Faculty, Staff and Student Publications

Language

English

Publication Date

3-20-2023

Journal

Journal of Clinical Oncology

DOI

10.1200/JCO.22.01285

PMID

36669146

PMCID

PMC10022862

PubMedCentral® Posted Date

1-20-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Purpose: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patients and methods: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and efficacy analyses included all patients who received milademetan.

Results: Between July 2013 and August 2018, 107 patients were enrolled and received milademetan. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%). Respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, ie, 3/14 days) were 15.0%, 5.0%, and 0%. Across all cohorts (N = 107), the disease control rate was 45.8% (95% CI, 36.1 to 55.7) and median progression-free survival was 4.0 months (95% CI, 3.4 to 5.7). In the subgroup with dedifferentiated liposarcomas, the disease control rate and median progression-free survival were 58.5% (95% CI, 44.1 to 71.9) and 7.2 months overall (n = 53), and 62.0% (95% CI, 35.4 to 84.8) and 7.4 months with the recommended intermittent schedule (n = 16), respectively.

Conclusion: An intermittent dosing schedule of 3/14 days of milademetan mitigates dose-limiting hematologic abnormalities while maintaining efficacy. Notable single-agent activity with milademetan in dedifferentiated liposarcomas has prompted a randomized phase III trial (MANTRA).

Keywords

Humans, Animals, Mice, Neoplasms, Antineoplastic Agents, Lymphoma, Pyridines, Liposarcoma, Maximum Tolerated Dose, Proto-Oncogene Proteins c-mdm2, Indoles, Pyrrolidines

Comments

Trial registration: ClinicalTrials.gov NCT01877382.

Published Open-Access

yes

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