A Study of Zolbetuximab (IMAB362) in Adults With Pancreatic Cancer

This study will have a safety lead in phase and a randomization phase.

Inclusion criteria

• A female subject is eligible to participate if she is not pregnant or lactating and at least 1 of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) OR
• WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration.
• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
• Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
• A male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration.
• A male subject must not donate sperm during the treatment period and for at least 6 months after the final study drug administration.
• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
• Subject agrees not to participate in other interventional studies while receiving study drug in present study.
• Subject has histologically or cytologically confirmed adenocarcinoma of pancreas.
• Subjects must have metastatic pancreatic adenocarcinoma that has not been previously treated with chemotherapy.

• Prior treatment with fluorouracil (5-FU) or GEM administered as a radiation sensitizer during and up to 4 weeks after radiation therapy is allowed
• If a subject received adjuvant therapy, tumor recurrence or disease progression must have occurred at least 6 months after completing the last dose of the adjuvant therapy.
• Subjects whose disease progressed on prior treatment with Nab-P and GEM are not eligible.
• Subject has a measurable lesion(s) on at least 1 metastatic site based on RECIST 1.1 within 28 days prior to randomization. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
• Subject's tumor sample has CLDN18.2 expression in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central immunohistochemistry (IHC) testing
• Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Subject has predicted life expectancy ≥ 12 weeks.
• Subject must meet all of the following criteria based on the laboratory tests that will be collected within 14 days prior to randomization. In case of multiple laboratory data within this period, the most recent data should be used.

• Hemoglobin ≥ 9 g/dl (no transfusion within 14 days of start of study treatment)
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Albumin ≥ 2.5 g/dL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (≤ 5 x ULN if liver metastases are present)
• Estimated creatinine clearance ≥ 30 mL/min
• Prothrombin time/international normalized ratio (INR) and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)

Exclusion criteria

• Subject has received other investigational treatment within 28 days prior to randomization.
• Subject has received radiotherapy for metastatic pancreatic adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
• Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
• Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibody, including humanized or chimeric antibodies.
• Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
• Subject has a known history of a positive test for human immunodeficiency virus infection or known active hepatitis B (positive HBs antigen [Ag]) or hepatitis C infection. NOTE: Screening for these infections should be conducted per local requirements.

• For subjects who are negative for HBs Ag, but hepatitis B core antibody positive, a hepatitis B virus DNA test will be performed and if positive, the subject will be excluded.
• Subjects with positive hepatitis C serology but negative hepatitis C virus RNA test results are eligible.
• Subjects treated for hepatitis C with undetectable viral load results are eligible.
• Subject has a history of interstitial pneumonia or pulmonary fibrosis.
• Subject has pleural effusion or ascites ≥ Grade 3.
• Subject has an active autoimmune disease that has required systemic treatment in the past 3 months prior to randomization.
• Subject has active infection requiring systemic therapy that has not completely resolved per investigator judgment within 7 days prior to randomization.
• Subject has significant cardiovascular disease, including:

• Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization;
• History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects;
• Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to randomization.)
• Subject has a history of central nervous system metastases and/or carcinomatous meningitis from pancreatic adenocarcinoma.
• Subject has known peripheral sensory neuropathy ≥ Grade 2 unless the absence of deep tendon reflexes is the sole neurological abnormality.
• Subject has had a major surgical procedure ≤ 28 days prior to randomization.
• Subject without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
• Psychiatric illness or social situations that would preclude study compliance.
• Subject has another malignancy for which treatment is required.
• Subject has any concurrent disease, infection or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.