TW202038964A - Combination therapy - Google Patents

Combination therapy Download PDF

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TW202038964A
TW202038964A TW108147073A TW108147073A TW202038964A TW 202038964 A TW202038964 A TW 202038964A TW 108147073 A TW108147073 A TW 108147073A TW 108147073 A TW108147073 A TW 108147073A TW 202038964 A TW202038964 A TW 202038964A
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pharmaceutically acceptable
acceptable salt
inhibitor
cancer
combination
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吉歐丹諾 卡伯尼吉洛
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瑞士商諾華公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor as defined herein, or a pharmaceutically acceptable salt thereof and (b) a CKD4/6 inhibitor, particularly ribociclib, particularly for use in the treatment of a proliferative disease. This invention also relates to uses of such combination for preparation of a medicament for the treatment of a proliferative disease; methods of treating a proliferative disease in a subject in need thereof comprising administering to said subject a jointly therapeutically effective amount of said combination; use of such combination for the treatment of proliferative disease; pharmaceutical compositions comprising such combination and commercial packages thereto.

Description

組合療法 Combination therapy

本發明關於藥物組合，該組合包含(a)Raf抑制劑，該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受鹽；和(b)CDK4/6抑制劑，特別是瑞博西尼(ribociclib)或其藥學上可接受的鹽。 The present invention relates to a pharmaceutical combination comprising (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein; and (b) a CDK4/6 inhibitor, particularly It is ribociclib or a pharmaceutically acceptable salt thereof.

本發明還關於用於在癌症的治療中使用的此類組合；關於此類組合用於製備治療癌症的藥物之用途；關於在有需要的受試者中治療癌症之方法，該等方法包括向所述受試者投與聯合治療有效量的所述組合；關於此類組合用於治療癌症之用途；還關於包含此類組合的藥物組成物。 The present invention also relates to such combinations for use in the treatment of cancer; regarding the use of such combinations for the preparation of drugs for the treatment of cancer; regarding methods for treating cancer in subjects in need, the methods include The subject is administered a combination therapy effective amount of the combination; regarding the use of such combination for the treatment of cancer; and also regarding the pharmaceutical composition comprising such combination.

本發明還關於本文定義的具有式(I)之化合物或其藥學上可接受的鹽，用於在與CDK4/6抑制劑(特別是瑞博西尼)或其藥學上可接受的鹽的組合療法中使用。本文還提供CDK4/6抑制劑，特別是瑞博西尼，或其藥學上可接受的鹽，用於在與本文定義的具有式(I)之化合物或其藥學上可接受的鹽的組合療法中使用。 The present invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, for use in combination with a CDK4/6 inhibitor (especially Rebocinil) or a pharmaceutically acceptable salt thereof Used in therapy. Also provided herein are CDK4/6 inhibitors, particularly Reboxinil, or a pharmaceutically acceptable salt thereof, for use in combination therapy with a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein Used in.

超過30%的人類癌症攜帶絲裂原活化蛋白激酶(MAPK)途徑中的突變，其中最普遍的是RAS或BRAF突變。MAPK途徑(也稱為RAS/RAF/CDK4/6/ERK途徑)係驅動細胞增殖、分化和存活的關鍵訊號級聯反 應。該途徑的失調係許多腫瘤發生包括黑色素瘤實例的基礎(Kirkwood等人，Clin Cancer Res[臨床癌症研究]18(2)：555-67,2012)。該途徑包括RAS小胍三磷酸酶(GTP酶)，當RAS小胍三磷酸酶被激活時，可以促進RAF家族蛋白(ARAF、BRAF和CRAF，也稱為RAF1)的激活。激活的RAF蛋白導致CDK4/61/2蛋白的磷酸化和激活，該等磷酸化和激活的CDK4/61/2蛋白隨後使胞外訊號調節的激酶(ERK)磷酸化並將其激活。ERK使多種底物(包括多個轉錄因子)磷酸化，並調節數種關鍵的細胞活性(包括增殖、分化、遷移、存活和血管生成)。此外，RAS或BRAF突變組成性激活細胞週期蛋白D-CDK4/6複合體，其中它們與CDK4活化作用協同並導致腫瘤進展(Chudnovsky Y等人2005；Monahan KB等人2010)。 More than 30% of human cancers carry mutations in the mitogen-activated protein kinase (MAPK) pathway, the most common of which are RAS or BRAF mutations. The MAPK pathway (also known as the RAS/RAF/CDK4/6/ERK pathway) is a cascade of key signals that drive cell proliferation, differentiation and survival. should. Disregulation of this pathway is the basis of many tumorigenesis including melanoma examples (Kirkwood et al., Clin Cancer Res 18(2):555-67, 2012). This pathway includes RAS small guanidine triphosphatase (GTPase). When RAS small guanidine triphosphatase is activated, it can promote the activation of RAF family proteins (ARAF, BRAF and CRAF, also known as RAF1). The activated RAF protein causes the phosphorylation and activation of the CDK4/61/2 protein, and the phosphorylated and activated CDK4/61/2 protein then phosphorylates and activates the extracellular signal-regulated kinase (ERK). ERK phosphorylates multiple substrates (including multiple transcription factors) and regulates several key cell activities (including proliferation, differentiation, migration, survival, and angiogenesis). In addition, RAS or BRAF mutations constitutively activate the cyclin D-CDK4/6 complex, where they cooperate with CDK4 activation and lead to tumor progression (Chudnovsky Y et al. 2005; Monahan KB et al. 2010).

在黑色素瘤中，MAPK途徑的蛋白的激活性突變頻率很高。RAS突變型黑色素瘤表現出侵襲性行為，在初次診斷時已經存在高肝和腦轉移率(Bergamasco等人，Value in Health Journal[健康價值期刊]19 A347-A766,2016)並且因此預後較差。對標準化療治療的反應非常有限。一項3期研究表明，與使用達卡巴嗪(dacarbazine)的標準化療治療相比，CDK4/6抑制劑貝美替尼(Binimetinib)有一些益處，例如整體反應率從7%改善至15%。402名患者以2：1的方式隨機分配。已經觀察到中值PFS為2.8(95% CI：2.8-3.6)對比1.5(1.5-1.7)，HR 0.62(0.47-0.80)，支持貝美替尼。然而，懷疑與研究藥物相關的不良事件導致的停藥率很高(20%對比5%)，並且PFS中的益處並沒有轉化為總體存活率的改善(11.0(95% CI：8.9-13.6)個月對比10.1(7.0-16.5)個月)(Dummer等人，Lancet Oncol[柳葉刀腫瘤學]18(4)：435-445,2017)。 In melanoma, the frequency of activating mutations in MAPK pathway proteins is high. RAS mutant melanoma exhibits aggressive behavior, has high liver and brain metastasis rates at the time of initial diagnosis (Bergamasco et al., Value in Health Journal 19 A347-A766, 2016) and therefore has a poor prognosis. The response to standard chemotherapy treatments is very limited. A phase 3 study showed that compared with standard chemotherapy treatment with dacarbazine, the CDK4/6 inhibitor Binimetinib has some benefits, such as an improvement in the overall response rate from 7% to 15%. 402 patients were randomly assigned in a 2:1 manner. It has been observed that the median PFS is 2.8 (95% CI: 2.8-3.6) vs. 1.5 (1.5-1.7), and the HR is 0.62 (0.47-0.80), which supports bemetinib. However, it is suspected that adverse events related to the study drug resulted in a high discontinuation rate (20% vs. 5%), and the benefits in PFS did not translate into an improvement in overall survival (11.0 (95% CI: 8.9-13.6) Months versus 10.1 (7.0-16.5) months) (Dummer et al., Lancet Oncol [The Lancet Oncol] 18(4): 435-445, 2017).

NRAS基因在15%-20%的黑色素瘤(相對常見的黑色素瘤亞型)中發生了突變。在黑色素瘤中，NRAS中的大多數激活性變異都發生在密碼子61上，而密碼子12和13上的變異發生頻率較低(Gao等人，Sci Signal[科學訊號]，2013；van Elsas,Recent Results Cancer Res[癌症研究最新結果]，1995)。黑色素瘤中NRAS突變的存在導致MAPK訊號從BRAF轉換為CRAF，cAMP訊號開始失調，這允許CRAF向CDK4/6發出訊號(Dumaz 2006)。NRAS中的突變不包括PTEN中的改變，這意味著僅NRAS中的突變可以激活MAPK和PI3K途徑的傳訊(Goel等人，J Invest Dermatol[皮膚病學研究雜誌]6(269)：pl1,2006,Davies等人，Clin Cancer Res[臨床癌症研究]15(24)：7538-46,2009)。與其他黑色素瘤亞型相比，具有NRAS突變的黑色素瘤與預後較差相關聯(Devitt等人，Pigment Cell Melanoma Res[色素細胞和黑色素瘤研究]24(4)：666-72,2011)，並且對標準化療治療的反應非常有限。 The NRAS gene is mutated in 15%-20% of melanomas (a relatively common subtype of melanoma). In melanoma, most of the activating mutations in NRAS occur at codon 61, while the mutations at codons 12 and 13 occur less frequently (Gao et al., Sci Signal [科学信], 2013; van Elsas ,Recent Results Cancer Res[The latest results of cancer research], 1995). The presence of NRAS mutations in melanoma causes the MAPK signal to switch from BRAF to CRAF, and the cAMP signal becomes dysregulated, which allows CRAF to signal CDK4/6 (Dumaz 2006). Mutations in NRAS do not include changes in PTEN, which means that only mutations in NRAS can activate MAPK and PI3K pathways (Goel et al., J Invest Dermatol [Journal of Dermatology Research] 6(269): pl1, 2006 , Davies et al., Clin Cancer Res [Clinical Cancer Research] 15(24): 7538-46, 2009). Compared with other melanoma subtypes, melanoma with NRAS mutations is associated with a worse prognosis (Devitt et al. Pigment Cell Melanoma Res 24(4):666-72, 2011), and The response to standard chemotherapy treatments is very limited.

在胰臟癌中頻繁發現KRAS突變(di Magliano MP & Logsdon CD,Gastroenterology[胃腸病學]2013；144(6)：1220-9)。對PDAC患者樣本的研究表明，所有樣本的93%具有KRAS突變(Biankin等人.Nature[自然]2012；491,399-405)。KRAS具有與NRAS相同的下游效應子。但是，在NRAS和KRAS突變型癌症中仍然存在高度未滿足的醫療需求。 KRAS mutations are frequently found in pancreatic cancer (di Magliano MP & Logsdon CD, Gastroenterology [Gastroenterology] 2013; 144(6): 1220-9). A study of samples from PDAC patients showed that 93% of all samples had KRAS mutations (Biankin et al. Nature [Natural] 2012; 491,399-405). KRAS has the same downstream effectors as NRAS. However, there are still highly unmet medical needs in NRAS and KRAS mutant cancers.

NRAS的選擇性藥理抑制仍然存在技術上的挑戰性，因為迄今為止，針對其GTP酶活性一直未能成功設計出特異性小分子拮抗劑。Muñoz-Couselo E，等人，OncoTargets and Therapy[腫瘤靶標和療法]，2017：10第3941-3947頁提示與MEK抑制劑和免疫療法組合係最有希望的策略。然而，當前方法的有效性尚未確定。 The selective pharmacological inhibition of NRAS is still technically challenging, because so far, specific small molecule antagonists have not been successfully designed for its GTPase activity. Muñoz-Couselo E, et al., OncoTargets and Therapy, 2017:10, pages 3941-3947 suggest that the combination of MEK inhibitors and immunotherapy is the most promising strategy. However, the effectiveness of the current method has not been determined.

最近有報導稱，泛Raf抑制劑LY3009120與CDK4/6抑制劑阿貝西利(abcmaciclib)組合抑制某些具有KRAS或BRAF突變的腫瘤細胞的增殖(Chen SH等人，Oncogene[致癌基因]，2018,37,821-832)。然而，LY3009120抑制幾種其他激酶，包括在癌症中具有重要作用的激酶，如肝配蛋白(Ephrin)受體、JNK和SRC家族成員，因此有可能導致脫靶毒性。 It has recently been reported that the combination of the pan-Raf inhibitor LY3009120 and the CDK4/6 inhibitor abcmaciclib (abcmaciclib) inhibits the proliferation of certain tumor cells with KRAS or BRAF mutations (Chen SH et al., Oncogene [oncogene], 2018, 37,821-832). However, LY3009120 inhibits several other kinases, including kinases that play an important role in cancer, such as Ephrin receptors, JNK and SRC family members, and therefore may cause off-target toxicity.

因此，靶向RAS突變型癌症(包括NRAS突變型黑色素瘤和KRAS胰腺導管腺癌(PDAC))的有效療法存在未滿足的醫療需求。 Therefore, there is an unmet medical need for effective therapies that target RAS mutant cancers, including NRAS mutant melanoma and KRAS pancreatic ductal adenocarcinoma (PDAC).

已經發現，CDK4/6抑制劑瑞博西尼與選擇性Raf抑制劑如具有式(I)之化合物組合在體外協同抑制腫瘤細胞。該組合還導致衍生自患者的黑色素瘤異種移植，特別是NRAS突變型黑色素瘤異種移植的顯著腫瘤消退，並增加了臨床前模型中的中值存活百分比。 It has been found that the combination of the CDK4/6 inhibitor Ribocinil and the selective Raf inhibitor such as the compound of formula (I) synergistically inhibit tumor cells in vitro. The combination also resulted in significant tumor regression of melanoma xenografts derived from patients, especially NRAS mutant melanoma xenografts, and increased the median survival percentage in preclinical models.

在衍生自患者的腫瘤異種移植中，與單一藥劑相比，具有式(I)之化合物和瑞博西尼組合治療的耐受性很好並導致增加的抗腫瘤活性。該等數據指示，在患有RAS突變型癌症(如黑色素瘤)，特別是NRAS突變型癌症，更具體地是NRAS突變型黑素瘤的患者中，具有式(I)之化合物和瑞博西尼的組合活性可以實現更大和更持久的反應。重要的是，當將具有式(I)之化合物和瑞博西尼用作單一藥劑時引起很小的作用相同劑量在兩種藥劑組合時引起很大的作用。 In tumor xenotransplantation derived from patients, the combination therapy of the compound of formula (I) and reboxinil is well tolerated and leads to increased anti-tumor activity compared to a single agent. These data indicate that in patients with RAS mutant cancers (such as melanoma), especially NRAS mutant cancers, more specifically NRAS mutant melanoma, the compound of formula (I) and Reboxi The combined activity of nigra can achieve a larger and longer lasting response. What is important is that when the compound of formula (I) and ribocinil are used as a single agent, they cause a small effect. The same dose causes a large effect when the two agents are combined.

因此，具有式(I)之化合物與CDK4/6抑制劑(尤其是瑞博西尼)或其藥學上活性的鹽的組合可在具有激活的MAPK途徑(特別是NRAS突變型癌症，如NRAS突變型黑色素瘤或KRAS突變型癌症，如KRAS突變型胰腺導管腺癌 (PDAC))的患者中可以實現更大和更持久的反應。組合療法還可以提供較少的副作用和/或使需要其的患者更耐受。 Therefore, the combination of a compound of formula (I) and a CDK4/6 inhibitor (especially ribocinil) or a pharmaceutically active salt thereof can be used in an activated MAPK pathway (especially NRAS mutant cancers, such as NRAS mutations). Type melanoma or KRAS mutant cancer, such as KRAS mutant pancreatic ductal adenocarcinoma (PDAC)) can achieve a larger and longer-lasting response in patients. Combination therapy can also provide fewer side effects and/or be more tolerated by patients in need.

具有式(I)之化合物(選擇性Raf抑制劑)與CDK4/6抑制劑(瑞博西尼)也可以優化NRAS突變型黑色素瘤中MAPK訊號的抑制。具有式(I)之化合物和瑞博西尼的組合也可以說明預防在NRAS突變型黑色素瘤或KRAS突變型PDAC中出現對BRAF和CDK4/6(絲裂原活化蛋白激酶激酶)抑制劑的組合的抗性。 Compounds of formula (I) (selective Raf inhibitors) and CDK4/6 inhibitors (ribocinil) can also optimize the suppression of MAPK signals in NRAS mutant melanoma. The combination of the compound of formula (I) and Rebocinil can also be illustrated to prevent the combination of BRAF and CDK4/6 (mitogen activated protein kinase kinase) inhibitors in NRAS mutant melanoma or KRAS mutant PDAC Resistance.

對於NRAS突變型黑色素瘤患者，目前尚無靶向療法可用於臨床研究。Raf抑制劑和CDK4/6抑制劑的協同組合可以在患有NRAS突變型癌症特別是NRAS突變型黑色素瘤的患者中發揮強大的臨床益處。 For patients with NRAS mutant melanoma, there is currently no targeted therapy available for clinical research. The synergistic combination of Raf inhibitors and CDK4/6 inhibitors can exert powerful clinical benefits in patients with NRAS mutant cancers, especially NRAS mutant melanoma.

因此，本發明提供了Raf抑制劑和CDK4/6抑制劑之藥物組合，其中Raf抑制劑係具有式(I)之化合物， Therefore, the present invention provides a drug combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is a compound of formula (I),

Figure 108147073-A0202-12-0005-2
或其藥學上可接受的鹽。
Figure 108147073-A0202-12-0005-2
 Or a pharmaceutically acceptable salt thereof.

在另一方面，本發明提供了Raf抑制劑和CDK4/6抑制劑之藥物組合，其中CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 In another aspect, the present invention provides a drug combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof.

在另一方面，本發明提供了Raf抑制劑和CDK4/6抑制劑之藥物組合，其中 In another aspect, the present invention provides a drug combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein

(i)Raf抑制劑係具有式(I)之化合物或其藥學上可接受的鹽；以及 (i) The Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; and

(ii)CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 (ii) The CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof.

在另一方面，本發明提供了用於在癌症的治療中使用的該等藥物組合。 In another aspect, the present invention provides such drug combinations for use in the treatment of cancer.

本發明特別關於用於在癌症的治療中使用的本發明組合，該癌症的特徵在於MAPK途徑中的激活性突變，並且特別是NRAS或KRAS中的一個或多個突變。特別地，本發明的組合可以用於黑色素瘤的治療，特別是NRAS突變型黑色素瘤。而且，本發明的組合可以用於胰臟癌的治療，特別是KRAS突變型PDAC。 The present invention particularly relates to the combination of the invention for use in the treatment of cancer, which is characterized by activating mutations in the MAPK pathway, and in particular one or more mutations in NRAS or KRAS. In particular, the combination of the present invention can be used for the treatment of melanoma, especially NRAS mutant melanoma. Moreover, the combination of the present invention can be used for the treatment of pancreatic cancer, especially KRAS mutant PDAC.

本發明提供了藉由與CDK4/6抑制劑，例如瑞博西尼或其藥學上可接受的鹽共同投與用於治療癌症的具有式(I)之化合物。 The present invention provides a compound of formula (I) for the treatment of cancer by co-administering with a CDK4/6 inhibitor, such as reboxinil or a pharmaceutically acceptable salt thereof.

本發明還提供了藉由與具有式(I)之化合物或其藥學上可接受的鹽共同投與用於治療癌症的瑞博西尼或其藥學上可接受的鹽。 The present invention also provides reboxinil or a pharmaceutically acceptable salt thereof for the treatment of cancer by co-administering with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

在另一方面，本發明提供了Raf抑制劑(其為具有式(I)之化合物)和CDK4/6抑制劑的藥物組合在製備用於治療癌症的藥物中之用途。 In another aspect, the present invention provides the use of a drug combination of a Raf inhibitor (which is a compound of formula (I)) and a CDK4/6 inhibitor in the preparation of a medicament for the treatment of cancer.

在另一方面，本發明提供了一種在有需要的受試者中治療癌症之方法，該方法包括向有需要的受試者投與治療有效量的Raf抑制劑(其為具有式(I)之化合物)和CDK4/6抑制劑的藥物組合。 In another aspect, the present invention provides a method of treating cancer in a subject in need, the method comprising administering to the subject in need a therapeutically effective amount of a Raf inhibitor (which is of formula (I) The compound) and CDK4/6 inhibitor drug combination.

本發明還提供了治療癌症之方法，該方法包括同時地、單獨地或順序地向有需要的受試者投與本發明的組合，該組合的量對於所述癌症具有聯合治療有效性。 The present invention also provides a method of treating cancer, which comprises administering the combination of the present invention to a subject in need at the same time, individually or sequentially, and the amount of the combination has a combined therapeutic effect on the cancer.

本發明還提供了藥物組成物或組合製劑，其包含一定量的本發明組合(該量對癌症具有聯合治療有效性)，以及視需要至少一種藥學上可接受的載體。 The present invention also provides a pharmaceutical composition or a combined preparation, which contains a certain amount of the combination of the present invention (the amount has a combined therapeutic effect on cancer), and at least one pharmaceutically acceptable carrier as needed.

本發明還提供了用於在癌症的治療中使用的組合製劑，該組合製劑包含(a)一個或多個劑量單位的Raf抑制劑，該Raf抑制劑選自由以下組成的組： (i)有式(I)之化合物或其藥學上可接受的鹽；以及(b)一個或多個劑量單位的CDK4/6抑制劑(較佳的是瑞博西尼)或其藥學上可接受的鹽。 The present invention also provides a combination preparation for use in the treatment of cancer, the combination preparation comprising (a) one or more dosage units of a Raf inhibitor, the Raf inhibitor being selected from the group consisting of: (i) a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) one or more dosage units of a CDK4/6 inhibitor (preferably ribocinil) or a pharmaceutically acceptable salt thereof Accepted salt.

本發明還提供了商業包裝物，該商業包裝物包含作為活性成分的本發明的組合和用於向有需要的患者同時、分開或順序投與本發明的組合的說明書，用於治療癌症如黑色素瘤，以及特別是NRAS突變型黑色素瘤或胰臟癌如KRAS突變型PDAC。 The present invention also provides a commercial package containing the combination of the present invention as an active ingredient and instructions for simultaneous, separate or sequential administration of the combination of the present invention to patients in need, for the treatment of cancer such as melanin Tumors, and especially NRAS mutant melanoma or pancreatic cancer such as KRAS mutant PDAC.

下面進一步詳細描述了本發明的各個方面。另外的定義在整個申請書中陳述。 Various aspects of the present invention are described in further detail below. Additional definitions are stated throughout the application.

具有式(I)之化合物在本文中也稱作「LXH254」或「NVP-LXH254」。瑞博西尼在本文中稱作「LEE011」或「NVP-LEE011」。 The compound of formula (I) is also referred to herein as "LXH254" or "NVP-LXH254". Ribosini is referred to as "LEE011" or "NVP-LEE011" in this article.

[圖1]：在SK-MEL-30黑色素瘤細胞系中，相對於單一處理，具有式(I)之化合物和瑞博西尼的組合在抗增殖和pho-Rb抑制作用中的影響[Figure 1]: In the SK-MEL-30 melanoma cell line, the effect of the combination of the compound of formula (I) and reboxinil on the anti-proliferation and pho-Rb inhibitory effects relative to single treatment

(圖1a、圖1b、圖1c)顯示的是，在攜帶NRAS(Q61K)和BRAF(D287H)共同突變的SK-MEL-30黑色素瘤細胞系中，藉由CyQUANT®直接細胞增殖測定而測量的瑞博西尼與具有式(I)之化合物的組合的增殖抑制(圖1a)、Loewe(ADD)過量抑制(圖1b)、和生長抑制(GI)(圖1c)的組合矩陣。在所有情況下，沿著底行從左至右顯示出增加的瑞博西尼濃度，並且沿著最左列自下至上顯示出增加的具有式(I)之化合物的濃度。網格中的所有其餘點顯示了由對應於兩個軸上指示的單一藥劑濃度的兩種抑制劑的組合產生的抑制百分比。過量抑制矩陣顯示實驗值(左網格)相對於Loewe劑量可加性模型的預測值的過量抑制百分比，Loewe劑量可加性模型預測僅由劑量可加性引起的抑制(Lehar等 人，2009)。正數代表協同作用增強的區域，負數代表拮抗作用的區域。生長抑制(GI)測量基於使用附加的計時起點媒介物參考水平(添加藥物的時間點)歸一化實驗抑制測量。GI測量在兩個不同的線性歸一化比例部分上產生效果值，其中在計時起點(即在GI=100%)水平有一個「中斷點」。如果超過停滯點，GI值將>100%(Lehar等人，2009)。(圖1d)在SK-MEL-20細胞中用瑞博西尼和具有式(I)之化合物進行單一藥劑或組合處理後，磷酸化的RB1、CDK4/61/2、ERK1/2和RSK3的蛋白質印跡分析。在蛋白質印跡圖像上方注明了藥物處理，包括納莫耳濃度(nM)。所有樣本的藥物處理持續時間為48小時。每組圖板的右邊都注明了要探測的特定蛋白質。 (Figure 1a, Figure 1b, Figure 1c) shows the measurement of the SK-MEL-30 melanoma cell line with the co-mutation of NRAS (Q61K) and BRAF (D287H) by CyQUANT® direct cell proliferation assay Combination matrix of proliferation inhibition (FIG. 1 a ), Loewe (ADD) excess inhibition (FIG. 1 b ), and growth inhibition (GI) (FIG. 1 c) of the combination of Ribocinil and a compound of formula (I). In all cases, the increasing concentration of Rebosini is shown from left to right along the bottom row, and the increasing concentration of the compound of formula (I) is shown from bottom to top along the leftmost column. All remaining points in the grid show the percentage of inhibition produced by the combination of the two inhibitors corresponding to the single agent concentration indicated on the two axes. The excess inhibition matrix shows the percentage of excess inhibition of the experimental value (left grid) relative to the predicted value of the Loewe dose additivity model. The Loewe dose additivity model predicts the inhibition caused only by dose additivity (Lehar et al., 2009) . Positive numbers represent areas of enhanced synergy, and negative numbers represent areas of antagonism. The growth inhibition (GI) measurement is based on normalizing the experimental inhibition measurement using an additional timing starting vehicle reference level (time point of drug addition). The GI measurement produces effect values on two different linear normalized proportions, where there is a "break point" at the starting point of the timing (ie, at GI=100%). If the stagnation point is exceeded, the GI value will be >100% (Lehar et al., 2009). (Figure 1d) In SK-MEL-20 cells, the phosphorylated RB1, CDK4/61/2, ERK1/2 and RSK3 were treated with a single agent or a combination of Rebocinil and a compound of formula (I) Western blot analysis. The drug treatment, including nanomolar concentration (nM), is noted above the western blot image. The duration of drug treatment for all samples was 48 hours. The right side of each set of panels indicates the specific protein to be detected.

[圖2]：在IPC-298黑色素瘤細胞系中，相對於單一處理，具有式(I)之化合物和瑞博西尼的組合證實改善的抗增殖和pho-Rb抑制作用[Figure 2]: In the IPC-298 melanoma cell line, the combination of the compound of formula (I) and Reboxinil demonstrated improved anti-proliferation and pho-Rb inhibitory effects relative to single treatment

顯示的是NRAS突變型黑素瘤細胞系IPC298(NRASQ61L)中關鍵訊號蛋白的抗增殖作用(圖2a、圖2b、圖2c)和蛋白質分析(圖2d)。圖2a、圖2b、圖2c中的實驗方案和數據點如以上針對圖1所描述的。Shown are the anti-proliferative effects of key signaling proteins in the NRAS mutant melanoma cell line IPC298 (NRASQ61L) (Figure 2a, Figure 2b, Figure 2c) and protein analysis (Figure 2d). The experimental schemes and data points in Fig. 2a, Fig. 2b, and Fig. 2c are as described above for Fig. 1.

[圖3]：在Meljuso黑色素瘤細胞系中，相對於單一處理，具有式(I)之化合物和瑞博西尼的組合證實改善的抗增殖和pho-Rb抑制作用[Figure 3]: In the Meljuso melanoma cell line, the combination of the compound of formula (I) and Reboxinil demonstrated improved anti-proliferation and pho-Rb inhibitory effects relative to single treatment

顯示的是NRAS突變黑素瘤細胞系Meljuso(NRASQ61L)中關鍵訊號蛋白的抗增殖作用(圖3a、圖3b、和圖3c)和蛋白質分析(圖3d)。圖3a、圖3b、和圖3c中的實驗方案和數據點如以上針對圖1所描述的。Shown are the anti-proliferative effects of key signaling proteins in the NRAS mutant melanoma cell line Meljuso (NRASQ61L) (Figure 3a, Figure 3b, and Figure 3c) and protein analysis (Figure 3d). The experimental schemes and data points in Figure 3a, Figure 3b, and Figure 3c are as described above for Figure 1.

[圖4]：在Meljuso黑色素瘤細胞系中，相對於單一處理，具有式(I)之化合物和瑞博西尼的組合證實改善的抗增殖和pho-Rb抑制作用[Figure 4]: In the Meljuso melanoma cell line, the combination of the compound of formula (I) and reboxinil demonstrated improved anti-proliferation and pho-Rb inhibitory effects relative to single treatment

顯示的是NRAS突變黑素瘤細胞系SK-MEL-2(NRASQ61R)中關鍵訊號蛋白的抗增殖作用(圖4a、圖4b、和圖4c)和蛋白質分析(圖4d)。圖4a、圖4b、和圖4c中的實驗方案和數據點如以上針對圖1所描述的。Shown are the anti-proliferative effects of key signal proteins in the NRAS mutant melanoma cell line SK-MEL-2 (NRASQ61R) (Figure 4a, Figure 4b, and Figure 4c) and protein analysis (Figure 4d). The experimental schemes and data points in Figure 4a, Figure 4b, and Figure 4c are as described above for Figure 1.

[圖5]：具有式(I)之化合物和瑞博西尼在九個衍生自患者的NRASmut黑色素瘤腫瘤異種移植的小鼠模型中的抗腫瘤活性。[Figure 5]: Anti-tumor activity of the compound of formula (I) and Reboxinil in nine mouse models of NRASmut melanoma tumor xenografts derived from patients.

每個橫條圖代表在衍生自個體患者異種移植(PDX)模型中，每種處理所獲得的最佳反應(繪製為3-5隻小鼠/處理的平均值)。每種處理的模型按以下順序從左到右繪製：HMEX20864、HMEX20744、HMEX4339、HMEX5727、HMEX21124、HMEX3486、HMEX20667、HMEX20585、和HMEX2921。Each bar graph represents the best response (drawn as an average of 3-5 mice/treatment) for each treatment in a xenograft (PDX) model derived from an individual patient. The models for each treatment are drawn from left to right in the following order: HMEX20864, HMEX20744, HMEX4339, HMEX5727, HMEX21124, HMEX3486, HMEX20667, HMEX20585, and HMEX2921.

[圖6]：在具有式(I)之化合物、瑞博西尼的單一藥劑或兩者的組合的每日處理期間腫瘤達到700mm[Figure 6]: Tumor reaches 700 mm during daily treatment with a compound of formula (I), a single agent of Rebocinil or a combination of both 33 大小的卡普蘭-梅爾(Kaplan-Meier)時間圖Large and small Kaplan-Meier (Kaplan-Meier) time chart

當每個模型的平均腫瘤大小為350mmWhen the average tumor size of each model is 350mm 33 左右時開始處理，並且在研究持續期間所有動物都接受連續的每日藥物處理。當對動物處理>/=90天或腫瘤大小達到>/=700mmTreatment started around the time, and all animals received continuous daily drug treatment during the duration of the study. When treating animals >/=90 days or tumor size reaches >/=700mm 33 時，終止研究。與每種單一藥劑或未經處理的對照相比，組合組的存活曲線具有統計學意義[*p<0.05對數秩(曼特爾-考克斯(Mantel-Cox)檢驗)]。At that time, the study was terminated. Compared with each single agent or untreated control, the survival curve of the combination group was statistically significant [*p<0.05 log rank (Mantel-Cox test)].

本發明提供藥物組合，該組合包含(a)Raf抑制劑，該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受鹽；和(b)CDK4/6抑制劑，特別地用於癌症的治療。The present invention provides a pharmaceutical combination comprising (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein; and (b) a CDK4/6 inhibitor, particularly Used in the treatment of cancer.

如本文使用的，術語「Raf抑制劑」係指B-Raf蛋白激酶(本文也稱為b-RAF、BRAF或b-Raf)和C-Raf蛋白激酶(本文也稱為c-RAF、CRAF或c-Raf)的三磷酸腺苷(ATP)競爭性抑制劑。Raf抑制劑較佳的是抑制Raf單體和Raf二聚體兩者。As used herein, the term "Raf inhibitor" refers to B-Raf protein kinase (also referred to herein as b-RAF, BRAF or b-Raf) and C-Raf protein kinase (also referred to herein as c-RAF, CRAF or c-Raf) is a competitive inhibitor of adenosine triphosphate (ATP). The Raf inhibitor preferably inhibits both Raf monomer and Raf dimer.

具有式(I)之化合物具有以下結構： The compound of formula (I) has the following structure:

Figure 108147073-A0202-12-0010-3
Figure 108147073-A0202-12-0010-3

為方便起見，將該化合物及其鹽的組統稱為「具有式(I)之化合物」或「化合物(I)」，意指提及「具有式(I)之化合物」或「化合物(I)」將指可替代的任何化合物或其藥學上可接受的鹽。 For convenience, this group of compounds and their salts are collectively referred to as "compounds of formula (I)" or "compounds (I)", which means referring to "compounds of formula (I)" or "compounds (I) )" will refer to any compound or a pharmaceutically acceptable salt thereof that can be substituted.

Raf抑制劑即具有式(I)之化合物及其藥學上可接受的鹽描述於WO 2014/151616(藉由引用以其全文特此併入)中，並且其製備方法已描述於例如其中的實例1156中。具有式(I)之化合物係有效且選擇性的抑制劑，其在生化測定中以亞nM抑制濃度50%(IC50)值靶向BRAF和CRAF激酶兩者，同時以相似的程度抑制456種激酶中的僅兩種(盤狀蛋白結構域受體酪胺酸激酶1(DDR1)和血小板源生長因子受體，β多肽(PDGFRβ))的結合。已證明具有式(I)之化合物在多種MAPK途徑驅動的人癌細胞系和體內腫瘤異種移植中有效，該體內腫瘤異種移植包括在KRAS、NRAS和BRAF癌基因中攜帶活化損傷的模型。例如，具有式(I)之化合物對表現KRAS中的突變的人胰臟癌細胞系表現出低uM範圍的活性(參見WO/2018/203219 A1，實例1B，表2)。 Raf inhibitors, ie compounds of formula (I) and pharmaceutically acceptable salts thereof, are described in WO 2014/151616 (incorporated in its entirety by reference), and the preparation method thereof has been described in, for example, Example 1156 in. The compound of formula (I) is an effective and selective inhibitor, which targets both BRAF and CRAF kinases with a sub-nM inhibitory concentration 50% (IC50) value in biochemical assays, while inhibiting 456 kinases to a similar degree Only two of them (the discoid protein domain receptor tyrosine kinase 1 (DDR1) and platelet-derived growth factor receptor, β polypeptide (PDGFR β)) are combined. The compounds of formula (I) have been shown to be effective in a variety of MAPK pathway-driven human cancer cell lines and tumor xenografts in vivo, including models that carry activation damage in KRAS, NRAS and BRAF oncogenes. For example, the compound of formula (I) exhibits activity in the low uM range against human pancreatic cancer cell lines exhibiting mutations in KRAS (see WO/2018/203219 A1, Example 1B, Table 2).

本發明的藥物組合進一步包含CDK4/6抑制劑。D-細胞週期蛋白-CDK4/6-RB1軸係MAPK訊號下游的控制細胞從細胞週期的G1至S期轉變的主要效應子途徑。 The pharmaceutical combination of the present invention further comprises a CDK4/6 inhibitor. D-Cyclin-CDK4/6-RB1 axis system MAPK signal downstream of the main effector pathway that controls the transition of cells from G1 to S phase of the cell cycle.

用於本發明的合適的CDK4/6抑制劑包括瑞博西尼或其藥學上可接受的鹽，和帕博西尼(palbociclib)或其藥學上可接受的鹽。 Suitable CDK4/6 inhibitors for use in the present invention include reboxinil or a pharmaceutically acceptable salt thereof, and pambociclib or a pharmaceutically acceptable salt thereof.

用於本發明藥物組合的CDK4/6抑制劑包括瑞博西尼或帕博西尼。 The CDK4/6 inhibitor used in the drug combination of the present invention includes reboxinil or paboxinil.

瑞博西尼(Kisqali®)係一種口服生物利用的且高選擇性的小分子抑制劑，對CDK4/細胞週期蛋白-D1和CDK6/細胞週期蛋白-D3酶複合體具有高度特異性的抑制活性。瑞博西尼的特別有用的鹽係其琥珀酸鹽。 Ribocinil (Kisqali®) is an oral bioavailable and highly selective small molecule inhibitor with highly specific inhibitory activity against CDK4/cyclin-D1 and CDK6/cyclin-D3 enzyme complex . A particularly useful salt of Ribocinil is its succinate.

本發明進一步關於藥物組合，該組合包含(a)Raf抑制劑，該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受鹽；和(b)CDK4/6抑制劑，特別地同時地、單獨地或順序地用於癌症的治療。 The present invention further relates to a pharmaceutical combination comprising (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein; and (b) a CDK4/6 inhibitor, Especially for the treatment of cancer simultaneously, individually or sequentially.

在下面和整個申請中定義所選擇的術語。使用標準命名法描述本發明的化合物。除非另外限定，否則本文使用的所有技術術語和科學術語均具有與本發明所屬領域的技術人員通常理解的相同的含義。除非另有說明，否則以下通用定義應當適用於本說明書。 Define the selected terms below and throughout the application. Standard nomenclature is used to describe the compounds of the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. Unless otherwise stated, the following general definitions shall apply to this specification.

如本文所用，術語「本發明的組合」係指(a)Raf抑制劑，該Raf抑制劑係具有式(I)之化合物或其藥學上可接受鹽，和(b)CDK4/6抑制劑，較佳的是瑞博西尼(ribociclib)或其藥學上可接受的鹽的藥物組合。如本文所用，術語「本發明的組合」也是指(a)Raf抑制劑，該Raf抑制劑係具有式(I)之化合物或其藥學上可接受鹽，和(b)CDK4/6抑制劑，較佳的是瑞博西尼(ribociclib)或其藥學上可接受的鹽的共同投與或組合投與。根據本發明，具有式(I)之化合物或其藥學上可接受的鹽和CDK4/6抑制劑(較佳的是瑞博西尼)或其藥學上可接受的鹽可以藉由包括這兩種化合物的單一藥物組成物的同時投與來以組合採用。可替代地，能以分開的藥物組成物單獨投與該組合，每種藥物組成物以順序方式包含Raf抑制劑和CDK4/6抑制劑，其中例如，首先投與Raf抑制劑或CDK4/6抑制劑，並且接下來投與另一種。這種順序投與可以在時間上接近(例如，同時地)或在時間上遠離。 As used herein, the term "combination of the present invention" refers to (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, Preferably, it is a drug combination of ribociclib or a pharmaceutically acceptable salt thereof. As used herein, the term "combination of the present invention" also refers to (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, Preferably, ribociclib or a pharmaceutically acceptable salt thereof is co-administered or administered in combination. According to the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor (preferably reboxinil) or a pharmaceutically acceptable salt thereof can be obtained by including these two Simultaneous administration of a single pharmaceutical composition of the compound is used in combination. Alternatively, the combination can be administered separately in separate pharmaceutical compositions, each pharmaceutical composition comprising a Raf inhibitor and a CDK4/6 inhibitor in a sequential manner, wherein for example, the Raf inhibitor or CDK4/6 inhibitor is administered first And then another one is administered. This sequential administration can be close in time (e.g., simultaneously) or distant in time.

除非本文另外指示或與上下文明顯矛盾，否則在描述本發明的上下文中，如本文使用的術語「一個/種(a/an)」和「該(the)」以及類似提及應解釋為包括單數和複數二者。當複數形式用於化合物、鹽等時，這也意指單數的化合物、鹽等。 Unless otherwise indicated herein or clearly contradictory to the context, in the context of describing the present invention, the terms "a/an" and "the" and similar references as used herein should be interpreted as including the singular And both. When the plural form is used for a compound, salt, etc., this also means a singular compound, salt, etc.

除非上下文另有明確說明，否則術語「或」在本文中用於表示術語「和/或」並且可與術語「和/或」互換使用。 Unless the context clearly dictates otherwise, the term "or" is used herein to mean the term "and/or" and can be used interchangeably with the term "and/or".

「約」和「大約」通常意指在給定測量的性質或精度的情況下測量的量的可接受的誤差度。示例性誤差度在給定值或值範圍的20%內，典型地在10%內，並且更典型地，在5%內。當將本文中的劑量描述為「約」指定量時，實際劑量可以從該量變化高達10%：這種「約」的使用承認，給定劑型中的精確量可能由於各種原因而與預期量略有不同，但不會實質上影響所投與化合物的體內作用。 "About" and "approximately" generally mean the acceptable degree of error in a measured quantity given the nature or accuracy of the measurement. An exemplary degree of error is within 20% of a given value or range of values, typically within 10%, and more typically within 5%. When the dosage in this document is described as the "about" specified amount, the actual dosage can vary from that amount by up to 10%: the use of this "about" recognizes that the precise amount in a given dosage form may differ from the expected amount for various reasons. Slightly different, but will not substantially affect the in vivo effects of the administered compound.

當將本文中的劑量描述為指定量時，即，不使用術語「約」，實際劑量可以從該量變化高達10%(較佳的是高達5%)：這種使用承認，給定劑型中的精確量可能由於各種原因而與預期量略有不同，但不會實質上影響所投與化合物的體內作用。 When the dosage herein is described as a specified amount, that is, without the use of the term "about", the actual dosage may vary from this amount by up to 10% (preferably up to 5%): this use acknowledges that in a given dosage form The precise amount may be slightly different from the expected amount for various reasons, but it will not substantially affect the in vivo effects of the administered compound.

除非另外指明，否則術語「包含」和「包括」在本文中以其開放式和非限制性的含義使用。 Unless otherwise specified, the terms "including" and "including" are used herein in their open-ended and non-limiting meanings.

「組合」或「與......組合」或「共同投與」並不旨在暗示必須物理混合或同時投與療法或治療劑和/或配製該等治療劑用於一起遞送，儘管該等遞送方法在本文所述的範圍內。該等組合中的治療劑可以與一種或多種其他另外的療法或治療劑同時、在其之前或之後投與。可以按任何順序投與治療劑。一般而言，每種藥劑將以針對該藥劑所確定的劑量和/或時間排程投與。還應理解，該組合中使用的另外的治療劑可以按單一組成物一起投與或按不同組成物單獨 投與。一般而言，預期組合中使用的另外的治療劑以不超過它們單獨使用時的水平使用。在一些實施方式中，組合中使用的水平將低於單一藥劑療法中使用的水平。 "Combination" or "in combination with" or "co-administration" is not intended to imply that the therapies or therapeutic agents must be physically mixed or administered simultaneously and/or formulated for co-delivery, although These delivery methods are within the scope described herein. The therapeutic agents in such combinations can be administered at the same time, before or after one or more other additional therapies or therapeutic agents. The therapeutic agents can be administered in any order. In general, each agent will be administered at a dose and/or time schedule determined for that agent. It should also be understood that the additional therapeutic agents used in the combination can be administered together as a single composition or separately as different compositions. Vote. In general, it is expected that the additional therapeutic agents used in the combination will be used at a level not exceeding their level when used alone. In some embodiments, the levels used in the combination will be lower than the levels used in single agent therapy.

本發明的組合具有治療或保護功能或兩者。例如，可以將該等分子投與人受試者，以治療和/或預防多種障礙，如本文所述的癌症。 The combination of the present invention has therapeutic or protective functions or both. For example, these molecules can be administered to human subjects to treat and/or prevent various disorders, such as cancers as described herein.

如本文使用的，術語「組合」、「治療性組合」或「藥物組合」係指在一個劑量單位形式中的固定組合、或非固定組合、或用於組合投與(共同投與)的成套套組(kit of parts)，其中兩種或更多種治療劑可以一起、在同一時間獨立地或在時間間隔內單獨地投與，尤其在該等時間間隔允許組合配偶體顯示合作(例如協同)效應的情況下。 As used herein, the terms "combination", "therapeutic combination" or "drug combination" refer to a fixed combination, or a non-fixed combination, or a set for combined administration (co-administration) in one dosage unit form Kit of parts, in which two or more therapeutic agents can be administered together, independently at the same time, or separately within a time interval, especially during such time intervals allowing the combination partners to show cooperation (such as synergy) ) Effect.

術語「組合療法」係指投與兩種或更多種治療劑以治療本揭露中描述的治療性病症或障礙。這種投與涵蓋以基本上同時的方式共同投與該等治療劑，如以具有固定比率的活性成分的單個配製物投與或以每種活性成分的單獨配製物(例如，膠囊和/或靜脈內配製物)投與。此外，這種投與和共同投與也涵蓋在大致相同的時間或在不同的時間以順序或單獨的方式使用每種類型的治療劑。無論活性成分係作為單一配製物投與還是以分開的配製物投與，將藥物作為同一療程的一部分投與同一患者。在任何情況下，治療方案將在治療本文所述的病症或障礙方面提供有益作用。 The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic conditions or disorders described in this disclosure. Such administration encompasses co-administration of the therapeutic agents in a substantially simultaneous manner, such as administration in a single formulation with fixed ratios of active ingredients or in separate formulations for each active ingredient (e.g., capsules and/or Intravenous formulation) administration. In addition, such administration and co-administration also encompass the use of each type of therapeutic agent in a sequential or separate manner at approximately the same time or at different times. Whether the active ingredients are administered as a single formulation or as separate formulations, the drug is administered to the same patient as part of the same course of treatment. In any case, the treatment regimen will provide a beneficial effect in treating the conditions or disorders described herein.

在本發明的含義內，同時的治療性使用係指藉由相同途徑並同時或基本上同時投與至少兩種活性成分。 Within the meaning of the present invention, simultaneous therapeutic use refers to the simultaneous or substantially simultaneous administration of at least two active ingredients by the same route.

在本發明的含義內，單獨使用特別是指藉由不同途徑同時或基本上同時投與至少兩種活性成分。 Within the meaning of the present invention, use alone especially refers to the simultaneous or substantially simultaneous administration of at least two active ingredients via different routes.

順序的治療性使用係指在不同的時間投與至少兩種活性成分，投與途徑相同或不同。更特別地，投與方法意指根據該方法，在一種或多種其他活性成分開始投與之前進行一種活性成分的全部投與。 Sequential therapeutic use refers to the administration of at least two active ingredients at different times, with the same or different routes of administration. More particularly, the administration method means that according to the method, the entire administration of one active ingredient is performed before the administration of one or more other active ingredients is started.

如本文使用的，術語「固定組合」、「固定劑量」和「單一配製物」係指配製的單一載體或媒介物或劑型，以向患者遞送一定量的兩種治療劑，該量對於癌症的治療具有聯合治療有效性。單一媒介物被設計為遞送一定量的每種藥劑連同任何藥學上可接受的載體或賦形劑。在一些實施方式中，媒介物係片劑、膠囊劑、丸劑或貼劑。在其他實施方式中，媒介物係溶液或懸浮液。 As used herein, the terms "fixed combination", "fixed dose" and "single formulation" refer to a single carrier or vehicle or dosage form formulated to deliver a certain amount of two therapeutic agents to a patient, which is effective for cancer The treatment is effective in combination therapy. A single vehicle is designed to deliver a certain amount of each agent together with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

術語「非固定組合」或「成套套組」意指本發明組合的治療劑作為分開的實體同時地、並行地或順序地投與至患者(沒有特定的時間限制)，其中這種投與在有需要的受試者體內提供治療有效水平的兩種化合物。後者也適用於混合物療法，例如三種或更多種活性成分的投與。 The term "non-fixed combination" or "kit" means that the therapeutic agents of the combination of the present invention are administered to the patient simultaneously, concurrently or sequentially (without a specific time limit) as separate entities, wherein such administration is in A subject in need provides therapeutically effective levels of the two compounds. The latter also applies to mixture therapy, such as the administration of three or more active ingredients.

如本文使用的，術語「藥學上可接受的」係指在合理醫學判斷的範圍內適合用於與受試者(例如，哺乳動物或人)的組織相接觸而無過度毒性、刺激、過敏反應和其他問題或併發症，並且與合理的益處/風險比相稱的那些化合物、材料、組成物和/或劑型。 As used herein, the term "pharmaceutically acceptable" refers to being suitable for use in contact with the tissue of a subject (e.g., mammal or human) within the scope of reasonable medical judgment without excessive toxicity, irritation, or allergic reaction Those compounds, materials, compositions and/or dosage forms that are commensurate with other problems or complications and are commensurate with a reasonable benefit/risk ratio.

如本文使用的，術語「藥學上可接受的賦形劑」或「藥學上可接受的載體」包括如熟悉該項技術者應已知的任何和所有溶劑、分散介質、包衣、表面活性劑、抗氧化劑、防腐劑(例如，抗細菌劑、抗真菌劑)、等滲劑、吸收延遲劑、鹽、防腐劑、藥物、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調味劑、染料、類似材料及其組合。除了任何常規載體與活性成分不相容的情況外，考慮了其在治療或藥物組成物中之用途。 As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, and surfactants known to those skilled in the art. , Antioxidants, preservatives (for example, antibacterial agents, antifungals), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants , Sweeteners, flavoring agents, dyes, similar materials and combinations thereof. Except for any incompatibility between conventional carriers and active ingredients, their use in therapeutic or pharmaceutical compositions is considered.

術語「藥物組成物」在本文中被定義為係指包含有待投與受試者(例如，哺乳動物或人)的至少一種治療劑的混合物或溶液，以治療影響該受試 者的特定疾病或病症。本發明的藥物組合可以配製成合適的藥物組成物用於腸內或腸胃外投與，例如糖衣片劑、片劑、膠囊或栓劑或安瓿劑。如果未另外指明，那麼該等以本身已知的方式進行製備，例如借助各種常規的混合、粉碎、直接壓片、製粒、糖包衣、溶解、凍乾方法或對熟悉該項技術者來說顯而易見的製造技術。應當理解，包含在每種劑型的單獨劑量中的組合配偶體的單位含量本身不必構成有效量，因為必需的有效量可以藉由投與多個劑量單位達到。該藥物組成物可以含有約0.1%至約99.9%、較佳的是約1%至約60%的一種或多種治療劑。熟悉該項技術者可以關於劑型的特定所希望的特性，藉由常規實驗而沒有任何不適的負擔來選擇前述載體中的一種或多種。所使用的每種載體的量可以在本領域常規的範圍之內變化。以下參考文獻揭露了用於配製口服劑型的技術和賦形劑：The Handbook of Pharmaceutical Excipients[藥用輔料手冊]，第4版，Rowe等人編，American Pharmaceuticals Association[美國藥師協會](2003年)；以及Remington：the Science and Practice of Pharmacy[雷明頓：藥學的科學與實踐]，第20版，Gennaro編，Lippincott Williams & Wilkins[威爾金斯出版公司](2003)。該等視需要的附加的常規載體可以摻入到口服劑型中，方式為在製粒之前或期間將一種或多種常規載體摻入到初始混合物中，或將一種或多種常規載體與包含該藥劑組合的顆粒或呈口服劑型的該藥劑組合的單獨藥劑組合。在後一個實施方式中，該組合的混合物可以進一步共混(例如藉由V-共混器)，然後壓製或模塑成片劑(例如整塊片劑)、用膠囊包封，或填充到小袋中。 The term "pharmaceutical composition" is defined herein as referring to a mixture or solution containing at least one therapeutic agent to be administered to a subject (e.g., a mammal or a human) in order to therapeutically affect the subject The specific disease or condition of the person. The pharmaceutical combination of the present invention can be formulated into a suitable pharmaceutical composition for enteral or parenteral administration, such as sugar-coated tablets, tablets, capsules or suppositories or ampoules. If not otherwise specified, these are prepared in a manner known per se, such as by various conventional mixing, pulverization, direct compression, granulation, sugar coating, dissolution, freeze-drying methods or to those familiar with the technology. Say obvious manufacturing technology. It should be understood that the unit content of the combination partner contained in the individual doses of each dosage form does not necessarily constitute an effective amount by itself, because the necessary effective amount can be achieved by administering multiple dosage units. The pharmaceutical composition may contain about 0.1% to about 99.9%, preferably about 1% to about 60%, of one or more therapeutic agents. Those skilled in the art can select one or more of the aforementioned carriers by routine experimentation without any uncomfortable burden regarding the specific desired characteristics of the dosage form. The amount of each carrier used can vary within a range conventional in the art. The following references disclose techniques and excipients used to formulate oral dosage forms: The Handbook of Pharmaceutical Excipients, 4th edition, edited by Rowe et al., American Pharmaceuticals Association [American Pharmacists Association] (2003) ; And Remington: the Science and Practice of Pharmacy, 20th edition, edited by Gennaro, Lippincott Williams & Wilkins [Wilkins Publishing Company] (2003). The optional additional conventional carriers can be incorporated into the oral dosage form by incorporating one or more conventional carriers into the initial mixture before or during granulation, or combining one or more conventional carriers with the agent containing the agent The granule or the single agent combination of the agent combination in oral dosage form. In the latter embodiment, the combined mixture can be further blended (for example, by a V-blender), then compressed or molded into tablets (for example, monoliths), encapsulated, or filled into In a small bag.

藥物組成物可以按每單位劑量包含預定量的活性成分的單位劑型呈現。在某些實施方式中，單位劑量包括一種或多種媒介物，使得每種媒介物包括有效量的至少一種治療劑連同藥學上可接受的載體和賦形劑。在一些實施方式中，單位劑量係在相同時間投與患者的一種或多種片劑、膠囊、丸劑、注射劑、輸注劑、貼劑等。如熟悉該項技術者已知的，活性成分/劑量的量將取決於 所治療的病症；投與途徑；以及患者的年齡、體重和健康狀況。較佳的單位劑量組成物係含有活性成分的每日劑量或亞劑量、或其適當部分的那些。此外，此類藥物組成物可以藉由藥學領域熟知的任何方法製備。 The pharmaceutical composition may be presented in a unit dosage form containing a predetermined amount of active ingredient per unit dose. In certain embodiments, the unit dose includes one or more vehicles, such that each vehicle includes an effective amount of at least one therapeutic agent together with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, injections, infusions, patches, etc., administered to the patient at the same time. As known to those skilled in the art, the amount of active ingredient/dose will depend on The condition being treated; the route of administration; and the patient's age, weight, and health status. Preferred unit dose compositions are those containing the daily dose or sub-dose of the active ingredient, or an appropriate portion thereof. In addition, such pharmaceutical compositions can be prepared by any method well known in the pharmaceutical field.

本發明的藥物組成物可以包括「治療有效量」或「有效量」的本發明化合物。治療劑組合的術語「藥學有效量」、「治療有效量」或「臨床有效量」係以必要的劑量和在必要的時間段內足以提供超過用該組合治療的障礙的臨床可觀察的體征和症狀的基線的、可觀察的或臨床上顯著改善的量。治療有效量將根據以下因素而變化：如個體的疾病狀態、年齡、性別、和體重。治療有效量也是治療有益效果超過治療劑的任何毒性或有害作用的量。「治療有效劑量」較佳的是以所需方式調節可測量的參數，例如腫瘤生長速率或疾病進展。可以在預測人腫瘤中的功效的動物模型系統中評估化合物調節可測量參數的能力，以幫助建立合適的劑量水平和方案。可替代地，組成物的此性質可以藉由使用熟悉該項技術者已知的體外測定檢查化合物調節不希望的參數的能力來評估。 The pharmaceutical composition of the present invention may include a "therapeutically effective amount" or an "effective amount" of the compound of the present invention. The term "pharmaceutical effective amount", "therapeutically effective amount" or "clinically effective amount" of the therapeutic agent combination refers to the necessary dose and within the necessary time period sufficient to provide clinically observable signs and symptoms that exceed the disorder treated with the combination The amount of baseline, observable, or clinically significant improvement in symptoms. The therapeutically effective amount will vary according to factors such as the individual's disease state, age, sex, and weight. A therapeutically effective amount is also an amount in which the therapeutic benefit exceeds any toxic or deleterious effects of the therapeutic agent. The "therapeutically effective dose" is preferably to adjust a measurable parameter such as tumor growth rate or disease progression in a desired manner. The ability of compounds to modulate measurable parameters can be evaluated in animal model systems that predict efficacy in human tumors to help establish appropriate dosage levels and regimens. Alternatively, this property of the composition can be assessed by examining the compound's ability to adjust undesirable parameters using in vitro assays known to those skilled in the art.

如本文使用的，術語「聯合治療活性」或「聯合治療作用」意指可以將治療劑在其較佳的時間間隔內聯合地、單獨地或順序地給予，使得待治療的受試者(特別是人)仍顯示出(較佳的是協同性)相互作用(聯合治療作用)。情況是否如此尤其可以藉由以下方式確定：跟蹤化合物的血液水平，證實兩種化合物至少在某些時間間隔期間皆存在於待治療的人的血液中。 As used herein, the term "combined therapeutic activity" or "combined therapeutic effect" means that therapeutic agents can be administered jointly, separately or sequentially within their preferred time intervals, so that the subject to be treated (particularly Is human) still shows (preferably synergistic) interaction (combination therapy effect). Whether this is the case can be determined in particular by tracking the blood levels of the compounds and confirming that both compounds are present in the blood of the person to be treated at least during certain time intervals.

如本文使用的，術語「藥劑」應理解為意指在組織、系統、動物、哺乳動物、人或其他受試者中產生所希望作用的物質。還應理解，「藥劑」可以是單一化合物、或兩種或更多種化合物的組合或組成物。 As used herein, the term "medicament" should be understood to mean a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. It should also be understood that "agent" can be a single compound, or a combination or composition of two or more compounds.

術語「癌症」較佳的是癌症。 The term "cancer" is preferably cancer.

如本文使用的，術語「癌症」係指以異常細胞的不希望和不受控制的生長為特徵的疾病。癌細胞可以局部或通過血流和淋巴系統擴散到身體的 其他部位。如本文所用，該術語「癌症」或「腫瘤」包括惡化前以及惡性癌症和腫瘤。術語「癌症」在本文中用於意指廣譜的腫瘤，包括所有實體瘤和血液惡性腫瘤。 As used herein, the term "cancer" refers to a disease characterized by the undesirable and uncontrolled growth of abnormal cells. Cancer cells can spread to the body locally or through the bloodstream and lymphatic system Other parts. As used herein, the term "cancer" or "tumor" includes premalignant as well as malignant cancers and tumors. The term "cancer" is used herein to mean a broad spectrum of tumors, including all solid tumors and hematological malignancies.

術語「增殖性疾病」或「增殖性障礙」還是指一般癌症或本文定義的癌症。 The term "proliferative disease" or "proliferative disorder" also refers to general cancer or cancer as defined herein.

「口服劑型」包括開處方或意欲用於口服投與的單位劑型。 "Oral dosage form" includes a unit dosage form prescribed or intended for oral administration.

如本文使用的，術語「治療(treat、treatment和treating)」係指由投與一種或多種療法導致的障礙(例如增殖性障礙)的進展、嚴重性和/或持續時間的減少或緩解，或者障礙的一種或多種症狀(適當地，一種或多種可辨別的症狀)的緩解。在具體的實施方式中，術語「治療(treat、treatment和treating)」係指改善增殖性障礙的至少一種可測量的物理參數，如腫瘤的生長，這不一定係患者可辨別的。在其他實施方式中，術語「治療(treat、treatment和treating)」係指藉由例如穩定可辨別的症狀來物理地，或藉由例如穩定物理參數來生理地，或藉由兩者，抑制增殖性障礙的進展。在其他實施方式中，該術語「治療(treat、treatment和treating)」係指減少或穩定腫瘤大小或癌細胞計數。 As used herein, the term "treat (treat, treatment, and treating)" refers to the reduction or alleviation of the progression, severity, and/or duration of a disorder (e.g., proliferative disorder) caused by the administration of one or more therapies, or Relief of one or more symptoms of the disorder (suitably one or more discernible symptoms). In specific embodiments, the term "treat (treat, treatment, and treating)" refers to at least one measurable physical parameter that improves proliferative disorders, such as tumor growth, which is not necessarily discernible by the patient. In other embodiments, the term "treat (treat, treatment, and treating)" refers to inhibiting proliferation by, for example, stabilizing discernible symptoms physically, or by stabilizing physical parameters, for example, physiologically, or by both. The progress of sexual disorders. In other embodiments, the term "treat, treatment, and treating" refers to reducing or stabilizing tumor size or cancer cell count.

術語「治療(treat、treatment和treating)」包括降低患者或患者群體中的不良事件(AE)和嚴重AE(SAE)的發生率和嚴重性，包括實驗室值、生命體征和心電圖(ECG)的變化。 The term "treat (treat, treatment, and treating)" includes reducing the incidence and severity of adverse events (AE) and severe AE (SAE) in a patient or patient population, including laboratory values, vital signs, and electrocardiogram (ECG) Variety.

術語「治療(treat、treatment和treating)」包括改善患者或患者群體中的整體反應率(ORR)、疾病控制率(DCR)、反應持續時間(DOR)、無進展存活期(PES)，例如，根據實體瘤反應評估標準(RECIST)版本1.1。 The term "treat (treat, treatment, and treating)" includes improving overall response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PES) in a patient or patient population, for example, According to the Solid Tumor Response Evaluation Criteria (RECIST) version 1.1.

在本揭露的含義範圍內，術語「治療」還表示阻止、延遲發作(即在疾病的臨床表現之前的時間段)和/或降低疾病發展或疾病惡化的風險。術語 「保護」在本文中用於表示阻止、延遲或治療，或者視情況而定既阻止、延遲又治療受試者(例如哺乳動物或人)體內疾病的發展、持續或惡化。 Within the meaning of the present disclosure, the term "treatment" also means preventing, delaying the onset (that is, the time period before the clinical manifestation of the disease) and/or reducing the risk of disease development or disease deterioration. the term "Protection" is used herein to mean preventing, delaying or treating, or as the case may be, both preventing, delaying and treating the development, continuation or deterioration of the disease in the subject (for example, mammal or human).

如本文使用的，術語「受試者」或「患者」旨在包括易於患有癌症或任何障礙(直接或間接涉及癌症)或受其折磨的動物。受試者的實例包括哺乳動物，例如人、猿、猴、狗、乳牛、馬、豬、綿羊、山羊、貓、小鼠、兔、大鼠和轉基因非人動物。在一個較佳的實施方式中，受試者係人，例如患有、有風險患有或潛在能患有癌症(例如癌症)的人。 As used herein, the term "subject" or "patient" is intended to include animals that are susceptible to or afflicted by cancer or any disorder (directly or indirectly related to cancer). Examples of subjects include mammals such as humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In a preferred embodiment, the subject is a human, such as a person who has, is at risk of, or is potentially able to have cancer (such as cancer).

術語「抑制」、「抑制劑」或「拮抗劑」包括給定分子或途徑的某些參數(例如活性)的降低。例如，此術語包括將靶激酶(Raf或CDK4/6)的活性抑制5%、10%、20%、30%、40%或更多。因此，抑制可以是但不必是100%。 The terms "inhibition", "inhibitor" or "antagonist" include the reduction of certain parameters (eg, activity) of a given molecule or pathway. For example, this term includes inhibiting the activity of the target kinase (Raf or CDK4/6) by 5%, 10%, 20%, 30%, 40% or more. Therefore, suppression can be but need not be 100%.

如本文使用的，「鹽」(其由「或其多種鹽」或「或其一種鹽」表示)可以單獨存在或以與本發明組合的游離化合物(例如Raf抑制劑即具有式(I)之化合物或CDK4/6抑制劑(較佳的是瑞博西尼))的混合物存在，並且較佳的是藥學上可接受的鹽。較佳的是由具有鹼性氮原子的本發明組合的化合物與有機酸或無機酸形成此類鹽，例如作為酸加成鹽，尤其是藥學上可接受的鹽。術語「藥學上可接受的鹽」係指保留化合物的生物有效性和特性的鹽，並且該等鹽典型地不是生物學上或其他方面不希望的。由於胺基基團的存在，該化合物可能能夠形成酸加成鹽。 As used herein, "salt" (which is represented by "or a plurality of salts thereof" or "or a salt thereof) can exist alone or as a free compound in combination with the present invention (e.g., a Raf inhibitor having formula (I) A mixture of the compound or CDK4/6 inhibitor (preferably reboxinil)) is present, and preferably a pharmaceutically acceptable salt. It is preferable to form such a salt from a compound of the present combination having a basic nitrogen atom with an organic acid or an inorganic acid, for example as an acid addition salt, especially a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, and such salts are typically not biologically or otherwise undesirable. Due to the presence of the amine group, the compound may be able to form acid addition salts.

合適的鹽的列表可見於「Remington’s Pharmaceutical Sciences[雷明頓藥物科學]」，第20版，Mack Publishing Company[麥克出版公司]，伊斯頓(Easton)，賓夕法尼亞州(Pa.),(1985)；新版本：「Remington：the science and practice of pharmacy[雷明頓：藥學科學與實踐]」，第22版，Pharmaceutical Press,London[倫敦醫藥出版社](2012)；以及Stahl和Wermuth的「Handbook of Pharmaceutical Salts：Properties,Selection,and Use[藥物鹽手冊：特性、選擇和使用]」(Wiley-VCH出版社，德國魏因海姆，2011)。 A list of suitable salts can be found in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pennsylvania (Pa.), (1985); New edition: "Remington: the science and practice of pharmacy", 22nd edition, Pharmaceutical Press, London [London Medical Press] (2012); and Stahl and Wermuth’s "Handbook of Pharmaceutical Salts: Properties, Selection, and Use [Pharmaceutical Salt Handbook: Properties, Selection and Use]" (Wiley-VCH Press, Weinheim, Germany, 2011).

出於分離或純化的目的，還可能使用藥學上不可接受的鹽，例如苦味酸鹽或過氯酸鹽。對於治療用途，僅使用藥學上可接受的鹽或游離化合物(適用於藥物製劑形式的情況下)，並且因此該等係較佳的。鑒於游離形式的新穎的化合物與呈其鹽(包括例如在新穎化合物的純化或鑒定中可用作中間體的那些鹽)形式的化合物之間的密切關係，任何對游離化合物的提及應理解為在適當和方便的情況下也指相應的鹽。在本發明的組合中使用的化合物的鹽較佳的是藥學上可接受的鹽；形成藥學上可接受的鹽的合適的反荷離子係本領域已知的。除非文中另有說明或明確指出，否則提及本文提供的藥物組合中有用的治療劑包括化合物的游離鹼和化合物的所有藥學上可接受的鹽。 For separation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, such as picrate or perchlorate. For therapeutic use, only pharmaceutically acceptable salts or free compounds (applicable in the form of pharmaceutical preparations) are used, and therefore these are preferred. In view of the close relationship between a novel compound in free form and a compound in the form of its salt (including, for example, those salts useful as intermediates in the purification or identification of the novel compound), any reference to a free compound should be understood as Where appropriate and convenient, the corresponding salt is also referred to. The salt of the compound used in the combination of the present invention is preferably a pharmaceutically acceptable salt; suitable counterions to form a pharmaceutically acceptable salt are known in the art. Unless otherwise stated or clearly indicated in the context, references to therapeutic agents useful in the pharmaceutical combinations provided herein include the free base of the compound and all pharmaceutically acceptable salts of the compound.

如本文使用的，術語「協同作用」係指兩種藥劑的作用，這兩種藥劑例如像，Raf抑制劑即具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(較佳的是瑞博西尼)或其藥學上可接受的鹽，以產生如下作用，例如減緩癌症或其症狀的症狀進展，這比自身投與的每種藥物的作用的簡單加和要大。 As used herein, the term "synergistic effect" refers to the effect of two agents, such as, for example, Raf inhibitors, ie, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and CDK4/6 inhibition Agent (preferably Ribocinil) or a pharmaceutically acceptable salt thereof to produce the following effects, such as slowing down the progression of cancer or its symptoms, which is simpler than the addition of the effects of each drug administered by itself Be big.

在一個實施方式中，本發明的組合包含(a)Raf抑制劑，該Raf抑制劑係具有式(I)之化合物 In one embodiment, the combination of the present invention comprises (a) a Raf inhibitor, which is a compound of formula (I)

Figure 108147073-A0202-12-0019-4
或其藥學上可接受的鹽；以及(b)CDK4/6抑制劑。
Figure 108147073-A0202-12-0019-4
 Or a pharmaceutically acceptable salt thereof; and (b) a CDK4/6 inhibitor.

在一個實施方式中，本發明的組合包含(a)Raf抑制劑具有式(I)之化合物 In one embodiment, the combination of the present invention comprises (a) a Raf inhibitor compound of formula (I)

Figure 108147073-A0202-12-0020-5
或其藥學上可接受的鹽，以及(b)CDK4/6抑制劑，該CDK4/6抑制劑選自瑞博西尼和帕博西尼，和其藥學上可接受的鹽。該CDK4/6抑制劑較佳的是瑞博西尼或其藥學上可接受的鹽。
Figure 108147073-A0202-12-0020-5
 Or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor, the CDK4/6 inhibitor is selected from the group consisting of Rebocinil and Pabocinil, and a pharmaceutically acceptable salt thereof. The CDK4/6 inhibitor is preferably reboxinil or a pharmaceutically acceptable salt thereof.

與細胞系和人異種移植物模型(參見實例)中的任一單一藥劑療法相比，本發明的組合證明了腫瘤應答的增加的深度和持久性，並因此對於癌症的治療可能是有效的。因此，本發明提供了使用具有式(I)之化合物的Raf抑制劑或其藥學上可接受的鹽與CDK4/6抑制劑(並且特別是瑞博西尼)或其藥學上可接受的鹽的組成物和方法，用於治療實體瘤，特別是攜帶一個或多個MAPK途徑改變的腫瘤(例如，NRAS突變型癌症和KRAS突變型癌症)。 Compared to any single agent therapy in cell lines and human xenograft models (see Examples), the combination of the present invention demonstrates the increased depth and durability of tumor response, and therefore may be effective for the treatment of cancer. Therefore, the present invention provides a combination of a Raf inhibitor or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor (and particularly Rebocinil) or a pharmaceutically acceptable salt thereof having a compound of formula (I) The composition and method are used to treat solid tumors, especially tumors that carry one or more changes in the MAPK pathway (for example, NRAS mutant cancers and KRAS mutant cancers).

較佳的是，將該等治療劑按治療有效的劑量投與，當組合時其提供有益的作用。本發明特別關於本發明的組合，其可用於向有需要的受試者進行單獨、同時或順序投與以治療癌症。可替代地闡明，本發明特別關於用於在癌症的治療中使用的本發明的組合。 Preferably, these therapeutic agents are administered in therapeutically effective doses, which provide beneficial effects when combined. The present invention particularly relates to the combination of the present invention, which can be used for individual, simultaneous or sequential administration to a subject in need to treat cancer. Alternatively stated, the present invention specifically relates to the combination of the present invention for use in the treatment of cancer.

癌症的性質係多因素的。在某些情況下，可以組合具有不同作用機制的治療劑。然而，僅考慮具有不同作用方式的治療劑的任何組合並不一定導致具有有利效果的組合，並且不一定轉化為患有某些癌症的患者的臨床益處。 The nature of cancer is multifactorial. In some cases, therapeutic agents with different mechanisms of action can be combined. However, just considering any combination of therapeutic agents with different modes of action does not necessarily lead to a combination with advantageous effects, and does not necessarily translate into clinical benefits for patients with certain cancers.

在本發明中，預期本發明的組合的投與會產生更有益的作用，例如協同的或改善的抗增殖作用，例如關於延緩進展或抑制癌症或其症狀，並且還可能提供另外有益的作用，如以下任何一種或多種：與先前技術中的任何療法或與任何一種組合配偶體的單一療法相比，與皮膚相關的毒性(例如皮疹)和胃腸道毒性(例如腹瀉)的副作用更少、耐受性改善、生活品質更高且發病率降低。 In the present invention, the administration of the combination of the present invention is expected to produce more beneficial effects, such as synergistic or improved anti-proliferative effects, for example with regard to delaying progression or inhibiting cancer or its symptoms, and may also provide additional beneficial effects, such as Any one or more of the following: Compared with any therapy in the prior art or with any combination of partner monotherapy, skin-related toxicity (such as rash) and gastrointestinal toxicity (such as diarrhea) have fewer side effects and are tolerable Improved sex, higher quality of life and reduced morbidity.

本發明的組合的治療劑可以單獨地、同時地或順序地投與有需要的受試者。較佳的是，將該等治療劑按治療有效的劑量投與，當組合時其提供有益的作用。因此，在本發明的一個實施方式中，本發明的組合用於在癌症特別是如本文所描述的癌症的治療中使用。 The therapeutic agents of the combination of the present invention can be administered to a subject in need thereof individually, simultaneously or sequentially. Preferably, these therapeutic agents are administered in therapeutically effective doses, which provide beneficial effects when combined. Therefore, in one embodiment of the present invention, the combination of the present invention is for use in the treatment of cancer, particularly cancer as described herein.

術語「癌症」在本文中用於意指廣譜的腫瘤，包括所有實體瘤和血液惡性腫瘤。癌症可以處於早期、中期或晚期階段。癌症可以是局部晚期的或轉移性的。 The term "cancer" is used herein to mean a broad spectrum of tumors, including all solid tumors and hematological malignancies. The cancer can be in the early, middle or late stages. The cancer can be locally advanced or metastatic.

藉由本文所述的組合療法治療的癌症可能在標準治療後已經進展，或者對於其沒有有效的標準療法。 Cancers treated by the combination therapies described herein may have progressed after standard treatment, or there is no effective standard treatment for them.

在一個實施方式中，癌症係黑色素瘤。 In one embodiment, the cancer is melanoma.

本發明的組合特別地可用於治療癌症，例如攜帶一個或多個絲裂原活化蛋白激酶(MAPK)途徑改變的癌症，例如NRAS-突變型腫瘤，並且特別地是，如本文所述的表現Ras的至少一種功能獲得性突變的腫瘤，和/或如本文所述的Raf的至少一種功能獲得性突變。 The combination of the present invention is particularly useful for the treatment of cancers, such as cancers that carry one or more mitogen-activated protein kinase (MAPK) pathway changes, such as NRAS-mutant tumors, and in particular, expressing Ras as described herein At least one gain-of-function mutation of the tumor, and/or at least one gain-of-function mutation of Raf as described herein.

包括NRAS突變型癌症或腫瘤。感興趣的NRAS突變可選自G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P和Q61E。術語「NRAS突變型」腫瘤或癌症包括展現突變的NRAS蛋白(特別是功能獲得性NRAS突變)的任何腫瘤；尤其是任何G13R、Q61K、Q61L、Q61R NRAS突變型腫瘤。因此，NRAS突變型 黑色素瘤包括具有至少一個對應於Q61K、Q61L或Q61R的NRAS突變的黑色素瘤。癌症可以是NRAS QG13R突變型黑色素瘤。還包括KRAS突變型癌症或腫瘤。感興趣的KRAS突變可選自G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P和Q61E。術語「KRAS突變型」腫瘤或癌症包括展現突變的KRAS蛋白質的任何腫瘤。癌症可以處於早期、中期或晚期階段。癌症可以是局部晚期的或轉移性的。 Including NRAS mutant cancers or tumors. The NRAS mutation of interest can be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, and Q61E. The term "NRAS mutant" tumor or cancer includes any tumor that exhibits a mutated NRAS protein (especially a gain-of-function NRAS mutation); especially any G13R, Q61K, Q61L, Q61R NRAS mutant tumor. Therefore, the NRAS mutant Melanoma includes melanomas that have at least one NRAS mutation corresponding to Q61K, Q61L, or Q61R. The cancer may be NRAS QG13R mutant melanoma. It also includes KRAS mutant cancers or tumors. The KRAS mutation of interest can be selected from G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P and Q61E. The term "KRAS mutant" tumor or cancer includes any tumor that exhibits a mutated KRAS protein. The cancer can be in the early, middle or late stages. The cancer can be locally advanced or metastatic.

在另一個實施方式中，該癌症對於標準治療具有抗性或難治性。 In another embodiment, the cancer is resistant or refractory to standard treatments.

在另一個實施方式中，該癌症對於用達卡巴嗪的標準治療具有抗性或難治性。 In another embodiment, the cancer is resistant or refractory to standard treatment with dacarbazine.

在另一個實施方式中，該癌症對於用MEK抑制劑的治療具有抗性或難治性。 In another embodiment, the cancer is resistant or refractory to treatment with MEK inhibitors.

在另一個實施方式中，該癌症對與用免疫療法的治療(包括使用一種或多種免疫檢查點抑制劑的療法)具有抗性或難治性。 In another embodiment, the cancer is resistant or refractory to treatment with immunotherapy (including therapy with one or more immune checkpoint inhibitors).

在另一個實施方式中，該癌症對於用細胞毒素劑如亞硝基脲和/或絲裂黴素C的治療具有抗性或難治性。 In another embodiment, the cancer is resistant or refractory to treatment with cytotoxic agents such as nitrosourea and/or mitomycin C.

在一個實施方式中，該癌症的特徵在於選自包含NRAS蛋白的組的至少一個突變。 In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising NRAS protein.

在一實施方式中，該癌症的特徵在於NRAS突變。 In one embodiment, the cancer is characterized by NRAS mutations.

在一個實施方式中，本發明的組合關於用於治療癌症特別是黑色素瘤的方法。 In one embodiment, the combination of the present invention relates to a method for treating cancer, especially melanoma.

本發明的組合在NRAS突變型黑色素瘤的治療中尤其有用。 The combination of the present invention is particularly useful in the treatment of NRAS mutant melanoma.

在一個實施方式中，該癌症的特徵在於選自包含KRAS蛋白的組的至少一個突變。 In one embodiment, the cancer is characterized by at least one mutation selected from the group comprising KRAS protein.

在一實施方式中，該癌症的特徵在於KRAS突變。 In one embodiment, the cancer is characterized by a KRAS mutation.

在一個實施方式中，本發明的組合關於用於治療癌症，特別是胰臟癌的方法。 In one embodiment, the combination of the invention relates to a method for treating cancer, particularly pancreatic cancer.

本發明的組合在KRAS突變型PDAC的治療中尤其有用。 The combination of the present invention is particularly useful in the treatment of KRAS mutant PDAC.

在一個實施方式中，本文提供了用於在有需要的受試者中治療癌症之方法，該方法包括投與治療有效量的本發明的藥物組合，該藥物組合包含(a)Raf抑制劑，該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受的鹽，和(b)CDK4/6抑制劑。在較佳的實施方式，CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 In one embodiment, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of the pharmaceutical combination of the present invention, the pharmaceutical combination comprising (a) a Raf inhibitor, The Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and (b) a CDK4/6 inhibitor. In a preferred embodiment, the CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof.

在一個實施方式中，本文提供了用於在有需要的受試者中治療癌症之方法，該方法包括向有需要的受試者以針對所述癌症係聯合治療有效的量同時地、單獨地或順序地投與本發明的組合，其中本發明組合包含(a)Raf抑制劑，該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受的鹽，和(b)CDK4/6抑制劑。在較佳的實施方式，CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 In one embodiment, provided herein is a method for treating cancer in a subject in need, the method comprising administering to the subject in need an amount effective for combined treatment of the cancer line simultaneously and separately Or sequentially administer the combination of the present invention, wherein the combination of the present invention comprises (a) a Raf inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein, and (b) CDK4/6 inhibitor. In a preferred embodiment, the CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof.

在另外的實施方式中，本發明特別關於治療攜帶一個或多個絲裂原活化蛋白激酶(MAPK)途徑改變的癌症的方法。在一個實施方式中，本發明關於治療癌症的方法，該癌症的特徵在於在NRAS中的至少一個突變。在另一個實施方式中，本發明關於治療癌症的方法，該癌症的特徵在於在KRAS中的至少一個突變。在一個實施方式中，本發明關於本發明組合用於製備治療癌症特別是如本文所描述的癌症的藥物之用途。在一個實施方式中，本發明的組合用於製備用於治療癌症的藥物。 In another embodiment, the invention specifically relates to methods of treating cancers that carry one or more mitogen activated protein kinase (MAPK) pathway changes. In one embodiment, the present invention relates to a method of treating cancer, which cancer is characterized by at least one mutation in NRAS. In another embodiment, the invention relates to a method of treating cancer which is characterized by at least one mutation in KRAS. In one embodiment, the invention relates to the use of the combination of the invention for the preparation of a medicament for the treatment of cancer, particularly cancer as described herein. In one embodiment, the combination of the present invention is used to prepare a medicament for the treatment of cancer.

在另外的實施方式中，本發明關於本發明的組合用於製備治療以MAPK途徑中的功能獲得性突變為特徵的癌症的藥物之用途。 In another embodiment, the present invention relates to the use of the combination of the present invention for the preparation of a medicament for the treatment of cancer characterized by gain-of-function mutations in the MAPK pathway.

在一個實施方式中，本文提供的組合或組成物、或兩者展示出協同作用。 In one embodiment, the combination or composition provided herein, or both, exhibit a synergistic effect.

因此，在一方面，本發明可以提供藉由使用一種抗癌化合物與另一種抗癌化合物的組合來增強該抗癌化合物的功效的方法，特別是使用Raf抑制劑(該Raf抑制劑係本文定義的具有式(I)之化合物或其藥學上可接受的鹽)和CDK4/6抑制劑(適合地是瑞博西尼)或其藥學上可接受的鹽的方法，以提供藉由投與相似劑量的作為單一藥劑(單一療法)的具有式(I)之化合物或其藥學上可接受的鹽或CDK4/6抑制劑無法獲得的增強的功效。 Therefore, in one aspect, the present invention can provide a method for enhancing the efficacy of the anticancer compound by using a combination of an anticancer compound and another anticancer compound, in particular using a Raf inhibitor (the Raf inhibitor is defined herein) A compound of formula (I) or a pharmaceutically acceptable salt thereof) and a CDK4/6 inhibitor (suitably Reboxinil) or a pharmaceutically acceptable salt thereof, to provide a method by administering similar A dose of the compound of formula (I) or its pharmaceutically acceptable salt or CDK4/6 inhibitor as a single agent (monotherapy) has enhanced efficacy that cannot be obtained.

本發明提供的另外的益處可以是可以使用較低劑量的本發明組合的治療劑，例如，這樣使得劑量不僅可以通常更小，而且還可以不頻繁地施用，或可以按順序使用以減少僅使用組合配偶體之一觀察到的副作用的發生率。 An additional benefit provided by the present invention may be that lower doses of the therapeutic agents of the combination of the present invention can be used, for example, so that the dose can not only be generally smaller, but can also be administered infrequently, or can be used sequentially to reduce the use of The incidence of side effects observed in one of the combination partners.

在一些實施方式中，相對於單一藥劑劑量水平，本文定義的具有式(I)之化合物或其藥學上可接受的鹽和/或CDK4/6抑制劑(較佳的是瑞博西尼)或其藥學上可接受的鹽可以以治療劑量或低於治療劑量投與。在某些實施方式中，實現抑制(例如，生長抑制或腫瘤縮小)所需的一種治療劑的濃度或劑量比當使用另一治療劑時或與第一治療劑組合投與時、比單獨投與每種治療劑時更低。在某些實施方式中，在組合療法中，實現抑制(例如，生長抑制)所需的一種治療劑的濃度或劑量比作為單一療法的治療劑量更低，例如低10%-20%、20%-30%、30%-40%、40%-50%、50%-60%、60%-70%、70%-80%、或80%-90%。 In some embodiments, relative to a single agent dosage level, the compound of formula (I) defined herein or a pharmaceutically acceptable salt thereof and/or a CDK4/6 inhibitor (preferably Ribocinil) or The pharmaceutically acceptable salt can be administered at or below the therapeutic dose. In certain embodiments, the concentration or dose of one therapeutic agent required to achieve inhibition (e.g., growth inhibition or tumor shrinkage) is greater than when another therapeutic agent is used or when administered in combination with the first therapeutic agent than when administered alone. It is lower with each therapeutic agent. In certain embodiments, in combination therapy, the concentration or dose of a therapeutic agent required to achieve inhibition (eg, growth inhibition) is lower than the therapeutic dose as a monotherapy, such as 10%-20%, 20% lower -30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, or 80%-90%.

在確定一種或多種組分之間的協同相互作用時，可以藉由向需要治療的患者投與不同w/w比率的範圍和劑量的組分來最終測量針對該作用的最佳範圍和針對該作用的每種組分的絕對劑量範圍。對於人而言，對患者進行臨床研究的複雜性和成本可能使得使用這種測試形式作為協同作用的主要模型變得不切實際。然而，在某些實驗中觀察到的協同作用可以預測在其他物種中的作 用，並且可以將現有的動物模型用於進一步量化協同作用。在一種物種中觀察到的協同作用可以預測在其他物種中的作用，並且使用如本文所述的動物模型可以測量協同作用，並且還可以將此類研究的結果用於藉由應用藥物動力學/藥效學(PK/PD)方法預測其他物種所需的有效劑量比率範圍和絕對劑量、以及血漿濃度。在腫瘤模型與在人中觀察到的作用之間已建立的相關性表明，可以例如藉由異種移植物模型或在適當的細胞系中證明動物體內的協同作用。藉由已建立的測試模型可以表明，本發明的組合產生了本文所述的有益作用。熟悉該項技術者完全能夠選擇相關的測試模型來證明這樣的有益作用。本發明的組合的藥理學活性可以例如在臨床研究中或如在本文基本描述的體內或體外測試方法中得到證明。 When determining the synergistic interaction between one or more components, the optimal range for the effect and the optimal range for the effect can be measured by administering to the patient in need of treatment a range of different w/w ratios and doses of the components. The absolute dose range of each component that acts. For humans, the complexity and cost of conducting clinical studies on patients may make it impractical to use this form of testing as the primary model for synergy. However, the synergy observed in some experiments can predict the effect in other species. And can use existing animal models to further quantify synergy. The synergy observed in one species can predict the effect in other species, and the synergy can be measured using animal models as described herein, and the results of such studies can also be used by applying pharmacokinetics/ The pharmacodynamic (PK/PD) method predicts the effective dose ratio range and absolute dose required by other species, as well as plasma concentration. The established correlations between tumor models and the effects observed in humans indicate that synergy in animals can be demonstrated, for example, by xenograft models or in appropriate cell lines. The established test model can show that the combination of the present invention produces the beneficial effects described herein. Those who are familiar with the technology are fully able to select relevant test models to prove such beneficial effects. The pharmacological activity of the combination of the present invention can be demonstrated, for example, in clinical studies or in in vivo or in vitro test methods as basically described herein.

組合(換言之，將一種治療劑與另一種組合配偶體一起投與，即「共同投與」)的投與包括以單一配製物或單位劑型投與該組合，同時但單獨地投與該組合的各個劑，或藉由任何合適的途徑順序地投與該組合的各個劑。可以將本發明的組合的各個組合配偶體在治療過程中的不同的時間單獨地投與，或以分開的或單一的組合形式以任何順序地或並行地投與，例如同時地投與，或以聯合治療有效量，較佳的是以協同有效量，例如以對應於本文所述的量的每日劑量或間隔(即，非每日)劑量投與。 The administration of a combination (in other words, one therapeutic agent is administered together with another combination partner, that is, "co-administration") includes administration of the combination in a single formulation or unit dosage form, and simultaneous but separate administration of the combination Each agent, or each agent of the combination is administered sequentially by any suitable route. Each combination partner of the combination of the present invention can be administered separately at different times during the course of treatment, or in separate or single combination form in any order or in parallel, for example, simultaneously, or A combined therapeutically effective amount, preferably a synergistic effective amount, for example, administered in a daily dose or interval (ie, non-daily) dose corresponding to the amount described herein.

用於在本文所揭露的方法、治療、組合和組成物中使用的具有式(I)之化合物或其藥學上可接受的鹽係BRAF和CRAF的強效抑制劑。在一些實施方式中，將具有式(I)之化合物或其藥學上可接受的鹽口服投與。在一個實施方式中，將具有式(I)之化合物或其藥學上可接受的鹽，以約200-1200mg、約300-1000mg、約400-800mg、或約500-600mg的總日劑量投與(例如，每日一次)。具有式(I)之化合物或其藥學上可接受的鹽可以以約200mg、約250mg、約300mg、約350mg、約400mg、約450mg、約500mg約550mg、約600mg、約650 mg、約700mg、約750mg、約800mg、約850mg、約900mg、約950mg、約1000mg、約1050mg、約1100mg、約1150mg或約1200mg的總日劑量投與。在較佳的實施方式中，具有式(I)之化合物或其藥學上可接受的鹽可以以選自約200mg、400mg、600mg、800mg和1200mg的總日劑量投與。 The compound of formula (I) or its pharmaceutically acceptable salt is a potent inhibitor of BRAF and CRAF for use in the methods, treatments, combinations and compositions disclosed herein. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a total daily dose of about 200-1200 mg, about 300-1000 mg, about 400-800 mg, or about 500-600 mg (For example, once a day). The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used at about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg. A total daily dose of mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg is administered. In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in a total daily dose selected from about 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg.

具有式(I)之化合物或其藥學上可接受的鹽的總劑量，可以每日一次投與或可以分成兩份，每個劑量的具有式(I)之化合物每日兩次投與，其中實際投與劑量和投與時間由多個標準確定，如患者年齡、體重和性別；待治療的癌症的程度和嚴重性；和主治醫師的判斷。較佳的是，將具有式(I)之化合物的總劑量每日一次投與。在另一個較佳的實施方式中，將具有式(I)之化合物的總劑量每日兩次投與。 The total dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered once a day or divided into two parts, and each dose of the compound of formula (I) is administered twice a day, wherein The actual dosage and time of administration are determined by multiple criteria, such as the age, weight, and gender of the patient; the degree and severity of the cancer to be treated; and the judgment of the attending physician. Preferably, the total dose of the compound of formula (I) is administered once a day. In another preferred embodiment, the total dose of the compound of formula (I) is administered twice daily.

作為根據本發明的組合的一部分的CDK4/6抑制劑以治療有效量投與有需要的受試者。 The CDK4/6 inhibitor as part of the combination according to the invention is administered to a subject in need thereof in a therapeutically effective amount.

在較佳的實施方式中，在有需要的受試者中每日投與的、作為根據本發明的組合的一部分的CDK4/6抑制劑瑞博西尼或其藥學上可接受的鹽的總日劑量的量將選自每日從約100mg至約600mg；適合地，該量將選自每日約200mg至約400mg。在較佳的實施方式中，瑞博西尼或其藥學上可接受的鹽以選自約100、約200mg、約400mg和約600mg的日劑量投與。可替代地，總劑量可以分為兩份劑量，將其每日兩次投與。 In a preferred embodiment, the total amount of the CDK4/6 inhibitor ribocinil or its pharmaceutically acceptable salt administered daily as part of the combination according to the invention in a subject in need The amount of the daily dose will be selected from about 100 mg to about 600 mg per day; suitably, the amount will be selected from about 200 mg to about 400 mg per day. In a preferred embodiment, Reboxinil or a pharmaceutically acceptable salt thereof is administered in a daily dose selected from about 100, about 200 mg, about 400 mg, and about 600 mg. Alternatively, the total dose can be divided into two doses, which are administered twice daily.

特別地，可以設想以下每日劑量： In particular, the following daily doses can be envisaged:

Figure 108147073-A0202-12-0026-6
Figure 108147073-A0202-12-0026-6

在本文中提及劑量(dose/dosage)時，提及的量係指治療劑的量。例如，當投與200mg劑量的瑞博西尼並且將瑞博西尼以含有瑞博西尼琥珀酸鹽的片劑投與時，該片劑將含有相當於200mg瑞博西尼的瑞博西尼琥珀酸鹽。 When referring to dose/dosage herein, the amount mentioned refers to the amount of the therapeutic agent. For example, when a 200 mg dose of reboxinil is administered and reboxinil is administered as a tablet containing reboxinil succinate, the tablet will contain the equivalent of 200 mg reboxinil. Nisuccinate.

在一些實施方式中，將瑞博西尼或其藥學上可接受的鹽口服投與。在一個實施方式中，製備瑞博西尼用於經由口服遞送投與，並且可以鹽形式使用，例如琥珀酸鹽形式。在一些實施方式中，以片劑形式製備該化合物用於口服投與。能以多種劑量生產片劑，以便靈活投與。 In some embodiments, Reboxinil or a pharmaceutically acceptable salt thereof is administered orally. In one embodiment, Reboxinil is prepared for administration via oral delivery, and can be used in the form of a salt, such as the succinate salt form. In some embodiments, the compound is prepared in tablet form for oral administration. Tablets can be produced in multiple doses for flexible administration.

可以將瑞博西尼的劑量或其藥學上可接受的鹽每日一次、或每日兩次、或每日三次、或每日四次投與。可以將瑞博西尼或其藥學上可接受的鹽的總日劑量每日一次或兩次投與。 The dose of Rebocinil or its pharmaceutically acceptable salt can be administered once a day, or twice a day, or three times a day, or four times a day. The total daily dose of Ribocinil or a pharmaceutically acceptable salt thereof can be administered once or twice a day.

例如，作為組合療法的一部分，具有式(I)之化合物或其藥學上可接受的鹽可以以約200mg、約400mg、約600mg、約800mg或約1200mg的總日劑量投與，以及瑞博西尼，例如以琥珀酸鹽的形式，可以以選自約100mg、約200mg、約400mg和約600mg的總日劑量投與。可以將具有式(1)之化合物的日劑量每日一次或兩次投與。因此，可以將劑量為約200mg的具有式(I)之化合物以每日兩次投與(日總劑量約400mg)，並且可以將劑量為約100mg或約200mg的瑞博西尼以每日一次投與。可替代地，可以將劑量為約200mg的該具有式(I)之化合物以每日兩次投與(日總劑量約400mg)，並且可以將劑量為約100mg或約200mg的瑞博西尼以每日兩次投與。 For example, as part of a combination therapy, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered in a total daily dose of about 200 mg, about 400 mg, about 600 mg, about 800 mg, or about 1200 mg, and reboxi Nitraria, for example, in the form of succinate, can be administered in a total daily dose selected from about 100 mg, about 200 mg, about 400 mg, and about 600 mg. The daily dose of the compound of formula (1) can be administered once or twice a day. Therefore, a compound of formula (I) at a dose of about 200 mg can be administered twice a day (total daily dose of about 400 mg), and a dose of about 100 mg or about 200 mg of Ribocinil can be administered once a day Vote. Alternatively, the compound of formula (I) at a dose of about 200 mg may be administered twice a day (total daily dose of about 400 mg), and a dose of about 100 mg or about 200 mg of Rebocinil may be administered as Administer twice daily.

可替代地，可以將具有式(I)之化合物以600mg一天兩次投與(b.i.d或BID)以及將瑞博西尼以600mg一天一次投與。也可以將具有式(I)之化合物以400mg一天兩次投與(b.i.d或BID)以及將瑞博西尼以200mg一天一次投與。 Alternatively, the compound of formula (I) may be administered at 600 mg twice a day (b.i.d or BID) and rebocinil may be administered at 600 mg once a day. It is also possible to administer the compound of formula (I) at 400 mg twice a day (b.i.d or BID) and rebocinil at 200 mg once a day.

較佳的是將具有式(I)之化合物連續地投與，即沒有藥物假期。 It is preferable to administer the compound of formula (I) continuously, that is, without drug holidays.

CDK4/6抑制劑也可以連續投與，即在治療期間沒有間斷或沒有藥物假期。 CDK4/6 inhibitors can also be administered continuously, that is, there is no interruption or no drug vacation during the treatment period.

例如，CDK4/6抑制劑，例如瑞博西尼或其藥學上可接受的鹽可以以投與3週停止1週，或投與2週停止2週的方式投與；較佳的是施用3週停止1週。特別地，根據本發明可以使用以下方案： For example, a CDK4/6 inhibitor, such as reboxinil or a pharmaceutically acceptable salt thereof, can be administered for 3 weeks and stop for 1 week, or for 2 weeks and stop for 2 weeks; preferably, 3 Week stop for 1 week. In particular, the following schemes can be used according to the present invention:

Figure 108147073-A0202-12-0028-7
Figure 108147073-A0202-12-0028-7

例如，具有式(I)之化合物可以一天一次或兩次無藥物假期地給予，並且CDK4/6抑制劑(例如瑞博西尼或其藥學上可接受的鹽)可以以投與三週停止一週的方式投與。 For example, a compound of formula (I) can be administered once or twice a day without a drug holiday, and a CDK4/6 inhibitor (for example, Rebocinil or a pharmaceutically acceptable salt thereof) can be administered for three weeks and stop for one week Way to invest.

在設想的藥物方案中，具有式(I)之化合物和CDK4/6抑制劑的總日劑量如上文和整個說明書中所描述。 In the envisaged drug regimen, the total daily dose of the compound of formula (I) and CDK4/6 inhibitor is as described above and throughout the specification.

例如，可以一天一次或兩次，較佳的是一天兩次，給予400mg或600mg的劑量的具有式(I)之化合物，並且可以一天一次，施用三週停止一週給予200mg的劑量的瑞博西尼。 For example, the compound of formula (I) can be administered at a dose of 400 mg or 600 mg once or twice a day, preferably twice a day, and reboxi can be administered at a dose of 200 mg once a day for three weeks. Ni.

例如，可以一天一次或兩次，較佳的是一天兩次，給予600mg的劑量的具有式(I)之化合物，並且可以一天一次，施用三週停止一週給予600mg的劑量的瑞博西尼。 For example, the compound of formula (I) may be administered at a dose of 600 mg once or twice a day, preferably twice a day, and reboxinib may be administered at a dose of 600 mg once a day for three weeks and a week to stop the administration of 600 mg.

根據本文揭露的方法，具有式(I)之化合物或其藥學上可接受的鹽和CDK4/6抑制劑，較佳的是瑞博西尼或其藥學上可接受的鹽可以一起使用。 取決於預期的給藥劑量和頻率，兩種化合物能一起投與或單獨投與，因為預期本發明的治療可以持續如治療醫師認為合適的以及進一步使用本文所述的確定合適的劑量和投與頻率的方法指導的2天、3天、4天、5天、6天、1週、2週、3週、4週或超過4週。劑量的頻率可以根據所使用的化合物和待治療的具體病症而變化。通常，較佳的是使用足以提供有效治療的最小劑量，並且其可以藉由以下標準來確定，例如患者的年齡、體重和性別；待治療的癌症的程度和嚴重性；和主治醫師的判斷。通常可以使用適合於正在治療的病症的測定法來監測患者的治療效果，該等測定法為熟悉該項技術者所熟悉。 According to the method disclosed herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor, preferably reboxinil or a pharmaceutically acceptable salt thereof, can be used together. Depending on the expected dosage and frequency of administration, the two compounds can be administered together or separately, because the treatment of the present invention is expected to last as deemed appropriate by the treating physician and further use as described herein to determine the appropriate dosage and administration The frequency method is guided by 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks or more than 4 weeks. The frequency of dosage can vary depending on the compound used and the specific condition to be treated. Generally, it is preferable to use the minimum dose sufficient to provide effective treatment, and it can be determined by the following criteria, such as the age, weight, and gender of the patient; the degree and severity of the cancer to be treated; and the judgment of the attending physician. The treatment effect of the patient can usually be monitored using assays suitable for the condition being treated, and these assays are familiar to those skilled in the art.

產生功效而無毒性的本發明組合的組合配偶體(即，具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽)的最佳比率、單個劑量和組合劑量、以及濃度係基於治療劑對靶部位的可用性的動力學和多種因素，該等因素包括但不限於疾病的進展程度；個體的年齡、體重、總體健康狀況、性別和飲食；投與的時間和途徑；以及個體正在服用的其他藥物。可以使用本領域熟知的常規測試和程式來確定最佳劑量。例如，如由治療情況的緊急狀態所指示的，可以投與單次推注，可以隨著時間的推移投與若干個分次劑量，或可以按比例地減少或增加劑量。 The combination partner of the combination of the present invention that produces efficacy without toxicity (ie, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof The optimal ratio, single and combined dose, and concentration of the acceptable salt) are based on the kinetics of the availability of the therapeutic agent to the target site and various factors, including but not limited to the degree of disease progression; the age of the individual, Weight, general health, gender, and diet; time and route of administration; and other medications the individual is taking. Routine tests and procedures well known in the art can be used to determine the optimal dosage. For example, as indicated by the emergency of the treatment situation, a single bolus can be administered, several divided doses can be administered over time, or the dose can be reduced or increased proportionally.

可以藉由任何合適的途徑投與本發明的組合的治療劑。應當理解，較佳的途徑可以根據例如該組合的接受者的健康狀況和待治療的癌症位置而變化。還應理解，可以藉由相同或不同的途徑投與每種治療劑，並且可以將該等治療劑，例如具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽，一起複合在藥物組成物中。 The combined therapeutic agent of the present invention can be administered by any suitable route. It should be understood that the preferred route may vary according to, for example, the health of the recipient of the combination and the location of the cancer to be treated. It should also be understood that each therapeutic agent can be administered by the same or different routes, and the therapeutic agents can be, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (Suitable for direbocinil) or a pharmaceutically acceptable salt thereof, together in the pharmaceutical composition.

如本文揭露，具有式(I)之化合物或其藥學上可接受的鹽，和CDK4/6抑制劑，適合地瑞博西尼或其藥學上可接受的鹽可以一起使用。可以將本發明的組合的兩種治療劑一起(同時地)、順序地或單獨地投與。 As disclosed herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor, suitably direbocinil or a pharmaceutically acceptable salt thereof, can be used together. The two therapeutic agents of the combination of the present invention can be administered together (simultaneously), sequentially or separately.

此外，是否將化合物以相同的劑型投與並不重要，例如，可以將一種化合物局部投與而可以將另一種化合物口服投與。適合地，將兩種治療劑口服投與。化合物可以以相同或不同劑型投與。 In addition, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered locally while the other compound may be administered orally. Suitably, both therapeutic agents are administered orally. The compounds can be administered in the same or different dosage forms.

因此，在一個實施方式中，將一個或多個劑量的具有式(I)之化合物或其藥學上可接受的鹽與一個或多個劑量的CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽同時地、順序地或單獨地投與。 Therefore, in one embodiment, one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are combined with one or more doses of a CDK4/6 inhibitor (suitable for deribocinib) Or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately.

在一個實施方式中，將多劑量的具有式(I)之化合物或其藥學上可接受的鹽與多劑量的CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽同時地、順序地或單獨地投與。 In one embodiment, multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are combined with multiple doses of a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof Administer simultaneously, sequentially or separately.

在一個實施方式中，將多劑量的具有式(I)之化合物或其藥學上可接受的鹽與一個劑量的CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽同時地、順序地或單獨地投與。 In one embodiment, multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are combined with one dose of a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof Administer simultaneously, sequentially or separately.

在一個實施方式中，將一個劑量的具有式(I)之化合物或其藥學上可接受的鹽與多劑量的CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽同時地、順序地或單獨地投與。 In one embodiment, one dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with multiple doses of a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof Administer simultaneously, sequentially or separately.

在一個實施方式中，將一個劑量的具有式(I)之化合物或其藥學上可接受的鹽與一個劑量的CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽同時地、順序地或單獨地投與。 In one embodiment, a dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is combined with a dose of a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof Administer simultaneously, sequentially or separately.

在所有上述實施方式中，可以首先投與具有式(I)之化合物或其藥學上可接受的鹽，或可以首先投與CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽。 In all of the above embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered first, or a CDK4/6 inhibitor (suitable for deribocinil) or a pharmaceutically acceptable salt thereof may be administered first Accepted salt.

在一個實施方式中，本文提供藥物組成物，該藥物組成物包含用於本發明方法之(a)具有式(I)之化合物或其藥學上可接受的鹽和(b)CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽。在一個實施方式中，藥物組成 物進一步包含一種或多種藥學上可接受的稀釋劑、賦形劑或載體。一種或多種載體、稀釋劑或賦形劑在與配製物(能夠係藥物配製物)的其他成分相容的意義上必須是可接受的，並且對其接受者無害。所使用的藥物組成物的此類元素可以按單獨的藥物組合形式呈現或一起配製於一種藥物組成物中。可以將本文揭露的組合以單一的組成物一起投與或以兩種或更多種不同的組成物單獨地投與，例如，如該的組成物或劑型，並且該等組分可以作為相同的配製物或作為單獨的配製物單獨地(例如，如上所示)投與或藉由任何合適的途徑與一種或多種藥學上可接受的載體組合地投與。 In one embodiment, provided herein is a pharmaceutical composition comprising (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) a CDK4/6 inhibitor used in the method of the present invention (Suitable for direbocinil) or a pharmaceutically acceptable salt thereof. In one embodiment, the drug composition The substance further comprises one or more pharmaceutically acceptable diluents, excipients or carriers. The one or more carriers, diluents or excipients must be acceptable in the sense of being compatible with the other ingredients of the formulation (capable of being a pharmaceutical formulation) and not harmful to the recipient thereof. Such elements of the pharmaceutical composition used can be presented as a single pharmaceutical combination or formulated together in one pharmaceutical composition. The combination disclosed herein can be administered together as a single composition or separately administered as two or more different compositions, for example, the composition or dosage form, and these components can be the same The formulations are either administered as a separate formulation alone (e.g., as shown above) or by any suitable route in combination with one or more pharmaceutically acceptable carriers.

如本文所用的劑量單位形式係指適合作為用於要治療的受試者的單元劑量的物理上離散的單位；每個單位包含經計算以產生與所需的藥物載體相關聯的所需治療效果的預定量的活性化合物(例如，具有式(I)之化合物或其藥學上可接受的鹽，或CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽)。該單位劑型還可以是固定組合。 Dosage unit form as used herein refers to physically discrete units suitable as unit doses for the subject to be treated; each unit contains calculations to produce the desired therapeutic effect associated with the required pharmaceutical carrier A predetermined amount of active compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a CDK4/6 inhibitor (suitable for direbocinil) or a pharmaceutically acceptable salt thereof). The unit dosage form can also be a fixed combination.

該等組合配偶體中的每一者的有效劑量可能需要當與組合中的其他治療劑相比時更頻繁地投與該治療劑中的一種。因此，為了允許適當地給藥，包裝的藥物產品可以包含一種或多種含有該化合物組合的劑型，以及一種或多種含有本發明組合的治療劑中的一種治療劑、但不含有本發明組合的另一治療劑的劑型。 The effective dose of each of the combination partners may require that one of the therapeutic agents be administered more frequently when compared to the other therapeutic agents in the combination. Therefore, in order to allow proper administration, the packaged pharmaceutical product may contain one or more dosage forms containing the compound combination, and one or more containing one of the therapeutic agents of the combination of the present invention, but not containing the other of the combination of the present invention. A dosage form of a therapeutic agent.

當在本發明的組合中採用的組合配偶體以作為單一藥物銷售的形式使用時，如果沒有另外提及，則它們的劑量和投與方式可以依據相應市售藥物的包裝說明書上提供的資訊。 When the combination partners used in the combination of the present invention are used in the form of being sold as a single drug, if not mentioned otherwise, their dosage and administration method can be based on the information provided on the package insert of the corresponding commercially available drug.

因此，為允許適當地給藥，包裝的藥物產品可以包含一種或多種含有該藥劑組合的劑型，以及一種或多種含有該組合的治療劑中的一種治療劑、但不含有該組合的另一治療劑的劑型。 Therefore, in order to allow proper administration, the packaged drug product may contain one or more dosage forms containing the combination of agents, and one or more of the therapeutic agents containing the combination, but not the other of the combination. The dosage form of the agent.

還在本發明範圍內的是組合套組，其包含作為治療劑的本發明的組合，如本文所述用於同時、單獨或順序地投與，以及一種或多種其他的元素：使用說明書；用於與本發明的組合一起使用的其他試劑；用於製備投與化合物的裝置或其他材料，如混合容器；藥學上可接受的載體；以及用於向受試者投與的裝置或其他材料，如注射器。 Also within the scope of the present invention is a combination kit comprising a combination of the present invention as a therapeutic agent for simultaneous, separate or sequential administration as described herein, and one or more other elements: instructions for use; Other reagents for use with the combination of the present invention; devices or other materials for preparing compounds for administration, such as mixing containers; pharmaceutically acceptable carriers; and devices or other materials for administration to subjects, Such as a syringe.

如本文使用的術語「組合套組」或「成套套組」意指根據本發明使用的一種或多種藥物組成物。當同時投與兩種化合物時，組合套組可以包含呈單一藥物組成物(例如片劑)或分開的藥物組成物的具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽。當未同時投與具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽，和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽時，組合套組將包含呈以單一包裝的單獨藥物組成物或以分開包裝的分開藥物組成物的具有式(I)之化合物或其藥學上可接受的鹽、和CDK4/6抑制劑(適合地瑞博西尼)或其藥學上可接受的鹽。 The term "combination kit" or "kitchen kit" as used herein means one or more pharmaceutical compositions used in accordance with the present invention. When two compounds are administered at the same time, the combination kit may include a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single pharmaceutical composition (for example, a tablet) or separate pharmaceutical compositions, and CDK4/ 6 Inhibitors (suitable for Deribosini) or a pharmaceutically acceptable salt thereof, and CDK4/6 inhibitors (suitable for Deribosine) or a pharmaceutically acceptable salt thereof. When the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (suitable for direbocinil) or a pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor are not administered at the same time (Suitable for dribocinil) or a pharmaceutically acceptable salt thereof, the combination kit will comprise the compound of formula (I) or the compound of formula (I) in a single package of separate drug compositions or separate drug compositions in separate packages A pharmaceutically acceptable salt thereof, and a CDK4/6 inhibitor (suitable for direbocinil) or a pharmaceutically acceptable salt thereof.

在本發明的一個實施方式中，該成套套組包含以下組分：(a)Raf抑制劑化合物，該化合物選自由以下組成的組：(i)與藥學上可接受的賦形劑、稀釋劑和/或載體關聯的、具有式(I)之化合物或其藥學上可接受的鹽，和(b)與藥學上可接受的賦形劑、稀釋劑或載體關聯的CDK4/6抑制劑(較佳的是瑞博西尼)或其藥學上可接受的鹽，其中將該等組分以適合用於順序地、單獨地和/或同時地投與的形式提供。組合套組還可以提供有說明書，例如劑量說明書和投與說明書。這樣的劑量說明書和給藥說明書可以屬於提供給醫生的種類(例如藉由藥品產品標籤)，或者它們可以屬於醫生提供的種類(例如對患者的說明)。 In one embodiment of the present invention, the kit includes the following components: (a) a Raf inhibitor compound, the compound is selected from the group consisting of: (i) with pharmaceutically acceptable excipients and diluents And/or a carrier-related compound having formula (I) or a pharmaceutically acceptable salt thereof, and (b) a CDK4/6 inhibitor (compared with a pharmaceutically acceptable excipient, diluent or carrier) Preferably, ribocinil) or a pharmaceutically acceptable salt thereof, wherein the components are provided in a form suitable for sequential, separate and/or simultaneous administration. The combination kit may also be provided with instructions, such as dosage instructions and administration instructions. Such dosage instructions and administration instructions may belong to the type provided to the doctor (for example, by drug product label), or they may belong to the type provided by the doctor (for example, instructions to the patient).

根據說明書和附圖並且如申請專利範圍，本發明的其他特徵、目標和優點將是清楚的。 From the specification and drawings and as in the scope of the patent application, other features, objectives and advantages of the present invention will be clear.

以下實例展示了上述發明；然而，該等實例並不旨在以任何方式限制本發明的範圍。本發明的藥物組合的有益作用還可以藉由相關領域技術人員已知的像這樣的其他測試模型來確定。 The following examples illustrate the above-mentioned invention; however, these examples are not intended to limit the scope of the invention in any way. The beneficial effects of the drug combination of the present invention can also be determined by other test models like this known to those skilled in the relevant art.

實例Instance

實例1：NRAS突變型黑色素瘤細胞系中RAF抑制與CDK4/CDK6抑制的增強的組合作用Example 1: Enhanced combined effect of RAF inhibition and CDK4/CDK6 inhibition in NRAS mutant melanoma cell lines

方法method

合成具有式(I)之化合物(NVP-LXH254)和瑞博西尼(NVP-瑞博西尼)，並在DMSO中以10mM的終濃度製備瑞博西尼的化合物儲備液。對於組合試驗，將工作儲備液在適當的細胞培養基中以3倍的增量進行連續稀釋(對於瑞博西尼，2倍增量)，以達到最終測定濃度：NVP-LXH254的範圍為10μM至1.5nM，NVP-瑞博西尼為10μM至39nM(琥珀酸鹽形式)。The compound of formula (I) (NVP-LXH254) and Rebocinil (NVP-Rebocinil) were synthesized, and the compound stock solution of Rebocinil was prepared in DMSO at a final concentration of 10 mM. For the combination test, serially dilute the working stock solution in the appropriate cell culture medium in 3-fold increments (for ribocinil, 2-fold increments) to reach the final measured concentration: the range of NVP-LXH254 is 10 μM to 1.5 nM, NVP-Ribocinil is 10 μM to 39 nM (succinate form).

SK-MEL-2細胞購自美國菌種保藏中心(ATCC)，MEL-JUSO細胞購自德國微生物和細胞培養系列有限公司(DSMZ)，MM415細胞購自澳大利亞細胞庫，以及IPC-298和SK-MEL-30細胞獲自GNF。將IPC-298、MEL-JUSO、MM415、和SK-MEL-30細胞培養於RPMI培養基(ATCC)中，且將SK-MEL-2細胞培養於BMEM培養基(ATCC)中，這兩種培養基均補充有10%胎牛血清(Gibco)，然後在37℃/5%CO2下孵育。對於組合活性，將細胞以每孔5,000個細胞的密度接種在96孔板(康寧公司#3904)中的80μl培養基中，並在添加化合物之前孵育過夜。在適當培養基中新鮮製備化合物儲備液(10x)且藉由電子多通道移液管一式三份手動添加至板中以創建完整的10x10組合矩陣網格。在至少三個重複孔中，根據製造商的方案藉由基於螢光的DNA結合增殖測定 CyQUANT®(賽默飛公司#C35011)評價在化合物添加時細胞的數量和生存能力，以及72小時後組合效應的定量。使用諾華內部軟體「組合分析模組」進行組合數據分析。該應用程式利用Loewe劑量加和模型計算每個劑量矩陣的加權協同作用得分，該得分對劑量採樣和覆蓋範圍進行了調整，並且針對高抑制水平下的有利組合效應進行權重(Lehar等人，2009)。 SK-MEL-2 cells were purchased from American Type Culture Collection (ATCC), MEL-JUSO cells were purchased from German Microorganism and Cell Culture Series Limited (DSMZ), MM415 cells were purchased from Australian Cell Bank, and IPC-298 and SK- MEL-30 cells were obtained from GNF. IPC-298, MEL-JUSO, MM415, and SK-MEL-30 cells were cultured in RPMI medium (ATCC), and SK-MEL-2 cells were cultured in BMEM medium (ATCC), both of which were supplemented With 10% fetal bovine serum (Gibco), then incubate at 37°C/5% CO2. For combinatorial activity, cells were seeded in 80 μl of medium in a 96-well plate (Corning #3904) at a density of 5,000 cells per well and incubated overnight before adding compounds. The compound stock solution (10x) was freshly prepared in the appropriate medium and manually added to the plate in triplicate with an electronic multichannel pipette to create a complete 10x10 combinatorial matrix grid. In at least three replicate wells, the fluorescence-based DNA binding proliferation assay CyQUANT® (Thermo Fisher #C35011) was used to evaluate the number and viability of the cells at the time of compound addition according to the manufacturer’s protocol , and the combination after 72 hours Quantitative effect. Use Novartis' internal software "Combination Analysis Module" for combination data analysis. The application uses the Loewe dose summation model to calculate a weighted synergy score for each dose matrix, which adjusts the dose sampling and coverage, and weights the favorable combination effects at high levels of inhibition (Lehar et al., 2009 ).

將細胞以0.5 x 106個細胞/孔的密度鋪在6孔培養皿(#3506，康寧公司，NY)中。鋪板後一天，將品系用200nM、400nM和800nM的單一藥劑瑞博西尼和具有式(I)之化合物(300nM)的組合處理48小時。在含有蛋白酶抑制劑(#87785，賽默飛世爾公司(Thermo Fisher)，沃爾瑟姆，麻塞諸塞州)和磷酸酶抑制劑(#78420，賽默飛世爾公司，沃爾瑟姆，麻塞諸塞州)的RIPA裂解緩衝液(#89900，賽默飛世爾公司，沃爾瑟姆，麻塞諸塞州)中收穫細胞。在4%-12% Bis-Tris NuPAGE SDS凝膠(#WG1403Bx10，美國生命技術公司(Life Technologies)，卡爾斯巴德，加利福尼亞州)上分離蛋白質，並使用Trans-Blot Turbo系統(伯樂公司(Bio-Rad)，赫拉克勒斯(Hercules)，加利福尼亞州)將其轉移至硝化纖維素。用識別pRB(#8516，細胞訊號技術，Beverly，MA)、pCDK4/61/2(#9154，細胞訊號技術，Beverly，MA)、pERK1/2(#4730，細胞訊號技術，Beverly，MA)和pRSK(#9348，細胞訊號技術，Beverly，MA)的抗體以1：1000稀釋度和識別β-肌動蛋白的抗體(#AM4302，生命技術公司，卡爾斯巴德，加利福尼亞州)以1：5000稀釋度檢測蛋白質。使用抗小鼠HRP或抗兔HRP二抗檢測蛋白水平，並在GE Image Quant LAS 4000成像系統(GE健康醫療公司(GE Healthcare)，沃本，麻塞諸塞州)上用SuperSignal West Femto(#34096，賽默飛科學公司(Thermo Scientific)，沃爾瑟姆，麻塞諸塞州)或Dura化學發光底物(#34076，賽默飛科學公司，沃爾瑟姆，麻塞諸塞州)進行顯影。 The cells were plated in a 6-well culture dish (#3506, Corning, NY) at a density of 0.5 x 106 cells/well. One day after plating, the strains were treated with a combination of 200 nM, 400 nM and 800 nM of the single agent Rebocinil and the compound of formula (I) (300 nM) for 48 hours. It contains protease inhibitors (#87785, Thermo Fisher (Thermo Fisher), Waltham, Massachusetts) and phosphatase inhibitors (#78420, Thermo Fisher, Waltham, The cells were harvested in RIPA lysis buffer (#89900, Thermo Fisher Scientific, Waltham, Massachusetts) in Massachusetts). The protein was separated on 4%-12% Bis-Tris NuPAGE SDS gel (#WG1403Bx10, Life Technologies, Carlsbad, California), and the Trans-Blot Turbo system (Bio -Rad), Hercules (California) transferred it to nitrocellulose. Use to identify pRB (#8516, Cell Signal Technology, Beverly, MA), pCDK4/61/2 (#9154, Cell Signal Technology, Beverly, MA), pERK1/2 (#4730, Cell Signal Technology, Beverly, MA) and The antibody of pRSK (#9348, Cell Signaling Technology, Beverly, MA) is diluted 1:1000 and the antibody that recognizes β-actin (#AM4302, Life Technologies, Carlsbad, California) is 1:5000 Dilution test protein. Use anti-mouse HRP or anti-rabbit HRP secondary antibodies to detect protein levels, and use SuperSignal West Femto(#) on the GE Image Quant LAS 4000 imaging system (GE Healthcare, Woburn, Massachusetts) 34096, Thermo Scientific (Thermo Scientific, Waltham, Massachusetts) or Dura chemiluminescent substrate (#34076, Thermo Scientific, Waltham, Massachusetts) Perform development.

結果result

相對於SK-MEL-30黑色素瘤細胞系中的單一處理，具有式(I)之化合物和瑞博西尼的組合證實了改善抗增殖和pho-Rb抑制作用(圖1)。SK-MEL-30黑色素瘤細胞系在NRAS(Q61K)和BRAF(D287H)中攜帶同時突變。 Compared to a single treatment in the SK-MEL-30 melanoma cell line, the combination of the compound of formula (I) and Reboxinil demonstrated improved anti-proliferation and pho-Rb inhibition (Figure 1). The SK-MEL-30 melanoma cell line carries simultaneous mutations in NRAS (Q61K) and BRAF (D287H).

相對於IPC-298黑色素瘤細胞系中的單一處理，具有式(I)之化合物和瑞博西尼的組合證實了改善抗增殖和pho-Rb抑制作用(圖2)。IPC-298黑色素瘤細胞系攜帶NRAS突變(NRASQ61L)。 Relative to a single treatment in the IPC-298 melanoma cell line, the combination of a compound of formula (I) and reboxinil demonstrated improved anti-proliferation and pho-Rb inhibition (Figure 2). The IPC-298 melanoma cell line carries the NRAS mutation (NRASQ61L).

相對於Meljuso黑色素瘤細胞系中的單一處理，具有式(I)之化合物和瑞博西尼的組合證實了改善抗增殖和pho-Rb抑制作用(圖3)。Meljuso黑色素瘤細胞系攜帶NRAS突變(NRASQ61L)。 Relative to a single treatment in the Meljuso melanoma cell line, the combination of a compound of formula (I) and reboxinil demonstrated improved anti-proliferation and pho-Rb inhibition (Figure 3). Meljuso melanoma cell line carries the NRAS mutation (NRASQ61L).

相對於Meljuso黑色素瘤細胞系中的單一處理，具有式(I)之化合物和瑞博西尼的組合證實了改善抗增殖和pho-Rb抑制作用(圖4)。 Relative to a single treatment in the Meljuso melanoma cell line, the combination of a compound of formula (I) and Reboxinil demonstrated improved anti-proliferation and pho-Rb inhibition (Figure 4).

實例2：具有式(I)之化合物和瑞博西尼在衍生自NRAS突變型黑色素瘤患者的異種移植中的組合功效Example 2: Combined Efficacy of Compound of Formula (I) and Reboxinil in Xenotransplantation Derived from Patients with NRAS Mutant Melanoma

藉由將具有式(I)之化合物和瑞博西尼在九個衍生自NRAS突變型黑色素瘤患者的異種移植中組合，研究了選擇性雙重RAF和CDK4/6抑制在體內的作用。The effects of selective dual RAF and CDK4/6 inhibition in vivo were studied by combining a compound of formula (I) and Rebocinil in nine xenografts derived from NRAS mutant melanoma patients.

方法method

動物和維持條件：在操作前至少3天，允許遠系雜交無胸腺的(nu/nu)雌性小鼠(Athymic Nude-nu」)(查理斯河，印弟安納波里斯)在隨意獲取食物和水的諾華公司NIBR動物設施中適應新環境(表1)。Animals and maintenance conditions: At least 3 days before the operation, allow outbred athymic (nu/nu) female mice (Athymic Nude-nu") (Charles River, Indianapolis) to get food and The water adapts to the new environment in the NIBR animal facility of Novartis (Table 1).

Figure 108147073-A0202-12-0035-8
Figure 108147073-A0202-12-0035-8

Figure 108147073-A0202-12-0036-9
Figure 108147073-A0202-12-0036-9

關於動物福利的聲明：根據諾華NIBR ACUC條例和指南處理動物。 Statement on animal welfare: handling of animals in accordance with Novartis NIBR ACUC regulations and guidelines.

測試化合物和配方：將具有式(I)之化合物(游離鹼形式)在MEPC4媒介物(45%克列莫佛(Cremophor)RH40+27%PEG400+18%玉米油甘油酯+10%乙醇)中經口(口服)給藥。將具有式(I)之化合物配製為5mg/mL。將瑞博西尼琥珀酸鹽在0.5%甲基纖維素的媒介物中經口(口服)給藥；將瑞博西尼配製為7.5mg/mL。 Test compound and formula: Put the compound of formula (I) (free base form) in MEPC4 vehicle (45% Cremophor RH40+27%PEG400+18% corn oil glyceride+10% ethanol) Oral (oral) administration. The compound of formula (I) is formulated at 5 mg/mL. Rebocinil succinate was administered orally (orally) in a 0.5% methylcellulose vehicle; Rebocinil was formulated at 7.5 mg/mL.

在裸小鼠中開發衍生自患者的異種移植(PDX)模型Development of patient-derived xenograft (PDX) models in nude mice

衍生自患者的腫瘤異種移植(PDX)HMEX5727、HMEX3486、HMEX20667、HMEX2921、HMEX20864、HMEX20585、HMEX4339、HMEX20744、和HMEX21124藉由腫瘤漿液的連續傳代在裸鼠中繁殖。簡而言之，使用溫和的MACS分離器(MACS美天旎生物技術公司(MACS Miltenyi Biotec)、#120-005-331)將先前傳代的新鮮腫瘤片段勻漿，通過組織研磨機(Chemglass生命科學公司(Chemglass lifeSciences)# CLS-5020-085)，在PBS中稀釋，並與等體積的MatrigelTumor xenografts (PDX) derived from patients HMEX5727, HMEX3486, HMEX20667, HMEX2921, HMEX20864, HMEX20585, HMEX4339, HMEX20744, and HMEX21124 were reproduced in nude mice by serial passage of tumor serum. In short, a gentle MACS separator (MACS Miltenyi Biotec, #120-005-331) was used to homogenize fresh tumor fragments from previous passages, and pass through a tissue grinder (Chemglass Life Science company (Chemglass lifeSciences)# CLS-5020-085), diluted in PBS, and equal volume of Matrigel TMTM 基質(康寧#354234)混合。然後將200ul腫瘤漿液皮下植入雌性裸小鼠的右側。藉由用卡尺測量並使用公式計算腫瘤體積，其中腫瘤體積(VSubstrate (Corning #354234) was mixed. Then 200ul tumor slurry was implanted subcutaneously into the right side of female nude mice. Calculate the tumor volume by measuring with a caliper and using the formula, where the tumor volume (V TT )(mm)(mm 33 )=(l x w2)/2，其中l係腫瘤的最長軸並且w垂直於l。監測小鼠的腫瘤生長、體重和身體狀況，兩次/週。)=(l x w2)/2, where l is the longest axis of the tumor and w is perpendicular to l. Monitor the tumor growth, body weight and physical condition of the mice twice a week.

在PDX模型中的功效研究設計Efficacy study design in PDX model

表2描述了所有模型的功效研究設計。以根據體重調整的10mL/kg的劑量體積給予測試劑。在隨機分組時收集腫瘤尺寸和體重，之後在研究持續時 間內每週收集兩次。當平均腫瘤體積為大約350mm3時，將小鼠隨機分為處理組(n=3-5/組)，並實施處理直至腫瘤長大(腫瘤體積>/=700mm3)或大約90天。藉由將時間t處的腫瘤體積變化與其基線進行比較，確定所有模型的腫瘤體積變化百分比。最佳反應係t

Figure 108147073-A0202-12-0037-44
10天的腫瘤體積變化百分比的最小值。在處死未經處理的對照小鼠時，也處死來自每組的2隻小鼠，並收集腫瘤用於將來的藥效學(PD)分析。對超過這一點的3隻小鼠/組進行功效研究。 Table 2 describes the efficacy study design for all models. The test agent was administered in a dose volume of 10 mL/kg adjusted according to body weight. Tumor size and body weight were collected at randomization, and then collected twice a week for the duration of the study . When the average tumor volume was about 350 mm 3 , the mice were randomly divided into treatment groups (n=3-5/group), and the treatment was performed until the tumor grew (tumor volume>/=700 mm 3 ) or about 90 days. By comparing the tumor volume change at time t with its baseline, the percentage of tumor volume change for all models is determined. Best response system t
Figure 108147073-A0202-12-0037-44
The minimum value of tumor volume change percentage for 10 days. When the untreated control mice were sacrificed, 2 mice from each group were also sacrificed, and tumors were collected for future pharmacodynamic (PD) analysis. The efficacy study was performed on 3 mice/group exceeding this point.

Figure 108147073-A0202-12-0037-10
Figure 108147073-A0202-12-0037-10

數據分析data analysis

體重：體重變化百分比計算為(BWWeight: The percentage of weight change is calculated as (BW 當前current -BW-BW 初始initial )/(BW)/(BW 初始initial )×100%。數據表示為相比處理開始日的體重變化平均百分比±SEM。)×100%. The data are expressed as the mean percentage of body weight change from the day of treatment start ± SEM.

腫瘤體積：藉由將時間t處的腫瘤體積變化與其基線使用以下公式進行比較，確定腫瘤體積變化百分比：%腫瘤體積變化=△V t =100%×((V t -V 初始 )/V 初始 )。最佳反應係t

Figure 108147073-A0202-12-0037-45
10天的△V t 的最小值。 Tumor volume: tumor volume by the time t to its baseline using the following formula determined by comparing the percent change in tumor volume: tumor volume change% = △ V t = 100% × ((V t -V initial) / V Initial ). Best response system t
Figure 108147073-A0202-12-0037-45
The minimum value of ΔV t for 10 days .

其中：among them:

△V△V tt =腫瘤體積變化= Tumor volume change

VV tt =研究給定日藥物處理(或未經處理)組的腫瘤體積；= Study the tumor volume of the drug-treated (or untreated) group on a given day;

V初始=給藥初始日藥物處理(或未經處理)組的腫瘤體積。最佳反應>/=-30%考被認為腫瘤消退。 Vinitial =the tumor volume of the drug-treated (or untreated) group on the first day of administration. The best response>/=-30% test is considered tumor regression.

使用GraphPad Prism軟體為達到腫瘤大小>/=700mm3的終點的個體小鼠生成卡普蘭-梅爾存活圖。使用對數秩(曼特爾-考克斯)檢驗對組之間的顯著性進行統計學分析。p<0.05被認為係顯著的。 GraphPad Prism software was used to generate Kaplan-Meier survival maps for individual mice reaching the end point of tumor size >/=700mm 3 . The log-rank (Mantel-Cox) test was used to statistically analyze the significance between groups. p<0.05 was considered significant.

結果：具有式(I)之化合物和瑞博西尼在衍生自患者的NRAS突變型黑色素瘤異種移植裸小鼠模型中的組合功效Results: The combined efficacy of the compound of formula (I) and Reboxinil in a nude mouse model of NRAS mutant melanoma xenograft derived from a patient

使用九個衍生自NRAS突變型黑色素瘤患者的異種移植裸小鼠模型確定具有式(I)之化合物與瑞博西尼組合使用時的抗腫瘤功效：HMEX5727(NRASQ61K)、HMEX3486(NRASQ61K)、HMEX20667(NRASQ61R)、HMEX2921(NRASQ61R)、HMEX20585(NRASQ61R)、HMEX20864(NRASQ61R)、HMEX21124(NRASQ61H)、HMEX20744(NRASQ61K)、和HMEX4339(NRASQ61R)。將小鼠處理大約90-100天或直到每組中的腫瘤大小達到>/=700mmNine xenograft nude mouse models derived from patients with NRAS mutant melanoma were used to determine the anti-tumor efficacy of the compound of formula (I) when used in combination with Reboxinil: HMEX5727 (NRASQ61K), HMEX3486 (NRASQ61K), HMEX20667 (NRASQ61R), HMEX2921 (NRASQ61R), HMEX20585 (NRASQ61R), HMEX20864 (NRASQ61R), HMEX21124 (NRASQ61H), HMEX20744 (NRASQ61K), and HMEX4339 (NRASQ61R). Treat the mice for approximately 90-100 days or until the tumor size in each group reaches >/=700mm 33 。表3、圖5和圖6報告了腫瘤體積變化百分比(最佳反應)、體重變化百分比和存活率。. Table 3, Figure 5 and Figure 6 report the percentage change in tumor volume (best response), percentage change in body weight, and survival rate.

以50mg/kg bid(具有式(I)之化合物)+75mg/kg qd(瑞博西尼)給藥的具有式(I)之化合物+瑞博西尼的組合活性在44%的測試模型中導致腫瘤消退。相比之下，在任何測試的模型中，以50mg/kg bid給藥的具有式(I)之化合物的單一藥劑或以75mg/kg qd給藥的瑞博西尼的單一藥劑均未實現腫瘤消退(表3和圖5)。此外，與每種單一藥劑或未經處理的對照相比，具有式(I)之化合物+瑞博西尼的組合導致生存中值顯著增加(圖6)。The combined activity of the compound with formula (I) and the compound of formula (I) administered at 50 mg/kg bid (compound of formula (I)) + 75 mg/kg qd (ribocinil) in 44% of the test models Lead to tumor regression. In contrast, in any model tested, a single agent with a compound of formula (I) administered at 50 mg/kg bid or a single agent of Rebocinil administered at 75 mg/kg qd did not achieve tumor Recessed (Table 3 and Figure 5). In addition, the combination of compound of formula (I) + Rebocinil resulted in a significant increase in median survival compared to each single agent or untreated control (Figure 6).

根據各模型缺乏體重減輕的判斷，單一藥劑和組合處理的耐受性都很好。由於體重減輕，在較早的時間點處死了用具有式(I)之化合物處理的一隻小鼠。According to the judgment of lack of weight loss in each model, the single agent and the combination treatment are well tolerated. Due to weight loss, one mouse treated with the compound of formula (I) was sacrificed at an earlier time point.

Figure 108147073-A0202-12-0039-11
Figure 108147073-A0202-12-0039-11

Figure 108147073-A0202-12-0040-12
Figure 108147073-A0202-12-0040-12

Figure 108147073-A0202-12-0041-13
Figure 108147073-A0202-12-0041-13

結論與討論conclusion and discussion

在一組九個衍生自患者的NRAS突變型黑色素瘤異種移植中，描述了具有式(I)之化合物+瑞博西尼組合在NRAS突變型黑色素瘤中的體內活性。以50mg/kg bid(具有式(I)之化合物)+75mg/kg qd(瑞博西尼)給藥的具有式(I)之化合物+瑞博西尼的組合活性在44%的測試模型中導致腫瘤消退。相比之下，在任何測試的模型中，以50mg/kg bid給藥的具有式(I)之化合物的單一藥劑或以75mg/kg qd給藥的瑞博西尼的單一藥劑均未實現腫瘤消退。此外，與每種單一藥劑或未經處理的對照相比，具有式(I)之化合物+瑞博西尼的組合耐受性很好並導致生存中值百分比顯著增加。在衍生自NRAS突變型患者的黑色素瘤異種移植中，已觀察到CDK4/6抑制劑瑞博西尼與具有式(I)之化合物強效協同 作用，且導致臨床前模型中顯著的腫瘤消退和生存中值百分比增加。總體而言，該等數據表明，在NRAS突變型黑色素瘤患者中，具有式(I)之化合物+瑞博西尼的組合可實現更大和更持久的反應。 In a group of nine NRAS mutant melanoma xenografts derived from patients, the in vivo activity of the compound of formula (I) + Rebocinil combination in NRAS mutant melanoma is described. The combined activity of the compound with formula (I) and the compound of formula (I) administered at 50 mg/kg bid (compound of formula (I)) + 75 mg/kg qd (ribocinil) in 44% of the test models Lead to tumor regression. In contrast, in any model tested, a single agent with a compound of formula (I) administered at 50 mg/kg bid or a single agent of Rebocinil administered at 75 mg/kg qd did not achieve tumor Subside. In addition, compared with each single agent or untreated control, the combination of compound of formula (I) + Rebocinil was well tolerated and resulted in a significant increase in the median survival percentage. In melanoma xenografts derived from patients with NRAS mutants, it has been observed that the CDK4/6 inhibitor Ribocinil has a strong synergistic effect with the compound of formula (I) , and leads to significant tumor regression and The median survival percentage increased. Overall, these data indicate that in patients with NRAS mutant melanoma, the combination of a compound of formula (I) + Rebocinil can achieve a larger and longer-lasting response.

實例3：在NRAS突變型黑色素瘤患者中進行的、具有式(I)之化合物與瑞博西尼組合的Ib期、非盲、多中心研究Example 3: Phase Ib, non-blind, multi-center study of the combination of a compound of formula (I) and Rebocinil in patients with NRAS mutant melanoma

這項研究的目的是表徵在NRAS突變型黑色素瘤患者中的具有式(I)之化合物和瑞博西尼雙重組合的安全性和耐受性，並確定推薦劑量。The purpose of this study is to characterize the safety and tolerability of the dual combination of the compound of formula (I) and Reboxinil in patients with NRAS mutant melanoma, and to determine the recommended dosage.

主要終點係Primary endpoint

(1)安全性：不良事件(AE)和嚴重AE(SAE)的發生率和嚴重程度，包括實驗室值、生命體征和心電圖(ECG)的變化，第一個週期(僅劑量遞增)期間劑量限制毒性(DLT)的發生率和性質，(1) Safety: The incidence and severity of adverse events (AE) and severe AE (SAE), including changes in laboratory values, vital signs, and electrocardiogram (ECG), and dose during the first cycle (dose escalation only) The incidence and nature of limited toxicity (DLT),

(2)耐受性：劑量中斷、減少和劑量強度。(2) Tolerability: dose interruption, reduction and dose intensity.

次要目的和終點係：Secondary goals and end points:

(a)評估具有式(I)之化合物與瑞博西尼組合的初始抗腫瘤活性。根據實體瘤反應評估標準(RECIST)版本1.1的整體反應率(ORR)、疾病控制率(DCR)、反應持續時間(DOR)、無進展存活期(PFS)。僅對於劑量擴展部分：總體存活(OS)、血漿濃度和推導的PK參數(a) Assess the initial anti-tumor activity of the combination of the compound of formula (I) and reboxinil. According to the solid tumor response assessment criteria (RECIST) version 1.1, the overall response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). For the dose expansion part only: overall survival (OS), plasma concentration and derived PK parameters

(b)表徵具有式(I)之化合物和瑞博西尼的組合的藥物動力學(PK)曲線。在腫瘤組織中PD標記DUSP6從基線的變化。(b) Characterizing the pharmacokinetic (PK) curve of the combination of the compound of formula (I) and Reboxinil. The change of PD marker DUSP6 from baseline in tumor tissue.

(c)評估具有式(I)之化合物和瑞博西尼的組合在腫瘤中的藥效學(PD)效應(DUSP6)(c) Assess the pharmacodynamic (PD) effect of the combination of the compound of formula (I) and Reboxinil in tumors (DUSP6)

探索性目標和終點係：Exploratory goals and end points:

(a)評價腫瘤樣本(腫瘤和血漿(循環游離DNA(cfDNA))中多種癌症相關基因的遺傳改變，以評估它們與臨床結果/抗性發展的關係。在基線和給藥後 (包括疾病進展時)在腫瘤樣本中發現的多種癌症相關基因中的遺傳改變，以及它們與臨床結果終點的關係。 (a) Evaluate the genetic changes of multiple cancer-related genes in tumor samples (tumor and plasma (circulating free DNA (cfDNA)) to assess their relationship with clinical outcome/development of resistance. At baseline and after administration (including disease progression) Time) Genetic changes in multiple cancer-related genes found in tumor samples, and their relationship with clinical outcome endpoints.

(b)進一步評價具有式(I)之化合物與瑞博西尼組合的PD效應。在血液中PD標記(例如，DUSP6)從基線的變化。 (b) To further evaluate the PD effect of the combination of the compound of formula (I) and reboxinil. Changes from baseline in PD markers (for example, DUSP6) in the blood.

(c)評估具有式(I)之化合物與瑞博西尼之間的藥物-藥物相互作用(DDI)。具有式(I)之化合物和瑞博西尼血漿濃度和推導的PK參數。 (c) Evaluate the drug-drug interaction (DDI) between the compound of formula (I) and reboxinil. Plasma concentrations of the compound of formula (I) and ribocinil and the derived PK parameters.

(d)調查cfDNA改變如何反映文件和(如果有)新獲得的腫瘤樣本的遺傳改變。在給定的時間點(給藥前和給藥後)，來自同一患者腫瘤和作為替代組織的血漿樣本中測得的遺傳改變的差異。 (d) Investigate how changes in cfDNA reflect genetic changes in files and (if any) newly obtained tumor samples. At a given time point (pre-dose and post-dose), the difference in genetic changes measured in plasma samples from the same patient’s tumor and as a replacement tissue.

這係一項多中心、非盲、Ib期劑量遞增研究，後面係劑量擴展部分。具有式(I)之化合物與瑞博西尼的組合將在攜帶NRAS突變的黑素瘤患者中投與。研究治療將一直進行，直到患者出現無法接受的毒性、進展性疾病和/或根據研究者或患者的判斷或由於撤回同意而中斷治療。一個週期定義為28天。 This is a multicenter, unblinded, phase Ib dose escalation study, followed by dose expansion. The combination of a compound of formula (I) and reboxinil will be administered in melanoma patients carrying NRAS mutations. The study treatment will continue until the patient has unacceptable toxicity, progressive disease and/or the treatment is interrupted based on the judgment of the investigator or the patient or due to withdrawal of consent. One cycle is defined as 28 days.

入選標準：患有診斷為局部晚期或轉移性NRAS突變的黑色素瘤的成年(18歲或以上)黑色素瘤患者，他們遵循標準治療進展，或對其尚無有效的標準療法，不耐受，不適當或不被認為與研究治療等效，該等患者將有資格參加本研究。腫瘤組織中NRAS突變的存在先於由當地實驗室或諾華指定的中心實驗室確定的研究治療，或KRAS、BRAF或NRAS突變的書面文件。ECOG(美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group)體能狀態

Figure 108147073-A0202-12-0043-43
2。患者必須具有適合活檢的疾病部位，並且必須願意根據治療機構自己的指導方針和此類程序的要求在基線和治療期間接受新的腫瘤活檢。根據RECIST v1.1要求存在至少一個可測量的病變。 Inclusion criteria: Adult (18 years or older) melanoma patients with melanoma diagnosed as locally advanced or metastatic NRAS mutations, they follow the standard treatment progress, or there is no effective standard treatment for them, intolerance, not Appropriate or not considered equivalent to the study treatment, such patients will be eligible to participate in this study. The presence of NRAS mutations in tumor tissues precedes research treatments determined by local laboratories or central laboratories designated by Novartis, or written documents of KRAS, BRAF or NRAS mutations. ECOG (Eastern Cooperative Oncology Group) fitness status
Figure 108147073-A0202-12-0043-43
2. The patient must have a disease site suitable for biopsy, and must be willing to receive a new tumor biopsy at baseline and during treatment in accordance with the treatment organization’s own guidelines and requirements of such procedures. According to RECIST v1.1, there is at least one measurable lesion.

排除標準： Exclusion criteria:

(a)先前用RAF抑制劑(包括任何BRAF抑制劑和Raf抑制劑)或CDK4/6抑制劑治療。 (a) Previous treatment with RAF inhibitors (including any BRAF inhibitor and Raf inhibitor) or CDK4/6 inhibitor.

(b)在規定的時間範圍內，在研究治療的第一劑量之前，使用以下任何抗癌療法治療： (b) Within the prescribed time frame, before the first dose of the study treatment, use any of the following anti-cancer therapies:

(i)在研究治療的第一劑量之前，放射療法

Figure 108147073-A0202-12-0044-37
4週或緩解性有限域放射
Figure 108147073-A0202-12-0044-38
2週。 (i) Before the first dose of study treatment, radiotherapy
Figure 108147073-A0202-12-0044-37
4 weeks or remission limited field radiation
Figure 108147073-A0202-12-0044-38
2 weeks.

(ii)化學療法或生物療法(免疫療法除外)或連續或間歇性小分子療法或任何其他試驗劑的

Figure 108147073-A0202-12-0044-39
4週或
Figure 108147073-A0202-12-0044-40
5個半衰期(以較短者為准)。 (ii) Chemotherapy or biological therapy (except immunotherapy) or continuous or intermittent small molecule therapy or any other test agent
Figure 108147073-A0202-12-0044-39
4 weeks or
Figure 108147073-A0202-12-0044-40
5 half-lives (whichever is shorter).

(iii)包括免疫檢查點抑制劑的任何免疫療法

Figure 108147073-A0202-12-0044-41
4週。 (iii) Any immunotherapy including immune checkpoint inhibitors
Figure 108147073-A0202-12-0044-41
4 weeks.

(iv)具有主要延遲毒性的細胞毒性劑

Figure 108147073-A0202-12-0044-42
6週，如亞硝基脲和絲裂黴素C。 (iv) Cytotoxic agents with major delayed toxicity
Figure 108147073-A0202-12-0044-42
6 weeks, such as nitrosourea and mitomycin C.

(c)視網膜靜脈阻塞(RVO)或當前RVO危險因素(例如不受控制的青光眼或高眼壓症，高黏血症或血凝過快綜合症的病史)的病史或當前證據。 (c) History or current evidence of retinal vein occlusion (RVO) or current RVO risk factors (such as uncontrolled glaucoma or ocular hypertension, hyperviscosity or rapid blood clotting syndrome).

(d)研究者判斷，由於安全問題或遵守臨床研究程序而妨礙患者參加臨床研究的任何醫療狀況。可增加與研究參與或研究治療投與有關的風險或可干擾研究結果的判讀和在研究者判斷下將使患者不適於該研究的任何嚴重、急性或慢性醫學或精神病症或實驗異常。 (d) The investigator judges any medical condition that prevents the patient from participating in clinical research due to safety issues or compliance with clinical research procedures. Any serious, acute or chronic medical or psychiatric disorder or experimental abnormality that can increase the risk associated with research participation or research treatment administration or can interfere with the interpretation of research results and, at the judgment of the researcher, will make the patient unsuitable for the research.

(e)接受已知係CYP3A和CYP2C8的強抑制劑和/或誘導劑；UGT2B7的抑制劑或誘導劑；UGT1A1的底物和抑制劑；具有較窄的治療指數的CYP2C8、CYP2C9和CYP3A的底物；以及CYP3A的敏感底物、已知會引起肝毒性的草藥(該等在開始研究治療前7天和整個研究期間不能中斷)的藥物治療的患者。 (e) Accept strong inhibitors and/or inducers of known CYP3A and CYP2C8; inhibitors or inducers of UGT2B7; substrates and inhibitors of UGT1A1; substrates and inhibitors of CYP2C8, CYP2C9 and CYP3A with a narrow therapeutic index As well as sensitive substrates of CYP3A, and herbal medicines known to cause hepatotoxicity (these cannot be interrupted 7 days before the start of the study treatment and during the entire study period).

(f)接受質子泵抑制劑(PPI)(其在開始研究治療前3天和整個研究期間不能中斷)的患者。 (f) Patients receiving proton pump inhibitor (PPI) (which cannot be interrupted 3 days before the start of study treatment and throughout the study period).

(g)具有除了在本研究中接受治療的之外的惡性疾病的患者。此排除標準的例外情況包括：在研究治療前2年內已治癒並且未復發的惡性腫瘤；完全切除的基底細胞和鱗狀細胞皮膚癌；以及完全切除的任何類型的原位癌。 (g) Patients with malignant diseases other than those treated in this study. Exceptions to this exclusion criterion include: malignant tumors that have been cured and have not recurred within 2 years before study treatment; basal cell and squamous cell skin cancers that have been completely resected; and any type of carcinoma in situ that has been completely resected.

評估臨床功效，根據RECIST版本1.1和總體存活(OS)(僅在劑量擴展部分)測量整體反應率(ORR)、疾病控制率(DCR)、響應持續時間(DOR)、無進展存活(PFS)。 To evaluate the clinical efficacy, the overall response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) were measured according to RECIST version 1.1 and overall survival (OS) (only in the dose expansion part).

來自Calu-6異種移植物中的劑量分級功效研究的數據證明，在不同給藥水平下，QD(qd)給藥和每日兩次(BID)分次給藥具有式(I)之化合物顯示出相似水平的抗腫瘤活性。該等結果支持在臨床中探索QD或BID劑量方案。 The data from the dose-grading efficacy study in Calu-6 xenografts prove that QD (qd) dosing and twice daily (BID) divided doses of compounds with formula (I) at different dosing levels show A similar level of anti-tumor activity. These results support the exploration of QD or BID dosage regimens in the clinic.

將進行臨床功效潛在體征的評價，包括ORR、PFS和OS評價。 Evaluation of potential signs of clinical efficacy, including ORR, PFS and OS evaluation will be conducted.

在研究的劑量遞增部分期間招募的所有患者，將被分配接受與瑞博西尼組合的具有式(I)之化合物，以評估組合的安全性和耐受性。 All patients enrolled during the dose escalation portion of the study will be assigned to receive the compound of formula (I) in combination with reboxinib to assess the safety and tolerability of the combination.

每個測試方案的劑量遞增將由基於第一週期DLT數據的貝葉斯邏輯回歸模型(BLRM)指導。 The dose escalation of each test protocol will be guided by the Bayesian Logistic Regression Model (BLRM) based on the DLT data of the first cycle.

BLRM/BHLRM係一種公認的在癌症患者中評估MTD的方法。自我調整BLRM/BHLRM將由控制劑量過量的遞增設計(EWOC)原理指導以控制研究中未來患者的DLT風險。針對小數據集使用貝葉斯響應自我調整模型已經被EMEA(「Guideline on clinical trials in small populations[群體臨床試驗指南]」，2007年2月13日)接受並得到眾多出版物(Babb等人1998，Neuenschwander等人2008，Neuenschwander等人2010)的認可，其開發和適當使用係FDA關鍵路徑計畫的一個方面。 BLRM/BHLRM is a recognized method for evaluating MTD in cancer patients. The self-adjusting BLRM/BHLRM will be guided by the principle of overdose controlled incremental design (EWOC) to control the risk of DLT in future patients in the study. The Bayesian response self-adjustment model for small data sets has been accepted by EMEA ("Guideline on clinical trials in small populations", February 13, 2007) and received numerous publications (Babb et al. 1998 , Neuenschwander et al. 2008, Neuenschwander et al. 2010), its development and proper use are an aspect of the FDA’s critical path plan.

進入該擴展部分的患者將以推薦的具有式(I)之化合物和瑞博西尼的劑量組合(MTD或較低劑量組合)治療。 Patients entering this extended section will be treated with the recommended dose combination (MTD or lower dose combination) of the compound of formula (I) and reboxinil.

將評價組合的安全性(包括劑量-DLT關係)和耐受性；基於該等數據的審查，將確定用於劑量擴展的一個或多個劑量和一個或多個方案。推薦的擴展劑量也將由有關PK、PD和初步抗腫瘤活性的可用資訊來指導。 The safety (including the dose-DLT relationship) and tolerability of the combination will be evaluated; based on the review of such data, one or more doses and one or more regimens for dose expansion will be determined. The recommended extended dose will also be guided by available information about PK, PD and preliminary anti-tumor activity.

治療treatment

研究治療將在禁食狀態下按28天給藥週期投與。The study treatment will be administered in a 28-day dosing cycle under fasting conditions.

口服使用片劑和膠囊劑，分配劑量，每日劑量，持續28天。Tablets and capsules are used orally, and the dose is divided into daily doses for 28 days.

研究者或負責的研究中心人員應指導患者按如規定服用研究藥物提高順應性。The investigator or the responsible research center personnel should instruct the patient to take the study drug as prescribed to improve compliance.

患者應將任何錯過或延遲的劑量告知研究工作人員。Patients should inform the research staff of any missed or delayed doses.

如果研究者或患者自行決定中斷治療和/或患者撤回同意，則由於不可接受的毒性、進展性疾病，患者較早中斷研究治療。If the investigator or the patient decides to discontinue treatment and/or the patient withdraws consent, the patient will discontinue the study treatment early due to unacceptable toxicity and progressive disease.

下表描述了可在該試驗期間評估的單獨研究藥物(非組合)的起始劑量和臨時劑量水平。The following table describes the starting and provisional dose levels of the individual study drugs (not combination) that can be evaluated during this trial.

具有式(I)之化合物和瑞博西尼的組合的建議劑量水平Suggested dosage levels for the combination of a compound of formula (I) and Rebocinil

Figure 108147073-A0202-12-0046-14
Figure 108147073-A0202-12-0046-14

任何組合的一個或多個MTD均定義為該組合的最高劑量組合，該組合在研究的遞增部分中，在具有式(I)之化合物和瑞博西尼治療的第一個週期中不太可能(<25%的後驗概率)導致33%或更多的接受治療的患者產生DLT。 One or more MTDs of any combination are defined as the highest dose combination of the combination, which is unlikely in the escalating part of the study in the first cycle of treatment with the compound of formula (I) and Rebocinil (<25% posterior probability) cause 33% or more of the treated patients to develop DLT.

研究者和諾華研究人員認為，RD將是小於或等於MTD並具有基於對安全性和耐受性、PK、PD和活性資訊的審查而最適當的利益風險評價的劑量。應當注意的是在某些情況下可能無法達到MTD。 Researchers and Novartis researchers believe that RD will be less than or equal to MTD and have the most appropriate benefit and risk evaluation based on the review of safety and tolerability, PK, PD and activity information. It should be noted that in some cases the MTD may not be reached.

CDK4/6抑制劑也可以連續投與(即在治療期間沒有間斷)或在具有假期期間的情況下投與。 CDK4/6 inhibitors can also be administered continuously (that is, without interruption during the treatment period) or when there is a holiday period.

例如，CDK4/6抑制劑，例如瑞博西尼或其藥學上可接受的鹽可以以投與3週停止1週，或投與2週停止2週的方式投與；較佳的是施用3週停止1週。特別地，根據本發明可以使用以下方案： For example, a CDK4/6 inhibitor, such as reboxinil or a pharmaceutically acceptable salt thereof, can be administered for 3 weeks and stop for 1 week, or for 2 weeks and stop for 2 weeks; preferably, 3 Week stop for 1 week. In particular, the following schemes can be used according to the present invention:

Figure 108147073-A0202-12-0047-15
Figure 108147073-A0202-12-0047-15

Figure 108147073-A0202-11-0002-1
Figure 108147073-A0202-11-0002-1

Claims (26)

Raf抑制劑和CDK4/6抑制劑之藥物組合，其中該Raf抑制劑係具有式(I)之化合物， A drug combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the Raf inhibitor is a compound of formula (I),
Figure 108147073-A0202-13-0001-17
Figure 108147073-A0202-13-0001-17
 或其藥學上可接受的鹽。 Or a pharmaceutically acceptable salt thereof. Raf抑制劑和CDK4/6抑制劑之藥物組合，其中該CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 A drug combination of a Raf inhibitor and a CDK4/6 inhibitor, wherein the CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof. 如申請專利範圍第1項所述之藥物組合，其中 The drug combination as described in item 1 of the scope of patent application, wherein (i)該Raf抑制劑係具有式(I)之化合物或其藥學上可接受的鹽；以及 (i) The Raf inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (ii)該CDK4/6抑制劑係瑞博西尼或其藥學上可接受的鹽。 (ii) The CDK4/6 inhibitor is Reboxinil or a pharmaceutically acceptable salt thereof. 如申請專利範圍第1-3項中任一項所述之藥物組合，用於在癌症的治療中使用。 The drug combination described in any one of items 1 to 3 in the scope of the patent application is used in the treatment of cancer. 用於如申請專利範圍第4項所述使用之藥物組合，其中該癌症具有NRAS突變。 For the drug combination used as described in item 4 of the scope of patent application, wherein the cancer has an NRAS mutation. 用於如申請專利範圍第4項所述使用之藥物組合，其中該癌症具有KRAS突變。 The drug combination used as described in item 4 of the scope of patent application, wherein the cancer has a KRAS mutation. 用於如申請專利範圍第4或5項所述使用之藥物組合，其中該癌症係黑色素瘤。 For the drug combination used as described in item 4 or 5 of the scope of patent application, wherein the cancer is melanoma. 用於如申請專利範圍第7項所述使用之藥物組合，其中該癌症係突變型黑色素瘤，較佳的是NRAS突變型黑色素瘤。 For the drug combination used as described in item 7 of the scope of patent application, wherein the cancer is a mutant melanoma, preferably NRAS mutant melanoma. 用於如申請專利範圍第8項所述使用之藥物組合，其中該黑色素瘤表現至少一個選自由以下組成之群組之突變：NRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、和Q61E。 For the drug combination used as described in item 8 of the scope of patent application, wherein the melanoma exhibits at least one mutation selected from the group consisting of: NRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D , G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, and Q61E. 用於如申請專利範圍第4或6項所述使用之藥物組合，其中該癌症係胰臟癌，例如胰腺導管腺癌(PDAC)。 For the drug combination used as described in item 4 or 6, wherein the cancer is pancreatic cancer, such as pancreatic ductal adenocarcinoma (PDAC). 用於如申請專利範圍第10項所述使用之藥物組合，其中該癌症係突變型胰臟癌，例如突變型PDAC，較佳的是KRAS突變型PDAC。 The drug combination used as described in item 10 of the scope of patent application, wherein the cancer is a mutant pancreatic cancer, such as mutant PDAC, preferably KRAS mutant PDAC. 用於如申請專利範圍第11項所述使用之藥物組合，其中該PDAC表現至少一個選自由以下組成之群組之突變：KRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、和Q61E。 For the drug combination used as described in claim 11, wherein the PDAC exhibits at least one mutation selected from the group consisting of: KRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, and Q61E. 用於如申請專利範圍第4至12項中任一項所述使用之藥物組合，其中該兩種化合物或其藥學上可接受的鹽分開地、同時地或順序地投與。 The drug combination for use as described in any one of the claims 4 to 12, wherein the two compounds or pharmaceutically acceptable salts thereof are administered separately, simultaneously or sequentially. 用於如申請專利範圍第4至13項中任一項所述使用之藥物組合，其中口服投與一種或兩種化合物或其藥學上可接受的鹽。 The drug combination for use as described in any one of items 4 to 13 in the scope of the patent application, wherein one or two compounds or pharmaceutically acceptable salts thereof are administered orally. 用於如申請專利範圍第4至14項中任一項所述使用之藥物組合，其中該Raf抑制劑或其藥學上可接受的鹽以約100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg、1300mg、1400mg、1500mg、或1600mg的總日劑量投與。 The drug combination for use as described in any one of items 4 to 14 in the scope of the patent application, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is at about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg , 800mg, 900mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg, or 1600mg total daily dose administration. 用於如申請專利範圍第4至15項中任一項所述使用之藥物組合，其中該Raf抑制劑每天一次或每天兩次投與。 The drug combination for use as described in any one of the claims 4 to 15, wherein the Raf inhibitor is administered once a day or twice a day. 用於如申請專利範圍第4至16項中任一項所述使用之藥物組合，其中在治療期間，該Raf抑制劑連續投與。 For the drug combination used as described in any one of the claims 4 to 16, wherein the Raf inhibitor is continuously administered during the treatment period. 用於如申請專利範圍第4至17項中任一項所述使用之藥物組合，其中該CDK4/6抑制劑或其藥學上可接受的鹽以約100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、或600mg的總日劑量投與。 For the drug combination used as described in any one of the claims 4 to 17, wherein the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is at about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg , 400mg, 450mg, 500mg, 550mg, or 600mg total daily dose administration. 用於如申請專利範圍第4至18項中任一項所述使用之藥物組合，其中該CDK4/6抑制劑每天一次或每天兩次投與。 The drug combination for use as described in any one of the claims 4 to 18, wherein the CDK4/6 inhibitor is administered once a day or twice a day. 用於如申請專利範圍第4至19項中任一項所述使用之藥物組合，其中該CDK4/6抑制劑在具有藥物假期的情況下投與，例如投與三週停止一週。 For the drug combination used as described in any one of items 4 to 19 in the scope of the patent application, wherein the CDK4/6 inhibitor is administered with a drug holiday, for example, the administration is stopped for three weeks for one week. 如申請專利範圍第1-3項中任一項所述之藥物組合，用於治療突變型黑色素瘤、較佳的是NRAS突變型黑色素瘤，該突變型黑色素瘤表現至少一個選自由以下組成之群組之突變：NRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、Q61E，或用於治療突變型胰臟癌，例如突變型PDAC，較佳的是KRAS突變型PDAC，該突變型胰臟癌表現至少一個選自由以下組成之群組之突變：KRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、Q61E，其中該Raf抑制劑或其藥學上可接受的鹽以約600mg bid的日劑量投與，且其中該CDK4/6抑制劑或其藥學上可接受的鹽以約600mg qd的日劑量投與。 The drug combination described in any one of items 1 to 3 in the scope of the patent application is used for the treatment of mutant melanoma, preferably NRAS mutant melanoma, and the mutant melanoma exhibits at least one selected from the following Group mutations: NRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E, or for the treatment of mutations Type of pancreatic cancer, such as mutant PDAC, preferably KRAS mutant PDAC, the mutant pancreatic cancer exhibits at least one mutation selected from the group consisting of: KRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg bid And wherein the CDK4/6 inhibitor or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 600 mg qd. 如申請專利範圍第1-3項中任一項所述之藥物組合，用於治療突變型黑色素瘤、較佳的是NRAS突變型黑色素瘤，該突變型黑色素瘤表現至少一個選自由以下組成之群組之突變：NRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、Q61E，或用於治療突變型胰臟癌，例如突變型PDAC，較佳的是 KRAS突變型PDAC，該突變型胰臟癌表現至少一個選自由以下組成之群組之突變：KRAS突變G12C、G12R、G12D、G12V、G12S、G12A、G13R、G13D、G13C、G13A、G13、G13S、G13V、Q61R、Q61L、Q61K、Q61H、Q61P、Q61E，其中該Raf抑制劑或其藥學上可接受的鹽以約600mg bid的日劑量連續地投與，且其中該CDK4/6抑制劑或其藥學上可接受的鹽以約600mg qd的日劑量投與，投與三週，停止一週。 The drug combination described in any one of items 1 to 3 in the scope of the patent application is used for the treatment of mutant melanoma, preferably NRAS mutant melanoma, and the mutant melanoma exhibits at least one selected from the following Group mutations: NRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E, or for the treatment of mutations Type pancreatic cancer, such as mutant PDAC, preferably KRAS mutant PDAC, the mutant pancreatic cancer exhibits at least one mutation selected from the group consisting of: KRAS mutations G12C, G12R, G12D, G12V, G12S, G12A, G13R, G13D, G13C, G13A, G13, G13S, G13V, Q61R, Q61L, Q61K, Q61H, Q61P, Q61E, wherein the Raf inhibitor or a pharmaceutically acceptable salt thereof is continuously administered at a daily dose of about 600 mg bid, and wherein the CDK4/6 inhibitor or the pharmaceutically acceptable salt thereof The above-acceptable salt is administered at a daily dose of about 600 mg qd for three weeks and one week off. 如申請專利範圍第1-3項中任一項所述之藥物組合用於製備用於治療癌症的藥物之用途。 The drug combination described in any one of items 1 to 3 in the scope of the patent application is used for the preparation of drugs for the treatment of cancer. 一種用於在有需要的受試者中治療癌症之方法，該方法包括向該受試者投與治療有效量的如申請專利範圍第1-3項中任一項所述之藥物組合。 A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the drug combination as described in any one of items 1 to 3 in the scope of the patent application. 具有式(I)之化合物 The compound of formula (I)
Figure 108147073-A0202-13-0004-18
Figure 108147073-A0202-13-0004-18
 或其藥學上可接受的鹽，用於藉由與瑞博西尼或其藥學上可接受的鹽共同投與來治療癌症。 Or a pharmaceutically acceptable salt thereof, for the treatment of cancer by co-administration with reboxinil or a pharmaceutically acceptable salt thereof. 瑞博西尼或其藥學上可接受的鹽，用於藉由與具有式(I)之化合物或其藥學上可接受的鹽共同投與來治療癌症。 Reboxinil or a pharmaceutically acceptable salt thereof is used for the treatment of cancer by co-administration with a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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