TW202146024A - A triple pharmaceutical combination comprising dabrafenib, an erk inhibitor and a raf inhibitor or a pd-1 inhibitor. - Google Patents
A triple pharmaceutical combination comprising dabrafenib, an erk inhibitor and a raf inhibitor or a pd-1 inhibitor. Download PDFInfo
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Abstract
Description
本發明關於藥物組合，該藥物組合包含：The present invention relates to a pharmaceutical combination comprising:
(i). 達拉菲尼（dabrafenib）或其藥學上可接受的鹽、Erk抑制劑（ERKi）例如4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（「化合物A（Compound A或compound A）」）或其藥學上可接受的鹽、和RAF抑制劑例如N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（「化合物C」）或其藥學上可接受的鹽；或(i). Dabrafenib or a pharmaceutically acceptable salt thereof, Erk inhibitors (ERKi) such as 4-(3-amino-6-((1S,3S,4S)-3-fluoro- 4-Hydroxycyclohexyl)pyridin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluoro Benzylamide ("Compound A or compound A") or a pharmaceutically acceptable salt thereof, and a RAF inhibitor such as N-(3-(2-(2-hydroxyethoxy)-6- 𠰌olinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide ("Compound C") or a pharmaceutically acceptable salt thereof; or
(ii). 達拉菲尼或其藥學上可接受的鹽、Erk抑制劑（ERKi）例如4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（「化合物A（Compound A或compound A）」）或其藥學上可接受的鹽、和PD-1抑制劑例如斯巴達珠單抗；以及包含該藥物組合的藥物組成物；包含該藥物組合的商業包裝；以及在治療或預防其中MAPK途徑抑制係有益的病症中、例如在治療癌症中使用此類組合和組成物之方法。本發明還提供了此類組合，用於在此類病症或癌症（包括大腸直腸癌（CRC），例如BRAF功能獲得性大腸直腸癌）的治療中使用。(ii). Dabrafenib or a pharmaceutically acceptable salt thereof, Erk inhibitors (ERKi) such as 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxy Cyclohexyl)pyridin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzyl An amine ("Compound A (or compound A)") or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor such as spartalizumab; and a pharmaceutical composition comprising the drug combination; comprising the drug Commercial packaging of the combinations; and methods of using such combinations and compositions in the treatment or prevention of disorders in which MAPK pathway inhibition is beneficial, such as in the treatment of cancer. The invention also provides such combinations for use in the treatment of such disorders or cancers, including colorectal cancer (CRC), eg, BRAF gain-of-function colorectal cancer.
MAPK途徑係驅動細胞增殖、分化和存活的關鍵傳訊級聯。此途徑的失調係許多腫瘤發生實例之基礎。MAPK途徑的異常傳訊或不當活化已顯示於多種腫瘤類型中，並且可以藉由幾種不同的機制發生，包括活化RAS和BRAF中的突變。MAPK途徑頻繁在人類癌症中發生突變，其中KRAS 突變和BRAF 突變係最常見的（大約30%）。已在所有癌症的9%-30%中檢測到RAS 突變，特別是功能獲得性突變，其中KRAS 突變的患病率最高（86%）。The MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. Aberrant signaling or inappropriate activation of the MAPK pathway has been shown in a variety of tumor types and can occur through several different mechanisms, including activating mutations in RAS and BRAF. The MAPK pathway is frequently mutated in human cancers, with KRAS mutations and BRAF mutations being the most common (approximately 30%). RAS mutations, especially gain-of-function mutations, have been detected in 9%-30% of all cancers , with KRAS mutations having the highest prevalence (86%).
胞外信號調節激酶（ERK）係一類涉及傳送細胞外信號到細胞和亞細胞器的傳訊激酶。ERK1和ERK2參與調節大範圍的活動，並且已知ERK1/2級聯的失調會導致多種疾病，包括神經變性疾病、發育疾病、糖尿病和癌症。ERK1/2在癌症中的作用係被特別關注的，因為在ERK1/2傳訊級聯中活化其上游的突變被認為係所有癌症半數以上的原因。此外，過度的ERK1/2活性也在癌症中被發現，其中上游元件沒有突變，這表明ERK1/2信號即使係在沒有突變活化的癌症中也在致癌作用中起作用。ERK途徑也顯示出控制腫瘤細胞的遷移和侵襲，並且因此與轉移有關。Extracellular signal-regulated kinases (ERKs) are a class of signaling kinases involved in the transmission of extracellular signals to cells and subcellular organelles. ERK1 and ERK2 are involved in regulating a wide range of activities, and dysregulation of the ERK1/2 cascade is known to contribute to a variety of diseases, including neurodegenerative diseases, developmental diseases, diabetes and cancer. The role of ERK1/2 in cancer is of particular interest because mutations that activate upstream of the ERK1/2 signaling cascade are thought to be responsible for more than half of all cancers. In addition, excessive ERK1/2 activity has also been found in cancers where upstream elements are not mutated, suggesting that ERK1/2 signaling plays a role in carcinogenesis even in cancers without mutational activation. The ERK pathway has also been shown to control tumor cell migration and invasion, and is thus implicated in metastasis.
計劃性死亡1（PD-1）蛋白係T細胞調節子的擴展的CD28/CTLA-4家族的抑制性成員。已經鑒定出PD-1的兩種配位基PD-L1（B7-H1）和PD-L2（B7-DC），已經證實兩者在結合PD-1時下調T細胞活化。PD-L1在多種人癌症中大量存在。PD-1被認為係負調節TCR信號的免疫抑制性蛋白。PD-1和PD-L1之間的相互作用可以充當免疫檢查點，該相互作用可以導致例如腫瘤浸潤性淋巴細胞的減少、T細胞受體介導的增殖的減少和/或癌細胞的免疫逃避。藉由抑制PD-1與PD-L1或PD-L2的局部相互作用可以逆轉免疫抑制；當PD-1與PD-L2的相互作用被阻斷時，效果也是累加的。Planned death 1 (PD-1) protein is an extended inhibitory member of the CD28/CTLA-4 family of T-cell regulators. Two ligands of PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified, and both have been shown to downregulate T cell activation when bound to PD-1. PD-L1 is abundant in a variety of human cancers. PD-1 is considered to be an immunosuppressive protein that negatively regulates TCR signaling. The interaction between PD-1 and PD-L1 can act as an immune checkpoint that can lead to, for example, a decrease in tumor-infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and/or immune evasion of cancer cells . Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; when the interaction of PD-1 with PD-L2 is blocked, the effect is also additive.
鑒於免疫檢查點途徑在調節免疫應答中的重要性，需要開發新的活化免疫系統的組合療法。患有某些癌症的患者的預後仍然差。對治療的抗性經常發生，並且不是所有患者都對可用治療有反應。例如，患有BRAF突變的晚期大腸直腸癌患者的中位生存期少於12個月。因此，重要的是為患有癌症的患者開發新的療法以達到更好的臨床結果。還需要具有更好的耐受性和/或提供持久的抗腫瘤應答的治療選擇。Given the importance of the immune checkpoint pathway in regulating immune responses, there is a need to develop new combination therapies that activate the immune system. The prognosis for patients with certain cancers remains poor. Resistance to therapy frequently occurs, and not all patients respond to available treatments. For example, patients with advanced colorectal cancer with BRAF mutations have a median survival of less than 12 months. Therefore, it is important to develop new therapies for patients with cancer to achieve better clinical outcomes. There is also a need for therapeutic options that are better tolerated and/or provide durable antitumor responses.
本發明 (i) 達拉菲尼；Erk-抑制劑（例如化合物A）、和RAF-抑制劑（例如化合物C）；或 (ii) 達拉菲尼、Erk-抑制劑（例如化合物A）、和PD-1抑制劑（例如斯巴達珠單抗）的三重組合可以用作用於治療由MAPK途徑的異常活性引起的疾病或障礙的療法，該疾病或障礙包括但不限於乳癌、膽管癌、唾液腺癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。達拉菲尼、Erk-抑制劑（例如化合物A）、和RAF-抑制劑（例如化合物C），或者達拉菲尼、Erk-抑制劑（例如化合物A）、和PD-1抑制劑（例如斯巴達珠單抗）的三重組合特別是用於治療BRAF功能獲得性或BRAFV600E/D/K突變型大腸直腸癌（CRC），包括晚期或轉移性大腸直腸癌。The present invention (i) Dabrafenib; Erk-inhibitor (eg Compound A), and RAF-inhibitor (eg Compound C); or (ii) Dabrafenib, Erk-inhibitor (eg Compound A), A triple combination with a PD-1 inhibitor such as spartalizumab can be used as a therapy for the treatment of diseases or disorders caused by abnormal activity of the MAPK pathway, including but not limited to breast cancer, cholangiocarcinoma, Salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer. Dabrafenib, an Erk-inhibitor (eg, Compound A), and a RAF-inhibitor (eg, Compound C), or dabrafenib, an Erk-inhibitor (eg, Compound A), and a PD-1 inhibitor (eg, The triple combination of spartalizumab) is specifically indicated for the treatment of BRAF gain-of-function or BRAFV600E/D/K mutant colorectal cancer (CRC), including advanced or metastatic colorectal cancer.
本發明提供包含以下的藥物組合：
(a) N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽，其具有以下結構：
本發明提供包含以下的藥物組合：
(a) N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽，其具有以下結構：
在本發明之另一個方面，PD-1抑制劑選自PDR001（斯巴達珠單抗；諾華公司（Novartis））、納武單抗（百時美施貴寶公司）、派姆單抗（默克公司（Merck & Co））、匹地利珠單抗（CureTech公司）、MEDI0680（醫學免疫公司）、REGN2810（再生元公司（Regeneron））、TSR-042（Tesaro公司）、PF-06801591（輝瑞製藥公司（Pfizer））、BGB-A317（百濟神州公司（Beigene））、BGB-108（百濟神州公司）、INCSHR1210（因賽特公司（Incyte））、或AMP-224（Amplimmune公司）。In another aspect of the present invention, the PD-1 inhibitor is selected from the group consisting of PDR001 (spartalizumab; Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck & Co. (Merck & Co), pidilizumab (CureTech), MEDI0680 (Medical Immunology), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer Pharmaceuticals) (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP-224 (Amplimmune).
在本發明之另一個方面，PD-1抑制劑係PDR001（斯巴達珠單抗）。In another aspect of the invention, the PD-1 inhibitor is PDR001 (spartalizumab).
(i) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、和化合物C或其藥學上可接受的鹽的藥物組合，或者 (ii) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、和PD-1抑制劑例如斯巴達珠單抗的藥物組合在本文中也稱為「本發明之組合」。(i) a pharmaceutical combination of Dabrafenib or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, and Compound C or a pharmaceutically acceptable salt thereof, or (ii) Dabrafenib A pharmaceutical combination thereof, or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor, such as spartalizumab, is also referred to herein as the "combination of the present invention."
提供了本發明之組合，用於在癌症的治療中使用，例如，用於在選自以下的癌症中使用：乳癌、膽管癌、唾液腺癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。Combinations of the invention are provided for use in the treatment of cancer, for example, for use in a cancer selected from the group consisting of breast cancer, bile duct cancer, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, Ovarian and thyroid cancer.
提供了 (i) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、和化合物C或其藥學上可接受的鹽的藥物組合，或者 (ii) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、和PD-1抑制劑例如斯巴達珠單抗的藥物組合，例如，用於在選自以下的癌症中使用：乳癌、膽管癌、唾液腺癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。There is provided a pharmaceutical combination of (i) Dabrafenib or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, and Compound C or a pharmaceutically acceptable salt thereof, or (ii) Dabrafenib A pharmaceutical combination of fenib, or a pharmaceutically acceptable salt thereof, Compound A, or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor such as spartalizumab, for example, for use in cancer selected from Uses: Breast cancer, bile duct cancer, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.
還提供了 (i) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、和化合物C或其藥學上可接受的鹽的組合，或者 (ii) 達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、PD-1抑制劑例如 斯巴達珠單抗的組合，用於在BRAF功能獲得性或BRAFV600E/D/K突變型大腸直腸癌（其包括晚期或轉移性大腸直腸癌）的治療中使用。Also provided is a combination of (i) Dabrafenib, or a pharmaceutically acceptable salt thereof, Compound A, or a pharmaceutically acceptable salt thereof, and Compound C, or a pharmaceutically acceptable salt thereof, or (ii) Dalafenib Combination of fenib or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, a PD-1 inhibitor such as spartatizumab, for use in BRAF gain-of-function or BRAFV600E/D/K Use in the treatment of mutant colorectal cancer, which includes advanced or metastatic colorectal cancer.
本文還提供的是本發明之組合，用於在BRAF功能獲得性或BRAFV600E/D/K突變型大腸直腸癌（其包括晚期或轉移性大腸直腸癌）的治療中使用。Also provided herein is a combination of the invention for use in the treatment of BRAF gain-of-function or BRAFV600E/D/K mutant colorectal cancer, which includes advanced or metastatic colorectal cancer.
在本發明之組合的另一個實施方式中，達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、以及化合物C或其藥學上可接受的鹽係在同一配製物中。In another embodiment of the combination of the present invention, Dabrafenib or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, and Compound C or a pharmaceutically acceptable salt thereof are in the same in the formulation.
在本發明之組合的另一個實施方式中，達拉菲尼或其藥學上可接受的鹽、化合物A或其藥學上可接受的鹽、以及化合物C或其藥學上可接受的鹽係在分開的配製物中。In another embodiment of the combination of the present invention, Dabrafenib or a pharmaceutically acceptable salt thereof, Compound A or a pharmaceutically acceptable salt thereof, and Compound C or a pharmaceutically acceptable salt thereof are separated in the formulation.
在另一個實施方式中，本發明之組合用於同時或依序（以任何順序）投與。In another embodiment, the combinations of the present invention are for simultaneous or sequential (in any order) administration.
在另一個實施方式中，本發明提供了用於治療有需要的受試者中的癌症之方法，該方法包括向該受試者投與治療有效量的本發明之組合。In another embodiment, the present invention provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the present invention.
在該方法的另一個實施方式中，該癌症選自乳癌、膽管癌、唾液腺癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。In another embodiment of the method, the cancer is selected from breast cancer, bile duct cancer, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.
在另一個實施方式中，本發明提供了本發明之組合，用於在製造治療選自以下的癌症的藥物中使用：乳癌、膽管癌、唾液腺癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。In another embodiment, the present invention provides a combination of the present invention for use in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of breast cancer, bile duct cancer, salivary gland cancer, colorectal cancer, melanoma, non-small cell Lung, ovarian and thyroid cancers.
在另一個實施方式中，提供了包含本發明之組合的藥物組成物或商業包裝（例如，成套套組（kit））。In another embodiment, a pharmaceutical composition or commercial package (eg, a kit) comprising a combination of the present invention is provided.
在另一個實施方式中，藥物組成物進一步包含一種或多種藥學上可接受的賦形劑。In another embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
說明instruction
除非另外說明，否則上文和下文中使用的通用術語較佳的是在本揭露之上下文中具有以下含義，其中無論在什麼情況下使用的更通用的術語可以彼此獨立地由更具體的定義代替或保留，從而定義本發明之更詳細實施方式：Unless otherwise specified, the generic terms used above and below preferably have the following meanings in the context of the present disclosure, wherein the more generic terms used in any case may be independently of each other replaced by the more specific definitions or reserved, thereby defining a more detailed embodiment of the present invention:
「達拉菲尼」係N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺，能夠在V600抑制BRAF（V600E）、BRAF（V600K）和BRAF（V600G）突變的突變的BRAF的選擇性抑制劑（也稱為N-{3-[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺醯胺；Tafinlar® ；和N-{3-[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺醯胺，甲磺酸鹽）。"Dabrafenib" is N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl)-2 ,6-Difluorobenzenesulfonamide, a selective inhibitor of mutant BRAF capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations at V600 (also known as N-{3-[5- (2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluoro Benzenesulfonamide; Tafinlar ® ; and N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazole-4 -yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, mesylate).
「西妥昔單抗」係表皮生長因子受體（EGFR）抑制劑用於治療轉移性大腸直腸癌、轉移性非小細胞肺癌和頭頸癌。西妥昔單抗係靶向表皮生長因子受體的IgG1單株抗體，已批准與伊立替康組合使用或作為治療轉移性CRC的單一療法。西妥昔單抗係藉由靜脈內輸注給予的嵌合（小鼠/人）單株抗體。"Cetuximab" is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer and head and neck cancer. Cetuximab is an epidermal growth factor receptor-targeting IgG1 monoclonal antibody approved for use in combination with irinotecan or as a monotherapy for the treatment of metastatic CRC. Cetuximab is a chimeric (mouse/human) monoclonal antibody administered by intravenous infusion.
化合物A係細胞外信號調節激酶（ERK）1/2的抑制劑。「化合物A」係4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺。化合物A的特別較佳的鹽係其鹽酸鹽。Compound A is an inhibitor of extracellular signal-regulated kinase (ERK) 1/2. "Compound A" is 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-((S)-1 -(3-Bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide. A particularly preferred salt of Compound A is its hydrochloride.
「化合物C」（N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)異菸醯胺）係BRAF和CRAF蛋白激酶的ATP競爭性抑制劑。"Compound C" (N-(3-(2-(2-hydroxyethoxy)-6-𠰌olinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl) Isonicotinamide) is an ATP-competitive inhibitor of BRAF and CRAF protein kinases.
術語PD-1抑制劑包括PDR001。PDR001也稱為斯巴達珠單抗（抗PD-1抗體分子），如題為「Antibody Molecules to PD-1 and Uses Thereof [PD-1的抗體分子及其用途]」的2015年7月30日公佈的US 2015/0210769（將其藉由引用以其全文併入）中所述之。The term PD-1 inhibitor includes PDR001. PDR001 is also known as spartanizumab (anti-PD-1 antibody molecule) as described in the article titled "Antibody Molecules to PD-1 and Uses Thereof" July 30, 2015 It is described in published US 2015/0210769, which is incorporated by reference in its entirety.
另外的抗PD-1抗體分子包括以下：Additional anti-PD-1 antibody molecules include the following:
納武單抗（百時美施貴寶公司），也稱為MDX-1106、MDX-1106-04、ONO-4538、BMS-936558或OPDIVO®。納武單抗（殖株5C4）和其他抗PD-1抗體揭露於US 8,008,449和WO 2006/121168（將其藉由引用以其全文併入）中；Nivolumab (Bristol-Myers Squibb), also known as MDX-1106, MDX-1106-04, ONO-4538, BMS-936558, or OPDIVO®. Nivolumab (strain 5C4) and other anti-PD-1 antibodies are disclosed in US 8,008,449 and WO 2006/121168 (incorporated by reference in their entirety);
派姆單抗（默克公司），也稱為帕博利珠單抗（Lambrolizumab）、MK-3475、MK03475、SCH-900475或KEYTRUDA®。派姆單抗和其他抗PD-1抗體揭露於Hamid, O. 等人 (2013)New England Journal of Medicine [新英格蘭醫學雜誌]369 (2): 134-44；US 8,354,509和WO 2009/114335中，將其藉由引用以其全文併入。Pembrolizumab (Merck & Co.), also known as pembrolizumab (Lambrolizumab), MK-3475, MK03475, SCH-900475, or KEYTRUDA®. Pembrolizumab and other anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2): 134-44; US 8,354,509 and WO 2009/114335 , which is incorporated by reference in its entirety.
匹地利珠單抗（CureTech公司）, 也稱為CT-011。匹地利珠單抗和其他抗PD-1抗體揭露於Rosenblatt, J. 等人, (2011)J Immunotherapy [免疫療法雜誌] 34 (5): 409-18，US 7,695,715，US 7,332,582和US 8,686,119（將其藉由引用以其全文併入）中；Pidilizumab (CureTech), also known as CT-011. Pidilizumab and other anti-PD-1 antibodies are disclosed in Rosenblatt, J. et al, (2011) J Immunotherapy 34(5): 409-18, US 7,695,715, US 7,332,582 and US 8,686,119 (the which is incorporated by reference in its entirety);
MEDI0680（米迪繆尼公司），也稱為AMP-514。MEDI0680和其他抗PD-1抗體揭露於US 9,205,148和WO 2012/145493（將其藉由引用以其全文併入）中；MEDI0680 (Midi Mooney), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493 (incorporated by reference in their entirety);
AMP-224（B7-DCIg（安普利穆尼公司）），例如，揭露於WO 2010/027827和WO 2011/066342（將其藉由引用以其全文併入）中；AMP-224 (B7-DCIg (Amplimone)), eg, disclosed in WO 2010/027827 and WO 2011/066342 (incorporated by reference in their entirety);
REGN2810（再生元公司）；PF-06801591（輝瑞公司）；BGB-A317或BGB-108（百濟神州公司）；INCSHR1210（因賽特公司）也稱為INCSHR01210或SHR-1210；TSR-042（泰薩羅公司），也稱為ANB011；以及其他已知的抗PD-1抗體，包括描述於例如以下中的那些：WO 2015/112800、WO 2016/092419、WO 2015/085847、WO 2014/179664、WO 2014/194302、WO 2014/209804、WO 2015/200119、US 8,735,553、US 7,488,802、US 8,927,697、US 8,993,731、和US 9,102,727（將其藉由引用以其全文併入）。REGN2810 (Regeneron); PF-06801591 (Pfizer); BGB-A317 or BGB-108 (BeiGene); INCSHR1210 (Insett) also known as INCSHR01210 or SHR-1210; TSR-042 (Thailand) Salo Corporation), also known as ANB011; and other known anti-PD-1 antibodies, including those described, for example, in: WO 2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727 (incorporated by reference in their entirety).
如本文所用的，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。在一個實施方式中，受試者係人，例如患有癌症、具有患癌症的風險或可能易於患有癌症的人。As used herein, the terms "subject" or "patient" are intended to include animals susceptible to or afflicted by cancer or any disorder (directly or indirectly involved in 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 one embodiment, the subject is a human, eg, a human who has, is at risk of, or may be predisposed to having cancer.
如本文所用的術語「治療（treating）」或「治療（treatment）」包括解除、減輕或緩解受試者的至少一種症狀或者實現疾病進展延遲的治療。例如，治療可以是減弱障礙的一種或幾種症狀或者完全根除障礙（如癌症）。在本揭露之含義範圍內，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。The terms "treating" or "treatment" as used herein include treatment that relieves, alleviates, or alleviates at least one symptom of a subject or achieves a delay in disease progression. For example, treatment may be to attenuate one or several symptoms of the disorder or completely eradicate the disorder (eg, cancer). Within the meaning of the present disclosure, the term "treating" also means preventing, delaying the onset (ie, the period of time preceding the clinical manifestation of the disease) and/or reducing the risk of disease progression or disease progression.
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 "comprising" and "including" are used herein in their open-ended and non-limiting senses.
除非本文另外指明或明顯與上下文矛盾，否則在描述本發明之上下文中（尤其是在以下請求項的上下文中），術語「一個」、「一種」和「該」以及類似的指示詞應當被解釋為涵蓋單數和複數這兩者。當將複數形式用於化合物、鹽等時，這也意指單一化合物、鹽等。In the context of describing the invention (especially in the context of the following claims), the terms "a," "an," and "the" and similar referents are to be construed unless otherwise indicated herein or otherwise clearly contradicted by context. to cover both singular and plural. When the plural is used for a compound, salt, etc., this also means a single compound, salt, etc.
「組合」或「與……組合」或「與……共同投與」等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之範圍內。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。該等治療劑或治療方案可以以任何順序投與。通常，每種藥劑將以針對該藥劑確定的劑量和/或日程表投與。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。通常，預期組合中使用的其他治療劑的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 "combined with" or "co-administered with" etc. are not intended to imply that the therapy or therapeutic agents must be physically mixed or administered simultaneously and/or formulated for delivery together, although Such delivery methods are within the scope of those described herein. The therapeutic agents in such combinations can be administered concurrently with, before, or after one or more other additional therapies or therapeutic agents. The therapeutic agents or regimens can be administered in any order. Typically, each agent will be administered at a dose and/or schedule determined for that agent. It will also be understood that the additional therapeutic agents used in the combination may be administered together in a single composition or administered separately in different compositions. Generally, the other therapeutic agents used in combination are expected to be used at levels no greater than when they are used alone. In some embodiments, the levels used in combination will be lower than those used in single agent therapy.
當將本文中的劑量（dosage或dose）描述為「約」指定量時，實際劑量（dosage或dose）可以從該量變化高達10%，例如5%：這種「約」的使用承認，給定劑量或劑型中的精確量可能由於多種原因而與預期量略有不同，但不會實質上影響所給予化合物的體內作用。技術人員將理解，當本文引用治療化合物的劑量（dosage或dose）時，該量係指游離形式或非溶劑化形式的治療化合物的量。When a dose (dosage or dose) is described herein as "about" the specified amount, the actual dose (dosage or dose) may vary from that amount by up to 10%, such as 5%: this use of "about" acknowledges that giving The precise amount in a metered dose or dosage form may vary slightly from the intended amount for a variety of reasons without materially affecting the in vivo effect of the administered compound. The skilled artisan will understand that when referring herein to a dose (dosage or dose) of a therapeutic compound, that amount refers to the amount of the therapeutic compound in free or unsolvated form.
如本文所用的短語「治療有效量」係指包含本發明化合物的化合物、材料或組成物的量，其對於在動物（包括人）中的至少一個細胞亞群中以適用於任何醫學治療的合理的受益/風險比產生一些所期望的治療效果係有效的。The phrase "therapeutically effective amount" as used herein refers to the amount of a compound, material or composition comprising a compound of the present invention that is suitable for use in any medical treatment in at least one subpopulation of cells in animals, including humans A reasonable benefit/risk ratio to produce some desired therapeutic effect is effective.
本文使用的短語「藥學上可接受的」係指在合理的醫學判斷的範圍，適合用於與人和動物的組織接觸而不產生過度毒性、刺激、過敏反應、或其他問題或併發症，同時具有相稱的合理受益/風險比的那些化合物、材料、組成物、和/或劑型。The phrase "pharmaceutically acceptable" as used herein means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without causing undue toxicity, irritation, allergic reaction, or other problems or complications, Those compounds, materials, compositions, and/or dosage forms that also have a commensurate and reasonable benefit/risk ratio.
本發明之組合（達拉菲尼、化合物A和化合物C或斯巴達珠單抗）還旨在表示化合物的未經標記的形式以及化合物的同位素標記形式。同位素標記的化合物的一個或多個原子被具有選定原子質量或質量數的原子取代。可以摻入達拉菲尼、化合物A和化合物C或斯巴達珠單抗的同位素的實例包括氫、碳、氮、氧、磷、氟和氯的同位素，例如，分別是2 H、3 H、11 C、13 C、14 C、15 N、18 F、31 P、32 P、35 S、36 Cl、123 I、124 I、125 I。本發明包括同位素標記的達拉菲尼、化合物A和化合物C或斯巴達珠單抗，例如其中存在放射性同位素（如3 H和14 C）或非放射性同位素（如2 H和13 C）。同位素標記的達拉菲尼、化合物A和化合物C或斯巴達珠單抗可用於代謝研究（用14 C）、反應動力學研究（例如用2 H或3 H）、檢測或成像技術，例如正電子發射斷層掃描（PET）或單光子發射電腦斷層掃描（SPECT），包括藥物或底物組織分佈測定，或用於患者的放射治療。特別地，用18 F標記的達拉菲尼、化合物A或化合物C或斯巴達珠單抗對於PET或SPECT研究可能是特別理想的。本發明之同位素標記的化合物通常可藉由熟悉該項技術者已知的常規技術或與在使用適當的同位素標記的試劑的所附實例中所述之那些類似之方法來製備。The combinations of the invention (dabrafenib, compound A and compound C or spartanizumab) are also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms of the compounds. One or more atoms of an isotopically-labeled compound are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into dabrafenib, Compound A and Compound C or spartalizumab include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, eg, 2 H, 3 H, respectively , 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. The present invention includes isotopically-labeled dabrafenib, Compound A and Compound C or spartalizumab, eg, in which radioactive isotopes (eg 3 H and 14 C) or non-radioactive isotopes (eg 2 H and 13 C) are present. Isotopically-labeled dabrafenib, Compound A and Compound C or spartanizumab can be used in metabolic studies (with 14 C), kinetic studies (eg with 2 H or 3 H), detection or imaging techniques such as Positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or for radiation therapy of patients. In particular, with 18 F-labeled Dallas Feeney, Compound A or Compound C or Spartan natalizumab for PET or SPECT studies may be particularly desirable. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.
此外，用較重的同位素，特別是氘（即，2 H或D）取代可以提供來源於更大的代謝穩定性（例如，體內半衰期延長或劑量需求減少或治療指數改善）的某些治療優點。應當理解，在此上下文中，氘被認為係達拉菲尼、化合物A或化合物C或斯巴達珠單抗的取代基。這種較重的同位素（特別是氘）的濃度可以由同位素富集因子來定義。如本文所用的術語「同位素富集因子」係指同位素豐度與指定同位素的天然豐度之間的比率。如果達拉菲尼、化合物A或化合物C或斯巴達珠單抗中的取代基指示氘，這種化合物具有針對每個指定的氘原子的同位素富集因子為至少3500（在每個指定的氘原子上52.5%氘摻入）、至少4000（60%氘摻入）、至少4500（67.5%氘摻入）、至少5000（75%氘摻入）、至少5500（82.5%氘摻入）、至少6000（90%氘摻入）、至少6333.3（95%氘摻入）、至少6466.7（97%氘摻入）、至少6600（99%氘摻入）、或至少6633.3（99.5%氘摻入）。 具體實施方式In addition, substitution with heavier isotopes, particularly deuterium (ie, 2 H or D), may provide certain therapeutic advantages derived from greater metabolic stability (eg, increased in vivo half-life or reduced dose requirements or improved therapeutic index). . It should be understood that in this context, deuterium is considered to be a substituent of dabrafenib, compound A or compound C or spartalizumab. The concentration of this heavier isotope (especially deuterium) can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If the substituent in dabrafenib, compound A or compound C or spartalizumab indicates deuterium, such compound has an isotopic enrichment factor of at least 3500 for each specified deuterium atom (at each specified deuterium atom) 52.5% deuterium incorporated on the deuterium atom), at least 4000 (60% deuterium incorporated), at least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated), at least 6466.7 (97% deuterium incorporated), at least 6600 (99% deuterium incorporated), or at least 6633.3 (99.5% deuterium incorporated) . detailed description
達拉菲尼係具有RAF抑制活性的口服生物可利用的小分子。化合物A係具有ERK抑制活性的口服生物可利用的小分子。其係細胞外信號調節激酶1和2（ERK 1/2）的抑制劑。化合物C係具有B/C-RAF抑制活性的口服生物可利用的小分子。斯巴達珠單抗係一種高親和力的配位基阻斷人源化抗計劃性死亡1（PD-1）IgG4抗體，可阻斷計劃性死亡配位基1（PD-L1）和計劃性死亡配位基2（PD-L2）與PD-1的結合。Dabrafenib is an orally bioavailable small molecule with RAF inhibitory activity. Compound A is an orally bioavailable small molecule with ERK inhibitory activity. It is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Compound C is an orally bioavailable small molecule with B/C-RAF inhibitory activity. Spartanizumab is a high-affinity ligand-blocking humanized anti-programmed death 1 (PD-1) IgG4 antibody that blocks programmed death ligand 1 (PD-L1) and programmed death ligand 1 (PD-L1) Binding of death ligand 2 (PD-L2) to PD-1.
在一個實施方式中，關於本發明之藥物組合係包含以下的藥物組合：N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）、或其藥學上可接受的鹽；4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）、或其藥學上可接受的鹽；和N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（化合物C）、或其藥學上可接受的鹽。In one embodiment, the pharmaceutical combination of the present invention comprises the following pharmaceutical combination: N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazole-4 -yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib), or a pharmaceutically acceptable salt thereof; 4-(3-amino-6-((1S ,3S,4S)-3-Fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methyl) Amino)ethyl)-2-fluorobenzamide (Compound A), or a pharmaceutically acceptable salt thereof; and N-(3-(2-(2-hydroxyethoxy)-6-𠰌line) pyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide (Compound C), or a pharmaceutically acceptable salt thereof.
在另一個實施方式中，將N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽、4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）或其藥學上可接受的鹽、和N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（化合物C）或其藥學上可接受的鹽分開地、同時地或以任何順序依序地投與。In another embodiment, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl)- 2,6-Difluorobenzenesulfonamide (dabrafenib) or a pharmaceutically acceptable salt thereof, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- Hydroxycyclohexyl)pyridin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzyl Amide (Compound A) or a pharmaceutically acceptable salt thereof, and N-(3-(2-(2-hydroxyethoxy)-6-𠰌linopyridin-4-yl)-4-methylbenzene base)-2-(trifluoromethyl)-isonicotinamide (Compound C) or a pharmaceutically acceptable salt thereof is administered separately, simultaneously or sequentially in any order.
在另一個實施方式中，藥物組合用於口服投與。In another embodiment, the drug combination is for oral administration.
在藥物組合的另一個實施方式中，N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）呈口服劑型。In another embodiment of the pharmaceutical combination, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl )-2,6-difluorobenzenesulfonamide (dabrafenib) is available in oral dosage form.
在藥物組合的另一個實施方式中，4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）呈口服劑型。In another embodiment of the pharmaceutical combination, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-( (S)-1-(3-Bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A) is in oral dosage form.
在藥物組合的另一個實施方式中，N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（化合物C）呈口服劑型。In another embodiment of the pharmaceutical combination, N-(3-(2-(2-hydroxyethoxy)-6-𠰌olinopyridin-4-yl)-4-methylphenyl)-2-( Trifluoromethyl)-isonicotinamide (Compound C) is in oral dosage form.
在另一個實施方式中是一種藥物組成物或商業包裝，該藥物組成物或商業包裝包含（上述實施方式中任一項所述之）藥物組合，和至少一種藥學上可接受的載劑。In another embodiment is a pharmaceutical composition or commercial package comprising a pharmaceutical combination (of any of the above embodiments), and at least one pharmaceutically acceptable carrier.
在另一個實施方式中是藥物組合（如在上述實施方式中任一項所述）或藥物組成物或商業包裝（如在上述實施方式中所述）用於在治療癌症中使用。In another embodiment is a pharmaceutical combination (as described in any of the above embodiments) or pharmaceutical composition or commercial package (as described in any of the above embodiments) for use in the treatment of cancer.
在另一個實施方式中，該癌症選自乳癌、膽管癌、大腸直腸癌（CRC）、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。In another embodiment, the cancer is selected from breast cancer, bile duct cancer, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.
在另一個實施方式中，該癌症係晚期或轉移性大腸直腸癌。In another embodiment, the cancer is advanced or metastatic colorectal cancer.
在另一個實施方式中，該癌症係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.
在另一個實施方式中是根據上述實施方式中任一項所述之藥物組合或根據上述實施方式所述之藥物組成物或商業包裝用於製造治療癌症的藥物的用途。In another embodiment is the use of a pharmaceutical combination according to any one of the above embodiments or a pharmaceutical composition or a commercial package according to any of the above embodiments for the manufacture of a medicament for the treatment of cancer.
在另一個實施方式中，該癌症選自乳癌、膽管癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌，視需要其中該癌症係晚期或轉移性大腸直腸癌，視需要其中該癌症係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is selected from breast cancer, bile duct cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, optionally wherein the cancer is advanced or metastatic colorectal cancer, depending on There is a need wherein the cancer is a BRAF gain-of-function CRC or a BRAF V600E, V600D or V600K CRC.
在另一個實施方式中是治療選自乳癌、膽管癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌的癌症之方法，該方法包括向有需要的患者投與上述實施方式中任一項所述之藥物組合或商業包裝或根據上述實施方式所述之藥物組成物。In another embodiment is a method of treating a cancer selected from the group consisting of breast cancer, bile duct cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, the method comprising administering to a patient in need thereof The pharmaceutical combination or commercial package according to any one of the modes or the pharmaceutical composition according to the above embodiment.
在另一個實施方式中，該大腸直腸癌係晚期或轉移性大腸直腸癌。In another embodiment, the colorectal cancer is advanced or metastatic colorectal cancer.
在另一個實施方式中，該大腸直腸癌係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the colorectal cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.
在另一個實施方式中，以約從約1至約150 mg/天（例如，1、2、5、10、50、100或150 mg/天）的劑量口服投與N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）。In another embodiment, N-(3-(5 is administered orally at a dose of about from about 1 to about 150 mg/day (eg, 1, 2, 5, 10, 50, 100, or 150 mg/day) -(2-Aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib ).
在另一個實施方式中，以75 mg BID的劑量口服投與N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）。In another embodiment, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl) is administered orally at a dose of 75 mg BID -2-Fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib).
在另一個實施方式中，以從約50至約200 mg/天的劑量（例如，以約50、75、100、125、150、175或200 mg/天的劑量）口服投與4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）。In another embodiment, 4-(3) is administered orally at a dose of from about 50 to about 200 mg/day (eg, at a dose of about 50, 75, 100, 125, 150, 175, or 200 mg/day). -Amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-((S)-1-(3-bromo-5-fluoro) Phenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A).
在另一個實施方式中，以100 mg QD的劑量口服投與4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）。In another embodiment, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2- is administered orally at a dose of 100 mg QD yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A).
在另一個實施方式中，以200 mg QD的劑量口服投與4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）。In another embodiment, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2- is administered orally at a dose of 200 mg QD yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A).
在另一個實施方式中，以從約100 mg/天、或200 mg/天、或300 mg/天至約400 mg/天的劑量口服施用N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（化合物C）。In another embodiment, N-(3-(2-(2-hydroxyethoxy) is administered orally at a dose of from about 100 mg/day, or 200 mg/day, or 300 mg/day to about 400 mg/day yl)-6-𠰌olinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)-isonicotinamide (compound C).
在另一個實施方式中，以200 mg BID的劑量口服施用N-(3-(2-(2-羥基乙氧基)-6-𠰌啉代吡啶-4-基)-4-甲基苯基)-2-(三氟甲基)-異菸醯胺（化合物C）。In another embodiment, N-(3-(2-(2-hydroxyethoxy)-6-𠰌olinopyridin-4-yl)-4-methylphenyl is administered orally at a dose of 200 mg BID )-2-(trifluoromethyl)-isonicotinamide (compound C).
在一個實施方式中，關於本發明之藥物組合係包含以下的藥物組合：N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）、或其藥學上可接受的鹽；4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）、或其藥學上可接受的鹽；和PD-1抑制劑、或其藥學上可接受的鹽。In one embodiment, the pharmaceutical combination of the present invention comprises the following pharmaceutical combination: N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazole-4 -yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib), or a pharmaceutically acceptable salt thereof; 4-(3-amino-6-((1S ,3S,4S)-3-Fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methyl) Amino)ethyl)-2-fluorobenzamide (Compound A), or a pharmaceutically acceptable salt thereof; and a PD-1 inhibitor, or a pharmaceutically acceptable salt thereof.
在另一個實施方式中，將N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽、4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）或其藥學上可接受的鹽、和PD-1抑制劑或其藥學上可接受的鹽分開地、同時地或以任何順序依序地投與。In another embodiment, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl)- 2,6-Difluorobenzenesulfonamide (dabrafenib) or a pharmaceutically acceptable salt thereof, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4- Hydroxycyclohexyl)pyridin-2-yl)-N-((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzyl The amide (Compound A), or a pharmaceutically acceptable salt thereof, and the PD-1 inhibitor, or a pharmaceutically acceptable salt thereof, are administered separately, simultaneously, or sequentially in any order.
在另一個實施方式中，PD-1抑制劑係抗PD-1抗體分子。In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule.
在另一個實施方式中，PD-1抑制劑係抗PD-1抗體分子，如題為「Antibody Molecules to PD-1 and Uses Thereof [PD-1的抗體分子及其用途]」的2015年7月30日公佈的US 2015/0210769（將其藉由引用以其全文併入）中所述之。在一些實施方式中，抗PD-1抗體分子係BAP049-殖株E或BAP049-殖株B。In another embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule, as described in "Antibody Molecules to PD-1 and Uses Thereof" on July 30, 2015 It is described in US 2015/0210769 published on , which is incorporated by reference in its entirety. In some embodiments, the anti-PD-1 antibody molecule is BAP049-clone E or BAP049-clone B.
在另一個實施方式中，抗PD-1抗體分子係斯巴達珠單抗（PDR001）。In another embodiment, the anti-PD-1 antibody molecule is spartalizumab (PDR001).
在一個實施方式中，抗PD-1抗體分子包含來自重鏈和輕鏈可變區的至少一個、兩個、三個、四個、五個或六個互補決定區（CDR）（或總體上全部CDR），該重鏈和輕鏈可變區包含表1（例如，來自表1中揭露的BAP049-殖株-E或BAP049-殖株-B的重鏈和輕鏈可變區序列）中所示的胺基酸序列，或由表1中所示的核苷酸序列編碼的胺基酸序列。在一些實施方式中，CDR根據卡巴特（Kabat）定義（例如，如表1中所列出的）。在一些實施方式中，CDR根據喬西亞（Chothia）定義（例如，如表1中所列出的）。在一些實施方式中，CDR根據卡巴特和喬西亞兩者的組合CDR定義（例如，如表1中所列出的）。在一個實施方式中，VH CDR1的卡巴特和喬西亞CDR的組合包含胺基酸序列GYTFTTYWMH（SEQ ID NO: 541）。在一個實施方式中，相對於表1中所示的胺基酸序列，或由表1中所示的核苷酸序列編碼的胺基酸序列，CDR中的一種或多種（或總體上全部CDR）具有一個、兩個、三個、四個、五個、六個或更多個變化，例如胺基酸取代（例如，保守胺基酸取代）或缺失。In one embodiment, the anti-PD-1 antibody molecule comprises at least one, two, three, four, five or six complementarity determining regions (CDRs) (or collectively) from the heavy and light chain variable regions all CDRs), the heavy and light chain variable regions contained in Table 1 (eg, heavy and light chain variable region sequences from BAP049-clone-E or BAP049-clone-B disclosed in Table 1) The amino acid sequence shown, or the amino acid sequence encoded by the nucleotide sequence shown in Table 1. In some embodiments, the CDRs are defined according to Kabat (eg, as listed in Table 1). In some embodiments, the CDRs are defined according to Chothia (eg, as listed in Table 1). In some embodiments, the CDRs are defined according to the combined CDRs of both Kabat and Josiah (eg, as listed in Table 1). In one embodiment, the combination of the Kabat and Josiah CDRs of VH CDRl comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 541). In one embodiment, with respect to the amino acid sequence shown in Table 1, or the amino acid sequence encoded by the nucleotide sequence shown in Table 1, one or more of the CDRs (or all of the CDRs in general) ) with one, two, three, four, five, six or more variations, such as amino acid substitutions (eg, conservative amino acid substitutions) or deletions.
在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 501的VHCDR1胺基酸序列、SEQ ID NO: 502的VHCDR2胺基酸序列、和SEQ ID NO: 503的VHCDR3胺基酸序列的重鏈可變區（VH）；以及含有SEQ ID NO: 510的VLCDR1胺基酸序列、SEQ ID NO: 511的VLCDR2胺基酸序列、和SEQ ID NO: 512的VLCDR3胺基酸序列的輕鏈可變區（VL），各自揭露於表1中。In one embodiment, the anti-PD-1 antibody molecule comprises: the VHCDR1 amino acid sequence comprising SEQ ID NO:501, the VHCDR2 amino acid sequence of SEQ ID NO:502, and the VHCDR3 amino acid sequence of SEQ ID NO:503 The heavy chain variable region (VH) of the sequence; and the VLCDR1 amino acid sequence of SEQ ID NO: 510, the VLCDR2 amino acid sequence of SEQ ID NO: 511, and the VLCDR3 amino acid sequence of SEQ ID NO: 512. Light chain variable regions (VL), each disclosed in Table 1.
在一個實施方式中，抗體分子包含：含有由SEQ ID NO: 524的核苷酸序列編碼的VHCDR1、由SEQ ID NO: 525的核苷酸序列編碼的VHCDR2、和由SEQ ID NO: 526的核苷酸序列編碼的VHCDR3的VH；以及含有由SEQ ID NO: 529的核苷酸序列編碼的VLCDR1、由SEQ ID NO: 530的核苷酸序列編碼的VLCDR2、和由SEQ ID NO: 531的核苷酸序列編碼的VLCDR3的VL，各自揭露於表1中。In one embodiment, the antibody molecule comprises: comprising a VHCDR1 encoded by the nucleotide sequence of SEQ ID NO: 524, a VHCDR2 encoded by the nucleotide sequence of SEQ ID NO: 525, and a core by the nucleotide sequence of SEQ ID NO: 526 The VH of VHCDR3 encoded by the nucleotide sequence; and the VLCDR1 encoded by the nucleotide sequence of SEQ ID NO: 529, the VLCDR2 encoded by the nucleotide sequence of SEQ ID NO: 530, and the nucleus by the nucleotide sequence of SEQ ID NO: 531 The VL of VLCDR3 encoded by the nucleotide sequence, each disclosed in Table 1.
在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 506的胺基酸序列、或與SEQ ID NO: 506具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的VH。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 520的胺基酸序列、或與SEQ ID NO: 520具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的VL。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 516的胺基酸序列、或與SEQ ID NO: 516具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的VL。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 506的胺基酸序列的VH和含有SEQ ID NO: 520的胺基酸序列的VL。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 506的胺基酸序列的VH和含有SEQ ID NO: 516的胺基酸序列的VL。In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 506, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 506 VHs of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 520, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 520 VL of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 516, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 516 VL of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:506 and a VL comprising the amino acid sequence of SEQ ID NO:520. In one embodiment, the anti-PD-1 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO:506 and a VL comprising the amino acid sequence of SEQ ID NO:516.
在一個實施方式中，抗體分子包含：由SEQ ID NO: 507的核苷酸序列、或與SEQ ID NO: 507具有至少85%、90%、95%、或99%、或更高同一性的核苷酸序列編碼的VH。在一個實施方式中，抗體分子包含：由SEQ ID NO: 521或517的核苷酸序列，或與SEQ ID NO: 521或517具有至少85%、90%、95%、或99%或更高同一性的核苷酸序列編碼的VL。在一個實施方式中，抗體分子包含由SEQ ID NO: 507的核苷酸序列編碼的VH和由SEQ ID NO: 521或517的核苷酸序列編碼的VL。In one embodiment, the antibody molecule comprises: the nucleotide sequence of SEQ ID NO: 507, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 507 The VH encoded by the nucleotide sequence. In one embodiment, the antibody molecule comprises: a nucleotide sequence consisting of, or at least 85%, 90%, 95%, or 99% or more from SEQ ID NO: 521 or 517 The identity of the nucleotide sequence encoded by the VL. In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence of SEQ ID NO: 507 and a VL encoded by the nucleotide sequence of SEQ ID NO: 521 or 517.
在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 508的胺基酸序列、或與SEQ ID NO: 508具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的重鏈。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 522的胺基酸序列、或與SEQ ID NO: 522具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的輕鏈。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 518的胺基酸序列、或與SEQ ID NO: 518具有至少85%、90%、95%、或99%、或更高同一性的胺基酸序列的輕鏈。在一個實施方式中，抗PD-1抗體分子包含：含有SEQ ID NO: 508的胺基酸序列的重鏈和含有SEQ ID NO: 522的胺基酸序列的輕鏈。在一個實施方式中，該抗PD-1抗體分子包含：含有SEQ ID NO: 508的胺基酸序列的重鏈和含有SEQ ID NO: 518的胺基酸序列的輕鏈。In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 508, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 508 Heavy chains of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 522, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 522 Light chains of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: the amino acid sequence comprising SEQ ID NO: 518, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 518 Light chains of amino acid sequences of high identity. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:508 and a light chain comprising the amino acid sequence of SEQ ID NO:522. In one embodiment, the anti-PD-1 antibody molecule comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:508 and a light chain comprising the amino acid sequence of SEQ ID NO:518.
在一個實施方式中，抗體分子包含：由SEQ ID NO: 509的核苷酸序列、或與SEQ ID NO: 509具有至少85%、90%、95%、或99%、或更高同一性的核苷酸序列編碼的重鏈。在一個實施方式中，抗體分子包含：由SEQ ID NO: 523或519的核苷酸序列，或與SEQ ID NO: 523或519具有至少85%、90%、95%、或99%或更高同一性的核苷酸序列編碼的輕鏈。在一個實施方式中，抗體分子包含由SEQ ID NO: 509的核苷酸序列編碼的重鏈和由SEQ ID NO: 523或519的核苷酸序列編碼的輕鏈。In one embodiment, the antibody molecule comprises: a nucleotide sequence consisting of SEQ ID NO: 509, or at least 85%, 90%, 95%, or 99%, or more identical to SEQ ID NO: 509 The heavy chain encoded by the nucleotide sequence. In one embodiment, the antibody molecule comprises: a nucleotide sequence consisting of, or at least 85%, 90%, 95%, or 99% or more from SEQ ID NO: 523 or 519 The identity of the nucleotide sequence encoded by the light chain. In one embodiment, the antibody molecule comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 509 and a light chain encoded by the nucleotide sequence of SEQ ID NO: 523 or 519.
本文所述之抗體分子可以藉由載體、宿主細胞、和在US 2015/0210769（將其藉由引用以其全文併入）中所述之方法製得。
[表 1
].
示例性抗PD-1抗體分子的胺基酸和核苷酸序列
在藥物組合的另一個實施方式中，N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）呈口服劑型。In another embodiment of the pharmaceutical combination, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl )-2,6-difluorobenzenesulfonamide (dabrafenib) is available in oral dosage form.
在藥物組合的另一個實施方式中，4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）呈口服劑型。In another embodiment of the pharmaceutical combination, 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-( (S)-1-(3-Bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A) is in oral dosage form.
在另一個實施方式中是一種藥物組成物或商業包裝，該藥物組成物或商業包裝包含（上述實施方式中任一項所述之）藥物組合，和至少一種藥學上可接受的載劑。In another embodiment is a pharmaceutical composition or commercial package comprising a pharmaceutical combination (of any of the above embodiments), and at least one pharmaceutically acceptable carrier.
在另一個實施方式中是藥物組合（如在上述實施方式中任一項所述）或藥物組成物或商業包裝（如在上述實施方式中所述）用於在治療癌症中使用。In another embodiment is a pharmaceutical combination (as described in any of the above embodiments) or pharmaceutical composition or commercial package (as described in any of the above embodiments) for use in the treatment of cancer.
在另一個實施方式中，該癌症選自乳癌、膽管癌、大腸直腸癌（CRC）、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。In another embodiment, the cancer is selected from breast cancer, bile duct cancer, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.
在另一個實施方式中，該癌症係晚期或轉移性大腸直腸癌。In another embodiment, the cancer is advanced or metastatic colorectal cancer.
在另一個實施方式中，該癌症係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.
在另一個實施方式中是根據上述實施方式中任一項所述之藥物組合或根據上述實施方式所述之藥物組成物或商業包裝用於製造治療癌症的藥物的用途。In another embodiment is the use of a pharmaceutical combination according to any one of the above embodiments or a pharmaceutical composition or a commercial package according to any of the above embodiments for the manufacture of a medicament for the treatment of cancer.
在另一個實施方式中，該癌症選自乳癌、膽管癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌，視需要其中該癌症係晚期或轉移性大腸直腸癌，視需要其中該癌症係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is selected from breast cancer, bile duct cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, optionally wherein the cancer is advanced or metastatic colorectal cancer, depending on There is a need wherein the cancer is a BRAF gain-of-function CRC or a BRAF V600E, V600D or V600K CRC.
在另一個實施方式中是治療選自乳癌、膽管癌、大腸直腸癌、黑素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌的癌症之方法，該方法包括向有需要的患者投與上述實施方式中任一項所述之藥物組合或商業包裝或根據上述實施方式所述之藥物組成物。In another embodiment is a method of treating a cancer selected from the group consisting of breast cancer, bile duct cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, the method comprising administering to a patient in need thereof The pharmaceutical combination or commercial package according to any one of the modes or the pharmaceutical composition according to the above embodiment.
在另一個實施方式中，該大腸直腸癌係晚期或轉移性大腸直腸癌。In another embodiment, the colorectal cancer is advanced or metastatic colorectal cancer.
在另一個實施方式中，該大腸直腸癌係BRAF功能獲得性CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the colorectal cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.
在另一個實施方式中，以約從約1至約150 mg/天（例如，1、2、5、10、50、100或150 mg/天）的劑量口服投與N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）。In another embodiment, N-(3-(5 is administered orally at a dose of about from about 1 to about 150 mg/day (eg, 1, 2, 5, 10, 50, 100, or 150 mg/day) -(2-Aminopyrimidin-4-yl)-2-(tertiarybutyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib ).
在另一個實施方式中，以從約50至約200 mg/天的劑量（例如，以約50、75、100、125、150、175或200 mg/天的劑量）口服投與4-(3-胺基-6-((1S,3S,4S)-3-氟-4-羥基環己基)吡𠯤-2-基)-N-((S)-1-(3-溴-5-氟苯基)-2-(甲基胺基)乙基)-2-氟苯甲醯胺（化合物A）。In another embodiment, 4-(3) is administered orally at a dose of from about 50 to about 200 mg/day (eg, at a dose of about 50, 75, 100, 125, 150, 175, or 200 mg/day). -Amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyridine-2-yl)-N-((S)-1-(3-bromo-5-fluoro) Phenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A).
在另一個實施方式中，以約300-400 mg的劑量投與PD-1抑制劑。In another embodiment, the PD-1 inhibitor is administered in a dose of about 300-400 mg.
在另一個實施方式中，每3週一次或每4週一次投與PD-1抑制劑。In another embodiment, the PD-1 inhibitor is administered every 3 weeks or every 4 weeks.
在另一個實施方式中，每3週一次以約300 mg的劑量投與PD-1抑制劑。In another embodiment, the PD-1 inhibitor is administered at a dose of about 300 mg once every 3 weeks.
在另一個實施方式中，每4週一次以約400 mg的劑量投與PD-1抑制劑。 藥理學及效用In another embodiment, the PD-1 inhibitor is administered at a dose of about 400 mg once every 4 weeks. Pharmacology and Utility
RAS/RAF/MEK/ERK或有絲***原活化的蛋白激酶（MAPK）途徑係關鍵的傳訊級聯，其整合上游細胞信號（例如來自生長因子受體酪胺酸激酶的信號）以協調細胞增殖、分化和存活。MAPK傳訊通路在人類癌症中常常失調，最常見的是藉由RAS基因家族成員的突變。該等突變促進GTP結合狀態，導致RAS活性，進而導致RAF、MEK和ERK蛋白活化。在多種癌症類型（包括大腸直腸癌、肺癌和胰臟癌）中發現了RAS突變。The RAS/RAF/MEK/ERK or mitogen-activated protein kinase (MAPK) pathways are key signaling cascades that integrate upstream cellular signals (eg, from growth factor receptor tyrosine kinases) to coordinate cell proliferation, differentiation and survive. The MAPK signaling pathway is frequently dysregulated in human cancers, most commonly through mutations in members of the RAS gene family. These mutations promote the GTP-bound state, leading to RAS activity, which in turn leads to RAF, MEK, and ERK protein activation. RAS mutations are found in multiple cancer types, including colorectal, lung, and pancreatic cancer.
RAF（快速加速纖維肉瘤）係一種作為逆轉錄病毒致癌基因發現的絲胺酸-蘇胺酸蛋白激酶。RAF蛋白家族（ARAF、BRAF、CRAF）在活化的RAS下游發出信號。活化的與GTP結合的RAS將胞漿失活的RAF單體募集到質膜，在那裡RAF與GTP-RAS結合，從而促進RAF的同源二聚作用和異源二聚作用。RAF的二聚化有助於構象變化，從而導致催化活化的RAF。活化的RAF二聚體磷酸化並活化MEK1/2（也稱為有絲***原活化的蛋白激酶）蛋白質，其隨後磷酸化並活化細胞外信號調節激酶（ERK1/2）。ERK使多種底物（包括多個轉錄因子）磷酸化，從而調節數種關鍵的細胞活性（包括增殖、代謝、遷移、和存活）。ERK1/2在癌症中的作用係被特別關注的，因為在ERK1/2傳訊級聯中活化其上游的突變被認為係所有癌症半數以上的原因。RAF (rapidly accelerated fibrosarcoma) is a serine-threonine protein kinase discovered as a retroviral oncogene. The RAF protein family (ARAF, BRAF, CRAF) signals downstream of activated RAS. Activated GTP-bound RAS recruits cytosolic inactive RAF monomers to the plasma membrane, where RAF binds to GTP-RAS, thereby promoting RAF homodimerization and heterodimerization. Dimerization of RAF contributes to the conformational change that results in catalytically activated RAF. Activated RAF dimers phosphorylate and activate MEK1/2 (also known as mitogen-activated protein kinase) proteins, which in turn phosphorylate and activate extracellular signal-regulated kinase (ERK1/2). ERK phosphorylates a variety of substrates, including multiple transcription factors, thereby regulating several key cellular activities, including proliferation, metabolism, migration, and survival. The role of ERK1/2 in cancer is of particular interest because mutations that activate upstream of the ERK1/2 signaling cascade are thought to be responsible for more than half of all cancers.
MAPK途徑中任何步驟的活化失調都有促成腫瘤發生。在大約7%的癌症中可以發現活化的BRAF突變，其中V600E占BRAF中觀察到的突變的90%以上。V600E突變編碼纈胺酸到麩胺酸的取代，從而暴露出BRAF的活性位點，從而使其能夠獨立於RAS地作為單體或二聚體進行組成型活化。活性的RAF抑制劑（例如維莫非尼、達拉菲尼和康奈非尼）已在BRAF V600E轉移性黑色素瘤中顯示出顯著活性，總體應答率（ORR）為50%-70%。在V600E黑色素瘤中，該等抑制劑的成功源自結合並抑制RAF的突變單體形式的能力，RAF係癌細胞的致癌驅動因子。然而，在表現野生型BRAF的癌細胞中，或在V600E驅動的癌症患者的正常細胞中，抑制劑（例如維莫非尼）反常活化RAF傳訊。在BRAF V600E依賴性黑色素瘤細胞死亡而含有野生型BRAF的正常表皮細胞過度增殖的患者中，單體RAF抑制劑存在時MAPK途徑傳訊的複雜性凸顯出來。RAF在野生型細胞中的這種反常活化係由於抑制劑與RAF二聚體的一個原聚體結合而引起的。這導致構象變化，其阻止抑制劑結合至第二原聚體，並且隨後發生二聚體的第二RAF原聚體的反式活化。用RAF和MEK指導的組合療法抑制MAPK途徑的順序節點可減弱正常細胞中的RAF二聚體傳訊，從而改善轉移性BRAF V600黑色素瘤的安全性和臨床活性。Dysregulation of activation of any step in the MAPK pathway contributes to tumorigenesis. Activating BRAF mutations can be found in approximately 7% of cancers, with V600E accounting for more than 90% of the mutations observed in BRAF. The V600E mutation encodes a valine to glutamic acid substitution that exposes the active site of BRAF, allowing it to constitutively activate as a monomer or dimer independently of RAS. Active RAF inhibitors (eg, vemurafenib, dabrafenib, and connefenib) have shown significant activity in BRAF V600E metastatic melanoma, with overall response rates (ORRs) of 50%-70%. In V600E melanoma, the success of these inhibitors stems from the ability to bind and inhibit the mutated monomeric form of RAF, an oncogenic driver of RAF lineage cancer cells. However, in cancer cells expressing wild-type BRAF, or in normal cells from patients with V600E-driven cancers, inhibitors such as vemurafenib paradoxically activate RAF signaling. The complexity of MAPK pathway signaling in the presence of monomeric RAF inhibitors is highlighted in patients with BRAF V600E-dependent melanoma cell death and hyperproliferation of normal epidermal cells harboring wild-type BRAF. This paradoxical activation of RAF in wild-type cells results from the binding of the inhibitor to a protomer of the RAF dimer. This results in a conformational change that prevents binding of the inhibitor to the second protomer and subsequent transactivation of the dimerized second RAF protomer. Inhibition of sequential nodes of the MAPK pathway with RAF and MEK-directed combination therapy attenuates RAF dimer signaling in normal cells, resulting in improved safety and clinical activity in metastatic BRAF V600 melanoma.
在BRAF V600E大腸直腸癌（CRC）中，單一藥劑RAF抑制劑或組合RAF/MEK抑制顯示出最小的活性；與黑色素瘤中觀察到的活性相比，臨床受益有限。對RAF抑制劑和MEK抑制劑的內源性和獲得性抗性在MAPK途徑的多個水平上發展。繞過BRAF抑制的傳訊回饋和替代途徑的複雜性係在CRC中靶向活化BRAF的挑戰的核心。在生理條件下，藉由突變BRAF活化的MAPK傳訊導致藉由活化的RAS產生的信號的ERK依賴性負反饋。之所以表現出對RAF抑制的內源性抗性，係因為例如維莫非尼或達拉菲尼的藥物有效抑制了藉由MEK向ERK的BRAF V600E傳訊；然而，這導致了將依賴ERK的負反饋釋放到RAS傳訊中。因此，上游信號能夠活化RAS，從而導致BRAF V600E和野生型同二聚體和異二聚體的誘導。因為例如達拉菲尼和維莫非尼之類的藥物會抑制BRAF依賴性CRC細胞中V600E活化的單體，而不影響RAS刺激的RAF二聚體傳訊，導致ERK的再活化程度高於BRAF V600E黑色素瘤中見到的，從而限制了在CRC中療法的有效性。In BRAF V600E colorectal cancer (CRC), single-agent RAF inhibitors or combined RAF/MEK inhibition showed minimal activity; clinical benefit was limited compared to the activity observed in melanoma. Endogenous and acquired resistance to RAF inhibitors and MEK inhibitors develops at multiple levels of the MAPK pathway. The complexity of signaling feedback and alternative pathways that bypass BRAF inhibition is at the heart of the challenge of targeting activated BRAF in CRC. Under physiological conditions, MAPK signaling activated by mutant BRAF results in an ERK-dependent negative feedback of signals generated by activated RAS. Endogenous resistance to RAF inhibition is shown because drugs such as vemurafenib or dabrafenib effectively inhibit BRAF V600E signaling to ERK by MEK; Feedback is released into RAS messaging. Thus, upstream signals are able to activate RAS, leading to the induction of BRAF V600E and wild-type homodimers and heterodimers. Because drugs such as dabrafenib and vemurafenib inhibit V600E-activated monomers in BRAF-dependent CRC cells without affecting RAS-stimulated RAF dimer signaling, resulting in a higher degree of ERK reactivation than BRAF V600E seen in melanoma, thus limiting the effectiveness of therapy in CRC.
在BRAF V600E CRC中受到BRAF和MEK抑制的壓力下，獲得性抗性迅速發展。例如，在對來自8位在MAPK抑制後經歷疾病進展的患者的9份腫瘤樣本進行的分析中，未發現導致MAPK再活化的基因改變。該等包括在KRAS 或NRAS 中的活化激活、野生型（WT）NRAS 或KRAS 或突變體BRAF V600E的擴增、和在BRAF V600E基因內缺失。還報導了獲得性遺傳改變，導致面對MAPK抑制劑的ERK傳訊再活化。獲得性抗性也可能藉由腫瘤微環境中的互補傳訊產生。Acquired resistance develops rapidly under the stress of BRAF and MEK inhibition in BRAF V600E CRC. For example, in an analysis of 9 tumor samples from 8 patients who experienced disease progression following MAPK inhibition, no genetic alterations that lead to MAPK reactivation were found. These include activation activation in KRAS or NRAS , amplification of wild-type (WT) NRAS or KRAS or mutant BRAF V600E, and deletion within the BRAF V600E gene. Acquired genetic alterations leading to reactivation of ERK signaling in the face of MAPK inhibitors have also been reported. Acquired resistance may also arise through complementary signaling in the tumor microenvironment.
儘管先前針對BRAF 突變CRC的治療方法集中於化學療法和/或靶向療法，但是免疫療法也起作用。在腫瘤發生期間，癌細胞利用免疫檢查點途徑來避免被適應性免疫系統檢測到。計劃性細胞死亡蛋白1（PD-1）和計劃性死亡配位基1（PD-L1）免疫檢查點的單株抗體（mAb）抑制劑已在患有各種實性瘤的患者中顯示出顯著的抗腫瘤活性。PD-1係一個特別重要的免疫學靶標，其抑制劑如派姆單抗和納武單抗在黑色素瘤、非小細胞肺癌（NSCLC）和其他實性瘤中表現出單一藥劑活性。Although previous treatments for BRAF- mutant CRC have focused on chemotherapy and/or targeted therapy, immunotherapy also plays a role. During tumorigenesis, cancer cells utilize the immune checkpoint pathway to avoid detection by the adaptive immune system. Monoclonal antibody (mAb) inhibitors of the programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoints have shown significant efficacy in patients with various solid tumors antitumor activity. PD-1 is a particularly important immunological target, and its inhibitors such as pembrolizumab and nivolumab have shown single-agent activity in melanoma, non-small cell lung cancer (NSCLC), and other solid tumors.
然而，除了具有微衛星不穩定性的腫瘤外，CRC通常對PD-1阻斷無應答。然而，有理由使用小分子抑制劑來調節免疫反應。抑制癌細胞中MAPK途徑的遺傳依賴性的相同療法會抑制免疫細胞中的傳訊級聯反應。例如，臨床前研究表明，MAPK通路抑制劑（例如BRAF和MEK抑制劑）可以藉由增加腫瘤中的腫瘤浸潤淋巴細胞來改善淋巴細胞歸巢和功能。However, with the exception of tumors with microsatellite instability, CRC generally does not respond to PD-1 blockade. However, there are reasons to use small molecule inhibitors to modulate immune responses. The same therapy that inhibits the genetic dependence of the MAPK pathway in cancer cells suppresses the signaling cascade in immune cells. For example, preclinical studies have shown that MAPK pathway inhibitors, such as BRAF and MEK inhibitors, can improve lymphocyte homing and function by increasing tumor-infiltrating lymphocytes in tumors.
因此，RAF和MEK抑制劑可以調節對腫瘤的免疫應答，並且將該等藥物與檢查點阻斷組合使用甚至可以提高「免疫冷（immune cold）」腫瘤（如CRC）對PD-1抑制的敏感性。此外，約20%的BRAF 突變CRC具有遺傳微衛星不穩定性（MSI-H：微衛星不穩定性高）的特徵。在MSI-H CRC中，無論BRAF的遺傳狀況如何，單一藥劑抗PD-1療法與30%-50%的應答率相關。此外，腫瘤免疫細胞中的靶向MAPK抑制作用可能會補充微衛星穩定和錯配修復缺陷的CRC中抗PD-1抗體的作用機制，從而潛在地增加抗癌免疫調節。Thus, RAF and MEK inhibitors can modulate immune responses to tumors, and combining these drugs with checkpoint blockade can even increase the sensitivity of "immune cold" tumors such as CRC to PD-1 inhibition sex. In addition, approximately 20% of BRAF- mutant CRCs are characterized by inherited microsatellite instability (MSI-H: microsatellite instability high). In MSI-H CRC, single-agent anti-PD-1 therapy was associated with a 30%-50% response rate regardless of BRAF genetic status. Furthermore, targeted MAPK inhibition in tumor immune cells may complement the mechanism of action of anti-PD-1 antibodies in microsatellite stabilization and mismatch repair-deficient CRC, potentially increasing anticancer immune regulation.
肺癌係影響全球男性和女性的常見癌症。NSCLC係最常見的肺癌類型（大致85%），其中近似70%的患者在診斷時呈現出疾病晚期（IIIB期或IV期）。約30%的NSCLC腫瘤含有活化的KRAS突變，並且該等突變與對EGFR酪胺酸激酶抑制劑（TKI）的抗性相關。在黑色素瘤、胰臟癌和卵巢癌中也經常發現活化的KRAS突變。在高達3%的NSCLC中觀察到BRAF突變，並且還被描述為EGFR突變陽性NSCLC中的抗性機制。Lung cancer is a common cancer affecting men and women worldwide. NSCLC is the most common type of lung cancer (roughly 85%), with approximately 70% of patients presenting with advanced disease (stage IIIB or IV) at diagnosis. Approximately 30% of NSCLC tumors contain activating KRAS mutations, and these mutations are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Activating KRAS mutations are also frequently found in melanoma, pancreatic and ovarian cancers. BRAF mutations are observed in up to 3% of NSCLC and have also been described as a resistance mechanism in EGFR mutation-positive NSCLC.
CRC係一種常見疾病，2018年全球估計有180萬新病例，死亡人數 ＞ 800,000（世界衛生組織，Globocan 2018）。編碼MAPK途徑成分的基因中的突變很常見，RAS 突變發生在大約50%的CRC中。大約10%-15%的CRC患者中存在編碼BRAF V600E的基因中的活化突變，並且突變的BRAF 導致不良預後。V600E突變發生在大約90%的BRAF 突變CRC中，儘管也可以看到其他突變，例如V600D或V600K突變。CRC is a common disease with an estimated 1.8 million new cases and >800,000 deaths globally in 2018 (World Health Organization, Globocan 2018). Mutations in genes encoding components of the MAPK pathway are common, and RAS mutations occur in approximately 50% of CRCs. Activating mutations in the gene encoding BRAF V600E are present in approximately 10%-15% of CRC patients , and mutated BRAF results in poor prognosis. The V600E mutation occurs in approximately 90% of BRAF- mutated CRCs, although other mutations, such as V600D or V600K mutations, are also seen.
對於BRAF 突變CRC的有效治療選擇係有限的。與黑色素瘤（其中單一藥劑BRAF抑制劑在轉移環境中的應答率約為70%）不同，用維莫非尼的單一藥劑抑制轉移性BRAF 突變CRC與約5%的ORR相關。儘管結果仍然很差，但是與靶向MAPK途徑的藥物的組合療法已改善了BRAF抑制的有效性。與MEK抑制劑曲美替尼組合的達拉菲尼與12%的ORR以及3.5個月的無進展生存期（PFS）相關。Effective treatment options for BRAF- mutant CRC are limited. Unlike melanoma, where single-agent BRAF inhibitors have an approximately 70% response rate in the metastatic setting, single-agent inhibition of metastatic BRAF- mutant CRC with vemurafenib was associated with an ORR of approximately 5%. Although results remain poor, combination therapy with drugs targeting the MAPK pathway has improved the effectiveness of BRAF inhibition. Dabrafenib in combination with the MEK inhibitor trametinib was associated with an ORR of 12% and progression-free survival (PFS) of 3.5 months.
在CRC中，藉由生長因子介導的受體酪胺酸激酶活化來刺激RAS支持致癌環境。在抑制BRAF的有效性後，EGFR抑制劑會適度改善；與EGFR抑制劑組合的BRAF抑制劑與4%-22%的ORR以及3.2-4.2個月的PFS相關。用達拉菲尼 + 曲美替尼 + 帕尼單抗治療的患者經歷21%的ORR以及4.2個月的PFS。在III期BEACON試驗中，將患者隨機化到第二線治療或更高級別的治療的三組中的一組：康奈非尼/比美替尼/西妥昔單抗、康奈非尼/西妥昔單抗、相對於伊立替康/西妥昔單抗或FOLFIRI/西妥昔單抗（對照）。接受三重療法的患者達到26%的ORR、4.3個月的PFS以及9個月的總生存期（OS）。康奈非尼加西妥昔單抗與20%的ORR、4.2個月的PFS以及8.4個月的OS相關。與伊立替康或FOLFIRI/西妥昔單抗相比，兩種方案均達到了統計學上的顯著改善，與2%的ORR、1.5個月的PFS以及5.4個月的OS相關。藉由組合抑制RAF、MEK和EGFR傳訊顯示出改善的結果，支持以下觀點：BRAF V600E CRC的治療需要抑制MAPK途徑內的多個節點。In CRC, stimulation of RAS through growth factor-mediated activation of receptor tyrosine kinase supports an oncogenic milieu. EGFR inhibitors improved modestly after inhibiting BRAF efficacy; BRAF inhibitors in combination with EGFR inhibitors were associated with 4%-22% ORR and 3.2-4.2 months PFS. Patients treated with dabrafenib + trametinib + panitumumab experienced an ORR of 21% and a PFS of 4.2 months. In the phase III BEACON trial, patients were randomized to one of three arms of second-line therapy or higher-grade therapy: connefenib/bimetinib/cetuximab, connefenib/ Cetuximab, versus irinotecan/cetuximab or FOLFIRI/cetuximab (control). Patients receiving triple therapy achieved an ORR of 26%, a PFS of 4.3 months, and an overall survival (OS) of 9 months. Connefenib plus cetuximab was associated with an ORR of 20%, PFS of 4.2 months, and OS of 8.4 months. Both regimens achieved statistically significant improvements compared with irinotecan or FOLFIRI/cetuximab, which were associated with an ORR of 2%, PFS of 1.5 months, and OS of 5.4 months. Improved results were shown by combined inhibition of RAF, MEK and EGFR signaling, supporting the notion that treatment of BRAF V600E CRC requires inhibition of multiple nodes within the MAPK pathway.
達拉菲尼（Tafinlar®）係口服生物可利用的、有效的和有選擇性的RAF激酶抑制劑，其作用機制與用結合三磷酸腺苷（ATP）競爭性抑制相一致。達拉菲尼抑制BRAF激酶的某些突變形式的能力係濃度依賴性的，BRAF V600E、BRAF V600K和BRAF V600D酶的體外IC50值分別為0.65、0.5和1.84 nM。抑制野生型BRAF和CRAF激酶需要更高的濃度，IC50值分別為3.2和5.0 nM。其他激酶（例如SIK1、NEK11和LIMK1）也可以在較高濃度下被抑制。在體外和體內，達拉菲尼抑制各種BRAF V600突變陽性腫瘤的細胞生長。Dabrafenib (Tafinlar®) is an orally bioavailable, potent and selective inhibitor of RAF kinase whose mechanism of action is consistent with competitive inhibition with conjugated adenosine triphosphate (ATP). The ability of dabrafenib to inhibit certain mutant forms of BRAF kinase is concentration-dependent, with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. Higher concentrations were required to inhibit wild-type BRAF and CRAF kinases, with IC50 values of 3.2 and 5.0 nM, respectively. Other kinases such as SIK1, NEK11 and LIMK1 can also be inhibited at higher concentrations. Dabrafenib inhibited cell growth in various BRAF V600 mutation-positive tumors in vitro and in vivo.
達拉菲尼於2013年首次獲得FDA批准，作為對於治療患有BRAF V600突變的成年患者中不可切除或轉移性黑色素瘤的單一藥劑口服治療，並在其他多個國家對於相同適應症獲得了批准。達拉菲尼與曲美替尼的組合還被多個國家批准用於以下適應症（批准的適應症因國家而異）：患有BRAFV600突變的不可切除或轉移性黑色素瘤患者的治療；患有BRAFV600突變的III期黑色素瘤（完全切除後）患者的輔助治療；患有BRAFV600突變的晚期非小細胞肺癌（NSCLC）患者的治療；和患有BRAFV600E突變局部晚期或轉移性間變性甲狀腺癌（ATC）患者的治療。Dabrafenib was first approved by the FDA in 2013 as a single-agent oral therapy for the treatment of unresectable or metastatic melanoma in adult patients with BRAF V600 mutations, and has been approved in several other countries for the same indication . The combination of dabrafenib and trametinib is also approved in multiple countries for the following indications (approved indications vary by country): treatment of patients with unresectable or metastatic melanoma with a BRAFV600 mutation; patients with Adjuvant treatment of patients with stage III melanoma (after complete resection) with BRAFV600 mutation; treatment of patients with advanced non-small cell lung cancer (NSCLC) with BRAFV600 mutation; and locally advanced or metastatic anaplastic thyroid cancer with BRAFV600E mutation ( ATC) treatment of patients.
達拉菲尼的推薦劑量為150 mg BID（相當於每日總劑量300 mg）。The recommended dose of dabrafenib is 150 mg BID (equivalent to a total daily dose of 300 mg).
化合物A係一種有效的、選擇性的、口服生物可利用的ATP競爭性ERK1/2激酶抑制劑，其表現出能夠與RAF和MEK抑制劑或其他靶向治療劑組合使用的物理化學性質。化合物A有效抑制pERK傳訊，並在多個MAPK活化的癌細胞和異種移植模型中顯示出腫瘤生長抑制。重要的是，化合物A表現出了靶向多種已知的對BRAF和MEK抑制劑抗性的機制的廣泛療效，包括RAS 突變、BRAF 剪接變體和MEK1/2 突變，如工程細胞系模型所示。化合物A的患者給藥劑量為45 mg至450 mg QD。Compound A is a potent, selective, orally bioavailable ATP-competitive ERK1/2 kinase inhibitor that exhibits physicochemical properties that enable use in combination with RAF and MEK inhibitors or other targeted therapeutics. Compound A potently inhibits pERK signaling and shows tumor growth inhibition in multiple MAPK-activated cancer cell and xenograft models. Importantly, Compound A exhibited broad efficacy targeting multiple known mechanisms of resistance to BRAF and MEK inhibitors, including RAS mutations, BRAF splice variants, and MEK1/2 mutations, as shown in engineered cell line models . Compound A is administered to patients at doses ranging from 45 mg to 450 mg QD.
在BRAF V600E CRC中進行的臨床研究表明，單獨的BRAF抑制劑或與MEK ± EGFR抑制劑組合的活性會受到MAPK途徑抑制不足的限制，並且在患者中，即使在最初臨床受益的情況下，抗性機制也會迅速出現。導致患者腫瘤中MAPK通路再活化的獲得性抗性機制主要涉及激活RAS、BRAF或MEK中的基因改變。這突顯了BRAF V600E CRC對MAPK信號的依賴，並表明對ERK（傳訊途徑的最下游點）的抑制可能會規避上游節點發生的抗性。Clinical studies in BRAF V600E CRC have shown that the activity of BRAF inhibitors alone or in combination with MEK ± EGFR inhibitors is limited by insufficient inhibition of the MAPK pathway, and that in patients, even in the setting of initial clinical benefit, the Sexual mechanisms also emerge quickly. The mechanisms of acquired resistance leading to reactivation of the MAPK pathway in patient tumors primarily involve activation of genetic alterations in RAS, BRAF, or MEK. This highlights the dependence of BRAF V600E CRC on MAPK signaling and suggests that inhibition of ERK (the most downstream point of the signaling pathway) may circumvent resistance occurring at upstream nodes.
工程化為BRAF V600E細胞系的RAS、RAF或MEK抗性突變的臨床前模型支持這一概念。儘管親代BRAF V600E細胞系對BRAF、MEK、EGFR和/或ERK抑制劑的組合敏感，但引入KRAS、NRAS、MEK1或MEK2抗性突變導致工程化BRAF V600E細胞對所有抑制劑組合的敏感性降低，但含有ERK抑制劑的除外。此外，與BRAF和MEK抑制劑相比，藉由使用含有BRAF和ERK抑制劑的藥物組合治療，可以更有效地抑制小鼠異種移植物中先前存在的低頻合併抗性殖株的生長。Preclinical models of RAS, RAF or MEK resistance mutations engineered into the BRAF V600E cell line support this concept. Although the parental BRAF V600E cell line was sensitive to combinations of BRAF, MEK, EGFR and/or ERK inhibitors, introduction of KRAS, NRAS, MEK1 or MEK2 resistance mutations resulted in reduced sensitivity of engineered BRAF V600E cells to all combinations of inhibitors , except those containing ERK inhibitors. Furthermore, the growth of preexisting low-frequency pooled resistant clones in mouse xenografts was more effectively inhibited by treatment with a drug combination containing BRAF and ERK inhibitors compared to BRAF and MEK inhibitors.
在BRAF突變人細胞系異種移植物HT29中體內測試了達拉菲尼 + 化合物A的組合。在臨床相關劑量下，與達拉菲尼 + 曲美替尼相比，用達拉菲尼 + 化合物A治療的小鼠獲得了相似的抗腫瘤應答（分別為36% T/C相對於28% T/C）。單一藥劑治療導致疾病進展，化合物A達到54% T/C，達拉菲尼達到59% T/C，曲美替尼達到48% T/C。如藉由缺少顯著的體重減輕所判斷的，所有方案具有良好的耐受性。該等數據表明，在患有BRAF突變的大腸直腸癌患者中，達拉菲尼+化合物A的組合可達到與達拉菲尼+曲美替尼相似的抗腫瘤活性，並為其在臨床中的使用提供了依據。The combination of Dabrafenib + Compound A was tested in vivo in the BRAF mutant human cell line xenograft HT29. At clinically relevant doses, mice treated with dabrafenib + compound A achieved similar antitumor responses compared to dabrafenib + trametinib (36% T/C vs. 28%, respectively T/C). Single-agent therapy resulted in disease progression, reaching 54% T/C for compound A, 59% T/C for dabrafenib, and 48% T/C for trametinib. All regimens were well tolerated as judged by the lack of significant weight loss. These data suggest that the combination of dabrafenib + compound A achieves antitumor activity similar to that of dabrafenib + trametinib in patients with BRAF-mutated colorectal cancer, and is a clinical use provides a basis.
藉由組合抑制BRAF、MEK和EGFR傳訊顯示出改善的結果，支持以下觀點：BRAF V600 CRC的治療需要抑制MAPK途徑內的多個節點。Improved results were shown by combined inhibition of BRAF, MEK and EGFR signaling, supporting the notion that treatment of BRAF V600 CRC requires inhibition of multiple nodes within the MAPK pathway.
然而，對治療的內源性和獲得性抗性仍然是重要的挑戰，並且臨床結果仍然很差。組合療法的作用係提供對MAPK傳訊的更強大抑制，並解決MAPK途徑內外的抗性機制的複雜性。鑒於表徵BRAF 突變CRC的訊息傳遞的適應性複雜性，需要抑制除RAF和ERK的蛋白質。舉例來說，一項針對218種BRAF -V600E突變CRC腫瘤的研究鑒定了以高KRAS/mTOR/AKT/4EBP1/EMT活化為特徵的腫瘤的不同子集，而細胞週期失調則以其他子集為特徵。However, endogenous and acquired resistance to therapy remains an important challenge, and clinical outcomes remain poor. The effect of combination therapy is to provide more robust inhibition of MAPK signaling and to address the complexity of resistance mechanisms within and outside the MAPK pathway. Given the adaptive complexity of characterizing message transduction in BRAF- mutant CRC, inhibition of proteins other than RAF and ERK is required. For example, a study of 218 BRAF- V600E mutant CRC tumors identified distinct subsets of tumors characterized by high KRAS/mTOR/AKT/4EBP1/EMT activation, while cell cycle dysregulation was characterized by other subsets. feature.
儘管有靶向療法組合已取得了進展，例如BEACON試驗中的研究（Kopetz等人，2019），但在癌細胞中關閉BRAF V600致癌驅動的能力受限於1.) 無法完全抑制BRAF活性（由於RAF激酶具有藉由無效抑制的二聚體發出信號的適應能力）和2.) 不僅藉由MAPK途徑內的適應機制，而且還藉由平行傳訊途徑刺激正在進行的ERK活化。達拉菲尼、威羅菲尼和康奈非尼有效地抑制BRAF在BRAF 突變癌細胞中的活性，其中單體V600E係致癌驅動因子。然而，該等藥物也可以藉由幾種機制導致ERK的反常活化。Despite advances in targeted therapy combinations, such as the study in the BEACON trial (Kopetz et al., 2019), the ability to turn off the BRAF V600 oncogenic driver in cancer cells is limited by 1.) the inability to completely inhibit BRAF activity (due to RAF kinases have the adaptive capacity to signal through ineffectively inhibited dimers) and 2.) stimulate ongoing ERK activation not only through adaptive mechanisms within the MAPK pathway, but also through parallel signaling pathways. Dabrafenib, vemurafenib, and connefenib potently inhibit BRAF activity in BRAF- mutant cancer cells, in which monomeric V600E is an oncogenic driver. However, these drugs can also cause paradoxical activation of ERK by several mechanisms.
BRAF和MEK的組合抑制作用可藉由抑制途徑來改善；然而，ERK傳訊的持久性係這種治療方法的限制。阻斷ERK係MAPK途徑的最終信號，可以繞開自我調整上游信號，並提供改善的療效和對獲得性抗性的恢復力。Combined inhibition of BRAF and MEK can be ameliorated by inhibiting the pathway; however, the persistence of ERK signaling is a limitation of this therapeutic approach. Blocking the final signal of the ERK-lineage MAPK pathway bypasses self-regulating upstream signaling and provides improved efficacy and resilience to acquired resistance.
BRAF選擇性抑制劑對組成型活化的單體BRAF V600有效；然而，對RAF抑制劑的內源性和獲得性抗性會在MAPK途徑的多個水平上發展。在穩態條件下，藉由BRAF V600E活化的MAPK傳訊導致藉由活化的RAS產生的信號的ERK依賴性負反饋。在BRAF V600 CRC中，之所以表現出對RAF抑制的內源性抗性，係因為例如達拉菲尼的藥物有效抑制了藉由MEK向ERK的單體BRAF V600E傳訊；然而，這導致了將依賴ERK的負反饋釋放到RAS傳訊中。因此，上游信號，例如藉由表皮生長因子受體（EGFR），能夠活化RAS。反過來，這導致了BRAF V600E和野生型同二聚體和異二聚體的誘導，包括向MEK提供信號的WT的同二聚體和異二聚體和BRAF-V600E、CRAF和BRAF-V600E和ARAF和BRAF-V600E。此外，RAF抑制劑（例如達拉菲尼）會變構地促進RAF家族成員的同源二聚作用和異源二聚作用，從而使抑制劑僅與一個RAF伴侶結合，而另一個未結合的二聚體伴侶在刺激下游傳訊方面具有催化活性。BRAF-selective inhibitors are effective against constitutively activated monomeric BRAF V600; however, both endogenous and acquired resistance to RAF inhibitors develop at multiple levels of the MAPK pathway. Under steady-state conditions, MAPK signaling activated by BRAF V600E results in an ERK-dependent negative feedback of signals generated by activated RAS. In BRAF V600 CRC, endogenous resistance to RAF inhibition is shown because drugs such as dabrafenib effectively inhibit monomeric BRAF V600E signaling to ERK by MEK; ERK-dependent negative feedback is released into RAS signaling. Thus, upstream signals, such as by epidermal growth factor receptor (EGFR), can activate RAS. This, in turn, resulted in the induction of BRAF V600E and wild-type homodimers and heterodimers, including WT homodimers and heterodimers and BRAF-V600E, CRAF, and BRAF-V600E that signal MEK and ARAF and BRAF-V600E. In addition, RAF inhibitors, such as dabrafenib, allosterically promote both homodimerization and heterodimerization of RAF family members such that the inhibitor binds only one RAF partner and the other unbound Dimeric partners are catalytically active in stimulating downstream signaling.
因此，例如達拉菲尼的藥物靶向BRAF依賴性CRC細胞中的V600E單體，而不影響RAS刺激的二聚體傳訊。這導致ERK再活化程度超過BRAF V600E黑色素瘤中所見的，從而限制了CRC中療法的有效性。此外，CRAF在BRAF抑制劑治療後介導反常活化中起重要作用。因此，有效抑制CRAF和BRAF 活性的RAF抑制劑（例如化合物C）可以有效地阻斷BRAF突變的腫瘤和RAS驅動的自我調整MAPK活化。CRAF在抗性中的作用係在三重組合中同時包含抑制B-和CRAF的藥物的基本原理。Thus, drugs such as dabrafenib target V600E monomers in BRAF-dependent CRC cells without affecting RAS-stimulated dimer signaling. This results in a degree of ERK reactivation beyond that seen in BRAF V600E melanoma, thereby limiting the effectiveness of therapy in CRC. Furthermore, CRAF plays an important role in mediating paradoxical activation following BRAF inhibitor treatment. Therefore, RAF inhibitors that effectively inhibit CRAF and BRAF activity, such as compound C, can effectively block BRAF-mutated tumors and RAS-driven self-regulating MAPK activation. The role of CRAF in resistance is the rationale for including both B- and CRAF-inhibiting drugs in a triple combination.
達拉菲尼 + 化合物 A + 化合物C的三重組合可藉由利用獨特地靶向BRAF V600驅動的癌細胞內源性和獲得性抗性機制的潛力來抑制BRAF V600E/K/D大腸直腸癌中的MAPK途徑。The triple combination of Dabrafenib + Compound A + Compound C inhibits BRAF V600 E/K/D colorectal cancer by exploiting the potential to uniquely target BRAF V600-driven mechanisms of endogenous and acquired resistance in cancer cells the MAPK pathway.
儘管單一藥劑檢查點阻斷在微衛星穩定CRC的治療中無效，但用抗PD-1抗體的MSI-H CRC治療與31%-50%的應答率相關。儘管大約有21%的BRAF V600E CRC可能顯示MSI-H狀態，但微衛星不穩定性似乎並未改變該疾病中對MAPK靶向療法的反應性。因此，患有MSI-H BRAF V600E CRC的受試者可能對RAF/MEK/ERK靶向療法或檢查點阻斷有應答。藉由解決MSI-HBRAF 突變型CRC中致癌性BRAF和免疫療法應答性的共同特徵，將MAPK途徑抑制與檢查點阻斷組合可以改善僅使用任一類療法所達到的結果。Although single-agent checkpoint blockade is ineffective in the treatment of microsatellite-stabilized CRC, MSI-H CRC treatment with anti-PD-1 antibodies is associated with a 31%-50% response rate. Although approximately 21% of BRAF V600E CRCs may show MSI-H status, microsatellite instability does not appear to alter responsiveness to MAPK-targeted therapy in this disease. Therefore, subjects with MSI-H BRAF V600E CRC may respond to RAF/MEK/ERK targeted therapy or checkpoint blockade. By addressing the common features of oncogenic BRAF and immunotherapy responsiveness in MSI-H BRAF mutant CRC, combining MAPK pathway inhibition with checkpoint blockade could improve outcomes achieved with either type of therapy alone.
此外，靶向的小分子抑制劑可以調節免疫微環境。例如，臨床前研究表明，MAPK途徑抑制劑可藉由增加腫瘤中的腫瘤浸潤淋巴細胞、減少上調的免疫抑制細胞介素來改善淋巴細胞的歸巢和功能，並通常抵消癌症的免疫耐受性。此外，BRAF-MAPK傳訊通路對於人黑素瘤細胞中的癌症免疫逃避至關重要。因此，RAF和MEK抑制劑可以調節對腫瘤的免疫應答，並且將該等藥物與檢查點阻斷組合使用甚至可以提高「免疫冷」腫瘤（如微衛星穩定CRC）對PD-1抑制的敏感性。In addition, targeted small-molecule inhibitors can modulate the immune microenvironment. For example, preclinical studies have shown that MAPK pathway inhibitors can improve lymphocyte homing and function by increasing tumor-infiltrating lymphocytes in tumors, reducing up-regulated immunosuppressive interleukins, and generally counteracting cancer immune tolerance . Furthermore, the BRAF-MAPK signaling pathway is critical for cancer immune evasion in human melanoma cells. Thus, RAF and MEK inhibitors can modulate immune responses to tumors, and combining these drugs with checkpoint blockade may even increase the sensitivity of "immune cold" tumors, such as microsatellite-stabilized CRC, to PD-1 inhibition .
達拉菲尼 + 化合物 A + 斯巴達珠單抗的三重組合可藉由利用獨特地靶向BRAF V600驅動的癌細胞內源性和獲得性抗性機制的潛力來抑制BRAF V600E/K/D大腸直腸癌中的MAPK途徑。藥物組成物 The triple combination of dabrafenib + compound A + spartalizumab inhibits BRAF V600E/K/D by exploiting the potential to uniquely target BRAF V600-driven mechanisms of endogenous and acquired resistance in cancer cells The MAPK pathway in colorectal cancer. pharmaceutical composition
在另一個方面，本發明提供了藥學上可接受的組成物，該藥學上可接受的組成物包含治療有效量的達拉菲尼、化合物A或化合物C，其與一種或多種藥學上可接受的載劑（添加劑）和/或稀釋劑配製在一起。如下面詳細描述的，本發明之藥物組成物可特別配製用於固體或液體形式投與（包括適合口服投與的那些，例如浸液（水性或非水性溶液或懸浮液）、片劑（例如，針對口腔、舌下和全身吸收的那些）、大丸劑、粉劑、顆粒劑、糊劑（應用於舌））。In another aspect, the present invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of Dabrafenib, Compound A or Compound C in combination with one or more pharmaceutically acceptable of carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form (including those suitable for oral administration, such as infusions (aqueous or non-aqueous solutions or suspensions), tablets (such as , those for oral, sublingual and systemic absorption), boluses, powders, granules, pastes (for application to the tongue)).
如本文所用的短語「藥學上可接受的載劑」係指藥學上可接受的材料、組成物或媒介物，如液體或固體填充劑、稀釋劑、賦形劑、製造助劑（例如潤滑劑、滑石鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸）或溶劑包封材料，參與將主題化合物從一個器官或身體的一部分運送或運輸到另一個器官或身體的一部分。在與配製物的其他成分相容並且對患者無害的意義上，每種載劑必須是「可接受的」。可用作藥學上可接受的載劑的材料的一些實例包括：(1) 糖類，如乳糖、葡萄糖和蔗糖；(2) 澱粉，如玉米澱粉和馬鈴薯澱粉；(3) 纖維素及其衍生物，如羧甲基纖維素鈉、乙基纖維素和乙酸纖維素；(4) 粉狀黃茋膠；(5) 麥芽；(6) 明膠；(7) 滑石；(8) 賦形劑，如可可脂和栓劑蠟；(9) 油類，如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油、大豆油等；(10) 二醇類，如丙二醇；(11) 多元醇類，如甘油、山梨醇、甘露醇和聚乙二醇；(12) 酯類，如油酸乙酯和月桂酸乙酯；(13) 瓊脂；(14) 緩衝劑，如氫氧化鎂和氫氧化鋁；(15) 海藻酸；(16) 無熱原水；(17) 等滲鹽水；(18) 林格氏溶液；(19) 乙醇；(20) pH緩衝溶液；(21) 聚酯，聚碳酸酯和/或聚酸酐；以及 (22) 藥物配製物中使用的其他無毒相容物質。The phrase "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as liquid or solid fillers, diluents, excipients, manufacturing aids (eg lubricating agents) agent, magnesium talc, calcium stearate or zinc stearate or stearic acid) or solvent encapsulating materials, involved in the transport or transport of the subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) carbohydrates, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, Such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.; (10) glycols, such as propylene glycol; (11) polyols , such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate and/or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.
如上文所述，本發明化合物的某些實施方式可含有鹼性官能基，例如胺基或烷基胺基，並且由此能夠與藥學上可接受的酸形成藥學上可接受的鹽。在這方面，術語「藥學上可接受的鹽」係指本發明之化合物的相對無毒的無機和有機酸加成鹽。該等鹽可以在投與媒介物或劑型製造過程中原位製備，或者藉由使純化的游離鹼形式的本發明化合物與合適的有機或無機酸分別反應，並在隨後的純化期間分離由此形成的鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、馬來酸鹽、富馬酸鹽、琥珀酸鹽、酒石酸鹽、萘酸鹽（napthylate）、甲磺酸鹽、葡庚糖酸鹽、乳糖醛酸鹽和月桂基磺酸鹽等。As described above, certain embodiments of the compounds of the present invention may contain basic functional groups, such as amine groups or alkylamine groups, and thus are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. Such salts can be prepared in situ during the manufacture of the administration vehicle or dosage form, or by separately reacting the purified free base form of a compound of the invention with a suitable organic or inorganic acid and isolating it during subsequent purification prepared with salt. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucose Heptonate, lactobionate and lauryl sulfonate, etc.
主題化合物的藥學上可接受的鹽包括化合物的常規的無毒鹽或季銨鹽，例如來自無毒的有機酸或無機酸。例如，此類常規無毒鹽包括衍生自無機酸的那些，該無機酸例如為鹽酸、氫溴酸、硫酸、胺磺酸、磷酸、硝酸等；以及從有機酸製備的鹽，該有機酸例如為乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、棕櫚酸、馬來酸、羥基馬來酸、苯乙酸、麩胺酸、苯甲酸、水楊酸、磺胺酸、2-乙醯氧基苯甲酸、富馬酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、異硫磺酸等。Pharmaceutically acceptable salts of the subject compounds include conventional nontoxic or quaternary ammonium salts of the compounds, eg, from nontoxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as Acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, water Sylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiosulfonic acid, etc.
在其他情況下，本發明之化合物可以含有一個或多個酸性官能基，並且因此能夠與藥學上可接受的鹼形成藥學上可接受的鹽。在該等例子中，術語「藥學上可接受的鹽」係指本發明化合物的相對無毒的無機和有機鹼加成鹽。該等鹽也可以在投與媒介物或劑型製造過程中原位製備，或者藉由使純化的游離酸形式的化合物與合適的鹼（例如，藥學上可接受的金屬陽離子的氫氧化物、碳酸鹽或碳酸氫鹽）與氨、或與藥學上可接受的有機一級、二級或三級胺分別反應來製備。代表性的鹼或鹼土金屬鹽包括鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽和鋁鹽等。可用於形成鹼加成鹽的代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌𠯤等。In other instances, the compounds of the present invention may contain one or more acidic functional groups and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of the compounds of the present invention. Such salts can also be prepared in situ during the manufacture of the administration vehicle or dosage form, or by combining the purified free acid form of the compound with a suitable base (eg, a pharmaceutically acceptable metal cation hydroxide, carbonate or bicarbonate) with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine, respectively. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, aluminum, and the like. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
達拉菲尼的特別較佳的鹽係其甲磺酸鹽。化合物A的特別較佳的溶劑化物係其鹽酸鹽。化合物C的特別較佳的形式係游離鹼晶體形式。A particularly preferred salt of dabrafenib is its mesylate salt. A particularly preferred solvate of Compound A is its hydrochloride salt. A particularly preferred form of Compound C is the free base crystalline form.
在組成物中還可以存在潤濕劑、乳化劑和潤滑劑，如十二烷基硫酸鈉和硬脂酸鎂，以及著色劑、釋放劑、包衣劑、甜味劑、調味劑和芳香劑、防腐劑和抗氧化劑。Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring, releasing, coating, sweetening, flavoring and perfuming agents can also be present in the composition , preservatives and antioxidants.
藥學上可接受的抗氧化劑的實例包括：(1) 水溶性抗氧化劑，如抗壞血酸、鹽酸半胱胺酸、硫酸氫鈉、焦亞硫酸鈉、亞硫酸鈉等；(2) 油溶性抗氧化劑，如抗壞血酸棕櫚酸酯、丁羥茴醚（BHA）、丁羥甲苯（BHT）、卵磷脂、沒食子酸丙酯、α-生育酚等；和 (3) 金屬螯合劑，如檸檬酸、乙二胺四乙酸（EDTA）、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitic acid Esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelators, such as citric acid, EDTA (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
本發明之配製物包括適合於口服、鼻、局部（包括口腔和舌下）、直腸、***和/或腸胃外投與的那些。配製物可以方便地以單位劑型存在並且可以藉由藥學領域熟知的任何方法製備。可以與載劑材料組合以產生單一劑型的活性成分的量將取決於所治療的宿主和特定的投與方式而變化。可以與載劑材料組合以產生單一劑型的活性成分的量通常為產生治療效果的化合物的量。通常，在百分之百的範圍內，量的範圍為從約0.1%至約99%的活性成分，較佳的是從約5%至約70%，最較佳的是從約10%至約30%。Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Typically, within one hundred percent, the amount will range from about 0.1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30% .
在某些實施方式中，本發明之配製物包含選自由以下組成之群組的賦形劑：環糊精、纖維素、脂質體、膠束形成劑（例如膽汁酸）和聚合物載劑（例如聚酯和聚酸酐）；和本發明之化合物。在某些實施方式中，前述配製物使得本發明化合物在口服方面係生物可利用的。In certain embodiments, the formulations of the invention comprise excipients selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle formers (eg bile acids) and polymeric carriers ( such as polyesters and polyanhydrides); and compounds of the present invention. In certain embodiments, the aforementioned formulations render the compounds of the present invention orally bioavailable.
製備該等配製物或組成物之方法包括將本發明之化合物與載劑和視需要的一種或多種輔助成分結合的步驟。通常，藉由將本發明之化合物與液體載劑或細碎固體載劑或兩者均勻且緊密地結合，並且然後如果需要，使產物成形來製備配製物。Methods of preparing such formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with a liquid carrier or finely divided solid carrier, or both, and then, if desired, shaping the product.
適用於口服投與的本發明之配製物可以呈膠囊、扁囊劑、丸劑、片劑、錠劑（使用調味基質，通常為蔗糖和***膠或黃茋膠）、粉劑、顆粒劑的形式，或作為在水性或非水性液體中的溶液、懸浮液或固體分散體，或作為水包油或油包水液體乳劑，或作為酏劑或糖漿，或作為軟錠劑（使用惰性基質，例如明膠和甘油，或蔗糖和***膠），和/或作為漱口水等等，每一形式含有預定量的本發明之化合物作為活性成分。本發明之化合物還能以大丸劑、藥糖劑或糊劑形式投與。Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as solutions, suspensions or solid dispersions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as pastilles (using an inert base such as gelatin) and glycerin, or sucrose and acacia), and/or as a mouthwash, etc., each form containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present invention can also be administered in the form of a bolus, electuary or paste.
在本發明用於口服投與的固體劑型（膠囊、片劑、丸劑、糖衣丸、粉劑、顆粒劑、含片（trouches）等）中，將活性成分與以下混合：一種或多種藥學上可接受的載劑，如檸檬酸鈉或磷酸二鈣，和/或以下任何一種：(1) 填充劑或增量劑，如澱粉、乳糖、蔗糖、葡萄糖、甘露醇和/或矽酸；(2) 黏合劑，例如像羧甲基纖維素、藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖和/或***膠；(3) 保濕劑，如甘油；(4) 崩解劑，如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽和碳酸鈉；(5) 溶液阻滯劑，如石蠟；(6) 吸收促進劑，如季銨化合物和表面活性劑，如泊洛沙姆和十二烷基硫酸鈉；(7) 潤濕劑，例如像鯨蠟醇、單硬脂酸甘油酯和非離子表面活性劑；(8) 吸收劑，如高嶺土和膨潤土；(9) 潤滑劑，如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉、硬脂酸鋅、硬脂酸鈉、硬脂酸及其混合物；(10) 著色劑；和 (11) 控釋劑，如交聚維酮或乙基纖維素。在膠囊、片劑和丸劑的情況下，藥物組成物還可以包含緩衝劑。還可以使用此類賦形劑，如乳糖（lactose或milk sugar）以及高分子量聚乙二醇等，將相似類型的固體組成物用作軟殼和硬殼明膠膠囊中的填料。In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, trouches, etc.) of the present invention for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) bulking or bulking agents such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agents (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, Calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution blockers such as paraffin wax; (6) absorption enhancers such as quaternary ammonium compounds and surfactants such as polox sham and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; (8) absorbents such as kaolin and bentonite; (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) Coloring and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft- and hard-shell gelatin capsules using such excipients as lactose (lactose or milk sugar), high molecular weight polyethylene glycols, and the like.
片劑可以藉由壓縮或模製（視需要與一種或多種輔助成分一起）來製備。可以使用黏合劑（例如，明膠或羥丙基甲基纖維素）、潤滑劑、惰性稀釋劑、防腐劑、崩解劑（例如，羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉）、表面活性劑或分散劑來製備壓縮片劑。模製片劑可以藉由在合適的機器中模製用惰性液體稀釋劑潤濕的粉狀化合物的混合物來製備。A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Binders (eg, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium starch glycolate or croscarmellose sodium), surface active or dispersing agent to prepare compressed tablets. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
片劑和本發明之藥物組成物的其他固體劑型（如糖衣丸、膠囊、丸劑和顆粒劑）可視需要進行刻痕或製備有包衣和外殼，例如腸溶包衣和藥物配製領域熟知的其他包衣。也可以使用例如不同比例的羥丙基甲基纖維素將它們配製成使其中的活性成分緩慢或受控釋放以提供所需的釋放曲線、其他聚合物基質、脂質體和/或微球。可以將它們配製用於快速釋放，例如冷凍乾燥。它們可以例如藉由細菌截留過濾器濾過，或藉由併入呈無菌固體組成物形式的滅菌劑來滅菌，該等無菌固體組成物可以在使用前立即溶解於無菌水或一些其他無菌可注射介質中。該等組成物也可以視需要包含遮光劑並且可以是如下組成物，該組成物在胃腸道的某一部分中，視需要以一種延遲的方式僅或者優先釋放一種或多種活性成分。可利用的嵌入式組成物的實例包括聚合物質以及蠟。活性成分還可以是微囊化形式，如果適當的話，可包含一種或多種上述賦形劑。Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention (such as dragees, capsules, pills and granules) can optionally be scored or prepared with coatings and shells, such as enteric coatings and others well known in the pharmaceutical formulation art. coating. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be formulated for rapid release, eg freeze drying. They can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use middle. The compositions may also optionally contain opacifying agents and may be compositions that release only or preferentially one or more of the active ingredients in a certain portion of the gastrointestinal tract, as desired, in a delayed manner. Examples of available embedded compositions include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
用於口服投與本發明之化合物的液體劑型包括藥學上可接受的乳劑、微乳劑、溶液、懸浮液、糖漿和酏劑。除了活性成分之外，液體劑型可以含有本領域常用的惰性稀釋劑（例如像水或其他溶劑）、增溶劑和乳化劑，例如乙醇、異丙醇、碳酸乙酯、醋酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油類（特別是棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油和芝麻油）、甘油、四氫呋喃甲醇、聚乙二醇和脫水山梨醇脂肪酸酯，及其混合物。Liquid dosage forms for oral administration of the compounds of this invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art (such as, for example, water or other solvents), solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene glycol and dehydration Sorbitol fatty acid esters, and mixtures thereof.
除了惰性稀釋劑之外，口服組成物還可包括輔助劑，例如潤濕劑、乳化劑和懸浮劑、甜味劑、調味劑、著色劑、芳香劑以及防腐劑。Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
除了含有活性化合物外，懸浮液還可以含有懸浮劑如，例如乙氧化異硬脂醇、聚氧乙烯山梨醇和山梨醇酯、微晶纖維素、偏氫氧化鋁（aluminum metahydroxide）、膨潤土、瓊脂-瓊脂和黃茋膠，及其混合物。In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar- Agar and tragacanth, and mixtures thereof.
可以在本發明之藥物組成物中使用的合適的水性和非水性載劑的實例包括水、乙醇、多元醇（如，甘油、丙二醇、聚乙二醇等）及其合適的混合物、植物油（如橄欖油）和可注射的有機酯（如油酸乙酯）。適當流動性可以例如藉由以下方式來維持：藉由使用包衣材料（如卵磷脂），在分散體的情況下藉由維持所需粒度，以及藉由使用表面活性劑。Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (eg, olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
該等組成物也可以含有輔助劑如防腐劑、潤濕劑、乳化劑和分散劑。可以藉由包括各種抗細菌劑和抗真菌劑（例如，對羥苯甲酸酯、三氯三級丁醇、山梨酸苯酚等）確保阻止微生物對主題化合物起作用。還令人希望的是在組成物中包括等滲劑，如糖、氯化鈉等。The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by including various antibacterial and antifungal agents (eg, parabens, trichlorobutanol, sorbic acid phenol, etc.). It is also desirable to include isotonic agents such as sugars, sodium chloride, and the like in the composition.
當將本發明之化合物作為藥物向人和動物投與時，它們可以本身或作為藥物組成物給予，該藥物組成物含有例如與藥學上可接受的載劑組合的0.1%至99%（更較佳的是10%至30%）的活性成分。When the compounds of the present invention are administered as medicaments to humans and animals, they can be administered by themselves or as pharmaceutical compositions containing, for example, 0.1% to 99% (more preferably in combination with a pharmaceutically acceptable carrier) preferably 10% to 30%) of the active ingredient.
藉由熟悉該項技術者已知的常規方法將本發明之化合物和/或本發明之藥物組成物配製成藥學上可接受的劑型。The compounds of the present invention and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.
可以改變本發明藥物組成物中活性成分的實際劑量水平，以便獲得一定量的活性成分，該活性成分的量有效地實現對於特定的患者、組成物和投與方式的所期望的治療應答，而對患者沒有毒性。The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention can be varied in order to obtain an amount of the active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, while No toxicity to patients.
選擇的劑量水平將取決於各種因素，包括所使用的本發明之具體化合物或其酯、鹽或醯胺的活性，投與途徑，投與時間，所採用的具體化合物的***率或代謝率，吸收的速度和程度，治療的持續時間，與所採用的具體化合物組合使用的其他藥物、化合物和/或材料，正被治療的患者的年齡、性別、體重、病症、一般健康狀況和先前病史，以及在醫學領域中熟知的類似因素。The dosage level selected will depend on various factors, including the activity of the particular compound of the invention or its ester, salt or amide employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, The rate and extent of absorption, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field.
具有本領域普通技術的醫師或獸醫可以容易地確定並開出所需的藥物組成物的有效量。例如，醫生或獸醫能以低於實現所期望的治療效果所需的水平開始給藥於藥物組成物中使用的本發明之化合物，並逐漸增加劑量直至達到所期望的效果。A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the desired effective amount of the pharmaceutical composition. For example, a physician or veterinarian can start doses of a compound of the invention used in a pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
通常，本發明之組合的合適日劑量將是每種化合物有效產生治療效果的最低劑量的量。這樣的有效劑量通常將取決於上述因素。In general, a suitable daily dosage of the combinations of the present invention will be the minimum amount of each compound effective to produce a therapeutic effect. Such effective doses will generally depend on the factors discussed above.
在另一個方面，本發明提供了藥學上可接受的組成物，該藥學上可接受的組成物包含治療有效量的一種或多種上述主題化合物，其與一種或多種藥學上可接受的載劑（添加劑）和/或稀釋劑配製在一起。實例 實例 1 達拉菲尼、化合物A和化合物CIn another aspect, the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the above-mentioned subject compounds in admixture with one or more pharmaceutically acceptable carriers ( additives) and/or diluents. EXAMPLES Example 1 Dabrafenib, Compound A and Compound C
根據WO 2009/137391的實例58a合成達拉菲尼。根據WO 2015/066188的實例184合成化合物A。根據WO 2014/151616的實例1156合成化合物C。WO 2009/137391、WO 2015/066188和WO 2014/151616藉由引用以其全文併入本文。本文所述之達拉菲尼、化合物A或化合物C的組合的效用可以藉由以下實例中的測試來證明。實例 2 MAPK途徑抑制劑在裸鼠中人BRAF突變CRC異種移植模型HT29中的組合功效Dabrafenib was synthesized according to Example 58a of WO 2009/137391. Compound A was synthesized according to Example 184 of WO 2015/066188. Compound C was synthesized according to Example 1156 of WO 2014/151616. WO 2009/137391, WO 2015/066188 and WO 2014/151616 are incorporated herein by reference in their entirety. The utility of the combinations of Dabrafenib, Compound A, or Compound C described herein can be demonstrated by the tests in the following examples. Example 2 Combination efficacy of MAPK pathway inhibitors in human BRAF mutant CRC xenograft model HT29 in nude mice
達拉菲尼（DRB436）：在V600的突變的BRAF的選擇性抑制劑，能夠抑制BRAF（V600E）、BRAF（V600K）和BRAF（V600G）突變。化合物A：選擇性ATP競爭性ERK1和ERK2激酶抑制劑。化合物C：BRAF和CRAF的ATP競爭性抑制劑。將達拉菲尼在媒介物（在pH 8 DI水中0.5% HPMC + 0.2% Tween 80）中口服給藥。將化合物A在媒介物（在pH 7.4磷酸鹽緩衝液中0.5% HPC/0.5%普朗尼克（Pluronic）F127（用酸調節至pH 4.0））中口服給藥。將化合物C（游離鹼結晶形式，呈粉末形式）在MEPC4媒介物（45% Cremophor RH40 + 27% PEG400 + 18% Capmul MCM C8 + 10%乙醇）中口服給藥。Dabrafenib (DRB436): Selective inhibitor of BRAF mutated at V600, able to inhibit BRAF (V600E), BRAF (V600K) and BRAF (V600G) mutations. Compound A: Selective ATP-competitive ERK1 and ERK2 kinase inhibitor. Compound C: ATP-competitive inhibitor of BRAF and CRAF. Dabrafenib was administered orally in vehicle (0.5% HPMC + 0.2% Tween 80 in pH 8 DI water). Compound A was administered orally in vehicle (0.5% HPC/0.5% Pluronic F127 (adjusted to pH 4.0 with acid) in pH 7.4 phosphate buffer). Compound C (free base crystalline form, in powder form) was administered orally in MEPC4 vehicle (45% Cremophor RH40 + 27% PEG400 + 18% Capmul MCM C8 + 10% ethanol).
HT29人大腸直腸癌（CRC）腫瘤細胞系購自ATCC，並已包括在諾華公司細胞系百科全書（Cell Line Encyclopedia（CLE））細胞系保藏中。在IMPACT-VIII PCR測定組中，該品系不含支原體和鼠類病毒（密蘇里州哥倫比亞密蘇裡大學（University of Missouri, Columbia, MO），動物研究診斷實驗室（Research Animal Diagnostic Laboratory（RADIL）））中進行。將細胞在含有5%二氧化碳的濕潤氣氛中於37°C保持在EMEM（龍沙基團（Lonza）#12-611F）加10% FBS（Gibco #26140-079）（56°C持續30分鐘，滅活的）中。將細胞在80%-95%匯合（用0.25%胰蛋白酶-EDTA（Gibco #25200-056））時收穫，在1200 rpm離心5分鐘後，用生長培養基中和，隨後將細胞沈澱重懸於冷HBSS（Gibco #14175-095）中並且然後用等體積的Matrigel™基質（康寧公司（Corning）#354234）混合以製備10 x 106 個細胞/mL的終濃度。然後將200 µl（2 x 106 個細胞）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（TV）（mm3 ）= (l x w2 )/2，其中l係腫瘤的最長軸並且w垂直於l。每週兩次監測小鼠的腫瘤生長和體重。每週兩次監測動物健康和行為，包括梳毛和移動。每天監測小鼠的總體健康狀況。The HT29 human colorectal cancer (CRC) tumor cell line was purchased from ATCC and has been included in the Novartis Cell Line Encyclopedia (CLE) cell line collection. This strain is free of mycoplasma and murine viruses in the IMPACT-VIII PCR assay set (University of Missouri, Columbia, MO, Research Animal Diagnostic Laboratory (RADIL)) conduct. Cells were maintained in EMEM (Lonza #12-611F) plus 10% FBS (Gibco #26140-079) at 37°C in a humidified atmosphere containing 5% carbon dioxide (56°C for 30 minutes, inactivated). Cells were harvested at 80%-95% confluency (with 0.25% trypsin-EDTA (Gibco #25200-056)), neutralized with growth medium after centrifugation at 1200 rpm for 5 min, and cell pellets were subsequently resuspended in cold HBSS (Gibco # 14175-095) and is then treated with an equal volume of Matrigel ™ matrix (Corning (Corning) # 354234) were mixed to prepare 10 x 10 6 cells / mL final concentration. Then 200 μl (2 x 10 6 cells) tumors in female nude mice implanted subcutaneously into the slurry to the right. Tumor volume was calculated by measuring with a caliper and using the formula, where tumor volume (TV) (mm 3 ) = (lxw 2 )/2, where l is the longest axis of the tumor and w is perpendicular to l. Mice were monitored for tumor growth and body weight twice a week. Animal health and behavior, including grooming and movement, were monitored twice a week. The general health of the mice was monitored daily.
HCOX1329 CRC患者源性腫瘤異種移植物（PDX）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，藉由組織研磨機（Chemglass生命科學公司（Chemglass lifeSciences）#CLS-5020-085），在PBS中稀釋。然後將100 µl腫瘤漿液中的4 x 10^6個細胞皮下植入雌性裸小鼠的右側作為傳代7代。藉由用卡尺測量並使用公式計算腫瘤體積，其中腫瘤體積（TV）（mm3 ）= (l x w2 )/2，其中l係腫瘤的最長軸並且w垂直於l。每週兩次監測小鼠的腫瘤生長和體重。每週兩次監測動物健康和行為，包括梳毛和移動。每天監測小鼠的總體健康狀況。HCOX1329 CRC patient-derived tumor xenografts (PDX) were propagated in nude mice by serial passaging of tumor sera. Briefly, fresh tumor fragments from previous passages were homogenized using a mild MACS separator (MACS Miltenyi Biotec, #120-005-331 ), by tissue grinder (Chemglass Chemglass lifeSciences #CLS-5020-085), diluted in PBS. 4 x 10^6 cells in 100 µl of tumor serum were then implanted subcutaneously into the right side of female nude mice for passage 7. Tumor volume was calculated by measuring with a caliper and using the formula, where tumor volume (TV) (mm 3 ) = (lxw 2 )/2, where l is the longest axis of the tumor and w is perpendicular to l. Mice were monitored for tumor growth and body weight twice a week. Animal health and behavior, including grooming and movement, were monitored twice a week. The general health of the mice was monitored daily.
表1、表2和表3描述了每個模型的功效研究設計。以根據體重調整的10 mL/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。
[表 1
]
在兩項研究中，使用在無胸腺裸鼠中BRAF突變HT29人CRC異種移植模型檢查了MAPK途徑抑制劑的抗腫瘤功效。在第一項研究（表1）中，用單一藥劑或按表1所述MAPK途徑抑制劑組合治療小鼠直到媒介物治療的腫瘤在治療開始後13天達到體積 ＞ 1000 mm3
。藉由評估移植後第39天（治療開始後第13天）的% T/C或%消退來確定抗腫瘤活性。在表3中報導了在治療開始後13天的抗腫瘤活性、平均腫瘤體積變化、平均體重變化和存活率。治療後的腫瘤體積和體重變化繪製於圖1中。與媒介物治療組相比，每天用化合物A、達拉菲尼或曲美替尼單一藥劑治療分別達到54% T/C、59% T/C、或48% T/C。化合物A + 達拉菲尼的組合的抗腫瘤活性（35% T/C）與曲美替尼+達拉菲尼組合達到的抗腫瘤活性（28% T/C）相似，且當與達拉菲尼治療相比，兩種組合的抗腫瘤活性顯著不同（對於達拉菲尼 + 曲美替尼相對於達拉菲尼，p = 0.0037；對於達拉菲尼+化合物A相對於達拉菲尼，p = 0.03），但與曲美替尼或化合物A治療相比兩種組合的抗腫瘤活性無顯著差異。相比之下，當與媒介物、所有單一藥劑、和每個雙重組合組相比，化合物A + 達拉菲尼 + 曲美替尼的三重組合達到了顯著的（p ＜ 0.05）康腫瘤活性（3% T/C）（表1和圖1）。在兩週研究結束時，所有治療組的耐受性良好，體重減輕最小（少於10%）；沒有觀察到毒性或死亡的跡象（圖1）。In two studies, the antitumor efficacy of MAPK pathway inhibitors was examined using a BRAF mutant HT29 human CRC xenograft model in athymic nude mice. In the first study (Table 1), with a single agent or in combination by the MAPK pathway inhibitor in Table 1 mice were treated to vehicle-treated until the
在第二項研究中，將達拉菲尼 + 曲美替尼 + 化合物A的三重組合的活性與達拉菲尼 + 化合物A + 化合物C的三重組合的活性進行了比較。用表2中所述之劑量和方案治療小鼠，直到在開始治療後24天用媒介物治療的腫瘤達到體積 ＞ 1000 mm3
。藉由評估移植後第52天（治療開始後第24天）的%T/C或%消退來確定抗腫瘤活性。在表4中報導了在治療開始後24天的抗腫瘤活性、平均腫瘤體積變化、平均體重變化和存活率。
[表 4
]
治療後的腫瘤體積和體重變化繪製於圖2中。當與化合物A + 化合物C + 達拉菲尼達到的抗腫瘤活性（5% T/C）相比，化合物A + 曲美替尼 + 達拉菲尼的組合抗腫瘤活性（14% T/C）相似且無顯著差異（p = 0.38）。與未治療對照組相比，兩種組合的抗腫瘤活性均得到顯著改善（兩組相對於未治療對照組，p ＜ 0.0001）（表4和圖2）。在研究結束時，所有治療組的耐受性良好，體重減輕最小（少於10%）；沒有觀察到毒性或死亡的跡象（圖2）。Post-treatment tumor volume and body weight changes are plotted in Figure 2. The combined antitumor activity of Compound A + trametinib + dabrafenib (14% T/C) was compared to the antitumor activity achieved by Compound A + Compound C + Dabrafenib (5% T/C). ) were similar and not significantly different (p = 0.38). The antitumor activity of both combinations was significantly improved compared to the untreated control group (p < 0.0001 in both groups vs. the untreated control group) (Table 4 and Figure 2). At the end of the study, all treatment groups were well tolerated with minimal weight loss (less than 10%); no signs of toxicity or death were observed (Figure 2).
接下來，使用在無胸腺裸鼠中BRAF突變患者源性CRC異種移植模型HCOX1329檢查了MAPK途徑抑制劑的抗腫瘤功效。用媒介物或按表3所述MAPK途徑抑制劑組合治療小鼠直到媒介物治療的腫瘤達到體積 ＞ 1000 mm3
、或MAPK途徑抑制劑治療開始後62-67天。藉由評估植入後38天（治療開始後26天）的%T/C或%消退來確定抗腫瘤活性，在此時處死用媒介物治療的小鼠並且用MAPK途徑抑制劑治療的小鼠再治療24-29天並在植入後第62天（達拉菲尼 + 化合物A + 曲美替尼）或第67天（達拉菲尼 + 曲美替尼和達拉菲尼 + 曲美替尼 + 西妥昔單抗）處死。在表4中報導了在治療開始後26天的抗腫瘤活性、平均腫瘤體積變化、平均體重變化和存活率。治療後26-55天的腫瘤體積和體重變化繪製於圖3中。當與藉由曲美替尼 + 達拉菲尼 + 西妥昔單抗達到的抗腫瘤活性（13% T/C）相比，達拉菲尼 + 曲美替尼的組合抗腫瘤活性（17% T/C）相似且無統計學意義（p = 0.68）。相比之下，化合物A + 達拉菲尼 + 曲美替尼的三重組合達到了腫瘤消退（70%消退），這與達拉菲尼 + 曲美替尼（p = 0.005）或達拉菲尼 + 曲美替尼 + 西妥昔單抗組合（p = 0.04）相比顯著不同（表4和圖3）。在兩週研究結束時，所有治療組的耐受性良好，體重減輕最小（少於10%）；沒有觀察到毒性或死亡的跡象（圖3）。Next, the antitumor efficacy of MAPK pathway inhibitors was examined using HCOX1329, a BRAF mutant patient-derived CRC xenograft model in athymic nude mice. With vehicle or by a combination of an inhibitor of the MAPK pathway in Table 3 mice treated with vehicle-treated until the tumor reached a volume> 1000 mm 3, or the treatment of MAPK pathway inhibitors 62-67 days after the start. Antitumor activity was determined by assessing % T/C or
在BRAF突變CRC腫瘤異種移植物中分析了MAPK途徑抑制劑組合的體內活性。在人BRAF突變細胞系來源的異種移植物HT29中，達拉菲尼+曲美替尼的組合活性類似於達拉菲尼 + 化合物A的組合活性，並且與每種單一藥劑相比，該活性適當地更好。相比之下，達拉菲尼 + 化合物A + 曲美替尼的三重組合或達拉菲尼 + 化合物A + 化合物C的三重組合在該異種移植模型中達到顯著的抗腫瘤活性。在人類患者源性BRAF突變CRC異種移植物HCOX1329中，達拉菲尼 + 化合物A + 曲美替尼的組合也比達拉菲尼 + 曲美替尼的組合和達拉菲尼 + 曲美替尼 + 西妥昔單抗的組合顯著地活性更高。總的來說，該等數據表明，在BRAF突變CRC患者中，達拉菲尼 + 化合物A + 曲美替尼的三重組合或達拉菲尼 + 化合物A + 化合物C的三重組合可達到更大和更持久的應答。The in vivo activity of combinations of MAPK pathway inhibitors was analyzed in BRAF-mutant CRC tumor xenografts. In the human BRAF mutant cell line-derived xenograft HT29, the combined activity of dabrafenib + trametinib was similar to that of dabrafenib + compound A, and compared to each single agent Appropriately better. In contrast, the triple combination of Dabrafenib + Compound A + Trametinib or the triple combination of Dabrafenib + Compound A + Compound C achieved significant antitumor activity in this xenograft model. In human patient-derived BRAF-mutant CRC xenograft HCOX1329, the combination of dabrafenib + Compound A + trametinib also outperformed the combination of dabrafenib + trametinib and dabrafenib + trametinib The combination of Nituximab + Cetuximab was significantly more active. Collectively, these data suggest that the triple combination of dabrafenib + Compound A + trametinib or the triple combination of dabrafenib + Compound A + Compound C can achieve greater and More durable responses.
應理解，本文所述之實例和實施方式僅用於舉例說明目的，其各種修飾或改變對於熟悉該項技術者將是明瞭的，並包括在本申請的精神和範圍內和所附申請專利範圍的範圍內。It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes thereof will be apparent to those skilled in the art and are included within the spirit and scope of this application and the scope of the appended claims In the range.
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[圖1]：在HT29腫瘤細胞植入後第26天，將小鼠隨機化到治療組中。治療在腫瘤細胞植入後第26天開始並持續至第39天。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。相對於隨機化後天數，繪製的腫瘤體積（A）或從治療組起始的體重變化百分比（B）。在第39天使用單因素方差分析（ANOVA）Tukey多重比較測驗計算腫瘤體積變化的顯著差異（N = 9隻小鼠/組）（對於達拉菲尼 + 化合物A + 曲美替尼治療組相對於媒介物、單一藥劑和雙重組合，p ＜ 0.05
）。[Figure 1]: On
[圖2]：在HT29腫瘤細胞移植後第28天，將小鼠隨機化到治療組中。治療在腫瘤細胞植入後第28天開始並持續至第52天。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。相對於隨機化後天數，繪製的腫瘤體積（A）或從治療組起始的體重變化百分比（B）。在第52天使用單因素方差分析（ANOVA）Tukey多重比較測驗計算顯著差異（N = 7隻小鼠/組，除未經治療對照組n = 4）（對於兩種組合治療組相對於非治療對照組，p ＜ 0.0001
）。[Figure 2]: On
[圖3]：在HCOX1329腫瘤植入後第12天，將小鼠隨機化到治療組中。治療在腫瘤植入後第12天開始並持續至第38天（媒介物）、第62天（達拉菲尼 + 化合物A + 曲美替尼）、或第67天（達拉菲尼 + 曲美替尼和達拉菲尼 + 曲美替尼 + 西妥昔單抗）。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。相對於隨機化後天數，繪製的腫瘤體積（A）或從治療組起始的體重變化百分比（B）。在第38天使用單因素方差分析（ANOVA）Tukey多重比較測驗計算顯著差異（N = 5隻小鼠/組，除達拉菲尼 + 化合物A + 曲美替尼組n = 4）（對於達拉菲尼 + 化合物A + 曲美替尼相對於達拉菲尼 + 曲美替尼，p = 0.005
；以及對於達拉菲尼 + 化合物A + 曲美替尼相對於達拉菲尼 + 曲美替尼 + 西妥昔單抗p = 0.04
）。[Figure 3]: On day 12 after HCOX1329 tumor implantation, mice were randomized into treatment groups. Treatment started on day 12 post tumor implantation and continued until day 38 (vehicle), day 62 (dabrafenib + Compound A + trametinib), or day 67 (dabrafenib + trametinib) metinib and dabrafenib + trametinib + cetuximab). Tumor size and body weight were collected at randomization and then twice weekly for the duration of the study. Tumor volume (A) or percent change in body weight from treatment group (B) plotted relative to days after randomization. Significant differences were calculated at
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