TW201309300A - Method for treatment of advanced solid tumors - Google Patents
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本發明係關於一種沃拉色替(Volasertib)或其鹽或其水合物與順鉑或卡鉑或其鹽或其水合物之組合於治療罹患晚期及/或轉移性實體腫瘤之患者之用途。 The present invention relates to the use of a combination of Volasertib or a salt thereof or a hydrate thereof and cisplatin or carboplatin or a salt thereof or a hydrate thereof for treating a patient suffering from advanced and/or metastatic solid tumors.
儘管可利用多種已確定之治療形式如手術、細胞毒性藥物、放射治療及此等組合，但是大多數晚期及/或轉移性實體腫瘤係不可治癒。雖然利用此等療法頻繁可見罹患晚期疾病之患者之客觀反應，但是隨後經常係腫瘤進展及死亡。因此，尋找新穎治療策略已成為當務之急。 Although a variety of established therapeutic modalities such as surgery, cytotoxic drugs, radiation therapy, and the like can be utilized, most advanced and/or metastatic solid tumors are incurable. Although the use of these therapies frequently shows an objective response in patients with advanced disease, tumor progression and death often follow. Therefore, finding novel treatment strategies has become a top priority.
藉由組合抗癌藥物與不同作用方式，以及藉由改良劑量方案，可提高化學治療劑之療效。即使已提出組合療法及改良劑量方案之概念，仍需要用於治療癌症之新穎及有效治療概念，其顯示優於標準療法之優勢。 The efficacy of chemotherapeutic agents can be enhanced by combining anticancer drugs with different modes of action, as well as by modifying dosage regimens. Even though the concept of combination therapy and modified dosage regimens has been proposed, there is a need for novel and effective therapeutic concepts for treating cancer that show advantages over standard therapies.
沃拉色替係絲胺酸-蘇胺酸Polo樣激酶1(Plk1)之極有效及選擇性抑制劑，其係細胞週期進展之關鍵調節劑。沃拉色替係具有明顯藥品動力學(PK)特徵之二氫喋啶酮衍生物。基於本發明之問題為開發用於晚期及/或轉移性實體腫瘤之組合療法之改良劑量方案。 A potent and selective inhibitor of voraxine-threonine Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression. Wolachrome is a dihydroacridone derivative with distinct pharmacokinetic (PK) characteristics. The problem based on the present invention is to develop a modified dosage regimen for combination therapies for advanced and/or metastatic solid tumors.
已知沃拉色替(I)為化合物N-[反式-4-[4-(環丙基甲基)-1-哌嗪基]環己基]-4-[[(7R)-7-乙基-5,6,7,8-四氫-5-甲基-8-(1-甲基乙基)-6-氧-2-喋啶基]胺基]-3-甲氧基-苯甲醯胺，
此化合物揭示於WO 04/076454中。此外，自WO 07/090844已知其三鹽酸鹽形式及其水合物。其具有使彼等形式尤其適用於藥物用途之特徵。上述專利申請案進一步揭示該化合物或其單乙磺酸鹽於製備醫藥組合物之用途，預期該醫藥組合物尤其適用於治療特徵為過量或異常細胞增殖之疾病。 This compound is disclosed in WO 04/076454. Furthermore, its trihydrochloride form and its hydrates are known from WO 07/090844. They have the feature that they are particularly suitable for pharmaceutical use. The above patent application further discloses the use of the compound or its monoethanesulfonate in the preparation of a pharmaceutical composition which is expected to be particularly useful for the treatment of conditions characterized by excessive or abnormal cell proliferation.
順鉑(順式-二胺二氯鉑(II)(CDDP)(商標名Platinol及Platinol-AQ)係化學治療藥物。其用於治療多種類型之癌症，其於活體內反應，結合至DNA並引起DNA之交聯，其最後引發細胞凋亡。 Cisplatin (cis-diamine dichloroplatinum (II) (CDDP) (trade name Platinol and Platinol-AQ) is a chemotherapeutic drug used to treat various types of cancer, which react in vivo and bind to DNA and This causes DNA cross-linking, which eventually triggers apoptosis.
卡鉑(順式-二胺(1,1-環丁烷二羧基)鉑(II)(商標名Paraplatin及Paraplatin-AQ)係用於抗不同形式之腫瘤之化學治療藥物。卡鉑與DNA相互作用，類似於烷化劑之機制。 Carboplatin (cis-diamine (1,1-cyclobutanedicarboxy) platinum (II) (trade names Paraplatin and Paraplatin-AQ) is a chemotherapeutic drug against different forms of tumors. Carboplatin and DNA Role, similar to the mechanism of alkylating agents.
於罹患晚期及/或轉移性實體腫瘤(包括NSCLC(非小細胞肺癌)、惡性毒瘤、直腸癌及黑素瘤)之患者之臨床試驗中，已發現高劑量之沃拉色替或其鹽或其水合物可與皆具有副作用(骨髓抑制)特性之高劑量之順鉑或卡鉑組合投 與，其與沃拉色替之副作用重疊而不會使彼等副作用增強。 High-dose voraxetine or its salts have been found in clinical trials in patients with advanced and/or metastatic solid tumors, including NSCLC (non-small cell lung cancer), malignant tumors, rectal cancer, and melanoma Its hydrate can be combined with high dose cisplatin or carboplatin, which have side effects (myelosuppression) properties. And it overlaps with the side effects of Worachrome without increasing their side effects.
因此，本發明之第一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與300至500 mg，較佳300或350 mg之沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期內，一天投與50至100 mg/m2體表面積(BSA)，較佳75至100 mg/m2 BSA之順鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案I)。本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與300 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，一天投與100 mg/m2 BSA之順鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案II)。 Accordingly, a first object of the invention is a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22 During the treatment cycle of 23, 24, 25, 26, 27, 28, 29, 30 or 31 days, 300 to 500 mg, preferably 300 or 350 mg of voraxit or a pharmaceutically acceptable salt thereof is administered a day. Or a hydrate thereof, and b) administration of 50 to 100 mg/m 2 body surface area (BSA), preferably 75 to 100 mg/m 2 BSA of cisplatin per day for the same treatment period, for advanced and/or Patients with metastatic solid tumors (dosage regimen I). Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 300 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle One day, 100 mg/m 2 BSA of cisplatin was administered to patients with advanced and/or metastatic solid tumors (Dose Protocol II).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一 天投與300 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，一天投與75 mg/m2 BSA之順鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案III)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 300 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle One day, 75 mg/m 2 BSA of cisplatin was administered to patients with advanced and/or metastatic solid tumors (Dose Protocol III).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與350 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，一天投與100 mg/m2 BSA之順鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案IV)。本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與350 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，一天投與75 mg/m2 BSA之順鉑給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案V)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 350 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle One day, 100 mg/m 2 BSA of cisplatin was administered to patients with advanced and/or metastatic solid tumors (dose regimen IV). Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 350 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle One day, 75 mg/m 2 BSA of cisplatin was administered to patients with advanced and/or metastatic solid tumors (dosage regimen V).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、 25、26、27、28、29、30或31天之治療週期期間，一天投與300至500 mg，較佳300或350 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，以目標為AUC(在濃度相對時間曲線下之面積)=4 mg．min/mL至AUC=6 mg．min/mL之劑量一天投與卡鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案VI)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 ,twenty four, During the treatment cycle of 25, 26, 27, 28, 29, 30 or 31 days, 300 to 500 mg, preferably 300 or 350 mg of voraxit or a pharmaceutically acceptable salt thereof or hydrate thereof, and b) In the same treatment cycle, the target is AUC (area under the concentration versus time curve) = 4 mg. Min/mL to AUC=6 mg. A dose of min/mL is administered to carboplatin a day for patients with advanced and/or metastatic solid tumors (dosage regimen VI).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與300 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，以目標為AUC=6 mg．min/mL之劑量一天投與卡鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案VII)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 300 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle In the target, the target is AUC=6 mg. A dose of min/mL is administered to carboplatin a day for patients with advanced and/or metastatic solid tumors (dosage regimen VII).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與300 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，以目標為AUC=5 mg．min/mL之劑 量一天投與卡鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案VIII)本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期期間，一天投與350 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中，以目標為AUC=6 mg．min/mL之劑量一天投與卡鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案IX)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) at 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 During the treatment cycle of 24, 25, 26, 27, 28, 29, 30 or 31 days, 300 mg of voraxit or a pharmaceutically acceptable salt or hydrate thereof, and b) during the same treatment cycle In the target, the target is AUC=5 mg. Min/mL agent One-day administration of carboplatin to patients suffering from advanced and/or metastatic solid tumors (Dose Protocol VIII) Another object of the present invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized Depending on: a) 350 during the treatment period of 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days of treatment Mg voraxetatin or a pharmaceutically acceptable salt thereof or hydrate thereof, and b) in the same treatment cycle, with a target of AUC = 6 mg. A dose of min/mL is administered to carboplatin a day for patients with advanced and/or metastatic solid tumors (dosage regimen IX).
本發明之另一目標係關於一種治療罹患晚期及/或轉移性實體腫瘤之患者之方法，其特徵在於：a)在一個14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30或31天之治療週期中於一天投與350 mg沃拉色替或其醫藥上可接受鹽或其水合物，及b)在相同治療週期中於一天以目標AUC=5 mg．min/mL之劑量投與卡鉑，給罹患晚期及/或轉移性實體腫瘤之患者(劑量方案X)。 Another object of the invention relates to a method of treating a patient suffering from advanced and/or metastatic solid tumors, characterized in that a) is at 14, 15, 16, 17, 18, 19, 20, 21, 22, In a treatment cycle of 23, 24, 25, 26, 27, 28, 29, 30 or 31 days, 350 mg of voraxetatin or a pharmaceutically acceptable salt thereof or hydrate thereof is administered in one day, and b) in the same treatment In the cycle, the target AUC=5 mg. A dose of min/mL is administered to carboplatin for patients with advanced and/or metastatic solid tumors (dosage regimen X).
對於所有上述劑量方案而言，較佳治療週期係14、21或28天/治療週期，更佳係21天之治療週期。在該治療週期期間，沃拉色替及順鉑，或沃拉色替及卡鉑可於相同日或不同日投與。較佳係在相同日投與該等化合物。該等化合 物較佳係在相同日或在投與之間小間斷(約30 min)連續地投與。例如，作為第一藥劑投與順鉑或卡鉑，且於順鉑或卡鉑投與結束之30 min間斷後，投與沃拉色替。 For all of the above dosage regimens, the preferred treatment period is 14, 21 or 28 days/treatment period, more preferably 21 days of treatment. During this treatment cycle, voraxit and cisplatin, or voraxit and carboplatin can be administered on the same day or on different days. Preferably, the compounds are administered on the same day. These combinations Preferably, the materials are administered continuously on the same day or between small doses (about 30 minutes). For example, cisplatin or carboplatin is administered as the first agent, and after being interrupted for 30 minutes after the end of administration of cisplatin or carboplatin, Worachrome is administered.
卡鉑清除率之主要決定因素係腎小球濾過率(GFR)。GFR係腎功能之參數，且在年長患者中通常降低。應使用給藥配方合併GFR評估以提供可預知之卡鉑血漿AUCs，特別於年長患者，以使毒性之風險最小。 The primary determinant of carboplatin clearance is glomerular filtration rate (GFR). GFR is a parameter of renal function and is usually reduced in older patients. The dosing formulation should be combined with the GFR assessment to provide predictable carboplatin plasma AUCs, particularly in older patients, to minimize the risk of toxicity.
卡鉑藉由目標AUC給藥描述於當前藥品標籤中。基於患者腎小球濾過率(GFR，mL/min)及濃度對時間曲線下之卡鉑注射目標面積(AUC，mg/mL˙min)計算劑量之簡單公式係由卡爾弗特(Calvert)基於卡爾弗特公式提出，卡鉑劑量可如下計算：總卡鉑劑量(mg)=(目標AUC)×(GFR+25)[卡爾弗特公式] Carboplatin is described in the current drug label by administration of the target AUC. A simple formula for calculating the dose based on the patient's glomerular filtration rate (GFR, mL/min) and concentration versus carboplatin injection target area (AUC, mg/mL ̇min) is calculated by Calvert based on Karl. The Furt formula suggests that the carboplatin dose can be calculated as follows: total carboplatin dose (mg) = (target AUC) × (GFR + 25) [Calvert formula]
如果基於藉由IDMS(同位素稀釋質譜分析)方法測得之血清肌酐測量值評估患者之GFR，則FDA建議內科醫師考慮所需暴露(AUC)之卡鉑給藥上限，以避免由於如下過量給藥導致潛在的毒性：對於具有正常腎功能之患者而言，基於GFR評估，最大劑量之上限為125 mL/min。 If the patient's GFR is assessed based on serum creatinine measurements as measured by the IDMS (Isotope Dilution Mass Spectrometry) method, the FDA recommends that the physician consider the upper limit of the required exposure (AUC) of the carboplatin to avoid overdosing as follows. Lead to potential toxicity: For patients with normal renal function, the maximum dose limit is 125 mL/min based on GFR assessment.
對於目標AUC=6，最大劑量係6×150=900 mg。 For the target AUC=6, the maximum dose is 6 x 150 = 900 mg.
對於目標AUC=5，最大劑量係5×150=750 mg。 For the target AUC = 5, the maximum dose is 5 x 150 = 750 mg.
對於目標AUC=4，最大劑量係4×150=600 mg。 For the target AUC=4, the maximum dose is 4 x 150 = 600 mg.
本發明之另一目標係關於一種沃拉色替或其醫藥上可接受的鹽或其水合物於治療罹患晚期及/或轉移性實體腫瘤 之患者之晚期及/或轉移性實體腫瘤之用途，其特徵在於根據劑量方案I至X中之一者投與沃拉色替或其醫藥上可接受的鹽或其水合物。 Another object of the invention relates to a voraxetib or a pharmaceutically acceptable salt thereof or a hydrate thereof for the treatment of advanced and/or metastatic solid tumors Use of a late-stage and/or metastatic solid tumor of a patient characterized by administering voraxetatin or a pharmaceutically acceptable salt thereof or a hydrate thereof according to one of the dosage regimens I to X.
本發明之另一目標係關於一種順鉑於治療罹患晚期及/或轉移性實體腫瘤之患者之晚期及/或轉移性實體腫瘤之用途，其特徵在於根據劑量方案I至X中之一者投與順鉑。 Another object of the invention relates to the use of cisplatin for the treatment of advanced and/or metastatic solid tumors in patients with advanced and/or metastatic solid tumors, characterized in that one of dose regimens I to X is administered With cisplatin.
本發明之另一目標係關於一種卡鉑於治療罹患晚期及/或轉移性實體腫瘤之患者之晚期及/或轉移性實體腫瘤之用途，其特徵在於根據劑量方案I至X中之一者投與卡鉑。 Another object of the invention relates to the use of carboplatin for the treatment of advanced and/or metastatic solid tumors in patients with advanced and/or metastatic solid tumors, characterized in that one of dose regimens I to X is administered With carboplatin.
本發明之另一目標係關於一種沃拉色替或其醫藥上可接受的鹽或其水合物於製造用於治療罹患晚期及/或轉移性實體腫瘤之患者之晚期及/或轉移性實體腫瘤之藥物之用途，其中製備該藥物用於根據劑量方案I至X中之一者投與。 Another object of the invention relates to a voraxetib or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of advanced and/or metastatic solid tumors for the treatment of patients with advanced and/or metastatic solid tumors Use of the medicament, wherein the medicament is prepared for administration according to one of the dosage regimens I to X.
本發明之另一目標係關於一種順鉑或其醫藥上可接受的鹽或其水合物於製造用於治療罹患晚期及/或轉移性實體腫瘤之患者之晚期及/或轉移性實體腫瘤之藥物之用途，其中製備該藥物用於根據劑量方案I至X中之一者投與。 Another object of the invention relates to a cisplatin or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of a medicament for the treatment of advanced and/or metastatic solid tumors in patients suffering from advanced and/or metastatic solid tumors Use of the medicament for the administration according to one of the dosage regimens I to X.
本發明之另一目標係關於一種卡鉑或其醫藥上可接受的鹽或其水合物於製造用於治療罹患晚期及/或轉移性實體腫瘤之患者之晚期及/或轉移性實體腫瘤之藥物之用途，其中製備該藥物用於根據劑量方案I至X中之一者投與。 Another object of the invention relates to a carboplatin or a pharmaceutically acceptable salt thereof or a hydrate thereof for the manufacture of a medicament for the treatment of advanced and/or metastatic solid tumors in patients suffering from advanced and/or metastatic solid tumors Use of the medicament for the administration according to one of the dosage regimens I to X.
本發明之另一目標係一種醫藥組合物，其包含有效量之沃拉色替及有效量之順鉑及投與兩種活性組分給罹患晚期 及/或轉移性實體腫瘤之患者之說明書，其中根據該說明書，將根據上述劑量方案I至X中之一者投與沃拉色替及/或順鉑。 Another object of the invention is a pharmaceutical composition comprising an effective amount of voraxital and an effective amount of cisplatin and administering two active components to the late stage And/or instructions for a patient with a metastatic solid tumor, wherein according to the instructions, one of the above dosage regimens I to X is administered to voraxetine and/or cisplatin.
本發明之另一目標係一種醫藥組合物，其包含有效量之沃拉色替及有效量之卡鉑及投與兩種活性組分給罹患晚期及/或轉移性實體腫瘤之患者之說明書，其中根據該說明書，將根據上述劑量方案I至X中之一者投與沃拉色替及/或卡鉑。 Another object of the invention is a pharmaceutical composition comprising an effective amount of voraxital and an effective amount of carboplatin and instructions for administering the two active components to a patient suffering from advanced and/or metastatic solid tumors, According to this specification, voraxetine and/or carboplatin will be administered according to one of the above dosage regimens I to X.
本發明之另一目標係一種醫藥組合物，其包含有效量之沃拉色替及投與沃拉色替及順鉑給罹患晚期及/或轉移性腫瘤之患者之說明書，其中根據該說明書，將根據上述劑量方案I至X投與沃拉色替及順鉑。 Another object of the present invention is a pharmaceutical composition comprising an effective amount of voraxidine and a patient administering voraxit and cisplatin to a patient suffering from advanced and/or metastatic tumors, wherein according to the instructions, Wolachrome and cisplatin will be administered according to the above dosage regimens I to X.
本發明之另一目標係一種醫藥組合物，其包含有效量之沃拉色替及投與沃拉色替及卡鉑給罹患晚期及/或轉移性腫瘤之患者之說明書，其中根據該說明書，將根據上述劑量方案I至X投與沃拉色替及卡鉑。 Another object of the present invention is a pharmaceutical composition comprising an effective amount of voraxitamine and a patient administering voraxetine and carboplatin to a patient suffering from advanced and/or metastatic tumors, wherein according to the instructions, Wolachrome and carboplatin will be administered according to the above dosage regimens I to X.
本發明之另一目標係一種醫藥套組，其包含有效量沃拉色替之第一隔室及包含有效量順鉑之第二隔室，及投與兩種活性組分給罹患晚期及/或轉移性腫瘤之患者之說明書，其中根據該說明書，將根據上述劑量方案I至X中之一者投與沃拉色替及順鉑。 Another object of the invention is a medical kit comprising an effective amount of a first compartment of voraxit and a second compartment comprising an effective amount of cisplatin, and administering two active components to the late stage and/or Or instructions for a patient having a metastatic tumor, wherein according to the instructions, one of the above dosage regimens I to X is administered to voraxit and cisplatin.
本發明之另一目標係一種醫藥套組，其包含有效量沃拉色替之第一隔室及包含有效量卡鉑之第二隔室，及投與兩種活性組分給罹患晚期及/或轉移性腫瘤之患者之說明 書，其中根據該說明書，將根據上述劑量方案I至X中之一者投與沃拉色替及卡鉑。 Another object of the invention is a medical kit comprising an effective amount of a first compartment of voraxit and a second compartment comprising an effective amount of carboplatin, and administering two active components to the late stage and/or Or instructions for patients with metastatic tumors The book, according to which one of the above dosage regimens I to X, will be administered to voraxetine and carboplatin.
該治療週期可重複，只要患者適合重複週期，即直到疾病進展或不可接受之毒性為止，且只要患者或研究人員不要求治療停止。 This treatment cycle can be repeated as long as the patient is suitable for a repeating cycle, ie until disease progression or unacceptable toxicity, and as long as the patient or researcher does not require treatment to stop.
如果需要停止鉑治療，則該患者可轉變為沃拉色替單療法。 If platinum therapy needs to be stopped, the patient can be converted to voraxine monotherapy.
該投與說明書可以呈任何適於醫藥之形式，例如，呈二次包裝內添加至劑型之活頁形式，或在一次及二次包裝上之壓印。 The instructions for administration may be in any form suitable for the pharmaceutical, for example, in the form of a leaflet that is added to the dosage form in a secondary package, or embossed on primary and secondary packaging.
對於靜脈內治療，可以300至500 mg/應用，較佳300或350 mg/應用之日劑量，投與沃拉色替給人類患者。例如，可以歷時若干小時，例如，歷時約1、2、4、6、10、12或24小時，較佳約1或2小時之緩慢靜脈輸注形式投與沃拉色替。 For intravenous therapy, a dose of 300 to 500 mg per application, preferably 300 or 350 mg per day, can be administered to a human patient. For example, voraxetine can be administered over a period of several hours, for example, a slow intravenous infusion of about 1, 2, 4, 6, 10, 12 or 24 hours, preferably about 1 or 2 hours.
然而，可視情況需要不同於針對沃拉色替所規定之劑量，其取決於體重或投與方法、對該藥物之個體反應、所使用之調配物之性質及投藥時間或投與間隔時間。因此，在一些情形中，使用少於上述所規定之最小用量可能為足夠，而在其他情形中將必須超過所規定之上限。當投與大量時，建議一天分成多次單劑量分散投與。 However, it may be desirable to differ from the dose prescribed for voraxine, depending on the weight or method of administration, the individual response to the drug, the nature of the formulation used, and the time of administration or duration of administration. Thus, in some cases, it may be sufficient to use less than the minimum amount specified above, while in other cases it will have to exceed the specified upper limit. When a large amount is administered, it is recommended to divide the single dose into multiple doses for one day.
關於本發明之任何態樣，可使用沃拉色替醫藥上可接受 的鹽或其水合物，較佳係如WO 07/090844中所揭示之三鹽酸鹽形式及其水合物形式。本發明之內容中所提供之活性物之劑量或用量在任何情況下係指游離鹼等效物，意即呈游離鹼形式之沃拉色替。 With respect to any aspect of the invention, Worachrome can be used as a pharmaceutically acceptable The salt or hydrate thereof is preferably in the form of the trihydrochloride salt as disclosed in WO 07/090844 and its hydrated form. The dose or amount of the active agent provided in the context of the present invention is in any case a free base equivalent, meaning that it is in the form of the free base.
術語「治療上有效量」應意指將引起研究者或臨床醫師正尋求之組織系統、動物或人類之生物學或醫學反應之藥物或醫藥製劑之用量，從而導致至少統計上顯著部份之患者之有利影響，如改良症狀、治療、減少疾病負擔、減少腫瘤質量、延長生命、或提高生活品質。對於沃拉色替而言，在本發明之含義內之治療上有效量係每天投與300至500 mg。對於順鉑而言，在本發明之含義內之治療上有效量係每天投與50至100 mg/m2 BSA。對於卡鉑而言，在本發明之含義內之治療上有效量係根據卡爾弗特公式計算：總卡鉑劑量(mg)=(目標AUC)×(GFR+25)[卡爾弗特公式]。 The term "therapeutically effective amount" shall mean the amount of a drug or pharmaceutical preparation that will cause a biological or medical response to the tissue system, animal or human being sought by the researcher or clinician, resulting in at least a statistically significant portion of the patient. The beneficial effects, such as improving symptoms, treatment, reducing the burden of disease, reducing tumor quality, prolonging life, or improving the quality of life. For voraxit, a therapeutically effective amount within the meaning of the present invention is administered from 300 to 500 mg per day. For cisplatin, a therapeutically effective amount within the meaning of the present invention is administered 50 to 100 mg/m 2 of BSA per day. For carboplatin, the therapeutically effective amount within the meaning of the present invention is calculated according to the Calvert formula: total carboplatin dose (mg) = (target AUC) x (GFR + 25) [Calvert formula].
例如，21天之治療週期之第1天係定義為投與沃拉色替之第一劑量之日子。 For example, the first day of the 21 day treatment cycle is defined as the day on which the first dose of voraxine is administered.
術語「晚期及/或轉移性實體腫瘤」係定義為組織學上或細胞學上所確認診斷之晚期，不可切除及/或轉移性復發或難治療之實體惡性腫瘤，其對於標準療法無效或針對其不存在證明有效之療法。 The term "late-stage and/or metastatic solid tumor" is defined as a late stage, unremovable and/or metastatic relapse or refractory solid malignancy that is confirmed by histological or cytological diagnosis, which is ineffective or targeted for standard therapy. There is no proven cure.
根據本發明，可藉由非經腸(例如，肌肉內、腹膜內、靜脈內、透皮或皮下注射)，較佳係靜脈內應用，投與沃拉色替、順鉑及卡鉑，且其可單獨或一起調配成適宜劑量單位調配物，其含有適於各種投與路徑之習知無毒醫藥上 可接受之載劑、佐劑及媒劑。本發明中適宜之兩種活性物之劑型及調配物係相關技術中已知。例如，此等劑型及調配物包括WO 2006/018221中針對沃拉色替所揭示之彼等。 According to the present invention, voraxetib, cisplatin and carboplatin can be administered parenterally (for example, intramuscularly, intraperitoneally, intravenously, transdermally or subcutaneously), preferably intravenously, and They can be formulated individually or together into a suitable dosage unit formulation containing conventional non-toxic pharmaceuticals suitable for various routes of administration. Acceptable carriers, adjuvants and vehicles. Dosage forms and formulations of two active agents suitable for use in the present invention are known in the art. For example, such dosage forms and formulations include those disclosed in WO 2006/018221 for Worachrome.
以下實例用於說明本發明而非限制其。 The following examples are intended to illustrate the invention and not to limit it.
3至6例患者(pts)之連續同年齡組在每3週之第1天接受沃拉色替(V)與順鉑(Cis)(A組)或卡鉑(Ca)(B組)之組合之單次2小時注射。提供Cis及Ca至多6個週期(Cy)，V係持續直到疾病進展或不可接受之毒性。 The consecutive same age group of 3 to 6 patients (pts) received voraxetine (V) and cisplatin (Cis) (group A) or carboplatin (Ca) (group B) on the first day of every 3 weeks. A single 2 hour injection of the combination. Cis and Ca are provided for up to 6 cycles (Cy), and the V system continues until disease progression or unacceptable toxicity.
46例患者已接受與順鉑或卡鉑組合之沃拉色替。在罹患晚期/轉移性實體腫瘤之患者中，與順鉑或卡鉑組合之沃拉色替之最大耐受劑量係約300 mg。患者已接受1至16週期之沃拉色替治療，其中中值(範圍)為3(1，6)週期與順鉑組合，及2(1，6)週期與卡鉑組合。 Forty-six patients have received voraxine in combination with cisplatin or carboplatin. In patients with advanced/metastatic solid tumors, the maximum tolerated dose of voraxidine in combination with cisplatin or carboplatin is approximately 300 mg. The patient has been treated with 1 to 16 cycles of voraxine treatment with a median (range) of 3 (1,6) cycles in combination with cisplatin and a 2 (1,6) cycle in combination with carboplatin.
已觀察到四例部份反應(PR)：A組中兩例罹患CHOP抗性囊狀樹枝狀網狀細胞肉瘤之患者(劑量水平[DL]A2，A4)，B組中一例罹患重度預治療之頭頸癌者(DL B4)，及一例罹患已預治療之肺癌之患者(DL A5)。 Four partial reactions (PR) have been observed: two patients in group A who had CHOP-resistant saccular dendritic cytoplasmic sarcoma (dose level [DL] A2, A4), and one patient in group B had severe pre-treatment Head cancer (DL B4), and a patient with pre-treated lung cancer (DL A5).
-一例罹患樹枝狀網狀細胞肉瘤之患者(DL A2)達成PR，保持治療直到由於進展性疾病(PD)在第15週期結束時停止。 - A patient with a dendritic cytopathic sarcoma (DL A2) achieved PR and maintained treatment until stopped at the end of the 15th cycle due to progressive disease (PD).
-另一例罹患樹枝狀網狀細胞肉瘤之患者(DL A4；由於發熱性嗜中性球減少症，自第15週期後沃拉色替劑量減至200 mg)，在首次評估時具有穩定疾病(SD)，且在第二次評估時相關腫瘤縮小。該患者在第4週期達成PR，且保持治療到第16週期。 - Another patient with dendritic reticulum sarcoma (DL A4; due to febrile neutropenia, reduced to a dose of 200 mg from the first dose after the 15th cycle), with stable disease in the first assessment ( SD), and the relevant tumor shrinks during the second assessment. The patient achieved PR at cycle 4 and maintained treatment until cycle 16.
-一例罹患咽喉癌之患者(DL B4；由於第1週期中DLT，第2週期中沃拉色替劑量減至200 mg)在第2週期中達成PR，其在第4週期中被確認。該患者繼續具有PR到第12週期。 - A patient with squamous cell carcinoma (DL B4; due to DLT in the first cycle, the dose of Worachrome in the second cycle was reduced to 200 mg) reached PR in the second cycle, which was confirmed in the fourth cycle. The patient continues to have PR to the 12th cycle.
-一例患有肺腺癌之患者(DL A5)在第4週期接受治療，在第2週期已達成PR，其有待確認。 - A patient with lung adenocarcinoma (DL A5) was treated in the fourth cycle, and a PR was reached in the second cycle, which is yet to be confirmed.
此等結果證明，根據劑量方案I至X，沃拉色替與順鉑或沃拉色替與卡鉑之組合投與之有利影響。 These results demonstrate that, depending on the dosage regimen I to X, the combination of voraxine and cisplatin or voraxine and carboplatin has a beneficial effect.
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