Inclusion Criteria:

• Male or female patients, ≥ 18 years.
• Patients with the ability to understand and give written informed consent for participation in this study including all evaluations and procedures as specified by this protocol.
• Patients agreeing to, and considered an acceptable and safe candidate for mandatory tumor tissue biopsy at screening and at the EoC1, with optional tumor biopsy at the time of disease progression.
  • Note: For baseline tissue samples, a specimen obtained up to 6 weeks prior to initiation of treatment on C1D1 and with no additional anticancer treatment given since biopsy collection.
• Patients with:
  • Sub-study 1 and Sub-study 2: Histologically diagnosed unresectable, locally advanced or metastatic BTC including adenocarcinoma of the intra- and/or extra-hepatic bile ducts and GBC. Patients with ampullary cancers are excluded.
  • Sub-study 3: Histologically diagnosed unresectable, locally advanced or metastatic ESCC.
• Patients must only have:
  • Sub-study 1 and Sub-study 2: Received and progressed on, or intolerant of, first-line gemcitabine and platinum-based chemotherapy in the 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.
  • Sub-study 3: Received and progressed on, or intolerant of, first-line platinum-based chemotherapy in the metastatic/advanced setting and should have received prior anti-PD- (L)1 therapy. Patients must have a best response of CR/PR or durable SD (defined as ≥ 3 months duration of SD) on prior anti-PD-(L)1 therapy. Patients with mixed adenosquamous histology cancers are excluded.
• 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 the following laboratory values:
• Hematological
  • Absolute neutrophil count (ANC) ≥ 1,500/µL;
  • Platelets ≥ 75,000/µL;
  • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L*.
• Renal
  • Serum creatinine or measured or calculated creatinine clearance (CrCL)** ≤ 1.5 × upper limit of normal (ULN) or CrCL ≥ 30 mL/min for patients with a creatinine level of > 1.5 × ULN;
• Hepatic
  • Serum total bilirubin and direct bilirubin ≤ 1.5 × ULN;
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for patients with liver metastases;
• Coagulation
  • International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT)  ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants***.  

*Criteria must be met without a transfusion within 2 weeks of the blood draw for screening.
**Glomerular filtration rate (GFR) can be used instead of serum creatinine or CrCL.
***Any patient receiving anticoagulant therapy should have coagulation factors monitored closely throughout the study. Patients receiving a factor Xa inhibitor who have abnormal PT/ partial thromboplastin time (PTT) may be eligible after discussion with the Sponsor’s Medical Monitor.

• Women of childbearing potential agreeing to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 6 months after the last study drug dose.
• Male patients agreeing to use an adequate method of contraception starting with the first dose of study drug through 6 months after the last dose of study drug and to refrain from sperm donation during this period.

Exclusion Criteria:

• Women who are pregnant or intending to become pregnant before, during, or within 6 months after the last dose of study drug; women who are breastfeeding; women of childbearing potential not using and not willing to use a highly effective method of contraception).
• Patients with central nervous system (CNS) malignancies; patients with known, untreated CNS or leptomeningeal metastases, or spinal cord compression, patients with any of the above not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
• Note: Patients with treated CNS metastases will be eligible if they:
  • had radiotherapy, surgery or stereotactic surgery for the brain or spinal metastases;
  • have no neurological symptoms (excluding Grade ≤ 2 neuropathy);
  • have stable brain or spinal disease on the Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) scan within 4 weeks before signing the informed consent form (ICF);
  • must not be undergoing acute corticosteroid therapy or steroid taper. Chronic steroid therapy is acceptable provided that the dose is stable for the last 14 days prior to screening (≤ 10 mg prednisone daily or equivalent).
  • Spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.
  • Patients with known or suspected CNS metastases will require baseline imaging to establish stability of known lesion(s), or to assess for appearance of new brain lesion(s) or progression of existing lesion(s). MRI imaging is preferred for assessment of CNS lesions.
• Patients with significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina.
  • Note: Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Patients with:
  • Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose, unless adequately treated and considered by the Investigator to be stable;
  • Active uncontrolled bleeding or a known bleeding diathesis.
• Patients with a significant pulmonary disease or condition, including:
  • History of interstitial lung disease, pulmonary fibrosis;
  • History of pulmonary inflammatory disease, interstitial or other pneumonitis*, acute respiratory distress syndrome (ARDS).
  • * Patients with prior evidence of Grade 1 pneumonitis will be eligible provided they were asymptomatic when diagnosed and did not require treatment and provided pneumonitis has resolved prior to entry to this study.
• Patients with a current or recent (within 6 months) significant gastrointestinal disease or condition, including:
  • History of inflammatory bowel disease;
  • Diarrhea ≥ Grade 2 within 2 weeks prior to the first study drug dose.
• Gilbert’s syndrome or patients with UGT1A1*28 homozygosity (also known as UGT1A1 7/7 genotype).
• Patients with a significant ocular disease or condition, including history of an autoimmune or inflammatory disorder; e.g., episcleritis, uveitis, iritis.
  • Note: Patients with a history of dry eye for reasons other than an autoimmune disease or condition may be included if adequately treated. Patients with non-significant, non-inflammatory disorders (e.g., cataracts, glaucoma) will be allowed.
• Patients with an active, known or suspected autoimmune disease, or a documented history of autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive medications).
  • Note: Exceptions are permitted for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders such as vitiligo, psoriasis or alopecia not requiring systemic treatment, conditions not expected to recur in the absence of an external trigger.
• Patients with a history of organ transplantation (e.g., stem cell or solid organ transplant).
• Patients with human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus (HBV) (e.g., HBsAg reactive) or hepatitis C virus (HCV) (e.g., HCV RNA [qualitative] is detected). (Inactive HBsAg carriers with prophylactic antiviral agent are allowed).
• Patients with any other serious/active/ uncontrolled infection, any infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to the first study drug dose.
• Patients with any other serious, life-threatening, or unstable preexisting medical condition (aside from the underlying malignancy) including significant organ system dysfunction or failure, clinically significant laboratory abnormality(ies), psychiatric disorder or altered mental status which, in the opinion of the Investigator, would either compromise the patient’s safety or interfere with obtaining informed consent, compliance with study procedures, or evaluation of the safety of the study drug(s).
• Prior therapy with irinotecan (effective with Protocol Version 3.0) or with:
  • 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 IO therapies. * Effective with Protocol Version 5.0, patients with prior anti-LAG-3 containing regimen are allowed. 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;
  • 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).
• Any antineoplastic agent for the primary malignancy (standard or investigational) with delayed toxicity within 4 weeks or 5 elimination half-lives, whichever is shortest, prior to the first study drug dose, except for nitrosoureas and mitomycin C within 6 weeks prior to the first study drug dose.
• Any other investigational treatments within 2 weeks prior to the study; this includes participation in any medical device or supportive care therapeutic intervention studies.
• Radiotherapy:
  • For target lesions within 4 weeks prior to the first study drug dose unless PD has been documented in the lesion following radiotherapy;
  • For non-target lesions within 1 week prior to the first study drug dose.
• Use of live and live-attenuated vaccines against infectious diseases (e.g., varicella) 4 weeks prior to the first study drug dose
• Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) within 2 weeks prior to the first study drug dose.
• Prophylactic use of hematopoietic growth factors within 1 week prior to the first study drug dose.
• Patients must not be on warfarin, strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors.
  • Note: Discontinue at least 1 week prior to starting study drug combination therapy. Do not administer with irinotecan unless there are no therapeutic alternatives.
• 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 except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, lymphopenia, hypomagnesemia, and/or end-organ failure being adequately managed by hormone replacement therapy (HRT).
• Patients with inadequate recovery from any prior surgical procedure, or patients having undergone any major surgical procedure within 4 weeks prior to the first study drug dose.
• Patients with known or foreseeable inability, in the opinion of the Investigator, to comply with the protocol requirements.
• Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation.
• 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. Investigators should ensure that all study enrollment criteria have been met prior to randomization/allocation and administration of the first study drug dose on Day 1. 

Eligibility last updated 4/18/22. Questions regarding updates should be directed to the study team contact.