The study consists of the following periods: screening; treatment; post-treatment follow up,
safety follow up, long term and survival follow-up.
Inclusion Criteria:
- Female subject eligible to participate if she is not pregnant (negative serum
pregnancy test at screening; female subjects with elevated serum beta human chorionic
gonadotropin and a demonstrated non-pregnant status through additional testing are
eligible) and at least one of the following conditions applies:
- Not a woman of child-bearing 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 agree not to donate ova starting at screening and throughout the
study period, and for 6 months after the final study drug administration.
- A sexually active male subject with a female partner(s) who is 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.
- Male subject must agree not to donate sperm starting at screening and throughout the
study period, and for 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 has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
- Subject has radiologically confirmed locally advanced unresectable or metastatic
disease within 28 days prior to randomization.
- Subject has radiologically evaluable disease (measurable and/or non-measurable disease
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.
- Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to
strong membranous staining as determined by central immunohistochemistry (IHC)
testing.
- Subject has a HER2-Negative tumor as determined by local or central testing on a
gastric or GEJ tumor specimen.
- 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 locally
analyzed laboratory tests collected within 14 days prior to randomization. In case of
multiple laboratory data within this period, the most recent data should be used to
determine eligibility.
- Hemoglobin (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if they
have a post-transfusion Hgb ≥ 9 g/dL.
- Absolute neutrophil count (ANC) ≥ 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) without liver metastases (or
< 3.0 x ULN if liver metastases are present)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
without liver metastases (or ≤ 5 x ULN if liver metastases are present)
- Estimated creatinine clearance ≥ 30 mL/min
- Prothrombin time (PT)/international normalized ratio (INR) and partial
thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving
anticoagulation therapy)
Exclusion Criteria:
- 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 as long as it was completed at least 6 months
prior to randomization. Subject may have received treatment with herbal medications
that have known antitumor activity > 28 days prior to randomization.
- 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.
- Subject has received systemic immunosuppressive therapy, including systemic
corticosteroids within 14 days prior to randomization. Subjects 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 received other investigational agents or devices within 28 days prior to
randomization.
- Subject has prior severe allergic reaction or intolerance to known ingredients of
zolbetuximab or other monoclonal antibodies, including humanized or chimeric
antibodies.
- Subject has known immediate or delayed hypersensitivity, intolerance or
contraindication to any component of study treatment.
- Subject has prior severe allergic reaction or intolerance to any component of
mFOLFOX6.
- Subject has known dihydropyrimidine dehydrogenase deficiency.
- Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome
with persistent/recurrent vomiting.
- Subject has significant gastric bleeding and/or untreated gastric ulcers that would
exclude the subject from participation.
- 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 (HBs Ag))
or 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 (HBc Ab)
positive, an HB deoxyribonucleic acid (DNA) test will be performed and if
positive, the subject will be excluded.
- Subjects with positive hepatitis C virus (HCV) serology, but negative HCV
ribonucleic acid (RNA) test are eligible.
- Subjects treated for HCV with undetectable viral load results are eligible.
- Subject has an active autoimmune disease that has required systemic treatment within
the past 3 months prior to randomization.
- Subject has active infection requiring systemic therapy that has not completely
resolved within 7 days prior to randomization.
- Subject has significant cardiovascular disease, including any of the following:
- Congestive heart failure (defined as New York Heart Association Class III or IV),
myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary
artery bypass graft, cerebrovascular accident (CVA) 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
- History or family history of congenital long QT syndrome
- Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate
controlled atrial fibrillation for > 1 month prior to randomization are
eligible).
- Subject has a history of central nervous system metastases and/or carcinomatous
meningitis from gastric/GEJ cancer.
- Subject has known peripheral sensory neuropathy > Grade 1 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 is without complete recovery from a major surgical procedure ≤ 14 days
prior to randomization.
- Subject has 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 comorbid 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.
