University of Kansas Medical Center

For Sub-study 1 and 2: - Patients with locally advanced or metastatic biliary tract carcinoma including adenocarcinoma of the intra- and/or extra-hepatic bile ducts and gallbladder carcinoma. Patients with ampullary cancers are excluded. - Patients must only have received and progressed on or be intolerant of first-line gemcitabine and platinum-based chemotherapy in metastatic/advanced setting and should not have received prior anti-PD-(L)1 therapy. Patients with known fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement, or isocitrate dehydrogenase 1 (IDH1) mutation will be excluded. Prior anti-PD-(L)1 therapy may be allowed during the trial if regulatory approval for such therapy is obtained while this trial is enrolling. For Sub-study 3: - Patients with with locally advanced or metastatic esophageal squamous cell carcinoma - Patients must only have received and progressed on or be intolerant of first-line platinum-based chemotherapy in metastatic/advanced setting and should have received prior anti-PD-(L)1 therapy. Patients with mixed adenosquamous histology cancers are excluded. For all Sub-studies : - Patients with measurable disease according to RECIST v1.1 - Patients with an ECOG PS of 0 or 1, and anticipated life expectancy of ≥3 months - Patients must have adequate organ function as indicated by laboratory values - Adequate contraception required as appropriate

• Patients with central nervous system (CNS) malignancy, untreated or unstable metastases - Patients with significant cardiovascular disease - Patients with 1. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose 2. Active uncontrolled bleeding or a known bleeding diathesis - Patients with a significant pulmonary disease or condition - Patients with a current or recent (within 6 months) significant gastrointestinal disease or condition - Patients with Gilbert's syndrome or patients with UGT1A1*28 homozygosity (also known as UGT1A1 7/7 genotype) - Patients with a significant ocular disease or condition - Patients with an active, known or suspected autoimmune disease - Patients with any other serious/active/uncontrolled infection - Patients with a history of organ transplantation - Patients with human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus or hepatitis C virus - Prior therapy with irinotecan - For Sub-study 1 and Sub-study 2: Anti-PD-(L)1, anti -LAG-3* or anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other immuno-oncology (IO) therapies. - For Sub-study 3: Anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies (other than anti-PD-(L)1 agents). - Patients must not be on warfarin, if they have a history of acute immune-related thrombocytopenia; patients must not be on strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors. - Patients with a known or suspected hypersensitivity to any of the excipients of formulated study drug - Patients with unresolved >Grade 1 toxicity associated with any prior antineoplastic therapy - Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation. - For Sub-study 3: Patients with a history of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy.