Article

MDM2 Inhibitor Milademetan Under Examination in Dedifferentiated Liposarcoma

Author(s):

The safety and efficacy of the oral MDM2 inhibitor milademetan is under investigation vs trabectedin, a current standard of care, in the treatment of patients with dedifferentiated liposarcoma as part of the recently initiated phase 3 MANTRA trial.

Richard Bryce, MBChB

Richard Bryce, MBChB

The safety and efficacy of the oral MDM2 inhibitor milademetan (RAIN-32) is under investigation vs trabectedin, a current standard of care, in the treatment of patients with dedifferentiated liposarcoma as part of the recently initiated phase 3 MANTRA trial, according to an announcement from Rain Therapeutics, Inc.1

MDM2 plays an important role in regulating tumor protein 53 (p53), which controls the cell cycle; this protein is critical to achieve tumor suppression.2 When MDM2 is overexpressed, p53 can be inactivated, which can result in tumor growth and disease progression. Milademetan inhibits MDM2, and it is hypothesized to reactivate p53, which can then continue to assist in controlling the disease.

The differentiated profile of the agent enables a dosing schedule that could preserve activity, while reducing toxicities. The investigational drug is under development for use in patients with MDM2-amplified or overexpressed cancers.

“The start of the phase 3 MANTRA study evaluating milademetan marks an important step forward in addressing a high unmet need for patients with dedifferentiated liposarcoma,” Richard Bryce, MBChB, chief medical officer at Rain Therapeutics, Inc., stated in a press release. “We are proud to have advanced milademetan into a pivotal study less than 12 months after acquiring the program, and believe it has the potential to be the best-in-class MDM2 inhibitor.”

The multicenter, open-label, phase 3 trial will enroll patients with unresectable or metastatic dedifferentiated liposarcoma with or without a well-differentiated liposarcoma component. To be eligible for enrollment, patients will need to have progressed on 1 or more previous systemic therapies, including at least 1 anthracycline-based therapy.

Investigators expect to enroll about 160 participants to the trial. Patients will then be randomized 1:1 to receive either the MDM2 inhibitor or trabectedin. The primary end point of the trial is progression-free survival (PFS) per blinded independent review. Key secondary end points comprise overall survival, investigator-assessed PFS, objective response rate, duration of response, disease control rate, safety, and patient-reported outcomes.

The safety of milademetan was evaluated in a phase 1 dose-escalation and expansion study. Here, the agent was examined across 4 dose schedules in a total of 107 patients with liposarcoma, solid tumors, or lymphomas.

Data previously presented during the 32nd EORTC-NCI-AACR Virtual Symposium showed that an intermittent dosing schedule (Schedule D) allowed for the highest maximum-tolerated dose for the agent, which was 260 mg, vs the more continuous dose schedules that were examined (Schedules A, B, and C).3

Schedule D was found to confer a numerical improvement in PFS vs the continuous dosing schedules. Among 17 evaluable patients who received Schedule D at doses up to 260 mg, the median PFS with the agent was 8.0 months. As such, this schedule was determined to be the dose and schedule for examination in future studies.

Notably, tumor shrinkage and objective responses were also reported in selected patients with non-liposarcoma and MDM2 gene amplification, which could indicate potential for future agnostic clinical trials utilizing biomarker selection.

Additionally, Schedule D was found to have a more favorable toxicity profile vs the other dosing schedules examined. The incidence of all grade 3 or higher treatment-emergent adverse effects (AEs) in the Schedule D cohort (n = 20) was just 20% vs 55% in the Schedules A, B, and C cohorts (n = 78).

Reductions in the incidence of grade 3 or higher thrombocytopenia, neutropenia, and anemia, were also reported with Schedule D vs Schedules A, B, and C. These rates were reduced from 35%, 18%, and 10%, respectively, to 15%, 5%, and 0%, respectively. Notably, no grade 4 or 5 AEs were reported in those who received the 260-mg dose in Schedule D.

Updated data from this trial showed that as of July 1, 2021, 3 patients with well-differentiated/ dedifferentiated liposarcoma received single-agent milademetan for longer than 51 months. Two of these patients are still receiving therapy with durations at 51 months and 57 months; these patients have not experienced progressive disease. An additional patient received treatment for longer than 59 months prior to discontinuation in the second quarter of 2021.

These data underscore potential long-term tolerability and safety with the agent, according to Rain Therapeutics, Inc.

References

  1. Rain Therapeutics initiates phase 3 MANTRA clinical trial of milademetan for de-differentiated liposarcoma and provides patient update from prior clinical program. News release. Rain Therapeutics, Inc. July 20, 2021. Accessed July 21, 2021. https://bit.ly/3hUEr3b
  2. Pipeline. Rain Therapeutics, Inc. Accessed July 21, 2021. https://bit.ly/3hRU1fM
  3. Rain Therapeutics announces a phase 1 trial update for the MDM2 inhibitor, RAIN-32, at the 32nd EORTC-NCI-AACR Virtual Symposium. News release. Rain Therapeutics, Inc. October 26, 2020. Accessed July 21, 2021. https://bit.ly/3kFy59s

Related Videos
Javier Martín Broto MD, PhD
Breelyn Wilky, director, Sarcoma Medical Oncology, The Cheryl Bennett and McNeilly Family Endowed Chair in Sarcoma Research, deputy associate director, Clinical Research, associate professor, medicine, medical oncology, the University of Colorado Medicine
R. Lor Randall, MD, FACS
Ciara Kelly, MBBCh, BAO
Mark Agulnik, MD
Hannah Walker-Mimms, MS
Christina L. Roland, MD, MS, FACS
Christina L. Roland, MD, MS, FACS
Meredith McKean, MD, MPH
Damon R. Reed, MD