# US 2022/0031697 A1 · Dose and regimen for an hdm2-p53 interaction inhibitor in hematological tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2022/0031697 A1 - Document ID: US20220031697A1 - Status: Published application - Kind: A1 - Application number: 17/401,600 - Filed: 2021-08-13 - Published: 2022-02-03 - Earliest claimed: 2017-03-31 - Assignees: Novartis AG - Applicants: Novartis AG - Inventors: Stephane FERRETTI; Nelson GUERREIRO; Sebastien JEAY; Astrid JULLION; Christophe MEILLE; Jens WUERTHNER; Claire Fabre - Web page: https://patentgrep.com/patent/US20220031697A1 ## CPC - A61K 31/506: not condensed and containing further heterocyclic rings - A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine - A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom - A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - 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 present invention relates to the HDM2-p53 interaction inhibitors (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one (HDM201), or a pharmaceutically acceptable non-covalent derivative thereof, for use in the treatment of patients with hematological tumors, wherein the drug is administered by an extended low dose dosing regimen. ## Claims ### Claim 1 A method of treating a hematological tumor comprising administering (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or a pharmaceutically acceptable non-covalent derivative thereof on each of the first 6 to 8 days of a 28 days treatment cycle, for at least two 28 days treatment cycles, and wherein the daily dose of (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one is from 40 mg to 90 mg. ### Claim 2 (depends on 1) The method according to claim 1, wherein the daily dose is from 40 mg to 60 mg. ### Claim 3 (depends on 1) The method according to claim 1, wherein the daily dose is from 40 mg to 50 mg. ### Claim 4 (depends on 1) The method according to claim 1, wherein the daily dose is 45 mg. ### Claim 5 (depends on 1) The method according to claim 1, wherein the (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or a pharmaceutically acceptable non-covalent derivative thereof is administered once daily on each of the first 7 days of the 28 days treatment cycle and the daily dose is 45 mg. ### Claim 6 (depends on 1) The method according to claim 1, wherein the (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or a pharmaceutically acceptable non-covalent derivative thereof is present as a co-crystal. ### Claim 7 (depends on 1) The method according to claim 1, wherein the (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or a pharmaceutically acceptable non-covalent derivative thereof is present as a solvate. ### Claim 8 (depends on 1) The method according to claim 1, wherein the (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one or a pharmaceutically acceptable non-covalent derivative thereof is present as a non-covalent derivative comprising succinic acid or water. ### Claim 9 (depends on 1) The method according to claim 1, wherein the hematological tumor is a leukemia. ### Claim 10 (depends on 1) The method according to claim 1, wherein the hematological tumor is selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL). ### Claim 11 (depends on 1) The method according to claim 1, wherein the hematological tumor is a TP53 wild-type hematological tumor. ### Claim 12 (depends on 1) The method according to claim 1, wherein the hematological tumor is a relapsed/refractory hematological tumor. ### Claim 13 (depends on 1) The method according to claim 1, wherein the hematological tumor is a relapsed/refractory TP53 wild-type hematological tumor selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL). ### Claim 14 A method of treating a relapsed/refractory TP53 wild-type hematological tumor selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL), comprising administering (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one as a succinic acid co-crystal on each of the first 7 days of a 28 days treatment cycle for at least two 28 days treatment cycles, and wherein the daily dose of (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one is 45 mg. ### Claim 15 A method of treating relapsed/refractory TP53 wild-type acute myeloid leukemia (AML) comprising administering (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one as a succinic acid co-crystal on each of the first 7 days of a 28 days treatment cycle, for at least two 28 days treatment cycles, and wherein the daily dose of (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one is 45 mg. ### Claim 16 (depends on 1) The method according to claim 1, further comprising administering one or more other anti-cancer agents selected from: FLT3 inhibitors, BCL2 inhibitors, HDM2 inhibitors, hypomethylating agents, anthracyclines, and anti-CD33 antibodies. ### Claim 17 (depends on 1) The method according to claim 1, further comprising administering one or more other therapeutically active agents selected from midostaurin, azacytidine, and cytarabine. ### Claim 18 (depends on 1) The method according to claim 1, further comprising administering one or more other anti-cancer agents selected from gilterinib, quizartinib, midostaurin, navitoclax, venetoclax, idasanutlin, AMG232, DS-3032B, ALRN6924/ATSP7041, azacytidine, 5-azacytidine, decitabine, guadecitabine, idarubicin, daunorubicin, doxorubicin, epirubicin, gemtuzumab, vadastuximab, cytarabine, and aracytine. ### Claim 19 (depends on 6) The method according to claim 6, wherein the co-crystal is a succinic acid co-crystal. ### Claim 20 (depends on 7) The method according to claim 7, wherein the solvate is a hydrate.