# US 12,109,221 B2 · Combination therapy for treating cancer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,109,221 B2 - Document ID: US12109221B2 - Status: Granted - Kind: B2 - Application number: 17/818,841 - Filed: 2022-08-10 - Published: 2023-04-20 - Granted: 2024-10-08 - Earliest claimed: 2017-01-16 - Assignees: Leukos Biotech, S.L.; Fundació Institut De Recerca Contra La LeucèMia Josep Carreras - Applicants: Leukos Biotech, S.L.; Fundació Institut De Recerca Contra La LeucèMia Josep Carreras - Inventors: Ruth Muñoz Risueño; Mari Carmen Lara Castillo; Amaia Etxabe Alberdi - Web page: https://patentgrep.com/patent/US12109221B2 ## CPC - A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines - A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61K 31/4965: Non-condensed pyrazines - A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole - A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom - A61P 35/02: specific for leukemia - 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 ## Abstract The invention relates to a combination comprising an antineoplastic agent, e.g. an antimetabolite antineoplastic agent and a type 1 serotonin receptor (HTR1) modulator, e.g. a HTR1 antagonist. In addition the invention relates to a pharmaceutical composition comprising a combination of the invention and a pharmaceutically acceptable excipient. The invention also relates to the combination and pharmaceutical composition according to the invention for use in medicine, particularly for use in the prevention and/or treatment of a hematological malignancy. ## Claims ### Claim 1 A synergistic combination for the treatment of a hematological malignancy comprising (a) an ATC/DDD L01B antimetabolite; and (b) a type 1A or type 1B HTR serotonin receptor (HTR1A or HTR1B) small molecule antagonist, at a molar ratio of HTR1A or HTR1B small molecule antagonist to ATC/DDD L01B antimetabolite between (i) 500:1 and 2:1 when the ATC/DDD L01B antimetabolite is a pyrimidine analogue; (ii) 1000:1 and 5:1 when the ATC/DDD L01B antimetabolite is a purine analogue; or (iii) 4000:1 to 400:1 when the ATC/DDD L01B antimetabolite is a folic acid analogue; wherein the synergistic combination comprising the ATC/DDD L01B antimetabolite and the HTR1A or HTR1B small molecule antagonist is capable of synergistically killing hematological malignancy cells expressing HTR1A or HTR1B. ### Claim 2 (depends on 1) The synergistic combination of claim 1, wherein the ATC/DDD L01B antimetabolite is a folic acid analogue selected from the group consisting of methotrexate, raltitrexed, pemetrexed, and pralatrexate. ### Claim 3 (depends on 1) The synergistic combination of claim 1, wherein the ATC/DDD L01B antimetabolite is a pyrimidine analogue selected from the group consisting of cytarabine, fluorouracil, tegafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, and trifluridine. ### Claim 4 (depends on 1) The synergistic combination of claim 1, wherein the ATC/DDD L01B antimetabolite is a purine analogue selected from the group consisting of mercaptopurine, tioguanine, cladribine, fludarabine, clofarabine, and nelarabine. ### Claim 5 (depends on 1) A pharmaceutical composition comprising a synergistic combination of claim 1 and a pharmaceutically acceptable excipient. ### Claim 6 (depends on 1) A method for treating a hematological malignancy comprising administering a synergistic combination of claim 1 to a subject in need thereof. ### Claim 7 (depends on 6) The method of claim 6, wherein the hematological malignancy is a myeloid neoplasm. ### Claim 8 (depends on 7) The method of claim 7, wherein the myeloid neoplasm is acute myeloid leukemia. ### Claim 9 (depends on 6) The method of claim 6, wherein the hematological malignancy is selected from the group consisting of a myelodysplastic syndrome and a myeloproliferative syndrome. ### Claim 10 (depends on 6) The method of claim 6, wherein the ATC/DDD L01B antimetabolite and the HTR1A or HTR1B small-molecule drug antagonist are administered independently or at the same time. ### Claim 11 (depends on 6) The method of claim 6, wherein the HTR1A or HTR1B small-molecule drug antagonist is in an amount between 0.1 mg/m2 and 100 mg/m2. ### Claim 12 A dosage form comprising a synergistic combination of (a) an ATC/DDD L01B antimetabolite; and (b) a type 1A or type 1B HTR serotonin receptor (HTR1A or HTR1B) small molecule antagonist, at a molar ratio of HTR1A or HTR1B small molecule antagonist to ATC/DDD L01B antimetabolite between (i) 500:1 and 2:1 when the ATC/DDD L01B antimetabolite is a pyrimidine analogue; (ii) 1000:1 and 5:1 when the ATC/DDD L01B antimetabolite is a purine analogue; or (iii) 4000:1 to 400:1 when the ATC/DDD L01B antimetabolite is a folic acid analogue; wherein the synergistic combination comprising the ATC/DDD L01B antimetabolite and the HTR1A or HTR1B small molecule antagonist is capable of synergistically killing hematological malignancy cells expressing HTR1A or HTR1B. ### Claim 13 (depends on 12) The dosage form of claim 12, wherein the HTR1A or HTR1B small-molecule drug antagonist is in an amount between 0.1 mg/m2 and 100 mg/m2. ### Claim 14 (depends on 12) The dosage form of claim 12, wherein the dosage form is suitable for intravenous administration. ### Claim 15 (depends on 14) The dosage form of claim 14, wherein the intravenous administration is by infusion or by bolus injection.