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Ref Type Journal Article
PMID (34862243)
Authors Stein EM, DeAngelo DJ, Chromik J, Chatterjee M, Bauer S, Lin CC, Suarez C, de Vos F, Steeghs N, Cassier PA, Tai D, Kiladjian JJ, Yamamoto N, Mous R, Esteve J, Minami H, Ferretti S, Guerreiro N, Meille C, Radhakrishnan R, Pereira B, Mariconti L, Halilovic E, Fabre C, Carpio C
Title Results from a First-in-Human Phase I Study of Siremadlin (HDM201) in Patients with Advanced Wild-Type TP53 Solid Tumors and Acute Leukemia.
Abstract Text This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers.Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1.Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively.A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 wild-type acute myeloid leukemia predicted - sensitive Siremadlin Phase I Actionable In a Phase I trial, Siremadlin (HDM201) treatment demonstrated safety and resulted in overall response rates of 4.2% (1/24), 20% (3/15), and 22.2% (6/27) for the recommended expansion doses of 120 mg, 250 mg, and 45 mg, respectively, in patients with TP53 wild-type acute myeloid leukemia (PMID: 34862243; NCT02143635). 34862243
TP53 wild-type Advanced Solid Tumor predicted - sensitive Siremadlin Phase I Actionable In a Phase I trial, Siremadlin (HDM201) treatment demonstrated safety and resulted in an overall response rate (ORR) of 3.5% (4/115; all partial responses) and disease control rate (DCR) of 36.5% in patients with TP53 wild-type advanced solid tumors, and at the recommended dose for expansion (120 mg), resulted in an ORR of 10.5% (3/29) and DCR of 44.8% in all patients, and a DCR of 83.3% (10/12) in patients with liposarcoma (PMID: 34862243; NCT02143635). 34862243