Abstract CT192: Orally administered MOMA-313 as monotherapy or combination therapy in participants with advanced or metastatic solid homologous recombination (HR)-deficient tumors: Phase 1 study design

Abstract Background: Genes required for homologous recombination (HR)-mediated DNA repair are commonly mutated or deleted in tumors, which can create a strong dependence on DNA polymerase theta (Polθ)-mediated end-joining (TMEJ) for the repair of double-stranded breaks and cell survival. MOMA-313 is a novel, potent, and selective inhibitor of Polθ helicase activity crafted to exploit the impaired DNA repair capabilities of HR-deficient tumors and accentuate the response to DNA-damaging poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors for potential therapeutic benefit. Methods: This is a Phase 1, first-in-human, multi-center, open-label, dose escalation and dose optimization study designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary clinical activity of MOMA-313. MOMA-313 will be administered orally either as a single agent or as combination therapy with a PARP inhibitor, olaparib, in patients with HR-deficient solid tumors. Participants must be ≥18 years old, have histologically confirmed advanced or metastatic solid tumors, have evaluable disease defined by measurable or non-measurable lesion(s) using Response Evaluation Criteria in Solid Tumors (RECIST) and/or Prostate Cancer Working Group (PCWG) guidelines, have Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, and be fully recovered from the effects of prior therapy. Participants are eligible for the study if they are not eligible for curative therapy. Participants are eligible for monotherapy if they are previously exposed to PARP inhibitors whereas either naïve or exposed to PARP inhibitors are eligible for combination therapy. Participants will be enrolled from multiple centers across the US, UK, and Spain. The primary endpoints are the number of participants with adverse events (AEs), dose-limiting toxicities (DLTs), serious AEs (SAEs), and/or AEs leading to discontinuation. Secondary endpoints include the determination of the optimal Phase 2 dose; plasma PK parameter endpoints for both MOMA-313 and olaparib including area under the curve, maximum concentration, time to maximum concentration, and half-life; and clinical activity endpoints including objective response rate, duration of response, time to response, progression free survival, disease control rate, and overall survival. ctDNA will be used to assess the emergence of reversion mutations in breast cancer genes (BRCA) and other HR genes during the course of therapy as an exploratory endpoint. Enrollment of initial cohorts began in the United States in August 2024, with sites in the UK and Spain planned to open in 2025. Clinical trial information: NCT06545942. Citation Format: Amita Patnaik, Wassim Abida, Kim A. Reiss, Johann De Bono, Rana McKay, Alan H. Bryce, Eileen M. O’Reilly, Neal Shore, Alex Spira, David R. Wise, Ramaswamy Govindan, Vivek Subbiah, Alexander Philipovskiy, Rahul Aggarwal, Louise Carter, Pasquale Rescigno, Joaquin Mateo, Victor Moreno, Marta Gil-Martin, Diana Manzanedo, David Waller, Salah Nabhan, Jordan Krall, Erica Evans, Marc S. Ballas. Orally administered MOMA-313 as monotherapy or combination therapy in participants with advanced or metastatic solid homologous recombination (HR)-deficient tumors: Phase 1 study design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT192.