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A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid
Mrinal M Gounder1, Todd M Bauer2, Gary K Schwartz3
1Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY.
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).
Insights
Milademetan, an MDM2 inhibitor, showed efficacy in advanced cancers, particularly dedifferentiated liposarcomas. An intermittent 3/14-day schedule reduced side effects, supporting further trials.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Murine double minute-2 (MDM2) is a key regulator of the tumor suppressor p53.
- Inhibiting MDM2 can restore p53 function, offering a therapeutic strategy for various cancers.
- Milademetan is a novel small-molecule inhibitor targeting MDM2.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan in patients with advanced cancers.
- To determine the recommended phase II dose and schedule for milademetan therapy.
Main Methods:
- A first-in-human phase I study enrolled 107 patients with advanced solid tumors or lymphomas.
- Patients received oral milademetan on various extended/continuous or intermittent schedules.
- Safety, pharmacokinetics, pharmacodynamics, and tumor response were assessed.
Main Results:
- The recommended intermittent dose was 260 mg once daily on days 1-3 and 15-17 every 28 days.
- Grade 3/4 drug-related adverse events, including thrombocytopenia, neutropenia, and anemia, were reduced at the recommended dose.
- Overall disease control rate was 45.8% and median progression-free survival was 4.0 months.
- In dedifferentiated liposarcoma patients, the disease control rate was 58.5% and median progression-free survival was 7.2 months.
Conclusions:
- An intermittent 3/14-day dosing schedule of milademetan effectively mitigates dose-limiting hematologic toxicities.
- Milademetan demonstrated notable single-agent activity in dedifferentiated liposarcomas.
- These findings led to a randomized phase III trial (MANTRA) for liposarcoma.
