Key Inclusion Criteria:  Participants age 18 or older with histologically or cytologically confirmed (by local laboratory and local clinical guidelines) metastatic colorectal adenocarcinoma that is not amenable to potentially curative surgery in the opinion of the investigator and progressed on or within 6 months after the last dose of one prior line of systemic anti-cancer therapy administered for metastatic disease. Presence of at least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. Adequate organ function (assessed by central laboratory for eligibility).  Key Exclusion Criteria:  Previously administered systemic TGF-β targeted therapies. Microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and/or BRAFV600 mutation positive colorectal cancer. Known complete or partial dipyrimidine dehydrogenase (DPD) enzyme deficiency (testing for DPD enzyme deficiency is not mandatory unless required by local regulations and can be conducted at a local laboratory). For participants treated with irinotecan: Known history or clinical evidence of reduced UGT1A1 activity (testing for UGT1A1 status is not mandatory unless required by local regulations and can be conducted at a local laboratory). Participants who have not recovered from a major surgery performed prior to start of study treatment or have had a major surgery within 4 weeks prior to start of study treatment. Impaired cardiac function or clinically significant cardio-vascular disease. Participants with conditions that are considered to have a high risk of clinically significant gastrointestinal tract bleeding or any other condition associated with or history of significant bleeding. Stroke or transient ischemic attack, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before start of study treatment. Pregnant or breast-feeding women. Women of childbearing potential, unless willing to use highly effective contraception methods during treatment and after stopping study treatments as required.  Other inclusion/exclusion criteria may apply