Abstract P031: MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan (RAIN-32) versus trabectedin in patients with de-differentiated liposarcoma
Authors: Gounder Mrinal , Schwartz Gary , Jones Robin , Patel Shreyaskumar , Stacchiotti Silvia , Wagner Andrew , Tirunagaru Vijaya , Shah Naisargee , Bryce Richard , Doebele Robert 
Published: December 2021

Abstract
Background: p53 plays a central role in tumor suppression and maintenance of genome integrity. Murine double minute 2 (MDM2) is a ubiquitin ligase that inhibits p53 transcriptional activity and induces p53 degradation through ubiquitination. MDM2 amplification occurs in many cancers but is universal in well-differentiated (WD) or de-differentiated (DD) liposarcomas (100% of cases) [Cancer Genome Atlas Research Network. Cell 2017]. Current therapies for WD/DD liposarcomas include anthracycline-based chemotherapy, eribulin, and trabectedin. Inhibition of the MDM2-p53 interaction is a promising therapeutic approach to restore p53 tumor suppressor activity in liposarcomas. Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor that inhibits the MDM2-p53 interaction and restores p53 function at nanomolar concentrations. In a phase 1 study, milademetan showed promising efficacy in patients with WD/DD liposarcoma when administered on an intermittent schedule (260 mg on Days 1–3 and 15–17 every 28 days), with a median progression-free survival (PFS) of 7.4 months [Gounder et al. AACR-NCI-EORTC 2020]. MANTRA (RAIN-3201) is a randomized, multicenter, open-label, phase 3 registration study designed to evaluate the efficacy and safety of milademetan versus trabectedin in patients with unresectable or metastatic DD liposarcoma with disease progression on ≥1 prior systemic therapies, including ≥1 anthracycline-based regimen (EudraCT: 2021-001394-23). Methods: Eligible patients are ≥18 years of age with histologically confirmed unresectable and/or metastatic DD liposarcoma, with or without a WD component, who have received ≥1 prior systemic therapies, including ≥1 anthracycline-based regimen, with radiographic evidence of progression within 6 months before study entry. Prior treatment with trabectedin or an MDM2 inhibitor is not permitted. Patients will be randomly assigned (1:1) to receive milademetan (260 mg once daily orally Days 1–3 and 15–17 on a 28-day cycle) or trabectedin (1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks). Randomization is stratified by Eastern Cooperative Oncology Group performance status (0 or 1) and number of prior treatments for liposarcoma (≤2 or &gt;2). Tumor response will be evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: PFS by blinded independent central review. Secondary endpoints: overall survival; disease control rate; objective response rate; duration of response; PFS by investigator assessment; safety; health-related quality of life. Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%. MANTRA is currently open to enrollment.
Citation Format: Mrinal Gounder, Gary Schwartz, Robin Jones, Shreyaskumar Patel, Silvia Stacchiotti, Andrew Wagner, Vijaya Tirunagaru, Naisargee Shah, Richard Bryce, Robert Doebele. MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan (RAIN-32) versus trabectedin in patients with de-differentiated liposarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P031.