Oral MDM2 Inhibitor Milademetan Enters Phase 3 Study for Patients with De-Differentiated Liposarcoma

A phase 3 study has been initiated in order to evaluate the efficacy of the oral MDM2 inhibitor milademetan (RAIN-32) for the treatment of de-differentiated liposarcoma (LPS), according to a press release by Rain Therapeutics.

MDM2 is an oncogene present in numerous cancers. The milademetan inhibitor has proven effective in a phase 1 trial on a MDM2-amplified subtype of LPS and other solid tumor types. The agent received an orphan drug designation from the FDA for its use in patients with LPS.

The phase 3 MANTRA study will be a randomized, multicenter, open-label, phase 3 registrational study with an aimed enrollment of 160 patients. Patients will be randomized 1:1 to receive either milademetan or trabectedin (Yondelis). The primary end points are progression-free survival (PFS) by blinded independent review. Secondary end points include overall survival, PFS by investigator assessment, objective response rate, duration of response, disease control rate, safety, and patients reported outcomes.

“The start of our phase 3 MANTRA study evaluating milademetan marks an important step forward in addressing a high unmet need for patients with de-differentiated LPS,” said Richard Bryce, MBChB, chief medical officer at Rain Therapeutics, in s statement. “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 phase 3 study comes on the heels of the phase 1 dose escalation and expansion study. Three patients have with well-differentiated or de-differentiated LPS have received milademetan monotherapy for more than 51 months as of July 1, 2021. Of those 3 patients, 1 patient continues to receive therapy at 51 months and 1 other continues to receive therapy at 57 months without disease progression. Another patient received therapy for more than 59 months before discontinuing treatment in the second quarter of 2021.

Plans to test the agent in combination with quizartinib (NCT03552029) with 5-azacitidine (Vidaza) (NCT02319369) are also underway.

The study of the agent in combination with quizartinib has a planned enrollment of 10 participants. The primary end points of the study include the number of participants with dose limiting toxicities, the number of participants with adverse events (AEs), and the number of participants who respond to treatment. Secondary end points include the maximum concentration of study drug in plasma.

During part 1 of the study, patients with relapsed/refractory FLT3-ITD-mutant acute myeloid leukemia (AML) at various doses and schedules. Part 2 will be split into 2 cohorts. In cohort 1, patients with AML will receive the recommended phase 2 dose. Cohort 2 will include AML patients who are unfit for chemotherapy.

That study is currently recruiting in California, Connecticut, Kansas, Michigan, New York, North Carolina, Pennsylvania, and Texas.

The study testing milademetan alone and in combination with 5-azacitidine has an actual enrollment of 74 participants. The primary end point of the study is the number of participants with dose-limiting toxicities, the number of patients with TEAEs, and participants who achieved a complete remission. Secondary end points include pharmacokinetics and pharmacodynamics.

Milademetan will be tested as both a monotherapy and combination at different dose levels.

_REFERENCE:

_{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. July 20, 2021. Accessed July 22, 2021. https://bit.ly/3xTUbsJ.}