Abstract B003: Orally administered MOMA-341 as monotherapy or combination therapy in participants with advanced or metastatic solid tumors: Phase 1 study design

Abstract Background: Patients with advanced or metastatic solid tumors harboring microsatellite instability high (MSI-H) or DNA mismatch repair deficiency (dMMR) alterations have benefited from immune check point inhibitors (ICIs). However, many patients show innate or acquired resistance to ICIs. Therefore, additional therapies with rapid response rates and longer durations of response are needed. Tumors with MSI-H or dMMR alterations rely heavily on DNA repair mechanisms to avoid apoptosis and may respond well to inhibition of Werner RecQ like helicase (WRN), a protein with a critical role in DNA replication and repair. WRN activity is required for successful DNA replication at expanded thymine and adenine (TA) dinucleotide repeats occurring from dMMR. Loss of WRN leads to DNA damage at TA repeat sites, resulting in cell death and tumor regression. MOMA-341 is a potent and selective oral inhibitor of WRN that has demonstrated antitumor activity in dMMR/MSI-H models. DNA damage and anti-tumor activity are enhanced when MOMA-341 is combined with standard chemotherapies (eg, irinotecan). The selective activity of MOMA-341 supports its development as monotherapy or combination therapy for treatment of dMMR/MSI-H solid tumors. Methods: This Phase 1, multi-center, open-label, dose escalation and dose optimization study is designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PDx), and preliminary anti-tumor activity of MOMA-341 in patients with MSI-H/dMMR alterations (NCT06974110). The monotherapy dose escalation phase (Arm 1A) will determine the presumptive optimal biological dose (OBD) and maximum tolerated dose (MTD); the dose optimization phase (Arm 1B) will assess safety, tolerability, PK, PDx, and antitumor activity of MOMA-341. Combination treatment arms with chemotherapy (e.g., irinotecan, Arm 2) or immunotherapies (Arm 3) will determine the presumptive OBD and MTD. Inclusion criteria are patients aged ≥18 years with histologically confirmed MSI-H/dMMR alterations, unresectable advanced or metastatic solid tumors, an Eastern Cooperative Oncology Group Performance Status ≤2, and those who have previously received and progressed on an anti-PD-L1 (USA) or who have been treated with anti-PD-L1 if approved/accessible (ex-USA). Participants are planned to enroll from centers across North America, Australia, and Europe. Primary endpoints include adverse events (AEs), dose-limiting toxicities, serious AEs, and/or AEs leading to discontinuation. Secondary endpoints include determination of the optimal Phase 2 dose; plasma PK parameters of MOMA-341 monotherapy and in combination with irinotecan or immunotherapies; and clinical activity assessments. Changes in DNA damage markers, covalent ligation of WRN by MOMA-341, and ctDNA responses will be assessed as exploratory endpoints. TA repeat expansions will be measured to further refine patient stratification biomarkers. Study sites are currently open and recruiting. Citation Format: Charlotte Lemech, Timothy Humphries, Tiago Biachi de Castria, Andrea Cercek, Michael Overman, Shivaani Kummar, Capucine Baldini, Josep Tabernero, Aaron Hansen, Adnan Nagrial, Kate Roberts, Rohit Joshi, Elizabeth Ahern, Douglas Orr, Najeeb Al Hallak, Brian A. Van Tine, David Waller, Salah Nabhan, Allison Drew, Marc Ballas. Orally administered MOMA-341 as monotherapy or combination therapy in participants with advanced or metastatic solid tumors: Phase 1 study design [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B003.