A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus CAPOX Compared with Placebo Plus CAPOX as First-line Treatment of Subjects with Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Waivers to the inclusion criteria will NOT be allowed.
General Criteria:
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved
written informed consent and privacy language as per national regulations
(e.g., Health Insurance Portability and Accountability Act [HIPAA]
Authorization for US sites) must be obtained from the subject or legally
authorized representative (if applicable) prior to any study-related procedures.
2. Subject is considered an adult (e.g., >= 18 years of age in the US) according
to local regulation at the time of signing the informed consent.
3. A female subject is eligible to participate if she is not pregnant
(negative serum pregnancy test at screening; female subjects with elevated
serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant
status through additional testing are eligible) and at least 1 of the following
conditions applies:
• Not a woman of childbearing potential (WOCBP) as defined in [protocol
appendix 12.3 Contraception Requirements]
OR
• WOCBP who agrees to follow the contraceptive guidance as defined in [protocol
appendix 12.3 Contraception Requirements] throughout the treatment period and
for
9 months after the final administration of oxaliplatin and 6 months after the
final
administration of all other study drugs.
4. Female subject must agree not to breastfeed starting at screening and
throughout the study period, and for 6 months after the final study treatment
administration.
5. Female subject must not donate ova starting at screening and throughout the
study period, and for 9 months after the final administration of oxaliplatin
and 6 months after the final administration of all other study drugs.
6. A male subject with female partner(s) of childbearing potential:
• must agree to use contraception as detailed in [Appendix 12.3 Contraception
Requirements] during the treatment period and for 6 months after the final
study treatment administration.
7. A male subject must not donate sperm during the treatment period and for 6
months after the final study treatment administration.
8. 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 treatment administration.
9. Subject agrees not to participate in another interventional study while
receiving study drug in present study.
Disease Specific Criteria:
10. Subject has histologically confirmed diagnosis of Gastric or GEJ
adenocarcinoma.
11. Subject has radiologically confirmed locally advanced unresectable or
metastatic disease within 28 days prior to randomization.
12. Subject has radiologically evaluable disease (measurable and/or
non-measurable) according to RECIST 1.1, per local assessment, <= 28 days prior
to randomization. For subjects with only 1 evaluable lesion and prior
radiotherapy <= 3 months before randomization, the lesion must either be outside
the field of prior radiotherapy or have documented progression following
radiation therapy.
13. Subject*s tumor expresses CLDN18.2 in >= 75% of tumor cells demonstrating
moderate to strong membranous staining as determined by central IHC testing.
14. Subject has a HER2-negative tumor as determined by local or central testing
on a gastric or GEJ tumor specimen.
Physical or Laboratory Findings:
15. Subject has ECOG performance status 0 or 1.
16. Subject has predicted life expectancy >= 12 weeks in the opinion of the
investigator.
17. Subject must meet all of the following criteria based on the centrally or
locally analyzed laboratory tests collected within 14 days prior to
randomization. In the sample collection within this period, the most recent
sample collection with available results should be used to determine
eligibility.
a. Hemoglobin (Hb) >= 9 g/dl. Subjects requiring transfusions are eligible if
they have post-transfusion Hgb >= 9 g/dL.
b. Absolute Neutrophil Count (ANC) >= 1.5x109/L
c. Platelets >= 100x109/L
d. Albumin >= 2.5 g/dL
e. Total Bilirubin <= 1.5 x upper limit of normal (ULN) without liver metastases
(or < 3.0 x ULN if liver metastases are present)
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 x
ULN without liver metastases (or <= 5 x ULN if liver metastases are present)
g. Estimated creatinine clearance >= 30 mL/min
h. Prothrombin time/international normalized ratio (PT/INR) and partial
thromboplastin time (PTT) <= 1.5 x ULN (except for subjects receiving
anticoagulation therapy)

Waivers to the exclusion criteria will NOT be allowed.
Subject who meets any of the following exclusion criteria prior to enrollment
is not eligible for enrollment:
Prohibited Treatment or Therapies:
1. Subject has received prior systemic chemotherapy for locally advanced
unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may
have received either neo-adjuvant or adjuvant chemotherapy , immunotherapy or
other systemic anticancer therapies as long as it was completed at least 6
months prior randomization.
2. Subject has received radiotherapy for locally advanced unresectable or
metastatic gastric or GEJ adenocarcinoma <= 14 days prior to randomization and
has not recovered from any related toxicity.
3. Subject has received treatment with herbal medications or other treatments
that have known antitumor activity within 28 days prior to randomization.
4. 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 is
eligible.
5. Subject has received other investigational agents or devices within 28 days
prior to randomization.
Medical History or Concurrent Disease:
6. Subject has prior severe allergic reaction or intolerance to known
ingredients of zolbetuximab or other monoclonal antibodies, including humanized
or chimeric antibodies.
7. Subject has known immediate or delayed hypersensitivity, intolerance or
contraindication to any component of study treatment.
8. Subject has prior severe allergic reaction or intolerance to any component
of CAPOX.
9. Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency. (NOTE:
Screening for DPD deficiency should be conducted per local requirements.)
10. Subject has a complete gastric outlet syndrome or partial gastric outlet
syndrome with persistent/recurrent vomiting.
11. Per investigator judgement, subject has significant gastric bleeding and/or
untreated gastric ulcers that exclude the subject from participation.
12. Subject has a known history of a positive test for human immunodeficiency
virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C
infection. NOTE: Screening for these infections should be conducted per local
requirements.
a. For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA
test will be performed and if positive, the subject will be excluded.
b. Subjects with positive hepatitis C virus (HCV) serology but negative HCV RNA
test results are eligible.
c. Subjects treated for HCV with undetectable viral load results are eligible.
13. Subject has an active autoimmune disease that has required systemic
treatment within the past 3 months prior to randomization.
14. Subject has active infection requiring systemic therapy that has not
completely resolved within 7 days prior to randomization.
15. Subject has significant cardiovascular disease, including any of the
following:
a. 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 randomization;
b. History of clinically significant ventricular arrhythmias (i.e., sustained
ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes);
c. QTc interval > 450 msec for male subjects; QTc interval > 470 msec for
female subjects;
d. History or family history of congenital long QT syndrome
e. Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with
rate controlled atrial fibrillation for > 1 month prior to randomization are
eligible.)
16. Subject has a history of central nervous system (CNS) metastases and/or
carcinomatous meningitis from gastric/GEJ cancer.
17. Subject has known peripheral sensory neuropathy > grade 1 unless the
absence of deep tendon reflexes is the sole neurological abnormality.
18. Subject has had a major surgical procedure <= 28 days prior to randomization.
a. Subject is without complete recovery from a major surgical procedure <= 14
days prior to randomization.
19. Subject has psychiatric illness or social situations that would preclude
study compliance, per investigator judgement.
20. Subject has another malignancy for which treatment is required per
investigator*s clinical judgment
21. 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 in
the opinion of the investigator.