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
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.
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.