This Phase 2 study will be conducted in different countries around the world with up to about 160 participants.

The purpose of this study is to evaluate how well Rina-S works against GI cancers.

The medication in this study is Rina-S monotherapy (by itself; no other cancer treatments). All participants will receive active drug; no one will be given placebo.

Participation in the study will require visits to the study site(s). During site visits, there will be various tests (such as blood draws) and procedures (such as recording of heart activity, imaging/X-rays) to monitor whether the study treatment is safe and effective.

The duration of the study will be different for every participant, but an average study duration of 22 months is expected for participants. This will include a treatment period (expected to last an average of 12 months), plus data collection periods before and after treatment. Participants will be asked to attend 1 to 5 visits at the study clinic for each cycle (duration of an individual cycle is 21 days). If a participant's cancer stays the same or gets better, and there are not any serious problems, participants can keep getting study treatment for as long as the study is open.

This is a Phase 2, open-label, multicenter, multi-cohort trial to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics of Rina-S as monotherapy in participants with GI cancers who have progressed on or after prior standard of care (SoC) therapies.

Key Inclusion Criteria:

• All study cohorts

• Participant has histologically or cytologically confirmed GI cancer.
• Participant has documented metastatic or unresectable disease, not amenable to treatment with curative intent.
• Participant has measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at baseline.
• Participant must have radiological disease progression while on or after receiving the most recent regimen.
• Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Participant has life expectancy ≥3 months.
• Participant must be able to provide a newly obtained or archival tissue sample.
• Participant must have adequate organ and bone marrow function, per laboratory test results prior to Rina-S administration.

Key Exclusion Criteria (all study cohorts):

• Participant has clinically significant non-malignant gastrointestinal disorders, including but not limited to, diarrhea > grade 1, ulcerative colitis, inflammatory bowel disease.
• Participants with recent (up to 4 weeks) history of significant gastrointestinal bleeding, current cancer related ulcerations, fistula, abscess or recent perforation (within 4 to 6 weeks).
• Participant has a past or current malignancy other than the inclusion diagnosis before the planned first dose of trial treatment, or any evidence of residual disease from a previously diagnosed malignancy.
• Participants with newly identified or known unstable (eg, progressing brain metastases) or symptomatic central nervous system (CNS) metastases or history of carcinomatous meningitis (also known as leptomeningeal disease).
• Prior treatment with topoisomerase-1 inhibitor containing antibody-drug conjugate (ADC).
• Treatment with an anticancer agent within 28 days prior to the first dose of trial treatment.

Note: Other protocol-defined Inclusion and Exclusion criteria may apply.