Milademetan Treatment Begins for MDM2-Mutated Solid Tumors in Phase 2 Basket Trial

The first patient has been dosed in the phase 2 basket trial of milademetan for MDM2-amplified advanced solid tumors, according to a press release by Rain Therapeutics.¹

Milademetan is an oral mouse MDM2 inhibitor that is meant for the treatment of MDM2-amplified solid tumors. A phase 1 clinical trial found that the agent demonstrated antitumor activity in an MDM2-amplified subtype of liposarcoma and other solid tumors.

“The opening of our phase 2 basket trial is a significant step forward in leveraging the safety profile of milademetan for patients with advanced tumors that exhibit wild-type p53 and amplified MDM2 who do not respond, or stop responding, to standard-of-care therapy,” said Richard Bryce, MBChB, chief medical officer of Rain Therapeutics in the press release.

The interventional, open-label study (NCT05012397) has a target enrollment of 65 participants and an estimated study completion date of August 2024. The primary end point is overall response rate. Secondary end points include duration of response, progression-free survival, growth modulation index, disease control rate, and overall survival.2

During the study, all patients will receive milademetan at a dose of 260 mg daily on days 1 to 3 and 15 to 17 of each 29-day cycle. Therapy will be continued until disease progression, unacceptable toxicity, or until other treatment discontinuation criteria are met. Treatment may be continued after progression occurs if the investigator determines the patient is experiencing clinical benefit.

In order to participate in the study, patients must be 18 years of age or older, have a confirmed diagnosis of a cancer that is locally advanced or metastatic solid tumor, measurable tumor lesions, have received all standard therapy that is appropriate for their tumor type and disease stage, have recovered from any clinical relevant toxic effects, an ECOG performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function.

Patients who received prior treatment with an MDM2 inhibitor, have a diagnosis of well-differentiated/dedifferentiated liposarcoma or initial sarcoma, a primary malignancy requiring systemic antineoplastic treatment within the past 2 years, a primary brain tumor, untreated brain metastases, gastrointestinal conditions that could affect the absorption of milademetan, known HIV infection, major surgery ≤ 3 weeks of the first dose of the study drug, curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy, or uncontrolled or significant cardiovascular disease are not eligible to participate.

“The Rain team has worked extraordinarily hard to now commence our second clinical trial for milademetan,” said Avanish Vellanki, chief executive officer of Rain Therapeutics, in the press release. “The MANTRA-2 study reflects our precision oncology focus to base our development strategy on the underlying biological drivers in cancer, now across a tumor-agnostic clinical trial. We have also identified a level of gene amplification of MDM2 that we believe will select for patients most likely to benefit.”

The study is currently recruiting at The University of Texas MD Anderson Cancer Center.

_REFERENCES:

_{1.Rain Therapeutics doses first patient in phase 2 basket trial of milademetan for MDM2-amplified advanced solid tumors (MANTRA-2). News release. Rain Therapeutics. November 19, 2021. Accessed November 23, 2021. https://bit.ly/3CHTG6B}

_{2.Milademetan in advanced/metastatic solid tumors. ClinicalTrials.gov. Accessed November 23, 2021. https://bit.ly/3oRIZJL}