MDM2 inhibitor shows efficacy in dedifferentiated liposarcomas, other cancers
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Key takeaways:
- Administration of the MDM2 inhibitor milademetan in an intermittent dosing schedule mitigated dose-limiting toxicities without reducing efficacy.
- Results showed notable activity in dedifferentiated liposarcomas.
Intermittent milademetan appeared effective and mitigated dose-limiting hematologic adverse events among patients with advanced solid tumors and lymphomas, according to study results published in Journal of Clinical Oncology.
The findings of the first-in-human phase 1 study laid the groundwork for a randomized phase 3 trial that will further assess the agent in patients with dedifferentiated liposarcomas.
Rationale and methodology
Milademetan (Rain Oncology) is a selective small-molecule murine double minute-2 (MDM2) inhibitor that activates p53 function at nanomolar concentrations in vitro, according to study background.
“In preclinical studies, milademetan induced p53-dependent apoptosis in human cancer cell lines and demonstrated antitumor activity in xenograft models of tumors with functional, wild-type p53,” Mrinal M. Gounder, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues wrote.
The first-in-human study included 107 patients diagnosed with various advanced cancer types between July 2013 and August 2018.
Researchers sought to examine the safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of 260 mg milademetan given orally once daily on either continuous (days 1 to 21 or 1 to 28, every 28 days) or intermittent schedules (days 1 to 7 or days 1 to 3 and 15 to 17, every 28 days).
Determining the recommended dose and schedule for a phase 2 trial served as the primary objective. Tumor response according to standard evaluation criteria served as a secondary objective.
Findings
The most common grade 3 to grade 4 treatment-associated adverse events with milademetan included thrombocytopenia (29%), neutropenia (15%) and anemia (13.1%). The rates at the recommended dose and schedule — 260 mg once a day on days 1-3 and 15-17 every 28 days — decreased to 15% for thrombocytopenia, 5% for neutropenia and zero for anemia.
Researchers additionally observed median PFS of 4 months (95% CI, 3.4-5.7) and a disease control rate of 45.8% (95% CI, 36.1-55.7) among all cohorts.
For the 53 patients with dedifferentiated liposarcomas, researchers observed an overall disease control rate of 58.5% (95% CI, 44.1-71.9) and median PFS of 7.2 months. For the 16 patients in that group on the recommended schedule, results showed a disease control rate of 62% (95% CI, 35.4-84.8) and median PFS of 7.4 months.
Limitations of the study included MDM2 amplification status not being required at study entry and performed only on a minority of patients, researchers noted.
Implications, next steps
The findings indicate “acceptable toxicity and activity in comparison with earlier trials of this class of anticancer agents, in which toxicity with continuous administration limited the ability to treat patients,” Gounder and colleagues wrote.
“MDM2 amplification is characteristic in well-differentiated and dedifferentiated liposarcoma and is also observed in a small fraction of other solid tumors, diagnoses that may benefit from this or similar agents,” they added. “On the basis of our observations, a randomized, phase III registration study (MANTRA; RAIN-3201) of milademetan vs. trabectedin [Yondelis; Janssen, PharmaMar] in patients with unresectable or metastatic [dedifferentiated liposarcoma] with disease progression on prior systemic therapies has recently started enrolling patients.”
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