The following is a summary of “A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid Tumors, or Lymphomas,” published in the March 2023 issue of Oncology by Gounder, et al.

For a study, researchers sought to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

It was a phase I study that included patients with advanced solid tumors or lymphomas who were administered milademetan orally once daily on 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, and secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were also performed.

A total of 107 patients were enrolled and received milademetan between July 2013 and August 2018. The most common grade 3/4 drug-related adverse events were thrombocytopenia (29.0%), neutropenia (15.0%), and anemia (13.1%), with respective rates at the recommended dose and schedule (260 mg once daily on days 1-3 and 15-17 every 28 days, i.e., 3/14 days) of 15.0%, 5.0%, and 0%. The disease control rate was 45.8% (95% CI, 36.1 to 55.7) across all cohorts (N = 107), and the 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.

Milademetan can be administered intermittently every 3 to 14 days while minimizing dose-limiting hematologic abnormalities. A randomized phase III trial has been triggered by notable single-agent activity with milademetan in dedifferentiated liposarcomas (MANTRA).

Reference: ascopubs.org/doi/full/10.1200/JCO.22.01285