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

Inclusion Criteria:

• Female subject eligible to participate if she is not pregnant and at least one ofthe following conditions applies:

• Not a woman of child-bearing potential (WOCBP) OR

• WOCBP who agrees to follow the contraceptive guidance throughout the treatmentperiod and for at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs.

• Female subject must agree not to breastfeed starting at screening and throughout thestudy period, and for 6 months after the final study drug administration.

• Female subject must agree not to donate ova starting at screening and throughout thestudy period, and for 9 months after the final oxaliplatin administration and 6months after the final administration of all other study drugs.

• A sexually active male subject with a female partner(s) who is of child-bearingpotential must agree to use contraception during the treatment period and for atleast 6 months after the final study drug administration.

• Male subject must agree not to donate sperm starting at screening and throughout thestudy period, and for 6 months after the final study drug administration.

• Male subject with a pregnant or breastfeeding partner(s) must agree to remainabstinent or use a condom for the duration of the pregnancy or time partner isbreastfeeding throughout the study period and for 6 months after the final studydrug administration.

• Subject has histologically confirmed gastric or GEJ adenocarcinoma.

• Cohorts 1-4: Subject has radiographically-confirmed, locally advanced, unresectableor metastatic disease within 28 days prior to the first dose of study treatment.

• Subject's tumor is positive for CLDN18.2 expression demonstrating moderate to strongmembranous staining as determined by central IHC testing.

• Subject agrees to not participate in another interventional study while ontreatment.

• Subject has ECOG performance status 0 to 1.

• Subject has predicted life expectancy ≥ 12 weeks.

• Subject must meet all of the following criteria based on the centrally or locallyanalyzed laboratory tests collected within 14 days prior to the first dose of studytreatment. In case of multiple central laboratory data within this period, the mostrecent data should be used.

• Hemoglobin (Hgb) ≥ 9 g/dL (transfusion is allowed, but post-transfusion Hgb [24hours or later following transfusion] must be ≥ 9 g/dL)

• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

• Platelets ≥ 100 × 10^9/L

• Albumin ≥ 2.5 g/dL

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULNin subjects without liver metastases (≤ 5 × ULN if liver metastases arepresent)

• Cohorts 1-4: Estimated creatinine clearance ≥ 30 mL/min

• Cohort 5: Serum creatinine ≤ 1.5 × ULN, or estimated creatinine clearance ≥ 50mL/min for subjects with serum creatinine levels > 1.5 × ULN

• Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × ULN (except for subjects receiving anticoagulation therapy)

Specific to Cohort 1A:

• Subject has measurable disease according to RECIST 1.1 within 28 days prior to thefirst dose of study treatment per investigator assessment. For subjects with only 1evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesionmust either be outside the field of prior radiotherapy or must have documentedprogression following radiation therapy.

• Subject has disease progression on or after at least 2 prior regimens for theiradvanced disease, including fluoropyrimidine and platinum-containing chemotherapy,and if appropriate, HER2/neu-targeted therapy and all associated side effects haveresolved to grade 1 or less.

• Subject must have an additional available tumor specimen collected within 3 monthsprior to the first dose of study treatment.

• Subject must be an appropriate candidate for a tumor biopsy and is amenable toundergo a tumor biopsy during the screening period (if applicable) and treatmentperiod as indicated in the Schedule of Assessments.

Specific to Cohort 2:

• Subject has measurable disease according to RECIST 1.1 within 28 days prior to thefirst dose of study treatment per investigator assessment. For subjects with only 1evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesionmust either be outside the field of prior radiotherapy or must have documentedprogression following radiation therapy.

• Subject has not received prior systemic anti-cancer therapy for their advanceddisease (subject may have received neoadjuvant and/or fluorouracil-containingadjuvant chemotherapy as long as it has been completed ≥ 6 months before the firstdose of study treatment).

• Subject has a gastric or GEJ tumor that is HER2-negative as determined by local orcentral testing.

• Subject must have an additional available tumor specimen collected within 3 monthsprior to the first dose of study treatment.

• Subject must be an appropriate candidate for a tumor biopsy and is amenable toundergo a tumor biopsy during the screening period (if applicable) and treatmentperiod as indicated in the Schedule of Assessments.

Specific to Cohort 3A:

• Subject has radiologically evaluable disease (measurable and/or non-measurable)according to RECIST 1.1, per local assessment, ≤ 28 days prior to the first dose ofstudy treatment. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must either be outside the field of priorradiotherapy or must have documented progression following radiation therapy.

• Subject has disease progression on or after at least 2 prior regimens for theiradvanced disease, including fluoropyrimidine and platinum-containing chemotherapy,and if appropriate, HER2/neu-targeted therapy.

• Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4A and 4B:

• Subject has radiologically evaluable disease.

• Subject has not received prior systemic anti-cancer therapy for their advanceddisease.

• Subject has a gastric or GEJ tumor that is HER2-negative as determined by local orcentral testing.

• Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4B Only:

• Subject must have an additional available tumor specimen collected within 3 monthsprior to the first dose of study treatment.

• Subject must be an appropriate candidate for a tumor biopsy and is amenable toundergo a tumor biopsy during the screening period (if applicable) and treatmentperiod.

Specific to Cohort 5 Only:

• Subject has new histologically confirmed primary gastric or GEJ adenocarcinoma thatis amenable to curative resection.

• Subject has locoregional, resectable gastric or GEJ adenocarcinoma. GEJ may includetype I-III Siewert classification. Clinical stage will be determined by endoscopicultrasound (EUS) and/or CT or MRI. Diagnostic laparoscopy may be used as perinstitutional guidelines and clinical practices.

• Subject meets one of the following criteria of locoregional disease by clinical TNMstaging:

• GEJ: cT2,N0 (high risk-lesions: ≥ 3 cm, poorly differentiated), cT1b-cT2,N+ orcT3-cT4a,Any N.

• Gastric: T2 to T4a, and/or N1-3,M0.

• Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate tostrong membranous staining as determined by central IHC testing

Exclusion Criteria:

• Subject has had prior severe allergic reaction or intolerance to known ingredientsof zolbetuximab or other monoclonal antibodies, including humanized or chimericantibodies.

• Subject has known immediate or delayed hypersensitivity or contraindication to anycomponent of study treatment.

• Subject has received other investigational agents or devices concurrently or within 28 days prior to first dose of study treatment.

• Subject has received systemic immunosuppressive therapy, including systemiccorticosteroids 14 days prior to first dose of study treatment.

• Subject has a complete gastric outlet syndrome or a partial gastric outlet syndromewith persistent recurrent vomiting.

• Subject has significant gastric bleeding and/or untreated gastric ulcers that wouldpreclude the subject from participation.

• Subject has history of central nervous system metastases and/or carcinomatousmeningitis from gastric/GEJ cancer.

• Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive hepatitis B surface antigen [HBsAg]) or hepatitis C infection.

• Subject has had within 6 months prior to first dose of study treatment any of thefollowing: unstable angina, myocardial infarction, ventricular arrhythmia requiringintervention or hospitalization for heart failure.

• Subject has active infection requiring systemic therapy that has not completelyresolved within 7 days prior to the start of study treatment.

• Subject has active autoimmune disease that has required systemic treatment withinthe past 3 months prior to the start of study treatment.

• Subject has a clinically significant disease or co-morbidity that may adverselyaffect the safe delivery of treatment within this study or make the subjectunsuitable for study participation.

• Subject has psychiatric illness or social situations that would preclude studycompliance.

• Subject has had a major surgical procedure ≤ 28 days before start of studytreatment.

• Subject is without complete recovery from a major surgical procedure ≤ 14 daysbefore start of study treatment

• Subject has received radiotherapy for locally advanced unresectable ormetastatic gastric or GEJ adenocarcinoma ≤ 14 days (Cohorts 1 and 3A) and ≤ 28days (Cohorts 2 and 4A or 4B) prior to start of study treatment and has NOTrecovered from any related toxicity.

• Subject has another malignancy, for which treatment is required.

• Cohort 2, 4 and 5 Only, subject has any of the following:

• Prior severe allergic reaction or intolerance to any component of mFOLFOX6 orFLOT chemotherapeutics in this study

• Known dihydropyrimidine dehydrogenase deficiency (DPD).

• Known peripheral neuropathy > Grade 1 (absence of deep tendon reflexes as thesole neurological abnormality does not render the subject ineligible).

• Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, ifpresent, should be stable or improving.

• History of clinically significant ventricular arrhythmias.

• QTc interval > 450 msec for male subjects; QTc interval > 470 msec for femalesubjects.

• History or family history of congenital long QT syndrome.

• Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with ratecontrolled atrial fibrillation for > 1 month prior to first dose of studytreatment are eligible).

• Cohorts 3A, 4A and 4B Only, subject has any of the following:

• Ongoing or previous autoimmune disease or interstitial lung disease, activediverticulitis or gastrointestinal ulcerative disease, or solid organ or stemcell transplant (for Cohort 4) or other uncontrolled or clinically significantmedical disorders.

• Type 1 diabetes mellitus, endocrinopathies stably maintained on appropriatereplacement therapy or skin disorders (e.g., vitiligo, psoriasis, or alopecia)not requiring systemic treatment are allowed.

• Known history of serious hypersensitivity reaction to a known ingredient ofpembrolizumab or nivolumab.

• Cohort 4B Only: Subjects has microsatellite instability-high or mismatch repairdeficient tumors.

• Cohort 5 Only, subject has either of the following:

• Subject cannot undergo curative resection per the investigator's judgment

• Subject meets the following criterion of locoregional disease by clinical TNMstaging: cT1N0.