# US 10,869,864 B2 · Combinations for the treatment of cancer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,869,864 B2 - Document ID: US10869864B2 - Status: Granted - Kind: B2 - Application number: 16/063,170 - Filed: 2016-12-15 - Published: 2019-01-03 - Granted: 2020-12-22 - Earliest claimed: 2015-12-18 - Assignees: Ignyta, Inc. - Applicants: Ignyta, Inc. - Inventors: Gang Li; Ge Wei; Zachary D. Hornby; Jonathan Ee-ren Lim - Web page: https://patentgrep.com/patent/US10869864B2 ## CPC - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol - A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) - A61K 31/365: Lactones - A61K 31/416: condensed with carbocyclic ring systems, e.g. indazole - A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline - A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof - A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) - A61K 31/4523: containing further heterocyclic ring systems - A61K 31/519: ortho- or peri-condensed with heterocyclic rings - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - C12Q 1/68: involving nucleic acids - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/156: Polymorphic or mutational markers - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES ## Abstract Described herein are combinations comprising a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is an inhibitor of ALK, ROS1, TrkA, TrkB, or TrkC activity, or a combination thereof, and methods of using such combinations in the treatment of patients having cancer. ## Claims ### Claim 1 A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a combination comprising a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, or a pharmaceutically acceptable salt thereof, and the second agent is a MEK inhibitor selected from the group consisting of PD0325901, selumetinib, cobimetinib, refametinib, trametinib, pimasertib, binimetinib, AZD8330, R04987655, GDC-0623, TAK-733, sorafenib, and PD-184352; the cancer is selected from non-small cell lung cancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer, melanoma, and colorectal cancer; the patient has at least one mutation in the TrkA receptor tyrosine kinase polypeptide; and the at least one mutation in the TrkA receptor tyrosine kinase polypeptide is at a position corresponding to amino acid residue G595 or G667 of the TrkA polypeptide set forth in SEQ ID NO: 1. ### Claim 2 (depends on 1) The method of claim 1, wherein the at least one mutation in the TrkA receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G595 of the TrkA polypeptide set forth in SEQ ID NO: 1. ### Claim 3 (depends on 2) The method of claim 2, wherein the at least one mutation in the TrkA receptor tyrosine kinase polypeptide is Glu-to-Arg substitution (G595R). ### Claim 4 (depends on 1) The method of claim 1, wherein the at least one mutation in the TrkA receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G667 of the TrkA polypeptide set forth in SEQ ID NO: 1. ### Claim 5 (depends on 4) The method of claim 4, wherein the at least one mutation in the TrkA receptor tyrosine kinase polypeptide is Glu-to-Cys substitution (G667C). ### Claim 6 A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a combination comprising a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, or a pharmaceutically acceptable salt thereof, and the second agent is a MEK inhibitor selected from the group consisting of PD0325901, selumetinib, cobimetinib, refametinib, trametinib, pimasertib, binimetinib, AZD8330, R04987655, GDC-0623, TAK-733, sorafenib, and PD-184352; the cancer is selected from non-small cell lung cancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer, melanoma, and colorectal cancer; the patient has at least one mutation in the TrkB receptor tyrosine kinase polypeptide; and the at least one mutation in the TrkB receptor tyrosine kinase polypeptide is at a position corresponding to amino acid residue G639 or G709 of the TrkB polypeptide set forth in SEQ ID NO: 2. ### Claim 7 (depends on 6) The method of claim 6, wherein the at least one mutation in the TrkB receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G639 of the TrkB polypeptide set forth in SEQ ID NO: 2. ### Claim 8 (depends on 7) The method of claim 7, wherein the at least one mutation in the TrkB receptor tyrosine kinase polypeptide is Glu-to-Arg substitution (G639R). ### Claim 9 (depends on 6) The method of claim 6, wherein the at least one mutation in the TrkB receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G709 of the TrkB polypeptide set forth in SEQ ID NO: 2. ### Claim 10 (depends on 9) The method of claim 9, wherein the at least one mutation in the TrkB receptor tyrosine kinase polypeptide is Glu-to-Cys substitution (G709C). ### Claim 11 A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a combination comprising a therapeutically effective amount of a first agent and a therapeutically effective amount of a second agent, wherein the first agent is N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, or a pharmaceutically acceptable salt thereof, and the second agent is a MEK inhibitor selected from the group consisting of PD0325901, selumetinib, cobimetinib, refametinib, trametinib, pimasertib, binimetinib, AZD8330, R04987655, GDC-0623, TAK-733, sorafenib, and PD-184352; the cancer is selected from non-small cell lung cancer, papillary thyroid cancer, neuroblastoma, pancreatic cancer, melanoma, and colorectal cancer; the patient has at least one mutation in the TrkC receptor tyrosine kinase polypeptide; and the at least one mutation in the TrkC receptor tyrosine kinase polypeptide is at a position corresponding to amino acid residue G623 or G696 of the TrkC polypeptide set forth in SEQ ID NO: 3. ### Claim 12 (depends on 11) The method of claim 11, wherein the at least one mutation in the TrkC receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G623 of the TrkC polypeptide set forth in SEQ ID NO: 3. ### Claim 13 (depends on 12) The method of claim 12, wherein the at least one mutation in the TrkC receptor tyrosine kinase polypeptide is Glu-to-Arg substitution (G623R). ### Claim 14 (depends on 11) The method of claim 11, wherein the at least one mutation in the TrkC receptor tyrosine kinase polypeptide is at the position corresponding to amino acid residue G696 of the TrkC polypeptide set forth in SEQ ID NO: 3. ### Claim 15 (depends on 14) The method of claim 14, wherein the at least one mutation in the TrkC receptor tyrosine kinase polypeptide is Glu-to-Cys substitution (G696C).