Zolbetuximab With mFOLFOX6 or CAPOX in Claudin 18.2 Overexpressed Advanced or Metastatic Biliary Tract Cancers

Inclusion Criteria: 1. Age ≥ 18 years at the time of informed consent. 2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 at the time of registration. 3. Histological or cytological confirmation of biliary tract carcinoma per American Joint Committee on Cancer (AJCC) staging manual v8. 4. Radiologically confirmed locally advanced/unresectable (per treating investigator) or metastatic disease. 5. Evaluable disease per RECIST 1.1. 6. Expression of Claudin 18.2 (CLDN18.2) in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central immunohistochemical testing (IHC) from a CLIA certified lab using the VENTANA CLDN18 (43-14A) antibody (Roche Diagnostics). NOTE: A paraffin block or at least 5 unstained glass "positively charged" slides with 4-microns formalin-fixed, paraffin-embedded tissue are required for testing. Tissue must be from diagnosis via standard biopsy or surgery. Specimens that are from fine-needle aspirate (FNA), cytology, or metastatic bone lesions do not qualify for CLDN18.2 staining. If archival tissue is not available and the subject is undergoing a standard of care biopsy, part of that tissue may be used for testing. If tissue for Claudin 18.2 testing is not available, the subject is not eligible for the trial. 7. Receipt of only one prior line of systemic therapy for advanced disease. NOTE: Patients who received a single dose of mFOLFOX6 or CAPOX chemotherapy prior to registration may still be eligible for the trial, provided the tissue for CLDN18.2 for testing was obtained prior to the cycle of chemotherapy. 8. Prior cancer treatment must be completed at least 14 days prior to start of study treatment. 9. Recovery from all adverse events of the prior systemic therapy (other than alopecia) to grade ≤ 1 or baseline. NOTE: Known peripheral sensory neuropathy ≤ Grade 1 is allowed if the absence of deep tendon reflexes is the sole neurological abnormality. 10. Demonstrate adequate organ function at the time of screening as defined below. * Hematological * Platelets (Plt) ≥ 100,000 /mm3 * Absolute Neutrophil Count (ANC) ≥ 1500 K/mm3 * Hemoglobin (Hgb) ≥ 9 g/dL * Renal * Calculated creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula will be used to calculate creatinine clearance) * Hepatic * Total bilirubin ≤ 2 g/dl * Aspartate aminotransferase (AST) ≤ 2.5 × ULN without liver metastases and ≤ 5x ULN if liver metastases are present * Alanine aminotransferase (ALT) ≤ 2.5 × ULN without liver metastases and ≤ 5x ULN if liver metastases are present * Coagulation * International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN except for subjects receiving anticoagulation therapy. * Other * Albumin ≥ 2.5 g/dL Exclusion Criteria: 1. Receipt of 5-fluorouracil or capecitabine in the adjuvant setting within 6 months prior to registration or patients who progressed on FOLFOX or CAPOX regimens in the past. 2. Previous treatment with Claudin 18.2 directed treatment. 3. Active infection requiring systemic therapy. NOTE: Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study. 4. Pregnant or breastfeeding. NOTE: breast milk cannot be stored for future use while the subject is being treated on study. 5. Active central nervous system (CNS) metastases. NOTE: A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to registration, have been off corticosteroids (≤ 10 mg/day oral prednisone or equivalent) for ≥ 2 weeks, and are asymptomatic. 6. Known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment or other monoclonal antibody. 7. Known dihydropyrimidine dehydrogenase (DPD) deficiency. NOTE: Screening for DPD deficiency may be conducted per local requirements but is not required. 8. Treatment with any investigational drug within 7 days prior to registration. 9. Known additional malignancy that is progressing or requires active treatment, with the exception of patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or antitumor assessment of the investigational regimen. 10. Subject has significant cardiovascular disease, including any of the following: * Congestive heart failure (defined as New York Heart Association \[NYHA\] Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident (CVA), or hypertensive crisis within 6 months prior to registration * History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes) * History or family history of congenital long QT syndrome * Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for \> 28 days prior to registration are eligible.) 11. Major surgical procedure ≤ 28 days prior to registration. 12. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimen. 13. Known psychiatric illness or social situations such as incarceration that would preclude study compliance, per investigator judgment.