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

PURPOSE:

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.

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Eytan M Stein, Daniel J DeAngelo, Jörg Chromik, Manik Chatterjee, Sebastian Bauer, Chia-Chi Lin, Cristina Suarez, Filip de Vos, Neeltje Steeghs, Philippe A Cassier, David Tai, Jean-Jacques Kiladjian, Noboru Yamamoto, Rogier Mous, Jordi Esteve, Hironobu Minami, Stephane Ferretti, Nelson Guerreiro, Christophe Meille, Rajkumar Radhakrishnan, Bernard Pereira, Luisa Mariconti, Ensar Halilovic, Claire Fabre, Cecilia Carpio
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 5 Pg. 870-881 (Mar 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 34862243 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Imidazoles
• Pyrimidines
• Pyrroles
• TP53 protein, human
• Tumor Suppressor Protein p53
• siremadlin

Topics

• Dose-Response Relationship, Drug
• Hematologic Neoplasms (drug therapy, genetics)
• Humans
• Imidazoles
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Maximum Tolerated Dose
• Neoplasms (drug therapy)
• Pyrimidines
• Pyrroles
• Tumor Suppressor Protein p53 (genetics)