p //www. Cancer. The stage described in org/cancer/ovariancancer/detailedguide/ 〇varian-cancer_staging (last visit on May 3, 2011). In some embodiments of any of the methods provided herein, at least one therapeutic effect is obtained, the at least one therapeutic effect is ovarian tumor size reduction, metastasis reduction, π total remission, partial remission, pathological complete response, and overall response rate increase Or disease. In some embodiments, (iv) therapy is provided with and without 156510. Doc -21- 201206448 Increased clinical benefit rate compared to treatment with 4-indole-3-nitrobenzamine or its metabolites or their pharmaceutically acceptable salts. In some embodiments, an increase in clinical benefit rate is achieved compared to treatment with 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof (CBR=CR +PR+SD26 months). In some embodiments, the clinical benefit rate is increased by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, or higher. In some embodiments, the therapeutic effect is an increase in the overall response rate. In some embodiments, the overall reaction rate is increased by about 1%, 20%/〇, 30%, 40%, 50%, 60%, 70%, 80%, or higher. Any of the clinical efficacy parameters described herein can be measured in accordance with the RECIST i · 丨 version of the standard described in Eisenhauer EA et al, 2009, Eur J Cancer, 45(2): 228-47, the disclosure of which is incorporated by reference in its entirety. The citations are incorporated herein by reference. In some embodiments of any of the methods described herein, the method for treating platinum-sensitive recurrent rarex cancer further comprises administering 4-iodo-3-nitrate in combination with an antineoplastic agent (or at least one antineoplastic agent) Benzobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. For example, a method of treating a patient with a primary sensitive recurrent ovarian cancer comprising administering an effective amount of 4-iodo-3-nitrobenzamine or a metabolite thereof or a medicament thereof in combination with at least one other antineoplastic agent a physiologically acceptable salt, (b) an antimetabolite (eg, gemcitabine), and (c) a platinum complex (eg, carboplatin). In some embodiments, the antineoplastic agent is an anti-tumor alkylating agent, anti-tumor and anti-metabolite Products, anti-tumor antibiotics, plant-derived anti-tumor drugs, anti-tumor platinum complexes, anti-tumor camptothecin 156510. Doc -22- 201206448 (camptothecin) derivatives, anti-tumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, hormone antineoplastic agents, antineoplastic agents, angiogenesis inhibitors, differentiation agents Or other agent exhibiting antitumor activity, or a pharmaceutically acceptable salt thereof. In some embodiments, the platinum complex is cisplatin, carboplatin, platinum oxalate (xaplatin) or oxaliplatin. In some embodiments, the antimetabolite is citabine, capecitabine, gemcitabine or valprobine. In some embodiments, the methods further comprise administering 4_iodo-3-nitrobenzoguanamine or a metabolite thereof, or a pharmaceutically acceptable salt thereof, in combination with the patient and more than one antineoplastic agent. In some embodiments 'providing a method of treating platinum-sensitive recurrent ovarian cancer in a patient' includes administering to the patient an effective amount of 4-iodo-3-nitrophenylhydrazine in combination with at least one anti-neoplastic agent. An amine or a metabolite thereof, or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine), and a platinum compound (e.g., carboplatin). In some embodiments, the antineoplastic agent is administered 4_iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (eg, gemcitabine), and/or a platinum complex. The substance (such as carboplatin) is administered before, at the same time or after. In some embodiments, the antineoplastic agent is an anti-angiogenic agent, such as Avastin; or a receptor tyrosine kinase inhibitor, including but not limited to Sutent 'Nexavar, Recentin, ABT-869 and Axitinib. In some embodiments, the antineoplastic agent is a topoisomerase inhibitor including, but not limited to, irinotecan, topotecan (t〇p〇tecan) or euphorbia. In some embodiments, the anti-tumor drug is a taxane, including but not limited to, paclitaxel, docetaxel, and paclitaxel albumin 156510. Doc -23- 201206448 (Abraxane). In some embodiments, the antineoplastic agent is a Herceptin or Lapatinib drug that targets Her_2. In some embodiments, the antineoplastic agent is a hormone analog, such as a gonatum. In an embodiment, the antineoplastic agent is tamoxifen, a steroid aromatase inhibitor, a non-steroidal aromatase inhibitor, or a Fulvestrant. In some embodiments, the anti-tumor drug is an agent that targets a growth factor receptor. In some embodiments, the agent is an epidermal growth factor receptor (EGFR) inhibitor, including, but not limited to, Cetuximab and panitumimab. In some embodiments, the agent that targets the growth factor receptor is an insulin-like growth factor 1 (IGF-1) receptor (IGF1R) inhibitor, such as cp_751871. In other embodiments, the method further comprises surgery, radiation therapy, chemotherapy, gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, RNA therapy, immunotherapy, nanotherapy, or a combination thereof. In some embodiments, at least one therapeutic effect is obtained, which is tumor size reduction, metastasis reduction, complete remission, partial remission, complete disease response, or disease stabilization. In some embodiments of any of the methods described herein, the treatment comprises a treatment period of at least 11 days (eg, from about 11 days to about 30 days), wherein on the 1 to 10 separate days of the cycle, the patient It accepts about 1 mg/kg to about 100 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of its metabolite. In some embodiments, the patient receives from about 1 mg to about 50 mg/kg of 4-iodo-3-nitrobenzamide or a molar equivalent of the metabolism on 1 to 10 separate days of the cycle. product. In some embodiments, the patient receives about 1, 2, 3, 4, 5, 5 after 1 to 10 divisions of the cycle. 6, 6, 8, 156,510. Doc -24 - 201206448 10,11·2,12,14,16,18 or 2〇 mg/kg anal iodoxybenzamide. The treatment further includes an antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., a card flip). Some embodiments described herein provide a method of treating initially susceptible recurrent ovarian cancer in a patient (eg, a patient having a BRCA gene deficiency), including during the 21 day treatment cycle, on the first day of the cycle, 4th The patient was administered about 1 mg/kg to about 1.04 iodine-3-nitrobenzamide or a molar equivalent of the metabolite on day 8, day 8, and day 11. In some embodiments, 4-iodo-3-nitrobenzamide is administered orally, or is administered parenterally or by infusion, or by inhalation. The treatment further includes an anti-metabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin). Some embodiments described herein provide a method of treating platinum-sensitive recurrent ovarian cancer in a patient (eg, a patient having a BRCA gene deficiency), including. (a) establish a treatment cycle lasting from about 1 day to about 3 days; (b) on the day of separation from 1 to 1 of the cycle, about 1 paw to 2 mg to the patient. Kg 4-iodo-3_nitrobenzamide or a molar equivalent of its molecular weight. In some embodiments, 4-iodo-3-nitrobenzoguanamine is administered orally, or administered parenterally or by infusion, or by inhalation. The treatment further includes an antimetabolite (e.g., gemcitabine) and a compound (e.g., cardinal). Some embodiments provided herein include a method of treating ovarian cancer in a patient in need of such treatment, comprising: (a) obtaining a sample from the patient; (b) testing the sample to determine if the BRC A gene is defective; c) if the test indicates that the patient has a defect in the BRCA gene, the patient is treated with 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof; 156510. Doc •25- 201206448 and (d) If the test indicates that the patient is free of defects in the BRCA gene, choose a different treatment option. In some embodiments, at least one therapeutic effect is obtained. The at least one therapeutic effect is ovarian tumor size reduction, metastasis reduction, complete remission, partial remission, pathological complete response, elevated overall response rate, or disease stabilization. In some embodiments, an increase in clinical benefit rate is achieved compared to treatment with 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof (CBR=CR +PR+SD26 months)" In some embodiments, the clinical benefit rate is at least about 30%. In some embodiments, the sample is a tissue or body fluid sample. In some embodiments, the sample is a tumor sample, a blood sample, a plasma sample, a peritoneal fluid sample, exudate or effluent. In some embodiments, the ovarian cancer is metastatic ovarian cancer. In some embodiments, the BRCA gene is BRCA-1. In other embodiments, the BRCA gene is BRCA-2. In some embodiments, the BRCA genes are BRCA-1 and BRCA-2. In other embodiments, the defect is a genetic defect of the BRCA gene. In some embodiments, the genetic defect is a mutation, insertion, substitution, duplication or deletion of the BRCA gene. In some embodiments of any of the methods described herein, 4 moth-3 nitrobenzamide or a metabolite thereof, or a pharmaceutically acceptable "salt thereof, can exist in a variety of physical forms - eg, a free base, a salt ( Especially for the pharmaceutically acceptable J»·) ruler. A multi-day polymorph, a solvate, and the like. Unless otherwise defined herein, otherwise a chemical name is intended to cover all physical forms of the specified chemical. For example, without further limitation the following and 4-iodo-3-nitrobenzamine are intended to generally cover free assays as well as all pharmaceutically acceptable salts, polymorphs, hydrates and the like. Intended to make the invention or application 256510. Doc • 26-201206448 When the scope of the invention is limited to a particular physical form of a compound, it will be clear from the context of the paragraph or the scope of the patent application. In some embodiments of any of the methods described herein, a platinum compound (e.g., carboplatin) is administered by intravenous infusion. In some embodiments, the 4-formin-3-carbenamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is eloquently or administered parenterally or by infusion or inhalation. . In some embodiments, an antimetabolite (e.g., gemcitabine) is administered by intravenous infusion. In some embodiments of any of the methods described herein, the method comprises treating the patient with at least three chemically distinct substances, one of which is an antimetabolite (eg, gemcitabine), one of which is a platinum-containing complex ( For example, a card flip or a step) and 4|3_decylbenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof. In some embodiments, one or more of such materials may be present in a variety of physical forms - for example, a free base, a salt (especially a pharmaceutically acceptable salt), a hydrate, a polymorph, Solvates or metabolites, and the like. Unless otherwise defined herein, (4) a chemical name is intended to cover all physical forms of the specified chemical. For example, without further limitation the following and 4-iodo-3-nitrobenzamide are intended to cover the free base as well as all pharmaceutically acceptable salts, polymorphs, hydrates and metabolites thereof. It is intended that the scope of the invention or the specific scope of the invention may be construed as This: (1) 4-iodo-3-nitrobenzamide, its metabolites or its medicinally acceptable salts or solvates (9) antimetabolites, 156510. Doc -27- 201206448 Any of its pharmaceutically acceptable salts or solvates and (Hi) any of the platinum compounds, pharmaceutically acceptable salts or solvates thereof described herein Use of a medicament for the manufacture or treatment of platinum-sensitive recurrent ovarian cancer as described herein. Also provided herein is 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture of an anti-metabolite (eg, gemcitabine) and a platinum compound ( For example, carboplatin is used in combination to treat or prevent a drug of platinum-sensitive recurrent ovarian cancer as described herein. Also provided herein is 4 • iodine-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the manufacture or treatment of a platinum-sensitive relapse in a patient described herein. Use of a medicament for ovarian cancer, wherein 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof is intended to be combined with an antimetabolite (such as gemcitabine) and a platinum compound ( For example, the card is a combination to vote for the patient. Also provided herein is the use of any of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of platinum-sensitive recurrent ovarian cancer. For example, the uses provided herein are related or consistent with any of the methods described herein. Antineoplastic Agents In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of (1) 4-iodonitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable An acceptable salt; (ii) an antimetabolite (such as gemcitabine); and (d) a pure compound (such as a card flip) in combination with another antineoplastic agent. Antitumor agents that can be used in the present invention include, but are not limited to, an anti-tumor appearance. Chemical agent, anti-tumor and anti-metabolite product 'anti-tumor antibiotic, plant-derived anti-tumor drug, anti-coin compound compound, anti-tumor hi-tree test 156510. Doc -28· 201206448 Derivatives, anti-tumor (tetra)-amino acid kinase inhibitors, anti-tumor agents, single plants (IV), interferon's biological response modifiers and other agents exhibiting anti-tumor activity' or pharmaceutically acceptable Salt. In some embodiments, (1) anal iodine, nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (8) an antimetabolite (such as gemcitabine), and a (tetra) starting compound (such as carboplatin) An angiogenic agent is used in combination. In other embodiments, (1) cardiac iodide-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (π) an anti-metabolite (such as gemcitabine), and (iii) a platinum compound ( In combination with a topoisomerase inhibitor such as irinotecan, such as carboplatin, in other embodiments '(!) 4-iodo-3-nitrobenzamide, its metabolites or its medicinal Acceptable salts, (丨〇 anti-metabolites (such as gemcitabine), and (in) platinum compounds (such as carboplatin) are used in combination with hormonal therapies. In other embodiments, (1) 4-iodo-3-nitro Benzoylamine, its metabolites or its therapeutically acceptable salts, (U) antimetabolites (such as gemcitabine), and compounds (such as card flipping) and including but not limited to E(}FR!IGF1R inhibition The growth factor receptor inhibitor of the agent is used in combination. In some embodiments, the ovarian cancer is a metastatic cancer. In some embodiments of any of the methods provided herein, the antineoplastic agent is alkaneized. "Agent" generally refers herein to the alkyl group in the alkylation reaction. The agent 'where a certain hydrogen atom of an organic compound is substituted by an alkyl group. Examples of anti-tumor agents include, but are not limited to, nitrogen mustard N_oxide, cyclophosphamide, ifosfamide, Melphalan, busulfan, mitobronitol, carb〇qUOne, thiotepa, 156510. Doc •29· 201206448 Ramimustine, nimustine, temozolomide or carmustine. In some embodiments of any of the methods provided herein, the antineoplastic agent is an anti-metabolite. The term "antimetabolite" as used herein broadly includes substances that interfere with normal metabolism and inhibit electrons due to structural or functional similarities to metabolic products important to living organisms such as vitamins, coenzymes, amino acids, and sugars. Transfer systems to block the production of energy-rich intermediates. Examples of anti-metabolites having anti-tumor activity include, but are not limited to, methotrexate, 6-mercaptopurine riboside, and thiopurine. Mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, Cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine or pemetrexed disodium And preferably 5-fluorouridine, S-1, gemcitabine and the like. In some embodiments of any of the methods provided herein, the antineoplastic agent is an anti-tumor antibiotic. Examples of anti-tumor antibiotics include, but are not limited to, actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, Peplomycin, mitomycin C, aru I: aclarubicin, D pirarubicin, epirubicin, net statin Vinegar 156510. Doc -30- 201206448 (zinostatin stimalamer), idarubicin, sirolimus or vaimbicin. In some embodiments of any of the methods provided herein, the antineoplastic agent is a plant-derived antineoplastic agent. Examples of plant-derived antineoplastic agents include, but are not limited to, vincristine, vinbiastine, vindesine, etoposide, and Sobrozin (S〇bUZ) 〇xane), docetaxel, paclitaxel, and vinorelbine, and preferably docetaxel and paclitaxel. In some embodiments of any of the methods provided herein, the antineoplastic agent is a camptothecin derivative of the present antitumor activity. Examples of anti-tumor camptothecin derivatives include, but are not limited to, campptinthecin, monoterpene-hydroxycamptothecin, topotecan (t〇P〇tecan), irinotecan (irin〇tecan) Or 9-aminocamptothecin, preferably camptothecin, topotecan and irinotecan. In addition, irinotecan is metabolized in vivo and exhibits an anti-tumor effect as a purchase 8 . It is believed that the mechanism and activity of camptothecin are actually the same as those of camptothecin (eg

Nitta等人，Gan to Kagaku Ry〇h〇, 14, 850-857 (1987))。 在本文提供之任何方法的—些實施例中，抗腫瘤藥為具 有抗腫瘤活性之有機鉑化合物或鉑配位化合物◊如本文中 使用之術浯「有機鉑化合物」、「鉑化合物」或「鉑複合 物」及其類似術語指以離子形式提供銘之含始化合物。較 佳的有機鉑化合物包括但不限於順鉑；順_二胺二水合鉑 (Π)離子’氯（二伸乙基三胺）·始（π)氣化物；二氯（伸乙基 胺）鉑（π)，一胺（lsl_環丁烷二羧根基）鉑（11)(卡鉑）；螺 156510.doc 31· 201206448 鉑（Η);異丙鉑；二胺（2-乙基丙二酸根基）鉑（II);伸乙基 二胺丙二酸翻（Π);水合（1，2-二胺基二環己烷）硫酸鉑 (II)，水合（1，2_二胺基二環己烷）丙二酸鉑（11) ; (1，2二胺 基環己院）丙二酸鉑（11) ; (4_羧基酞酸）（1，2_二胺基環己烷） 銘（II) ; (1，2-二胺基環己烷）_(異檸檬酸）鉑（11) ; (1，2二胺 基環己烷）草酸鉑（II);奥馬鉑；四鉑；卡鉑；奈達鉑；及 奧沙利鉑，且較佳為卡鉑或奥沙利鉑。另外，說明書中提 及之其他抗腫瘤有機鉑化合物為已知的且為市售者及/或 可由熟習此項技術者藉由習知技術來產生。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為抗 腫瘤酪胺酸激酶抑制劑。本文中之術語「酪胺酸激酶抑制 劑」指抑制「酪胺酸激酶」（其將Ατρ之^磷酸根基團轉移 至蛋白質中之特定酪胺酸的羥基）之化學物質。抗腫瘤酪 胺酸激酶抑制劑之實例包括但不限於吉非替尼 (gefitinib)、伊馬替尼（imatinib)、埃羅替尼（erl〇tinib)、索 坦、蕾或瓦、雷森汀、aBT_869及阿西替尼（Axitinib)。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為展 現抗腫瘤活性之抗體或抗體之結合部分。在一些實施例 中，抗腫瘤藥為單株抗體。其實例包括但不限於阿昔單抗 (abciximab)阿達木單抗（adalimumab)、阿侖單抗 (alemtuzumab)、巴利昔單抗（basiliximab)、貝伐單抗 (bevacizumab)、西妥昔單抗（cetuximab)、達克珠單抗 (daclizumab)、依庫珠單抗（ecuHzumab)、依法珠單抗 (efalizumab)替伊莫單抗（ibritumomab tiuxetan)、英夫利 156510.doc -32- 201206448 昔單抗（infliximab)、莫羅單抗-CD3 (muromonab-CD3)、那 他珠單抗（natalizumab)、奥馬珠單抗（omalizumab)、帕利 珠單抗（palivizumab)、帕尼單抗（panitumumab)、雷尼珠單 抗（ranibizumab)、吉姆單抗奥佐米星（gemtuzumab ozogamicin)、利妥昔單抗（rituximab)、托西莫單抗 (tositumomab)、曲妥單抗（trastuzumab)或任何對抗原具特 異性之抗體片段。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為干 擾素。此類干擾素具有抗腫瘤活性，且其為由大多數動物 細胞在感染病毒時生成並分泌之醋蛋白。其不僅具有抑制 病毒生長之效果，而且還具有多種免疫效應機制，包括抑 制細胞（特別為腫瘤細胞）生長及增強天然殺手細胞活性， 因此被稱作一類細胞因子。抗腫瘤干擾素之實例包括但不 限於干擾素α、干擾素a-2a、干擾素a-2b、干擾素β、干擾 素γ-la及干擾素γ-ηΐ。 在本文提供之任何方法的一些實施例中，抗腫瘤藥為生 物反應調節劑。其一般為用於改變活生物體之防禦機制或 生物反應（諸如組織細胞之存活、生長或分化）以使其對腫 瘤、感染或其他疾病有用的物質或藥物之通稱。生物反應 調節劑之實例包括但不限於雲芝多糖（krestin)、香菇多糖 (lentinan)、西佐喃（sizoHran)、畢西巴尼（picibanil)及烏苯 美司（ubenimex)。 在本文提供之任何方法的一些實施例中，抗腫瘤藥包括 但不限於米托蒽i昆（mitoxantrone)、L-天冬醯胺酶（L- 156510.doc -33- 201206448 asparaginase)、丙卡巴肼（procarbazine)、達卡巴 σ桊 (dacarbazine)、經基腺（hydroxycarbamide)、喷司他丁 (pentostatin)、維曱酸（tretinoin)、阿法賽特（alefacept)、達 貝泊汀 a (darbepoetin alfa)、阿那曲唾（anastrozole)、依西 美坦（exemestane)、比卡魯胺（bicalutamide)、亮丙瑞林 (leuprorelin) 、 It 他胺（flutamide)、氣維司群 (fulvestrant)、σ底加他尼八鈉（pegaptanib octasodium)、地 尼白介素毒素連接物（denileukin diftitox)、阿地白介素 (aldesleukin)、促甲狀腺素 a (thyrotropin alfa)、三氧化一 石申（arsenic trioxide)、蝴替佐米（bortezomib)、卡培他續 (0&amp;卩6(^乱1^116)及戈舍瑞林（§〇36代1111)。 上述術語「抗腫瘤烷化劑」、「抗腫瘤抗代謝產物J、「抗 腫瘤抗生素」、「植物源性抗腫瘤藥」、「抗腫瘤鉑配位化合 物」、「抗腫瘤喜樹鹼衍生物」、「抗腫瘤酪胺酸激酶抑制 劑」、「單株抗體」、「干擾素」、「生物反應調節劑」及「其 他抗腫瘤藥」為公知的且為市售者或可由熟習此項技術者 藉由本身已知之方法或藉由熟知或習知方法來產生。用於 製備吉非替尼之方法例如描述於美國專利第5,770,599號； 用於製備西妥昔單抗之方法例如描述於WO 96/40210;用 於製備貝伐單抗之方法例如描述於wo 94/10202 ;用於製 備奥沙利鉑之方法例如描述於美國專利第5,420,3 19號及第 5,959,133號；用於製備吉西他濱之方法例如描述於美國專 利第5,434,254號及第5,223,608號；用於製備喜樹驗之方法 例如描述於美國專利第5，162,532號、第5,247,089號、第 156510.doc • 34· 201206448 5，191，082 號、第 5,200,524 號、第 5,243,050 號及第 5,321，140號；用於製備伊立替康之方法例如描述於美國專 利第4,604,463號；用於製備托泊替康之方法例如描述於美 國專利第5,734,056號；用於製備替莫唑胺之方法例如描述 於JP-B第4-5029號；及用於製備利妥昔單抗之方法例如描 述於 JP-W第 2-503 143號》 上述抗腫瘤烷化劑為市售者，例如下述：氮芥N-氧化 物，作為 Nitrorin(商品名）來自 Mitsubishi Pharma Corp.; 環填醯胺，作為Endoxan(商品名）來自Shionogi &amp; Co·, Ltd.;異環填醯胺，作為Ifomide(商品名）來自Shionogi &amp; Co·, Ltd.;美法命，作為Alkeran(商品名）來自 GlaxoSmithKline Corp·;白消安’作為 Mablin(商品名）來 自 Takeda Pharmaceutical Co·，Ltd·;二溴甘露醇’作為 Myebrol(商品名）來自 Kyorin Pharmaceutical Co” Ltd·;卡 波酿，作為Esquinon(商品名）來自Sankyo Co.，Ltd.;塞替 派，作為 Tespamin(商品名）來自 Sumitomo Pharmaceutical Co.，Ltd.;雷莫司汀，作為Cymerin(商品名）來自 Mitsubishi Pharma Corp·;尼莫司汀，作為 Nidran(商品名） 來自Sankyo Co.，Ltd.;替莫β坐胺，作為Temodar(商品名） 來自Schering Corp.;及卡莫司汀，作為Gliadel Wafer(商 0¾ 名）來自 Guilford Pharmaceuticals Inc. 〇 上述抗腫瘤抗代謝產物為市售者，例如下述：曱胺蝶 呤，作為 Methotrexate(商品名）來自 Takeda Pharmaceutical Co·，Ltd. ; 6-疏基嘌呤核苷，作為Thioinosine(商品名）來 156510.doc -35- 201206448 自Aventis Corp.;疏基嘌呤，作為Leukerin(商品名）來自 Takeda Pharmaceutical Co.，Ltd· ; 5-氟尿，咬，作為 5-FU(商品名）來自 Kyowa Hakko Kogyo Co·，Ltd.;喃 咬， 作為 Futraful(商品名）來自 Taiho Pharmaceutical Co·，Ltd.; 去氧It展苷，作為Furutulon(商品名）來自Nippon Roche Co.，Ltd.;卡莫乳，作為Yamafur(商品名）來自Yamanouchi Pharmaceutical Co·，Ltd.;阿糖胞苷，作為Cylocide(商品 名）來自Nippon Shinyaku Co., Ltd.;阿糖胞苦十八烧基填 酸鹽，作為 Strasid(商品名）來自 Nippon Kayaku Co.，Ltd.; 依諾他濱，作為Sanrabin(商品名）來自Asahi Kasei Corp.; S-1，作為 TS-1 (商品名）來自 Taiho Pharmaceutical Co., Ltd.;吉西他濱，作為Gemzar(商品名）來自Eli Lilly &amp; Co.;氟達拉濱，作為Fludara(商品名）來自Nippon Schering Co.，Ltd.;及培美曲塞二納，作為Alimta(商品名）來自Eli Lilly &amp; Co.。 上述抗腫瘤抗生素為市售者，例如下述：放線菌素D， 作為 Cosmegen(商品名）來自 Banyu Pharmaceutical Co., Ltd.;多柔比星，作為Adriacin(商品名）來自Kyowa Hakko Kogyo Co., Ltd.;柔紅黴素，作為道諾黴素（Daunomycin) 來自Meiji Seika Kaisha Ltd.;新制癌菌素，作為 Neocarzinostatin(商品名）來自 Yamanouchi Pharmaceutical Co_，Ltd.;博萊黴素，作為Bleo(商品名）來自Nippon Kayaku Co., Ltd.;培洛黴素，作為Pepro(商品名）來自 Nippon Kayaku Co, Ltd.;絲裂黴素C，作為Mitomycin(商 156510.doc • 36· 201206448 品名）來自Kyowa Hakko Kogyo Co.，Ltd.;阿柔比星，作為 Aclacinon(商品名）來自 Yamanouchi Pharmaceutical Co., Ltd. ; °比柔比星，作為Pinorubicin(商品名）來自Nippon Kayaku Co.，Ltd.;表柔比星，作為 Pharmorubicin(商品名） 來自Pharmacia Corp.;淨司他丁斯酯，作為Smancs(商品 名）來自 Yamanouchi Pharmaceutical Co.，Ltd·;伊達比星， 作為Idamycin(商品名）來自Pharmacia Corp.;西羅莫司， 作為Rapamune(商品名）來自Wyeth Corp.;及戊柔比星，作 為 Valstar(商品名）來自 Anthra Pharmaceuticals Inc.。 上述植物源性抗腫瘤藥為市售者，例如下述：長春新 驗，作為Oncovin(商品名）來自Shionogi &amp; Co.，Ltd.;長春 驗，作為 Vinblastine(商品名）來自 Kyorin Pharmaceutical Co·，Ltd.;長春地辛，作為Fildesin(商品名）來自Shionogi &amp; Co_, Ltd.;依託泊苷，作為Lastet(商品名）來自Nippon Kayaku Co·，Ltd.;索布佐生，作為Perazolin(商品名）來自 Zenyaku Kogyo Co.，Ltd·;多西他賽，作為 Taxsotere(商品 名）來自Aventis Corp.;太平洋紫杉醇，作為Taxol(商品名） 來自Bristol-Myers Squibb Co.;及長春瑞濱，作為 Navelbine(商品名）來自 Kyowa Hakko Kogyo Co.，Ltd.。 上述抗腫瘤鉑配位化合物為市售者，例如下述：順鉑， 作為 Randa(商品名）來自 Nippon Kayaku Co·，Ltd.;卡 16， 作為 Paraplatin(商品名）來自 Bristol-Myers Squibb Co.;奈 達銘，作為Aqupla(商品名）來自Shionogi &amp; Co.，Ltd.;及 奥沙利始，作為Eloxatin(商品名）來自Sanofi-Synthelabo 156510.doc -37- 201206448Nitta et al, Gan to Kagaku Ry〇h〇, 14, 850-857 (1987)). In some embodiments of any of the methods provided herein, the antineoplastic agent is an organoplatinum compound or a platinum coordination compound having antitumor activity, such as the "organoplatinum compound", "platinum compound" or " Platinum complexes and the like are meant to provide the initial compounds in the form of ions. Preferred organoplatinum compounds include, but are not limited to, cisplatin; cis-diamine dihydrate platinum (ruthenium) ion 'chlorine (diethylidene triamine) · initial (π) vapor; dichloro (ethylamine) Platinum (π), monoamine (lsl_cyclobutanedicarboxylate)platinum (11) (carboplatin); spiro 156510.doc 31· 201206448 platinum (iridium); isopropyl platinum; diamine (2-ethyl propyl) Diacid) platinum (II); ethyl diamine malonate (Π); hydrated (1,2-diaminodicyclohexane) platinum (II) sulfate, hydrated (1,2-diamine P-dicyclohexane) Platinum malonate (11); (1,2-diaminocyclohexyl) platinum propionate (11); (4-carboxyl decanoic acid) (1,2-diaminocyclohexyl) (II); (1,2-diaminocyclohexane)_(isocitrate)platinum (11); (1,2-diaminocyclohexane) oxalic acid platinum (II); omaplatin ; tetraplatin; carboplatin; nedaplatin; and oxaliplatin, and preferably carboplatin or oxaliplatin. Additionally, other anti-tumor organoplatinum compounds referred to in the specification are known and commercially available and/or can be produced by those skilled in the art by conventional techniques. In some embodiments of any of the methods provided herein, the antineoplastic agent is an anti-tumor tyrosine kinase inhibitor. The term "tyrosine kinase inhibitor" as used herein refers to a chemical substance which inhibits "tyrosine kinase" which transfers a hydroxy group of Ατρ to a specific tyrosine of a protein. Examples of anti-tumor tyrosine kinase inhibitors include, but are not limited to, gefitinib, imatinib, erlotinib, sultan, bud or watt, leisentin, aBT_869 and Axitinib. In some embodiments of any of the methods provided herein, the antineoplastic agent is a binding moiety of an antibody or antibody that exhibits anti-tumor activity. In some embodiments, the antineoplastic agent is a monoclonal antibody. Examples include, but are not limited to, abciximab adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab Anti-(cetuximab), daclizumab, ecuHzumab, efalizumab, ibritumomab tiuxetan, Inflix 156510.doc -32- 201206448 Monoclonal antibody (infliximab), morozumab-CD3 (muromonab-CD3), natalizumab (natalizumab), omalizumab (omalizumab), palivizumab (palivizumab), panitumumab ( Panitumumab), ranibizumab, gemtuzumab ozogamicin, rituximab, tositumomab, trastuzumab or Any antibody fragment specific for an antigen. In some embodiments of any of the methods provided herein, the antineoplastic agent is an interferon. Such interferons have antitumor activity and are vinegar proteins which are produced and secreted by most animal cells upon infection with a virus. It not only has the effect of inhibiting the growth of the virus, but also has various immune effect mechanisms, including inhibiting the growth of cells (especially tumor cells) and enhancing the activity of natural killer cells, and is therefore called a type of cytokine. Examples of anti-tumor interferons include, but are not limited to, interferon alpha, interferon a-2a, interferon a-2b, interferon beta, interferon gamma-la, and interferon gamma-n. In some embodiments of any of the methods provided herein, the antineoplastic agent is a biologic response modifier. It is generally a generic term for a substance or drug used to alter the defense mechanism or biological response of a living organism, such as the survival, growth or differentiation of tissue cells, to make it useful for tumors, infections or other diseases. Examples of biological response modifiers include, but are not limited to, krestin, lentinan, sizoHran, picibanil, and ubenimex. In some embodiments of any of the methods provided herein, the antineoplastic agent includes, but is not limited to, mitoxantrone, L-aspartate (L-156510.doc-33-201206448 asparaginase), procarba Procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin Alfa), anastrozole, exemestane, bicalutamide, leuprorelin, ittamide, fulvestrant, σ Pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib (bortezomib), capecita continued (0&amp;卩6(^乱1^116) and goserelin (§〇36代1111). The above terms "antitumor alkylating agent", "antitumor antimetabolite J , "anti-tumor antibiotics", "plants Antitumor drugs, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, and biological reactions "Modulators" and "other antineoplastic agents" are well known and commercially available or can be produced by those skilled in the art by methods known per se or by well-known or conventional methods for the preparation of gefitinib. The method is described, for example, in U.S. Patent No. 5,770,599; the method for preparing cetuximab is described, for example, in WO 96/40210; the method for preparing bevacizumab is described, for example, in wo 94/10202; The method for preparing gemcitabine is described, for example, in U.S. Patent Nos. 5,420,319 and 5,959,133; the methods for preparing gemcitabine are described, for example, in U.S. Patent Nos. 5,434,254 and 5,223,608; U.S. Patent Nos. 5,162,532, 5,247,089, 156,510, doc, 34, 201206448, 5,191,082, 5,200,524, 5,243,050, and 5,321,140; for the preparation of irinotecan The method is described, for example, in U.S. Patent No. 4,604,463; the method for the preparation of topotecan is described, for example, in U.S. Patent No. 5,734,056; the method for preparing temozolomide is described, for example, in JP-B No. 4-5029; The method of texexoma is described, for example, in JP-W No. 2-503 143. The above antitumor alkylating agent is commercially available, for example, the following: nitrogen mustard N-oxide, and Nitrorin (trade name) from Mitsubishi Pharma Corp.; ring-filled guanamine, as Endoxan (trade name) from Shionogi &amp; Co., Ltd.; heterocyclic guanamine, as Ifomide (trade name) from Shionogi &amp; Co·, Ltd.; As Alkeran (trade name) from GlaxoSmithKline Corp.; Busulfan's as Mablin (trade name) from Takeda Pharmaceutical Co., Ltd.; dibromomannitol' as Myebrol (trade name) from Kyorin Pharmaceutical Co" Ltd.; Wave, as Esquinon (trade name) from Sankyo Co., Ltd.; Seti, as Tespamin (trade name) from Sumitomo Pharmaceutical Co., Ltd.; Ramustine, as Cymerin (trade name) from Mitsubish i Pharma Corp.; Nimustine, as Nidran (trade name) from Sankyo Co., Ltd.; Temo beta octaamine, as Temodar (trade name) from Schering Corp.; and Carmustine, as Gliadel Wafer (Commercial 03⁄4) from Guilford Pharmaceuticals Inc. The above antitumor antimetabolite is commercially available, for example, the following: indole pterin, as Methotrexate (trade name) from Takeda Pharmaceutical Co., Ltd.; 6- Purine nucleoside, as Thiioinosine (trade name) 156510.doc -35- 201206448 from Aventis Corp.; thiophene, as Leukerin (trade name) from Takeda Pharmaceutical Co., Ltd.; 5-fluorourine, bite, as 5-FU (trade name) from Kyowa Hakko Kogyo Co., Ltd.; bite, as Futraful (trade name) from Taiho Pharmaceutical Co., Ltd.; deoxy It product, as Furutulon (trade name) from Nippon Roche Co., Ltd.; Camo milk, as Yamafur (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; cytarabine, as Cylocide (trade name) from Nippon Shinyaku Co., Ltd.; Octahydrate , as the Strasid (trade name) from Nippon Kayaku Co., Ltd.; Enoxata, as Sanrabin (trade name) from Asahi Kasei Corp.; S-1, as TS-1 (trade name) from Taiho Pharmaceutical Co. , Ltd.; Gemcitabine, as Gemzar (trade name) from Eli Lilly &amp;Co.; Fludarabine, as Fludara (trade name) from Nippon Schering Co., Ltd.; and Pemetrexe II, as Alimta (trade name) from Eli Lilly &amp; Co. The above antitumor antibiotic is commercially available, for example, as follows: actinomycin D, as Cosmegen (trade name) from Banyu Pharmaceutical Co., Ltd.; doxorubicin, as Adriacin (trade name) from Kyowa Hakko Kogyo Co. , Ltd.; daunorubicin, as daunomycin from Meiji Seika Kaisha Ltd.; neocarcincin, as Neocarzinostatin (trade name) from Yamanouchi Pharmaceutical Co_, Ltd.; bleomycin, as Bleo (trade name) from Nippon Kayaku Co., Ltd.; Pilomycin, as Pepro (trade name) from Nippon Kayaku Co, Ltd.; Mitomycin C, as Mitomycin (Business 156510.doc • 36· 201206448 ) from Kyowa Hakko Kogyo Co., Ltd.; Arubicin, as Aclacinon (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; °bibibistar, as Pinorubicin (trade name) from Nippon Kayaku Co.,Ltd .; epirubicin, as Pharmorubicin (trade name) from Pharmacia Corp.; net statin ester, as Smancs (trade name) from Yamanouchi Pharmaceutical Co., Ltd.; idabisin, as Idamycin (business The product name is from Pharmacia Corp.; sirolimus, as Rapamune (trade name) from Wyeth Corp.; and valrubicin, as Valstar (trade name) from Anthra Pharmaceuticals Inc. The above plant-derived antineoplastic agent is commercially available, for example, the following: Changchun Xinzheng, as Oncovin (trade name) from Shionogi &amp; Co., Ltd.; Changchun test, as Vinblastine (trade name) from Kyorin Pharmaceutical Co· , Ltd.; Vindesine, as Fildesin (trade name) from Shionogi &amp; Co_, Ltd.; Etoposide, as Lastet (trade name) from Nippon Kayaku Co., Ltd.; Sobzozo, as Perazolin (commodity) Name) from Zenyaku Kogyo Co., Ltd.; Docetaxel, as Taxsotere (trade name) from Aventis Corp.; Pacific paclitaxel, as Taxol (trade name) from Bristol-Myers Squibb Co.; and vinorelbine, as Navelbine (trade name) is from Kyowa Hakko Kogyo Co., Ltd. The above antitumor platinum coordination compound is commercially available, for example, as follows: cisplatin, as Randa (trade name) from Nippon Kayaku Co., Ltd.; card 16, as Paraplatin (trade name) from Bristol-Myers Squibb Co. Nida Ming, as Aqupla (trade name) from Shionogi &amp; Co., Ltd.; and Osali, as Eloxatin (trade name) from Sanofi-Synthelabo 156510.doc -37- 201206448

Co.。 上述抗腫瘤喜樹驗衍生物為市售者，例如下述：伊立替 康，作為 Campto(商品名）來自 Yakult H〇nsha Co.，Ltd.;托 泊替康，作為Hycamtin(商品名）來自GiaxoSmithKlineCo. The above antitumor camptothecin derivative is commercially available, for example, the following: irinotecan, as Campto (trade name) from Yakult H〇nsha Co., Ltd.; topotecan, as Hycamtin (trade name) from GiaxoSmithKline

Corp. ’ 及吾樹驗，來自 Aldrich Chemical Co., Inc.， U.S.A。 上述抗腫瘤酪胺酸激酶抑制劑為市售者，例如下述：吉 非替尼’作為Iressa(商品名）來自AstraZeneca Corp.;伊馬 替尼，作為格利維（Gleevec)(商品名）來自Novartis AG ;及 埃羅替尼’作為Tarceva(商品名）來自〇si pharmaceuticals Inc. 〇 上述單株抗體為市售者，例如下述：西妥昔單抗，作為 Erbitux(商品名）來自 Bristol-Myers Squibb Co.;貝伐單 抗，作為Avastin安維汀（商品名）來自Genentech，Inc·;利 妥昔單抗，作為Rituxan(商品名）來自Biogen Idee Inc.;阿 侖單抗，作為坎帕斯（Campath)(商品名）來自Berlex Inc.; 及曲妥單抗，作為赫赛汀（商品名）來自Chugai Pharmaceutical Co” Ltd. 〇 上述干擾素為市售者，例如下述：干擾素α，作為 Sumiferon(商品名）來自 Sumitomo Pharmaceutical Co·, Ltd·;干擾素a-2a，作為Canferon-A(商品名）來自Takeda Pharmaceutical Co.，Ltd.;干擾素 a-2b，作為 Intron A(商品 名）來自 Schering-Plough Corp.;干擾素 β，作為 IFN. β.(商 品名）來自 Mochida Pharmaceutical Co.，Ltd.;干擾素γ- 156510.doc -38 · 201206448 la，作為 Imunomax-γ(商品名）來自 Shionogi &amp; Co·，Ltd.; 及干擾素γ-nl，作為Ogamma(商品名）來自Otsuka Pharmaceutical Co.，Ltd.。 上述生物反應調節劑為市售者，例如下述：雲芝多糖， 作為Krestin(商品名）來自Sankyo Co·，Ltd.;香菇多糖，作 為Lentinan(商品名）來自Aventis Corp.；西佐喃，作為 Sonifiran(商品名）來自 Kaken Seiyaku Co·，Ltd.;畢西巴 尼，作為 Picibanil(商品名）來自 Chugai Pharmaceutical Co.， Ltd.;及烏苯美司，作為Bestatin(商品名）來自Nippon Kayaku Co., Ltd. ° 上述其他抗腫瘤藥為市售者，例如下述：米托蒽醌，作 為 Novantrone(商品名）來自 Wyeth Lederle Japan, Ltd. ; L-天冬醯胺酶，作為Leunase(商品名）來自Kyowa Hakko Kogyo Co.，Ltd.;丙卡巴肼，作為Natulan(商品名）來自 Nippon Roche Co.，Ltd.;達卡巴嗓，作為 Dacarbazine(商 品名）來自Kyowa Hakko Kogyo Co.，Ltd·;經基脲，作為 Hydrea(商品名）來自 Bristol-Myers Squibb Co.;喷司他 丁 ’作為Coforin(商品名）來自 Kagaku Oyobi Kessei Ryoho Kenkyusho ;維曱酸，作為Vesanoid(商品名）來自Nippon Roche Co·，Ltd.;阿法賽特，作為Amevive(商品名）來自 Biogen Idee Inc.;達貝泊、;丁 α，作為阿蘭内（Aranesp)(商品 名）來自Amgen Inc.;阿那曲吐，作為瑞寧德（Arimidex)(商 品名）來自AstraZeneca Corp.;依西美坦，作為阿諾新 (Aromasin)(商品名）來自pfizer lnc.;比卡魯胺，作為康士 156510.doc -39- 201206448 付（Casodex)(商品名）來自AstraZeneca Corp.;亮丙瑞林， 作為 Leuplin(商品名）來自 Takeda Pharmaceutical Co., Ltd.，氟他胺，作為優萊辛（Euiexin)(商品名）來自 Schering-Plough Corp·;氟維司群，作為Faslodex(商品名） 來自AstraZeneca Corp. ; 底加他尼八鈉，作為Macugen(商 品名）來自Gilead Sciences, Inc.;地尼白介素毒素連接物， 作為 Ontak(商品名）來自 Ligand Pharmaceuticals Inc.;阿地 白介素，作為Proleukin(商品名）來自Chiron Corp.;促曱狀 腺素α，作為Thyrogen(商品名）來自Genzyme Corp.;三氧 化二石申，作為Trisenox(商品名）來自Cell Therapeutics， Inc.，棚替佐米，作為Velcade(商品名）來自Millennium Pharmaceuticals，Inc.;卡培他濱，作為xei〇da(商品名）來 自Hoffmann-La Roche，Ltd.;及戈舍瑞林，作為 Zoladex(商品名）來自AstraZeneca Corp.。如本說明書中使 用之術語「抗腫瘤藥」包括上述抗腫瘤烧化劑、抗腫瘤抗 代謝產物、抗腫瘤抗生素、植物源性抗腫瘤藥、抗腫瘤鉑 配位化合物、抗腫瘤喜樹驗衍生物、抗腫瘤酷·胺酸激酶抑 制劑、單株抗體、干擾素、生物反應調節劑及其他抗腫瘤 藥。 其他抗腫瘤藥或抗贅生劑可與苯并η南酮化合物組合使 用。此類合適抗腫瘤藥或抗贅生劑包括但不限於13 -順·視 黃酸、2-CdA、2-氯脫氧腺苷、5-氮雜胞苷、5-乳尿嘧 咬、5-FU、6-疏基嗓吟、6-MP、6-TG、6-硫鳥°票吟、紫杉 醇白蛋白微粒、異維甲酸（Accutane)、放線菌素_d、阿黴 156510.doc •40· 201206448 素（Adriamycin)、阿德盧西（Adrucil)、安規寧（Agrylin)、 Ala-Cort、阿地白介素、阿舍單抗、ALIMTA、阿利維甲 酸（Alitretinoin)、愛卡班-AQ (Alkaban-AQ)、愛克蘭 (Alker an)、全-反式視黃酸、α干擾素、六甲蜜胺、胺曱嗓 呤（Amethopterin)、胺 _ 丁（Amifostine)、胺魯米特 (Aminoglutethimide)、阿那格雷（Anagrelide)、阿南屈 (Anandron)、阿那曲。坐、***糖胞σ密咬、Ara-C、阿蘭 内、阿可達（Aredia)、瑞寧德、阿諾新、阿侖恩 (Arranon)、三氧化二珅、天冬酿胺酶、ATRA、安維汀、 氮雜胞苷、BCG、BCNU、苯達莫司汀（Bendamustine)、貝 伐單抗、貝沙羅汀（Bexarotene)、BEXXAR、比卡魯胺、 BiCNU、布樂諾森（Blenoxane)、博萊黴素、硼替佐米、白 消安、白舒非（Busulfex)、C225、曱醯四氫葉酸鈣 (Calcium Leucovorin)、坎帕斯、卡普特瑟（Camptosar)、喜 樹驗-11、卡培他濱、卡拉庫（Carac)、卡翻、卡莫司汀、 卡莫司汀糯米紙囊劑、康士得、CC-5013、CCI-779、 CCNU、CDDP、CeeNU、舍魯比汀（Cerubidine)、西妥昔 單抗、苯丁酸氮芬（Chlorambucil)、順翻、嗜橙菌因子 (Citrovorum Factor)、克拉曲濱（Cladribine)、可的松 (Cortisone)、可美淨（Cosmegen)、CPT-11、環罐醢胺、赛 他屈（Cytadren)、阿糠胞苷、阿糖胞苷脂質體、赛德薩-U (Cytosar-U)、賽托森（Cytoxan)、達卡巴唤、達可根 (Dacogen)、放線菌素 D (Dactinomycin)、達貝泊；丁 阿爾 法、達沙替尼（Dasatinib)、道諾黴素、柔紅黴素、鹽酸柔 156510.doc -41- 201206448 紅黴素、柔紅黴素脂質體、道諾索米（DaunoXome)、地卡 特隆（Decadron)、地西他濱（Decitabine)、δ-庫特弗（Delta-Cortef)、德耳塔松（Deltasone)、地尼白介素毒素連接物、 DepoCyt™、***（Dexamethasone)、乙酸地塞求松、 ***構酸鈉、德薩美松（Dexasone)、右雷佐生 (Dexrazoxane)、DHAD、DIC、迪歐德（Diodex)、多西他 赛、多西爾（Doxil)、多柔比星、多柔比星脂質體、 DroxiaTM、DTIC、DTIC-Dome、杜拉隆（Duralone)、依弗 德（Efudex)、艾里咖（Eligard)、艾倫斯（Ellence)、艾羅薩 '汀（Eloxatin)、愛施巴（Elspar)、艾姆塞特（Emcyt)、表柔比 星、依泊汀a(Epoetin Alfa)、艾比特斯（Erbitux)、埃羅替 尼、歐文氏菌屬（Erwinia) L-天冬醯胺酶、雌莫司丁 (Estramustine)、艾索歐（Ethyol)、凡畢複（Etopophos)、依 託泊苷、磷酸依託泊苷、優萊辛、易維特（Evista)、依西 美坦、法樂通（Fareston)、芙仕得（Faslodex)、弗隆 (Femara)、 非格司亭（Filgrastim)、 弗速利定 (Floxuridine)、弗達拉（Fludara)、乾達拉濱、弗魯樂 (Fluoroplex)、氟尿嘴°定、氣尿0^。定（乳膏）、氟甲睪酮 (Fluoxymesterone)、氟他胺、亞葉酸、FUDR、氟維司 群、G-CSF、吉非替尼、吉西他濱、吉姆單抗奥佐米星、 Gemzar &amp; Gemzar副作用-化學療法藥物、格利維、格萊德 (Gliadel)糯米紙囊劑、GM-CSF、戈舍瑞林、粒細胞集落 刺激因子、粒細胞巨噬細胞集落刺激因子、哈羅特汀 (Halotestin)、赫赛汀、赫薩屈（Hexadrol)、赫薩勒 156510.doc -42- 201206448 (Hexalen)、六曱蜜胺、HMM、和美新（Hycamtin)、海德利 (Hydrea)、海屈可乙酸鹽（Hydrocort Acetate)、氫化可的 松、氫化可的松磷酸鈉、氫化可的松琥珀酸鈉、海屈可通 雄酸鹽（Hydrocortone Phosphate)、經基脲、伊利圖莫瑪 (Ibritumomab)、替伊莫單抗（Ibritumomab Tiuxetan)、伊達 邁辛（Idamycin)、伊達比星、艾非司（Ifex)、IFN-α、異環 磷醯胺、IL-11、IL-2、曱磺酸伊馬替尼、咪唑羧醯胺、干 擾素a、干擾素a-2b(PEG結合物）、白介素-2、白介素-11、 Intron A(干擾素a-2b)、艾瑞莎（Iressa)、伊立替康、異維 甲酸、伊沙匹隆（Ixabepilone)、伊西匹拉（Ixempra)、饥屈 拉司（Kidrolase)⑴.、拉納庫（Lanacort)、拉帕替尼、L-天 冬醯胺酶、LCR、來那度胺（Lenalidomide)、來曲嗤、曱酿 四氫葉酸（Leucovorin)、留可然（Leukeran)、勒飢 (Leukine)、 亮丙瑞德（Leuprolide)、 長春新驗 (Leurocristine)、留斯他汀（Leustatin)、脂質體 Ara-C、液 體Pred、洛莫司汀（Lomustine)、L-PAM、L-溶肉瘤素、魯 普隆（Lupron)、魯普隆儲槽劑（Lupron Depot)、馬土蘭 (Matulane)、 馬西德（Maxidex)、 雙氯乙基曱胺 (Mechlorethamine)、鹽酸雙氯乙基曱胺、米屈隆 (Medralone)、米屈爾（Medrol)、米格斯（Megace)、曱地孕 酮（Megestrol)、乙酸曱地孕酮、美法命、酼基嗓吟、美司 納（Mesna)、米司納斯（Mesnex)、甲胺蝶呤、甲胺蝶呤納、 甲潑尼龍（Methylprednisolone)、米替庫騰（Meticorten)、絲 裂黴素、絲裂黴素-C、米托蒽醌、M·潑尼松（M- 156510.doc -43- 201206448Corp. ’ and my tree, from Aldrich Chemical Co., Inc., U.S.A. The above antitumor tyrosine kinase inhibitor is commercially available, for example, as follows: gefitinib as Iressa (trade name) from AstraZeneca Corp.; imatinib, as Gleevec (trade name) from Novartis AG; and erlotinib 'as Tarceva (trade name) from 〇si pharmaceuticals Inc. 〇The above monoclonal antibodies are commercially available, for example, the following: cetuximab, as Erbitux (trade name) from Bristol- Myers Squibb Co.; Bevacizumab, as Avastin Avastin (trade name) from Genentech, Inc.; Rituximab, as Rituxan (trade name) from Biogen Idee Inc.; alemtuzumab, as a kan Campath (trade name) from Berlex Inc.; and trastuzumab as Herceptin (trade name) from Chugai Pharmaceutical Co" Ltd. 〇 The above interferon is commercially available, for example, the following: interferon α, as Sumiferon (trade name) from Sumitomo Pharmaceutical Co., Ltd.; interferon a-2a, as Canferon-A (trade name) from Takeda Pharmaceutical Co., Ltd.; interferon a-2b, as Intron A ( Product name) from Scherin g-Plough Corp.; interferon beta, as IFN. β. (trade name) from Mochida Pharmaceutical Co., Ltd.; interferon γ-156510.doc -38 · 201206448 la, as Imunomax-γ (trade name) from Shionogi &amp; Co., Ltd.; and interferon γ-nl, as Ogamma (trade name) from Otsuka Pharmaceutical Co., Ltd. The above biological reaction modifier is commercially available, for example, the following: Yunzhi polysaccharide, as Krestin (trade name) from Sankyo Co., Ltd.; Lentinus edodes, as Lentinan (trade name) from Aventis Corp.; Sizano, as Sonifiran (trade name) from Kaken Seiyaku Co., Ltd.; Bisibani As Picibanil (trade name) from Chugai Pharmaceutical Co., Ltd.; and Ubumex, as Bestatin (trade name) from Nippon Kayaku Co., Ltd. ° Other anti-tumor drugs mentioned above are commercially available, for example, the following : Mitoxantrone, as Novantrone (trade name) from Wyeth Lederle Japan, Ltd.; L-aspartate amidase, as Leunase (trade name) from Kyowa Hakko Kogyo Co., Ltd.; Procarbazine, as Natulan (Product name) from Nippon Roc He Co., Ltd.; Dhakabara, as Dacarbazine (trade name) from Kyowa Hakko Kogyo Co., Ltd.; via urea, as Hydrea (trade name) from Bristol-Myers Squibb Co.; pentastatin' Coforin (trade name) from Kagaku Oyobi Kessei Ryoho Kenkyusho; retinoic acid, as Vesanoid (trade name) from Nippon Roche Co., Ltd.; Afaset, as Amevive (trade name) from Biogen Idee Inc.; Beibo, Ding A, as Aranesp (trade name) from Amgen Inc.; Anastrax, as Arimidex (trade name) from AstraZeneca Corp.; Exemestane, as Arnold New (Aromasin) (trade name) from pfizer lnc.; bicalutamide, as Constance 156510.doc -39- 201206448 (Casodex) (trade name) from AstraZeneca Corp.; leuprolide, as Leuplin (trade name) From Takeda Pharmaceutical Co., Ltd., flutamide, as Eueixin (trade name) from Schering-Plough Corp.; fulvestrant, as Faslodex (trade name) from AstraZeneca Corp.; Nisal, as Macugen Name) from Gilead Sciences, Inc.; Dini interleukin toxin, as Ontak (trade name) from Ligand Pharmaceuticals Inc.; aldileukin, as Proleukin (trade name) from Chiron Corp.; gonadotropin alpha, As Thyrogen (trade name) from Genzyme Corp.; bismuth trioxide, as Trisenox (trade name) from Cell Therapeutics, Inc., shedezomib, as Velcade (trade name) from Millennium Pharmaceuticals, Inc.; capecita Ham, as xei〇da (trade name) from Hoffmann-La Roche, Ltd.; and Goserelin, as Zoladex (trade name) from AstraZeneca Corp. The term "anti-tumor drug" as used in the present specification includes the above-mentioned anti-tumor burning agent, anti-tumor anti-metabolite, anti-tumor antibiotic, plant-derived anti-tumor drug, anti-tumor platinum coordination compound, anti-tumor , anti-tumor cool amino acid kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers and other anti-tumor drugs. Other antineoplastic or antibiotic agents can be used in combination with the benzoanthone compound. Such suitable anti-tumor or anti-neoplastic agents include, but are not limited to, 13-cis retinoic acid, 2-CdA, 2-chlorodeoxyadenosine, 5-azacytidine, 5-lactic uridine, 5- FU, 6-mercaptopurine, 6-MP, 6-TG, 6-sulfoguanine, paclitaxel albumin, isosteric acid (Accutane), actinomycin _d, Agromycin 156510.doc •40 · 201206448 Adriamycin, Adrucil, Agrylin, Ala-Cort, Aldileucil, Asebeumab, ALIMTA, Alitretinoin, Akaban-AQ (Alkaban) -AQ), Alker an, all-trans retinoic acid, alpha interferon, hexamethylene melamine, Amethopterin, Amifostine, Aminoglutethimide , Anagrelide, Anandron, Anas. Sitting, arabinose squirt, Ara-C, Alane, Aredia, Reining, Arnold, Arranon, antimony trioxide, aspartame, ATRA, Avastin, azacytidine, BCG, BCNU, bendamustine, bevacizumab, bexarotene, BEXXAR, bicalutamide, BiCNU, Blenoxane , bleomycin, bortezomib, busulfan, Busulfex, C225, Calcium Leucovorin, Campas, Camptosar, Camptotheca - 11, capecitabine, Carac, card flip, carmustine, carmustine glutinous rice paper, Kang Shide, CC-5013, CCI-779, CCNU, CDDP, CeeNU, Sheruby Cerubidine, cetuximab, chlorambucil, cisplatin, Citrovorum factor, Cladribine, cortisone, kemeijing Cosmegen), CPT-11, cyclohexylamine, Cytadren, acytidine, cytarabine liposome, Cytosar-U, Cytosen (Cy) Toxan), Dacaba, Dacogen, Dactinomycin, Dabepo; Ding Alpha, Dasatinib, Daunorubicin, Daunorubicin, Hydrochloride 156510 .doc -41- 201206448 Erythromycin, daunorubicin liposomes, daunoXome, decadron, decitabine, delta-Cortef , Deltasone (Deltasone), Dini interleukin toxin conjugate, DepoCytTM, Dexamethasone, Dexamethasone acetate, Dexamethasone, Dexasone, dexrazoxane (Dexrazoxane), DHAD, DIC, Diodex, Docetaxel, Doxil, Doxorubicin, Doxorubicin Liposomes, DroxiaTM, DTIC, DTIC-Dome, Duralon (Duralone), Efudex, Eligard, Ellence, Eloxatin, Elspar, Emcyt, soft Epoetin Alfa, Erbitux, Erlotinib, Erwinia L-aspartate , Estramustine, Ethyol, Etopophos, Etoposide, Etoposide Phosphate, Ulysin, Evista, Exemestane, Fellow (Fareston), Faslodex, Femara, Filgrastim, Floxuridine, Fludara, Gandalarine, Fluoroplex ), fluoride urine mouth °, gas urine 0 ^. Ding (cream), Fluoxymesterone, Flutamide, Folinic Acid, FUDR, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Jimuzumab Ozomib, Gemzar & Gemzar Side effects - chemotherapeutic drugs, Glivi, Gliadel glutinous rice, GM-CSF, goserelin, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, Harrodine Halotestin), Herceptin, Hexadrol, Hessler 156510.doc -42- 201206448 (Hexalen), hexamethylene melamine, HMM, and Hycamtin, Hydra, Hydra Hydrocort Acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, Hydrocortone Phosphate, transurea urea, Ibritumomab, Ibritumomab Tiuxetan, Idamycin, idarubicin, Ifex, IFN-α, ifosfamide, IL-11, IL-2, sulfonate Martini, imidazole carboxamide, interferon alpha, interferon a-2b (PEG conjugate), interleukin-2 Interleukin-11, Intron A (interferon a-2b), Iressa, irinotecan, isotretinoin, Ixabepilone, Ixempra, Kidrolase (1)., Lanacort, Lapatinib, L-aspartate, LCR, Lenalidomide, Letrozin, brewed tetrahydrofolate (Leucovorin), Retainable (Leukeran), Leukine, Leuprolide, Leurocristine, Leustatin, liposome Ara-C, liquid Pred, Lomustine, L -PAM, L-lysin, Lupron, Lupron Depot, Matulane, Maxidex, Mechlorethamine , bischloroethyl decylamine hydrochloride, Medralone, Medrol, Megace, Megestrol, gestic acid acetate, methadone, thiol Mesna, Mesnex, methotrexate, methotrexate, methylprednisolone, mitic acid (Methylprednisolone) Meticorten), mitomycin, mitomycin-C, mitoxantrone, M. prednisone (M-156510.doc -43- 201206448

Prednisol)、MTC、ΜΤΧ、氮芥（Mustargen)、莫司汀 (Mustine)、莫他麥辛（Mutamycin)、馬利蘭（Myleran)、麥 羅瑟（Mylocel)、 美羅他格（Mylotarg).、諾維本 (Navelbine)、奈拉濱（Nelarabine)、尼歐薩（Neosar)、尼拉 斯塔（Neulasta)、尼米伽（Neumega)、尼普根（Neupogen)、 蕾莎瓦、尼蘭瓊（Nilandron)、尼魯米特（Nilutamide)、尼喷 提（Nipent)、氮芥、諾伐德斯（Novaldex)、諾伐屈 (Novantrone)、奥曲肽（Octreotide)、乙酸奥曲肽、歐可司 帕（Oncospar)、歐可維（Oncovin)、歐塔可（Ontak)、歐薩爾 (Onxal)、歐普維金（Oprevelkin)、歐拉瑞德（Orapred)、歐 拉松（Orasone)、奥沙利鉑、太平洋紫杉醇、太平洋紫杉醇 (蛋白質結合者）、帕米德諾内（Pamidronate)、帕尼單抗、 盤雷；丁（Panretin)、銘爾定（Paraplatin)、匹地瑞德 (Pediapred)、PEG干擾素、PEG天冬醯胺酶、PEG非格司 亭、PEG-INTRON、PEG-L-天冬酿胺酶、培美曲赛、喷司 他丁、***酸氮芥、帕拉替諾（Platinol)、帕拉替諾-AQ、潑尼松龍（Prednisolone)、潑尼松（Prednisone)、帕瑞 隆（Prelone)、丙卡巴肼、PROCRIT、普諾肯（Proleukin)、 普利非隆潘（Prolifeprospan)20及卡莫司汀植入物、普林索 (Purinethol)、雷洛昔芬、雷利米（Revlimid)、魯瑪曲 (Rheumatrex)、利托杉（Rituxan)、利妥昔單抗、羅弗隆-A(Roferon-A)(干擾素a-2a)、魯貝可司（Rubex)、鹽酸紅比 黴素（Rubidomycin hydrochloride)、善得定、善得定LAR、 沙莫司亭（Sargramostim)、破納氫可松（Solu-Cortef)、甲強 156510.doc • 44- 201206448 龍注射劑（Solu-Medrol)、索拉非尼（Sorafenib)、 SPRYCEL、STI-571、鏈佐星（Streptozocin)、SU11248、舒 尼替尼（Sunitinib)、索坦、他莫昔芬、他赛瓦（Tarceva)、 他格瑞汀（Targretin)、他索爾（Taxol)、他索特瑞 (Taxotere)、替莫達（Temodar)、替莫°坐胺、特西羅莫司 (Temsirolimus)、替尼泊苦（Teniposide)、TESPA、沙利度 胺（Thalidomide)、薩羅米德（Thalomid)、瑟拉塞斯 (TheraCys)、硫鳥嘌吟、硫鳥嘌呤小藥片、硫代膦酸酯、 赛歐樂（Thioplex)、塞替派、TICE、拓撲殺（Toposar)、托 泊替康、托瑞米芬（Toremifene)、托利塞（Torisel)、托西莫 單抗、曲妥單抗、維曱酸、Trexall™、曲森諾（Trisenox)、 TSPA、TYKERB、VCR、維替比（Vectibix)、維替比、維爾 班（Velban)、維爾卡德（Velcade)、維帕斯德（VePesid)、維 薩諾德（Vesanoid)、維阿杜（Viadur)、維達紮（Vidaza)、長 春驗、硫酸長春驗、維卡薩Pfs(Vincasar Pfs)、長春新 鹼、長春瑞濱、酒石酸長春瑞濱、VLB、VM-26、伏立諾 他（Vorinostat)、VP-16、威猛（Vumon)、希羅達（Xeloda)、 紮諾沙（Zanosar)、芝伐林（Zevalin)、芝内卡德 (Zinecard)、佐拉德斯（Zoladex)、°坐來膦酸、佐林紮 (Zolinza)、佐米他（Zometa)。 抗代謝產物 抗代謝產物為干擾正常細胞代謝過程之藥物。由於癌細 胞快速複製，因此干擾細胞代謝影響癌細胞之程度比宿主 細胞大。抗代謝產物（諸如吉西他濱）可用於本文中提供之 156510.doc •45- 201206448 任一方法，例如吉西他濱可依照本發明與4_碘_3_硝基苯甲 酿胺（或其代謝產物或其醫藥學上可接受之鹽）及鉑化合物 (諸如卡鉑）組合用於治療鉑敏感性復發性卵巢癌。 吉西他濱具有下述結構：Prednisol), MTC, sputum, Mustargen, Mustine, Mutamycin, Myleran, Mylocel, Mylotarg, Novo Navelbine, Nelarabine, Neosar, Neulasta, Neumega, Neupogen, Lysawa, Nilanqiong Nilandron), Nilutamide, Nipent, Nitrogen mustard, Novaldex, Novantrone, Octreotide, Octreotide Acetate, Oncospar ), Oncovin, Ontak, Onxal, Oprevelkin, Orapred, Orasone, Oxaliplatin, Paclitaxel, paclitaxel (protein binder), Pamidronate, panitumumab, Pan Lei; Panretin, Paraplatin, Pediapred, PEG interference , PEG aspartate glutaminase, PEG filgrastim, PEG-INTRON, PEG-L-aspartame, pemetrex , pentastatin, amphetamine, patatinol, palatinib-AQ, Prednisolone, Prednisone, Prelone, procarbazine , PROCRIT, Proleukin, Prolifeprospan 20 and Carmustine Implants, Purinethol, Raloxifene, Revlimid, Lumaqu (Rheumatrex), Rituxan, Rituximab, Roferon-A (Interferon a-2a), Rubex, Rubidoxine (Rubidomycin) Hydrochloride, good determinate, good LAR, Sargramostim, Solu-Cortef, Aiqiang 156510.doc • 44- 201206448 Dragon injection (Solu-Medrol), Solar Sorafenib, SPRYCEL, STI-571, Streptozocin, SU11248, Sunitinib, Sotan, Tamoxifen, Tarceva, Targretin ), his Taxol, his Taxotere, Temodar, Temoamine, Tesirolimus, Teniposide, TESPA, Thalidomide, Thalomid, TheraCys, thioguanine, thioguanine tablets, thiophosphonate, race Thioplex, thiotepa, TICE, Toposar, Topotecan, Toremifene, Torisel, Tosimizumab, Trastuzumab, Dimensions Tannin, TrexallTM, Trisenox, TSPA, TYKERB, VCR, Vectibix, Vitibbi, Velban, Velcade, VePesid , Vesanoid, Viadur, Vidaza, Changchun, Changchun Sulfuric Acid, Vincasa Pfs, Vincristine, Vinorelbine, Vinorelbine Tartrate Bin, VLB, VM-26, Vorinostat, VP-16, Vumon, Xeloda, Zanosar, Zevalin, Chineca Zinecard, Zoladex, °Delonic acid, Zolinza, Zometa. Anti-metabolites Anti-metabolites are drugs that interfere with the metabolism of normal cells. Because cancer cells replicate rapidly, interfering with cellular metabolism affects cancer cells to a greater extent than host cells. An antimetabolite (such as gemcitabine) can be used in any of the methods provided herein by 156510.doc • 45-201206448, for example, gemcitabine can be used in accordance with the present invention with 4_iodo-3-nitrobenzamide (or its metabolite or A combination of a pharmaceutically acceptable salt) and a platinum compound (such as carboplatin) is used to treat platinum-sensitive recurrent ovarian cancer. Gemcitabine has the following structure:

吉西他濱 吉西他濱為可得的’例如作為GEMZAR®來自Eli Lilly and Company。本文中使用之吉西他濱還包括任何醫藥學 上可接受之鹽形式（例如吉西他濱HC1或其他鹽形式）。吉 西他濱（亦稱作4-胺基-1-[(2心4尺，5尺)-3,3-二氣-4-羥基-5-(羥曱基）四氫呋喃-2-基]嘧啶_2(1H)-酮或2'-脫氧-2，，2，-二氟 胞’啶）為一種核苷類似物，其例如藉由阻斷DNA合成來 干擾細胞***，如此導致細胞死亡。可根據具體患者來調 整抗代謝產物（諸如吉西他濱）劑量。在成體中，吉西他濱 在與4-換-3-硝基苯甲醢胺（或其代謝產物或其醫藥學上可 接受之鹽）及钻化合物（諸如卡鉑）組合用於本文中提供之任 何方法時的劑直可在約1〇〇 mg/m2至約5000 mg/m2、約1〇〇 mg/m 至約 2000 mg/m2、約 2〇〇至約 4000 mg/m2、約 300至 約 3000 mg/m2、約 4〇〇 至約 2000 mg/m2、約 500 至約 1500 156510.doc -46- 201206448 mg/m2、約 750至約 1500 mg/m2、約 800至約 1500 mg/m2、 約 900至約 1400 mg/m2、約 900至約 1250 mg/m2、約 1000至 約1500 mg/m2之範圍内，為約1000 mg/m2、約1050 mg/m2、約 11〇〇 mg/m2、約 1150 mg/m2、約 1200 mg/m2、 約 1250 mg/m2、約 1300 mg/m2、約 1350 mg/m2、約 1400 mg/m2、約 1450 mg/m2或約 1500 mg/m2。量綱 mg/m2指每單 位患者表面積（平方米/m2)的吉西他濱用量（毫克/mg)。吉 西他濱可藉由靜脈内（IV)輸注，例如在約1〇至約3〇〇分 鐘、約15至約180分鐘、約20至約60分鐘、約1〇分鐘、約 2 0勿鐘或約3 0分鐘之時段長投與。在此語境中，術語 「約」表示正常用法’亦即大約；而在一些實施例中表示 ±10%或±5 %之容差。 紫杉烷 紫杉烧為自太平洋紅豆杉樹短葉紅豆杉 之細枝、針葉及樹皮衍生的藥物。特別地太 平洋各杉醇可經由已知合成方法衍生自1〇脫乙醯基漿果 赤黴素。紫杉烷，諸如太平洋紫杉醇及其衍生物多西他 赛，已在多種腫瘤類型中展現出抗腫瘤活性。紫杉烷藉由 超穩定化其結構來干擾微管生長之正常功能，由此破壞細 胞以正常方式使用其細胞骨架的能力。具體地紫杉烧結 合微管蛋白之β亞單位，其為微管之建構嵌段。所得紫杉 燒/微管蛋白複合物不能分解，此導致異常細胞功能及最 終細胞死亡。太平洋紫杉醇在癌細胞中藉由結合稱作Μ· 2(B細胞白血病2)之壯抑制蛋白，由此阻止Μ〗抑制〉周 156510.doc -47- 201206448 亡來誘導漸進式細胞死亡（凋亡）。因而，證明太平洋紫杉 醇為多種癌症之有效治療藥物，因為其藉由中斷細胞*** 期間之正常細胞骨架重排來下調細胞***且其經抗Bc1_2 機制來誘導凋亡。 在一些實施例中’提供一種治療患者之始敏感性復發性 卵巢癌的方法，包括投與該患者有效量之（i) 4碘_3•硝基 苯曱醯胺、其代謝產物或其醫藥學上可接受之鹽、（ϋ)吉 西他濱及（iii)卡鉑合併紫杉烷（例如太平洋紫杉醇、多西他 赛或紫杉醇白蛋白微粒）。紫杉烷（諸如太平洋紫杉醇）之劑 量可隨高度、重量、身體狀況、腫瘤大小及進展狀況等而 變化。在一些實施例中，紫杉烷（諸如太平洋紫杉醇）之劑 量會在約10至約2000 mg/m2、約10至約200 mg/m2或約1〇〇 至約175 mg/m2之範圍内。在一些實施例中，紫杉烷（諸如 太平洋紫杉醇）會在長至約1〇小時、長至約8小時或長至約 6小時之時段襄投與。在此語境中，術語「約」表示正常 用法，亦即大約；而在一些實施例中表示土1〇%或土5%的容 差。 紫杉烷之實例包括但不限於多西他赛、太平洋紫杉醇及 紫杉醇白蛋白微粒。 銘複合物 •叫X调；丞 合之至少一個鉑中心的藥物製劑或醫藥組八 、口切。翻複 劑 包括例如卡鉑、順鉑及奥沙利鉑。「鉬複合物 」及 可互換使用。鉑複合物（或鉑化合物諸如卡在白） 156310.doc -48 - 201206448 於本文令提供之任-方法，例如卡麵可依照本發明與心蛾_ 3-硝基苯甲醯胺（或其代謝產物或其醫藥學上可接受之鹽） 及抗代謝產物（諸如吉西他濱）組合用於治療始敏感性復發 性卵巢癌。 卡鉑具有下述結構：Gemcitabine Gemcitabine is available 'for example, as GEMZAR® from Eli Lilly and Company. Gemcitabine as used herein also includes any pharmaceutically acceptable salt form (e.g., gemcitabine HC1 or other salt forms). Gemcitabine (also known as 4-amino-1-[(2 heart, 4 ft, 5 ft)-3,3-dioxa-4-hydroxy-5-(hydroxyindolyl)tetrahydrofuran-2-yl]pyrimidine_2 (1H)-keto or 2'-deoxy-2,,2,-difluorocytosidine is a nucleoside analog that interferes with cell division, for example by blocking DNA synthesis, thus leading to cell death. The dose of an antimetabolite (such as gemcitabine) can be adjusted depending on the particular patient. In the adult, gemcitabine is used in combination with 4-trans-3-nitrobenzamide (or its metabolite or a pharmaceutically acceptable salt thereof) and a drilling compound such as carboplatin. The dosage of any method may be from about 1 〇〇 mg/m 2 to about 5000 mg/m 2 , from about 1 〇〇 mg/m to about 2000 mg/m 2 , from about 2 〇〇 to about 4000 mg/m 2 , about 300 to About 3000 mg/m2, about 4 to about 2000 mg/m2, about 500 to about 1500 156510.doc -46 to 201206448 mg/m2, about 750 to about 1500 mg/m2, about 800 to about 1500 mg/m2 , about 900 to about 1400 mg/m2, about 900 to about 1250 mg/m2, about 1000 to about 1500 mg/m2, about 1000 mg/m2, about 1050 mg/m2, about 11 〇〇mg/ M2, about 1150 mg/m2, about 1200 mg/m2, about 1250 mg/m2, about 1300 mg/m2, about 1350 mg/m2, about 1400 mg/m2, about 1450 mg/m2 or about 1500 mg/m2. The dimension mg/m2 refers to the amount of gemcitabine (mg/mg) per unit of patient surface area (m2/m2). Gemcitabine can be administered by intravenous (IV) infusion, for example, from about 1 to about 3 minutes, from about 15 to about 180 minutes, from about 20 to about 60 minutes, about 1 minute, about 20 minutes or about 3 minutes. Long time to vote in 0 minutes. In this context, the term "about" means normal usage', i.e., about; and in some embodiments, a tolerance of ±10% or ±5%. Taxanes Taxus is a drug derived from the twigs, needles and bark of the yew tree of the Pacific yew tree. In particular, the Pacific cedarol can be derived from 1 〇 deacetyl berry gibberellin by known synthetic methods. Taxanes, such as paclitaxel and its derivative docetaxel, have exhibited antitumor activity in a variety of tumor types. Taxanes interfere with the normal function of microtubule growth by ultra-stabilizing their structure, thereby disrupting the ability of cells to use their cytoskeleton in a normal manner. Specifically, the yew sinter is a beta subunit of tubulin, which is a building block of microtubules. The resulting yew/tubulin complex does not decompose, which results in abnormal cell function and terminal cell death. Pacific paclitaxel induces progressive cell death (apoptosis) by binding to a strong inhibitory protein called Μ·2 (B-cell leukemia 2) in cancer cells, thereby preventing Μ 抑制 inhibition 周 156510.doc -47- 201206448 死). Thus, paclitaxel has been shown to be an effective therapeutic agent for a variety of cancers because it downregulates cell division by disrupting normal cytoskeletal rearrangement during cell division and induces apoptosis via an anti-Bcl2 mechanism. In some embodiments, 'providing a method of treating a patient with a primary sensitive recurrent ovarian cancer comprising administering to the patient an effective amount of (i) 4 iodine-3 nitrobenzoguanamine, a metabolite thereof, or a pharmaceutical thereof A scientifically acceptable salt, (ϋ) gemcitabine and (iii) carboplatin combined with a taxane (eg, paclitaxel, docetaxel or paclitaxel albumin microparticles). The dosage of the taxane (such as paclitaxel) may vary depending on height, weight, physical condition, tumor size, and progression. In some embodiments, the dosage of the taxane (such as paclitaxel) will range from about 10 to about 2000 mg/m2, from about 10 to about 200 mg/m2, or from about 1 to about 175 mg/m2. In some embodiments, the taxane (such as paclitaxel) will be administered over a period of up to about 1 hour, up to about 8 hours, or up to about 6 hours. In this context, the term "about" means normal usage, i.e., approximately; and in some embodiments, indicates a tolerance of 1% or 5% of soil. Examples of taxanes include, but are not limited to, docetaxel, paclitaxel, and paclitaxel albumin microparticles. Ming complex • Called X-tone; at least one platinum-based pharmaceutical preparation or pharmaceutical group. The retanning agent includes, for example, carboplatin, cisplatin, and oxaliplatin. "Molybdenum composites" and are used interchangeably. a platinum complex (or a platinum compound such as a card in white) 156310.doc -48 - 201206448 Any of the methods provided herein, such as a card face, may be in accordance with the present invention with a heart moth _ 3-nitrobenzamide (or A metabolite or a pharmaceutically acceptable salt thereof, and an antimetabolite (such as gemcitabine) are used in combination to treat initially sensitive recurrent ovarian cancer. Carboplatin has the following structure:

卡錄可得自例如Bedford Lab〇rat〇ries。卡鉑，亦稱作 順·二胺(U-環丁烷二羧根基)鉑(„)，為一種鉑複合物(或 祐化合物），其亦以商標名Paraplatin⑧及parapiatin AQ出 售。本文中使用之卡_包括任何醫藥學上可接受之鹽形 式。可根據具體患者來調整鉑化合物（諸如卡鉑）之劑量。 翻化合物（例如卡翻）之劑量藉由計m農度_時間關係曲 線下面積(AUC ’ mg/mL.min)來確定，此藉由熟習癌症化 學療法技術之人貞已知的方法考慮㈣由㈣減清除率 或腎小球濾過率來評估的患者之腎活性來進行。在一些實 施例中，鉑複合物（諸如卡鉑）與抗代謝產物（例如吉西他 濱）及4-蛾-3_石肖基苯曱酿胺（或其代謝產物或其醫藥學 接受之鹽）組合使用之劑量經計算而提供約0.1 mg/Wmin、約（M_7 mg/ml.min、約 〇 16 叫⑽·^、約 1-6 mg/ml.min 約 1 5 mg/ml*min、約 2-5 mg/m卜min、約 156510.doc -49· 201206448 3-6 mg/ml*min、約 3-5 mg/ml*min、約 1-3 mg/m 卜 min、約 1.5 至約 2.5 mg/ml.niin、約 1.75 至約 2.25 mg/ml*min、約 2 mg/m卜min(AUC 2 ’ 例如，為 2 mg/ml.min之縮寫）、約 AUC 2.5、約 AUC 3、約 AUC 3.5、約 AUC 4、約 AUC 4.5、約 AUC 5、約 AUC 5.5、或約 AUC 6 的 AUC。或者， 基於患者之體表面積來計算舶化合物（例如卡始）之劑量。 在一些實施例中，卡鉑之合適劑量為約1〇至約4〇〇 mg/m2，例如約360 mg/m2。鉑複合物（諸如卡鉑）通常經靜 脈内（IV)投與約1〇至約300分鐘、約3〇至約ι8〇分鐘、約45 至約120分鐘或約60分鐘。在此等内容中，術語「約」具 有其正常含義，亦即大約。在一些實施例中，約意指 ±10%或±5%。 拓撲異構酶抑制劑 本文中提供之任何方法可進一步包含拓撲異構酶抑制 劑。拓撲異構酶抑制劑為經設計成干擾酵素拓撲異構酶 (拓撲異構酶I及II)作用之藥劑，拓撲異構酶為在正常細胞 週期期間藉由催化DNA股磷酸二酯主鏈之斷裂及再連接來 控制DNA結構變化的酶。拓撲異構酶已成為癌症化學療法 治療之流行靶物。認為拓撲異構酶抑制劑阻斷細胞週期之 連接步驟，形成損害基因組完整性之單股及雙股斷裂。此 等斷裂之引入隨後導致細胞洞亡及細胞死亡。拓撲異構酶 抑制劑常常依照其所抑制之酶類型來分類。托泊替康、伊 立替康、勒托替康（iurtotecan)及依沙替康（exatee叫（其均 為市售者）可靶向拓撲異構酶丨，亦即在真核生物中最常見 156510.doc •50· 201206448 之拓撲異構酶類型。托泊替康以商品名可得自 GlaX〇SmithKline。伊立替康以商品名以叫⑽訂⑧可得自 Pfizer。勒托替康可作為脂質體調配物得自⑴“以Card records are available, for example, from Bedford Lab〇rat〇ries. Carboplatin, also known as cis-diamine (U-cyclobutanedicarboxylate) platinum („), is a platinum complex (or a compound) sold under the trade names Paraplatin 8 and parapiatin AQ. The card _ includes any pharmaceutically acceptable salt form. The dose of the platinum compound (such as carboplatin) can be adjusted according to the specific patient. The dose of the compound (such as card flip) can be calculated by the m-agricultural _ time curve Area (AUC 'mg/mL.min) to determine, this is considered by methods known to those skilled in the art of cancer chemotherapy, and (4) renal activity of patients assessed by (4) reduced clearance or glomerular filtration rate. In some embodiments, a platinum complex (such as carboplatin) is used in combination with an antimetabolite (eg, gemcitabine) and 4-moth-3_salbenylbenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof). The dose is calculated to provide about 0.1 mg/Wmin, about (M_7 mg/ml.min, about 〇16 called (10)·^, about 1-6 mg/ml.min, about 15 mg/ml*min, about 2 5 mg/m b min, about 156510.doc -49· 201206448 3-6 mg/ml*min, about 3-5 mg/ml*min, about 1-3 mg /m 卜min, about 1.5 to about 2.5 mg/ml.niin, about 1.75 to about 2.25 mg/ml*min, about 2 mg/mb min (AUC 2 ' For example, an abbreviation of 2 mg/ml.min) , about AUC 2.5, about AUC 3, about AUC 3.5, about AUC 4, about AUC 4.5, about AUC 5, about AUC 5.5, or about AUC of about AUC 6. Alternatively, the shell compound (eg, card) is calculated based on the body surface area of the patient. A dose of carboplatin is in some embodiments from about 1 〇 to about 4 〇〇 mg/m 2 , for example about 360 mg/m 2 . Platinum complexes (such as carboplatin) are usually intravenous (IV) The administration of about 1 to about 300 minutes, about 3 to about ι 8 minutes, about 45 to about 120 minutes, or about 60 minutes. In these contexts, the term "about" has its normal meaning, that is, about. In some embodiments, about means ±10% or ±5%. Topoisomerase Inhibitors Any of the methods provided herein may further comprise a topoisomerase inhibitor. The topoisomerase inhibitor is designed to interfere An agent that acts as an enzyme topoisomerase (topoisomerase I and II), a topoisomerase that catalyzes DNA-phosphorus during normal cell cycle An enzyme that cleaves and rejoins the acid diester backbone to control changes in DNA structure. Topoisomerase has become a popular target for the treatment of cancer chemotherapy. It is believed that topoisomerase inhibitors block the cell cycle junction step and form damage. Single and double strand breaks in genomic integrity. The introduction of such breaks subsequently leads to cell death and cell death. Topoisomerase inhibitors are often classified according to the type of enzyme they inhibit. Topotecan, irinotecan, iurototecan and exenatide (expressed by the market) are targeted topoisomerases, the most common in eukaryotes. 156510.doc •50·201206448 Topoisomerase type. Topotecan is available under the trade name Glaz〇SmithKline. Irinotecan is available under the trade name (10) from Pfizer. Letoticon is available as Liposomal formulations were obtained from (1)

Inc。拓撲異構酶抑制劑可依有效劑量投與。在一些實施 例中，用於治療人類之有效劑量會在約〇 〇1至約1〇 mg/m2/ 天之範圍内。該治療可每天、每兩週、每半週、每週或每 月重複。在一些實施例中，治療期之後可為丨天至數天、 或1週至數週之休止期。在一些實施例中，（i) 4碘_3_硝基 苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽、（ii)吉 西他濱及/或（iii)卡鉑與拓撲異構酶抑制劑可在同一天給藥 或者可在分開的日子給藥。 靶向II型拓撲異構酶之化合物分成兩大類：靶向拓撲異 構酶-DNA複合物之拓撲異構酶毒物及破壞催化周轉之拓 撲異構酶抑制劑。Topo II毒物包括但不限於真核π型拓撲 異構酶抑制劑（t〇P〇 II):安吖啶（amsacrine)、依託泊芽、 磷酸依託泊苷、替尼泊苷、胺柔比星（amruMcin)及多柔比 星。此4藥物為抗癌療法。拓撲異構酶抑制劑之實例包括 ICRF-193 »此等抑制劑靶向top〇 π之]^端ATp酶結構域並 阻止 topo II 周轉。Ciassen (Pr〇ceedings 〇f theInc. Topoisomerase inhibitors can be administered in an effective amount. In some embodiments, an effective dose for treating a human will range from about 1 to about 1 mg/m2/day. The treatment can be repeated daily, every two weeks, every half week, every week or every month. In some embodiments, the treatment period may be a day of rest to several days, or a rest period of one week to several weeks. In some embodiments, (i) 4 iodine-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) gemcitabine and/or (iii) carboplatin and topological isomerism The enzyme inhibitor can be administered on the same day or can be administered on separate days. Compounds that target type II topoisomerases fall into two broad categories: topoisomerase poisons that target topoisomerase-DNA complexes and topoisomerase inhibitors that disrupt catalytic turnover. Topo II poisons include, but are not limited to, eukaryotic π-type topoisomerase inhibitors (t〇P〇II): amsacrine, etoposide, etoposide phosphate, teniposide, amrubicin (amruMcin) and doxorubicin. These 4 drugs are anti-cancer therapies. Examples of topoisomerase inhibitors include ICRF-193» These inhibitors target the top 〇 AT end ATp enzyme domain and prevent topo II turnover. Ciassen (Pr〇ceedings 〇f the

Academy of Science，2004)已解析了結合至ATp酶結構域之 此化合物的結構，顯示藥物以非競爭性方式結合並阻礙 (lock down) ATP酶結構域二聚化。 抗i管生成劑 本文中提供之任何方法可進一步包含抗血管生成劑。血 156510.doc -51 - 201206448 管生成抑制劑為抑制血管生成（新血管生長）之物質…旦 其達到某尺寸’母個實體瘤(與白血病不同)均需要生成血 管以保持其活著。腫瘤只在其形成新血管時才能生長。通 常’成體中其他部位不構造血管，除非組織修復在積極進 打中。血管抑制性（angi〇static)藥劑内皮他丁（endostatin) 及相關化學品能遏制血管之構造，阻止癌症無限生長。在 對患者進行的測試中’腫瘤變得不活躍且甚至在内皮他丁 治療結束後仍保持那樣。該治療具有很少之副作用但表現 出具有很有限的選擇性。其他血管抑制劑纟諸如沙利度⑴ 及基於天然植物之物質正處在積極研究中。 已知抑制劑包括藥物貝伐單抗（安維江），其結合企管内 皮生長因子（VEGF)，從而抑制其結合促進血管生成之受 體。其他抗血管生成劑包括但不限於羧基醯胺基*** (carboxyamidotriazole)、TNF_47〇、CM1〇1、IFN a、 IL-12、血小板因子_4、蘇拉明（suramin)、SU54i6、血小 板反應蛋白（thrombospondin)、血管抑制性類固醇+肝素、 軟骨衍生血管生成抑制性因子、基質金屬蛋白酶抑制劑、 血管他丁（angiostatin)、内皮他丁、2-甲氧基***、替可 加蘭（tecogalan)、血小板反應蛋白、促乳素（pr〇lactin)、 ανβ3抑制劑及利諾胺（nnomide)。The Academy of Science, 2004) has resolved the structure of this compound that binds to the ATp enzyme domain, showing that the drug binds in a non-competitive manner and locks down the ATPase domain dimerization. Anti-I tube generating agent Any of the methods provided herein may further comprise an anti-angiogenic agent. Blood 156510.doc -51 - 201206448 A tube-forming inhibitor is a substance that inhibits angiogenesis (new blood vessel growth). Once it reaches a certain size, a maternal solid tumor (unlike leukemia) requires blood vessels to be kept alive. Tumors only grow when they form new blood vessels. It is common for other parts of the adult to not construct blood vessels unless the tissue repair is actively involved. The angi〇static agent endostatin and related chemicals can suppress the structure of blood vessels and prevent the cancer from growing indefinitely. In the tests performed on patients, the tumor became inactive and remained the same even after the endothelin treatment. This treatment has few side effects but exhibits a very limited selectivity. Other vascular inhibitors such as Shali (1) and natural plant-based substances are in active research. Inhibitors are known to include the drug bevacizumab (Anvil River), which binds to the vascular endothelial growth factor (VEGF), thereby inhibiting its binding to promote angiogenesis. Other anti-angiogenic agents include, but are not limited to, carboxyamidotriazole, TNF_47〇, CM1〇1, IFN a, IL-12, platelet factor-4, suramin, SU54i6, thrombospondin (thrombospondin), vasopressive steroid + heparin, cartilage-derived angiogenesis inhibitory factor, matrix metalloproteinase inhibitor, angiostatin, endostatin, 2-methoxyestradiol, ticocapran Tecogalan), thrombospondin, pr〇lactin, ανβ3 inhibitor and nnomide.

Her-2靶向療法 本文中提供之任何方法可在治療鉑敏感性復發性卵巢癌 (例如HER2陽性卵巢癌）中進一步包含赫賽汀。已在卵巢癌 中發現Her-2過表現，且HER2過表現及擴增與晚期卵巢癌 156510.doc -52- 201206448 (AOC)有關（Hellstrdm 等人，Cawcer 61，2420- 2斗23，3月15日，2001)。赫賽汀可用於HER2過表現印巢癌 之辅助治療。可以數種不同方式使用赫賽汀：作為包括多 柔比星、環磷醯胺、及太平洋紫杉醇或多西他赛中之任一 者之治療方案的一部分；與多西他赛及卡鉑一起；或作為 繼多模態基於蒽環黴素之療法之後的單一藥劑。與太平洋 紫杉醇組合之赫赛汀被批准用於HER2過表現印巢癌之一 線治療。作為單一藥劑之赫赛汀被批准用於治療已為轉移 性疾病接受過一種或多種化學療法方案之患者的HER2過 表現卵巢癌。 拉帕替尼或二曱苯磺酸拉帕替尼為用於實體瘤（諸如乳 腺癌）之口服活性化療藥物治療。在開發期間，其被稱作 小分子GW572016。拉帕替尼可藉由阻斷細胞生長需要之 一些酶來終止腫瘤細胞生長。化學療法中使用之藥物（諸 如托泊替康）以不同方式起作用，以藉由殺死細胞或藉由 阻止其***來終止腫瘤細胞生長。與托泊替康一起給予拉 帕替尼可具有增強之抗腫瘤功效。 激素療法 曰本文中提供之任何方法可進一步包含激素療法。例如， 提供種治療患者之！自敏感性復發㈣ρ巢癌的方法，包括 投與該患者有效量之：⑴4m肖基苯f醯胺、其代謝 產物或其醫藥學上-可接受u、（ii)吉西他濱及⑽卡麵合 併激素療法。 他莫昔芬-激素拮抗劑 156510.doc •53- 201206448 —本文中提供之任何方法可進—步包含他莫昔芬。他莫昔 分（作為諾瓦得士（Nolvadex)出售）減緩或終止身體中存在 之癌細胞的生長。他莫昔芬為一類稱作選擇性雖激素受體 調節劑（SERM)之藥物。其作為抗雕激素來發揮功能。因 為他莫昔芬可穩定快速進展之復發性即巢癌，所以應當考 慮其與細胞毒性化學療法組合在印巢癌之主要治療中~:作 用。 本文中提供之任何方法可進一步包含芳香酶抑制劑(例 如類固醇或非類固醇芳香酶抑制劑)。芳香酶抑制劑(學 一類用於治療、絕經後女性之印巢癌的藥力，其阻斷酶芳香 酶。芳香酶抑制劑降低具有激素受體陽性印巢癌之絕經後 女性中的***量。當身體中之***較少時，激素受體 接受較少之生長信號，且癌症生長可被減緩或終止。 芳香酶抑制劑藥療包括瑞寧德（化學名：阿那曲唑卜阿 諾新（化學名：依西美坦）及弗隆（化學名：來曲唑）。每一 種以丸劑每天服用-次，持續長達五年。但是對於具有晚 期（轉移性）疾病之女性，只要其作用良好就繼續服用該藥 物。 AI被分成兩類：與酶芳香酶複合物形成永久鍵之不可逆 類固醇抑制劑（諸如依西美坦）；及藉由可逆競爭來抑制酶 之非類固醇抑制劑（諸如阿那曲唑、來曲唑）。 氣維司群，亦稱作ici 182,780及「Fasl〇dex」，為繼抗雌 激素療法後具有疾病進展之絕經後女性令的激素受體陽性 卵巢癌之一種藥物治療。***能引起卵巢上皮癌細胞生 156510.doc •54· 201206448 齊二氟= 為—種沒有促效劑效果之***受體括抗 一其藉由下調及藉由降解***受體二者來起作用。苴 以每月一次之注射形式來投與。 ” 靶向療法 本文令提供之任何方法可進一步包含靶向生長因子受體 (包括但不限於表皮生長因子受體（egfr)及姨島素樣生長 因子1受體（IGF1R))之抑制劑。 EGFR在某些類型之人類癌症（包括印巢癌）的細胞中過表 見已將卵巢癌中之EGFR過表現與較差之預後聯繫起 來。升高之EGFR表現可促成对藥性表型。臟尺抑制劑之 實例包括但不限於西妥昔單抗，其為—種篏合單株抗體， 藉由靜脈内注射來給予，用於治療癌症，包括但不限於轉 移性結腸直腸癌及頭頸癌。帕尼單抗為EGFR抑制劑之另 一個實例。其為一種針對£(51?尺之人類化單株抗體。帕尼 單抗已顯示在具有晚期結腸癌之患者中單獨使用時為有益 的且好於支持性醫療措施並得到FDA批准用於此用途。 活化1型胰島素樣生長因子受體（IGF 1R)在多種細胞類型 中促進增殖且抑制凋亡^ IGF 1R抑制劑之一個實例為 CP-751871。CP-751871為一種選擇性結合IGF1R，阻止 IGF1結合該受體及後續受體自體磷酸化之人類單株抗體。 抑制IGF1R自體磷酸化可導致表現1(}1?1尺之腫瘤細胞上的 受體表現降低、IGF之抗凋亡效果降低、及抑制腫瘤生 長。IGF 1R為一種在大多數腫瘤細胞上表現之受體酪胺酸 激酶且涉及有絲***、血管生成及腫瘤細胞存活。 156510.doc 55- 201206448 PI3K/mTOR 途徑 本文中提供之任何方法可進一步包含PI3K途徑抑制劑及/ 或mTOR抑制劑。磷脂酿肌醇-3-激酶（PI3K)途徑失調為人 類癌症中之一種常見事件，其由於腫瘤抑制基因磷酸酶之 失活及染色體10缺失張力蛋白（tensin)同源物或ρΐ 10-α之激 活突變而發生。此等熱點突變導致該酶之致癌活性且促成 對抗HER2抗體曲妥單抗之治療抗性。在卵巢癌中亦頻繁 檢測到Akt及mTOR磷酸化。因此，ΡΙ3Κ途徑為癌症治療之 一種誘人靶物。NVP-BEZ235(PI3K及雷帕黴素下游哺乳動 物靶物（mTOR)之一種雙重抑制劑）已顯示出在具有野生型 及突變型ρΐ 1〇-α二者之癌細胞中具有抗增殖及抗腫瘤活性 (Violeta Serra等人，Cancer Research 68，8022-8030，10月 1 曰，2008)。Her-2 Targeted Therapy Any of the methods provided herein can further include Herceptin in the treatment of platinum-sensitive recurrent ovarian cancer (e.g., HER2-positive ovarian cancer). Her-2 overexpression has been found in ovarian cancer, and HER2 overexpression and expansion are associated with advanced ovarian cancer 156510.doc -52- 201206448 (AOC) (Hellstrdm et al., Cawcer 61, 2420-2) 23, March 15th, 2001). Herceptin can be used as adjunctive therapy for HER2 over-expression of nested cancer. Herceptin can be used in several different ways: as part of a treatment regimen including either doxorubicin, cyclophosphamide, and paclitaxel or docetaxel; with docetaxel and carboplatin Or as a single agent following multimodal modal anthracycline-based therapy. Herceptin in combination with Pacific Paclitaxel has been approved for use in one of the lines of HER2 over-embedded cancer. Herceptin, a single agent, is approved for the treatment of HER2 overexpressing ovarian cancer in patients who have received one or more chemotherapy regimens for metastatic disease. Lapatinib or lapatinib dibenzoate is an oral active chemotherapeutic drug for solid tumors such as breast cancer. During development, it was called the small molecule GW572016. Lapatinib can stop tumor cell growth by blocking some of the enzymes required for cell growth. Drugs used in chemotherapy, such as topotecan, act in different ways to stop tumor cell growth by killing the cells or by preventing their division. Administration of lapatinib with topotecan has enhanced anti-tumor efficacy. Hormone Therapy Any of the methods provided herein may further comprise hormone therapy. For example, provide a treatment for patients! Self-sensitive recurrence (d) ρ nest cancer method, including administration of an effective amount of the patient: (1) 4m succinyl benzene f-amine, its metabolite or its pharmaceutically acceptable u, (ii) gemcitabine and (10) card surface combined hormone therapy. Tamoxifen-hormone antagonist 156510.doc • 53- 201206448 - Any of the methods provided herein may further comprise tamoxifen. Tamoxifen (sold as Nolvadex) slows or stops the growth of cancer cells present in the body. Tamoxifen is a class of drugs known as selective hormone receptor modulators (SERMs). It functions as an anti-engraving hormone. Because tamoxifen can stabilize the rapid progression of recurrent, nest cancer, it should be considered in combination with cytotoxic chemotherapy in the main treatment of Indian cancer. Any of the methods provided herein may further comprise an aromatase inhibitor (e.g., a steroid or a non-steroidal aromatase inhibitor). Aromatase inhibitors (a class of drugs used in the treatment of post-menopausal women's nest cancer, which block enzyme aromatase. Aromatase inhibitors reduce the amount of estrogen in postmenopausal women with hormone receptor-positive Indian cancer When there are fewer estrogens in the body, hormone receptors receive less growth signals, and cancer growth can be slowed or terminated. Aromatase inhibitors include Reynolds (chemical name: anastrozole Bunornoxin) (chemical name: exemestane) and furon (chemical name: letrozole). Each dose is taken once a day for up to five years, but for women with advanced (metastatic) disease, as long as it The drug continues to be administered in good condition. AI is divided into two categories: irreversible steroid inhibitors (such as exemestane) that form permanent bonds with the enzyme aromatase complex; and non-steroid inhibitors that inhibit enzymes by reversible competition ( Such as anastrozole, letrozole. Gasisin, also known as ici 182,780 and "Fasl〇dex", is a hormone receptor-positive postmenopausal female with disease progression following anti-estrogen therapy A drug treatment for ovarian cancer. Estrogen can cause ovarian epithelial cancer cells to grow 156510.doc •54· 201206448 齐Difluoro = as an activator-free estrogen receptor, as it is down-regulated and Degradation of both estrogen receptors works. 苴 is administered as a monthly injection.” Targeted Therapy Any method provided herein may further comprise targeting growth factor receptors (including but not limited to epidermal growth factors) Inhibitors of the receptor (egfr) and the simian-like growth factor 1 receptor (IGF1R). EGFR has been shown to have EGFR in ovarian cancer in cells of certain types of human cancers, including Indian cancer. Over performance is associated with poor prognosis. Elevated EGFR performance can contribute to a drug phenotype. Examples of visceral inhibitors include, but are not limited to, cetuximab, which is a monoclonal antibody, by vein Intra-injection for the treatment of cancer, including but not limited to metastatic colorectal cancer and head and neck cancer. Panitumumab is another example of an EGFR inhibitor. It is a humanized single plant for £(51? Antibody. Anti-resistance has been shown to be beneficial and better than supportive medical measures and is approved by the FDA for use in patients with advanced colon cancer. Activation of type 1 insulin-like growth factor receptor (IGF 1R) in multiple cell types An example of an IGF 1R inhibitor that promotes proliferation and inhibits apoptosis is CP-751871. CP-751871 is a human monoclonal antibody that selectively binds to IGF1R and prevents IGF1 from binding to the receptor and subsequent receptor autophosphorylation. Inhibition of IGF1R autophosphorylation leads to decreased expression of receptors on tumor cells expressing 1 (1 1 - 1 ft), decreased anti-apoptotic effect of IGF, and inhibition of tumor growth. IGF 1R is a manifestation on most tumor cells. The receptor tyrosine kinase is involved in mitosis, angiogenesis, and tumor cell survival. 156510.doc 55- 201206448 PI3K/mTOR pathway Any of the methods provided herein may further comprise a PI3K pathway inhibitor and/or an mTOR inhibitor. Phospholipid inositol-3-kinase (PI3K) pathway dysregulation is a common event in human cancer due to inactivation of tumor suppressor gene phosphatase and chromosome 10 deletion of tensin homolog or ρΐ 10-α Activating mutations occur. Such hotspot mutations result in the carcinogenic activity of the enzyme and contribute to the therapeutic resistance to the HER2 antibody trastuzumab. Akt and mTOR phosphorylation are also frequently detected in ovarian cancer. Therefore, the ΡΙ3Κ pathway is an attractive target for cancer treatment. NVP-BEZ235 (a dual inhibitor of PI3K and rapamycin downstream mammalian target (mTOR)) has been shown to have anti-proliferation and resistance in cancer cells with both wild-type and mutant ρΐ 1〇-α Tumor activity (Violeta Serra et al, Cancer Research 68, 8022-8030, October 1 曰, 2008).

Hsp90抑制劑 本文中提供之任何方法可進一步包含Hsp90抑制劑。此 等藥物靶向熱休克蛋白90 (hsp90)。Hsp90為一類伴隨蛋白 之一，其正常工作為幫助其他蛋白獲得及維持彼等蛋白實 行其工作所需之形狀。伴隨蛋白藉由與其他蛋白實體接觸 來工作。儘管有在正常情況下會引起癌細胞死亡之遺傳缺 陷，Hsp90亦能使此類細胞能夠存活及甚至旺盛生長。如 此，阻斷HSP90及相關伴隨蛋白之功能可引起癌細胞死 亡，若將阻斷伴隨蛋白功能與其他策略組合來阻斷癌細胞 存活尤為如此。 ' 微管蛋白抑制劑 156510.doc -56- 201206448 本文中提供之任何方法可進一步包含微管蛋白抑制劑。 微管蛋白為形成微管之蛋白質，其為細胞的細胞骨架（結 構網絡）之關鍵成分。微管為細胞***（有絲***）、細胞結 構、運輸、信號傳導及運動所必需的。繁於其在有絲*** 中，主要作用’微管已成為抗癌藥物(常常稱作抗有絲分 裂藥物、微管蛋白抑制劑及微管靶向劑）之一種重要靶 物。此等化合物結合微管中之微管蛋白並藉由干擾細胞分 裂所需之微官形成來阻止癌細胞增殖。此種干擾阻斷細胞 週期序列，導致凋亡。 凋亡抑制劑 本文中提供之任何方法可進—步包含〉周亡抑制劑。调亡 抑制劑（ΙΑΡ)為—組在功能上及在結構上相關之蛋白質， 其最初在桿狀病毒中得到表徵，充當〉周亡之内源抑制劑。 人類ΙΑΡ家族由至少6個成員組成，且已在眾多生物體中鑑 同系物10058·Ρ4為一種c-Myc抑制劑，其誘導細 胞週』停滯及/周亡。其為—種可透過細胞之嘆嗤咬嗣，其 特異！·生抑制互作用並阻止。询。乾基因表現 之反式激活。1〇〇58_F4在活體外及在活體内皆以c-Myc依 賴!·生方式抑制腫瘤細胞生長為一種⑻d抑制劑且 抗〉周亡。GNF-2麗&amp; 鸯於一類新的Bcr-abl抑制劑。GNF-2表現 出二。肉旦蔻醯結合袋（―個遠離活性位點之異位位點）， U匕無活性形式之激酶。其抑⑽。r_aM填酸化之1(^。為 267 nM ’但不抑制一組63種其他激酶，包括天然c-AM， 且顯不缺乏針對不表現心_观之細胞的毒性 。GNF-2 156510.doc -57- 201206448 顯示出極大的作為一類新抑制劑用於研究Bcr-abl活性及治 療由Bcr-Abl癌蛋白引起之耐藥性慢性髓細胞性白血病 (CML)的潛力。Pifithrin_〇^p53介導之凋亡及P53依賴性基 因轉錄（諸如細胞週期蛋白G、p21/wafl及mdm2表現）的一 種可逆抑制劑❶Pifithrin-α增強遺傳毒性壓力（諸如UV輻射 及用細胞毒性化合物（包括多柔比星、依託泊苷 (etopoxide)、太平洋紫杉醇及胞痛咬_β_〇_***吱喃糖 苦）處理）後的細胞存活^ Pifithrin-a防止小鼠受致死性全身 γ-輻射影響，且癌症發病率無升高。 4-碘-3-硝基苯甲醯胺 4-碘-3-硝基苯甲醯胺（ΒΑ)為一種小分子，其作用於腫瘤 細胞，在正常細胞中不發揮毒效應。4_碘_3_硝基苯曱醯胺 極具親知性且快速又廣泛地分佈於各組織，包括腦及腦脊 液（CSF)。其在活體外對廣泛的一系列癌細胞有活性，包 括對耐藥性細胞株有活性。熟習此項技術者會認識到4_碘_ 3-硝基苯甲醯胺可以任何醫藥學上可接受之形式例如作 為醫藥學上可接受之鹽、溶劑合物或複合物來投與。另 外，因為4-碘-3-硝基苯甲醯胺能夠在溶液中互變異構，所 以術語ΒΑ(或同義詞4_碘_3 _硝基苯曱醯胺）意欲涵蓋4_碘-% 硝基苯甲醯胺之互變異構體形式以及鹽、溶劑合物或複合 物。在一些實施例中，4_碘_3_硝基苯甲醯胺可與環糊精， 諸如羥丙基β環糊精組合投與。然而，熟習此項技術者會 認識到其他有活性及無活性之藥劑可與4_碘_3_硝基苯曱醯 胺組合；且除非另有說明，Μ述及4_m肖基苯甲酿胺 1565IO.doc •58- 201206448 會包括其所有醫藥學上可接受之形式。 4-碘-3-硝基苯曱醯胺、其代謝產物或其醫藥學上可接受 之鹽的劑量可隨患者年齡、高度、重量、總體健康等而變 化。在一些實施例中，4-碘-3-硝基苯甲醯胺（或其代謝產 物或其醫藥學上可接受之鹽）之劑量在約0.1 mg/kg至約5 0 mg/kg、約 1 mg/kg 至約 100 mg/kg、約 1 mg/kg 至約 50 mg/kg、約 1 mg/kg 至約 25 mg/kg、約 2至約 70 mg/kg、約 2 mg/kg至約 50 mg/kg、約 2 mg/kg至約 40 mg/kg、約 3 mg/kg 至約30 mg/kg、約4至約100 mg、約4至約25 mg/kg、約4至 約20 mg/kg、約4至約15 mg/kg、約5至約20 mg/kg、約5至 約 15 mg/kg、約 50至約 100 mg/kg、或約 25 至約 75 mg/kg 中 之任一者的範圍内。在一些實施例中，4-碘-3-硝基苯曱醯 胺（或其代謝產物或其醫藥學上可接受之鹽）以約1 mg/kg、 約 2 mg/kg、約 4 mg/kg、約 5 mg/kg、約 5.6 mg/kg、約 6 mg/kg、約 7 mg/kg、約 8 mg/kg、約 9 mg/kg、約 10 mg/kg、約 11 mg/kg、約 11.2 mg/kg、約 12 mg/kg、約 13 mg/kg、約 14 mg/kg、約 15 mg/kg、約 16 mg/kg、約 17 mg/kg、約 18 mg/kg、約 19 mg/kg、約 20 mg/kg、約 25 mg/kg、約 30 mg/kg、約 35 mg/kg、約 40 mg/kg、約 50 mg/kg、約 60 mg/kg、約 75 mg/kg、或約 90 mg/kg來投與。 在一些實施例中，4-碘-3-硝基苯曱醯胺（或其代謝產物或 其醫藥學上可接受之鹽）以至少約2 mg/kg、約4 mg/kg、約 5 mg/kg、約 5.6 mg/kg、約 6 mg/kg、約 7 mg/kg、約 8 mg/kg、約 9 mg/kg、約 10 mg/kg、約 11 mg/kg、約 11.2 156510.doc -59- 201206448 mg/kg、約 12 mg/kg、約 13 mg/kg、約 14 mg/kg、約 15 mg/kg、約 i6 mg/kg、約 17 mg/kg、約 18 mg/kg、約 i9 mg/kg、約 20 mg/kg、約 25 mg/kg、約 30 mg/kg、約 35 mg/kg、約 40 mg/kg、約 50 mg/kg、約 60 mg/kg、約 75 mg/kg、或約9〇 mg/kg中之任一劑量來投與。4碘_3硝基 苯甲醯胺（或其代謝產物或其醫藥學上可接受之鹽）可經靜 脈内投與’例如藉由IV輸注，在約1〇至約3〇〇分鐘，約3〇 至約180分鐘，約45至約120分鐘或約60分鐘（亦即約丄小時） 裏進行。在一些實施例中，提供一種治療患者之鉑敏感性 復發性卵巢癌的方法，包括投與該患者有效量之：（丨）4_ 碘-3-硝基苯曱醯胺、其代謝產物或其醫藥學上可接受之 鹽’（ι〇吉西他濱；及（iii)卡鉑，其中4-碘_3·硝基苯甲醯 胺、其代謝產物或其醫藥學上可接受之鹽以約5至約2〇 mg/kg或約5 mg/kg至約15 mg/kg經靜脈内投與該患者。在 一些貫施例中’ 4-块-3-硝基苯曱醯胺或者可口服投與。在 此語境中，術語「約」具有其正常含義，亦即大約。在一 些實施例中，約意指±2〇%、±10%、或±5%。 4-蛾-3-硝基苯甲醯胺之合成描述於美國專利第5,464,871 號，其以全文引用之方式併入本文中。4-峨-3-;b肖基苯甲醯 胺可以10 mg/mL之濃度來製備且可以便利形式來包裝，例 如在10 mL小瓶中。 4-碘-3-硝基苯甲醯胺（BA)代謝產物 如本文中使用之「BA」意指4-碘-3 -硝基苯甲醯胺； 「BNO」意指4-蛾-3-亞硝基苯曱酿胺；「BNHOH」意指4- 156510.doc •60· 201206448 碘-3-羥胺基苯甲醯胺。 在本發明中有用之前體化合物具有式（la): 0 II c—nh2Hsp90 Inhibitors Any of the methods provided herein can further comprise an Hsp90 inhibitor. These drugs target heat shock protein 90 (hsp90). Hsp90 is one of a class of accompanying proteins that work normally to help other proteins acquire and maintain the shape they need to perform their work. Accompanying proteins work by coming into contact with other protein entities. Hsp90 also enables such cells to survive and even thrive despite genetic defects that normally cause cancer cell death. Thus, blocking the function of HSP90 and related accompanying proteins can cause cancer cells to die, especially if the blocking of accompanying protein function is combined with other strategies to block cancer cell survival. 'Tubulin inhibitor 156510.doc -56- 201206448 Any of the methods provided herein may further comprise a tubulin inhibitor. Tubulin is a protein that forms microtubules, which is a key component of the cytoskeleton (structure network) of cells. Microtubules are required for cell division (mitosis), cellular structure, transport, signaling, and movement. In its mitosis, the main role of microtubules has become an important target for anticancer drugs (often referred to as anti-filamentation drugs, tubulin inhibitors, and microtubule targeting agents). These compounds bind to tubulin in the microtubules and prevent cancer cell proliferation by interfering with the formation of microtubules required for cell division. This interference blocks the cell cycle sequence and leads to apoptosis. Inhibitors of Apoptosis Any of the methods provided herein can further comprise a weekly inhibitor. Apoptosis inhibitors (ΙΑΡ) are groups of functionally and structurally related proteins that were initially characterized in baculovirus and act as endogenous inhibitors of stagnation. The human cockroach family consists of at least six members and has been identified in many organisms. 10058·Ρ4 is a c-Myc inhibitor that induces perivascular stagnation and/or perinatal death. It is a kind of sigh that can penetrate the cell, its specificity! · Health inhibits interaction and prevents it. Inquiry. Transactivation of dry gene expression. 1〇〇58_F4 relies on c-Myc in vitro and in vivo to inhibit tumor cell growth as a (8)d inhibitor and is resistant to death. GNF-2 Li &amp; is a new class of Bcr-abl inhibitors. GNF-2 showed two. A meat-and-density binding bag (a ectopic site away from the active site), U匕 an inactive form of the kinase. It is (10). r_aM is filled with acidified 1 (^. 267 nM ' but does not inhibit a group of 63 other kinases, including native c-AM, and is not deficient in toxicity to cells that do not express heart. GNF-2 156510.doc - 57- 201206448 shows great potential as a new class of inhibitors for studying Bcr-abl activity and treating chronic myelogenous leukemia (CML) induced by Bcr-Abl oncoprotein. Pifithrin_〇^p53 mediated A reversible inhibitor of apoptosis and P53-dependent gene transcription (such as cyclin G, p21/wafl and mdm2 expression) ❶Pifithrin-α enhances genotoxic stress (such as UV radiation and the use of cytotoxic compounds (including doxorubicin) Cell survival after treatment with etopoxide, paclitaxel, and cellulite bite _β_〇_arabinofuran) Pifithrin-a prevents mice from being affected by lethal systemic gamma-irradiation and cancer No increase in rate. 4-iodo-3-nitrobenzamide 4-iodo-3-nitrobenzamide (ΒΑ) is a small molecule that acts on tumor cells and does not play a role in normal cells. Effect. 4_Iodine_3_nitrobenzamide is very conscious and fast It is also widely distributed in various tissues, including brain and cerebrospinal fluid (CSF), which is active in a wide range of cancer cells in vitro, including active against drug-resistant cell lines. Those skilled in the art will recognize that 4_ Iodine-3-nitrobenzamide can be administered in any pharmaceutically acceptable form, for example as a pharmaceutically acceptable salt, solvate or complex. In addition, because of 4-iodo-3-nitro Benzamide can be tautomeric in solution, so the term ΒΑ (or the synonym 4_iodo_3 nitrobenzoguanamine) is intended to cover the tautomeric form of 4_iodo-% nitrobenzamide. And a salt, solvate or complex. In some embodiments, 4-iodo-3-nitrobenzamide can be administered in combination with a cyclodextrin, such as hydroxypropyl beta cyclodextrin. However, familiar with this The skilled artisan will recognize that other active and inactive agents can be combined with 4_iodo-3-nitrobenzamine; and unless otherwise stated, 4_m succinylbenzamide 1565IO.doc • 58- 201206448 will include all of its pharmaceutically acceptable forms. 4-iodo-3-nitrobenzamine, its metabolites or its doctor The dosage of a pharmaceutically acceptable salt can vary depending on the age, height, weight, general health, etc. of the patient. In some embodiments, 4-iodo-3-nitrobenzamide (or its metabolite or its medicinal science) The acceptable salt) is at a dose of from about 0.1 mg/kg to about 50 mg/kg, from about 1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 50 mg/kg, about 1 mg/ Kg to about 25 mg/kg, from about 2 to about 70 mg/kg, from about 2 mg/kg to about 50 mg/kg, from about 2 mg/kg to about 40 mg/kg, from about 3 mg/kg to about 30 mg /kg, from about 4 to about 100 mg, from about 4 to about 25 mg/kg, from about 4 to about 20 mg/kg, from about 4 to about 15 mg/kg, from about 5 to about 20 mg/kg, from about 5 to about Within the range of 15 mg/kg, from about 50 to about 100 mg/kg, or from about 25 to about 75 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamine (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is about 1 mg/kg, about 2 mg/kg, about 4 mg/ Kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, About 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 Mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/ Kg, or about 90 mg/kg for administration. In some embodiments, 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is at least about 2 mg/kg, about 4 mg/kg, about 5 mg /kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 156510.doc -59- 201206448 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about i6 mg/kg, about 17 mg/kg, about 18 mg/kg, About i9 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 Administration of any of mg/kg, or about 9 mg/kg. 4 Iodine-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) can be administered intravenously, for example, by IV infusion, at about 1 to about 3 minutes, about 3〇 to about 180 minutes, about 45 to about 120 minutes or about 60 minutes (that is, about 丄 hours). In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (丨) 4_iodo-3-nitrobenzamine, a metabolite thereof, or a pharmaceutically acceptable salt '(ι〇吉西他滨; and (iii) carboplatin, wherein 4-iodo-3 nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof is about 5 to The patient is administered intravenously at a dose of about 2 mg/kg or from about 5 mg/kg to about 15 mg/kg. In some embodiments, '4-block-3-nitrobenzamide can be administered orally. In this context, the term "about" has its normal meaning, that is, about. In some embodiments, about means ±2〇%, ±10%, or ±5%. 4-Moth-3-Nitrate The synthesis of benzyl benzamide is described in U.S. Patent No. 5,464,871, the disclosure of which is incorporated herein in its entirety in its entirety in its entirety in the the the the the the the the the the It can be packaged in a convenient form, for example in a 10 mL vial. 4-Iodo-3-nitrobenzamide (BA) metabolite As used herein, "BA" means 4-iodo-3-nitrobenzoic acid. Guanamine; "BNO Means 4-moth-3-nitrosobenzoquinone; "BNHOH" means 4-156510.doc • 60· 201206448 Iodo-3-hydroxyaminobenzamide. Useful precursor compounds in the present invention have Formula (la): 0 II c-nh2

r3 (la) 其中Ri、R2、R_3、R4及Rs獨立地選自由以下組成之群： 氫、羥基、胺基、硝基、碘基、（Cl_c6)烷基、（Ci_c6)烷氧 基’^-^環烧基及苯基’其中該等尺^尺广尺厂^及^ 五個取代基中有至少兩個始終為氫，該等五個取代基中有 至少一個始終為硝基，且至少一個位於硝基鄰位之取代基 始終為碘基’及其醫藥學上可接受之鹽、溶劑合物、異構 體、互變異構體、代謝產物、類似物或前藥。Ri、、 R3、R4及Rs亦可為鹵化物，諸如氯、氟或溴取代基。在一 些實施例中，該等Rl、R2、h、尺4及1取代基中有至少一 個始終為硝基或亞硝基且至少一個位於硝基或亞硝基鄰位 之取代基始終為碘。在一些實施例中，該式Ia化合物為式 IA之化合物或其代謝產物或醫藥學上可接受之鹽、溶劑合 物異構體或互變異構體。在一些實施例中，該等Rl、 R2、R3、R4及Rs取代基中有至少一個始終為硝基或亞硝基 且至少一個位於硝基或亞硝基鄰位之取代基始終為碘 '在 一些實施例中，該式Ia化合物為式IA之化合物或其醫藥學 上可接受之鹽、溶劑合物、異構體或互變異構體。 156510.doc •61 · 201206448 胺’亦稱作依尼帕（iniparib)或 4-碘I硝基笨曱醯 「BA」’具有下式：R3 (la) wherein Ri, R2, R_3, R4 and Rs are independently selected from the group consisting of hydrogen, hydroxy, amine, nitro, iodo, (Cl_c6)alkyl, (Ci_c6) alkoxy'^ -^cycloalkyl and phenyl' wherein the at least two of the five substituents are always hydrogen, at least one of the five substituents is always a nitro group, and At least one substituent ortho to the nitro group is always iodo" and its pharmaceutically acceptable salts, solvates, isomers, tautomers, metabolites, analogs or prodrugs. Ri, R3, R4 and Rs may also be halides such as chlorine, fluorine or bromine substituents. In some embodiments, at least one of the R1, R2, h, 4 and 1 substituents is always a nitro or nitroso group and at least one substituent at the ortho position of the nitro or nitroso is always iodine. . In some embodiments, the compound of Formula Ia is a compound of Formula IA or a metabolite thereof or a pharmaceutically acceptable salt, solvate isomer or tautomer thereof. In some embodiments, at least one of the R1, R2, R3, R4, and Rs substituents is always a nitro or nitroso group and at least one substituent at the ortho position of the nitro or nitroso is always iodine' In some embodiments, the compound of Formula Ia is a compound of Formula IA or a pharmaceutically acceptable salt, solvate, isomer or tautomer thereof. 156510.doc •61 · 201206448 Amine ‘also known as inipari or 4-iodine I nitro awkward “BA” has the following formula:

I 4-碘-3-硝基苯曱醯胺 (BA) 製成4-碘硝基苯甲醯胺之方法在此項技術中為已知 °美國專利第5,464,871號中揭示之方法，該文獻以 全文引用之方式併入本文中’特別為關於其中揭示之合成 方法4碟-3-端基苯甲醯胺可以1〇 mg/mL之濃度來製備 且可以便利形式來包裝，例如在10 mL小瓶中。 在本文中提供之任一方法的一些實施例中，投與4-蛾-3-硝基笨甲酿胺或其醫藥學上可接受之鹽。在一些實施例 中’投與4-碘-3-硝基苯甲醯胺之代謝產物（例如bn〇)或醫 藥學上可接受之鹽。 本文中亦提供具有式（Ila)之代謝產物： 〇I 4-Iodo-3-nitrobenzamine (BA) The method of making 4-iodonitrobenzamide is known in the art as disclosed in U.S. Patent No. 5,464,871, the disclosure of which is incorporated herein by reference. Incorporated herein by reference in its entirety, in particular for the synthetic method disclosed therein, 4-disc-3-ylbenzamide can be prepared at a concentration of 1 〇mg/mL and can be packaged in a convenient form, for example at 10 mL In the vial. In some embodiments of any of the methods provided herein, 4-moth-3-nitrobenzoic acid or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a metabolite of 4-iodo-3-nitrobenzamide (e.g., bn) or a pharmaceutically acceptable salt is administered. Metabolites of formula (Ila) are also provided herein:

r2 R5R2 R5

r3 m 156510.doc -62- 201206448 其中：⑴ 為含硫取代基，且Rl、R2、R3、R4AR5中其餘取代基獨立 地選自由以下組成之群：氫、羥基、胺基、硝基、碘、 /臭、氟、氣、（Ci-CJ烷基、（(^-(：6)烷氧基、（C3_C7)環烷基 及苯基，其中該等Rl、R2、R3、尺4及Rs五個取代基中有至 少兩個始終為氫；或（2)心、112、113、114及115取代基中有 至少一個不為含硫取代基且該等五個取代基&amp;、R2、R3、 R·4及Rs中有至少一個始終為碘，且其中該碘始終處於作為 硝基、亞硝基、羥胺基、羥基或胺基基團之Ri、R2、&amp;、 R4或R5基團的鄰位；及其醫藥學上可接受之鹽、溶劑合 物、異構體、互變異構體、代謝產物、類似物或前藥。在 一些實施例中，該等（2)化合物使得該碘基團始終處於作為 亞石肖基、羥胺基、羥基或胺基基團之Rl、r2、R3、心或心 基團的鄰位。在一些實施例中，該等（2)化合物使得該碘基 團始終處於作為亞硝基、羥胺基或胺基基團之Ri、I、 R3、R4或R5基團的鄰位。 任何具有結構式“或IIa之化合物可用於治療鉑敏感性復 發性卵巢癌。在一些實施例中，投與鉑敏感性復發性印巢 癌患者有效量的具有結構式ia或na之化合物合併吉西他濱 及卡翻。在一些實施例中，具有結構式“或na之化合物為 4-破-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可接受之 轉ί。 本文中提供代謝產物化合物，各由以下化學式表示： 156510.doc -63- 201206448 h2nR3 m 156510.doc -62- 201206448 wherein: (1) is a sulfur-containing substituent, and the remaining substituents in R1, R2, R3, and R4AR5 are independently selected from the group consisting of hydrogen, hydroxyl, amine, nitro, iodine / odor, fluorine, gas, (Ci-CJ alkyl, ((^-(:6) alkoxy, (C3_C7) cycloalkyl and phenyl, wherein these Rl, R2, R3, ruler 4 and Rs At least two of the five substituents are always hydrogen; or (2) at least one of the core, 112, 113, 114 and 115 substituents is not a sulfur-containing substituent and the five substituents &amp; R2 At least one of R3, R.4 and Rs is always iodine, and wherein the iodine is always in the Ri, R2, &amp; R4 or R5 group as a nitro, nitroso, hydroxylamine, hydroxyl or amine group. Oriented to the group; and a pharmaceutically acceptable salt, solvate, isomer, tautomer, metabolite, analog or prodrug thereof. In some embodiments, the (2) compound makes The iodine group is always in the ortho position to the R1, r2, R3, heart or heart group of the stetylene, hydroxylamine, hydroxyl or amine group. In some embodiments, the (2) The iodine group is always ortho to the Ri, I, R3, R4 or R5 group as a nitroso, hydroxylamine or amine group. Any compound of the formula "or IIa" can be used to treat platinum susceptibility. Recurrent ovarian cancer. In some embodiments, an effective amount of a compound having the structural formula ia or na is administered to a platinum-sensitive recurrent cancer cancer patient in combination with gemcitabine and a card flip. In some embodiments, the formula has the formula " Or the compound of na is 4-bromo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable transfer thereof. The metabolite compounds are provided herein, each represented by the following chemical formula: 156510.doc -63 - 201206448 h2n

MS328MS328

R6係選自由以下組成之群：氫、 烷基（CVC8)、烷氧基（CVCs)、 異喧淋酿I、°引》朵、嗟α坐、°惡°坐、 - 惡二。坐、嘆吩或苯基。R6 is selected from the group consisting of hydrogen, alkyl (CVC8), alkoxy (CVCs), isoindole, I, °, 嗟, °, °, - -, - 恶二. Sit, sigh or phenyl.

156510.doc -64- 201206448156510.doc -64- 201206448

/-V/-V

OH I I 1 MS263 MS276 MS278OH I I 1 MS263 MS276 MS278

雖然不限於任一具體機制，但下面提供經硝基還原酶或 麩胱甘肽結合機制達成的MS292代謝之一個實例： 梢基還原酶機制 156510.doc •65- 201206448Although not limited to any particular mechanism, an example of MS292 metabolism achieved by a nitroreductase or glutathione binding mechanism is provided below: Tip Reductase Mechanism 156510.doc •65- 201206448

NH &gt;^no2 h2oNH &gt;^no2 h2o

NADPH/H+ NADP+ ^V^no2NADPH/H+ NADP+ ^V^no2

NADPH/IT&quot;NADPH/IT&quot;

NADP+NADP+

nh2 nh2 h2oNh2 nh2 h2o

4-碘-3-硝基苯甲醯胺麩胱甘肽結合及代謝：4-iodo-3-nitrobenzamide glutathione binding and metabolism:

156510.doc 66- 201206448 本文中提供任何上述硝基苯甲醯胺代謝產物化合物依照 本文中提供之任何方法用於治療所述卵巢癌（例如治療 BRCA基因有遺傳缺陷之卵巢癌）的用途。 本文所述之4-碘-3-硝基苯甲醯胺的任一代謝產物可用於 本文中提供之任一方法。4-碘-3-硝基苯甲醯胺之代謝產物 包括例如4-碘-3-胺基苯曱酸（「ΙΑΒΑ」）、4-碘-3-胺基苯 甲酿胺（「ΙΑΒΜ」）、4-碘-3-亞硝基苯曱醯胺（「ΒΝΟ」）及 4-碘-3-羥胺基苯甲醯胺（「ΒΝΗ〇Η」）。代謝產物及製成代 謝產物之方法揭示於美國公開案第2008/01〇3 104號及美國 專利第5,877,185號，其以全文引用之方式併入本文中，特 別為關於代謝產物及製成代謝產物之方法。 在本文提供之任何方法的一些實施例中，投與4_磁_3 -硝 基苯甲醯胺或其代謝產物或其醫藥學上可接受之鹽。在一 些實施例中，投與4-碘-3-硝基苯甲醯胺或其醫藥學上可接 受之鹽。在一些實施例中，投與4_碘·3•硝基苯曱醯胺之代 謝產物。在一些實施例中，4-碘-3-硝基苯曱醯胺之代謝產 物為4-蛾-3-胺基笨曱酸或4-蛾-3-胺基苯甲醯胺。 已椒導硝基苯甲醯胺代謝產物化合物對惡性癌細胞具有 選擇性細胞毒性但對非惡性癌細胞沒有。參見Rice等人，156510.doc 66-201206448 Provided herein is the use of any of the above nitrobenzamide metabolite compounds for the treatment of said ovarian cancer (e.g., for the treatment of ovarian cancer having a genetic defect in the BRCA gene) according to any of the methods provided herein. Any of the metabolites of 4-iodo-3-nitrobenzamide described herein can be used in any of the methods provided herein. Metabolites of 4-iodo-3-nitrobenzamide include, for example, 4-iodo-3-aminobenzoic acid ("ΙΑΒΑ"), 4-iodo-3-aminobenzamide ("ΙΑΒΜ" ), 4-iodo-3-nitrosophenylamine ("ΒΝΟ") and 4-iodo-3-hydroxyaminobenzamide ("ΒΝΗ〇Η"). The metabolites and methods of making the metabolites are disclosed in U.S. Patent Publication No. 2008/01/3,104, and U.S. Patent No. 5,877,185, the disclosure of each of The method. In some embodiments of any of the methods provided herein, 4_magnetic-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered. In some embodiments, 4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a metabolite product of 4_iodo-3 nitrophenylguanamine is administered. In some embodiments, the metabolite of 4-iodo-3-nitrobenzamide is 4-moth-3-aminoindole or 4-moth-3-aminobenzamide. The nitrobenzamide metabolite compound has been selectively cytotoxic to malignant cancer cells but not to non-malignant cancer cells. See Rice et al.

Proc. Natl. Acad. Sci· USA 89 : 7703-7707 (1992)，其以全 文引用方式併入本文中。在一個實施例中，本發明方法中 利用之确基本甲酿胺代謝產物化合物對腫瘤細胞展現之_選 擇性毒性可高於非腫瘤細胞。因此可與至少一種抗代謝產 物（例如吉西他濱）以及至少一種鉑複合物（例如卡鉑、順鉑 156510.doc •67· 201206448 等）之化學療法聯合，將本發明之代謝產物投與需要此類 治療之患者。 本文所述之任何代謝產物用於治療鉑敏感性復發性卵巢 癌之劑量範圍可在約0 0004至約〇 5 mm〇l/kg(毫莫耳代謝 產物/公斤患者體重）之範圍内，該劑量以莫耳計對應於約 0.1至約100 mg/kg 4-碘-3-硝基苯甲醯胺的範圍。代謝產物 之其他有效劑量範圍為0.0024·05 mm〇l/kg&amp; 〇 〇〇48〇乃 mmol/kg。此類劑量可以每天、隔天、每週兩次、每週、 每兩週、每月或其他合適時間表來投與。4_碘_3_硝基苯甲 醯胺之代謝產物可採用基本上相同之投藥模式·例如口 服、靜脈内、腹膜内等。 在一些實施例中，投與4_碘_3_硝基笨曱醯胺或其醫藥學 上可接受之鹽。在-些實施例中，投與肖基苯甲酿 胺之代謝產物或4鲁3-確基苯甲醯胺之代謝產物的醫藥學 上可接受之鹽。術語「醫藥學上可接受之鹽」意指彼等保 留本文中使用之化合物的生物學有效性及特性且在生物學 上或其他方面皆無不良之處的鹽。例如，冑藥學上可接受 之鹽不干擾本文所述化合物在治㈣㈣性復發性卵巢癌 中的有益效果。 典型的鹽為無機離子（例如鈉、鉀、約及鎮離子）之鹽。 此類鹽包括與無機或有機酸（諸如鹽酸、氫溴酸、麟酸、 石肖酸一、硫酸、甲磺酸、對甲苯殘酸、乙酸、富馬酸、破王白 酸、乳酸、杏仁酸、蘋果酸、擦檬酸、酒石酸或馬來酸） 之鹽。另外，在化合物含有羧基或其他酸性基團之情況 156510.doc -68- 201206448 中，可用無機或有機鹼將其轉變成醫藥學上可接受之加成 鹽。合適鹼之實例包括氫氧化鈉、氫氧化鉀、氨、環己 胺、一環己基胺、乙醇胺、二乙醇胺及三乙醇胺。在一些 實施例中，在25% (w/v)羥丙基_β_環糊精及1〇 mM磷酸鹽 緩衝液中配製4-碘-3-硝基苯甲醯胺以供靜脈内投與，如描 述於美國專利申請公開案第2〇1〇/〇16〇442號其以引用方 式併入本文中。 組合療法Proc. Natl. Acad. Sci. USA 89: 7703-7707 (1992), which is incorporated herein by reference in its entirety. In one embodiment, the method of the present invention utilizes a substantially serotonin metabolite compound that exhibits a selective toxicity to tumor cells that is higher than non-tumor cells. Thus, the metabolites of the present invention can be administered in combination with the chemotherapy of at least one antimetabolite (eg, gemcitabine) and at least one platinum complex (eg, carboplatin, cisplatin 156510.doc • 67. 201206448, etc.) Treated patients. The dosage range for any of the metabolites described herein for the treatment of platinum-sensitive recurrent ovarian cancer can range from about 0 0004 to about 〇5 mm〇l/kg (mole of metabolites per kg of patient body weight), which The dose corresponds to a range of from about 0.1 to about 100 mg/kg 4-iodo-3-nitrobenzimidamide in moles. Other effective doses for metabolites are 0.0024.05 mm〇l/kg&amp; 〇 〇 48 〇 is mmol/kg. Such doses can be administered daily, every other day, twice a week, every week, every two weeks, every month, or other suitable schedule. The metabolite of 4_iodo_3_nitrobenzamide can be used in substantially the same mode of administration, for example, oral, intravenous, intraperitoneal, and the like. In some embodiments, 4_iodo_3_nitrostamine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, a pharmaceutically acceptable salt of a metabolite of Schottky benzoate or a metabolite of 4 leucine. The term "pharmaceutically acceptable salts" means salts which retain the biological effectiveness and properties of the compounds used herein and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt of bismuth does not interfere with the beneficial effects of the compounds described herein in the treatment of (iv) (four) recurrent ovarian cancer. Typical salts are salts of inorganic ions such as sodium, potassium, and town ions. Such salts include with inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, linonic acid, tartaric acid, sulfuric acid, methanesulfonic acid, p-toluene residual acid, acetic acid, fumaric acid, tolunic acid, lactic acid, almonds A salt of acid, malic acid, citric acid, tartaric acid or maleic acid). Further, in the case where the compound contains a carboxyl group or other acidic group, 156510.doc-68-201206448, it can be converted into a pharmaceutically acceptable addition salt by an inorganic or organic base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, monocyclohexylamine, ethanolamine, diethanolamine, and triethanolamine. In some embodiments, 4-iodo-3-nitrobenzamide is formulated for intravenous administration in 25% (w/v) hydroxypropyl-β-cyclodextrin and 1 mM mM phosphate buffer. And, as described in U.S. Patent Application Publication No. 2/1/16, 442, which is incorporated herein by reference. Combination therapy

本文所述之任何方法可進一步包括另一抗癌療法，包括 但不限於手術、放射療法（例如X射線）、基因療法、DNA 療法、輔助療法、新輔助療法、病毒療法、免疫療法、 RNA療法或奈米療法。 在組合療法進一步包括非藥物治療時，該非藥物治療可 在任何合適時間進行，只要自治療劑及非藥物治療之組合 的共作用實現了有益效果即可。例如，在適當情況下，在 自/α療劑之技與暫時去除該非藥物治療達到一個顯著時間 段時仍實現了有益效果。結合物及另_ f藥活性劑可同 時、依序或組合投與患者。應瞭解，在使用本發明之組合 時，本發明之化合物及另一醫藥活性劑可處於同一醫藥學 上可接受之載劑中，並因此同時投與。其可在分開的醫藥 學载劑中，諸如習知口服劑量形式，其可同時服用。術語 「組合」還指在分開的劑量形式中提供該等化合物並依^ 投與的情況。 放射療法 156510.doc -69- 201206448 放射療法（或放射治療）指離子化輻射作為癌症治療之一 部分來控制惡性細胞的醫療用途。放射治療可用於治癒或 輔助癌症治療《其被用作姑息治療（在不可能治癒且目的 為局部疾病控制或症狀緩解的情況中）或用作治療性治療 (在該療法具有存活好處且其可為治癒性的情況中）。放射 治療用於治療惡性腫瘤，且可用作主要療法。還通常組合 放射治療與手術、化療、激素療法或此三種之一些混合形 式。最常見的癌症類型在某些方面可用放射治療來治療。 明確的治療意圖（治癒、輔助、新輔助、治療或姑息）會取 決於腫瘤類型、位置及階段/期，以及患者之一般健康。 放射療法常用於癌性腫瘤》若輻射場在臨床上或在放射 學上涉及腫瘤’或者若認為有亞臨床惡性擴散之風險，則 轄射場還可包括引流淋巴結。有必要包括腫瘤周圍正常組 織之邊緣以容許日常設置及内部腫瘤運動之不確定性。 放射療法藉由損傷細胞DNA來進行。損傷由光子、電 子、質子、中子或離子射束引起，其直接地或間接地使構 成DNA鏈之原子離子化。間接離子化因水之離子化而發 生’形成游離的自由基’特別為經基自由基，其然後能損 傷DNA ^在最常見形式之發射療法中，大部分輻射效應經 由游離自由基達成。因為細胞具有修復DNA損傷之機制， 所以在兩股上斷裂DNA證明為改變細胞特徵之最重要技 術。因為癌細胞一般為未分化的且為幹細胞樣的，所以與 大多數健康之已分化細胞相比其繁殖更多，且修復亞致死 損傷之能力降低。DNA損傷經由細胞***而遺傳，將損傷 156510.doc •70· 201206448 積累至癌細胞，弓丨扭甘 、 5丨起其死亡或更加緩慢地繁殖。質子放射 治療藉由發送具有不同動能 千以在腫瘤處精確停止來 進行。 γ射線可用於治療本文所述之任”巢癌。在稱作伽馬 刀手術之程序中，⑯多束集中的γ射線引向生長物以殺死 癌性細胞。該等射束自不同角度猫準以將輻射聚焦於生長 物同時使對周圍組織之損害降至最低。 已知輻射敏化劑提高癌性細胞對電磁輻射之毒效應的敏 感陡夕種癌症治療方案當前採用由X射線之電磁輻射來 活化的輻射敏化劑。χ射線活化的輻射敏化劑之實例包括 但不限於下述：甲硝唑（metronidazole)、米索硝唑 (misomdazole)、去甲基米索硝唑、哌莫硝唑（pim〇nidaz〇le)、 依他硝唑（etanidazole)、尼莫唑（nim〇raz〇le)、絲裂黴素 C、RSU 1069、SR 4233、E09、RB 6145、菸酿胺、5-溴 脫氧尿苦（BUdR)、5-碘脫氧尿芽（iudR)、漠脫氧胞苦、氟 脫氧尿苷（FudR)、羥脲、順鉑，以及其治療有效類似物及 衍生物。 癌症之光動力療法（PDT)採用可見光作為致敏劑之輻射 活化劑。光動力韓射敏化劑之實例包括但不限於下述：血 卟啉衍生物、光卟啉、苯并卟啉衍生物、NPe6、錫本卟啉 SnET2、非帕比德-α (pheoborbide-α)、細菌葉綠素-α、萘 菁（naphthalocyanine)、酞菁、鋅酞菁，以及其治療有效類 似物及衍生物。 基因療法藥劑 156510.doc •71 · 201206448 基因療法藥劑將基因複本***特定的一組患者細胞中， 且能乾向癌細胞與非癌細胞二者。基因療法之目的可為使 用功能性基因替換所改變之基因、刺激患者針對癌症之免 疫反應、使癌細胞對化療更加敏感、將「自殺」基因置入 癌細胞中、或抑制血管生成。可使用病毒、脂質體或其他 載體或運載體將基因投遞至靶細胞。此可藉由直接地或離 體地將基因-載體組合物注射於患者來進行，其中將受到 感染之細胞引導回患者體中。此類組合物適合在本發明中 使用。 辅助療法 本文提供之任何方法可進一步包括辅助療法。輔助療法 包括在主要治療之後給予可提高治癒機會的治療。輔助療 法可包括化學療法、放射療法、激素療法或生物療法。在 本文所述之任何方法的一些實施例中該方法進一步包括 投與粒細胞集落刺激因子（「G_CSF」卜在一些實施例 中，該方法沒有進一步包括投與G_CSF。 因為輔助療法之主要目的為殺死任何可能已擴散之癌細 胞’所以治療通常為系統性（使用經由血流來運送，到達 並影響全身癌細胞之物質）。例如，卵巢癌之輔助療法涉 及化學療法或《療法，其可單獨使用或組合使用。 、助化學療法才曰使用藥物來殺死癌細胞。輔助化學療法 通常為抗癌藥物之組合，其已顯示比單-抗癌藥物更有 效。 放射療法有時用作局部輔助治療。當放射療法在手術治 15651〇.d〇c -72· 201206448 療（例如***切除術）之前或之後給予時，其被認為輔助治 療。此類治療意圖消滅已擴散至身體附近部分（諸如胸壁 或淋巴結）之癌細胞。 多種療法已用於治療卵巢癌，包括但不限於激素療法’ 例如他莫昔芬，或***釋放激素（GnRH)類似物，及 放射性單株抗體療法。 新辅助療法 新辅助療法指在主要治療之前給予的治療。新輔助療法 之實例包括化學療法、放射療法及激素療法。婦科學癌症 中的新輔助化學療法為一種顯示出對存活具有正面影響的 辦法。其提高卵巢及宮頸癌t的可切除率並因此有助於存 活（Ayhan A.等人，European j〇urnal 〇f gynaec〇1〇gicai oncology. 2006，第 27卷）。 溶瘤病毒療法 癌症之病毒療法利用一類稱作溶瘤病毒之病毒。溶瘤病 毒指能夠感染並溶解癌細胞，同時不損害正常細胞之病 ’使得其在癌症療法中潛在有用。溶瘤病毒之複製既促 進腫瘤細胞破壞又在腫瘤部位產生劑量放大。其還可作為 抗癌基因之載體起作用，容許其特異性投遞至腫瘤部位。 有兩種主要辦法來產生腫瘤選擇性：轉導及非轉導靶 向。轉導靶向涉及修飾病毒外殼蛋白之特異性，從而增加 進入靶細胞中之幾率同時減少進入非靶細胞中之幾率。非 轉導輕向涉及改變病毒之基因組，使得其只能在癌細胞中 複製。此可藉由轉錄靶向（其中將對病毒複製至關重要之 156510.doc •73- 201206448 基因置於腫瘤特異性啟動子控制下）或藉由減毒（此涉及將 缺失引入病毒基因組中，其消除在癌細胞中不必要但在正 常細胞中必要的功能）來進行。還有其他略微更加難憧之 方法。Any of the methods described herein may further comprise another anti-cancer therapy including, but not limited to, surgery, radiation therapy (eg, X-ray), gene therapy, DNA therapy, adjuvant therapy, neoadjuvant therapy, viral therapy, immunotherapy, RNA therapy Or nanotherapy. Where the combination therapy further comprises non-pharmacological treatment, the non-pharmacological treatment can be carried out at any suitable time as long as the synergistic effect of the combination of the therapeutic agent and the non-drug treatment achieves a beneficial effect. For example, where appropriate, a beneficial effect is achieved when the technique of &lt;RTIgt; The conjugate and the additional agent can be administered to the patient simultaneously, sequentially or in combination. It will be appreciated that when a combination of the invention is used, the compound of the invention and the other pharmaceutically active agent may be in the same pharmaceutically acceptable carrier and, therefore, administered simultaneously. It can be in separate pharmaceutical carriers, such as conventional oral dosage forms, which can be taken simultaneously. The term "combination" also refers to the condition in which the compounds are provided in separate dosage forms and administered. Radiation therapy 156510.doc -69- 201206448 Radiation therapy (or radiation therapy) refers to the use of ionizing radiation as part of cancer treatment to control the medical use of malignant cells. Radiation therapy can be used to cure or assist in the treatment of cancer, which is used as a palliative treatment (in cases where it is impossible to cure and for local disease control or symptom relief) or as a therapeutic treatment (therapy has a survival benefit and it can For a curative situation). Radiation therapy is used to treat malignant tumors and can be used as a primary therapy. It is also common to combine radiation therapy with surgery, chemotherapy, hormone therapy, or some combination of these three. The most common type of cancer can be treated with radiation therapy in some aspects. A clear indication of treatment (healing, assisting, neoadjuvant, treatment, or palliative) will depend on the type, location, and stage/period of the tumor, as well as the general health of the patient. Radiation therapy is often used for cancerous tumors. If the radiation field is clinically or radiologically involved in a tumor' or if there is a risk of subclinical malignant spread, the site can also include draining lymph nodes. It is necessary to include the edges of normal tissue around the tumor to allow for uncertainty in daily settings and internal tumor movement. Radiation therapy is performed by damaging cellular DNA. Damage is caused by photons, electrons, protons, neutrons, or ion beams that ionize the atoms that make up the DNA strand, either directly or indirectly. Indirect ionization occurs due to ionization of water. The formation of free radicals, especially merid radicals, can then damage DNA. In the most common forms of radiation therapy, most of the radiation effects are achieved by free radicals. Because cells have a mechanism to repair DNA damage, breaking DNA on both strands proves to be the most important technique for altering cellular characteristics. Because cancer cells are generally undifferentiated and stem cell-like, they multiply more than most healthy differentiated cells and have a reduced ability to repair sublethal damage. DNA damage is inherited through cell division, accumulating damage to cancer cells, causing death or slower reproduction. Proton radiation therapy is performed by sending different kinetic energy to stop at the tumor. Gamma rays can be used to treat any of the "nested cancers" described herein. In a procedure called gamma knife surgery, more than 16 concentrated gamma rays are directed to the growth to kill cancerous cells. The beams are from different angles. The cat is intended to focus the radiation on the growth while minimizing damage to the surrounding tissue. It is known that radiation sensitizers enhance the toxic effects of cancerous cells on electromagnetic radiation. Radiation sensitizers that are activated by electromagnetic radiation. Examples of xenon-ray activated radiation sensitizers include, but are not limited to, the following: metronidazole, misomdazole, demethylmethoxazole, Pipernidazole (pim〇nidaz〇le), etanidazole, nimazole (nim〇raz〇le), mitomycin C, RSU 1069, SR 4233, E09, RB 6145, tobacco Amine, 5-bromodeoxyuridine (BUdR), 5-iodooxyuridine (iudR), desertox, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogues and derivatives thereof Photodynamic Therapy for Cancer (PDT) uses visible light as a sensitizer for radiation activation Examples of photodynamic Korean sensitizers include, but are not limited to, hematoporphyrin derivatives, photoporphyrins, benzoporphyrin derivatives, NPe6, tin porphyrin SnET2, non-Pabid-α ( Phenoborbide-α), bacteriochlorophyll-α, naphthalocyanine, phthalocyanine, zinc phthalocyanine, and therapeutically effective analogs and derivatives thereof. Gene Therapy Agent 156510.doc •71 · 201206448 Gene Therapy Agent Inserts Gene Replica In a specific group of patient cells, and capable of both cancer cells and non-cancer cells. The purpose of gene therapy can be to replace the altered genes with functional genes, stimulate the patient's immune response against cancer, and make cancer cells to chemotherapy. More sensitive, put "suicide" genes into cancer cells, or inhibit angiogenesis. The gene can be delivered to the target cell using a virus, liposome or other vector or carrier. This can be done by injecting the gene-vector composition directly or ex vivo into the patient, wherein the infected cells are directed back into the patient. Such compositions are suitable for use in the present invention. Adjuvant Therapy Any of the methods provided herein can further include adjuvant therapy. Adjunctive Therapy includes treatment that increases the chance of cure after the primary treatment. Adjunctive therapy can include chemotherapy, radiation therapy, hormone therapy, or biological therapy. In some embodiments of any of the methods described herein, the method further comprises administering a granulocyte colony stimulating factor ("G_CSF". In some embodiments, the method does not further comprise administering G_CSF. Because the primary purpose of the adjuvant therapy is Kill any cancer cells that may have spread out' so treatment is usually systemic (using substances that are transported through the bloodstream to reach and affect the body's cancer cells). For example, adjuvant therapy for ovarian cancer involves chemotherapy or "therapy, which can Used alone or in combination. Chemotherapy is used to kill cancer cells. Auxiliary chemotherapy is usually a combination of anticancer drugs that have been shown to be more effective than mono-anticancer drugs. Radiation therapy is sometimes used as a topical Adjuvant therapy. When radiotherapy is given before or after surgery 15651〇.d〇c -72· 201206448 (eg mastectomy), it is considered adjuvant therapy. Such treatment is intended to eliminate the spread to the vicinity of the body ( Cancer cells such as the chest wall or lymph nodes. A variety of therapies have been used to treat ovarian cancer, including but not limited to hormonal therapy For example tamoxifen, or gonadotropin releasing hormone (GnRH) analogs, and radioactive monoclonal antibody therapy. Neoadjuvant therapy Neoadjuvant therapy refers to treatment given prior to primary treatment. Examples of neoadjuvant therapy include chemotherapy, Radiation therapy and hormonal therapy. Neoadjuvant chemotherapy in gynaecological cancer is a way to show positive effects on survival. It improves the resectability of ovarian and cervical cancer t and thus contributes to survival (Ayhan A. et al. , European j〇urnal 〇f gynaec〇1〇gicai oncology. 2006, Volume 27). Oncolytic virus therapy Cancer virus therapy uses a class of viruses called oncolytic viruses. Oncolytic viruses are those that infect and dissolve cancer cells. At the same time, it does not damage the disease of normal cells, making it potentially useful in cancer therapy. The replication of oncolytic virus not only promotes tumor cell destruction but also produces dose amplification at the tumor site. It also acts as a carrier of anti-cancer genes, allowing it to be specific. Sexual delivery to the tumor site. There are two main approaches to tumor selectivity: transduction and non-transduction targeting. The specificity involved in modifying the coat protein of the virus, thereby increasing the probability of entering the target cell while reducing the probability of entering the non-target cell. The non-transduction is directed to the genome that changes the virus so that it can only replicate in cancer cells. By transcription targeting (where the 156510.doc •73-201206448 gene essential for viral replication is placed under the control of a tumor-specific promoter) or by attenuating (this involves introducing a deletion into the viral genome, Eliminate unnecessary functions in cancer cells but necessary functions in normal cells. There are other slightly more difficult methods.

Chen等人’ i)在小鼠中對***癌與放射治療聯合使 用CV706 ’ -種***特異性腺病毒。該組合治 致細 胞死亡之協同增多，以及病毒釋出量（自每—次細胞分解 釋放之病毒顆粒數目）之顯著增多。 ONYX-015已進行了與化療聯合之試驗。該組合治療給 出比任-單獨治療更大之反應，但是結果並非完全結論性 的。ONYX-015已顯示與放射治療聯合之希望。 靜脈内投與之病毒劑針對習知方法尤其難以治療之轉移 癌可特別有效。然而，血液傳播病毒能被抗體滅活及例如 被庫弗（Kupffer)細胞（在肝中極有活性之吞噬細胞，其負 責腺病毒清除）自血流快速清除。躲避免疫系統直至腫瘤 被消滅可能為溶瘤病毒療法獲得成功之最大障礙。迄今， 用來規避免疫系統之技術中無一者完全令人滿意。正是在 與習知癌症療法聯合時，溶瘤病毒顯示出最有希望，因為 組合療法協同運作且沒有明顯負面作用。 溶瘤病毒之特異性及靈活性意指其具有以最小副作用治 療多種癌症（包括卵巢癌）之潛力。溶瘤病毒具有解決選擇 性殺死癌細胞之問題的潛力。 奈米療法 奈米大小之顆粒具有自分子個體或大塊固體不可獲得之 156510.doc -74· 201206448 新的光學、電子學及結構特性。在與腫瘤乾向部分（諸如 腫瘤特異性配體或單株抗體）連接時，此等奈米顆粒可用 於以高親和力及精確度靶向癌症特異性受體、腫瘤抗原 (生物標誌物）及腫.瘤脈管系統。癌症奈米療法之配製及製 造過程揭示於專利US7179484及論文Μ· N. Khalid，P. Simard &gt; D. Hoarau，A. Dragomir，J. Leroux，LongChen et al. 'i) used CV706' prostate-specific adenovirus in combination with prostate cancer in mice. This combination resulted in a synergistic increase in cell death and a significant increase in the amount of virus released (the number of viral particles released from each cell breakdown). ONYX-015 has been tested in combination with chemotherapy. This combination treatment gave a greater response than either-alone treatment, but the results were not completely conclusive. ONYX-015 has shown promise in combination with radiation therapy. Intravenous administration of a viral agent is particularly difficult to treat with a conventional method which is particularly difficult to treat. However, blood-borne viruses can be inactivated by antibodies and rapidly cleared from the bloodstream by, for example, Kupffer cells (very active phagocytic cells in the liver, which are responsible for adenovirus clearance). Avoiding the immune system until the tumor is eliminated may be the biggest obstacle to the success of oncolytic therapy. To date, none of the techniques used to circumvent the immune system is entirely satisfactory. It is in combination with conventional cancer therapies that oncolytic viruses have been shown to be the most promising because combination therapies work together and have no significant negative effects. The specificity and flexibility of oncolytic viruses means their potential to treat a variety of cancers, including ovarian cancer, with minimal side effects. Oncolytic viruses have the potential to address the problem of selective killing of cancer cells. Nanotherapy Nano-sized particles are not available from molecular individuals or bulk solids. 156510.doc -74· 201206448 New optical, electrical and structural properties. These nanoparticles can be used to target cancer-specific receptors, tumor antigens (biomarkers) with high affinity and precision when linked to tumor stems, such as tumor-specific ligands or monoclonal antibodies. Swollen. Tumor vasculature. The preparation and manufacturing process of cancer nanotherapy is disclosed in the patent US7179484 and the paper Μ·N. Khalid, P. Simard &gt; D. Hoarau, A. Dragomir, J. Leroux, Long

Circulating Poly(Ethylene Glycol) Decorated Lipid Nanocapsules Deliver Docetaxel to Solid Tumors ， Pharmaceutical Research，23(4)，2006，其均以全文弓I 用 方式併入本文中。 RNA療法 RNA(包括但不限於siRNA、shRNA、微小RNA)可用於 調節基因表現及治療癌症。藉由裝配兩條不同寡核苷酸序 列來形成雙股寡核苷酸，其中一股寡核苷酸序列與第二股 寡核苷酸序列互補；此類雙股寡核苷酸一般自兩條分開的 寡核苷酸（例如siRNA)或自單個可自身摺疊來形成雙股結 構之分子（例如shRNA或短髮夾RNA)裝配而成。此項技術 中已知之此等雙股寡核苷酸均具有一項共同特徵，亦即雙 鏈體之每一股具有不同的核苷酸序列，其中只有一個核苷 酸序列區（指導序列或反義序列）與靶核酸序列互補且另一 股（有義序列）包含與靶核酸序列同源之核苷酸序列。 微小RNA (miRNA)為長度為約21-23個核苷酸之單股 RNA分子，其調節基因表現。miRNA由自DNA轉錄但不轉 譯成蛋白質之基因編碼（非編碼RNA);替代地，其自稱作 156510.doc -75- 201206448 pri-miRNA之初級轉錄物加工成稱作pre-miRNA之短莖-環 結構並最終加工成功能性miRNA。成熟miRNA分子與一種 或多個信使RNA (mRNA)分子部分互補，且其主要功能為 下調基因表現。 某些RNA抑制劑可用於抑制與癌症表型有關之信使RNA (「mRNA」）的表現或轉譯。適合於在本文中使用之此類 藥劑的實例包括但不限於短干擾RNA (「siRNA」）、核酶 及反義寡核苷酸。適合於在本文中使用之RNA抑制劑的具 體實例包括但不限於Cand5、Sirna-027、福米韋生 (fomivirsen)及安格塞姆（angiozyme) 0 小分子酶抑制劑 某些小分子治療劑能夠靶向某些細胞受體（諸如表皮生 長因子受體（「EGFR」）或血管内皮生長因子受體 (「VEGFR」））的酪胺酸激酶酶活性或下游信號轉導信號。 小分子治療劑之此類靶向可產生抗癌效應。適合於在本文 中使用之此類藥劑的實例包括但不限於伊馬替尼、吉非替 尼 '埃羅替尼、拉帕替尼、卡拉替尼、ZD6474、索拉非 尼（BAY 43-9006)、ERB-569，以及其類似物及衍生物。 抗轉移劑 癌細胞自初始腫瘤部位擴散至身體周圍其他位置之過程 被稱作癌症轉移。某些藥劑具有抗轉移特性，經設計成抑 制癌細胞之擴散。適合於在本文中使用之此類藥劑的實例 包括但不限於馬立馬司他（marimastat)、貝伐單抗、曲妥 單抗、利妥昔單抗、埃羅替尼、MMI-166、GRN163L、獵 156510.doc -76- 201206448 人殺手肽（hunter-killer peptide)、金屬蛋白酶（τίΜΡ)之組 織抑制劑、其類似物、衍生物及變異體。 化學預防劑 某些醫藥劑（諸如化學預防劑）可與本文中提供之任何方 法組合使用。此等藥劑可用於預防癌症的初始發生，或者 用於預防復發或轉移。與本文所述任一種治療組合投與此 類化學預防劑能起治療及預防癌症復發之作用。適合於在 本文中使用之化學預防劑的實例包括但不限於他莫昔芬 (tamoxifen)、雷洛昔芬（ral〇xiferie)、替勃龍（tib〇i〇ne)、二 膦酸鹽（bisphosphonate)、伊班膦酸鹽（ibandronate)、雌激 素受體調卽劑、方香酶抑制劑（來曲β坐（ietr〇zole)、阿那曲 唑（anastrozole))、黃體生成激素釋放激素促效劑、戈舍瑞 林（goserelin)、維生素A、視黃醛、視黃酸、芬維a胺 (fenretinide)、9-順-類視黃酸、13-順-類視黃酸、全-反式_ 視黃酸、異維甲酸、維他命A酸（tretinoid)、維生素B6、維 生素B12、維生素C、維生素D、維生素E、環加氧酶抑制 劑、非類固醇抗炎藥（NSAID)、阿司匹林（aspirin)、布洛 芬（ibuprofen)、塞來考昔（celecoxib)、多紛類、多盼E、綠 茶提取物、葉酸、葡糖二酸（glucaric acid)、干擾素-α、茵 香腦二硫雜環戊二嫦硫酮（anethole dithiolethione)、鋅、 吡哆醇（pyridoxine)、非那雄胺（finasteride)、多沙唑嗪 (doxazosin)、石西、0弓丨0朵-3-甲醇（carbinal)、α-二氟甲基鳥胺 酸、類胡蘿蔔素類、β-胡蘿蔔素、番茄紅素、抗氧化劑、 輔酶Q10、類黃酮類、槲皮素、薑黃素、兒茶素類、沒食 156510.doc •77· 201206448 子酸表沒食子兒茶素（epigallocatechin gallate)、N-乙醯半 胱胺酸、°引D朵-3 -曱醇（carbinol)、六礙酸肌醇酯、異黃酮 類、葡糖二酸（glucanic acid)、迷迭香、大豆、沙巴棕， 及鈣。適合於在本發明中使用的化學預防劑之另一個實例 為癌症疫苗。此等可經由用該疫苗接種過程所靶向的整個 或部分癌細胞類型使患者免疫來創建。 臨床功效 可藉由此項技術中已知之任何方法來量測臨床功效。在 一些實施例中，可藉由量測臨床效益率（CBR)來測定本文 所述治療性治療之臨床功效。藉由確定在距治療結束至少 6個月之時間點時處於完全消退（CR)狀態之患者、處於部 分消退（PR)狀態之患者的數目及具有穩定疾病（SD)之患者 •的數目百分比之和來量測臨床效益率。此式之縮寫為 CBR=CR+PR+SD&gt;6個月。類似地，可將抗代謝產物（例如 吉西他濱）、鉑化合物（例如卡鉑）及4-碘-3-硝基苯曱醢胺之 組合療法的CBR(CBRgem/carbo/ba)與抗代謝產物（例如吉西 他濱）及鉑化合物（例如卡鉑）之雙重組合療法的CBR (CBRgem/carbo)比較。在一些實施例中 ’ CBRgem/carbo/ba 為至少約 10%、20%、30%、40%、50%、60%、70%、80% 或更多。在一些實施例中，CBR為至少約30%、至少約 40%或至少約50%。 在本文中提供之任一方法的一些實施例中，獲得了至少 一種治療效果，該至少一種治療效果為卵巢腫瘤大小縮 小、轉移減少、完全消退、部分消退、病理學部分反應、 156510.doc • 78 - 201206448 病理完全反應、總反應率或客觀反應率升高或疾病穩定。 在一些實施例中，用4-碘-3-硝基苯甲醯胺（或其代謝產物 或其醫藥學上可接受之鹽）合併吉西他濱及卡翻之治療獲 得了與用吉西他濱及卡鉑但未用4-碘-3-硝基苯甲醯胺（或 其代謝產物或其醫藥學上可接受之鹽）之治療相比相當的 臨床效益率（CBR=CR+PR+SD&gt;6個月）。在一些實施例中， 使臨床效益率提高至少約20%、30%、40%、50%、60%、 70%、80°/〇、90%或95%中之任一者。在一些實施例中，投 與4-碘-3-硝基笨曱醯胺（或其代謝產物或其醫藥學上可接 受之鹽）合併吉西他濱及卡鉑產生完全反應、部分反應或 穩定疾病。 在本文中提供之任一方法的一些實施例中，該患者患有 可測得的疾病。可測得的疾病可依據RECIST 1.1版標準來 破定’其描述於Eisenhauer EA等人，2009，Eur J Cancer 45(2)·_ 228-47，其揭示内容以全文引用方式併入本文中。 可測得的疾病亦可用至少一個如下的病變定義，該病變之 至少一個尺寸（欲記錄之最長尺寸）可被精確量測，且當藉 由習知技術（觸診、普通X-射線、電腦斷層攝影術（CT)或磁 共振成像（MRI))量測時220 mm或當藉由螺旋ct量測時&amp;工〇 mm ° 反應率可依照RECIST 1.1版標準來測定。例如，關於乾 病變，完全反應（CR)可定義為所有耙病變消失；任何病理 學淋巴結（無論目標或非目標）必須在短軸上縮小至 mm。關於靶病變，部分反應（PR)可定義為靶病變直徑之 156510.doc •79- 201206448 和減小至少30%，以基線直徑之和作為參照（基線直徑之和 可為所有靶病變之直徑（非結節病變（n〇dal lesi〇n)為最長， 結節病變（nodal lesion)為短軸）之和）。關於靶病變，進行 性疾病（PD)可定義為靶病變直徑之和增大至少2〇%，以研 究時之最小和作為參照（此包括基線之和，若其在研究時 為最小時）。除20%之相對增大以外，該和亦可顯示至少5 nrn的絕對增大。關於靶病變，疾病穩定（SD)可定義為既 沒有充分縮小以達到P R狀態亦沒有充分增大以達到p D狀 態（以研究時的最小直徑之和作為參照）。關於非靶病變， CR可為所有非靶病變消失及腫瘤標誌物水準正常化（所有 淋巴、、σ在大小上可為非病理的（短軸〈丨〇 mm)) ^關於非無 病變，非CR/非PD可為一或多個非靶病變持續存在及/或腫 瘤標誌物水準維持在正常限度以上。關於非靶病變，進行 性疾病（PD)可為現有非靶病變的明確進展。一或多個新病 變之出現可認為進展。 整體反應可依照Eisenhauer EA等人，2〇〇9，j Cancer.，45(2): 228_47(諸如表1-3)來測定，其揭示内容以 全文引用方式併人本文卜功效參數可藉由熟習此項技術 者已知之任何方法來測定。例如，其可依照L工版 標準來測疋例如，客觀反應率或總反應率可定義為具有 完全反應或部分反應之整體反應或最佳整體反應的患者之 比例（例如’總反應率可^義為完全反應率加上部分反應 率’或〇RR=CR+PR)e無進展存活可^義為自開始治療之 日（或啟動研究治療之日或隨機化之日）至首次觀察到疾病 156510.doc 201206448 進展之日或死亡之日的時間。整體存活可定義為自開始治 療之日（或啟動研究治療之日或隨機化之日）至死亡之日的 時間。 在一些實施例中，提供一種治療患者之鉑敏感性復發性 卵巢癌的方法，包括投與該患者有效量之：（i) 4_碘_3_硝 基本曱酿胺、其代謝產物或其醫藥學上可接受之鹽；（H) 抗代謝產物（諸如吉西他濱）；及（iii)鉑化合物（諸如卡鉑）， 其中該治療使得該患者之卵巢腫瘤大小縮小。在一些實施 例中，提供一種治療患者之鉑敏感性復發性卵巢癌的方 法’包括投與該患者有效量之：（i) 4-蛾-3-ί肖基苯曱醯 胺、其代謝產物或其醫藥學上可接受之鹽；（Η)吉西他 濱；及（iii)卡翻’其中該治療使得該患者之卵巢癌轉移減 少。在一些實施例中，提供一種治療患者之鉑敏感性復發 性印巢癌的方法，包括投與該患者有效量之：（丨）4_蛾_3_ 硝基苯曱醯胺、其代謝產物或其醫藥學上可接受之鹽； (ii)吉西他濱；及（iii)卡鉑，其中該治療使得該患者產生完 全反應。在一些實施例中，提供一種治療患者之鉑敏感性 復發性卵巢癌的方法，包括投與該患者有效量之：（丨）4_ 埃-3-硝基苯曱醯胺、其代謝產物或其醫藥學上可接受之 鹽，（11)吉西他濱；及（iii)卡鉑，其中該治療使得該患者產 生病理70全反應。在一些實施例中，提供一種治療患者之 鉑敏感性復發性卵巢癌的方法，包括投與該患者有效量 之：（i) 4·碘-3-硝基苯甲醯胺、其代謝產物或其醫藥學上 可接受之鹽，（η)吉西他濱；及（iii)卡鉑，其中該治療使得 156510.doc 201206448 該患者產生部分反應❶在一些實施例中’提供一種治療患 者之麵敏感性復發性卵巢癌的方法，包括投與該患者有效 量之·（i) 4-碘-3-硝基苯曱龜胺、其代謝產物或其醫藥學 上可接受之鹽；（ii)吉西他濱；及（iii)卡鉑，其中該治療使 得該患者之疾病穩定。 在一些實施例中’提供一種治療患者之鉑敏感性復發性 卵巢癌的方法’包括投與該患者有效量之·（i) 4碘_3硝 基笨甲醯胺、其代謝產物或其醫藥學上可接受之鹽；（H) 吉西他濱；及（iii)卡鉑，其中該治療使得該患者之卵巢癌 轉移減少。在一些實施例中，至少約1〇%(包括例如至少約 20〇/〇、30〇/〇、40〇/〇、60〇/0、70〇/〇、80。/〇、90〇/〇 或 100% 中之任 一者）之轉移得到抑制（例如與在投與⑴4•碘_3硝基苯甲醯 胺、其代謝產物或其醫藥學上可接受之鹽；（ii)吉西他 濱；及（iii)卡鉑之前的轉移相比）。在一些實施例中，使用 任何方法來抑制向淋巴結的轉移。 在一些實施例中，提供一種治療患者之鉑敏感性復發性 卵巢癌的方法，包括投與該患者有效量之：（i) 4碘_3_硝 基苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽；⑴） 吉西他濱；及（iii)卡鉑，其中該治療使得該患者之卵巢腫 瘤大小縮小。在-些實施例中，該腫瘤大小縮小至少約 10%(包括例如至少約 20%、30%、40%、6〇%、7〇%、 _、或1嶋中之任一者）(例如與在投與⑴4冬3_確 基苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽；（^) 吉西他濱，及（111)卡鉑之前的腫瘤大小相比）。 156510.doc .82· 201206448 在一些實施例中，投與4冬3·硝基苯f酿胺、其 物或其醫藥學上可接受之鹽、投與吉西他濱及/或投盘卡 始具有協同效應。在一些實施例中，使用與個別療法一般 使用之量相比較少量的各醫藥學活性化合物作為組合療法 之一部分。在—些實施财，使用組合療法實現與單獨使 用任何個別化合物相比相同或更大的治療益處。在一些實 施例中，在組合療法巾❹與個別療法—般使用之量:比 較少量（例如較低的劑量或較低頻率的給藥時間 學活性化合物實現相同或更大的治療益處。例如，使用少 量醫藥學活性化合物可使得一種或多種與該化合物有關之 副作用的數目、嚴重程度、頻率或持續時間減少/降低/缩 短。 調配物、投藥途徑及給藥方案 、在一些實施例中，提供包含4冬3“肖基苯甲酿胺（或其 代謝產物或其醫藥學上可接受之鹽或溶劑合物)、抗代謝 產物（例=吉西他濱）及/或翻化合物（例如卡始）及/或载劑 (古邊藥予上可接觉之載劑）的調配物（例如藥物調配 物）。調配物可包括本文卞揭示之化合物的光學異構體、 非對映異構體、載劑或醫藥學上可接受之鹽。在一些實施 例中，載劑為環糊精或其衍生物，例如經丙基_卜環糊精 (HPBCD)m施例中，配製調配物以供靜脈内投藥 用。 本發明之醫藥組合物可作為前藥來提供及/或可容許在 才又/、後在活體内轉變成4_碘_3 _硝基笨曱酼胺形式。亦即在 156510.doc -83- 201206448 開發用於本發明之調配物時可使用4-碘-3-硝基苯曱醯胺或 其代謝產物或醫藥學上可接受之鹽。本文中提供之4-碘-3-硝基苯甲醯胺（或其代謝產物）、抗代謝產物（例如吉西他 濱）及鉑化合物（例如卡鉑）可在分開的調配物中或在同一調 配物中配製。本文中提供之4-碘-3-硝基苯曱醯胺（或其代 謝產物）、抗代謝產物（例如吉西他濱）及鉑化合物（例如卡 翻）可經由不同投藥途徑或使用相同投藥途徑來投與。 本文中亦提供用於治療患者之鉑敏感性復發性卵巢癌的 協同組合物，包含（i) 4-碘-3-硝基苯甲醯胺或其代謝產物 或其醫藥學上可接受之鹽、（ii)吉西他濱，及（iii)卡鉑。 調配物可包含特定比例的4·碘-3-硝基苯甲醯胺化合物及 酸形式二者，此取決於各自之相對效力及預定適應症。此 兩種形式可以一起或在不同調配物中配製。其可在同一劑 量單位中，例如在一種乳膏、栓劑、錠劑、膠囊劑或欲在 飲料中溶解之散劑包中；或者各形式可在分開的單位中配 製，例如兩種乳膏、兩種栓劑、兩種錠劑、兩種膠囊劑、 一種旋劑及一種用於溶解該錠劑之液體、一種散劑包及一 種用於溶解該散劑之液體等。 本文中提供之4-碘-3-硝基苯甲醯胺（或其代謝產物）、抗 代謝產物（例如吉西他濱）及鉑化合物（例如卡鉑）可共投與 患者。共投與意欲包括化合物單獨或組合（超過一種化合 物）的同時或依序投與’諸如本文所描述。本文中提供之4_ 碘-3-硝基苯甲醢胺（或其代謝產物）、抗代謝產物（例如吉 西他濱）及/或鉑化合物（例如卡鉑）可連續地（c〇ntinu〇usly) 156510.doc •84· 201206448 或不連續地給予患者。「不連續地」意謂本文中⑽ 合物或組合物在—個時間段襄不投與患者，例如有休息 』在此期間患者不帛受該化合物或組合考勿。其可如下 -種化合物係連續地投與患者，而第二種化合物 續 地投與患者。 4-碘-3-硝基苯甲醯胺、抗代謝產物（例如吉西他濱）及鉑 化合物（例如卡鉑）之醫藥組合物可與其他活性成分（諸如本 文所述其他化療劑）組合。此三種化合物及/或化合物形式 可在同-劑量單位中，例如在一種乳膏、栓劑、錠劑、膠 囊劑或欲在飲料中溶解之散劑&amp;中一起配製；s戈者每一種 形式可在分開的單位中配製，例如三種乳膏、三種栓劑、 —種錠劑、二種膠囊劑、一種錠劑及一種用於溶解該錠劑 之液體、一種散劑包及一種用於溶解該散劑之液體等。 術語「醫藥學上可接受之鹽」意指彼等保留本發明中使 用之化合物的生物學有效性及特性且在生物學上或其他方 面皆無不良之處的鹽。例如，醫藥學上可接受之鹽不干擾 本文中提供之化合物在治療鉑敏感性復發性印巢癌中的有 益效果。 /、型的鹽為無機離子（例如鈉、鉀、飼及鎮離子）之鹽。 此類鹽包括與無機或有機酸（諸如鹽酸、氫溴酸、磷酸、 罐酸、硫酸、曱磺酸、對曱苯磺酸、乙酸、富馬酸、琥珀 酸、乳酸、杏仁酸、蘋果酸、檸檬酸、酒石酸或馬來酸） &lt;鹽。另外’在化合物含有羧基或其他酸性基團之情況 + ’可用無機或有機鹼將其轉變成醫藥學上可接受之加成 1565l〇itjoc •85· 201206448 鹽。合適驗之實例包括氫氧化鈉、氫氧化鉀、氨、環己 胺、二環己基胺、乙醇胺、二乙醇胺及三乙醇胺。 為了注射，可配製4-碘-3-硝基苯甲醯胺或其代謝產物或 其醫藥學上可接受之鹽以供在水性溶液中，較佳為在生理 學相容緩衝液（諸如磷酸鹽緩衝液、漢克氏溶液（Hank，s solution)或林格氏溶液（Ringeris s〇luti〇n))中投與。此類組 合物還可包括一種或多種賦形劑，例如防腐劑、增溶劑、 填充劑、潤滑劑、穩定劑、白蛋白及其類似物。4_碘_3_硝 基本甲酿胺之調配物描述於美國專利公開幸第 2008/0176946 A1號，其以全文引用方式併入本文中，特 別為關於靜脈内（例如羥丙基-β_環糊精等）及口服（例如月 桂基硫酸鈉等）調配物。在一些實施例中，在25% (w/v)羥 丙基-β-環糊精及10 mM磷酸鹽緩衝液中配製4_碘_3_硝基苯 甲醯胺以供靜脈内投與，如描述於美國專利申請公開案第 2010/0160442號，其以引用方式併入本文中。在_些實施 例中’調配物具有10 mg/mL 4-蛾-3-硝基苯曱醯胺、25% (w/v)羥丙基-β_環糊精及1〇 mM麟酸鹽緩衝液（pH 7.4)。 其他配製方法，諸如用於本文所述抗代謝產物（例如吉 西他濱）及鉑化合物（例如卡鉑）之方法，在此項技術中為已 知的’例如揭示於 Remingt〇n，s Pharmaceuticai sciences， 最新版本，Mack Publishing Co·，Easton，PA。本文所述組 合物還可經配製用於經黏膜投與、經頰投與、藉由吸入投 與、非經腸投與、經皮投與及經直腸投與。 適合於如本文所述使用之醫藥組合物包括其中包含有效 156510.doc • 86 - 201206448 量活性成分之組合物，亦即該有效量為可在至少一種本文 所述之鉑敏感性卵巢癌（例如復發性卵巢癌）中有效達成治 療及/或預防效益的量❹對特定投藥法的實際有效量會取 決於所治療之鉑敏感性復發性卵巢癌（例如復發性卵巢 癌）、個體狀況、調配物及投藥途徑，以及熟習此項技術 者鑒於本文中提供之具體教示已知之其他因素。根據本文 中之揭示内容，可在本文所提供4_碘_3_硝基苯曱醯胺、抗 代謝產物（例如吉西他濱）及/或鉑化合物（例如卡鉑）的指定 範圍内決定最佳有效量。 在本文中提供之任何組合物或調配物的一些實施例中， 組合物或調配物以單位劑量形式來投與。在一些實施例 中’該單位劑量形式適於口服或非經腸投與。在一些實施 例中，在投與組合物或調配物後，獲得了至少一種治療效 果’該至少一種治療效果為腫瘤大小縮小、轉移減少、完 全消退、部分消退、病理完全反應、總反應率升高或疾病 穩定。在一些實施例中，在投與組合物或調配物後，與用 抗代謝產物（例如吉西他濱）及鉑化合物（例如卡鉑）但未用 4-峨-3-硝基苯甲醯胺或其代謝產物或其醫藥學上可接受之 鹽的治療相比，提高了臨床效益率（CBR=CR+PR+SD&gt;6個 月）》在一些實施例中，使臨床效益率提高至少約2〇%。在 一些實施例中，使臨床效益率提高至少約25%、30%、 35%、40%、45%、50%、55%、60%、65%、70%、75%或 更而中之任一者。 在本文中提供之任一方法的一些實施例中，4-碘-3-硝基 156510.doc -87 - 201206448 苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽的量、吉 西他濱之量、及/或卡鉑之量為當與在同一患者中在開始 治療時相應的腫瘤大小、癌細胞數目或腫瘤生長速率相比 或與不接受該治療之其他患者中相應的活性相比時，足以 縮小腫瘤大小、減少癌細胞數目或降低腫瘤生長速率（包 括減少轉移）達至少約10%、20%、30%、40%、5〇%、 60%、70°/〇、80%、90%、950/〇 或 1〇〇〇/0 中之任一者之量。可 使用標準方法來量測此效果之程度。 在一些實施例中，4-碘-3-硝基苯甲醯胺、其代謝產物或 其醫藥學上可接受之鹽的量、吉西他濱之量、及/或卡鉑 之量低於誘導毒理學效應（例如超出臨床可接受之毒性水 準的效應）之水準或處於潛在副作用能被控制或耐受的水 準。 在一些實施例中，4-碘-3-硝基苯甲醯胺、其代謝產物或 其醫藥學上可接受之鹽的量、吉西他濱之量、及/或卡鉑 之量接近最大耐受劑量（MTD)。在一些實施例中，該量為 MTD的至少約80%、9〇%、95%或98%中之任一者。 本文所述之任何組合物或化合物可經由適宜路徑，諸如 但不限於皮内、肌肉内、腹膜内、靜脈内、動脈内、皮 下、鼻内、硬膜外及口服路徑投與患者。在一些實施例 中本文中提供之組合物或化合物藉由非經腸路徑，例如 靜脈内、腹膜内、皮下、皮内或肌肉内來投與。 本文所述之任何組合物或化合物可藉由任何便利路徑， 例如藉由輸注或推注，藉由經由上皮或黏膜皮膚襯裡（例 1565I0.doc •88· 201206448 如口腔黏膜 '直腸及腸黏膜等）吸收來投與，且可與盆他 生物學活性劑組合投與，例如諸如本文中所描述。投藥可 為全身的或局部的。另外，可能希望藉由任何合適路徑 (包括室内及鞠内注射）將本發明之醫藥組合物引入中柩神 經系統中；室内注射可藉由室内導管（例如附著至儲集 器，諸如Ommaya儲集器）來推動。 4_碘_3_硝基苯甲醯胺、其代謝產物或其醫藥學上可接受 之鹽的劑量可隨患者之年齡、高度、重量、整體健康等而 變化。在-些實施例中，4-蛾〜肖基苯甲醢胺（或其代謝 產物或其醫藥學上可接受之鹽）之劑量在約〇1 mg/kg至約 5〇 mg/kg、約 1 mg/kg 至約 100 mg/kg、2 mg/kg 至約 5〇 mg/kg、約 2 mg/kg 至約 1〇 mg/kg、約 4 mg/kg 至約 8 mg/kg、約 5 mg/kg 至約 7 mg/kg、約 1 mg/kg 至約 5〇 mg/kg、約1 mg/kg 至約25 mg/kg、約 2至約 70 mg/kg、約2 mg/kg至約 50 mg/kg、約 2 mg/kg至約 40 mg/kg、約 3 mg/kg 至約30 mg/kg、約4至約100 mg/kg、約4至約25 mg/kg、約 4至約20 mg/kg、約4至約15 mg/kg、約5至約20 mg/kg、約 5至約15 mg/kg、約50至約100 mg/kg、或約25至約75 mg/kg中之任一者的範圍内，為約2 mg/kg、約4 mg/kg、約 5 mg/kg、約 5.6 mg/kg、約 6 mg/kg、約 7 mg/kg ' 約 8 mg/kg、約 9 mg/kg、約 10 mg/kg、約 11 mg/kg、約 11.2 mg/kg、約 12 mg/kg、約 13 mg/kg、約 14 mg/kg、約 15 mg/kg、約 16 mg/kg、約 17 mg/kg ' 約 18 mg/kg、約 19 mg/kg、約 20 mg/kg、約 25 mg/kg、約 30 mg/kg、約 35 156510.doc •89- 201206448 mg/kg、約 40 mg/kg、約 50 mg/kg、約 60 mg/kg、約 75 mg/kg、或約90 mg/kg。在一些實施例中，4-蛾-3-石肖基苯 甲醯胺之劑量為約1 mg/kg、2 mg/kg、3 mg/kg、4 mg/kg、5 mg/kg、5.6 mg/kg、6 mg/kg、7 mg/kg、8 mg/kg、9 mg/kg、10 mg/kg、11 mg/kg、11.2 mg/kg、12.5 mg/kg、15 mg/kg、20 mg/kg、30 mg/kg、50 mg/kg、75 mg/kg或1 00 mg/kg中之任一者。在一些實施例中，4-埃-3-硝基苯甲醢胺（或其代謝產物或其醫藥學上可接受之鹽）以 至少約 1 mg/kg、2 mg/kg、約 4 mg/kg、約 5 mg/kg、約 5.6 mg/kg、約 6 mg/kg、約 7 mg/kg、約 8 mg/kg、約 9 mg/kg、 約 10 mg/kg、約 11 mg/kg、約 11.2 mg/kg、約 12 mg/kg、約 13 mg/kg、約 14 mg/kg、約 15 mg/kg、約 16 mg/kg、約 17 mg/kg、約 18 mg/kg、約 19 mg/kg、約 20 mg/kg、約 25 mg/kg、約 30 mg/kg、約 35 mg/kg、約 40 mg/kg、約 50 mg/kg、約 60 mg/kg、約 75 mg/kg、或約 90 mg/kg 中之任一 者的劑量投與。4-碘-3-硝基苯曱醯胺（或其代謝產物或其 醫藥學上可接受之鹽）可在約10至約300分鐘、約30至約 180分鐘、約45至約120分鐘或約60分鐘（亦即約1小時）裏經 靜脈内，例如藉由IV輸注來投與。4-碘-3-硝基苯曱醯胺或 其代謝產物或其醫藥學上可接受之鹽可每週、每週兩次、 每三週一次、每三週兩次、四週三次、三週四次、五週四 次或六週五次投與。例如，4-碘-3-硝基苯甲醯胺或其代謝 產物或其醫藥學上可接受之鹽可在治療週期之2天或4天 裏，例如在21天治療週期之第1天及第8天（以約11.2 mg/kg 156510.doc -90- 201206448 之劑量）或在第1天、第4天、第8天及第Μ (以約5·6 mg/kg之劑量）投與。在一些實施例中，提供一種治療患者 之純感性復發性印巢癌的方法，包括投與該患者有效量 之.（1) 44 _3_硝基苯甲醯胺、其代謝產物或其醫藥學上 可接受之鹽；(ii)吉西他濱；及(出)卡鉑，其中4碘_3硝基 苯曱醯胺、其代謝產物或其醫藥學上可接受之鹽以約5至 約20 mg/kg或約5 mg/kg至約15 mg/kg經靜脈内投與該患 者。在一些實施例中，4_碘_3_硝基笨曱醯胺或者可口服投 與。 可用於本文中提供之任何方法中的本文中提供之抗代謝 產物（例如吉西他濱）的劑量可隨患者之年齡、高度、重 量、整體健康等而變化。在一些實施例中，本文中提供之 抗代謝產物（例如吉西他濱）的劑量在約丨〇〇 mg/m2至約5000 mg/m 、約 100 mg/m2 至約 2000 mg/m2、約 200 至約 4000 mg/m2、約 300至約 3000 mg/m2、約 4〇〇至約 2000 mg/m2、 約 500 至約 1500 mg/m2、約 750 至約 1500 mg/m2、約 800 至 約 1500 mg/m2、約 900 至約 1400 mg/m2、約 900 至約 1250 mg/m2、約 1000 至約 15〇〇 mg/m2、約 10 mg/m2 至約 1〇〇〇 mg/m2、約 25 mg/m2 至約 500 mg/m2、約 50 mg/m2 至約 200 mg/m2、或約75 mg/m2至約200 mg/m2之範圍内。在一些實 施例中’抗代謝產物（例如吉西他濱）以約50 mg/m2、75 mg/m2、100 mg/m2、125 mg/m2、150 mg/m2、175 mg/m2 ' 200 mg/m2、250 mg/m2、300 mg/m2、400 mg/m2、450 mg/m2、500 mg/m2 ' 550 mg/m2、600 156510.doc -91- 201206448 mg/m2、650 mg/m2、700 mg/m2、750 mg/m2、800 mg/m2、850 mg/m2、900 mg/m2、1000 mg/m2、1050 mg/m2 ' 1100 mg/m2、1150 mg/m2、1200 mg/m2、1250 mg/m2、1300 mg/m2、1350 mg/m2、1400 mg/m2、1450 mg/m2、1500 mg/m2、1550 mg/m2、1600 mg/m2、1700 mg/m2、1800 mg/m2、1900 mg/m2、或 2000 mg/m2 中之任 一者投與。抗代謝產物（例如吉西他濱）可以至少約50 mg/m2、75 mg/m.2、100 mg/m2、125 mg/m2、150 mg/m2、 175 mg/m2、200 mg/m2 ' 250 mg/m2 ' 3 00 mg/m2 ' 400 mg/m2、450 mg/m2、500 mg/m2、550 mg/m2、600 mg/m2 ' 650 mg/m2、700 mg/m2、750 mg/m2、800 mg/m2、850 mg/m2、900 mg/m2、1000 mg/m2、1050 mg/m2、1100 mg/m2、1150 mg/m2、1200 mg/m2、1250 mg/m2、1300 mg/m2、1350 mg/m2、1400 mg/m2、1450 mg/m2、1500 mg/m2、1550 mg/m2、1600 mg/m2、1700 mg/m2、1800 mg/m2、1900 mg/m2、或 2000 mg/m2 中之任 一者的劑量投與。本文中提供之抗代謝產物（例如吉西他 濱）可每週、每三週一次、每週兩次、每三週兩次、四週 三次、三週四次、五週四次或六週五次投與。例如，本文 中提供之抗代謝產物（例如吉西他濱）可在治療週期之2天 裏，例如在21天治療週期之第i天及第8天（以約1000 mg/m2之劑量）投與。本文中提供之抗代謝產物（例如吉西 他濱）可在約10至約500分鐘、約1〇至約3〇〇分鐘、約15至 約180分知、約30至約180分鐘、約30至約60分鐘、約45至 156510.doc -92- 201206448 約120分鐘、約2〇至約6〇分鐘、約1〇分鐘、約2〇分鐘約 30分鐘、約60分鐘（亦即約1小時）或約3〇分鐘裏經靜脈内， 例如藉由IV輸注來投與。抗代謝產物（例如吉西他濱）或者 可口服投與。 可用於本文中提供之任何方法中的本文中提供之鉑化合 物（例如卡鉑）的劑量可隨患者之年齡、高度、重量、整體 健康等而變化。銘化合物（例如卡紐）之劑量藉由計算灰聚 $辰度時間關係曲線下面積（Auc，mg/mL，min)來確定，此 藉由熟習癌症化學療法技術之人員已知的方法考慮到藉由 量測肌酐清除率或腎小球濾過率來評估的患者之腎活性來 進行。在一些實施例中，本文中提供之鉑化合物（例如卡 鉑）與抗代謝產物（例如吉西他濱）及4_碘_3_硝基苯甲醯胺組 合使用的劑量經計算而提供約〇」至約8 mg/ml,min、約〇」 至約 7 mg/ml.min、約（M 至約 6 mg/mbmin、約 i 至約 6 mg/ml.min、約 1 至約 5 mg/mi.min、約 2至約 5 mg/ml,min、 約3至約6 mg/m卜min、約3至約5 mg/m卜min、約1至約3 mg/ml*min、約 1.5 至約 2.5 mg/mNmin、約 1.75 至約 2.25 mg/m卜min、約 2 mg/ml.min(或 AXJC 2(「AUC 2」為 2 mg/ml.min之縮寫））、約 AUC 2 5、約AUC 3、約AUC 3 5、Circulating Poly (Ethylene Glycol) Decorated Lipid Nanocapsules Deliver Docetaxel to Solid Tumors, Pharmaceutical Research, 23(4), 2006, which is incorporated herein by reference in its entirety. RNA Therapy RNA (including but not limited to siRNA, shRNA, microRNA) can be used to regulate gene expression and treat cancer. A double-stranded oligonucleotide is formed by assembling two different oligonucleotide sequences, wherein one oligonucleotide sequence is complementary to the second strand oligonucleotide sequence; such double-stranded oligonucleotides are generally from two A separate oligonucleotide (eg, siRNA) or assembled from a single molecule that folds to form a double-stranded structure (eg, shRNA or short hairpin RNA). All of the double-stranded oligonucleotides known in the art have a common feature, that is, each strand of the duplex has a different nucleotide sequence, wherein there is only one nucleotide sequence region (guide sequence or The antisense sequence) is complementary to the target nucleic acid sequence and the other strand (sense sequence) comprises a nucleotide sequence homologous to the target nucleic acid sequence. MicroRNAs (miRNAs) are single-stranded RNA molecules of approximately 21-23 nucleotides in length that regulate gene expression. A miRNA is encoded by a gene that is transcribed from DNA but not translated into a protein (non-coding RNA); alternatively, its primary transcript, 156510.doc-75-201206448 pri-miRNA, is processed into a short stem called pre-miRNA. - Ring structure and final processing into functional miRNAs. A mature miRNA molecule is partially complementary to one or more messenger RNA (mRNA) molecules and its primary function is to down-regulate gene expression. Certain RNA inhibitors can be used to inhibit the expression or translation of messenger RNA ("mRNA") associated with a cancer phenotype. Examples of such agents suitable for use herein include, but are not limited to, short interfering RNA ("siRNA"), ribozymes, and antisense oligonucleotides. Specific examples of RNA inhibitors suitable for use herein include, but are not limited to, Cand5, Sirna-027, fomivirsen, and angiozyme 0 small molecule enzyme inhibitors, certain small molecule therapeutic agents capable of Tyrosinase kinase activity or downstream signal transduction signaling targeting certain cellular receptors, such as the epidermal growth factor receptor ("EGFR") or vascular endothelial growth factor receptor ("VEGFR"). Such targeting of small molecule therapeutics can produce an anti-cancer effect. Examples of such agents suitable for use herein include, but are not limited to, imatinib, gefitinib, erlotinib, lapatinib, carartinib, ZD6474, sorafenib (BAY 43-9006) ), ERB-569, and analogs and derivatives thereof. Anti-metastatic agents The process by which cancer cells spread from the initial tumor site to other locations around the body is called cancer metastasis. Certain agents have anti-metastatic properties and are designed to inhibit the spread of cancer cells. Examples of such agents suitable for use herein include, but are not limited to, marimastat, bevacizumab, trastuzumab, rituximab, erlotinib, MMI-166, GRN163L Hunting 156510.doc -76- 201206448 hunter-killer peptide, tissue inhibitor of metalloproteinase (τίΜΡ), analogs, derivatives and variants thereof. Chemopreventive Agents Certain pharmaceutical agents, such as chemopreventive agents, can be used in combination with any of the methods provided herein. These agents can be used to prevent the onset of cancer or to prevent recurrence or metastasis. Administration of such chemopreventive agents in combination with any of the treatments described herein can serve to treat and prevent cancer recurrence. Examples of chemopreventive agents suitable for use herein include, but are not limited to, tamoxifen, raloxifene, tibolone (tib〇i〇ne), bisphosphonate ( Bisphosphonate, ibandronate, estrogen receptor sputum, serotonin inhibitor (ie tr〇zole, anastrozole), luteinizing hormone releasing hormone Agent, goserelin, vitamin A, retinal, retinoic acid, fenretinide, 9-cis-retinoic acid, 13-cis-retinoic acid, all- Trans _ retinoic acid, isotretinoin, tretinoid, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, cyclooxygenase inhibitor, non-steroidal anti-inflammatory drug (NSAID), aspirin (aspirin), ibuprofen, celecoxib, many species, more hope E, green tea extract, folic acid, glucaric acid, interferon-α, aroma Anethole dithiolethione, zinc, pyridoxine, finasteride Finasteride), doxazosin, shixi, 0 bowel-3-carbocarb, alpha-difluoromethylornithine, carotenoids, beta-carotene, lycopene , antioxidants, coenzyme Q10, flavonoids, quercetin, curcumin, catechins, 156510.doc •77· 201206448 epigallocatechin gallate, N-acetamidine Cysteamine, carbinol, carbamate, isoflavones, glucanic acid, rosemary, soy, sabah brown, and calcium. Another example of a chemopreventive agent suitable for use in the present invention is a cancer vaccine. These can be created by immunizing the patient with all or part of the cancer cell type targeted by the vaccination process. Clinical Efficacy Clinical efficacy can be measured by any method known in the art. In some embodiments, the clinical efficacy of the therapeutic treatments described herein can be determined by measuring the clinical benefit rate (CBR). By determining the number of patients in a complete regression (CR) state, the number of patients in a partial regression (PR) state, and the number of patients with stable disease (SD) at a time point of at least 6 months from the end of treatment And to measure the clinical benefit rate. The abbreviation for this formula is CBR=CR+PR+SD&gt; 6 months. Similarly, CBR (CBRgem/carbo/ba) and antimetabolites of combination therapy with antimetabolite (eg, gemcitabine), a platinum compound (eg, carboplatin), and 4-iodo-3-nitrobenzamine can be used ( A CBR (CBRgem/carbo) comparison of dual combination therapies such as gemcitabine and platinum compounds such as carboplatin. In some embodiments 'CBRgem/carbo/ba is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more. In some embodiments, the CBR is at least about 30%, at least about 40%, or at least about 50%. In some embodiments of any of the methods provided herein, at least one therapeutic effect is obtained, the ovarian tumor size reduction, metastasis reduction, complete regression, partial regression, pathological partial response, 156510.doc • 78 - 201206448 Pathological complete response, elevated overall response rate or objective response rate or stable disease. In some embodiments, the combination of 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) in combination with gemcitabine and carbamazepine is obtained with gemcitabine and carboplatin but The clinical benefit rate of treatment without 4-iodo-3-nitrobenzamide (or its metabolite or its pharmaceutically acceptable salt) (CBR=CR+PR+SD>6 months ). In some embodiments, the clinical benefit rate is increased by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80°/〇, 90%, or 95%. In some embodiments, administration of 4-iodo-3-nitroclumamine (or a metabolite thereof or a pharmaceutically acceptable salt thereof) in combination with gemcitabine and carboplatin produces a fully, partially or stabilized disease. In some embodiments of any of the methods provided herein, the patient has a measurable disease. The measurable disease can be broken according to the RECIST version 1.1 standard, which is described in Eisenhauer EA et al, 2009, Eur J Cancer 45(2) _ 228-47, the disclosure of which is incorporated herein in its entirety by reference. The measurable disease can also be defined by at least one of the lesions, at least one of which (the longest dimension to be recorded) can be accurately measured, and by conventional techniques (palpation, general X-ray, computer Tomography (CT) or magnetic resonance imaging (MRI) measurements of 220 mm or when measured by spiral ct &amp; mm ° reaction rate can be determined according to RECIST version 1.1 standards. For example, with regard to dry lesions, complete response (CR) can be defined as the disappearance of all sputum lesions; any pathological lymph nodes (whether target or non-target) must be reduced to mm on the short axis. Regarding the target lesion, the partial response (PR) can be defined as the target lesion diameter of 156510.doc •79-201206448 and a decrease of at least 30%, based on the sum of the baseline diameters (the sum of the baseline diameters can be the diameter of all target lesions ( Non-nodular lesions (n〇dal lesi〇n) are the longest, nodal lesions are the sum of the short axes). With regard to target lesions, progressive disease (PD) can be defined as an increase in the sum of the target lesion diameters by at least 2%, based on the minimum sum of the studies (this includes the sum of the baselines if they are minimal at the time of the study). In addition to the relative increase of 20%, the sum can also exhibit an absolute increase of at least 5 nrn. With regard to target lesions, disease stabilization (SD) can be defined as neither sufficiently reducing to reach the P R state nor sufficiently increasing to reach the p D state (as a reference to the sum of the smallest diameters at the time of the study). Regarding non-target lesions, CR can be used for the disappearance of all non-target lesions and the normalization of tumor markers (all lymphoids, σ can be non-pathological in size (short axis <丨〇mm)) ^About non-pathological, non- CR/non-PD may persist for one or more non-target lesions and/or maintain tumor marker levels above normal limits. With regard to non-target lesions, progressive disease (PD) can be a clear progression of existing non-target lesions. The emergence of one or more new conditions can be considered progress. The overall response can be determined according to Eisenhauer EA et al, 2, 9, j Cancer., 45(2): 228_47 (such as Tables 1-3), the disclosure of which is incorporated by reference in its entirety. Any method known to those skilled in the art to determine. For example, it can be measured according to the L-working standard. For example, the objective reaction rate or the total reaction rate can be defined as the proportion of patients with a complete reaction or partial reaction overall response or optimal overall response (eg 'total response rate can be ^ The complete response rate plus partial response rate 'or 〇RR=CR+PR)e progression-free survival can be determined from the date of initiation of treatment (or the date of initiation of study or randomization) to the first observed disease 156510.doc 201206448 The date of progress or the date of death. Overall survival can be defined as the time from the date of initiation of treatment (or the date of initiation of study or treatment or randomization) to the date of death. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering an effective amount to the patient: (i) 4_iodo_3_nitrobenzamine, a metabolite thereof, or a pharmaceutically acceptable salt; (H) an antimetabolite (such as gemcitabine); and (iii) a platinum compound (such as carboplatin), wherein the treatment results in a reduction in the size of the ovarian tumor of the patient. In some embodiments, a method of treating platinum-susceptible recurrent ovarian cancer in a patient is provided comprising: administering to the patient an effective amount of: (i) 4-Moth-3-L-succinylbenzamide, a metabolite thereof Or a pharmaceutically acceptable salt thereof; (Η) gemcitabine; and (iii) a card flip wherein the treatment results in a reduction in ovarian cancer metastasis in the patient. In some embodiments, a method of treating platinum-sensitive recurrent nested cancer in a patient comprising administering to the patient an effective amount of: (丨) 4_ moth_3_nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein the treatment results in complete response of the patient. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (丨) 4_ 埃-3-nitrobenzamine, a metabolite thereof, or A pharmaceutically acceptable salt, (11) gemcitabine; and (iii) carboplatin, wherein the treatment results in a pathological 70 full response in the patient. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, (η) gemcitabine; and (iii) carboplatin, wherein the treatment results in a partial response of the patient 156510.doc 201206448. In some embodiments, 'providing a patient's facial sensitivity recurrence A method of ovarian cancer comprising administering to the patient an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; (iii) carboplatin, wherein the treatment stabilizes the disease in the patient. In some embodiments 'providing a method of treating platinum-sensitive recurrent ovarian cancer in a patient' includes administering to the patient an effective amount of (i) 4 iodine-3 nitrobenzamide, a metabolite thereof or a medicament thereof a scientifically acceptable salt; (H) gemcitabine; and (iii) carboplatin, wherein the treatment results in a reduction in ovarian cancer metastasis in the patient. In some embodiments, at least about 1% (including, for example, at least about 20 〇/〇, 30〇/〇, 40〇/〇, 60〇/0, 70〇/〇, 80./〇, 90〇/〇 Or the transfer of either 100% is inhibited (eg, with administration of (1) 4 • iodine-3 nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; (iii) compared to the transfer before carboplatin). In some embodiments, any method is used to inhibit metastasis to lymph nodes. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient comprising administering to the patient an effective amount of: (i) 4 iodine-3-nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt; (1) gemcitabine; and (iii) carboplatin, wherein the treatment results in a reduction in the size of the patient's ovarian tumor. In some embodiments, the tumor size is reduced by at least about 10% (including, for example, at least about 20%, 30%, 40%, 6%, 7%, _, or 1嶋) (eg, In the administration of (1) 4 winter 3 - benzyl carbamide, its metabolite or its pharmaceutically acceptable salt; (^) gemcitabine, and (111) carboplatin before the tumor size). 156510.doc .82· 201206448 In some embodiments, administration of 4 winter 3 nitrobenzene f-amine, its or its pharmaceutically acceptable salt, administration of gemcitabine and/or a discarding card has synergy effect. In some embodiments, a small amount of each pharmaceutically active compound is used as part of a combination therapy as compared to the amount typically used in the individual therapies. In some implementations, combination therapy is used to achieve the same or greater therapeutic benefit as compared to the use of any individual compound alone. In some embodiments, the combination therapy is used in an amount that is generally used in combination with a single therapy: a relatively small amount (eg, a lower dose or a lower frequency of administration of the active compound to achieve the same or greater therapeutic benefit. For example, The use of a small amount of a pharmaceutically active compound can reduce/reduce/reduce the number, severity, frequency or duration of one or more side effects associated with the compound. Formulations, routes of administration, and dosing regimens, in some embodiments, provide Including 4 Winter 3 "Schottky Benzoylamine (or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof thereof), an antimetabolite (eg = gemcitabine) and/or a compound (such as a card) and a formulation (eg, a pharmaceutical formulation) of a carrier (an ancient drug to a sensible carrier). The formulation may include optical isomers, diastereomers, and Or a pharmaceutically acceptable salt. In some embodiments, the carrier is a cyclodextrin or a derivative thereof, for example, in a propyl-cyclodextrin (HPBCD) m embodiment, a formulation is formulated for intravenous administration. Internal investment Medicinal. The pharmaceutical composition of the present invention can be provided as a prodrug and/or can be allowed to be converted into a 4_iodo_3_nitrostamine form in vivo after being and/or after. In 156510. Doc-83-201206448 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof may be used in the formulation for use in the present invention. 4-iodo-3 provided herein. -Nitrobenzamide (or a metabolite thereof), an antimetabolite (such as gemcitabine), and a platinum compound (such as carboplatin) can be formulated in separate formulations or in the same formulation. Iodo-3-nitrobenzamine (or a metabolite thereof), an antimetabolite (such as gemcitabine), and a platinum compound (eg, a cardinal) can be administered via different routes of administration or using the same route of administration. A synergistic composition for treating platinum-sensitive recurrent ovarian cancer in a patient comprising (i) 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, (ii) Gemcitabine, and (iii) carboplatin. Formulations may contain a specific ratio of 4·iodo-3-nitrate Both the benzamide compound and the acid form, depending on the respective relative potency and the intended indication. These two forms may be formulated together or in different formulations. They may be in the same dosage unit, for example in a cream , suppositories, troches, capsules or powder packages to be dissolved in a beverage; or each form may be formulated in separate units, such as two creams, two suppositories, two lozenges, two capsules, A spinning agent and a liquid for dissolving the tablet, a powder package, a liquid for dissolving the powder, etc. 4-iodo-3-nitrobenzamide (or a metabolite thereof) provided herein An antimetabolite (e.g., gemcitabine) and a platinum compound (e.g., carboplatin) can be co-administered to the patient. Co-administration is intended to include simultaneous or sequential administration of the compounds, either alone or in combination (more than one compound), such as described herein. The 4-iodo-3-nitrobenzamide (or a metabolite thereof), an antimetabolite (such as gemcitabine), and/or a platinum compound (such as carboplatin) provided herein can be continuously (c〇ntinu〇usly) 156510 .doc •84·201206448 or discontinuously given to the patient. By "discontinuously" it is meant that the (10) compound or composition herein is not administered to a patient for a period of time, such as having a rest, during which time the patient is not afflicted with the compound or combination. It can be administered to a patient continuously as follows, while the second compound is continuously administered to the patient. Pharmaceutical compositions of 4-iodo-3-nitrobenzamide, antimetabolite (e.g., gemcitabine), and a platinum compound (e.g., carboplatin) can be combined with other active ingredients, such as other chemotherapeutic agents described herein. The three compounds and/or compound forms may be formulated in the same dosage unit, for example, in a cream, suppository, lozenge, capsule, or powder to be dissolved in a beverage; Formulated in separate units, such as three creams, three suppositories, a tablet, two capsules, a tablet and a liquid for dissolving the tablet, a powder package and a powder for dissolving the powder. Liquid, etc. The term "pharmaceutically acceptable salts" means salts which retain the biological effectiveness and properties of the compounds used in the present invention and which are not biologically or otherwise undesirable. For example, a pharmaceutically acceptable salt does not interfere with the beneficial effects of the compounds provided herein in the treatment of platinum-sensitive recurrent nested cancer. The salt of the type is a salt of an inorganic ion such as sodium, potassium, feed and town ions. Such salts include with inorganic or organic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, can acid, sulfuric acid, sulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid). , citric acid, tartaric acid or maleic acid) &lt;salt. Further, in the case where the compound contains a carboxyl group or other acidic group + ' can be converted into a pharmaceutically acceptable addition by an inorganic or organic base 1565 l〇itjoc • 85· 201206448 salt. Examples of suitable tests include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine. For injection, 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be formulated for use in an aqueous solution, preferably in a physiologically compatible buffer (such as phosphoric acid). It is administered in a salt buffer, Hank's solution or Ringeris s〇luti〇n. Such compositions may also include one or more excipients such as preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, and the like. Formulations of 4 - iodine - 3 - nitrobenzamide are described in U.S. Patent Publication No. 2008/0176946 A1, which is incorporated herein in its entirety by reference in its entirety, in particular in the s s Cyclodextrin, etc.) and oral (eg, sodium lauryl sulfate, etc.) formulations. In some embodiments, 4-iodo-3-nitrobenzamide is formulated for intravenous administration in 25% (w/v) hydroxypropyl-beta-cyclodextrin and 10 mM phosphate buffer. , as described in US Patent Application Publication No. 2010/0160442, which is incorporated herein by reference. In some embodiments, the formulation has 10 mg/mL 4-moth-3-nitrobenzamine, 25% (w/v) hydroxypropyl-β-cyclodextrin, and 1 mM linoleate. Buffer (pH 7.4). Other methods of formulation, such as those for use in the anti-metabolites (e.g., gemcitabine) and platinum compounds (e.g., carboplatin) described herein, are known in the art&apos;, for example, as disclosed in Remingt〇n, s Pharmaceuticai sciences, Version, Mack Publishing Co., Easton, PA. The compositions described herein may also be formulated for transmucosal administration, buccal administration, administration by inhalation, parenteral administration, transdermal administration, and rectal administration. Pharmaceutical compositions suitable for use as described herein include compositions comprising an effective amount of 156510.doc • 86 - 201206448 active ingredient, i.e., the effective amount is at least one of the platinum-sensitive ovarian cancers described herein (eg, The amount effective to achieve therapeutic and/or prophylactic benefits in recurrent ovarian cancer) The actual effective amount of a particular administration will depend on the platinum-sensitive recurrent ovarian cancer (eg, recurrent ovarian cancer), individual condition, and deployment. And the route of administration, as well as other factors known to those skilled in the art in view of the specific teachings provided herein. According to the disclosure herein, the optimal range can be determined within the specified range of 4_iodo-3-nitrobenzamine, antimetabolite (eg, gemcitabine), and/or a platinum compound (eg, carboplatin) provided herein. the amount. In some embodiments of any of the compositions or formulations provided herein, the compositions or formulations are administered in unit dosage form. In some embodiments the unit dosage form is suitable for oral or parenteral administration. In some embodiments, at least one therapeutic effect is obtained after administration of the composition or formulation. The at least one therapeutic effect is tumor size reduction, metastasis reduction, complete regression, partial regression, pathological complete response, total response rate High or stable disease. In some embodiments, after administration of the composition or formulation, with an antimetabolite (eg, gemcitabine) and a platinum compound (eg, carboplatin) but without 4-indole-3-nitrobenzamide or Increased clinical benefit rate (CBR=CR+PR+SD&gt; 6 months) compared to treatment of metabolites or pharmaceutically acceptable salts thereof. In some embodiments, the clinical benefit rate is increased by at least about 2〇 %. In some embodiments, increasing the clinical benefit rate by at least about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more Either. In some embodiments of any of the methods provided herein, 4-iodo-3-nitro156510.doc -87 - 201206448 benzoguanamine, a metabolite thereof or a pharmaceutically acceptable salt thereof, gemcitabine The amount, and/or the amount of carboplatin, is compared to the corresponding tumor size, number of cancer cells, or tumor growth rate at the start of treatment in the same patient or compared to the corresponding activity in other patients who do not receive the treatment. At least enough to reduce tumor size, reduce the number of cancer cells or reduce the rate of tumor growth (including reduced metastasis) by at least about 10%, 20%, 30%, 40%, 5%, 60%, 70°/〇, 80% , the amount of either 90%, 950/〇 or 1〇〇〇/0. Standard methods can be used to measure the extent of this effect. In some embodiments, the amount of 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof, the amount of gemcitabine, and/or carboplatin is lower than the induced toxicology The level of effects (eg, effects that exceed clinically acceptable levels of toxicity) or levels at which potential side effects can be controlled or tolerated. In some embodiments, the amount of 4-iodo-3-nitrobenzamide, its metabolite or its pharmaceutically acceptable salt, the amount of gemcitabine, and/or carboplatin is near the maximum tolerated dose. (MTD). In some embodiments, the amount is at least about any of 80%, 9%, 95%, or 98% of the MTD. Any of the compositions or compounds described herein can be administered to a patient via a suitable route such as, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, intraarterial, subcutaneous, intranasal, epidural, and oral routes. In some embodiments, the compositions or compounds provided herein are administered by parenteral routes, such as intravenous, intraperitoneal, subcutaneous, intradermal or intramuscular. Any of the compositions or compounds described herein can be lining through the epithelial or mucosal skin by any convenient route, such as by infusion or bolus injection (eg, 1565 I0.doc •88·201206448, such as oral mucosa, rectal and intestinal mucosa, etc.) The absorption is administered and can be administered in combination with a potent biologically active agent, such as for example as described herein. Administration can be systemic or topical. In addition, it may be desirable to introduce the pharmaceutical composition of the present invention into the middle sacral nervous system by any suitable route, including indoor and intra-orbital injection; indoor injection may be by an internal catheter (eg, attached to a reservoir, such as Ommaya reservoir). To promote. The dose of 4_iodo_3_nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof may vary depending on the age, height, weight, overall health, and the like of the patient. In some embodiments, the dose of 4-moth-Schottylbenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is from about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 100 mg/kg, 2 mg/kg to about 5 mg/kg, about 2 mg/kg to about 1 mg/kg, about 4 mg/kg to about 8 mg/kg, about 5 From mg/kg to about 7 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 1 mg/kg to about 25 mg/kg, from about 2 to about 70 mg/kg, from about 2 mg/kg to About 50 mg/kg, about 2 mg/kg to about 40 mg/kg, about 3 mg/kg to about 30 mg/kg, about 4 to about 100 mg/kg, about 4 to about 25 mg/kg, about 4 To about 20 mg/kg, from about 4 to about 15 mg/kg, from about 5 to about 20 mg/kg, from about 5 to about 15 mg/kg, from about 50 to about 100 mg/kg, or from about 25 to about 75 mg Within the range of /kg, about 2 mg/kg, about 4 mg/kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg' about 8 Mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/ Kg, about 16 mg/kg, about 17 mg/kg 'about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, Approximately 35 156510.doc •89-201206448 mg/kg, approximately 40 mg/kg, approximately 50 mg/kg, approximately 60 mg/kg, approximately 75 mg/kg, or approximately 90 mg/kg. In some embodiments, the dose of 4-moth-3-stone benzyl methamine is about 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 5.6 mg/kg. , 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 11.2 mg/kg, 12.5 mg/kg, 15 mg/kg, 20 mg/kg , 30 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg. In some embodiments, 4-A-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) is at least about 1 mg/kg, 2 mg/kg, about 4 mg/ Kg, about 5 mg/kg, about 5.6 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, About 11.2 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 Mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 75 mg/ A dose of either kg, or about 90 mg/kg, is administered. 4-iodo-3-nitrobenzamide (or a metabolite thereof or a pharmaceutically acceptable salt thereof) may be from about 10 to about 300 minutes, from about 30 to about 180 minutes, from about 45 to about 120 minutes or It is administered intravenously, for example by IV infusion, for about 60 minutes (i.e., about 1 hour). 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof may be administered once a week, twice a week, once every three weeks, twice every three weeks, three times three weeks, three weeks Four, five, four or six Fridays. For example, 4-iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof may be administered within 2 or 4 days of the treatment cycle, for example, on the first day of the 21-day treatment cycle and On day 8 (at a dose of approximately 11.2 mg/kg 156510.doc -90-201206448) or on days 1, 4, 8 and Μ (at a dose of approximately 5.6 mg/kg) . In some embodiments, a method of treating a purely susceptible recurrent cancer of a patient comprising administering an effective amount to the patient. (1) 44 _3_nitrobenzamide, a metabolite thereof, or a medicinal thereof An acceptable salt; (ii) gemcitabine; and (out) carboplatin, wherein 4 iodine-3-nitrobenzamine, a metabolite thereof or a pharmaceutically acceptable salt thereof is from about 5 to about 20 mg/ The patient is administered intravenously at a dose of kg or from about 5 mg/kg to about 15 mg/kg. In some embodiments, 4-iodo-3-nitrobenzamide may be administered orally. The dosage of an antimetabolite (e.g., gemcitabine) provided herein for use in any of the methods provided herein can vary with the age, height, weight, overall health, and the like of the patient. In some embodiments, the dosage of an antimetabolite (eg, gemcitabine) provided herein is from about 丨〇〇mg/m2 to about 5000 mg/m, from about 100 mg/m2 to about 2000 mg/m2, from about 200 to about 4000 mg/m2, from about 300 to about 3000 mg/m2, from about 4 to about 2000 mg/m2, from about 500 to about 1500 mg/m2, from about 750 to about 1500 mg/m2, from about 800 to about 1500 mg/ M2, from about 900 to about 1400 mg/m2, from about 900 to about 1250 mg/m2, from about 1000 to about 15 mg/m2, from about 10 mg/m2 to about 1 mg/m2, about 25 mg/ From m2 to about 500 mg/m2, from about 50 mg/m2 to about 200 mg/m2, or from about 75 mg/m2 to about 200 mg/m2. In some embodiments, an antimetabolite (eg, gemcitabine) is about 50 mg/m2, 75 mg/m2, 100 mg/m2, 125 mg/m2, 150 mg/m2, 175 mg/m2' 200 mg/m2. 250 mg/m2, 300 mg/m2, 400 mg/m2, 450 mg/m2, 500 mg/m2 ' 550 mg/m2, 600 156510.doc -91- 201206448 mg/m2, 650 mg/m2, 700 mg/ M2, 750 mg/m2, 800 mg/m2, 850 mg/m2, 900 mg/m2, 1000 mg/m2, 1050 mg/m2 '1100 mg/m2, 1150 mg/m2, 1200 mg/m2, 1250 mg/ M2, 1300 mg/m2, 1350 mg/m2, 1400 mg/m2, 1450 mg/m2, 1500 mg/m2, 1550 mg/m2, 1600 mg/m2, 1700 mg/m2, 1800 mg/m2, 1900 mg/ M2, or 2000 mg/m2, is administered. Antimetabolites (eg, gemcitabine) can be at least about 50 mg/m2, 75 mg/m.2, 100 mg/m2, 125 mg/m2, 150 mg/m2, 175 mg/m2, 200 mg/m2' 250 mg/ M2 ' 3 00 mg/m2 ' 400 mg/m2, 450 mg/m2, 500 mg/m2, 550 mg/m2, 600 mg/m2 ' 650 mg/m2, 700 mg/m2, 750 mg/m2, 800 mg /m2, 850 mg/m2, 900 mg/m2, 1000 mg/m2, 1050 mg/m2, 1100 mg/m2, 1150 mg/m2, 1200 mg/m2, 1250 mg/m2, 1300 mg/m2, 1350 mg /m2, 1400 mg/m2, 1450 mg/m2, 1500 mg/m2, 1550 mg/m2, 1600 mg/m2, 1700 mg/m2, 1800 mg/m2, 1900 mg/m2, or 2000 mg/m2 Dosage of either dose is administered. The anti-metabolites (eg, gemcitabine) provided herein can be administered weekly, every three weeks, twice a week, twice every three weeks, three times a week, three times a week, five weeks, four weeks, or six weeks. . For example, an antimetabolite (e.g., gemcitabine) provided herein can be administered during 2 days of the treatment cycle, e.g., on days ith and 8 (at a dose of about 1000 mg/m2) of the 21 day treatment cycle. The antimetabolite (e.g., gemcitabine) provided herein can be from about 10 to about 500 minutes, from about 1 to about 3 minutes, from about 15 to about 180 minutes, from about 30 to about 180 minutes, from about 30 to about 60 minutes. Minutes, about 45 to 156510.doc -92 - 201206448 about 120 minutes, about 2 inches to about 6 minutes, about 1 minute, about 2 minutes, about 30 minutes, about 60 minutes (that is, about 1 hour) or about It is administered intravenously within 3 minutes, for example by IV infusion. Antimetabolites (such as gemcitabine) can be administered orally. The dosage of the platinum compound (e.g., carboplatin) provided herein for use in any of the methods provided herein can vary with the age, height, weight, overall health, and the like of the patient. The dose of the indicating compound (eg, carb) is determined by calculating the area under the ash-growth time curve (Auc, mg/mL, min), which is considered by methods known to those skilled in the art of cancer chemotherapeutics. The renal activity of the patient as assessed by measuring creatinine clearance or glomerular filtration rate is performed. In some embodiments, the dosage of the platinum compound (eg, carboplatin) provided herein in combination with an antimetabolite (eg, gemcitabine) and 4-iodo-3-nitrobenzamide is calculated to provide a About 8 mg/ml, min, about 〇 to about 7 mg/ml.min, about (M to about 6 mg/mbmin, about i to about 6 mg/ml.min, about 1 to about 5 mg/mi. Min, from about 2 to about 5 mg/ml, min, from about 3 to about 6 mg/m b min, from about 3 to about 5 mg/m b min, from about 1 to about 3 mg/ml*min, from about 1.5 to about 2.5 mg/mNmin, about 1.75 to about 2.25 mg/m b min, about 2 mg/ml.min (or AXJC 2 ("AUC 2" is an abbreviation for 2 mg/ml.min), about AUC 2 5, about AUC 3, about AUC 3 5,

約 AUC 4、約 AUC 4.5、約 AUC 5、約 AUC 5.5、或約 AUC 6之AUC »或者，基於患者之體表面積來計算鉑化合物（例 如卡鉑）劑量。在一些實施例中，鉑化合物（例如卡鉑）之合 適劑量為約10至約400 mg/m2，例如約360 mg/m2。本文中 提供之鉑化合物（例如卡鉑）可每週、每週兩次、每三週一 156510.doc -93· 201206448 -人母二週兩次、四週三次、三週四次、五週四次或六週 五次投與。例如，卡鉑可在治療週期之1天裏，例如在21 天治療週期之第丨天（以約Auc 4之劑量）投與。鉑複合物鉑 化σ物（例如卡始）通常在約1 〇至約5〇〇分鐘約至約3⑽ 如鐘、約30至約180分鐘、約45至約120分鐘或約60分鐘之 時段裏經靜脈内（IV)投與。在此語境中，術語「約」具有 其正㊉含義，亦即大約。在一些實施例中，約意指 ±20%、±1〇〇/0或±5%。 在些情況中’在自4-碘-3-硝基苯甲醯胺（或其醫藥學 上可接受之鹽或溶劑化物或其代謝產物）之投與暫時去除 抗代謝產物（例如吉西他濱）及鉑化合物（例如卡鉑）之投與 達到一個顯著時間段（例如約12小時、約24小時、約36小 時、約48小時等）時，或者例如在投與相隔至少】天、2 天、3天、4天、5天、6天、7天、8天、9天、10天等）時， 仍實現了有益效果。例如，可在治療週期（諸如本文所述 之⑺療週期）的不同日子投與。4_碘_3_硝基苯甲醯胺、抗 代謝產物（例如吉西他濱）及鉑化合物（例如卡鉑）的投與之 間的間隔可在治療週期内變化（例如投與不總為相隔丨天， 但是可以間隔1天，接著間隔3天，等）。類似地，舡碘_3_ 硝基苯甲醯胺、抗代謝產物（例如吉西他濱）及鉑化合物（例 如卡鉑）可在治療週期期間的某些時間在相同時間投與， 且在治療期間的其他時間點在不同時間投與。 在本文提供之任何方法的一些實施例中，該治療包括i 個週期、2個週期、3個週期、4個週期、5個週期、6個週 1565I0.doc -94- 201206448 期、7個週期、 朋8個週期、9個週期、1〇個阴#n 期、12個週期 0個週期、11個週 〜4、13個週期、14個週 期、17個週期 5個週期、16個週 個週期、19個週期或20個週期“旁 使用之術語「调勒* ,t Γ 圮d。如此處 巧期J意心治療週期 中，該方法包括$ /丨、加， 些貫施例 一個治療週期（例如一個週期、雨個 週期、三個週期、乪徊，Η如 调砑期、兩個 週期、八彻、ra « ，、個週期、七個 巧期八個週期'九個週期或十 期、兩個週期、三個^者至少一個週 期、七個_ 四個週期、五個週期、六個週 朋七個週期、八個週 週期、十四個週期+ 期、十個週期、十二個 者)，… 六個週期或二十個週期中之任- 者）該治療週期包括投與有效量之卩^ 4 ώ 胺或其代謝產物或其料學上轉Ο 4冬3_硝基苯甲酿 ⑷卡鉑…， 接受之鹽、(b)吉西他濱及 在些實施例中，贫、、A底—』 0療包括至多2個週期、3個 週期、4個週期、5個 细&amp;個週期、7個週期、8個週 期、9個週期或1〇個週 ^ ,, 仕者。在一些實施例中， 該週期（例如治療週期）為約〗 % 10天、2週、3週、4週、5 週、6週、7週、8週、9週 ^ ^ &quot; 週中之任一者的時段^在一 些貫施例中，該週期（例如 _ σ縻週期）為至少約1週、10天、 2週、3週、4週、5週、6週、7 、’週、8週、9週或10週的時 段。在一些實施例中，兮 、 '^週^ (例如治療週期）為不超過約1 週、10天、2週、3週、4週、5 Μ ：&gt;週、6週、7週、8週、9週或 1〇週中之任一者的時段。在一 ^ ^貫施例中，該治療包括至 少約1週、10天、2週、3週、 μ *週、5週、6週、7週、8週、 9週、10週、12週或15週 w Τ之任—者的治療週期。本文中 156510.doc •95· 201206448 提供之任何方法可包括至少一個治療週期(例如2個週期、 刺期、伟週期、5個週期、6個週期、7個週期、8個週 期、9個週期、1〇個週期、u個週期I個週期a個週 期、14個週期或15個週期），纟中該週期為⑽之時段，其 中該週期包括投與⑷4-蛾I硝基苯甲酿胺或其代謝產物 或其醫樂學上可接受之鹽、（b)吉西他濱及⑷卡翻。 4-峨〜肖基苯甲醯胺可在治療週期之每—天投與，或者 在治療週期之每-天，或者在治療週期之某些曰子而非每 一天投與°在—些實施例中，4冬3_硝基苯甲醯胺每天、 一週一次、一週兩次、一週三次、一週四次、一週五次、 -週六次、每10天一次、每兩週一次、每三週一次、每四 週一次、每六週-次或每八週一次投與。4冬3石肖基苯甲 «可在各個治療週期之選定日子投與，例如，4_雄_3_硝 基苯甲醯胺在治療週期之！（或2、3、4、5、6、7、8、9、 10)天時段裏每天投與’且4_蛾_3_確基苯甲醯胺在治療週 期之其他日子不投與。在—些實施例中，每—次投與心碰_ 3·硝基苯甲醯胺、其代謝產物或其醫藥學上可接受之鹽之 間的間隔不到約6個月、3個月、i個月' 2〇天、15天、14 天13天、12天、11天、10天' 9天、8天、7天、6天、$ 天、4天、3天、2天或i天中之任—者。在一些實施例中， 在給藥時間表中沒有間斷。在一些實施例中，每一次投與 之間的間隔不超過約3週、2週或丨週中之任一者^在一些 實施例中，每-次投與之間的間隔為約1週、約2週或約3 週。4-蛾·3·硝基苯甲酿胺（或其代謝產物或其醫藥學上可 156510.doc •96· 201206448 接受之鹽）可在治療週期之4天裏，例如在21天治療週期之 第1天、第4天、第8天、第u天投與（例如以約56 mg/kg^ 4-碘··3-硝基苯曱醯胺（或其代謝產物或其醫藥學 上可接文之鹽）可在治療週期之2天裏，例如在21天治療週 期之第1天及第8天投與（例如以約u 2 mg/kg、12 mg/kg、 13 mg/kg、14 mg/kg、15 mg/kg、16 mg/kg、17 mg/kg、18 mg/kg、19mg/kg 或 20mg/kg 中之任—者）。 本文中提供之抗代謝產物（例如吉西他濱）可每天投與， 例^在治療週期之每一天，或者在治療週期之某些曰子而 非每天才又與。在一些實施例中，本文中提供之抗代謝產 物（例如吉西他濱）每天、一週一次、一週兩次、一週三 次、-週四次、一週五次、一週六次、每1〇天一次、每兩 ，：次、每三週一次、每四週一次、每六週一次或每八週 投與本文中提供之抗代謝產物（例如吉西他濱）可在 各治療週期之選定日子投與，例如，抗代謝產物（例如吉 西他濱)在治療週期之K或2、3、4、5、6、7、8、9 天時段襄每天投盥，a &gt;方地 〃且抗代謝產物（例如吉西他濱）在治療 週期之其他日子不投與。在一些實施例中，每一次投與士 西他濱之間的間隔不到約6個月、3個月、】個月、21天、 天、15 天、14夭、iijn 天、12天、11天、10天、9天、8 在一此.？天、5天、4天、3天、2天或1天令之任-者。 —⑯财，在給藥時間表中在—此實施 例t，每一次投盥 仗二實施 之任m::超過㈣、2遇或1週中 i/t，母一次投與之間的間隔為约 I56510.doc •97- 201206448 1週、約2職約3週。吉西他濱可在治療週期之2天裏，例 如在^天治療週期之第】天及第8天投與（例如以约ι〇〇〇 mg/m2) 0 本文中提供之鉑化合物（例如卡鉑）可每天投與，例如在 治療週期之每一天，或者在治療週期之某些日子而非每一 天投與。在一些實施例中，本文令提供之翻化合物（例如 卡銘）每天、-週-次、一週兩次、一週三次、一週四 次、-週五次、一週六次、每1〇天一次、每兩週一次、每 三週一次、每四週一次、每六週一次或每八週一次投與。 本文中提供之鉑化合物（例如卡鉑）可在每一個治療週期之 選定日子投與，例如，鉑化合物（例如卡鉑）在治療週期之 1(或2 ' 3 ' 4、5、6、7、8、9、10)天時段襄每天投與，且 鉑化合物（例如卡鉑）在治療週期之其他日子不投與。在一 些實施例中，每一次投與卡鉑之間的間隔不到約6個月、3 個月、1個月、21天、20天、15天、14天、13天、12天、 11天、10天、9天、8天、7天、6天、5天、4天、3天、2天 或1天中之任一者。在一些實施例中，在給藥時間表中沒 有間斷。在一些實施例中，每一次投與之間的間隔不超過 約3週、2週或1週中之任一者。在一些實施例中，每一次 投與之間的間隔為約丨週、約2週或約3週。卡鉑可在治療 週期之1天裏’例如在21天治療週期之第1天投與（例如以 約 AUC4)。 在本文中提供之用於治療鉑敏感性復發性卵巢癌之任一 方法的一些實施例中，方法包括15、12、10、9、8、7、6 156510.doc -98· 201206448 或更少個給藥週期’其中每一個週期含有21天之時段。在 一些實施例中’ 4-碘-3-硝基苯甲醯胺或其醫藥學上可接受 之鹽在每一個週期之第1天、第4天、第8天及第11天以約 5.1 mg/kg至約8.6 mg/kg投與，抗代謝產物（例如吉西他濱） 在每一個週期之第1天及第8天以1000 mg/m2每天投與’且 鉑化合物（例如卡鉑）在每一個週期之第丨天以4 mg/m卜min(AUC 4)投與》 在一些實施例中，提供一種治療患者之鉑敏感性復發性 卵巢癌的方法，包括至少一個治療週期，該治療週期包括 投與該患者（i) 4-碘-3-硝基苯曱醯胺、其代謝產物或其醫 藥學上可接受之鹽；（ii)吉西他濱；及（iii)卡鉑，其中⑴卡 鉑在治療週期裏一次（例如在治療週期（諸如21天週期）之第 1天）以約AUC3至約AUC5(例如AUC4)投與該患者，其中 (π)吉西他濱在治療週期裏兩次（例如在治療週期（諸如21天 週期）之第1天及第8天）以約500至約1500 mg/m2(例如1〇〇〇 mg/m2)投與該患者，且其中（iH) 4_碘_3_硝基苯甲醯胺或其 代謝產物或其醫藥學上可接受之鹽在治療週期裏一次、兩 次、三次或四次（例如在治療週期（諸如21天週期）之第i天 及第8天，或者在治療週期（諸如21天週期）之第1天第* 天、第8天及第η天）以約5 mg/kg至約2〇 (或約$ mg/kg至約15 mg/kg)(例如5 6 mg/kg)投與該患者。在一些 實施例中，提供-種治療患者之⑽感性復發性卵巢癌的 方法’包括至少-個治療週期’該治療週期包括投與該患 者⑴4_碘-3-硝基苯甲醯胺、其代謝產物或其醫藥學上可 156510.doc -99· 201206448 接爻之鹽；（π)吉西他濱；及（iii)卡鉑，其中⑴卡鉑在治療 週期襄一次（例如在治療週期（諸如21天週期）之第1天）以約 AUC4投與該患者’其中（ii)吉西他濱在治療週期襄兩次（例 如在治療週期（諸如21天週期）之第i天及第8天）以約1000 mg/m2投與該患者，其中4_碘_3_硝基苯甲醯胺或其代謝產 物或其醫藥學上可接受之鹽在治療週期裏四次（例如在治 療週期（諸如21天週期）之第1天、第4天、第8天及第丨丨天） 以約5.6 mg/kg投與該患者。在一些實施例中，提供一種治 療患者之鉑敏感性復發性卵巢癌的方法，包括至少一個治 療週期，該治療週期包括投與該患者（丨）4_蛾_3_硝基苯甲 醯胺、其代謝產物或其醫藥學上可接受之鹽；（Η)吉西他 濱’及（111)卡鉑’其中⑴卡鉑在治療週期裏一次（例如在治 療週期（諸如21天週期）之第1天）以約AUC4投與該患者，其 中（η)吉西他濱在治療週期裏兩次（例如在治療週期（諸如2丄 天週期）之第1天及第8天）以約looo mg/m2投與該患者，其 中4-碘-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可接受 之鹽在治療週期裏兩次（例如在治療週期（諸如21天週期）之 第1天及第8天）以約11.2 mg/kg投與該患者。 套組、製品及用途 亦提供用於投與如本文中提供之4_碘_3_硝基苯甲醯胺或 其代謝產物或其醫藥學上可接受之鹽、抗代謝產物（諸如 吉西他濱）及鉑化合物（諸如卡鉑）的套組及製品。在一些 實施例中’該等套組或製品包含用於治療患者之麵敏感性 復發性卵巢癌的⑴4-碘_3_硝基苯甲醯胺或其代謝產物或 156510.doc •100· 201206448 其醫藥學上可接受之鹽、（π)抗代謝產物（例如吉西他濱）及 (iii)在白化合物（例如卡始）。本文戶斤述之任何套組可進一步 包含關於依照本文中提供之任何方法使用（i) 4•碘_3_硝基 苯甲酿胺或其代謝產物或其醫藥學上可接受之鹽、（ii)吉 西他濱及（iii)卡鉑的用法說明（例如在產品插頁、包裝插頁 或標籤上）。在一些實施例中’該等套组包含4_填肖基 笨甲酿胺或其代謝產物或其醫藥學上可接受之鹽或溶劑合 物及產品或包裝插頁或標籤，其包含關於依照本文所述之 任何方法與吉西他濱及卡銘組合使用4-峨-3 -jg肖基苯甲酿胺 或其代謝產物或其醫藥學上可接受之鹽或溶劑合物治療患 者之鉑敏感性復發性卵巢癌的用法說明及/或資訊。在一 些實施例中，該鉑敏感性復發性卵巢癌為上皮印巢癌、法 婁皮歐氏管癌或原發性腹膜癌。在一些實施例中，該患者 在復發背景下先前未曾接受過細胞毒性化學療法。在一些 實施例中，該患者患有可測得的疾病。 例如’套組可包含關於治療患者之鉑敏感性復發性印巢 癌的用法說明’包括至少一個治療週期，該治療週期包括 投與該患者（i) 4-蛾-3-硝基笨曱醯胺、其代謝產物或其醫 藥學上可接受之鹽；（H)吉西他濱；及（iii)卡鉑，其中⑴卡 鉑在治療週期裏一次（例如在治療週期（諸如21天週期）之第 1天）以約AUC3至約AUC5投與該患者，其中（ii)吉西他濱在 治療週期裏兩次（例如在治療週期（諸如21天週期）之第i天 及第8天）以約500至約1500 mg/m2投與該患者，且其中（出) 4-碘-3-硝基苯曱醯胺或其代謝產物或其醫藥學上可接受之 156510.doc •101- 201206448 鹽在治療週期裏一次、兩次、三次或四次（例如在治療週 期（諸如21天週期）之第1天及第8天，或在治療週期（諸如21 天週期）之第1天、第4天、第8天及第11天）以約5 mg/kg至 約20 mg/kg(或約5 mg/kg至約15 mg/kg)投與該患者。在一 些實施例中’該治療包含21天之治療週期，其中⑴卡鉑在 治療週期之第1天以4 mg/ml*min (AUC 4)投與該患者；（ii) 吉西他濱在治療週期之第1天及第8天以1000 mg/m2之劑量 投與該患者；且（iii) 4-碘-3-硝基苯曱醯胺或其代謝產物或 醫藥學上可接受之鹽在治療週期之第1天、第4天、第8天 及第11天每週兩次以5.6 mg/kg之劑量投與該患者。 在某些實施例中，套組可包括一劑量的本文中揭示之至 少一種組合物。套組可進一步包含合適包裝及/或關於使 用調配物之用法說明。套組亦可包含用於投遞其調配物之 構件。 套組可包括其他醫藥劑（諸如副作用限制藥劑、化學療 法藥劑、基因療法藥劑、DNA療法藥劑、RNA療法藥劑、 病毒療法藥劑、奈米療法藥劑、小分子酶抑制劑、抗轉移 劑等）’以供與4_碘_3_硝基苯甲醯胺或其代謝產物或其醫 樂：上可接受之鹽、本文中提供之抗代謝產物(例如吉西 他Μ )及本文中提供之鉑化合物（例如卡鉑）聯合使用。此等 藥劑可以分開的形式提供，或者與4冬3_石肖基苯甲酿胺或 其代謝產物或其醫藥學上可接受之鹽、本文中提供之抗代 謝產物(例如吉西他濱)及本文中提供之鉑化合物(例如卡 鉑）混。’别提為此類混合不會降低4_峨_3_補基苯甲酿胺 156510.doc 201206448 (或其代謝產物或其醫藥學上可接受之鹽）、本文中提供之 抗代謝產物(例如吉西他濱)或本文中提供之鉑化合物(例如 卡麵）的有效性，且與投藥途徑相容。類似地，套組可包 括用於輔助療法之其他藥劑或熟習此項技術者已知在治療 或預防本文所述之鉑敏感性卵巢癌（例如復發性卵巢癌）方 面有效的其他藥劑。 套組可視情況包括關於組合物之製備及投與、組合物之 田J作用及任何其他有關資訊的適宜用法說明。該等用法說 明可為任何合適格式，包括但不限於基於印刷品、錄影 帶、電腦可讀磁碟、光碟或網際網路指示之用法說明。 在另一個態樣中，提供用於治療罹患或易於患上本文所 述之鉑敏感性卵巢癌（例如復發性卵巢癌）之患者的套組， 包括裝有一劑量的如本文中揭示之調配物的第一容器及關 於使用之用法說明。該容器可為此項技術中已知且適合於 貯存及投遞靜脈内調配物之任何容器。在某些實施例中， 套組進一步包括第二容器，其裝有用於製備欲投與患者之 組合物的醫藥學上可接受之載劑、稀釋劑、佐劑等。 亦可提供含有足夠劑量的如本文中揭示之4_蛾_3-确基苯 甲酿胺、其代謝產物或其醫藥學上可接受之鹽（包括其調 配物）的套組’以便為患者提供較長時段（諸如1_3天、1_5 天、1週、2週、3週、4週、6週、8週、3個月、4個月、5 個月、6個月、7個月、8個月、9個月或更久）之有效治 療。 套組亦可包括多劑本文所述之任何化合物及關於使用之 156510.doc •103· 201206448 用法說明，且以足以在藥 '、（例如醫院藥房及配藥藥房）中 貯存及使用之量包裝。 艰萊厉 套組可包括以單位劑晉形4 4、 重t式或以多次使用形式包梦的太 文所述之化合物。套组飞匕裝的本 式。在某此實施&quot;由 個單位之單位劑量形 :物提供單位劑量形式的本文所述之化 〇物。在其他實施例中， 泡殼包裝等）提供。物可以多次使用形式（例如 下述實例意欲僅僅例子 ^ 惶例不本發明且因此不應認為以任何方 式限制本發明。提供以下皆 捉伢Μ下貫例及詳細描述作為例子，但不 具限制性。其他實例可見於美國專利公開案第us 2009/0123419 A1號，其以Μ方式併人本文中。 實例 實例1 4碘3-硝基苯甲醯胺與吉西他濱及卡鉑組合在鉑 敏感性復發性卵巢癌中之π期研究 進行一項Π期試驗來評估4_碘_3_硝基苯甲醯胺（β α)與吉 西他濱及卡㈣合在治療㈣感性復發性㈣癌中的功 效。鉑敏感性係定義為在接受最後一劑基於鉑之化療劑之 後六個月或更久卵巢癌復發或再發。 主要終點：評估吉西他濱/卡鉑與4_碘_3_硝基苯甲醢胺 組合之客觀反應率（ORR)[時間範圍：直至進行性疾病或 死亡]» 次要终點：（1)測定吉西他濱/卡鉑與4_破_3_硝基苯甲醯 胺組合之毒性性質及程度[時間範圍：最後一次4_碘_3_琐 基本甲醯胺暴露後30天];及（2)評估吉西他濱/卡翻與4_蛾- 156510.doc -104- 201206448 3-硝基苯甲醯胺組合之無進展存活（PFS)[時間範圍：直至 進行性疾病或死亡]。 納入準則：（1)年齡至少18歲；（2)上皮卵巢癌、法婁皮 歐氏管癌或原發性腹膜癌之組織學診斷；（3)完成至少一個 先前的含有鉑療法之化學療法療程’對該方案有敏感性。 「始敏感性」係定義為在基於鉑之化學療法結束後超過6 個月復發，（4)可測得的疾病’用至少一個如下的病變定 義，該病變之至少一個尺寸（欲記錄之最長尺寸）可被精確 3：測’且當藉由習知技術（觸診、普通χ_射線、電腦斷層攝 影術[CT]或磁共振成像[MRI])量測時之2〇 mm或當藉由螺旋 CT量測時do mm ; (5)適當之器官功能，定義為：絕對嗜 中性球計數（ANC)21，500/mm3 ’ 血小板&gt;l〇〇,〇〇〇/mm3 ,肌 酐清除率&gt;50 mL/min，丙胺酸胺基轉移酶（ALT)及天冬胺 酸胺基轉移酶（AST)&lt;2.5倍正常上限（ULN ;或在肝轉移的 情況中&lt;5倍ULN);總膽紅素^」mg/dL ; (6)對於有懷孕 可此之女性’在研究進入兩週内之陰性姓娠測試記錄及同 意研究療法持續期間可接受之生育控制；（7)東部合作腫瘤 于小組（Eastern Cooperative Oncology Group ; ECOG)體 力狀態（performance status) 〇、1或2 ;及（8)簽署經制度審 查委員會（IRB)批准之書面知情同意書。 排除準則：（1)併發的侵襲性惡性腫瘤，不包括：⑴非 黑素瘤皮膚癌；（Π)原位惡性腫瘤；（in)併發的淺表子宮内 膜癌，若其子宮内膜癌位於淺表或侵入不到子宮肌層厚度 之50% ; (lv)以治癒意圖治療之低風險乳癌（侷限性的，非 156510.doc •105- 201206448 炎性的），（V)只能藉由正子發射斷層攝影術（pET)來鑑定的 病k，（vi)先則用4-蛾·3-硝基苯曱醯胺或聚（ADp_核糖）聚 β酶（PARP)抑制劑之治療；（vU)可能影響研究參與之重大 醫學狀況（亦即不受控制之肺、腎或肝功能障礙，不受控 制之感染）’（vm)研究人員認為可能損害研究中之有效及 安全參與的其他重大共同罹病狀況，包括充血性心力衰竭 歷史或顯出明顯傳導缺陷或心肌缺血之心電圖（ECg) ; (ix) 參與另一項調查性裝置或藥物研究，或當前用其他調查性 藥劑之治療；（X)整個研究過程中同時進行放射療法來治療 原發性疾病；（xi)不能達到研究之要求；（χΗ)妊娠或哺 乳；及（xiii)要求類固醇或其他治療性干預之軟腦膜疾病 (Leptomeningeal disease)或腦轉移。上述資訊並非意欲包 括所有與患者潛在參與臨床試驗有關之考慮因素。 使用Simon兩階段設計在此研究中治療最多41名具有鉑 敏感性復發性卵巢癌之患者。主要終點為與接受單獨用吉 西他濱及卡鉑治療之患者相比改善的總反應率，使用來自 一項先前試驗之歷史數據來確定。次要終點為改善之無進 展存活及患者安全性。探索性終點為BRCA狀態及轉化醫 學（translational medicine) 〇 在第一階段期間，研究參與者（n=17)在每一個週期之第 1天、第4天、第8天及第11天經靜脈内接受5.6 mg/kg劑量 之4-破-3-琐基苯甲酿胺’在每一個週期之第1天及第8天接 受1000 mg/m2劑量之吉西他濱，且在每一個週期之第丄天 接受AUC4(亦即4mg/ml*min)之卡翻。 156510.doc -106- 201206448 此實驗之第-階段已結束，進行中期分析。該組合療法 可被較好地耐受，輕度噁心為最常見之副作用。在最少四 個週期/十二週後’總反應率為41%，17名患者中1〇名疾病 穩定’ 17名患、者中7名&amp;處於完全消退狀態或處於部分消 退狀態。中值追蹤會在十五週時實施。進行第二階段 (η=24)之前要求在該試驗之第一階段有最少8例反應。 實例2 : 4_碘-3-硝基苯甲醯胺與吉西他濱及卡鉑組合在鉑 敏感性復發性卵巢癌中之Η期研究 使用Simon兩階段設計進行一項2期、多中心、單臂 '安 全性及功效研究，其中參與多至41名個體（階段1，n=i7， 而階段2，n=24)。在每一個階段投與相同的治療方案。 此研究之主要目的為評估吉西他濱/卡鉑與4_碘_3•硝基 苯曱醯胺組合之客觀反應率（0RR)。此研究之次要目的為 (1)測定吉西他濱/卡鉑與4-碘-3-硝基苯曱醯胺組合之毒性 性質及程度及（2)評估無進展存活（PFS)。此研究之探索性 目的可包括BRCA狀態與反應之相關性。 所有給藥方案以21.天週期重複：每一個21天週期，在第 1天卡鉑（AUC 4 ; 60分鐘靜脈内（IV)輸注），在第i天及第8 天吉西他濱（1000 mg/m2 ; 30分鐘IV輸注），及在第！天、第 4天、第8天及第U天4-碘-3-硝基苯甲醯胺（56 mg/kg; 6〇 分鐘IV輸注）。 合格個體必須滿足下述準則才能參與該研究（納入準 則）：1)年齡至少18歲；2)上皮卵巢癌、法婁皮歐氏管癌或 原發性腹膜癌之組織學診斷；3)只完成—個先前的必須含 156510.doc •107- 201206448 有翻療法之細胞毒性介舉敗 化學療法療程，對該方案有敏感性。 在白敏感性」係定義為力县你 我马在最後一劑基於鉑之化學療法後超 過6個月復發；4)可測捲沾，左&amp; , # 4寻的疾病（其定義為可被精確量測到 至少一個病灶之至少—摘纪 個尺寸（所記錄到之最長尺寸））當藉 由I知技術（觸移、普通χ_射線、電腦斷層攝影術（CT)或磁 共振成像（MRD)量測物〇 mm或當藉由螺旋CT量測時y 〇 mm，5)適當之盗官功能，其定義為：絕對嗜中性球計數 (ANC)一l，500/mm ,血小板21〇〇 〇〇〇/mm3，肌針清除率 mL/min，丙胺酸胺基轉移酶（ALT)及天冬胺酸胺基轉移酶 (AST)&lt;2.5倍正常上限（ULN ;或在肝轉移的情況中&lt;5倍 ULN);總膽紅素&lt;1.5 mg/dL ; 6)對於有懷孕可能之女性， 在研究開始兩週内之妊娠測試記錄為陰性及同意在研究療 法持續期間進行可接受之生育控制；7)東部合作腫瘤學小 組（ECOG)體力狀態0、1或2 ;及8)簽署經制度審查委員會 (IRB)批准之書面知情同意書。 合格個體必須沒有任何下述各項才能參與該研究（排除 準則）：1)併發的侵襲性惡性腫瘤，不包括：（a)非黑素瘤 皮膚癌；（b)原位惡性腫瘤；（c)併發的淺表子宮内膜癌， 若其子宮内膜癌位於淺表或侵入不到子宮肌層厚度之 50% ; (d)以治癒意圖治療之低風險乳癌（侷限性的，非炎 性的）；2)只能藉由正子發射斷層攝影術（PET)來鑑定的病 變；3)曾使用超過1線的細胞毒性化學療法及1線生物製品 (諸如安維汀）治療超過6個月（激素不算作一線治療）；4)在 參與前3週内曾使用化學療法/生物製劑治療；5)先前曾使 156510.doc -108- 201206448 用4-碘_3_硝基苯甲醯胺或聚(ADp_核糖)聚合酶(pARp)抑制 劑治療；6)可能影響研究參與之重大醫學狀況（亦即不受控 制之肺 '腎或肝功能障礙，不受控制之感染）；7)研究人^ 認為可能損害研究中之有效及安全參與的其他重大共同罹 病狀況，包括充血性心力衰竭歷史或顯出明顯傳導缺陷或 心肌缺血之心電圖（ECG) ; 8)參與另一項調查性裝置或藥 物研究，或當前用其他調查性藥劑之治療；9)整個研究過 程中同時進行放射療法來治療原發性疾病；1〇)不能達到 研究之要求；11)妊娠或哺乳；12)要求類固醇或其他治療 性干預之軟腦膜疾病或腦轉移》 治療在沒有疾病進展或不可接受之毒性的情況下持續至 少6個週期。根據内科醫師之判斷，個體可再持續*個週 期，可能多達10個週期。根據内科醫師之判斷，作為維 持，4_碘-3·硝基苯曱醯胺可持續超過10個週期，直至進行 性疾病（PD)。在PD前中止治療之個體將每9〇(±1〇)天進行 客觀反應率之定期分階段評估，直至PD或死亡。 除基線時之初始分階段以外，每隔一個週期或大約每6 週後對可測得的疾病進行第一次預定腫瘤反應量測。藉由 CT或MRI(必須使用篩選期間使用之相同技術）使用符合改 良之貫體瘤反應s平估準則（ReSp〇nse Evaluation Criteria in Solid Tumors，RECIST)的腫瘤反應來證實疾病進展。 實例3: 4_蛾-3-硝基笨甲醯胺與吉西他濱及卡鉑 (「GC」）組合在鉑敏感性復發性卵巢癌中之 研究 156510.doc -109· 201206448 方法·.此項多中心、單臂2期研究使用Si〇lon兩階段設計 (階段1 ’ 11=17 ;總共N=41)。合格患者為218歲，有上皮卵 巢癌 '法婁皮歐氏管癌或原發性腹膜癌之組織學診斷及顯 出有銷敏感性疾病，定義為在主要治療結束後26個月復 發。卡麵（AUC 4 ;靜脈内（IV);第1天）、吉西他濱（1〇〇〇 mg/m ，IV ;第丨天及第8天）及4-碘-3-硝基苯甲醯胺（5.6 mg/kg，IV;第1天、第4天、第8天及第11天）以21天週期 給予。主要終點為總反應率（「〇Rr」；RECIST 1.0);次要 終點為安全性及無進展存活（「PFS」）。 結果：對前17名患者（其完成階段丨）之分析展示7〇6%之 ORR，由12例經證實之反應組成。初步分析沒有指示 BRCA狀態與客觀反應之間的相關性。安全性概況與在4· 碘-3-硝基苯甲醯胺與吉西他濱及卡鉑組合之先前臨床研究 中所觀察到的彼等概況一致。 結論：4-琪-3-硝基苯甲酿胺與吉西他濱及卡鉑組合在具 有始敏感性復發性卵巢癌之患者中展現出活性，〇RR與先 前研究數據（例如 Pfisterer等人，J Clin Oncol 2006，24: 4699-707)相比有升高（70.6%比47.2%)。據報告，無出乎意 料之毒性。 雖然本文中已顯示及描述了本發明之較佳實施例，但是 對熟習此項技術者會顯而易見的是，此等實施例只是作為 舉例而提供。熟習此項技術者現在將會想到眾多不會偏離 本發明之變型、變化及替代。應瞭解，在實踐本發明時可 採用本文中描述之本發明貫施例的各種替代方案。意欲由 156510.doc -110- 201206448 以下申請專利範圍限定本發明㈣且其涵蓋此等權利要求 及其等同形式之範圍内的方法及結構。 實例4 ·· 4-碘_3_硝基苯甲醢胺與吉西他濱及卡鉑 (「GC」）組合在鉑敏感性復發性卵巢癌中之π期 研究 此項多中心、單臂2期研究使用simon兩階段設計（階段 I ’ n-17，階段π，n=24 ;總共，n=41)。研究設計及治療 時間表顯示於圖1。卡鉑（AUC 4 ;靜脈内（IV);第i天）、 吉西他濱（1000 mg/m2 ; IV ;第i天及第8天）及4碘_3硝基 苯甲醯胺（5.6 mg/kg ; IV;第1天、第4天、第8天及第u 天）以21天週期給予。 合格患者218歲，具有上皮卵巢癌、法婁皮歐氏管癌或 原發性腹膜癌及顯出有鉑敏感性疾病，定義為在最後一劑 基於鉑之化學療法後&gt;6個月放射學復發。患者先前沒有在 復發为景下用細胞毒性化學療法治療。有或無BrcA突變 之患者均合格》合格患者具有可測得的疾病（RECIST丨」） 及 ECOG PS 0-2。 主要終點為基於接受至少1劑研究藥物且具有2次基線後 評估或在最後一次評估60天内具有進展/死亡之患者的總 反應率（「ORR」）。次要終點為（1)基於接受至少1劑研究 藥物且具有1次基線後評估或在最後一次評估6 〇天内具有 進展/死亡之患者的無進展存活（「PFS」）及（2)基於所有接 受至少1劑研究藥物之患者的安全性（NCI-CTCAE 3.0版）。 探索性終點為BRCA狀態與反應之間的相關性。 156510.doc • 111- 201206448 此研究使用Simon兩階段設計：在此鉑敏感性患者群中 假設所估算的歷史對照ORR為約47%(Pfisterer等人，J Clin Oncol 2006, 24: 4699-707)。設計試驗來檢測〇RR自 40%至 60%的改善。患者特徵顯示於表1。 表1 :基線患者特徵 n=411 年齡歲中值(範圍） 59 (35-82) ECOGPS(%) 0 63% 1 37% 無鉑間隔期月中值(範圍） 12.4(7-74) 6-12個月；&gt;12-24個月；&gt;24個月 54% 29% 17% 腫瘤等級。/〇 等級1 / 2/3 0% 9% 91% 組織學n(%) 漿液 35(85) 子宮内膜樣 1(2.4) 透明細胞 1(2.4) 其他 4(9.8) 患者之BRCA狀態顯示於表2。 表2 : BRCA狀態 n=411 n(%) 已測試了BRCA之患者： 27(66) BRCA11 11(41) BRCA21 2⑺ 無突變1 14(52) BRCA測試未決之患者 14(34) 156510.doc •112· 1 基於已測試了 BRCA之患者數目的百分比。 201206448 基於n=40之群體的功效數據顯示於表3。 表3 :反應-功效群體 最佳反應 可評估之反應(n=40) n(%) CR 0 PR 26(65) PR(未經證實） 1(2.5) SD 13(32.5) ORR(CR+PR) 65% 量測腫瘤反應〜每隔一個週期後，依照RECIST 1.1 表4顯示功效群體在BRCA突變狀態下之反應。 表4 :在突變狀態下之反應-功效群體 最佳反應 BRCA突變狀態 n(%) BRCA1 (n=10) BRCA 2 (n=2) 無突變 (n=14) 未決 (n=14) CR 0 0 0 0 PR 7(70) 1(50) 10(71) 8(57) PR(未經證實） 0 1(50) 0 0 SD 3(30) 0 4(29) 6(43) ORR(CR+PR) 70% 50% 71% 57% *可評估之反應。量測腫瘤反應〜每隔一個週期後，依照 RECIST 1.1。 圖2顯示可評估反應之患者（n=40)之最佳靶病變反應。 圖2還顯示彼等患者之無鉑間隔期。圖3及圖4顯示可評估 反應之患者之BRCA1/2突變狀態。可評估患者（n=41)之 PFS為9_47個月。見圖5。 156510.doc -113- 201206448 與不利事件（「AE」）數目有關之安全性數據顯示於表 表5 :治療緊急不利事件*(&gt;1 5%) 毒性 所有等級％ 等級3/4% AGO-OVAR GC 卞 等級3/4% 疲勞 90 0 2 嗜中性球減少 81 59 70 °惡心 76 2 便秘 66 0 - 血小板減少 56 42 35 貧血 42 5 27 π區吐 29 2 3 藥物過敏 29 0 2 周圍神經病 29 2 - 腹瀉 27 7 2 低鎮血 24 0 背部疼痛 20 0 頭痛 20 0 - 皮疹 20 0 脫髮 17 n/a n/a 口 中異味(Dysguesia) 15 0 焦慮 15 0 腹部疼痛 15 2 - 尿道感染 15 2 *與相關性無關；安全性群體；t NCI-CTCAE ver 2 ; ί只 有1例FN事件；n/a :不適用。 關於所治療患者之給藥的詳細資訊顯示於表6。 156510.doc •114- 201206448 表6 :給藥 n=41 n(%) 服藥減少 33(81) 服藥延遲 13(32) AE所致服藥減少或延遲 36(89) AE所致停藥 0 完成的週期數 0-3 1(2) 4-6 15(37) 7-12 22(54) 10-18 2(5) &gt;18 1(2) 料妾受G-CSF之患者數 30(73) 在研究時或在最後一劑研究藥物60天内沒有死亡。12名 患者（29%)經歷嚴重的治療緊急不利事件（「SAE」）（嗜中 性球減少及血小板減少為最常見的）。對於5名患者 (12%)，SAE被認為與研究藥物有關：血小板減少-2名患 者；嗜中性球減少-1名患者；尿道感染-1名患者；肺栓塞-1名患者。 使用4-碘-3-硝基苯甲醯胺與吉西他濱及卡鉑組合之治療 在此鉑敏感性患者群體中產生經證實之65°/。的ORR。在 BRCA突變型及野生型患者中均觀察到反應。中值PFS為 9.5個月（95% CI 8.25-12.0個月）。到收集此實例數據時， 41名患者中17名仍然在接受治療，沒有進展事件 (progression event)。安全性概況與先前用吉西他濱與卡鉑 156510.doc -115- 201206448 之組合的臨床研究中所觀察到的彼等概況一致。在此組合 下准許進行進一步的隨機化研究。 雖然已為了清楚理解的目的而藉由舉例說明較為詳細地 描述了上述發明’但是該等描述及實例不應理解為限制本 發明之範疇。 【圖式簡單說明】 圖1顯示關於使用4-碘-3 -硝基苯甲醯胺（亦稱作「依尼 帕」）合併卡銘及吉西他濱來治療鉑敏感性復發性印巢癌 之研究設計及治療時間表的圖解（Simon兩階段設計， N=41)。「GCI」指吉西他濱、卡鉑及依尼帕。rpD」指進 行性疾病（progressive disease)。 圖2顯示可評估反應之患者（N=4〇)之無鉑間隔期 (platinum-free interval)及最佳靶病變反應卬⑻ lesion response) ’後者以在靶病變之基線後腫瘤負荷最低 時所計算的相對於基線之變化百分比顯示。根據研究人員 對經證實之反應的評估形成條形圖。超過反應軸之無鉑間 隔期標有星號*。有實線圖案之方形表示經證實之穩定疾 病（「SD」）(n=13)及未經證實之部分反應（rpR」）(n=1)。 有虛線圖案之方形表示經證實之完全反應（rCR」）(n=〇) 及 PR(n=26) 〇 圖3顯示可評估反應之患者（Ν=4〇)之無鉑間隔期及最佳 靶病變反應，後者以在靶病變之基線後腫瘤負荷最低時所 汁算的相對於基線之變化百分比顯示，且顯示了患者之 BRCA突變狀態❶根據研究人員對經證實之反應的評估形 156510.doc •116· 201206448 成條形圖。有實線圖案之方形表示經證實之SD及未經證實 之PR。有虛線圖案之方形表示經證實之CR及PR。「A」表 示無BRCA突變。「M」表示BRCA1或BRCA2有突變。 圖4顯示可評估反應之患者（N=40)之無鉑間隔期及最佳 '靶病變反應，後者以在靶病變之基線後腫瘤負荷最低時所 •計算的相對於基線之變化百分比顯示，還顯示了患者之 BRCA突變狀態。根據研究人員對經證實之反應的評估形 成條形圖。有實線圖案之方形表示經證實之SD及未經證實 之PR。有虛線圖案之方形表示經證實之CR及PR。「A」表 示無BRCA突變。「M」表示BRCA1或BRCA2有突變。 圖 5 顯示無進展存活（progression-free survival, 「PFS」）可評估患者（N=41)之PFS中值為9.47個月。95% CI : 8.25至12個月；經檢查者：80.5% ;進展事件：8例 (19_50/〇)。 156510.doc -117-AUC 4, about AUC 4.5, about AUC 5, about AUC 5.5, or about AUC 6 AUC » or, based on the body surface area of the patient, the platinum compound (e.g., carboplatin) dose is calculated. In some embodiments, a suitable dose of a platinum compound (e.g., carboplatin) is from about 10 to about 400 mg/m2, such as about 360 mg/m2. The platinum compounds (such as carboplatin) provided herein can be weekly, twice a week, every three weeks 156510.doc -93· 201206448 - twice a week, three times a week, three times a week, five weeks a week Second or six Fridays. For example, carboplatin can be administered during the first day of the treatment cycle, for example, on the third day of the 21-day treatment cycle (at a dose of about Auc 4). The platinum complex platinum sigma (e.g., card start) is typically in the range of from about 1 Torr to about 5 Torr to about 3 (10), for about 30 to about 180 minutes, about 45 to about 120 minutes, or about 60 minutes. Intravenous (IV) administration. In this context, the term "about" has its positive ten meaning, that is, approximately. In some embodiments, about means ±20%, ±1〇〇/0 or ±5%. In some cases, the administration of 4-iodo-3-nitrobenzamide (or a pharmaceutically acceptable salt or solvate thereof or a metabolite thereof thereof) temporarily removes an antimetabolite (eg, gemcitabine) and Administration of a platinum compound (e.g., carboplatin) for a significant period of time (e.g., about 12 hours, about 24 hours, about 36 hours, about 48 hours, etc.), or for example, at least a day, 2 days, 3 At days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, etc., beneficial effects are still achieved. For example, it can be administered on different days of a treatment cycle, such as the (7) treatment cycle described herein. The interval between administration of 4_iodo_3_nitrobenzamide, antimetabolite (eg, gemcitabine), and a platinum compound (eg, carboplatin) may vary during the treatment cycle (eg, administration is not always separated) Days, but can be separated by 1 day, followed by 3 days, etc.). Similarly, guanidine iodide-3 nitrobenzamide, antimetabolite (eg, gemcitabine), and a platinum compound (eg, carboplatin) can be administered at the same time at certain times during the treatment cycle, and other during the treatment period Time points are invested at different times. In some embodiments of any of the methods provided herein, the treatment comprises i cycles, 2 cycles, 3 cycles, 4 cycles, 5 cycles, 6 weeks, 1565 I0.doc -94 - 201206448, 7 cycles , 8 cycles, 9 cycles, 1〇## period, 12 cycles 0 cycles, 11 weeks~4, 13 cycles, 14 cycles, 17 cycles, 5 cycles, 16 weeks Cycle, 19 cycles or 20 cycles "The terminology used in the side" is adjusted to *, Γ Γ 。d. As in the case of the hearty treatment cycle, the method includes $ / 丨, plus, some treatments Cycle (for example, one cycle, rain cycle, three cycles, 乪徊, such as 砑 、, two cycles, eight octaves, ra « , , cycles, seven cycles, eight cycles 'nine cycles or ten Period, two periods, three ^ at least one period, seven _ four periods, five periods, six weeks, seven periods, eight weeks, fourteen periods + periods, ten periods, ten Two), ... of six cycles or twenty cycles - the treatment cycle consists of administering an effective amount of 4^ 4 ώ amine Or its metabolites or its metabolites 4 winter 3_nitrobenzyl (4) carboplatin..., salt accepted, (b) gemcitabine and, in some embodiments, poor, A bottom - 0 treatment includes Up to 2 cycles, 3 cycles, 4 cycles, 5 fine &amp; cycles, 7 cycles, 8 cycles, 9 cycles, or 1 week. In some embodiments, The period (for example, the treatment period) is about 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks ^ ^ &quot; the period of any of the weeks ^ In some embodiments, the period (eg, _ σ 縻 period) is at least about 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 'weeks, 8 weeks, 9 weeks, or A 10-week period. In some embodiments, 兮, '^周^ (eg, treatment cycle) is no more than about 1 week, 10 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks: &gt; weeks, 6 weeks a period of any of 7 weeks, 8 weeks, 9 weeks, or 1 week. In one embodiment, the treatment includes at least about 1 week, 10 days, 2 weeks, 3 weeks, μ* weeks. , 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 12 weeks, or 15 weeks. Treatment cycle. Any method provided in 156510.doc •95· 201206448 may include at least one treatment cycle (eg, 2 cycles, thorns, miles, 5 cycles, 6 cycles, 7 cycles, 8 cycles, 9 cycles, 1 cycle, u cycles I cycle a cycle, 14 cycles or 15 cycles), the cycle is the period of (10), wherein the cycle includes the administration of (4) 4-moth I nitrobenzene Inulin or its metabolites or its pharmaceutically acceptable salts, (b) gemcitabine and (4) card turnover. 4-峨~Schottylbenzamide can be administered every day of the treatment cycle, or every day during the treatment cycle, or during some of the treatment cycles rather than every day. In the case, 4 winter 3 nitrobenzamide daily, once a week, twice a week, three times a week, four times a week, one Friday, - Saturday, every 10 days, once every two weeks, Once every three weeks, every four weeks, every six weeks - every time, or every eight weeks. 4 Winter 3 Shi Xiaoji Bengal «Can be administered on selected days of each treatment cycle, for example, 4_Xiong_3_nitrobenzamide in the treatment cycle! (or 2, 3, 4, 5, 6, 7, 8, 9, 10) days of daily dosing and 4_ moth Benzene decylamine is not administered on other days of the treatment cycle. In some embodiments, the interval between each dose of 碰3·nitrobenzamide, a metabolite thereof, or a pharmaceutically acceptable salt thereof is less than about 6 months, 3 months. , i months ' 2 days, 15 days, 14 days 13 days, 12 days, 11 days, 10 days ' 9 days, 8 days, 7 days, 6 days, $ days, 4 days, 3 days, 2 days or The task of i-day. In some embodiments, there are no discontinuities in the dosing schedule. In some embodiments, the interval between each administration does not exceed any of about 3 weeks, 2 weeks, or weeks. In some embodiments, the interval between each administration is about 1 week. , about 2 weeks or about 3 weeks. 4- moth·3·nitrobenzamide (or its metabolites or its pharmaceutically acceptable salt) can be administered within 4 days of the treatment cycle, for example, during the 21-day treatment cycle. On day 1, day 4, day 8, and day u (eg, about 56 mg/kg^ 4-iodo-3-nitrobenzamine (or its metabolite or its pharmaceutically acceptable The salt of the invention can be administered within 2 days of the treatment cycle, for example, on days 1 and 8 of the 21-day treatment cycle (eg, at about u 2 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg or 20 mg/kg). Anti-metabolites (eg gemcitabine) provided herein. May be administered daily, for example, every day of the treatment cycle, or during some of the treatment cycles, rather than daily. In some embodiments, the anti-metabolites (eg, gemcitabine) provided herein are daily, one week. Once, twice a week, three times a week, - Thursday, one Friday, one Saturday, once every two days, every two, every time, once every three weeks, once every four weeks, every six Mondays Or administration of an antimetabolite (eg, gemcitabine) provided herein every eight weeks may be administered on selected days of each treatment cycle, eg, an anti-metabolite (eg, gemcitabine) at the K or 2, 3, 4, 5 of the treatment cycle. During the 6th, 7th, 8th, and 9th day period, a &gt; squared and anti-metabolites (such as gemcitabine) are not administered on other days of the treatment cycle. In some embodiments, each time a person is administered The interval between the citabine is less than about 6 months, 3 months, 】 months, 21 days, days, 15 days, 14 夭, iijn days, 12 days, 11 days, 10 days, 9 days, 8 One day, five days, four days, three days, two days or one day order - 16 money, in the dosing schedule - this example t, each time the second implementation m:: exceeds (four), 2 or 1 week of i/t, the interval between mothers' one-time administration is about I56510.doc •97-201206448 1 week, about 2 jobs for about 3 weeks. Gemcitabine can be in the treatment cycle In 2 days, for example, on the day of the treatment cycle and on the 8th day (for example, about ι〇〇〇mg/m2) 0 The platinum compound (such as carboplatin) provided herein. May be administered daily, for example, every day of the treatment cycle, or on certain days of the treatment cycle rather than every day. In some embodiments, the compounds provided herein (eg, Kaming) are daily, - week - Times, twice a week, three times a week, four times a week, - Friday, one Saturday, once every day, once every two weeks, every three weeks, every four weeks, every six weeks or every Administration once every eight weeks. The platinum compounds provided herein (eg, carboplatin) can be administered on selected days of each treatment cycle, for example, a platinum compound (eg, carboplatin) at 1 of the treatment cycle (or 2 ' 3 ' 4 , 5, 6, 7, 8, 9, 10) days of daily dosing, and platinum compounds (such as carboplatin) are not administered on other days of the treatment cycle. In some embodiments, the interval between each administration of carboplatin is less than about 6 months, 3 months, 1 month, 21 days, 20 days, 15 days, 14 days, 13 days, 12 days, 11 Any of days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, there are no interruptions in the dosing schedule. In some embodiments, the interval between each administration does not exceed any of about 3 weeks, 2 weeks, or 1 week. In some embodiments, the interval between each administration is about weeks, about 2 weeks, or about 3 weeks. Carboplatin can be administered on the first day of the treatment cycle, e.g., on day 1 of the 21 day treatment cycle (e.g., at about AUC4). In some embodiments of any of the methods for treating platinum-sensitive recurrent ovarian cancer provided herein, the method comprises 15, 12, 10, 9, 8, 7, 6, 156, 510, doc - 98, 201206448 or less Each dosing cycle 'each of these cycles contains a period of 21 days. In some embodiments, '4-iodo-3-nitrobenzamide or a pharmaceutically acceptable salt thereof is about 5.1 on the first, fourth, eighth, and eleventh days of each cycle. Administration of mg/kg to about 8.6 mg/kg, anti-metabolites (eg, gemcitabine) are administered daily at 1000 mg/m2 on days 1 and 8 of each cycle and platinum compounds (eg, carboplatin) are present at each Administration of 4 mg/m b min (AUC 4) on the third day of a cycle. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient is provided, comprising at least one treatment cycle, the treatment cycle Including administration to the patient (i) 4-iodo-3-nitrobenzamine, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin The patient is administered once every treatment cycle (eg, on the first day of a treatment cycle (such as a 21-day cycle) at about AUC3 to about AUC5 (eg, AUC4), wherein (π) gemcitabine is twice in the treatment cycle (eg, in The treatment cycle (such as the 21st day and the 8th day) is administered at about 500 to about 1500 mg/m2 (eg 1 〇〇〇 mg/m2) The patient, and wherein (iH) 4_iodo_3_nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered once, twice, three times or four times during the treatment cycle (eg, in therapy) The i-day and the eighth day of the cycle (such as the 21-day cycle), or on the first day, the eighth day, the eighth day, and the ηth day of the treatment cycle (such as the 21-day cycle), from about 5 mg/kg to about 2 〇 (or about $ mg/kg to about 15 mg/kg) (eg, 5 6 mg/kg) is administered to the patient. In some embodiments, a method of treating (10) a sensory recurrent ovarian cancer in a patient comprises: at least one treatment cycle comprising administering to the patient (1) 4-iodo-3-nitrobenzamide, Metabolites or their pharmaceutically acceptable 156510.doc-99·201206448 salt; (π) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin is once in the treatment cycle (eg during treatment cycles (such as 21 days) On day 1 of the cycle), the patient was administered at approximately AUC4, wherein (ii) gemcitabine was administered twice during the treatment cycle (eg, on days i and 8 of the treatment cycle (such as the 21-day cycle)) at approximately 1000 mg /m2 is administered to the patient, wherein 4_iodo-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered four times during the treatment cycle (eg, during a treatment cycle (such as a 21-day cycle) On Day 1, Day 4, Day 8, and Day 3, the patient was administered at approximately 5.6 mg/kg. In some embodiments, a method of treating platinum-sensitive recurrent ovarian cancer in a patient, comprising at least one treatment cycle comprising administering to the patient (丨) 4_ moth_3_nitrobenzamide , its metabolites or pharmaceutically acceptable salts thereof; (Η) gemcitabine 'and (111) carboplatin' (1) carboplatin once during the treatment cycle (eg on the first day of the treatment cycle (such as the 21-day cycle) Administering the patient at about AUC4, wherein (η) gemcitabine is administered twice at the treatment cycle (eg, on days 1 and 8 of the treatment cycle (such as the 2-day cycle)) at about looo mg/m2 a patient wherein 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof is administered twice during the treatment cycle (eg, on the first day of the treatment cycle (such as a 21-day cycle) and Day 8) The patient was administered at approximately 11.2 mg/kg. Kits, articles, and uses are also provided for administration of 4_iodo-3-nitrobenzamide or a metabolite thereof, or a pharmaceutically acceptable salt thereof, an antimetabolite (such as gemcitabine) as provided herein. And kits and articles of platinum compounds such as carboplatin. In some embodiments, the kits or articles comprise (1) 4-iodo-3-nitrobenzamide or a metabolite thereof for the treatment of a patient's facial sensitive recurrent ovarian cancer or 156510.doc •100·201206448 Its pharmaceutically acceptable salts, (π) antimetabolites (eg, gemcitabine), and (iii) in white compounds (eg, card). Any of the kits described herein may further comprise the use of (i) 4 iodine-3-nitrobenzamide or a metabolite thereof or a pharmaceutically acceptable salt thereof, in accordance with any of the methods provided herein, Ii) instructions for gemcitabine and (iii) carboplatin (eg on product inserts, package inserts or labels). In some embodiments, the kits comprise 4-filled chitosan or a metabolite thereof, or a pharmaceutically acceptable salt or solvate thereof, and a product or package insert or label, comprising Any of the methods described herein in combination with gemcitabine and kamin using 4-峨-3 -jg succinylbenzamide or a metabolite thereof or a pharmaceutically acceptable salt or solvate thereof to treat a platinum-sensitive relapse in a patient Instructions and/or information on sexual ovarian cancer. In some embodiments, the platinum-sensitive recurrent ovarian cancer is epithelial-sex cancer, sputum epithelial carcinoma, or primary peritoneal cancer. In some embodiments, the patient has not previously received cytotoxic chemotherapy in the context of relapse. In some embodiments, the patient has a measurable disease. For example, the 'set can include instructions for the treatment of platinum-sensitive recurrent nested cancer in a patient' including at least one treatment cycle comprising administering to the patient (i) 4-moth-3-nitro awkward An amine, a metabolite thereof or a pharmaceutically acceptable salt thereof; (H) gemcitabine; and (iii) carboplatin, wherein (1) carboplatin is administered once during the treatment cycle (eg, during the treatment cycle (such as a 21-day cycle) Days) The patient is administered from about AUC3 to about AUC5, wherein (ii) gemcitabine is administered twice in the treatment cycle (eg, on the i-day and the eighth day of the treatment cycle (such as the 21-day cycle) from about 500 to about 1500) Mg/m2 is administered to the patient, and wherein 4-iodo-3-nitrobenzamine or its metabolite or its pharmaceutically acceptable 156510.doc •101-201206448 salt is once in the treatment cycle , two, three or four times (eg on days 1 and 8 of the treatment cycle (such as the 21-day cycle), or on the first, fourth, and eighth days of the treatment cycle (such as the 21-day cycle) And day 11) the patient is administered from about 5 mg/kg to about 20 mg/kg (or from about 5 mg/kg to about 15 mg/kg). In some embodiments, the treatment comprises a 21 day treatment cycle, wherein (1) carboplatin is administered to the patient at 4 mg/ml*min (AUC4) on the first day of the treatment cycle; (ii) gemcitabine is in the treatment cycle The patient was administered at a dose of 1000 mg/m2 on days 1 and 8; and (iii) 4-iodo-3-nitrobenzamine or a metabolite thereof or a pharmaceutically acceptable salt thereof during the treatment cycle The patient was administered twice a week at a dose of 5.6 mg/kg on Days 1, 4, 8, and 11 of the day. In certain embodiments, the kit can include a dose of at least one of the compositions disclosed herein. The kit may further comprise suitable packaging and/or instructions for use of the formulation. The kit may also include components for delivering the formulation. The kit may include other pharmaceutical agents (such as side effect limiting agents, chemotherapeutic agents, gene therapy agents, DNA therapy agents, RNA therapy agents, viral therapy agents, nanotherapy agents, small molecule enzyme inhibitors, anti-metastatic agents, etc.) For the administration of 4_iodo_3_nitrobenzamide or a metabolite thereof or its therapeutic: an acceptable salt, an anti-metabolite product provided herein (eg, gemcitabine), and platinum provided herein Compounds such as carboplatin are used in combination. Such agents may be provided in a separate form, or together with 4 Winter 3 Shishiji Benzoylamine or a metabolite thereof or a pharmaceutically acceptable salt thereof, an antimetabolite (eg, gemcitabine) provided herein, and as provided herein A platinum compound (such as carboplatin) is mixed. 'Don't mention that this type of mixing does not reduce 4_峨_3_complement benzoylamine 156510.doc 201206448 (or its metabolites or pharmaceutically acceptable salts thereof), anti-metabolites provided herein (eg Gemcitabine) or the platinum compound (eg, card face) provided herein is effective and compatible with the route of administration. Similarly, a kit can include other agents for adjuvant therapy or other agents known to those skilled in the art to be effective in treating or preventing platinum-sensitive ovarian cancer (e.g., recurrent ovarian cancer) as described herein. The kit may include appropriate instructions for the preparation and administration of the composition, the action of the composition, and any other relevant information. Such instructions may be in any suitable format including, but not limited to, instructions for use on printed materials, video tapes, computer readable disks, optical disks or internet instructions. In another aspect, a kit for treating a patient suffering from or susceptible to platinum-sensitive ovarian cancer (eg, recurrent ovarian cancer) described herein is provided, comprising a dose of a formulation as disclosed herein The first container and instructions for use. The container can be any container known in the art and suitable for storing and delivering intravenous formulations. In certain embodiments, the kit further includes a second container containing a pharmaceutically acceptable carrier, diluent, adjuvant, and the like for preparing a composition for administration to a patient. A kit comprising a sufficient dose of 4_Moth-3-actylbenzamide as disclosed herein, a metabolite thereof, or a pharmaceutically acceptable salt thereof (including a formulation thereof) may also be provided for the patient Provide a longer period of time (such as 1_3 days, 1_5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, Effective treatment for 8 months, 9 months or longer). The kit may also include multiple doses of any of the compounds described herein and instructions for use 156510.doc •103.201206448, and packaged in an amount sufficient to be stored and used in the drug's (eg, hospital pharmacy and pharmaceutical pharmacy). The rigorous group may include a compound described in Taiwen in the form of a unit dosage form, a heavy t-type or a multi-use form. The set of flying suits. In a certain implementation, the unit dosage form of the unit is provided in the form of a unit dosage form as described herein. In other embodiments, a blister pack, etc., is provided. The invention may be used in multiple instances (for example, the following examples are intended to be merely exemplary) and the invention is not to be construed as limiting the invention in any way. The following examples and detailed description are provided as examples, but without limitation Other examples can be found in U.S. Patent Publication No. 2009/0123419 A1, which is incorporated herein by reference. Example Example 1 4 Iodine 3-nitrobenzamide combined with gemcitabine and carboplatin in platinum sensitivity π phase study in recurrent ovarian cancer was performed in a phased trial to evaluate the efficacy of 4_iodo_3_nitrobenzamide (βα) combined with gemcitabine and card (4) in the treatment of (4) inductive recurrent (four) cancer Platinum sensitivity is defined as recurrence or recurrence of ovarian cancer six months or more after receiving the last dose of platinum-based chemotherapeutic agent. Primary endpoint: assessment of gemcitabine/carboplatin with 4_iodine_3_nitrobyl Objective response rate (ORR) of guanamine combination [Time range: until progressive disease or death]» Secondary endpoint: (1) Determination of gemcitabine/carboplatin in combination with 4_____nitrobenzamide Toxicity and extent of toxicity [Time range: last time 4 _Iodine_3_30 days after exposure to basic methotrexate]; and (2) evaluation of gemcitabine/card flip and 4_ moth - 156510.doc -104- 201206448 Progressive survival of 3-nitrobenzamide combination (PFS) [Time frame: until progressive disease or death] Inclusion criteria: (1) at least 18 years of age; (2) histological diagnosis of epithelial ovarian cancer, sputum epithelial carcinoma or primary peritoneal cancer (3) Completion of at least one previous chemotherapy regimen containing platinum therapy' sensitivity to the regimen. "Initial sensitivity" is defined as recurrence over 6 months after the end of platinum-based chemotherapy, (4) The measured disease 'is defined by at least one of the following lesions, at least one size of the lesion (the longest dimension to be recorded) can be accurately 3: measured 'and by conventional techniques (palpation, common χ ray, computer Tomography [CT] or magnetic resonance imaging [MRI]) 2 〇 mm when measured or do mm when measured by spiral CT; (5) appropriate organ function, defined as: absolute neutrophil count (ANC) 21,500/mm3 'platelets> 〇〇, 〇〇〇/mm3, creatinine clearance &gt; 50 mL/min, C Amino acid aminotransferase (ALT) and aspartate aminotransferase (AST) &lt;2.5 times normal upper limit (ULN; or in the case of liver metastasis &lt;5 times ULN); total bilirubin^"mg/dL; (6) For women who are pregnant, 'the test record of negative surnames within two weeks of the study and the fertile fertility acceptable for the duration of the study therapy (7) East Cooperative Oncology Group (ECOG) performance status 〇, 1 or 2; and (8) signed written informed consent form approved by the Institutional Review Board (IRB). Exclusion criteria: (1) concurrent invasive malignancies, excluding: (1) non-melanoma skin cancer; (Π) in situ malignancy; (in) concurrent superficial endometrial cancer, if its endometrial cancer Located in superficial or invasive less than 50% of the thickness of the myometrium; (lv) low-risk breast cancer treated with curative intentions (limited, non-156510.doc •105-201206448 inflammatory), (V) can only borrow Disease k identified by positron emission tomography (pET), (vi) treatment with 4-moth-3-nitrobenzamine or poly(ADp_ribose) poly-β-enzyme (PARP) inhibitor (vU) may affect the major medical conditions in which the study is involved (ie, uncontrolled lung, kidney, or liver dysfunction, uncontrolled infection)' (vm) the investigator believes that it may compromise the effective and safe participation of the study. Other major common rickets, including a history of congestive heart failure or an electrocardiogram (ECg) showing significant conduction defects or myocardial ischemia; (ix) participating in another investigative device or drug study, or currently using other investigative agents Treatment; (X) simultaneous radiation throughout the study Method for the treatment of primary disease; (xi) can not meet the requirements of research; (χΗ) pregnancy or breast-feeding; and (xiii) required steroids or other diseases pia mater of therapeutic interventions (Leptomeningeal disease) or brain metastases. The above information is not intended to include all considerations related to the potential involvement of patients in clinical trials. A maximum of 41 patients with platinum-sensitive recurrent ovarian cancer were treated in this study using the Simon two-stage design. The primary end point was the improved overall response rate compared to patients receiving gemcitabine and carboplatin alone, using historical data from a prior trial to determine. The secondary endpoint was improved progression-free survival and patient safety. The exploratory endpoint was BRCA status and translational medicine. During the first phase, study participants (n=17) received veins on days 1st, 4th, 8th, and 11th of each cycle. 4-D--3-bromobenzamide at a dose of 5.6 mg/kg received a dose of 1000 mg/m2 of gemcitabine on days 1 and 8 of each cycle, and at the end of each cycle The card accepts AUC4 (ie 4mg/ml*min). 156510.doc -106- 201206448 The first phase of this experiment has ended with an interim analysis. This combination therapy is well tolerated and mild nausea is the most common side effect. After a minimum of four cycles/twelve weeks, the total response rate was 41%, and one of the 17 patients had a stable disease. Of the 17 patients, 7 of them had a complete regression or were partially regressed. The median tracking will be implemented at fifteen weeks. A minimum of 8 reactions were required during the first phase of the test before proceeding to the second stage (η = 24). Example 2: Study of the combination of 4_iodo-3-nitrobenzamide with gemcitabine and carboplatin in platinum-sensitive recurrent ovarian cancer A two-stage, multicenter, one-arm design using Simon's two-stage design 'Safety and efficacy studies, involving up to 41 individuals (stage 1, n = i7, and stage 2, n = 24). The same treatment regimen is administered at each stage. The primary objective of this study was to evaluate the objective response rate (0RR) of the combination of gemcitabine/carboplatin with 4_iodo-3 nitrobenzamide. The secondary objectives of this study were (1) determination of the toxicity and extent of gemcitabine/carboplatin in combination with 4-iodo-3-nitrobenzamide and (2) assessment of progression-free survival (PFS). The exploratory purpose of this study may include the correlation of BRCA status with response. All dosing regimens were repeated in a 21. day cycle: each 21 day cycle, on day 1 carboplatin (AUC 4; 60 minutes intravenous (IV) infusion), on day i and day 8 gemcitabine (1000 mg/ M2; 30 minutes IV infusion), and in the first! Day IV, Day 4, Day 8, and Day U 4-iodo-3-nitrobenzamide (56 mg/kg; 6〇 min IV infusion). Qualified individuals must meet the following criteria in order to participate in the study (inclusion criteria): 1) at least 18 years of age; 2) histological diagnosis of epithelial ovarian cancer, esculent epithelial carcinoma or primary peritoneal cancer; 3) only Completion - a previous 156510.doc •107-201206448 cytotoxic regimen with remedy therapy, which is sensitive to this regimen. "White Sensitivity" is defined as the recurrence of Lixian You and Ma after more than 6 months after the last dose of platinum-based chemotherapy; 4) measurable, left &amp;##寻的病( Accurately measuring at least one lesion at least - the size of the episode (the longest recorded size)) by I know technique (touch, common χ ray, computed tomography (CT) or magnetic resonance imaging (MRD) measure 〇mm or y 〇mm when measured by spiral CT, 5) appropriate piracy function, defined as: absolute neutrophil count (ANC) - 1,500 / mm, platelets 21〇〇〇〇〇/mm3, myocardial clearance rate mL/min, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt;2.5 times normal upper limit (ULN; or in the case of liver metastasis) &lt;5 times ULN); total bilirubin &lt;1.5 mg/dL; 6) For women who are likely to have a pregnancy, the pregnancy test is negative during the first two weeks of the study and agrees to an acceptable birth control during the duration of the study; 7) Eastern Cooperative Oncology Group ( ECOG) physical status 0, 1 or 2; and 8) signed written informed consent form approved by the Institutional Review Board (IRB). Eligible individuals must not have any of the following to participate in the study (exclusion criteria): 1) concurrent invasive malignancies, excluding: (a) non-melanoma skin cancer; (b) in situ malignancy; Superficial endometrial cancer, if its endometrial cancer is superficial or invasive to less than 50% of the thickness of the myometrium; (d) Low-risk breast cancer treated with curative intentions (localized, non-inflammatory) 2) lesions that can only be identified by positron emission tomography (PET); 3) more than 1 month of cytotoxic chemotherapy and 1 line of biological products (such as Avastin) have been used for more than 6 months (The hormone does not count as first-line treatment); 4) has been treated with chemotherapy/biologics within 3 weeks prior to participation; 5) has previously used 4-iodo_3_nitrobenzidine 156510.doc -108- 201206448 Treatment with amine or poly(ADp_ribose) polymerase (pARp) inhibitors; 6) major medical conditions that may affect the study participation (ie uncontrolled lung 'kidney or liver dysfunction, uncontrolled infection); 7 The researcher ^ considers other significant common denominators that may compromise effective and safe participation in the study Status, including history of congestive heart failure or electrocardiogram (ECG) showing significant conduction defects or myocardial ischemia; 8) involvement in another investigative device or drug study, or current treatment with other investigative agents; 9) entire Radiotherapy is used to treat primary disease during the study; 1) cannot meet the requirements of the study; 11) pregnancy or breastfeeding; 12) pia mater disease or brain metastasis requiring steroid or other therapeutic intervention. Progress or unacceptable toxicity for at least 6 cycles. At the discretion of the physician, the individual can continue for up to * cycles, possibly as many as 10 cycles. According to the judgment of the physician, as a maintenance, 4_iodo-3·nitrobenzamine can last for more than 10 cycles until progressive disease (PD). Individuals who discontinued treatment prior to PD will undergo a periodic, phased assessment of the objective response rate every 9 〇 (±1 〇) days until PD or death. The first scheduled tumor response measurement was performed on the measurable disease every other cycle or approximately every 6 weeks, except for the initial stage at baseline. The disease progression was confirmed by CT or MRI (the same technique used during screening must be used) using a tumor response consistent with the modified ResP〇nse Evaluation Criteria in Solid Tumors (RECIST). Example 3: Study of the combination of 4_Moth-3-nitro-benzamide with gemcitabine and carboplatin ("GC") in platinum-sensitive recurrent ovarian cancer 156510.doc -109· 201206448 Method·. The center, one-arm phase 2 study used a two-stage design of Si〇lon (stage 1 '11=17; total N=41). Qualified patients were 218 years old with histological diagnosis of epithelial ovarian cancer or squamous cell carcinoma of the squamous cell carcinoma and primary sales of the disease. The disease was defined as a recurrence 26 months after the end of the main treatment. Card surface (AUC 4; intravenous (IV); day 1), gemcitabine (1 〇〇〇 mg/m, IV; day and day 8) and 4-iodo-3-nitrobenzamide (5.6 mg/kg, IV; Day 1, Day 4, Day 8, and Day 11) were administered over a 21 day period. The primary endpoint was the overall response rate ("〇Rr"; RECIST 1.0); the secondary endpoint was safety and progression-free survival ("PFS"). RESULTS: Analysis of the top 17 patients (when they completed the stage) showed 7 6% of the ORR, consisting of 12 confirmed responses. The preliminary analysis did not indicate a correlation between the BRCA status and the objective response. The safety profile is consistent with their observations in previous clinical studies of the combination of iodo-3-nitrobenzamide with gemcitabine and carboplatin. CONCLUSIONS: 4-Chloro-3-nitrobenzamide combined with gemcitabine and carboplatin exhibits activity in patients with initially susceptible recurrent ovarian cancer, 〇RR and previous study data (eg Pfisterer et al, J Clin Oncol 2006, 24: 4699-707) was higher (70.6% vs. 47.2%). No unexpected toxicity was reported. Although the preferred embodiment of the invention has been shown and described, it will be apparent to those skilled in the art Those skilled in the art will now be able to devise numerous variations, changes and substitutions without departing from the invention. It will be appreciated that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. The invention is intended to be limited to the scope of the claims and the scope of the claims. Example 4 ··· 4-Iodine_3_nitrobenzamide combined with gemcitabine and carboplatin (“GC”) in π-phase study of platinum-sensitive recurrent ovarian cancer This multicenter, one-arm, phase 2 study Use simon two-stage design (stage I 'n-17, stage π, n=24; total, n=41). The study design and treatment schedule are shown in Figure 1. Carboplatin (AUC 4 ; intravenous (IV); day i), gemcitabine (1000 mg/m2; IV; day i and day 8) and 4 iodine-3-nitrobenzamide (5.6 mg/kg) ; IV; Day 1, Day 4, Day 8, and Day u) were administered on a 21-day cycle. Qualified patient 218 years old with epithelial ovarian cancer, esculent epithelial carcinoma or primary peritoneal carcinoma and showed platinum-sensitive disease, defined as the last dose of platinum-based chemotherapy > 6 months of radiation Learn to relapse. The patient has not previously been treated with cytotoxic chemotherapy under relapse. Patients with or without the BrcA mutation were eligible. Qualified patients had measurable disease (RECIST丨) and ECOG PS 0-2. The primary endpoint was the overall response rate ("ORR") based on patients who received at least 1 dose of study drug and had 2 post-baseline assessments or had progression/death within 60 days of the last assessment. Secondary endpoints were (1) progression-free survival ("PFS") and (2) based on all patients who received at least 1 dose of study drug and had 1 post-baseline assessment or had progression/death within 6 days of the last assessment. Safety of patients receiving at least one dose of study drug (NCI-CTCAE version 3.0). The exploratory endpoint is the correlation between BRCA status and response. 156510.doc • 111- 201206448 This study used Simon's two-stage design: assume that the estimated historical control ORR is approximately 47% in this platinum-sensitive patient population (Pfisterer et al, J Clin Oncol 2006, 24: 4699-707) . Design tests were conducted to detect improvements in 〇RR from 40% to 60%. Patient characteristics are shown in Table 1. Table 1: Baseline patient characteristics n=411 Age median (range) 59 (35-82) ECOGPS (%) 0 63% 1 37% No platinum interval mid-month (range) 12.4 (7-74) 6- 12 months; &gt; 12-24 months; &gt; 24 months 54% 29% 17% Tumor grade. /〇 grade 1 / 2/3 0% 9% 91% histology n (%) Serum 35 (85) Endometrioid 1 (2.4) Clear cells 1 (2.4) Other 4 (9.8) The BRCA status of the patient is shown in Table 2. Table 2: BRCA status n=411 n (%) Patients who have been tested for BRCA: 27 (66) BRCA11 11 (41) BRCA21 2 (7) No mutation 1 14 (52) BRCA test pending patients 14 (34) 156510.doc • 112· 1 Based on the percentage of patients who have tested BRCA. 201206448 Efficacy data for a population based on n=40 is shown in Table 3. Table 3: Reaction-Efficacy Population Optimal Response evaluable response (n=40) n(%) CR 0 PR 26(65) PR (unconfirmed) 1(2.5) SD 13(32.5) ORR(CR+PR 65% Measurement of tumor response ~ After every other cycle, according to RECIST 1.1 Table 4 shows the response of the efficacy population in the BRCA mutation state. Table 4: Reaction in the mutated state - efficacy population optimal response BRCA mutation status n (%) BRCA1 (n = 10) BRCA 2 (n = 2) no mutation (n = 14) pending (n = 14) CR 0 0 0 0 PR 7(70) 1(50) 10(71) 8(57) PR (unconfirmed) 0 1(50) 0 0 SD 3(30) 0 4(29) 6(43) ORR(CR +PR) 70% 50% 71% 57% *Evaluable reaction. Measure tumor response ~ every other cycle, according to RECIST 1.1. Figure 2 shows the optimal target lesion response for patients who can be evaluated for response (n = 40). Figure 2 also shows the platinum-free interval of their patients. Figures 3 and 4 show the BRCA1/2 mutation status of patients who can be evaluated for response. The PFS of the evaluable patients (n=41) was 9-47 months. See Figure 5. 156510.doc -113- 201206448 Safety data relating to the number of adverse events ("AE") is shown in Table 5: Treatment of emergency adverse events* (&gt;1 5%) Toxicity All grades % Level 3/4% AGO- OVAR GC 卞 grade 3/4% fatigue 90 0 2 neutrophil reduction 81 59 70 ° nausea 76 2 constipation 66 0 - thrombocytopenia 56 42 35 anemia 42 5 27 π zone spit 29 2 3 drug allergy 29 0 2 around Neuropathy 29 2 - Diarrhea 27 7 2 Low oxysis 24 0 Back pain 20 0 Headache 20 0 - Rash 20 0 Hair loss 17 n/an/a Dysguesia 15 0 Anxiety 15 0 Abdominal pain 15 2 - Urinary tract infection 15 2 *Not related to relevance; security group; t NCI-CTCAE ver 2 ; ί only 1 case of FN event; n/a : not applicable. Detailed information on the administration of the treated patients is shown in Table 6. 156510.doc •114- 201206448 Table 6: Administration n=41 n (%) medication reduction 33 (81) medication delay 13 (32) AE caused by medication reduction or delay 36 (89) AE caused by withdrawal 0 completed Cycle number 0-3 1(2) 4-6 15(37) 7-12 22(54) 10-18 2(5) &gt;18 1(2) Number of patients receiving G-CSF 30 (73) There was no death at the time of the study or within 60 days of the last dose of study drug. Twelve patients (29%) experienced severe treatment for emergency adverse events ("SAE") (neutrophil reduction and thrombocytopenia were the most common). For 5 patients (12%), SAE was considered to be related to study drug: thrombocytopenia - 2 patients; neutrophil reduction - 1 patient; urinary tract infection - 1 patient; pulmonary embolism - 1 patient. Treatment with 4-iodo-3-nitrobenzamide in combination with gemcitabine and carboplatin produced a proven 65°/ in this platinum-sensitive patient population. ORR. Responses were observed in both BRCA mutant and wild type patients. The median PFS was 9.5 months (95% CI 8.25-12.0 months). By the time this data was collected, 17 of the 41 patients were still receiving treatment and there was no progression event. The safety profile is consistent with their previous observations in clinical studies using a combination of gemcitabine and carboplatin 156510.doc-115-201206448. Further randomization studies are permitted under this combination. The above described invention has been described in detail by way of example only, and the description and examples should not be construed as limiting the scope of the invention. [Simplified Schematic] Figure 1 shows the use of 4-iodo-3-nitrobenzamide (also known as "enipa") combined with Kaming and gemcitabine to treat platinum-sensitive recurrent nested cancer. Graphical design and treatment schedule (Simon two-stage design, N=41). "GCI" means gemcitabine, carboplatin and enalapip. "rpD" refers to progressive disease. Figure 2 shows the platinum-free interval and optimal lesion response in patients with measurable response (N=4〇). The latter is the lowest tumor burden after baseline at the target lesion. The calculated percentage change from baseline is shown. A bar chart was formed based on the researchers' assessment of the confirmed response. The platinum-free interval above the reaction axis is marked with an asterisk *. Squares with solid lines indicate confirmed stable disease ("SD") (n = 13) and unconfirmed partial response (rpR") (n = 1). The square with the dotted pattern indicates the confirmed complete response (rCR) (n = 〇) and PR (n = 26) 〇 Figure 3 shows the platinum-free interval and best for patients who can evaluate the response (Ν = 4〇) The target lesion response, which is shown as a percentage change from the baseline calculated at the lowest tumor load after the baseline of the target lesion, and shows the patient's BRCA mutation status ❶ according to the investigator's assessment of the confirmed response 156510. Doc •116· 201206448 A bar chart. Squares with solid lines indicate proven SD and unproven PR. A square with a dotted pattern indicates the confirmed CR and PR. "A" indicates no BRCA mutation. "M" indicates a mutation in BRCA1 or BRCA2. Figure 4 shows the platinum-free interval and the best 'target lesion response in patients who can be evaluated for response (N=40), which is shown as a percentage change from baseline calculated at the lowest tumor load after baseline at the target lesion. The patient's BRCA mutation status is also shown. A bar chart was formed based on the researchers' assessment of the confirmed response. Squares with solid lines indicate proven SD and unproven PR. A square with a dotted pattern indicates the confirmed CR and PR. "A" indicates no BRCA mutation. "M" indicates a mutation in BRCA1 or BRCA2. Figure 5 shows that the median PFS for patients with progression-free survival ("PFS") evaluable patients (N = 41) was 9.47 months. 95% CI: 8.25 to 12 months; those who passed the examination: 80.5%; progress events: 8 cases (19_50/〇). 156510.doc -117-

Claims (1)

201206448 七、申請專利範圍： 1. 一種治療患者之鉑敏感性復發性卵巢癌的方法，包括投 與患有該鉑敏感性復發性卵巢癌之該患者有效量的：⑴ 4-硖-3-硝基苯甲醯胺、其代謝產物或其醫藥學上可接受 之鹽；（ii)吉西他濱（gemcitabine);及（iii)卡麵 (carboplatin) 〇 2. 如請求項1之方法’其中該治療包括至少約4個至約12個 治療週期，其中該等週期中之每一者包括投與有效量之 (i) 4-碘-3-硝基苯甲醯胺、其代謝產物或其醫藥學上可 接受之鹽；（ii)吉西他濱；及（iii)卡鉑。 3. 如請求項1或2之方法，其中該鉑敏感性復發性卵巢癌為 上皮卵巢癌、法婁皮歐氏管癌（fall〇pian tube cancer)或 原發性腹膜癌。 4. 如請求項1至3中任一項之方法，其中該患者在該復發背 景下先刚未曾接受過細胞毒性化學療法。 5. 如請求項丨至4中任一項之方法，其中該患者患有可測得 的疾病0 6. 如研求項1至5中任一項之方法，其中該有效量產生至少 一種選自由以下組成之群的治療效果：卵巢腫瘤大小縮 小、轉移減少、完全消退、部分消退、疾病穩定、及病 理完全反應。 7. 如請求項1至6中任一項之古 本6 k 哨4方法，進一步包括手術、放射 療法、化學療法、基因療法、dna療法、病毒療法、 職療法、輔助療法、新辅助療法、免疫療法、奈米療 156510.doc 201206448 法或其組合。 進一步包括投與該患者 其中該鉑敏感性復發性 上皮腫瘤、生殖細胞腫 其中該鉑敏感性復發性 ，其中4-碘-3-硝基苯甲 可接受之鹽係經靜脈内 其中吉西他濱係經靜 其中卡鉑係經靜脈内 8.如請求項丨至7中任一項之方法 γ輻射。 9. 如請求項1至8中任一項之方法 卵巢癌係選自由以下組成之群 瘤及基質細胞腫瘤。 10. 如請求項1至9中任一項之方法 卵巢癌為轉移性。 11. 如請求項1至10中任一項之方法 醯胺、其代謝產物或其醫藥學上 投與。 12.如請求項1至11中任一項之方法 脈内投與。 13·如請求項1至12中任一項之方法 投與。 14.如請求項13之方法，其t該有效量在21天之治療週期内 投與，其中（i)卡始在該治療週期之第】天以4 (AUC 4)投與該患者；（ii)吉西他濱在肖治療週期之第^天 及第8天以1000 mg/m2之劑量投與該患者；且（出）*碘_ 3-硝基笨f醯胺在該治療週期之第丨天、第4天、第8天及 第11天依每週兩次之5.6 mg/kg之劑量投與該患者。 15. —種用於治療患者之鉑敏感性復發性卵巢癌的套組，其 包含（i) 4-碘-3-硝基苯f醯胺、其代謝產物或其醫藥學 上可接受之鹽；（ii)吉西他濱；及（in)卡鉑。 156510.doc • 2 · 201206448 16.如請求項15之套組，其進一步包含關於使用有效量的⑴ 4-碘-3-硝基苯曱醯胺、其代謝產物或其醫藥學上可接受 之鹽、（ii)吉西他濱及（iii)卡鉑來治療該患者之鉑敏感性 復發性卵巢癌的用法說明。 1 7.如請求項16之套組’其中該有效量在21天之治療週期内 投與，其中⑴卡鉑在該治療週期之第1天以4 mg/ml«min (AUC 4)投與該患者；（ii)吉西他濱在該治療週期之第1天 及第8天以1000 mg/m2之劑量投與該患者；且（Ui) 4_碘_ 3-硝基苯甲醯胺在該治療週期之第1天、第4天、第8天及 第11天依每週兩次之5.6 mg/kg之劑量投與該患者。 18. —種套組，其包含（i) 4-碘-3-硝基苯甲醯胺、其代謝產 物或醫藥學上可接受之鹽及（Π)關於使用有效量的4_碘_ 3 -石肖基苯甲酿胺或其代謝產物或醫藥學上可接受之鹽合 併吉西他濱及卡鉑來治療患者之鉑敏感性復發性卵巢癌 的用法說明》 19. 如請求項18之套組，其中該有效量在21天之治療週期内 投與’其中（1)卡始在該治療週期之第1天以4瓜“爪卜瓜化 (AUC 4)投與該患者；（ii)吉西他濱在該治療週期之第丄天 及第8天以1〇〇〇 mg/m2之劑量投與該患者；且（Ui) 4碘_ 3-硝基苯曱醯胺在該治療週期之第丨天、第4天、第8天及 第11天依每週兩次之5.6 mg/kg之劑量投與該患者。 20. 如請求項15至19中任-項之套組，其中該翻敏感性復發 )生卵巢癌為上皮卵巢癌 '法婁皮歐氏管癌或原發性腹膜 癌0 ， 156510.doc 201206448 21. 如請求項15至2〇中任一項之套組，其中該患者在該復發 背景下先前未曾接受過細胞毒性化學療法。 22. 如請求項15至2丨中任一項之套組，其中該患者患有可測 得的疾病。 23. 如請求項16至22中任一項之套組纟中該有效量產生至 少-種選自由以下組成之群的治療效果：印巢腫瘤大小 縮小、轉移減少、完全消退、部分消退、疾病穩定、及 病理完全反應。 156510.doc -4.201206448 VII. Patent Application Range: 1. A method for treating platinum-sensitive recurrent ovarian cancer in a patient, comprising administering an effective amount to the patient having the platinum-sensitive recurrent ovarian cancer: (1) 4-硖-3- Nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof; (ii) gemcitabine; and (iii) carboplatin 〇 2. The method of claim 1 wherein the treatment Included in at least about 4 to about 12 treatment cycles, wherein each of the cycles comprises administering an effective amount of (i) 4-iodo-3-nitrobenzamide, a metabolite thereof, or a pharmaceutical thereof An acceptable salt; (ii) gemcitabine; and (iii) carboplatin. 3. The method of claim 1 or 2, wherein the platinum-sensitive recurrent ovarian cancer is epithelial ovarian cancer, fall〇pian tube cancer or primary peritoneal cancer. 4. The method of any one of claims 1 to 3, wherein the patient has not previously received cytotoxic chemotherapy in the relapsed context. 5. The method of any one of the preceding claims, wherein the patient has a measurable disease. The method of any one of the items 1 to 5, wherein the effective amount produces at least one selected Therapeutic effects of the following groups of free ovarian tumors: reduced size of the ovarian tumor, decreased metastasis, complete regression, partial regression, stable disease, and complete pathological response. 7. The Guben 6k whistle 4 method according to any one of claims 1 to 6, further comprising surgery, radiation therapy, chemotherapy, gene therapy, dna therapy, viral therapy, occupational therapy, adjuvant therapy, neoadjuvant therapy, immunity Therapy, nanotherapy 156510.doc 201206448 method or a combination thereof. Further comprising administering to the patient the platinum-sensitive recurrent epithelial tumor, the germ cell swell, wherein the platinum-sensitive relapse is wherein the salt of 4-iodo-3-nitrobenzoic acid is intravenously administered by the gemcitabine system The method in which the carboplatin is intravenously. The method of any one of claims 7 to 7 is gamma radiation. 9. The method according to any one of claims 1 to 8, wherein the ovarian cancer is selected from the group consisting of a tumor and a stromal cell tumor composed of the following. 10. The method of any one of claims 1 to 9 wherein the ovarian cancer is metastatic. 11. The method of any one of claims 1 to 10, wherein the guanamine, a metabolite thereof or a pharmaceutically acceptable substance thereof. 12. The method of any of claims 1 to 11 administered intrapulmonally. 13. A method of claiming any one of claims 1 to 12. 14. The method of claim 13, wherein the effective amount is administered over a 21 day treatment period, wherein (i) the card is administered to the patient at 4 (AUC 4) on the first day of the treatment cycle; Ii) Gemcitabine is administered to the patient at a dose of 1000 mg/m2 on the second and eighth days of the treatment cycle; and (out) *iodine-3-nitrost-f-amine in the third day of the treatment cycle On day 4, day 8, and day 11, the patient was administered at a dose of 5.6 mg/kg twice a week. 15. A kit for treating platinum-sensitive recurrent ovarian cancer in a patient comprising (i) 4-iodo-3-nitrobenzenef-amine, a metabolite thereof or a pharmaceutically acceptable salt thereof (ii) gemcitabine; and (in) carboplatin. 156510.doc • 2 · 201206448 16. The kit of claim 15 further comprising the use of an effective amount of (1) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable Instructions for the use of salt, (ii) gemcitabine, and (iii) carboplatin to treat platinum-sensitive recurrent ovarian cancer in this patient. 1 7. The kit of claim 16, wherein the effective amount is administered over a 21 day treatment period, wherein (1) carboplatin is administered at 4 mg/ml «min (AUC 4) on the first day of the treatment cycle The patient; (ii) gemcitabine was administered to the patient at a dose of 1000 mg/m2 on days 1 and 8 of the treatment cycle; and (Ui) 4_iodo-3-nitrobenzamide was used in the treatment The patient was administered on the first, fourth, eighth, and eleventh days of the cycle at a dose of 5.6 mg/kg twice a week. 18. A kit comprising (i) 4-iodo-3-nitrobenzamide, a metabolite thereof or a pharmaceutically acceptable salt thereof and (Π) for the use of an effective amount of 4_iodine-3 - Instructions for the use of gemcitabine or its metabolites or pharmaceutically acceptable salts in combination with gemcitabine and carboplatin for the treatment of platinum-sensitive recurrent ovarian cancer in patients. 19. The kit of claim 18, wherein The effective amount was administered within 21 days of the treatment cycle, where (1) the card was administered to the patient on the first day of the treatment cycle with 4 melons (AUC 4); (ii) gemcitabine in the treatment The patient was administered at a dose of 1 〇〇〇 mg/m 2 on the third and eighth day of the cycle; and (Ui) 4 iodine-3-nitrobenzamine was on the third day of the treatment cycle, 4th On days, 8 and 11 days, the patient was administered at a dose of 5.6 mg/kg twice a week. 20. In the case of any of the items 15 to 19, where the sensitivity was recurring Ovarian cancer is epithelial ovarian cancer 'French squamous cell carcinoma or primary peritoneal cancer 0, 156510.doc 201206448 21. The kit according to any one of claims 15 to 2, wherein the patient A cytotoxic chemotherapy has not been previously administered in the context of this relapse. 22. A kit according to any one of claims 15 to 2, wherein the patient has a measurable disease. 23. Requests 16 to 22 In any of the kits, the effective amount produces at least one therapeutic effect selected from the group consisting of: reduced size of the tumor, reduced metastasis, complete regression, partial regression, stable disease, and complete pathological response. .doc -4.