Treating Advanced MSI-High or dMMR Cancers Using the Targeted Therapy MOMA-341 Given Alone or In Combination with Standard Therapies

This trial will study an investigational drug called MOMA-341 given alone or together with a standard chemotherapy (irinotecan) or together with an immunotherapy. MOMA-341 is a targeted therapy that blocks the activity of an enzyme called “Werner helicase (WRN).” People with certain advanced or metastatic cancers with a biomarker known as MSI-High (microsatellite instability high) or dMMR (mismatch repair deficient) may be eligible for this trial. These biomarkers are often seen in Lynch syndrome cancers. The eligible tumor types may depend on the stage of the study. The trial aims to understand MOMA-341 safety, tolerability, initial effectiveness, and how the drug moves through and affects the body.

This is a phase 1 trial that will study whether it is safe for participants with certain advanced or metastatic cancers to take a drug called “MOMA‑341” by itself or together with a drug called “irinotecan” or together with an immunotherapy. MOMA-341 will be administered orally. Irinotecan and the immunotherapy will be administered via intravenous (IV) infusion.

Participants will be enrolled into one of three groups, depending on when they join the study.

• Group 1: The trial will begin by giving MOMA-341 by itself to a group of participants. If doctors and researchers determine that this dose is safe, another group of participants will receive a higher dose of MOMA-341 by itself. This process of increasing the dose will continue until unacceptable side effects occur, or until it is clear that further dose increases will not be helpful.
• Group 2 and Group 3: After MOMA-341 has been deemed safe in Group 1 in at least two doses, participants may enroll in Group 2 or Group 3. These groups will receive MOMA-341 and irinotecan together (Group 2), or MOMA-341 and an immunotherapy together (Group 3). Group 2 and Group 3 will use the same process of increasing the dose as Group 1.

Once a dose is determined safe and acceptable in any group of the study, additional participants may be enrolled to that group to further confirm the safety, tolerability, and effectiveness of the dose, as well as to confirm the acceptability of the dose for future studies. Participants who receive MOMA-341 by itself in Group 1 may be able to add irinotecan or immunotherapy to their regimen later in the study.

The study involves the following study periods and visits.

• A screening period to determine your eligibility in the study.
• A treatment period where you will receive your study treatment and be carefully monitored for safety and your cancer. There is no defined maximum length of treatment. As long as the study remains open, participants may continue treatment if they are tolerating it well and are benefitting from treatment, unless their physicians or researchers determine that they should stop (for example, if they determine it is not safe or if disease worsens).
• An end of treatment visit and safety follow-up visit to evaluate your health once you have completed study treatment. End of treatment is usually conducted within 5 days from your last dose of study treatment and the safety follow-up visit is performed within 28 days from the end of treatment visit. 
• A long-term follow-up phone call every 3 months to assess your status.

Study procedures will include blood samples, vital signs, physical examinations, cardiac monitoring, scans to evaluate the extent of disease, and daily dosing diary completion. Tumor biopsy samples will also be obtained but this is optional.  

Reimbursement is being offered to participants, which may include travel, lodging, and meals.

This trial will include adult participants (18 years or older) with cancer who have solid tumors that are “advanced” (large, complex, or aggressive) or “metastatic” (have spread to other parts of the body). Some requirements for participation include the following:

• You must have a specific gene mutation or alteration in your tumor that affects the ability of cells to repair DNA damage in a process called mismatch repair (MMR). MSI-H or dMMR alterations may qualify you for inclusion into the study. These tumor alterations are common in people with Lynch syndrome. The eligible tumor types may depend on the stage of the study.
• You must have previously received and progressed on an immunotherapy-based regimen (anti-PD-(L)1), unless you are ineligible for these therapies.
• You must be fully recovered from effects of prior therapy, radiotherapy, and/or surgery.
• You must not be pregnant or breastfeeding.

Some exclusions into this trial include the following:

• You have a severe or uncontrolled systemic disease or infection.
• You have active liver disease or known HIV/AIDS-related illness (there are some exceptions).
• You have an active prior or ongoing cancer (there are some exceptions).
• You have impaired gastrointestinal function.
• You are receiving other systemic anticancer therapies.