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

A Single Arm Phase II Trial of Zolbetuximab in Combination With mFOLFOX6 or CAPOX Chemotherapy in Claudin 18.2 Overexpressed Advanced or Metastatic Biliary Tract Cancers

Subjects will receive zolbetuximab with either CAPOX every 3 weeks or mFOLFOX6 every 2 weeks. The chemotherapy regimen chosen, mFOLFOX6 or CAPOX is per the treating investigator discretion and subject preference.

Study treatment will continue for a maximum of 2 years, or until disease progression per RECIST 1.1, intolerable side effects, or investigator/subject preference. Disease evaluation will occur every 8 to 9 weeks.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Biliary Tract Cancer; Metastatic Biliary Tract Carcinoma
• Intervention / Treatment: Drug: Zolbetuximab; Drug: mFOLFOX6; Drug: CAPOX

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Amber Ryba; Phone Number: 13 317-634-5842; Email: aryba@hoosiercancer.org
• Study Contact Backup: Name: Midhun Malla, MD, MS; Phone Number: 205-996-9740; Email: midhunmalla@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years at the time of informed consent.
2. ECOG Performance Status of 0-1 at the time of registration.
3. Histological or cytological confirmation of biliary tract carcinoma per 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Zolbetuximab and CAPOX or mFOLFOX6; Subjects will receive zolbetuximab with CAPOX every 3 weeks or with mFOLFOX6 every 2 weeks.

Drug: Zolbetuximab; Zolbetuximab (800 mg/m^2) will be administered with CAPOX or mFOLFOX6 for Cycle 1. When administered with CAPOX, for every subsequent cycle Zolbetuximab (600 mg/m^2) will be administered. When administered with mFOLFOX6, for every subsequent cycle Zolbetuximab (400 mg/m^2).; Drug: mFOLFOX6; Oxaliplatin (85 mg/m^2), Leucovorin (400 mg/m^2), and 5-FU continuous infusion (2400 mg/m^2) will be administered every 2 weeks.; Drug: CAPOX; Oxaliplatin (130 mg/m^2) and Capecitabine (750-800 mg/m^2) will be administered every 3 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) rate	PFS will be defined as the percentage of evaluable patients alive and progression-free (radiologically per RECIST 1.1 or clinically per treating investigator discretion) at 6 months from date of registration.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Progression Free Survival (PFS)	Median PFS is defined as time from registration to date of radiological (per RECIST 1.1) or clinical (per treating investigator discretion) progression or death from any cause, whichever comes first.	24 months
Overall Survival (OS)	• OS will be defined as time from registration to either date of death due to any cause or last follow-up date.	24 months
Objective Response Rate (ORR)	ORR is defined as the proportion of subjects, in the evaluable population, who achieve a complete or partial response (CR or PR), per RECIST v 1.1.	24 months
Disease Control Rate (DCR)	DCR is defined as the proportion of subjects, in the evaluable population, who achieve a complete or partial response (CR or PR), or stable disease (SD) per RECIST v1.1.	24 months
Adverse Events	Adverse events and reportable serious events are defined by the study protocol per NCI Common Toxicity Criteria for Adverse Events (CTCAE) v5.0.	24 months

Collaborators and Investigators

• Sponsor: Midhun Malla
• Collaborators: University of Alabama at Birmingham; Astellas Pharma Inc; University of Michigan
• Investigators: Principal Investigator: Vaibhav Sahai, MBBS, MS, University of Michigan; Principal Investigator: Midhun Malla, MD, MS, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): February 1, 2029
• Study Completion (Estimated): August 1, 2030

Study Registration Dates

• First Submitted: July 20, 2026
• First Submitted That Met QC Criteria: July 20, 2026
• First Posted (Actual): July 23, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 20, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Overexpressed Claudin 18.2
• Additional Relevant MeSH Terms: zolbetuximab
• Other Study ID Numbers: HCRN-GI24-690

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No