Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor being developed for the treatment of MDM2-dependent, TP53-wildtype tumors. In a first-in-human phase I study, milademetan showed promising clinical activity in dedifferentiated liposarcomas (DDLPS). An intermittent schedule (3/14d) was identified to address on-target cytopenic toxicities and recommended for future clinical development. Two other studies of milademetan are in progress: MANTRA, a randomized phase III study of milademetan vs trabectedin in unresectable/metastatic DDLPS with progression on ≥1 prior systemic therapies; and MANTRA-2, a phase II basket study of milademetan in MDM2-amplified TP53-wildtype advanced solid tumors. We present an overview of milademetan safety data from phase I and II studies and guidance on management of key AEs.
Phase I: Patients with advanced solid tumors received milademetan qd via four schedules (21/28d; 28/28d; 7/28d; 3/14d). MANTRA-2: patients with MDM2-amplified TP53-wildtype solid tumors received milademetan 260 mg qd 3/14d. Management recommendations were based on clinical experience from different centers (n=9).
Milademetan safety is characterized by hematological and gastrointestinal AEs (Table). The optimum schedule was the intermittent dosing (3/14d) schedule. Preliminary phase II data are consistent with phase I findings. No bleeding events were reported. Data are treatment-related AEs. aData cutoff: 26 Oct 2022 b21/28 days; 28/28 days; 7/28 days
Phase I Phase II (MANTRA-2)a Other schedulesb (n=78) 3/14 days 260 mg (n=20) 3/14 days 260 mg (n=15) All grade Grade ≥3 All grade Grade ≥3 All grade Grade ≥3 Hematological, % Thrombocytopenia 67 35 45 15 27 20 Anemia 42 18 20 0 7 0 Neutropenia 29 19 10 5 7 7 Non-hematological, % Nausea 73 3 80 0 20 0 Vomiting 28 3 50 5 27 0 Diarrhea 33 0 25 0 13 0
Milademetan has a well-established safety profile with hematological and gastrointestinal AEs, common MDM2 inhibitor class effects. Antiemetics should be considered as prophylaxis for nausea/vomiting. An intermittent dosing schedule (3/14d) mitigates the risk of myelosuppression and findings from the MANTRA study of this schedule are awaited with interest. Education of healthcare providers, physicians, and patients in the management of these AEs is important for adherence and maximizing the potential benefit of therapy.
NCT01877382 and NCT05012397.
Medical writing/editorial assistance was provided by Lee Miller and Harriet Lamb (Miller Medical Communications Ltd.). This work was funded by the study sponsor (Rain Oncology Inc.).
Rain Oncology Inc.
Rain Oncology Inc.
C. Fabbroni: Financial Interests, Institutional, Funding: Advenchen, Amgen Dompe, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, GlaxoSmithKline, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks Therapeutics, Rain Therapeutics, Boehringer Ingelheim. R.L. Jones: Financial Interests, Institutional, Research Grant: MSD, GSK; Financial Interests, Personal, Other, Consultation fees: Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, PharmaMar, Springworks, SynOx, Tracon, UpToDate. T. Linback, E. MacNeilly, F. Xu: Financial Interests, Personal, Full or part-time Employment: Rain Oncology Inc.; Financial Interests, Personal, Stocks/Shares: Rain Oncology Inc. All other authors have declared no conflicts of interest.