In a first-in-human, phase I, dose-escalation and dose-expansion study reported in the Journal of Clinical Oncology, Mrinal M. Gounder, MD, and colleagues identified the dose and schedule for further evaluation of the oral MDM2 inhibitor milademetan in a population of patients with advanced liposarcoma, solid tumors, or lymphoma. The researchers found that the agent was particularly active in patients with dedifferentiated liposarcoma.
Milademetan is a small-molecule inhibitor of the MDM2-p53 interaction, allowing activation of p53 tumor-suppressor activity.
Mrinal M. Gounder, MD
Study Details
A total of 107 patients (87 in the dose-escalation phase and 20 in the dose-expansion phase) were enrolled in the trial between July 2013 and August 2018. In the dose-escalation phase, patients received milademetan at doses of 15 mg to 340 mg once daily across four schedules of 28-day cycles: on days 1 to 21; on days 1 to 28; on days 1 to 7; and on days 1 to 3 and 15 to 17. Among all 107 patients, 53 had dedifferentiated liposarcoma (a population known to be enriched for MDM2 amplification and wild-type TP53), 22 had melanoma, 4 had lymphoma, 3 had osteosarcoma, and 25 had other malignancies. Overall, 79% of patients had stage IV disease and 62% had received three or more prior systemic therapies.
Key Findings
The dose and schedule recommended for further evaluation was 260 mg once daily on days 1 to 3 and 15 to 17 every 28 days.
Among all patients, the most common grade 3 or 4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%); at the recommended dose and schedule, respective rates were 15.0%, 5.0%, and 0%.
Among all patients, the disease control rate was 45.8% (95% confidence interval [CI] = 36.1%–55.7%) and median progression-free survival was 4.0 months (95% CI = 3.4–5.7 months).
Among the 53 patients with dedifferentiated liposarcoma, the disease control rate was 58.5% (95% CI = 44.1%–71.9%) and median progression-free survival was 7.2 months (95% CI = 3.8–10.1 months). Among the 16 who received the recommended dose and schedule, the disease control rate was 62.0% (95% CI = 35.4%–84.8%) and median progression-free survival was 7.4 months (95% CI = 1.8–14.6 months).
The investigators concluded: “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).”
David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Daiichi Sankyo Inc. For full disclosures of the study authors, visit ascopubs.org.
