WO2021100677A1 - 併用医薬 - Google Patents
併用医薬 Download PDFInfo
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- WO2021100677A1 WO2021100677A1 PCT/JP2020/042696 JP2020042696W WO2021100677A1 WO 2021100677 A1 WO2021100677 A1 WO 2021100677A1 JP 2020042696 W JP2020042696 W JP 2020042696W WO 2021100677 A1 WO2021100677 A1 WO 2021100677A1
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- cancer
- compound
- ret
- inhibitory activity
- cdk4
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Definitions
- the present invention comprises a drug, a combination, which is a combination of a compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor, which is useful for the treatment or prevention of cancer.
- a drug a combination, which is a combination of a compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor, which is useful for the treatment or prevention of cancer.
- CDK4 / 6 cyclin-dependent kinase 6
- RET Realranged during transfection
- Non-Patent Document 1 Realranged during transfection (RET) is a receptor tyrosine kinase proto-oncogene identified in 1985 (Non-Patent Document 1). It has been reported so far that as a result of genetic abnormality (point mutation or translocation) of RET, it causes the production of abnormal kinase and is involved in canceration (Non-Patent Document 2).
- RET binds to the kinesin family protein KIF5B and Coiled-Coil Domain Contining 6 (CCDC6) by translocation of chromosomes to produce KIF5B-RET and CCDC6-RET with active tyrosine kinase activity, resulting in cancer.
- CCDC6 Coiled-Coil Domain Contining 6
- Non-Patent Documents 3 and 4 It has been reported to obtain a kinase (Non-Patent Documents 3 and 4). Also, in thyroid cancer, it has been reported that a point mutation such as cysteine at position 634 of RET and translocation with H4 gene and the like produce abnormal kinases (Non-Patent Documents 5 and 6). It has been reported that compounds having RET kinase inhibitory activity are useful for cancers having these genetic abnormalities (Non-Patent Documents 7 and 8).
- Alecensa (generic name: alectinib hydrochloride, Alectinib) has been approved as an ALK inhibitor in Japan and overseas, but it has also been reported to have RET kinase inhibitory activity, and CCDC6-RET fusion gene-positive lung cancer cells. It has been shown in non-clinical studies that it has an antitumor effect on the drug (Non-Patent Documents 9 and 10). Cyclin dependent kinases 4 and / or 6 (CDK4 / 6) are cell cycle promoters and are involved in the initiation and progression of various malignancies.
- CDK4 / 6 inhibitor induces G1 phase arrest by suppressing phosphorylation of the Retinoblastoma protein (Rb) that controls the cell cycle and suppresses the growth of cancer cells
- Non-Patent Documents 11 to 13 CDK4 / 6 inhibitors approved in Japan and abroad include Ibrance (generic name: Palbociclib), Kiscali (generic name: Ribociclib), Verzenio (generic name: Abemaciclib).
- Palbociclib has been approved in Japan for use in combination with endocrine therapies for hormone receptor-positive, HER2-negative inoperable or recurrent breast cancer, but is currently approved for use in combination with targeted drugs. Absent.
- Patent Document 1 In non-clinical studies, there are some reports on the effect of the combined use of a CDK4 / 6 inhibitor and other molecular-targeted therapeutic agents (Patent Document 1). For example, in a PDX model transplanted with HER2-positive breast cancer cells, it has been shown that when used in combination with an EGFR family kinase inhibitor, Rb and S6RP are strongly suppressed and a high antitumor effect is exhibited (Non-Patent Document 14). It was also reported that the combined use with an ALK inhibitor strongly induced cell cycle arrest and caspase-independent cell death to suppress tumor growth in SCID mice transplanted with neuroblastoma cells having ALK gene abnormalities. (Patent Document 2, Non-Patent Document 15). However, no report has been made on the combined use of a CDK4 / 6 inhibitor and a compound having a RET kinase inhibitory activity.
- a novel drug, combination, pharmaceutical composition or preparation obtained by combining a plurality of drugs, and a cancer using the same.
- the purpose is to provide treatment methods and products for cancer.
- a drug for treating or preventing cancer which comprises a combination of a compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor.
- ⁇ 1B> To treat or prevent cancer, which comprises a compound having RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor separately or in combination.
- CDK4 / 6 a compound having RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor separately or in combination.
- CDK4 / 6 cyclin-dependent kinase 6
- ⁇ 1D> A compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor for treating or preventing cancer, which is administered separately or simultaneously. combination.
- ⁇ 1E> A pharmaceutical composition for treating or preventing cancer, which comprises a compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor in combination.
- a pharmaceutical preparation for treating or preventing cancer which comprises a combination of a compound having a RET kinase inhibitory activity and a cyclin-dependent kinase 4 and / or a cyclin-dependent kinase 6 (CDK4 / 6) inhibitor.
- CDK4 / 6 cyclin-dependent kinase 6
- ⁇ 1-2> The pharmaceuticals, combinations, pharmaceutical compositions, or formulations according to ⁇ 1A> to ⁇ 1E>, which are in the form of a combination drug.
- ⁇ 1-3> The drug, combination, or preparation according to ⁇ 1A> to ⁇ 1-2>, wherein the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor are separately administered.
- ⁇ 1-4> The drug, combination, or preparation according to ⁇ 1A> to ⁇ 1-2>, wherein the compound having RET kinase inhibitory activity and the CDK4 / 6 inhibitor are administered simultaneously or sequentially.
- ⁇ 2-2> The drug or pharmaceutical composition according to ⁇ 2>, wherein the compound having RET kinase inhibitory activity is administered at the same time as the CDK4 / 6 inhibitor.
- ⁇ 2-3> The drug or pharmaceutical composition according to ⁇ 2> to ⁇ 2-2>, wherein the compound having RET kinase inhibitory activity is administered before or after administration of the CDK4 / 6 inhibitor.
- ⁇ 3-2> The drug or pharmaceutical composition according to ⁇ 3>, wherein the CDK4 / 6 inhibitor is administered at the same time as the compound having the RET kinase inhibitory activity.
- ⁇ 3-3> The drug or pharmaceutical composition according to ⁇ 3> to ⁇ 3-2>, wherein the CDK4 / 6 inhibitor is administered before or after administration of the compound having RET kinase inhibitory activity.
- the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- ⁇ 1A> The drug, combination, pharmaceutical composition, or pharmaceutical preparation according to any one of ⁇ 3-3>.
- the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, vandetanib, cabozantinib, and selpercatinib, or a salt thereof, or a hydrate thereof.
- ⁇ 1A> The drug, combination, pharmaceutical composition, or pharmaceutical preparation according to any one of ⁇ 3-3>.
- ⁇ 4-3> The pharmaceutical, combination, pharmaceutical composition according to any one of ⁇ 1A> to ⁇ 3-3>, wherein the compound having the RET kinase inhibitory activity is alectinib, serpercatinib, or a salt thereof. Or pharmaceutical preparation.
- ⁇ 4-4> The drug, combination, pharmaceutical composition, or pharmaceutical preparation according to any one of ⁇ 1A> to ⁇ 3-3>, wherein the compound having the RET kinase inhibitory activity is alectinib or a salt thereof.
- the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- ⁇ 1A> to ⁇ 3-3> the drug, combination, pharmaceutical composition, or pharmaceutical preparation.
- the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, vandetanib, cabozantinib, and selpercatinib, or a salt thereof, or a hydrate thereof.
- 1A> The medicine, combination, pharmaceutical composition, or pharmaceutical preparation according to any one of ⁇ 3-3>.
- ⁇ 4-7> The pharmaceutical or combination according to any one of ⁇ 1A> to ⁇ 3-3>, wherein the compound having the RET kinase inhibitory activity is alectinib, pralcetinib, vandetanib, or serpercatinib, or a salt thereof.
- compositions, or pharmaceutical formulations comprising: ⁇ 4-8> The pharmaceutical, combination, or pharmaceutical composition according to any one of ⁇ 1A> to ⁇ 3-3>, wherein the compound having the RET kinase inhibitory activity is alectinib, pralcetinib, vandetanib, or a salt thereof. , Or a pharmaceutical product.
- ⁇ 1A> to ⁇ 3-n> are ⁇ 1A> to ⁇ 1F>, ⁇ 2>, ⁇ 2-2> to ⁇ 2-n>, ⁇ 3>, It means that ⁇ 3-2> to ⁇ 3-n> are included. The same applies below.
- ⁇ 5> Administration of 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 220 mg, 240 mg, 300 mg, 460 mg, 600 mg, 760 mg or 900 mg of alectinib or a salt thereof twice a day in terms of free form.
- ⁇ 5-2> The preparation according to ⁇ 1A> to ⁇ 4-9>, which comprises 20 mg, 40 mg, or 150 mg of alectinib or a salt thereof per unit dosage form of the preparation in terms of a free form.
- ⁇ 6> The CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, vandetanib, and 2-hydroxy-1- [2-[[9- (4-methylcyclohexyl) pyrido [4,5] pyrrolo [1,2]. -D] Pyrimidine-2-yl] Amino] -7,8-dihydro-5H-1,6-naphthylidine-6-yl] Any of ⁇ 1A> to ⁇ 5-2> selected from the group consisting of ethenone.
- ⁇ 6-2> The drug, combination, pharmaceutical composition, or preparation according to any one of ⁇ 1A> to ⁇ 5-2>, wherein the CDK4 / 6 inhibitor is palbociclib or abemaciclib.
- ⁇ 7> The medicament according to any one of ⁇ 1A> to ⁇ 6-2>, wherein the cancer has a fusion gene of a RET gene and another gene and / or a fusion protein of a RET protein and another protein.
- ⁇ 7-2> The drug, combination, pharmaceutical composition, or preparation according to ⁇ 7>, wherein the other gene and protein are KIF5B, CCDC6, NCOA4 or TRIM33.
- a fusion gene of the RET gene and another gene and a fusion protein of a RET protein and another protein include a tyrosine kinase domain of the RET gene or protein, and a coiled coil domain of another gene or protein.
- ⁇ 8-2> The drug, combination, pharmaceutical composition, or preparation according to ⁇ 8>, wherein the mutation in RET is a mutation that causes activation of RET tyrosine kinase.
- the cancers are acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hodgkin lymphoma, non-hodgkin lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer, bone marrow.
- ⁇ 9-2> The medicament according to any one of ⁇ 1A> to ⁇ 8-2>, wherein the cancer is selected from the group consisting of thyroid cancer, lung cancer, colon cancer, malignant melanoma, and chronic myelogenous leukemia. , Combination, pharmaceutical composition, or formulation.
- the cancer is selected from the group consisting of medullary thyroid cancer, non-small cell lung cancer, colon cancer, Spitz-like neoplasm, and chronic myelomonocytic leukemia ⁇ 1A> to ⁇ 8-2.
- ⁇ 10> The drug, combination, or drug according to any one of ⁇ 1A> to ⁇ 9-3>, wherein the cancer is selected from the group consisting of medullary thyroid cancer, non-small cell lung cancer, and Spitz-like neoplasm. Composition or formulation.
- ⁇ 10-2> The drug, combination, pharmaceutical composition, or preparation according to any one of ⁇ 1A> to ⁇ 9-3>, wherein the cancer is medullary thyroid cancer or non-small cell lung cancer.
- ⁇ 10-3> The drug, combination, pharmaceutical composition, or preparation according to any one of ⁇ 1A> to ⁇ 9-3>, wherein the cancer is non-small cell lung cancer.
- a method for treating or preventing cancer which comprises administering an effective amount of a compound having RET kinase inhibitory activity and an effective amount of a CDK4 / 6 inhibitor in combination to a subject.
- a method for treating or preventing cancer which comprises administering an effective amount of a compound having RET kinase inhibitory activity and an effective amount of a CDK4 / 6 inhibitor in combination to a subject.
- ⁇ 11-2> The method according to ⁇ 11>, wherein the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor are separately administered.
- ⁇ 11-3> The method according to ⁇ 11>, wherein the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor are administered simultaneously or sequentially.
- ⁇ 12> A method for enhancing the effect of treating cancer with a compound having a RET kinase inhibitory activity, which comprises administering an effective amount of a CDK4 / 6 inhibitor to a subject.
- ⁇ 12-2> The method according to ⁇ 12>, wherein the CDK4 / 6 inhibitor is administered at the same time as the compound having the RET kinase inhibitory activity.
- ⁇ 12-3> The method according to ⁇ 12>, wherein the CDK4 / 6 inhibitor is administered before or after administration of the compound having RET kinase inhibitory activity.
- a method for prolonging progression-free survival of a tumor which comprises administering an effective amount of a compound having RET kinase inhibitory activity and an effective amount of a CDK4 / 6 inhibitor in combination to a subject.
- ⁇ 14> The method according to any one of ⁇ 12> to ⁇ 13-3>, wherein the cancer has a fusion gene of a RET gene and another gene and / or a fusion protein of a RET protein and another protein. .. ⁇ 14-2> The method according to ⁇ 14>, wherein the other gene and protein is KIF5B, CCDC6, NCOA4 or TRIM33. ⁇ 14-3> The fusion gene of the RET gene and another gene, and the fusion protein of the RET protein and another protein form the tyrosine kinase domain of the RET gene or protein, and the coiled coil domain of the other gene or protein. The method according to ⁇ 14>, which includes.
- ⁇ 15> The method according to any one of ⁇ 12> to ⁇ 13-3>, wherein the cancer has a mutation in RET.
- ⁇ 15-2> The method according to ⁇ 15>, wherein the mutation in RET is a mutation that causes activation of RET tyrosine kinase.
- the cancers are acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hodgkin lymphoma, non-hodgkin lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer, bone marrow.
- Hepatic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, colonic rectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, bile sac cancer, skin cancer, malignant melanoma, renal cancer, renal pelvis cancer The method according to any one of ⁇ 12> to ⁇ 15-2>, which is selected from the group consisting of bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumor metastasized from the tumor.
- ⁇ 16-2> The method according to any one of ⁇ 12> to ⁇ 15-2>, wherein the cancer is thyroid cancer, colon cancer or lung cancer.
- ⁇ 16-3> The method according to any one of ⁇ 12> to ⁇ 15-2>, wherein the cancer is medullary thyroid cancer or non-small cell lung cancer.
- ⁇ 17> The method according to any one of ⁇ 12> to ⁇ 16-3>, wherein the cancer is non-small cell lung cancer.
- a method for suppressing tumor growth which comprises administering to a subject a combination of an effective amount of a compound having an RET kinase inhibitory activity and an effective amount of a CDK4 / 6 inhibitor.
- ⁇ 18-2> The method according to ⁇ 18>, wherein the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor are separately administered.
- ⁇ 18-3> The method according to ⁇ 18>, wherein the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor are administered simultaneously or sequentially.
- ⁇ 19> The method according to any one of ⁇ 18> to ⁇ 18-3>, wherein the cancer has a fusion gene of a RET gene and another gene and / or a fusion protein of a RET protein and another protein. .. ⁇ 19-1>
- the fusion gene of the RET gene and another gene and the fusion protein of a RET protein and another protein include a tyrosine kinase domain of the RET gene or protein, and a coiled coil domain of another gene or protein.
- ⁇ 19-3> The method according to any one of ⁇ 18> to ⁇ 18-3>, wherein the cancer has a mutation in RET.
- ⁇ 19-4> The method according to any one of ⁇ 19-3>, wherein the mutation in RET is a mutation that causes activation of RET tyrosine kinase.
- the cancers are acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, hodgkin lymphoma, non-hodgkin lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer.
- ⁇ 18> to ⁇ 18-3> which is selected from the group consisting of tube cancer, bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumor metastasized from the tumor.
- ⁇ 19-6> The method according to any one of ⁇ 18> to ⁇ 18-3>, wherein the cancer is thyroid cancer, colon cancer or lung cancer.
- ⁇ 19-7> The method according to any one of ⁇ 18> to ⁇ 18-3>, wherein the cancer is medullary thyroid cancer or non-small cell lung cancer.
- ⁇ 19-8> The method agent according to any one of ⁇ 18> to ⁇ 18-3>, wherein the cancer is non-small cell lung cancer.
- the compound having RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- ⁇ 18> The method according to any one of ⁇ 19-8>.
- the compound having RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- alectinib vandetanib
- cabozantinib sorafenib
- serpercatinib or a salt thereof, or a hydrate thereof.
- ⁇ 20-3> The compound according to any one of ⁇ 18> to ⁇ 19-8>, wherein the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib and selpercatinib, or a salt thereof. the method of.
- ⁇ 20-4> The method according to any one of ⁇ 18> to ⁇ 19-8>, wherein the compound having RET kinase inhibitory activity is alectinib or a salt thereof.
- the compound having RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- ⁇ 18> to ⁇ 19-8> are compounds selected from the group consisting of alectinib, pralcetinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- the compound having RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, vandetanib, cabozantinib, sorafenib, and serpercatinib, or a salt thereof, or a hydrate thereof.
- the compound having the RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, vandetanib, and selpercatinib, or a salt thereof, ⁇ 18> to ⁇ 19-8>. The method described in either.
- ⁇ 20-8> The compound according to any one of ⁇ 18> to ⁇ 19-8>, wherein the compound having RET kinase inhibitory activity is a compound selected from the group consisting of alectinib, pralcetinib, and vandetanib, or a salt thereof.
- Method. ⁇ 20-9> The method according to any one of ⁇ 18> to ⁇ 19-8>, wherein the compound having RET kinase inhibitory activity is alectinib hydrochloride.
- ⁇ 21> Administration of 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 220 mg, 240 mg, 300 mg, 460 mg, 600 mg, 760 mg or 900 mg of alectinib or a salt thereof twice a day in terms of free form.
- the CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, and 2-hydroxy-1- [2-[[9- (4-methylcyclohexyl) pyrido [4,5] pyrrolo [1,2-d.
- a preparation containing a compound having a RET kinase inhibitory activity, (2) a container, and (3) the compound having the RET kinase inhibitory activity for treating cancer and at least one kind of CDK4 / 6 A product that contains an instruction or label, indicating that it should be administered to a subject in combination with an inhibitor.
- the graph which shows the change of the annexin V binding amount with respect to LC-2 / ad cell and Ba / F3-KIF5B-RET cell by the use and combination of alectinib and palbociclib.
- FIG. 5 shows the expression levels of RET, S6, Rb and their respective phosphorylated proteins in LC-2 / ad cells and Ba / F3-KIF5B-RET cells with and without alectinib and palbociclib.
- Actin ACTB
- Graph showing 50% cell proliferation inhibitory concentration of BLU-667 or vandetanib and palbociclib alone or in combination with LC-2 / ad cells and Ba / F3-KIF5B-RET cells.
- the present invention is a combination of a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor, which is effective for treating cancer, and is a drug, combination, pharmaceutical composition, preparation, or cancer for treating or preventing cancer.
- a compound having a RET kinase inhibitory activity is also referred to as a RET inhibitor and means a drug that inhibits the activity of RET kinase, preferably binding to RET kinase and inhibiting the activity. It is a drug that has an action.
- -Alectinib (Compound name: 9-ethyl-6,6-dimethyl-8- [4- (morpholine-4-yl) -piperidine-1-yl]-11-oxo-6,11-dihydro-5H-benzo [ b] Carbazole-3-carbonitrile) or a salt thereof, preferably alectinib hydrochloride.
- Vandetanib Compound name: N (-4-bromo-2-fluorophenyl) -6-methoxy-7-[(1-methylpiperidin-4-yl) methoxy] quinazoline-4-amine) or a salt thereof
- BLU-667 pralcetinib; compound name: cis-N- ⁇ (1S) -1- [6- (4-fluoro-1H-pyrazole-1-yl) pyridin-3-yl] ethyl ⁇ -1-methoxy- 4- ⁇ 4-Methyl-6-[(5-Methyl-1H-pyrazole-3-yl) pyrimidin-2-caroimide] or a salt thereof
- Cabozantinib chemical name: N- (4- (6,7-dimethoxyquinoline-4-yloxy) phenyl) -N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide
- alectinib hydrochloride pralcetinib, vandetanib, cabozantinib (2S) -hydroxybutanediate, sorafenib, or serpercatinib. More preferably, it is alectinib hydrochloride, vandetanib, cabozantinib (2S) -hydroxybutanediate, sorafenib, or serpercatinib.
- the following compounds are also known to have RET kinase inhibitory activity (Oncology Review 2018, Vol12: 352) and can be used in the present invention.
- These compounds or salts thereof can be manufactured and sold as pharmaceutical preparations, can be obtained as research reagents, or can be manufactured by a known method or a conventional method. These compounds or salts thereof also include hydrates, various pharmaceutically acceptable solvates, polymorphs of crystals, and the like.
- the route of administration of the compound having RET kinase inhibitory activity used in the present invention is preferably oral or parenteral, but oral administration is preferably used.
- the dosage form used for oral administration can be appropriately selected from any dosage form such as, for example, liquid preparation, powder, granule, tablet, enteric solvent and capsule.
- Compounds having such a dosage form with RET kinase inhibitory activity are formulated by a method known to those skilled in the art.
- pharmaceutically acceptable carriers or vehicles specifically sterilized water or physiological saline, vegetable oils, emulsifiers, suspensions, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives.
- compositions for injection can be formulated according to conventional formulation practices using vehicles such as distilled water for injection.
- Aqueous solutions for injection include, for example, saline, isotonic solutions containing glucose and other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, sodium chloride, and suitable solubilizers such as. It can be appropriately used in combination with alcohol, specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM), HCO-50.
- alcohol specifically ethanol, polyalcohol such as propylene glycol, polyethylene glycol, nonionic surfactants such as polysorbate 80 (TM), HCO-50.
- examples of the oily liquid include sesame oil and soybean oil, and benzyl benzoate and benzyl alcohol may be used in combination as a solubilizing agent.
- the dose of the compound having the RET kinase inhibitory activity according to the present invention can be selected in the range of 0.0001 mg to 1000 mg per 1 kg of body weight per administration. Alternatively, for example, the dose may be selected in the range of 0.001 mg to 100,000 mg / body per patient. However, the dose of the compound having the RET kinase inhibitory activity of the present invention is not limited to these doses.
- a more specific dose of the alectinib, a salt thereof, or a hydrate thereof 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg twice a day in terms of free form. , 220 mg, 240 mg, 300 mg, 460 mg, 600 mg, 760 mg or 900 mg.
- a more specific dose of pralcetinib, a salt thereof, or a hydrate thereof is 300 mg to 800 mg, preferably 400 mg, in terms of free form once a day.
- a more specific dose of vandetanib, a salt thereof, or a hydrate thereof is 100 mg to 600 mg, preferably 300 mg, in terms of free form once daily.
- the administration period of the compound having the RET kinase inhibitory activity of the present invention is appropriately determined according to the degree of symptoms and side effects, and can be administered until the cancer is treated or the desired therapeutic effect is achieved.
- CDK4 / 6 Inhibitor The CDK4 / 6 inhibitor used in the present invention directly or indirectly neutralizes and blocks the activity of cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6 (CDK6).
- CDK4 and / or CDK6 are family proteins of cyclin-dependent kinases (CDKs) that regulate the initiation, progression, and termination of the mammalian cell cycle. Important for growth, dysregulation of this pathway is often found in breast cancer.
- CDK4 / 6 is activated early in the cell cycle by cyclin D1 and other D-type cyclins, facilitating the progression of the cell cycle through the G1 restriction point (R point).
- the activated cyclin-CDK complex inactivates the tumor suppressor Rb by phosphorylation, induces the release of the transcriptional activator E2F, and exhibits abnormal cell proliferation.
- CDK4 / 6 inhibitors are known to be used to suppress the growth of cancer cells, for example, palbociclib (compound name: 6-acetyl-8-cyclopentyl-5-methyl-2- ⁇ [5-( Piperazine-1-yl) pyridin-2-yl] amino ⁇ pyrido [2,3-d] pyrimidin-7 (8H) -one) or a salt thereof, Ribociclib (Compound name: 7-cyclopentyl-N, N-dimethyl-2-((5- (piperazin-1-yl) pyridin-2-yl) amino) -7H-pyrrolo [2,3-d] pyrimidine) Or its salt, Abemacyclib (Compound name: N ⁇ -5 [-(4-ethylpiperazin-1-yl) methyl] pyridine-2-yl ⁇ -5-fluoro-4- [4-fluoro-2-methyl-1- (1) -Methylethyl) -1H-
- it is palbociclib, abemaciclib, ribociclib, and AMG-925 or a salt thereof.
- These compounds or salts thereof can be manufactured and sold as pharmaceutical preparations, obtained as research reagents, or manufactured by a conventional method.
- These compounds or salts thereof also include hydrates, various pharmaceutically acceptable solvates, polymorphs of crystals, and the like.
- the CDK4 / 6 inhibitor is formulated according to a conventional method (for example, Remington's Pharmaceutical Science, latest edition, Mack Publishing Company, Easton, U.S.A.) and may contain both pharmaceutically acceptable carriers and additives.
- pharmaceutically acceptable carriers and additives for example, surfactants, excipients, colorants, flavoring agents, preservatives, stabilizers, buffers, suspending agents, tonicity agents, binders, disintegrants, lubricants, fluidity promoters, flavoring agents.
- the present invention is not limited to these, and other commonly used carriers may be used as appropriate.
- trehalose light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium chain fatty acids.
- Preferable examples include triglyceride, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch, inorganic salts, polysorbate and the like.
- the method of administering the CDK4 / 6 inhibitor can be carried out by either oral administration or parenteral administration.
- it is an administration method by oral administration, and specifically, administration by a liquid agent, a powder, a granule, a tablet, an enteric solvent, a capsule or the like is preferably exemplified.
- the therapeutic agent of the present invention may be administered systemically or locally by, for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection and the like.
- the administration method can be appropriately selected depending on the age and symptoms of the patient.
- the dose for example, in the case of an oral preparation, the dose can be selected in the range of 0.1 mg / kg to 100 mg / kg, preferably 1 mg / kg to 10 mg / kg per administration.
- the dose may be selected in the range of 50 mg to 500 mg per patient.
- the dose of the CDK4 / 6 inhibitor used in the present invention is not limited to these doses.
- the preferred dose of palbociclib is, but is not limited to, in the range of 1-5 mg / kg and may be graded down depending on the severity of symptoms and side effects.
- a predetermined drug holiday for example, 1 week
- the number of cycles varies depending on the type and severity of the disease.
- Treatment is measured by methods known in the art and is maintained until the cancer is treated or the desired therapeutic effect is achieved.
- palbociclib is administered at 125 mg once a day for 3 consecutive weeks, and when side effects are observed, the dose is reduced to 100 mg as the primary dose and 75 mg as the secondary dose.
- the CDK4 / 6 inhibitor can be administered every three weeks as one cycle until the cancer is treated or the desired therapeutic effect is achieved. Specifically, it can be administered over 1 to 36 cycles.
- 150 mg of abemaciclib is administered once a day, and when side effects or the like occur, the dose is reduced to 100 mg as a primary dose and 50 mg as a secondary dose.
- One embodiment of the present invention is a drug for treating or preventing cancer, which comprises a combination of a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor.
- the "pharmaceutical for treating or preventing cancer which is a combination of a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor" means a compound having a RET kinase inhibitory activity and CDK4 / 6 inhibition.
- the medicament of the present invention can also be provided in the form of a combination drug containing both a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor.
- a preparation containing a compound having a RET kinase inhibitory activity and a preparation containing a CDK4 / 6 inhibitor are provided separately, and these preparations may be used simultaneously or sequentially.
- simultaneous administration means that a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor are administered and used at the same timing, and may be administered as a combination drug, and is adjusted at the time of administration. It may be administered as a mixture thereof, or another form of the preparation may be administered at the same time.
- the dosage forms may be the same, or they may be administered separately.
- the order of administration of the compound having RET kinase inhibitory activity and the CDK4 / 6 inhibitor is the administration of the CDK4 / 6 inhibitor.
- a compound having RET kinase inhibitory activity can be administered later, a compound having RET kinase inhibitory activity and a CDK4 / 6 inhibitor can be administered at the same time, and CDK4 / 6 can be administered after administration of the compound having RET kinase inhibitory activity.
- Inhibitors can be administered.
- the sequential administration of the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor according to the present invention means that the other drug is administered after the administration of one drug, and the compound having the RET kinase inhibitory activity.
- the administration interval of the CDK4 / 6 inhibitor is not particularly limited, and can be set in consideration of factors such as the administration route and the dosage form.
- the administration interval between the compound having RET kinase inhibitory activity and the CDK4 / 6 inhibitor is 0 hours to 168 hours, preferably 0 hours to 72 hours, and preferably 0 to 24 hours, more preferably 0 to 24 hours. It is 0 to 12 hours.
- the residual concentrations of the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor according to the present invention can also be taken into consideration. That is, when a compound having a RET kinase inhibitory activity is administered before administration of the CDK4 / 6 inhibitor, the subject has the RET kinase inhibitory activity so that the desired effect of the CDK4 / 6 inhibitor can be obtained.
- a CDK4 / 6 inhibitor can be administered when the residual concentration of the compound is detected. The concentration can be determined based on the result of separating the sample collected from the subject using a separation device such as various chromatographies and analyzing it by an analysis method known to those skilled in the art.
- the CDK4 in the subject can obtain the desired effect by the compound having the RET kinase inhibitory activity.
- a compound having RET kinase inhibitory activity can be administered. The concentration can be determined based on the results of analysis of a sample taken from a subject by an immunoassay method such as Elisa known to those skilled in the art.
- the dosage forms of these formulations are different even if they are the same dosage form. It may be a dosage form.
- both may be selected from oral preparation, parenteral preparation, injection, drip, and intravenous drip and have different dosage forms, and both may be oral, parenteral, injection, drip, intravenous. It may be the same type of dosage form selected from the internal drip infusion.
- both dosage forms are oral preparations.
- the above-mentioned pharmaceuticals may be combined with one or more different formulations.
- the pharmaceutical composition contains a compound having RET kinase inhibitory activity and / or a CDK4 / 6 inhibitor used for the treatment and / or prevention of the present invention, and is pharmaceutically acceptable.
- Carrier may be included.
- the term "pharmaceutically acceptable carrier” is one or more compatible solid or liquid excipients or encapsulating materials as exemplified above for mammals. Means suitable for administration.
- the term “combination" refers to a compound in which a compound having a RET kinase inhibitory activity and a compound which is a CDK4 / 6 inhibitor can be used separately for the same subject, or a compound in which these compounds are not mixed.
- the "pharmaceutical preparation" formed by combining a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor is a tablet in which these active ingredients are separately formulated or contained in the same preparation.
- Solid formulations such as capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions filled in containers suitable for subdivision into individual dosages. Includes a liquid agent, a freeze-drying agent that can be dissolved before use, or a formulation that combines any of these dosage forms.
- the pharmaceutical preparation contains 150 mg to 800 mg, preferably 150 mg to 400 mg, particularly preferably 150 mg to 300 mg of alectinib or a salt thereof per unit dosage form in terms of free form.
- the separate formulations of alectinib or S salt include, specifically, 150 mg capsule formulations, 150 mg, 300 mg, 600 mg tablets and the like.
- the present invention provides a medicament for treating or preventing cancer in combination with a CDK4 / 6 inhibitor, which comprises a compound having a RET kinase inhibitory activity as an active ingredient.
- a drug for treating or preventing cancer in combination with a CDK4 / 6 inhibitor containing a compound having a RET kinase inhibitory activity as an active ingredient is a condition that it is used in combination with a CDK4 / 6 inhibitor. It means a drug containing a compound having a RET kinase inhibitory activity as an active ingredient, which is used for treating or preventing sickness.
- the medicament of the present invention containing a compound having RET kinase inhibitory activity as an active ingredient is used in combination with a CDK4 / 6 inhibitor, it can be administered at the same time as the CDK4 / 6 inhibitor, and before administration of the CDK4 / 6 inhibitor. Alternatively, it can be administered after administration.
- a compound having RET kinase inhibitory activity is administered before or after administration of the CDK4 / 6 inhibitor
- the administration timing is optimized by measuring the residual concentration of the CDK4 / 6 inhibitor in the subject. obtain. The concentration can be determined based on an immunoassay method such as ELISA, which will be described later, which is known to those skilled in the art for a sample collected from a subject.
- the present invention provides a medicament for treating or preventing cancer in combination with a compound having RET kinase inhibitory activity, which comprises a CDK4 / 6 inhibitor as an active ingredient.
- a drug for treating or preventing cancer in combination with a compound having a RET kinase inhibitory activity containing a CDK4 / 6 inhibitor as an active ingredient is used in combination with a compound having a RET kinase inhibitory activity. It means a drug containing a CDK4 / 6 inhibitor as an active ingredient, which is used to treat or prevent cancer on condition that it is used.
- a drug containing a CDK4 / 6 inhibitor as an active ingredient when used in combination with a compound having a RET kinase inhibitory activity, it can be administered at the same time as a compound having a RET kinase inhibitory activity, or a compound having a RET kinase inhibitory activity is administered. It can be administered before or after administration.
- a CDK4 / 6 inhibitor is administered before or after administration of a compound having RET kinase inhibitory activity
- the optimal administration time is measured by measuring the residual concentration of the compound having RET kinase inhibitory activity in the subject. Can be transformed.
- the concentration can be determined based on an analytical method known to those skilled in the art by separating the sample collected from the subject using a separation device such as various chromatographies.
- a separation device such as various chromatographies.
- the above invention means that a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor are administered or used together (hereinafter, simply referred to as "administration"), and the order of administration is defined. And administration intervals are not limited and interpreted.
- administration can also be used as a product in which a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor are combined.
- each is administered at a dose smaller than the dose at which one is used alone, if desired. Can be done.
- Pharmaceutical cancer types present invention include acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer (e.g.
- Thyroid medullary cancer bone marrow dysplasia syndrome, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer (eg, non-small cell lung cancer), pancreatic cancer, liver cancer, Various cancers such as bile sac cancer, skin cancer (for example, Spitz-like neoplasm), malignant melanoma, renal cancer, renal pelvis tract cancer, bladder cancer, uterine cancer, testis cancer, prostate cancer, tumor metastasized from the tumor, etc. It is useful for the prevention or treatment of diseases such as. Further, the compound of the present invention is useful for prevention or treatment of infiltration / metastasis of the above cancer.
- the medicament of the present invention is useful for the prevention or treatment of cancer of a fusion gene of a RET gene and another gene and / or a fusion protein of a RET protein and another protein.
- “other genes” and “other proteins” include KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, ERC1 and the like. Preferred are KIF5B, CCDC6, NCOA4 and TRIM33.
- the tyrosine kinase domain of the RET gene or protein is a catalytic domain responsible for the reaction of transferring the ⁇ -position phosphate group of ATP to the tyrosine residue of the protein.
- the "coiled coil domain of another gene or protein” is a protein-protein interaction in which the hydrophobic site of ⁇ -helix consisting of a heptad of FPPFPPP (F: hydrophobic, P: polar amino acid residue) interacts. It is a domain.
- the medicament of the present invention is useful for the prevention or treatment of cancer caused by a tumor having a mutation in RET and / or cancer positive for a RET fusion gene.
- RET fusion gene-positive cancers include, but are not limited to, thyroid cancer, non-small cell lung cancer, and the like.
- a tumor having a mutation in RET means that a mutation that causes activation of RET tyrosine kinase has occurred in the RET gene and / or RET protein, that the tumor activates RET tyrosine kinase and becomes cancerous (for example, thyroid cancer). It includes the occurrence of mutations that induce cancer, lung cancer). Activation of RET tyrosine kinase can be confirmed by detecting phosphorylated RET in tumor tissue by immunostaining with an anti-phosphorylated RET antibody or the like.
- activation of RET tyrosine kinase means that an amino acid residue contained in RET tyrosine kinase, for example, a tyrosine residue is phosphorylated, and phosphorylation in a subject (for example, a sample collected from the subject). Includes an increase in the amount of RET tyrosine kinase protein (eg, compared to healthy individuals). Further, phosphorylation of RET tyrosine kinase includes phosphorylation of a protein targeted by RET tyrosine kinase (hereinafter referred to as target protein). "Activation of RET tyrosine kinase" includes an increase in the amount of phosphorylated RET tyrosine kinase protein as well as the phosphorylated target protein.
- Mutations that cause activation of RET tyrosine kinase include (1) mutations in the cysteine-rich domain of RET, (2) mutations in the tyrosine kinase domain of RET, and (3) fusion genes of RET genes with other genes and RET proteins. The formation of fusion proteins with other proteins has been reported (TRENDS in Genetics, 2006, Vol. 22, p. 627-636).
- the human RET gene is located on chromosome 10 (10q11.2) and consists of 21 exons.
- the "cysteine-rich domain of RET" is a cysteine-rich region of the RET tyrosine kinase, and the polynucleotides encoding the domain are located at exons 10 and 11.
- RET tyrosine kinase domain is a region having tyrosine kinase activity in RET tyrosine kinase, and the polynucleotide encoding the domain is located at exons 12-18 (TRENDS in Genetics, 2006, Vol. 22, p. .627-636).
- RET fusion gene positive means that a fusion gene of RET and another gene such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1 is a known method, for example, reverse transcription PCR method. It means a tumor detected by a method combining the Sanger sequencing method or by using an in situ hybridization technique.
- Specific examples of RET fusion gene-positive cancers include, but are not limited to, those described in WO2014 / 050781.
- the enhancement of the therapeutic effect means that the response rate of the treatment is increased, the amount of the compound having the RET kinase inhibitory activity administered for the treatment is reduced, and the therapeutic effect for more serious cases.
- the treatment period with a compound having RET kinase inhibitory activity due to the disappearance of cancer, etc. is the treatment period expected by single administration or treatment by combined administration.
- RET kinase inhibition for producing a pharmaceutical composition for treating or preventing cancer, which comprises a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor as active ingredients. Methods of use of active compounds or CDK4 / 6 inhibitors are provided.
- the inclusion of a compound having RET kinase inhibitory activity and / or a CDK4 / 6 inhibitor as an active ingredient means that a compound having RET kinase inhibitory activity and / or a CDK4 / 6 inhibitor is included as a main active ingredient. In that sense, it does not limit the content of compounds having RET kinase inhibitory activity and / or CDK4 / 6 inhibitors.
- treatment refers to the death of cancer cells or a decrease in the number of cancer cells, the suppression of the growth of cancer cells, and the metastasis of cancer cells when the drug according to the present invention is administered to a subject. It means either suppression or improvement of various symptoms caused by cancer.
- the term "prevention” means either preventing an increase in the number of decreased cancer cells due to re-growth, or preventing the re-growth of cancer cells whose growth has been suppressed.
- the "effective amount” means a daily dose for each inhibitor when a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor are administered in combination.
- the dose in the present invention may be the same as the dose when each inhibitor is used alone, or may be lower than the dose when each inhibitor is used alone.
- the effective dose in the present invention may be the same as the dose when one is used alone, and may be lower than the dose when the other is used alone.
- progression-free survival refers to the time from treatment (or randomization) to the first disease progression or death.
- PFS can be evaluated by the therapeutic evaluation criteria (RECIST) for solid tumors.
- PFS can be assessed by CA-125 levels as a determinant of progression.
- a combination of a compound having a RET kinase inhibitory activity and a CDK4 / 6 inhibitor inhibitor is a compound having a RET kinase inhibitory activity or CDK4 / 6 inhibition.
- the PFS is prolonged as compared with the PFS when the drug is administered at the same dose as the dose used when the drug is used as a single agent in combination.
- the “subject” is, but is not limited to, a human or non-human mammal, such as a cow, a horse, which is a subject of administration of the medicament of the present invention or requires administration of the medicament of the present invention.
- the subject is a human.
- Subjects include patients (including humans and non-human mammals).
- acute myeloid leukemia chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, brain tumor, neuroblastoma, glioma, thyroid cancer (eg, thyroid spinal cord) Cancer), myelodystrophy syndrome, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer (eg, non-small cell lung cancer), pancreatic cancer, liver cancer, bile sac cancer, Affected by various cancers such as skin cancer (for example, Spitz-like neoplasm), malignant melanoma, renal cancer, renal pelvis cancer, bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumor metastasized from the tumor.
- skin cancer for example, Spitz-like neoplasm
- malignant melanoma malignant melanoma
- renal cancer renal
- the product is provided to treat or prevent cancer in a subject, (a) (1) a formulation containing a CDK4 / 6 inhibitor, (2) a container, (3) cancer in a subject. Instructions or labels indicating that the CDK4 / 6 inhibitor is administered to a subject in combination with at least one compound having RET kinase inhibitory activity for treatment, or (b) (1) having RET kinase inhibitory activity.
- the product contains a container containing a preparation containing a CDK4 / 6 inhibitor or a compound having RET kinase inhibitory activity.
- the product may further include labels or instructions on or attached to the container.
- "instruction” means a document usually contained in a commercial package of a drug, which contains information on an indication, usage, dosage, administration, contraindication and / or warning regarding the use of the drug. ..
- a "label” is a sheet-like article containing an indication of the product name, dose, dosage form, indication, etc. of a preparation containing a CDK4 / 6 inhibitor or a compound having a RET kinase inhibitory activity, and is directly attached to a container. Means what is done.
- Labels or instructions indicate that the drug is indicated for use in the treatment of an indication, such as cancer.
- the label or instructions indicate that the formulation can be used to treat cancer.
- Labels or instructions may also indicate that the formulation can be used to treat other disorders.
- Suitable containers include, for example, PTPs, bottles, vials, syringes, blister packs and the like.
- the container can be made of various materials such as glass or plastic. These containers may be further packed in a paper outer box on which the contents of the label and the like are printed.
- a “side effect” is an intended treatment with clinical, medical, physical, physiological, and / or biochemical effects observed and / or measured in a patient receiving treatment for the disease. Means an effect that is not part of the result.
- the effects reduce the health and / or comfort of the patient being treated, the health risks to the patient being treated, and / or the treatment tolerance for the patient being treated. It makes continuous treatment difficult because it requires appropriate measures such as drug suspension and dose reduction.
- side effects include myelosuppression (neutropenia, leukocytopenia, anemia, thrombocytopenia, febrile neutropenia, lymphopenia), interstitial pneumonia, liver dysfunction (ALT elevation, AST elevation, Al). -P elevation, birylbin elevation), gastrointestinal symptoms (diarrhea, nausea, vomiting, stomatitis, lipase elevation, loss of appetite, amylase elevation, constipation, digestive disorders, swallowing disorders, abdominal pain, gastrointestinal perforation), skin symptoms (limb syndrome, Exfoliative dermatitis, alopecia, rash, skin debris, pruritus, dry skin, erythema, acne, hypersensitivity reaction), respiratory symptoms (cough, respiratory distress, pneumonia, lung infection, pneumococcal), neuropsychiatric symptoms (Taste abnormality, immobility dizziness), cardiovascular symptoms (hypertension) fatigue, joint pain, muscle pain, infection (upper airway infection, urinary tract infection), abnormal clinical test values (increased blood creatinine, hypo, hypo
- Example 1 Human RET fusion gene-positive non-small cell lung cancer strain LC-2 / ad cells (RIKEN, J Thorac Oncol. 2012 Dec, 7 (12), 1872-6) were seeded on a 96-well plate with 1 ⁇ 10 4 cells each and alectinib. (Synthesized in-house) was used in combination with an anticancer drug selected from the following 12 compounds among the drugs used for the treatment of non-small cell lung cancer or clinically developed.
- the compounds are the folic acid metabolism antagonist pemetrexed (Fuji Film Wako Pure Drug), the microtube inhibitor palbociclib (Fuji Film Wako Pure Drug), the alkylating agent carboplatin (Fuji Film Wako Pure Drug), and the microtube inhibitor Vinorelvin (Fuji Film Sum).
- Gemcitabine (Fuji Film Wako Pure Drug), topoisomerase I inhibitor irinotecan (Fuji Film Wako Pure Drug), CDK4 / 6 inhibitor palbociclib (Sigma-Aldrich), HDAC inhibitor SAHA (Tokyo Kasei Kogyo) , PI3K inhibitor BKM120 (AdoQ BioScience), PI3K and mTOR inhibitor gemcitabine (Selleck Chemicals LLC), mTOR inhibitor everolimus (AdoQ BioScience), HSP90 inhibitor Luminec. Each single agent and combination were treated for 4 days and a cell proliferation test was performed. The drug treatment concentrations are shown in Table 1.
- FIG. 1 The results of analyzing the combined effect by the IC50 isobologram method (Pharmacol Res Perspect. 2015 Jun; 3 (3): e00149) are shown in FIG.
- the horizontal axis and the vertical axis indicate the concentrations of alectinib and the concomitant partner compound, respectively.
- the points on each axis indicate the 50% cell proliferation inhibitory concentration of each drug alone
- the dotted line connecting the two points on the axis indicates the additive effect.
- both drugs mean synergistic, additive, and antagonistic effects, respectively.
- alectinib with pemetrexed, paclitaxel, carboplatin, vinorelbine, irinotecan, or luminespib showed an antagonistic effect.
- the combination with gemcitabine, SAHA, gedatricib, or everolimus showed an additive effect.
- the combined use with BKM120 showed a synergistic effect at some concentrations. When used in combination with palbociclib, all points in the frame were inside the dotted line, showing a synergistic effect.
- Example 2 Ba / F3-KIF5B-RET cells (Mol Cancer Ther. 2014; 13: 2910-2918) in which the KIF5B-RET fusion gene was introduced into the mouse pro B cell line Ba / F3 were seeded on a 96-well plate of 5 ⁇ 10 3 cells each. Then, a cell proliferation test was carried out by treating with alectinib and the CDK4 / 6 inhibitor palbociclib or the CDK4 / 6 inhibitor abemaciclib (Selleck Chemicals LLC) in combination and with a single agent for 4 days. The drug treatment concentrations are shown in Table 1. The result of analyzing the combined effect by the isobologram method is shown in FIG. In FIG.
- the horizontal axis and the vertical axis indicate the concentrations of alectinib / palbociclib or abemaciclib, respectively.
- alectinib and palbociclib also showed a synergistic effect on Ba / F3-KIF5B-RET cells.
- a synergistic effect was also shown when used in combination with another CDK4 / 6 inhibitor, abemaciclib. From these results, it is considered that the combined use of alectinib and the CDK4 / 6 inhibitor has a synergistic effect regardless of the type of the CDK4 / 6 inhibitor.
- Example 3 Alectinib (20 mg / 20 mg /) was transplanted to BALB / c-nu (nude) mice (Nippon Charles River) in which 5 ⁇ 10 6 cells of Ba / F3-KIF5B-RET cells were transplanted, 11 days after the cells were transplanted. Kg (orally administered once daily for 15 days) and palbociclib (75 mg / kg orally administered once daily for 15 days) were used in combination. The tumor volume (mean value + standard deviation) and the rate of change in body weight (mean value + standard deviation) of each administration group are shown in FIG. In FIG.
- the horizontal axis represents the number of days elapsed when the first day of drug administration is 1
- the vertical axis represents the tumor volume and the rate of change in body weight (Relative body weight)
- Vehicle is a solvent administration control.
- ALC indicates alectinib monotherapy group
- PD indicates palbociclib monotherapy group
- ALC + PD indicates alectinib and palbociclib combination therapy group.
- the combination-administered group showed a statistically significantly higher antitumor effect than the single-agent-administered group and the solvent-administered control group. No weight loss was observed in any of the groups as compared with the solvent-administered group.
- Example 4 LC-2 / ad cells and Ba / F3-KIF5B-RET cells were seeded on 96-well plates with 2 ⁇ 10 4 cells or 1 ⁇ 10 4 cells, respectively, and alectinib (100 nM) and palbociclib (100 nM) were added. After 3 days, Annexin V binding was observed using a reagent for Annexin V detection in the RealTime Glo Annexin V Apoptosis and Necrosis Assay (Promega) kit. The ratio of the fluorescence intensity of each drug-treated group to Control is shown in FIG. In FIG.
- Control indicates a solvent control group
- ALC indicates an alectinib monotherapy group
- PD indicates a palbociclib monotherapy group
- ALC + PD indicates an alectinib and palbociclib combination treatment group.
- Example 5 LC-2 / ad cells and Ba / F3-KIF5B-RET cells were treated with alectinib (100 nM) and palbociclib (100 nM), and after 24 hours, proteins were purified from each cell.
- the results of observing the expression level of each protein using the capillary electrophoresis protein analysis system Sally Sue (Protein Simple) are shown in FIG.
- ALC indicates alectinib
- PD indicates palbociclib
- -and + indicate drug-untreated and treated, respectively.
- Example 6 LC-2 / ad cells 1 ⁇ 10 4 cells each and Ba / F3-KIF5B-RET cells 5 ⁇ 10 3 cells each were seeded on a 96-well plate, and BLU-667 (pralcetinib), which is a compound having RET kinase inhibitory activity, was seeded.
- BLU-667 pralcetinib
- Palbociclib were treated in combination and with a single agent for 4 days to perform cell proliferation tests.
- the drug treatment concentrations are shown in Table 2.
- the result of analyzing the combined effect by the isobologram method is shown in FIG. In FIG.
- the horizontal axis and the vertical axis indicate the concentrations of BLU-667 or vantedanib / palbociclib, respectively.
- the combined use of the compound having any RET kinase inhibitory activity and palbociclib in both cells showed a synergistic effect. From these results, it is considered that the combined use of the compound having the RET kinase inhibitory activity and the CDK4 / 6 inhibitor has a synergistic effect regardless of the type of the compound having the RET kinase inhibitory activity.
- the concomitant drug of the present invention has a synergistic effect on various tumor cells positive for the RET fusion gene and mice transplanted with the cells in suppressing cell proliferation or reducing the tumor volume. It is useful for the prevention or treatment of tumors.
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Abstract
Description
これまでにRETの遺伝子異常(点変異や転座)の結果、異常キナーゼの生成を引き起こし、癌化に関与することが報告されている(非特許文献2)。例えば、肺がんでは、RETが染色体の転座によりキネシンファミリータンパク質KIF5BやCoiled-Coil Domain Containing 6(CCDC6)と結合して、活性型チロシンキナーゼ活性をもつKIF5B-RETやCCDC6-RETを生成し、癌化能を得ることが報告されている(非特許文献3、4)。また、甲状腺がんにおいてもRETの634番目のcystein等の点変異やH4遺伝子等との転座による異常キナーゼの生成が報告されている(非特許文献5、6)。これらの遺伝子異常を有するがんに対してRETキナーゼ阻害活性を有する化合物が有用であることが報告されている(非特許文献7、8)。
アレセンサ(一般名:アレクチニブ塩酸塩、Alectinib)はALK阻害剤として日本および海外にて承認を受けているが、RETキナーゼ阻害活性も有することが報告されており、CCDC6-RET融合遺伝子陽性の肺がん細胞に対して抗腫瘍効果を示すことが非臨床研究で示されている(非特許文献9、10)。
Cyclin dependent kinase4および/または6(CDK4/6)は細胞周期促成因子であり、さまざまな悪性腫瘍のイニシエーションとプログレッションに関与している。CDK4/6阻害剤は細胞周期を制御するRetinoblastomaタンパク質(Rb)のリン酸化を抑制することでG1期停止を誘導し癌細胞の増殖を抑制することが知られている(非特許文献11~13)
日本および海外において承認を受けているCDK4/6阻害剤としてイブランス(一般名:Palbociclib)、Kisqali(一般名:Ribociclib)、Verzenio(一般名Abemaciclib)が挙げられる。
パルボシクリブは、ホルモン受容体陽性、HER2陰性の手術不能または再発乳癌に対して内分泌療法剤との併用を用法として日本で承認を受けているものの、現時点で分子標的薬との併用では承認を受けていない。しかし、非臨床研究においてはCDK4/6阻害剤と他の分子標的治療薬との併用の効果についていくつかの報告がある(特許文献1)。例えば 、HER2陽性乳がん細胞を移植したPDXモデルにおいて、EGFRファミリーキナーゼ阻害剤との併用によりRbとS6RPを強く抑制し、高い抗腫瘍効果を発揮することが示されている(非特許文献14)。また、ALK阻害剤との併用により細胞周期停止やカスパーゼ非依存的な細胞死を強く誘導することでALK遺伝子異常を有する神経芽細胞腫細胞を移植したSCIDマウスにおける腫瘍増殖を抑制したことが報告されている(特許文献2、非特許文献15)。
しかしながら、CDK4/6阻害剤とRETキナーゼ阻害活性を有する化合物との併用についての報告はなされていない。
本発明は、各種がんの治療・予防や、無増悪生存期間の延長に用いるため、複数の医薬を組み合わせてなる新規な医薬、組み合わせ、医薬組成物、または製剤、およびそれを用いたがんの治療方法や製品等を提供することを目的とする。
即ち、本発明は以下の発明に関する。
<1A> RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤とを組み合わせてなる、がんを治療または予防するための医薬。
<1B> RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤とを別々にまたは一緒に組み合わせてなる、がんを治療または予防するための医薬。
<1C> がんを治療または予防するための、RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤との組み合わせ。
<1D> 別個にまたは同時に投与され、がんを治療または予防するための、RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤との組み合わせ。
<1E> RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤とを組み合わせてなる、がんを治療または予防するための医薬組成物。
<1F> RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤とを組み合わせてなる、がんを治療または予防するための医薬製剤。
<1-2> 配合剤の形態である、<1A>~<1E>に記載の医薬、組み合わせ、医薬組成物、または製剤。
<1-3> 前記RETキナーゼ阻害活性を有する化合物と前記CDK4/6阻害剤とが別個に投与される、<1A>~<1-2>に記載の医薬、組み合わせ、または製剤。
<1-4> 前記RETキナーゼ阻害活性を有する化合物と前記CDK4/6阻害剤が同時にまたは順次に投与される、<1A>~<1-2>に記載の医薬、組み合わせ、または製剤。
<2> RETキナーゼ阻害活性を有する化合物を有効成分として含む、CDK4/6阻害剤と併用してがんを治療または予防するための医薬、または医薬組成物。
<2-2> 前記RETキナーゼ阻害活性を有する化合物が、前記CDK4/6阻害剤と同時に投与される、<2>に記載の医薬、または医薬組成物。
<2-3> 前記RETキナーゼ阻害活性を有する化合物が、前記CDK4/6阻害剤の投与前または投与後に投与される、<2>~<2-2>に記載の医薬、または医薬組成物。
<3> CDK4/6阻害剤を有効成分として含む、RETキナーゼ阻害活性を有する化合物と併用してがんを治療または予防するための医薬、または医薬組成物。
<3-2> 前記CDK4/6阻害剤が、前記RETキナーゼ阻害活性を有する化合物と同時に投与される、<3>に記載の医薬、または医薬組成物。
<3-3> 前記CDK4/6阻害剤が、前記RETキナーゼ阻害活性を有する化合物の投与前または投与後に投与される、<3>~<3-2>に記載の医薬、または医薬組成物。
<4> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-2> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、バンデタニブ、カボザンチニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-3> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブまたはセルパーカチニブ、またはその塩である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-4> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブまたはその塩である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-5> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-6> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、カボザンチニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-7> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、またはセルパーカチニブ、またはその塩である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-8> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、またはバンデタニブ、またはその塩である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
<4-9> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ塩酸塩である、<1A>~<3-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または医薬製剤。
なお、例えば<1A>~<3-n>(nは枝番の整数)は、<1A>~<1F>、<2>、<2-2>~<2-n>、<3>、<3-2>~<3-n>を含むことを意味する。以下同様。
<5-2> 前記製剤の単位剤型あたり、アレクチニブまたはその塩を、フリー体に換算して20mg、40mg、または150mgを含む、<1A>~<4-9>に記載の製剤。
<6> 前記CDK4/6阻害剤が、パルボシクリブ、アベマシクリブ、リボシクリブ、バンデタニブ、および2-ヒドロキシ-1-[2-[[9-(4-メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2-d]ピリミジン-2-イル]アミノ]-7,8-ジヒドロ-5H-1,6-ナフチリジン-6-イル]エテノンからなる群から選択される、<1A>~<5-2>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<6-2> 前記CDK4/6阻害剤が、パルボシクリブまたはアベマシクリブである、<1A>~<5-2>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<7> 前記がんが、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質を有する、<1A>~<6-2>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<7-2> 前記他の遺伝子およびタンパク質が、KIF5B、CCDC6、NCOA4またはTRIM33である、<7>に記載の医薬、組み合わせ、医薬組成物、または製剤。
<7-3> 前記RET遺伝子と他の遺伝子との融合遺伝子およびRETタンパク質と他のタンパク質との融合タンパク質が、RET遺伝子またはタンパク質のチロシンキナーゼドメイン、および他の遺伝子またはタンパク質のコイルドコイルドメインを含む、<7>に記載の医薬、組み合わせ、医薬組成物、または製剤。
<8> 前記がんが、RETに変異を有する、<1A>~<7-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<8-2> 前記RETにおける変異が、RETチロシンキナーゼの活性化を引き起こす変異である、<8>に記載の医薬、組み合わせ、医薬組成物、または製剤。
<9-2> 前記がんが、甲状腺癌、肺癌、大腸癌、悪性黒色腫、および慢性骨髄性白血病からなる群より選択される<1A>~<8-2>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<9-3> 前記がんが、甲状腺髄様癌、非小細胞肺癌、大腸癌、スピッツ様新生物、および慢性骨髄単球性白血病からなる群より選択される<1A>~<8-2>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<10> 前記がんが、甲状腺髄様癌、非小細胞肺癌、およびスピッツ様新生物からなる群より選択される<1A>~<9-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<10-2> 前記がんが、甲状腺髄様癌または非小細胞肺癌である、<1A>~<9-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<10-3> 前記がんが非小細胞肺癌である、<1A>~<9-3>のいずれかに記載の医薬、組み合わせ、医薬組成物、または製剤。
<11> 対象に有効量のRETキナーゼ阻害活性を有する化合物および有効量のCDK4/6阻害剤を組み合わせて投与することを含む、がんを治療または予防する方法。
<11-2> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが別個に投与される<11>に記載の方法。
<11-3> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが同時または順次に投与される<11>に記載の方法。
<12> 対象に有効量のCDK4/6阻害剤を投与することを含む、RETキナーゼ阻害活性を有する化合物によるがんの治療の効果を増強させる方法。
<12-2> 前記CDK4/6阻害剤が、前記RETキナーゼ阻害活性を有する化合物と同時に投与される、<12>に記載の方法。
<12-3> 前記RETキナーゼ阻害活性を有する化合物の投与前または投与後に、前記CDK4/6阻害剤が投与される、<12>に記載の方法。
<13-2> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが、別個に投与される<13>に記載の方法。
<13-3> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが、同時または順次に投与される<13>に記載の方法。
<14> 前記がんが、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質を有する、<12>~<13-3>のいずれかに記載の方法。
<14-2> 前記他の遺伝子およびタンパク質が、KIF5B、CCDC6、NCOA4またはTRIM33である、<14>に記載の方法。
<14-3> 前記RET遺伝子と他の遺伝子との融合遺伝子、および前記RETタンパク質と他のタンパク質との融合タンパク質が、RET遺伝子またはタンパク質のチロシンキナーゼドメイン、および他の遺伝子またはタンパク質のコイルドコイルドメインを含む、<14>に記載の方法。
<15> 前記がんが、RETに変異を有する、<12>~<13-3>のいずれかに記載の方法。
<15-2> 前記RETにおける変異が、RETチロシンキナーゼの活性化を引き起こす変異である、<15>に記載の方法。
<16> 前記がんが、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌、膵臓癌、肝臓癌、胆嚢癌、皮膚癌、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、および該腫瘍から転移した腫瘍からなる群より選択される、<12>~<15-2>のいずれかに記載の方法。
<16-2> 前記がんが、甲状腺癌、大腸癌または肺癌である、<12>~<15-2>のいずれかに記載の方法。
<16-3> 前記がんが、甲状腺髄様癌または非小細胞肺癌である、<12>~<15-2>のいずれかに記載の方法。
<18>対象に有効量のRETキナーゼ阻害活性を有する化合物および有効量のCDK4/6阻害剤を組み合わせて投与することを含む、腫瘍の増殖を抑制するための方法。
<18-2> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが、別個に投与される<18>に記載の方法。
<18―3> 前記RETキナーゼ阻害活性を有する化合物と、前記CDK4/6阻害剤とが、同時または順次に投与される<18>に記載の方法。
<19> 前記がんが、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質を有する、<18>~<18-3>のいずれかに記載の方法。
<19-1> 前記他の遺伝子およびタンパク質が、KIF5B、CCDC6、NCOA4またはTRIM33である、<19>に記載の方法。
<19-2> 前記RET遺伝子と他の遺伝子との融合遺伝子およびRETタンパク質と他のタンパク質との融合タンパク質が、RET遺伝子またはタンパク質のチロシンキナーゼドメイン、および他の遺伝子またはタンパク質のコイルドコイルドメインを含む、請求<19>に記載の方法。
<19-3> 前記がんが、RETに変異を有する、<18>~<18-3>のいずれかに記載の方法。
<19-4> 前記RETにおける変異が、RETチロシンキナーゼの活性化を引き起こす変異である、<19-3>のいずれかに記載の方法。
<19-5> 前記がんが、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌、膵臓癌、肝臓癌、胆嚢癌、皮膚癌、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、および該腫瘍から転移した腫瘍からなる群より選択される、<18>~<18-3>のいずれかに記載の方法。
<19-6> 前記がんが、甲状腺癌、大腸癌または肺癌である、<18>~<18-3>のいずれかに記載の方法。
<19-7> 前記がんが、甲状腺髄様癌または非小細胞肺癌である<18>~<18-3>のいずれかに記載の方法。
<19-8> 前記がんが、非小細胞肺癌である、<18>~<18-3>のいずれかに記載の方法薬。
<20> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<18>~<19-8>のいずれかに記載の方法。
<20-2> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、およびセルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<18>~<19-8>のいずれかに記載の方法。
<20-3> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、およびセルパーカチニブからなる群から選択される化合物、またはその塩である、<18>~<19-8>のいずれかに記載の方法。
<20-4> RETキナーゼ阻害活性を有する化合物が、アレクチニブまたはその塩である、<18>~<19-8>のいずれかに記載の方法。
<20-5> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<18>~<19-8>のいずれかに記載の方法。
<20-6> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、およびセルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、<18>~<19-8>のいずれかに記載の方法。
<20-7> 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、およびセルパーカチニブからなる群から選択される化合物、またはその塩である、<18>~<19-8>のいずれかに記載の方法。
<20-8> RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、およびバンデタニブからなる群から選択される化合物、またはその塩である、<18>~<19-8>のいずれかに記載の方法。
<20-9> RETキナーゼ阻害活性を有する化合物が、アレクチニブ塩酸塩である、<18>~<19-8>のいずれかに記載の方法。
<21> 前記アレクチニブまたはその塩が、1日2回、1回につきフリー体に換算して20mg、40mg、60mg、80mg、120mg、160mg、220mg、240mg、300mg、460mg、600mg、760mgまたは900mg投与される<18>~<19-8>のいずれかに記載の方法。
<22> 前記CDK4/6阻害剤が、パルボシクリブ、アベマシクリブ、リボシクリブ、および2-ヒドロキシ-1-[2-[[9-(4-メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2-d]ピリミジン-2-イル]アミノ]-7,8-ジヒドロ-5H-1,6-ナフチリジン-6-イル]エテノンからなる群から選択される、<18>~<21>のいずれかに記載の方法。
<22-2> 前記CDK4/6阻害剤が、パルボシクリブまたはアベマシクリブである、<18>~<21>のいずれかに記載の方法。
<23> (1)RETキナーゼ阻害活性を有する化合物を含有する製剤と、(2)容器、および(3)がんを治療するために前記RETキナーゼ阻害活性を有する化合物と少なくとも一種のCDK4/6阻害剤とを組み合わせて対象に投与することを示す指示書またはラベル、を含む製品。
<23-2> (1)CDK4/6阻害剤を含有する製剤と、(2)容器、および(3)がんを治療するために前記CDK4/6阻害剤と少なくとも一種のRETキナーゼ阻害活性を有する化合物とを組み合わせて対象に投与することを示す指示書またはラベル、を含む製品。
「RETキナーゼ阻害活性を有する化合物」とは、RET阻害剤とも称し、RETキナーゼの活性を阻害する薬剤を意味し、好ましくはRETキナーゼに結合し、当該活性を阻害する作用を有する薬剤である。
具体的な例としては、
・アレクチニブ(化合物名:9-エチル-6,6-ジメチル-8-[4-(モルホリン-4-イル)-ピペリジン-1-イル]-11-オキソ-6,11-ジヒドロ-5H-ベンゾ[b]カルバゾール-3-カルボニトリル)またはその塩、好ましくは、アレクチニブ塩酸塩であり、
・バンデタニブ(化合物名:N(-4-ブロモ-2-フルオロフェニル)-6-メトキシ-7-[(1-メチルピペリジン-4-イル)メトキシ]キナゾリン-4-アミン)またはその塩、
・BLU-667(プラルセチニブ;化合物名:cis-N-{(1S)-1-[6-(4-フルオロ-1H-ピラゾール-1-yl)ピリジン-3-イル]エチル}-1-メトキシ-4-{4-メチル-6-[(5-メチル-1H-ピラゾール-3-yl)ピリミジン-2-カロイミド]またはその塩、
・カボザンチニブ(化学名:N-(4-(6,7-ジメトキシキノリン-4-イルオキシ)フェニル)-N’-(4-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミド)またはその塩、好ましくはカボザンチニブ(2S)-ヒドロキシブタン二酸塩、
・ソラフェニブ(化合物名:4-{4-[3-(4-クロロ-3-トリフルオロメチルフェニル)ウレイド]フェノキシ}-N2-メチルピリジン-2-カルボキサミド モノ(4-メチルベンゼンスルホネート))またはその塩、および、
・セルパーカチニブ(化合物名:6-(2-ヒドロキシ-2-メチルプロポキシ)-4-(6-(6-((6-メトキシピリジン-3-イル)メチル)-3,6-ジアザビシクロ(3.1.1)ヘプタン-3-イル)ピリジン-3-イル)ピラゾロ(1,5-a)ピリジン-3-カルボニトリル)またはその塩、からなる群より選択される化合物などが挙げられる。
好ましくは、アレクチニブ塩酸塩、プラルセチニブ、バンデタニブ、カボザンチニブ(2S)-ヒドロキシブタン二酸塩、ソラフェニブ、またはセルパーカチニブである。
さらに好ましくは、アレクチニブ塩酸塩、バンデタニブ、カボザンチニブ(2S)-ヒドロキシブタン二酸塩、ソラフェニブ、またはセルパーカチニブである。
上記化合物のほかに、下記化合物もRETキナーゼ阻害活性を有することが知られている(Oncology Review 2018, Vol12: 352)ため、本願発明に用いることができる。
RETキナーゼ阻害活性を有する化合物は、水もしくはそれ以外の製薬学的に許容し得る液との無菌性溶液または懸濁液剤等の注射剤の形で、非経口的にも使用され得る。これら製剤における有効成分量は指示された範囲の適当な用量を投与し得るように適宜選択される。注射のための無菌組成物は注射用蒸留水のようなベヒクルを用いて通常の製剤実施に従って処方され得る。注射用の水溶液としては、例えば生理食塩水、ブドウ糖やその他の補助薬を含む等張液、例えばD-ソルビトール、D-マンノース、D-マンニトール、塩化ナトリウムが例示され、適当な溶解補助剤、例えばアルコール、具体的にはエタノール、ポリアルコール、例えばプロピレングリコール、ポリエチレングリコール、非イオン性界面活性剤、例えばポリソルベート80(TM)、HCO-50と適宜併用され得る。油性液としてはゴマ油、大豆油が例示され、溶解補助剤として安息香酸ベンジル、ベンジルアルコールと併用してもよい。また、緩衝剤、例えばリン酸塩緩衝液、酢酸ナトリウム緩衝液、無痛化剤、例えば、塩酸プロカイン、安定剤、例えばベンジルアルコール、フェノール、酸化防止剤と好適に配合され得る。
本発明に係るRETキナーゼ阻害活性を有する化合物の投与量としては、例えば、一回の投与につき体重1kgあたり0.0001mgから1000mgの範囲で投与量が選択され得る。あるいは、例えば、患者あたり0.001mgから100000mg/bodyの範囲で投与量が選択され得る。しかしながら、本発明のRETキナーゼ阻害活性を有する化合物の投与量はこれらの投与量に制限されるものではない。
例えば、前記アレクチニブ、その塩、またはそれらの水和物のより具体的な投与量としては、1日2回、1回につきフリー体に換算して、20mg、40mg、60mg、80mg、120mg、160mg、220mg、240mg、300mg、460mg、600mg、760mgまたは900mgがあげられる。
また、プラルセチニブ、その塩、またはそれらの水和物のより具体的な投与量は、1日1回につきフリー体に換算して、300mg~800mg、好ましくは400mgである。バンデタニブ、その塩、またはそれらの水和物のより具体的な投与量は、1日1回につきフリー体に換算して、100mg~600mg、好ましくは300mgである。
本発明のRETキナーゼ阻害活性を有する化合物の投与期間は、適宜症状や副作用の程度に応じて決定され、がんが治療されまたは所望の治療効果が達成されるまでの間投与することができる。
本発明に用いられるCDK4/6阻害剤は、サイクリン依存性キナーゼ4(CDK4)またはサイクリン依存性キナーゼ6(CDK6)の活性を直接的または間接的に中和し、遮断し、阻害し、低減しまたは妨害することが可能な物質を意味する。前記物質には、低分子化合物、抗体、アンチセンス、転写阻害剤、低分子干渉RNA(siRNA)などが含まれる。
CDK4および/またはCDK6は、サイクリン依存性キナーゼ(CDK)のファミリータンパク質であり、哺乳動物の細胞周期の開始、進行、および終了を調節する。増殖にとって重要であり、この経路の調節不全は乳癌においてしばしば認められる。CDK4/6はサイクリンD1および他のD型サイクリンによって細胞周期の早期に活性化され、G1制限点(R点)を通過する細胞周期の進行を促進する。活性化されたサイクリン-CDK複合体は、癌抑制因子であるRbをリン酸化により不活性化し、転写活性化因子E2Fの放出を誘導し、細胞増殖の異常を呈する。
したがって、CDK4/6阻害剤は、がん細胞の増殖抑制に用いられることが公知であり、例えば、パルボシクリブ(化合物名:6-アセチル-8-シクロペンチル-5-メチル-2-{[5-(ピペラジン-1-イル)ピリジン-2-イル]アミノ}ピリド[2,3-d]ピリミジン-7(8H)-オン)またはその塩、
・リボシクリブ(化合物名:7-シクロペンチル-N、N-ジメチル-2-((5-(ピペラジン-1-イル)ピリジン-2-イル)アミノ)-7H-ピロロ[2,3-d]ピリミジン)またはその塩、
・アベマシクリブ(化合物名:N{-5[-(4-エチルピペラジン-1-イル)メチル]ピリジン-2-イル}-5-フロロ-4-[4-フルオロ-2-メチル-1-(1-メチルエチル)-1H-ベンズイミダゾール-6-イル]ピリミジン-2-アミン)またはその塩、
パンデタニブ(化合物名:N-(4-ブロモ-2-フルオロフェニル)-6-メトキシ-7-[(1-メチルピペリジン-4-イル)メトキシ]キナゾリン-4-アミン)またはその塩、
・ソラフェニブトシル(4-{4-[3-(4-クロロ-3-トリフルオロメチルフェニル)ウレイド]フェノキシ}-N 2-メチルピリジン-2-カルボキサミドモノ(4-メチルベンゼンスルホネート))またはその塩、好ましくは、ソラフェニブトシル塩酸塩、
・AMG-925(化合物名:2-ヒドロキシ-1-[2-[[9-(4-メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2-d]ピリミジン-2-イル]アミノ]-7,8-ジヒドロ-5H-1,6-ナフチリジン-6-イル]エテノン)またはその塩、
・ファスカプリシン(化合物名:12,13-ジヒドロ-13-オキソ-ピリド[1,2-a:3,4-b’]ジインドール-5-イウム)またはその塩、
などの化合物が臨床で用いられている。
好ましくは、パルボシクリブ、アベマシクリブ、リボシクリブ、およびAMG-925またはその塩である。
これらの化合物またはその塩は医薬品製剤として製造販売され、または研究用試薬として入手することができ、あるいは、常法により、製造することができる。これらの化合物またはその塩には、水和物、製薬学的に許容可能な各種溶媒和物や結晶多形等も含まれる。
疾患のタイプおよび重篤度に応じて、例えばパルボシクリブの好ましい用量は、限定されないが、1~5mg/kgの範囲であり、症状や副作用の程度に応じて段階的に減量してもよい。投与の頻度は通常1日1回投与を所定の期間(例えば3週間)投与を1サイクルとし、所定の休薬期間(例えば1週間)を設け、当該サイクルを繰り返す。サイクルの回数は、疾患のタイプと重篤度に応じて変動する。治療は、当該分野で知られている方法によって測定して、がんが治療されまたは所望の治療効果が達成されるまで維持される。一例では、パルボシクリブは、125mgを一日一回、3週間継続投与し、副作用等の発現がみられた場合には、一次減量として100mg、二次減量として75mgに減量して投与される。しかしながら、他の用量レジメンも有用であり得る。
CDK4/6阻害剤は、上記3週毎の投与を1サイクルとして、がんが治療されまたは所望の治療効果が達成されるまでの間投与することができる。具体的には1~36サイクルに渡り投与することができる。
また、例えば、アベマシクリブは、150mgを一日一回投与し、副作用等の発現がみられた場合には、一次減量として100mg、二次減量として50mgに減量して投与される。
本発明の1つの態様は、RETキナーゼ阻害活性を有する化合物およびCDK4/6阻害剤を組み合わせてなる、がんを治療または予防するための医薬である。
上記態様における、「RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤とを組み合わせてなる、がんを治療または予防するための医薬」とは、RETキナーゼ阻害活性を有する化合物およびCDK4/6阻害剤を、がんの治療または予防において同時に、別個に、または、順次に投与するために組み合わせた医薬を意味する。本発明の医薬は、RETキナーゼ阻害活性を有する化合物およびCDK4/6阻害剤を共に含有する配合剤の形で提供することもできる。また、RETキナーゼ阻害活性を有する化合物を含有する製剤とCDK4/6阻害剤を含有する製剤とが別々に提供され、これらの製剤が、同時に、または順次に使用されてもよい。
本発明において、同時に投与するとは、RETキナーゼ阻害活性を有する化合物と、CDK4/6阻害剤とを同じタイミングで投与して用いることをいい、配合剤として投与してもよく、投与時に用時調整した混合物として投与してもよく、別形態の製剤を同時期に投与してもよい。同時に投与して用いる場合、別々の経路から投与してもよく、同一の経路から投与してもよく、投与剤型も同一であってもよく、別々であってもよい。
本発明において、RETキナーゼ阻害活性を有する化合物およびCDK4/6阻害剤を別個に投与する場合、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤の投与の順番は、CDK4/6阻害剤の投与後にRETキナーゼ阻害活性を有する化合物が投与され得るし、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤とが同時に投与され得るし、また、RETキナーゼ阻害活性を有する化合物の投与後にCDK4/6阻害剤が投与され得る。
これとは逆に、RETキナーゼ阻害活性を有する化合物の投与前にCDK4/6阻害剤が投与される場合には、RETキナーゼ阻害活性を有する化合物による所望の効果が得られるような、対象におけるCDK4/6阻害剤の残留濃度が検出される時点で、RETキナーゼ阻害活性を有する化合物が投与され得る。当該濃度は、対象から採取された試料を当業者において公知のELISA等の免疫的測定法で分析した結果に基づいて決定され得る。
なお、本発明において、医薬組成物は、本発明の治療および/または予防に用いられるRETキナーゼ阻害活性を有する化合物および/またはCDK4/6阻害剤を含むものであり、さらに製薬学的に許容される担体を含んでいてもよい。
本発明において、「製薬学的に許容される担体」という用語は、先に例示されるような一種以上の適合性の固体または液体の賦形希釈剤またはカプセル化材料であって、哺乳類への投与に適したものを意味する。
本発明において、「組み合わせ」とは、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤である化合物を、別個に同一の対象に使用できる形態のもの、あるいはこれらの化合物を混合せずにそれぞれで製剤化し、組み合わせた物を意味する。
本発明において、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤とを組み合わせてなる「医薬製剤」とは、これらの活性成分を別個に製剤化したもの、または同一製剤中に含む、錠剤、カプセル剤、顆粒剤、散剤、丸剤などの固形製剤、水性および非水性の経口用溶液および懸濁液、および個々の投与量に小分けするのに適応した容器に充填した非経口用溶液などの液剤、用時溶解して用いることができる凍結乾燥性剤、またはこれらのいずれかの剤型を組み合わせた製剤を含む。当該医薬製剤は、単位剤型あたり、アレクチニブまたはその塩を、フリー体に換算して150mg~800mg、好ましくは150mg~400mg、特に好ましくは、150mg~300mg含有する。アレクチニブまたはSの塩を、別個に製剤化したものは、具体的には、150mgカプセル製剤、150mg、300mg、600mg錠剤などがある。
別の観点においては、本発明は、CDK4/6阻害剤を有効成分として含む、RETキナーゼ阻害活性を有する化合物と併用してがんを治療または予防するための医薬を提供する。本発明における、「CDK4/6阻害剤を有効成分として含む、RETキナーゼ阻害活性を有する化合物と併用してがんを治療または予防するための医薬」とは、RETキナーゼ阻害活性を有する化合物と併用することを条件にがんを治療または予防することに用いられる、CDK4/6阻害剤を有効成分として含む医薬を意味する。CDK4/6阻害剤を有効成分として含む医薬がRETキナーゼ阻害活性を有する化合物と併用される際には、RETキナーゼ阻害活性を有する化合物と同時に投与され得るし、RETキナーゼ阻害活性を有する化合物の投与前または投与後に投与され得る。RETキナーゼ阻害活性を有する化合物の投与前または投与後にCDK4/6阻害剤が投与される場合には、対象における当該RETキナーゼ阻害活性を有する化合物の残留濃度を測定することにより、その投与時期が最適化され得る。当該濃度は、対象から採取された試料を各種のクロマトグラフィー等の分離装置を用いて分離し、当業者において公知の分析方法に基づいて決定され得る。
上記発明は、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤とが共に投与または使用(以下、単に「投与」と指称される。)されることを意味するものであって、投与の順番や投与間隔等が限定されて解釈されるものでない。また、本発明は、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤とが組み合わされた製品としても使用され得る。さらに、本発明にしたがって、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤が併用される場合には、いずれか一方が単独で用いられる投与量よりも、所望により各々が少ない投与量で投与され得る。
本発明の医薬は、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌(例えば、甲状腺髄様癌)、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌(例えば、非小細胞肺癌など)、膵臓癌、肝臓癌、胆嚢癌、皮膚癌(例えば、スピッツ様新生物など)、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、該腫瘍から転移した腫瘍等の種々の癌などの疾患の予防または治療に有用である。さらに本発明の化合物は、上記癌の浸潤・転移の予防または治療に有用である。
また、本発明の医薬は、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質の癌の予防または治療に有用である。「他の遺伝子」および「他のたんぱく質」としては、KIF5B、CCDC6、NCOA4、TRIM33、CLIP1、およびERC1等が挙げられる。好ましくは、KIF5B、CCDC6、NCOA4およびTRIM33である。
本発明において、RET遺伝子またはタンパク質のチロシンキナーゼドメインとは、ATPのγ位のリン酸基をタンパク質のチロシン残基に転移する反応を担う触媒ドメインである。
本発明において、「他の遺伝子またはタンパク質のコイルドコイルドメイン」とは、FPPFPPP(F:疎水性,P:極性アミノ酸残基)のヘプタッドからなるαへリックスの疎水性部位が相互作用するタンパク質間相互作用ドメインである。
特に、本発明の医薬は、RETに変異を有する腫瘍によるがん、および/または、RET融合遺伝子陽性のがんの予防または治療に有用である。RET融合遺伝子陽性のがんの例としては、甲状腺癌、非小細胞肺癌などがあげられるが、これらに限定されない。
本発明において、RETに変異を有する腫瘍とは、RET遺伝子および/またはRETタンパク質において、RETチロシンキナーゼの活性化を引き起こす変異が生じていること、RETチロシンキナーゼを活性化させ、癌化(例えば甲状腺癌、肺癌)を誘発する変異が生じていること、が含まれる。RETチロシンキナーゼの活性化は、腫瘍組織におけるリン酸化RETを抗リン酸化RET抗体による免疫染色などで検出することにより確認することができる。
本発明において、RETチロシンキナーゼの活性化とは、RETチロシンキナーゼに含まれるアミノ酸残基、例えばチロシン残基がリン酸化されていることを意味し、被験者(例えば被験者から採取した試料)におけるリン酸化RETチロシンキナーゼタンパク質の量が(例えば健常者と比較して)増大することが含まれる。さらに、RETチロシンキナーゼのリン酸化によりRETチロシンキナーゼが標的とするタンパク質(以下標的タンパク質)がリン酸化されることが含まれる。「RETチロシンキナーゼの活性化」には、リン酸化RETチロシンキナーゼタンパク質の他、リン酸化された前記標的タンパク質の量が増大することが含まれる。
本発明において、RET融合遺伝子陽性とは、RETと、他の遺伝子、例えば、KIF5B、CCDC6、NCOA4、TRIM33、CLIP1、およびERC1等との融合遺伝子が、公知の方法、例えば、逆転写PCR法とサンガーシーケンス法を組み合わせた方法や、インサイチュー・ハイブリダイゼーション技術などを用いて検出された腫瘍を意味する。RET融合遺伝子陽性の癌の具体例は、WO2014/050781に記載されているものがあげられるが、これらに限定されない。
本発明において、「有効量」とは、RETキナーゼ阻害活性を有する化合物およびCDK4/6阻害剤を組み合わせて投与する場合における、それぞれの阻害剤についての1日投与量を意味する。本発明における投与量は、それぞれの阻害剤が単独で用いられる場合の投与量と同じであってもよく、単独でも用いられる場合の投与量よりも低い投与量であってもよい。あるいは、本発明における有効量は、一方が単独で用いられる場合の投与量と同じであり、他方が単独で用いられる場合の投与量よりも低い投与量であってもよい。
本発明において、「無増悪生存期間を延長させる」の具体例としては、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤阻害剤の併用が、RETキナーゼ阻害活性を有する化合物またはCDK4/6阻害剤を単剤で併用の際に用いた投与量と同じ用量で投与した際のPFSと比較して、PFSが延長することが挙げられる。
本発明において、「対象」とは、限定しないが、本発明の医薬の投与対象となる、または、本発明の医薬の投与が必要とされる、ヒトまたは非ヒト哺乳動物、例えばウシ、ウマ、イヌ、ヒツジ、またはネコを含む哺乳動物を意味する。好ましくは、対象はヒトである。対象には患者(ヒトおよび非ヒト哺乳動物を含む)が含まれる。具体的には、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌(例えば、甲状腺髄様癌)、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌(例えば、非小細胞肺癌など)、膵臓癌、肝臓癌、胆嚢癌、皮膚癌(例えば、スピッツ様新生物など)、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、該腫瘍から転移した腫瘍等の種々の癌に罹患する患者、または罹患する可能性の高いヒトまたは非ヒト哺乳動物である。
本発明の別の態様として、製品が提供される。一実施態様では、製品は対象におけるがんを治療または予防するために提供され、(a)(1)CDK4/6阻害剤を含有する製剤、(2)容器、(3)対象におけるがんを治療するために前記CDK4/6阻害剤と少なくとも一種のRETキナーゼ阻害活性を有する化合物とを組み合わせて対象に投与することを示す指示書またはラベル、または(b)(1)RETキナーゼ阻害活性を有する化合物を含有する製剤、(2)容器、(3)対象におけるがんを治療するために前記RETキナーゼ阻害活性を有する化合物と少なくとも一種のCDK4/6阻害剤とを組み合わせて対象に投与することを示す指示書またはラベル、を含む。
製品は、CDK4/6阻害剤またはRETキナーゼ阻害活性を有する化合物を含有する製剤を含む容器を含む。
製品は、容器上または容器に付随したラベルまたは指示書をさらに含み得る。
本発明において「指示書」とは、製剤の使用に関する適応症、用法、投与量、投与、禁忌症および/または警告についての情報を含む、製剤の商業用パッケージ中に通常含まれる書類を意味する。「ラベル」とは、CDK4/6阻害剤またはRETキナーゼ阻害活性を有する化合物を含有する製剤の製品名、用量、剤型、適応症等の表示を含むシート状の物品であり、容器に直接貼付されるものを意味する。
ラベルまたは指示書は、製剤の適応症、すなわちがんなどの治療に使用されることを示す。一実施態様では、ラベルまたは指示書は、製剤ががんを治療するために使用することができることを示す。ラベルまたは指示書はまた、製剤が他の障害を治療するために使用することができることを示し得る。
適切な容器には、例えば、PTP、ビン、バイアル、シリンジ、ブリスターパックなどが挙げられる。容器は、ガラスまたはプラスチックなどの種々の材料から形成し得る。これらの容器が更に上記ラベルの内容等を印刷した紙製の外箱に梱包されていてもよい。
以下、本発明を実施例の記載によって具体的に説明するが本発明は当該記載によって限定して解釈されるものではない。
ヒトRET融合遺伝子陽性非小細胞肺がん株LC-2/ad細胞(RIKEN、J Thorac Oncol.2012 Dec,7(12),1872-6)を1×104細胞ずつ96穴プレートに播種し、アレクチニブ(社内で合成)を非小細胞肺がんの治療に使用されるあるいは臨床開発が行われた薬剤の内の下記12化合物から選択される抗がん剤と併用した。化合物は、葉酸代謝拮抗薬ペメトレキセド(富士フィルム和光純薬)、微小管阻害剤パクリタキセル(富士フィルム和光純薬)、アルキル化剤カルボプラチン(富士フィルム和光純薬)、微小管阻害剤ビノレルビン(富士フィルム和光純薬)、代謝拮抗薬ゲムシタビン(富士フィルム和光純薬)、トポイソメラーゼI阻害剤イリノテカン(富士フィルム和光純薬)、CDK4/6阻害剤パルボシクリブ(Sigma-Aldrich)、HDAC阻害剤SAHA(東京化成工業)、PI3K阻害剤BKM120(AdooQ BioScience)、PI3KおよびmTOR阻害剤ゲダトリシブ(Selleck Chemicals LLC)、mTOR阻害剤エベロリムス(AdooQ BioScience)、HSP90阻害剤ルミネスピブ(Akt Pharm, Inc.)である。各単剤および併用で4日間処理し細胞増殖試験を実施した。薬剤処理濃度は表1に示した。IC50アイソボログラム法(Pharmacol Res Perspect.2015 Jun;3(3):e00149)により併用効果を解析した結果を図1に示した。なお、図1において、横軸・縦軸はそれぞれアレクチニブ・併用相手化合物の濃度を示す。ここで、各軸上の点は各薬剤単剤の50%細胞増殖阻害濃度を、軸上の二点を結んだ点線は相加効果を示す。枠内の点が点線の内側・線上・点線の外側にある場合両薬剤はそれぞれ相乗・相加・拮抗効果を意味する。
その結果、アレクチニブとペメトレキセド、パクリタキセル、カルボプラチン、ビノレルビン、イリノテカン、またはルミネスピブとの併用は拮抗効果を示した。ゲムシタビン、SAHA、ゲダトリシブ、またはエベロリムスとの併用は相加程度の効果を示した。BKM120との併用は一部の濃度で相乗効果を示した。パルボシクリブとの併用は枠内の全ての点が点線の内側にあり、相乗効果を示した。
マウスプロB細胞株Ba/F3にKIF5B-RET融合遺伝子を導入したBa/F3-KIF5B-RET細胞(Mol Cancer Ther. 2014;13: 2910-2918)を5×103細胞ずつ96穴プレートに播種し、アレクチニブおよびCDK4/6阻害剤パルボシクリブあるいはCDK4/6阻害剤アベマシクリブ(Selleck Chemicals LLC)を併用および単剤で4日間処理し細胞増殖試験を実施した。薬剤処理濃度は表1に示した。アイソボログラム法により併用効果を解析した結果を図2に示した。
なお、図2において、横軸・縦軸はそれぞれアレクチニブ・パルボシクリブあるいはアベマシクリブの濃度を示す。
その結果、Ba/F3-KIF5B-RET細胞においてもアレクチニブとパルボシクリブは相乗効果を示した。更に、別のCDK4/6阻害剤であるアベマシクリブとの併用でも相乗効果を示した。これらの結果から、アレクチニブとCDK4/6阻害剤の併用はCDK4/6阻害剤の種類に依らず相乗効果を有すると考えられる。
Ba/F3-KIF5B-RET細胞を1匹あたり5×106細胞移植したBALB/c-nu(ヌード)マウス(日本チャールスリバー)に対して、細胞を移植した後11日目にアレクチニブ(20mg/kg、1日1回15日間経口投与)とパルボシクリブ(75mg/kg、1日1回15日間経口投与)を併用した。各投与群の腫瘍体積(平均値+標準偏差)と体重の変化率(平均値+標準偏差)を図3に示した。
なお、図3において、横軸は、薬剤投与初日を1とした際の経過日数、縦軸は、腫瘍体積(Tumor volume)と体重の変化率(Relative body weight)を示し、Vehicleは溶媒投与対照群、ALCはアレクチニブ単剤投与群、PDはパルボシクリブ単剤投与群、ALC+PDはアレクチニブおよびパルボシクリブ併用投与群を示す。
その結果、併用投与群はアレクチニブ単剤投与群およびパルボシクリブ単剤投与群と比較して高い抗腫瘍効果を示した。薬剤投与後11日目において、併用投与群は各単剤投与群および溶媒投与対照群と比較して統計学的に有意に高い抗腫瘍効果を示した。いずれの群においても溶媒投与群と比較して体重減少は見られなかった。
LC-2/ad細胞およびBa/F3-KIF5B-RET細胞をそれぞれ2×104細胞あるいは1×104細胞ずつ96穴プレートに播種し、アレクチニブ(100nM)およびパルボシクリブ(100nM)を添加した。3日後RealTime Glo Annexin V Apoptosis and Necrosis Assay(Promega)キットの内Annexin V検出用の試薬を用いてAnnexin Vの結合を観察した。Controlに対する各薬剤処理群の蛍光強度の比を図4に示した。
なお、図4において、Controlは溶媒対照群を、ALCはアレクチニブ単剤処理群を、PDはパルボシクリブ単剤処理群を、ALC+PDはアレクチニブとパルボシクリブ併用処理群を示す。
その結果、併用処理群は各単剤群および溶媒対照群と比較して有意に高いAnnexin Vの結合を示した。この結果から、両併用によりアポトーシスが増強されることが示唆された。
LC-2/ad細胞およびBa/F3-KIF5B-RET細胞をアレクチニブ(100nM)およびパルボシクリブ(100nM)で処理し、24時間後各細胞からタンパク質を精製した。各タンパク質の発現量をキャピラリー電気泳動タンパク質解析システムSally Sue(ProteinSimple)を用いて観察した結果を図5に示した。
なお、図5において、ALCはアレクチニブを、PDはパルボシクリブを示し、-および+はそれぞれ薬剤非処理、処理を示す。
その結果、両薬剤の併用により、単剤と比較して細胞周期進展に関与するタンパク質をコードする遺伝子の転写を促進するタンパク質であるS6のリン酸化を抑制することが確認された。また、両薬剤の併用により、単剤と比較して細胞周期進展に関与するRbのリン酸化を抑制することが確認された。
LC-2/ad細胞を1×104細胞ずつ、Ba/F3-KIF5B-RET細胞を5×103細胞ずつ96穴プレートに播種し、RETキナーゼ阻害活性を有する化合物であるBLU-667(プラルセチニブ;Sellck Chemicals LLC)あるいはバンデタニブ(Cellagen Technology)と、パルボシクリブを併用および単剤で4日間処理し細胞増殖試験を実施した。薬剤処理濃度は表2に示した。アイソボログラム法により併用効果を解析した結果を図6に示した。
その結果、両細胞においていずれのRETキナーゼ阻害活性を有する化合物とパルボシクリブの併用も相乗効果を示した。これらの結果から、RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤の併用はRETキナーゼ阻害活性を有する化合物の種類に依らず相乗効果を有すると考えられる。
Claims (20)
- RETキナーゼ阻害活性を有する化合物とサイクリン依存性キナーゼ4および/またはサイクリン依存性キナーゼ6(CDK4/6)阻害剤とを別々にまたは一緒に組み合わせてなる、がんを治療または予防するための医薬。
- RETキナーゼ阻害活性を有する化合物を有効成分として含む、CDK4/6阻害剤と併用してがんを治療または予防するための医薬。
- CDK4/6阻害剤を有効成分として含む、RETキナーゼ阻害活性を有する化合物と併用してがんを治療または予防するための医薬。
- 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、バンデタニブ、カボザンチニブ、ソラフェニブ、および、セルパーカチニブからなる群から選択される化合物、またはその塩、またはその水和物である、請求項1~3のいずれかに記載の医薬。
- 前記CDK4/6阻害剤が、パルボシクリブ、アベマシクリブ、リボシクリブ、および2-ヒドロキシ-1-[2-[[9-(4-メチルシクロヘキシル)ピリド[4,5]ピロロ[1,2-d]ピリミジン-2-イル]アミノ]-7,8-ジヒドロ-5H-1,6-ナフチリジン-6-イル]エテノンからなる群から選択される、請求項1~4のいずれかに記載の医薬。
- 前記がんが、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質を有する、請求項1~5のいずれかに記載の医薬。
- 前記がんが、RETに変異を有する、請求項1~6のいずれかに記載の医薬。
- 前記がんが、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌、膵臓癌、肝臓癌、胆嚢癌、皮膚癌、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、および該がんから転移したがんからなる群より選択される、請求項1~7のいずれかに記載の医薬。
- 対象に有効量のRETキナーゼ阻害活性を有する化合物および有効量のCDK4/6阻害剤を組み合わせて投与することを含む、がんを治療または予防する方法。
- 対象に有効量のCDK4/6阻害剤を投与することを含む、RETキナーゼ阻害活性を有する化合物によるがんの治療の効果を増強させる方法。
- 対象に有効量のRETキナーゼ阻害活性を有する化合物を投与することを含む、CDK4/6阻害剤によるがんの治療の効果を増強させる方法。
- 前記がんが、RET遺伝子と他の遺伝子との融合遺伝子および/またはRETタンパク質と他のタンパク質との融合タンパク質を有する、請求項9~11のいずれかに記載の方法。
- 前記がんがRETに変異を有する、請求項9~12のいずれかに記載の方法。
- 前記がんが、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、ホジキンリンパ腫、非ホジキンリンパ腫、脳腫瘍、神経芽細胞腫、神経膠腫、甲状腺癌、骨髄異形成症候群、頭頸部癌、食道癌、胃癌、大腸癌、結腸直腸癌、乳癌、卵巣癌、肺癌、膵臓癌、肝臓癌、胆嚢癌、皮膚癌、悪性黒色腫、腎癌、腎盂尿管癌、膀胱癌、子宮癌、精巣癌、前立腺癌、および該腫瘍から転移した腫瘍からなる群より選択される、請求項9~13のいずれかに記載の方法。
- 前記がんが、甲状腺髄様癌、大腸癌または非小細胞肺癌である、請求項9~14のいずれかに記載の方法。
- 前記がんが、非小細胞肺癌である、請求項9~15のいずれかに記載の方法。
- 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ、プラルセチニブ、およびバンデタニブからなる群から選択される化合物、またはその塩である、請求項9~16のいずれかに記載の方法。
- 前記RETキナーゼ阻害活性を有する化合物が、アレクチニブ塩酸塩である、請求項9~17のいずれかに記載の方法。
- 前記CDK4/6阻害剤が、パルボシクリブまたはアベマシクリブである請求項9~18のいずれかに記載の方法。
- (1)RETキナーゼ阻害活性を有する化合物を含有する製剤と、(2)容器、および(3)がんを治療するために前記RETキナーゼ阻害活性を有する化合物とCDK4/6阻害剤の少なくとも一種とを組み合わせて対象に投与することを示す指示書またはラベル、を含む製品。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5832647B2 (ja) | 1975-12-29 | 1983-07-14 | オオクラデンキ カブシキガイシヤ | トレンドキロクホウシキ |
JP2018052878A (ja) * | 2016-09-29 | 2018-04-05 | 第一三共株式会社 | ピリジン化合物 |
JP6479812B2 (ja) | 2013-08-28 | 2019-03-06 | ノバルティス アーゲー | 細胞増殖性疾患を治療するためのalk阻害剤とcdk阻害剤との組合せ |
US20190134044A1 (en) * | 2017-11-06 | 2019-05-09 | Tiziana Life Sciences Plc | Formulations of milciclib and therapeutic combinations of the same for use in the treatment of cancer |
US20200190062A1 (en) * | 2015-02-04 | 2020-06-18 | Beyondbio Inc. | Heterocyclic compound and pharmaceutical composition comprising same |
WO2020136642A1 (en) * | 2018-12-23 | 2020-07-02 | Mor Research Applications Ltd. | Combination therapy of solid cancer |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019199883A1 (en) * | 2018-04-09 | 2019-10-17 | G1 Therapeutics, Inc. | Treatment of cancers having driving oncogenic mutations |
-
2020
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5832647B2 (ja) | 1975-12-29 | 1983-07-14 | オオクラデンキ カブシキガイシヤ | トレンドキロクホウシキ |
JP6479812B2 (ja) | 2013-08-28 | 2019-03-06 | ノバルティス アーゲー | 細胞増殖性疾患を治療するためのalk阻害剤とcdk阻害剤との組合せ |
US20200190062A1 (en) * | 2015-02-04 | 2020-06-18 | Beyondbio Inc. | Heterocyclic compound and pharmaceutical composition comprising same |
JP2018052878A (ja) * | 2016-09-29 | 2018-04-05 | 第一三共株式会社 | ピリジン化合物 |
US20190134044A1 (en) * | 2017-11-06 | 2019-05-09 | Tiziana Life Sciences Plc | Formulations of milciclib and therapeutic combinations of the same for use in the treatment of cancer |
WO2020136642A1 (en) * | 2018-12-23 | 2020-07-02 | Mor Research Applications Ltd. | Combination therapy of solid cancer |
Non-Patent Citations (21)
Title |
---|
CANCER CELL, vol. 29, no. 3, 14 March 2016 (2016-03-14), pages 255 - 269 |
CANCER, vol. 122, no. 24, 15 December 2016 (2016-12-15), pages 3856 - 3864 |
CELL, vol. 42, no. 2, September 1985 (1985-09-01), pages 581 - 588 |
CLIN CANCER RES., vol. 20, no. 14, 15 July 2014 (2014-07-15), pages 3763 - 3774 |
CLIN CANCER RES., vol. 23, no. 11, 1 June 2017 (2017-06-01), pages 2856 - 2868 |
CRIT REV CLIN LAB SCI., vol. 53, no. 4, August 2016 (2016-08-01), pages 217 - 227 |
DIGIACOMO, GRAZIANA ET AL.: "Simultaneous combination of the CDK4/6 inhibitor palbociclib with regorfenib induces enhanced anti-tumor effects in hepatocarcinoma cell lines", FRONTIERS IN ONCOL, vol. 10, 23 September 2020 (2020-09-23), pages 563249, XP055825540 * |
FUJIMURA, TAKAAKI ET AL.: "Enhanced antitumor effect of alectinib in combination with cyclin- dependent kinase 4/6 inhibitor against RET-fusion- positive non-small cell lung cancer cells", CANCER BIOL THER, vol. 21, no. 9, 1 September 2020 (2020-09-01), pages 863 - 870, XP055825537 * |
GENOME RES, vol. 22, no. 3, March 2012 (2012-03-01), pages 436 - 445 |
J BIOL CHEM., vol. 272, no. 14, 4 April 1997 (1997-04-04), pages 9043 - 9047 |
LANCET RESPIR MED, vol. 5, no. 1, January 2017 (2017-01-01), pages 42 - 50 |
MOL CANCER THER, vol. 13, 2014, pages 2910 - 2918 |
MOL CANCER THER, vol. 3, no. 11, November 2004 (2004-11-01), pages 1427 - 1438 |
MOL CANCER THER., vol. 13, 2014, pages 2910 - 2918 |
NAT MED, vol. 18, no. 3, 12 February 2012 (2012-02-12), pages 378 - 381 |
ONCOTARGET, vol. 8, no. 27, 4 July 2017 (2017-07-04), pages 43678 - 43691 |
PHARMACOL RES. PERSPECT., vol. 3, no. 3, June 2015 (2015-06-01), pages e00149 |
PLOS ONE, vol. 11, no. 11, 1 November 2016 (2016-11-01), pages e0165596 |
REITER, P. FLORIAN ET AL.: "Predictors of ribociclib-mediated antitumour effects in native and sorafenib-resistant human hepatocellular carcinoma cells", CELLULAR ONCOL, vol. 42, 27 June 2019 (2019-06-27), pages 705 - 715, XP036890534, DOI: 10.1007/s13402-019-00458-8 * |
RIKEN, J THORAC ONCOL, no. 12, 7 December 2012 (2012-12-07), pages 1872 - 6 |
See also references of EP4062938A4 |
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