Clinical trials on MDM2 inhibitors in hematological malignancies including responses and toxicities
| Type of MDM2 inhibitor . | Trial name . | Response rates . | Toxicity . | Reference NCT number . |
|---|---|---|---|---|
| RG7112 | A study of RO5045337 (RG7112) in patients with hematological neoplasms | For acute leukemias, at maximum tolerated dose: CR, 6.1%; CRp, 3.0%; and PR, 6.1% | Nausea, 71%; diarrhea, 60%; vomiting, 41%; febrile neutropenia, 30%; fatigue, 29%; abdominal pain, 28%; and hypokalemia, 26% | Andreeff et al45 NCT00623870 |
| MK-8242 | Study of MK-8242 alone and in combination with cytarabine in participants AML (P07649) | 1 PR (4%), 1 CRri (4%) | Diarrhea, 23%; nausea, 42%; vomiting, 34%; fatigue, 19%; and decreased appetite, 23%. | Ravandi et al46 NCT01451437 |
| Idasanutlin | Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial | CR rates, all dosages: 26.0% CR rates, idasanutlin 150/200 mg: 34.3% IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity | Diarrhea, 87%; nausea, 74%; vomiting, 52%; hypokalemia, 50%; and febrile neutropenia, 45% | Daver et al47 NCT02670044 |
| Idasanutlin | A study of RO5503781 as a single agent or in combination with cytarabine in participants with AML | CR rates: 18.9% with monotherapy and 35.6% with combination therapy | Gastrointestinal side effects, 90%. | Yee et al48 NCT01773408 |
| RO6839921 (an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin) | A study of the safety and pharmacokinetics of RO6839921, an MDM2 antagonist, in patients with advanced cancers, including AML | CR, 3.8%; CRp, 0%; CRi/MLFS, 3.8%; and PR, 7.7% Maximum tolerated dose: 200 mg DLTs at 250 mg (2 of 8 patients) and 300 mg (2 of 5) | Nausea, 57%; decreased appetite, 53%; febrile neutropenia, 53%; diarrhea, 50%; hypomagnesemia, 50%; and hypokalemia, 42.3% | Uy et al49 NCT02098967 |
| Idasanutlin | A study of idasanutlin with cytarabine vs cytarabine plus placebo in participants with relapsed or refractory AML (MIRROS) | Overall response rate (CR + Crp + CRi) was 38.8% (combination therapy) vs 22.0% (monotherapy) CR, 20.3% combination therapy vs 17.1% monotherapy; CRp, 9.9% combination therapy vs 3.3% monotherapy; Cri, 8.6% combination therapy vs 1.6% monotherapy | Common any-grade adverse events (combination therapy vs monotherapy): diarrhea, 87% vs 32%; febrile neutropenia, 52.8 vs 49.3%; and nausea, 52.5% vs 31.5% | Konopleva et al8 NCT02545283 |
| Siremadlin | Study to determine and evaluate a safe and tolerated dose of HDM201 in patients with selected advanced tumors that are TP53wt | CR rates, all dosages: 5.5%; Cri, 7.7% Responses were 4.2% (CR, n = 1), 20% (CR, n = 1; and Cri, n = 2), and 22.2% (CR, n = 2; and CRi, n = 4) in those treated at the identified RDEs in high-dose 1B, high-dose 1A, and low-dose 2C, respectively | Nausea, 44%; vomiting, 18%; decreased appetite, 17%; anemia, 42%; neutropenia, 28%; thrombocytopenia, 43%; fatigue, 13%; and tumor lysis syndrome, 24% | Stein et al50 NCT02143635 |
| Milademetan | Study of milademetan in Japanese patients with relapsed or refractory AML | None of the 12 patients in the efficacy analysis set had CR, CRh, CRi, or PR at 90, 120, or 160 mg doses of milademetan | Decreased appetite, 64%; nausea, 42%; anemia, 35%; thrombocytopenia, 28%; pneumonia, 28%; hypokalemia, 28%; and vomiting, 28% | Sekiguchi et al51 NCT03671564 |
| AMG 232 | A phase 1b study evaluating AMG 232 alone and in combination with trametinib in AML | CR rate: monotherapy, 0%; combination therapy, 3% PR rate: monotherapy, 0%; combination therapy, 3% MLFS rate: monotherapy, 11%; combination therapy, 0% | Nausea, 58%; diarrhea, 56%; vomiting, 33%; decreased appetite, 25%; anemia, 22%; leukopenia, 17%; thrombocytopenia, 17%; and fatigue, 14% | Erba et al52 NCT02016729 |
| APR-246 (PRIMA-1(MET)) | Safety study of APR-246 in patients with refractory hematological cancer or prostate cancer | Entities: AML, CML, T-prolymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, and prostate cancer | Fatigue, dizziness, headache, confusion, and other neurologic AEs such as muscle spasms and sensory disturbances | Lehmann et al53 NCT00900614 |
| Type of MDM2 inhibitor . | Trial name . | Response rates . | Toxicity . | Reference NCT number . |
|---|---|---|---|---|
| RG7112 | A study of RO5045337 (RG7112) in patients with hematological neoplasms | For acute leukemias, at maximum tolerated dose: CR, 6.1%; CRp, 3.0%; and PR, 6.1% | Nausea, 71%; diarrhea, 60%; vomiting, 41%; febrile neutropenia, 30%; fatigue, 29%; abdominal pain, 28%; and hypokalemia, 26% | Andreeff et al45 NCT00623870 |
| MK-8242 | Study of MK-8242 alone and in combination with cytarabine in participants AML (P07649) | 1 PR (4%), 1 CRri (4%) | Diarrhea, 23%; nausea, 42%; vomiting, 34%; fatigue, 19%; and decreased appetite, 23%. | Ravandi et al46 NCT01451437 |
| Idasanutlin | Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial | CR rates, all dosages: 26.0% CR rates, idasanutlin 150/200 mg: 34.3% IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity | Diarrhea, 87%; nausea, 74%; vomiting, 52%; hypokalemia, 50%; and febrile neutropenia, 45% | Daver et al47 NCT02670044 |
| Idasanutlin | A study of RO5503781 as a single agent or in combination with cytarabine in participants with AML | CR rates: 18.9% with monotherapy and 35.6% with combination therapy | Gastrointestinal side effects, 90%. | Yee et al48 NCT01773408 |
| RO6839921 (an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin) | A study of the safety and pharmacokinetics of RO6839921, an MDM2 antagonist, in patients with advanced cancers, including AML | CR, 3.8%; CRp, 0%; CRi/MLFS, 3.8%; and PR, 7.7% Maximum tolerated dose: 200 mg DLTs at 250 mg (2 of 8 patients) and 300 mg (2 of 5) | Nausea, 57%; decreased appetite, 53%; febrile neutropenia, 53%; diarrhea, 50%; hypomagnesemia, 50%; and hypokalemia, 42.3% | Uy et al49 NCT02098967 |
| Idasanutlin | A study of idasanutlin with cytarabine vs cytarabine plus placebo in participants with relapsed or refractory AML (MIRROS) | Overall response rate (CR + Crp + CRi) was 38.8% (combination therapy) vs 22.0% (monotherapy) CR, 20.3% combination therapy vs 17.1% monotherapy; CRp, 9.9% combination therapy vs 3.3% monotherapy; Cri, 8.6% combination therapy vs 1.6% monotherapy | Common any-grade adverse events (combination therapy vs monotherapy): diarrhea, 87% vs 32%; febrile neutropenia, 52.8 vs 49.3%; and nausea, 52.5% vs 31.5% | Konopleva et al8 NCT02545283 |
| Siremadlin | Study to determine and evaluate a safe and tolerated dose of HDM201 in patients with selected advanced tumors that are TP53wt | CR rates, all dosages: 5.5%; Cri, 7.7% Responses were 4.2% (CR, n = 1), 20% (CR, n = 1; and Cri, n = 2), and 22.2% (CR, n = 2; and CRi, n = 4) in those treated at the identified RDEs in high-dose 1B, high-dose 1A, and low-dose 2C, respectively | Nausea, 44%; vomiting, 18%; decreased appetite, 17%; anemia, 42%; neutropenia, 28%; thrombocytopenia, 43%; fatigue, 13%; and tumor lysis syndrome, 24% | Stein et al50 NCT02143635 |
| Milademetan | Study of milademetan in Japanese patients with relapsed or refractory AML | None of the 12 patients in the efficacy analysis set had CR, CRh, CRi, or PR at 90, 120, or 160 mg doses of milademetan | Decreased appetite, 64%; nausea, 42%; anemia, 35%; thrombocytopenia, 28%; pneumonia, 28%; hypokalemia, 28%; and vomiting, 28% | Sekiguchi et al51 NCT03671564 |
| AMG 232 | A phase 1b study evaluating AMG 232 alone and in combination with trametinib in AML | CR rate: monotherapy, 0%; combination therapy, 3% PR rate: monotherapy, 0%; combination therapy, 3% MLFS rate: monotherapy, 11%; combination therapy, 0% | Nausea, 58%; diarrhea, 56%; vomiting, 33%; decreased appetite, 25%; anemia, 22%; leukopenia, 17%; thrombocytopenia, 17%; and fatigue, 14% | Erba et al52 NCT02016729 |
| APR-246 (PRIMA-1(MET)) | Safety study of APR-246 in patients with refractory hematological cancer or prostate cancer | Entities: AML, CML, T-prolymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, and prostate cancer | Fatigue, dizziness, headache, confusion, and other neurologic AEs such as muscle spasms and sensory disturbances | Lehmann et al53 NCT00900614 |
AEs, adverse events; CML, chronic myeloid leukemia; CR, complete remission; CRh, complete remission with hematological recovery; CRi, complete remission with incomplete recovery of peripheral counts; DLTs, dose-limiting toxicities; MLFS, morphological leukemia-free state; PR, partial remission; RDE, recommended dose for expansion.