Principal Investigator: Daniel Anderson, MD
Study sponsor: Astellas
Location: Frauenshuh Cancer Center
Phase of Study: Phase 3
Purpose of study: A study to assess the efficacy of IMAB362 plus mFOLFOX6 compared with placebo plus mFOLFOX6 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 (Spotlight).
Waivers to the inclusion criteria will NOT be allowed.
– Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., HIPAA Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any study-related procedures.
– 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.
– Subject agrees not to participate in another interventional study while on study treatment.
– 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:
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 Contraception Requirements OR
b. WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.3 Contraception Requirements 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 treatment 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 sexually active male subject with female partner(s) who are of childbearing potential must agree to use contraception as detailed in Appendix 12.3 Contraception Requirements during the treatment period and for at least 6 months after the final study drug administration.
– Male subject must not 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 for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
Disease Specific Criteria:
– 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 the first dose of study treatment.
– Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment. 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 expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
– Subject has a HER2-Negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
Physical or Laboratory Findings
– Subject has ECOG performance status 0 to 1.
– Subject has predicted life expectancy 12 weeks in the opinion of the investigator.
– Subject must meet all of the following criteria based on the centrally analyzed laboratory tests within 14 days prior to the first dose of study treatment. In case of multiple laboratory data within this period, the most recent data should be used to determine eligibility.
a. Hemoglobin (Hgb) ≥ 9 g/dL. NOTE: subject must not have received any growth factor or blood transfusions within 14 days prior to the hematology values obtained at screening. Subjects requiring transfusions to meet eligibility criteria are not eligible.
b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
c. Platelets ≥ 100 x 109/L
d. Albumin ≥ 2.5 g/dL
e. Total bilirubin < 1.5 x upper limit of normal (ULN)
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. PT/international normalized ratio (INR) and 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
– 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 the first dose of study treatment. Subject may have received treatment with herbal medications that have known antitumor activity > 28 days prior to first dose of study treatment.
– Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma unless the radiotherapy was completed >28 days prior to start of study treatment. Subject who received palliative radiotherapy to peripheral bone metastases ≥14 days prior to start of study treatment and has recovered from all acute toxicities is allowed.
– Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to first dose of study treatment. 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) or a single dose of systemic corticosteroids are allowed.
– Subject has received other investigational agents or devices within 28 days prior to first dose of study treatment.
Medical History or Concurrent Disease
– 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 (DPD) deficiency. (NOTE: Screening for DPD deficiency should be conducted per local requirements.)
– Subject has gastric outlet syndrome or persistent/recurrent vomiting.
– Subject with recent gastric bleeding or symptomatic subjects with proven gastric ulcers that would exclude the subject from participation per investigator judgment.
– 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. 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. Subjects with positive serology but negative HCV RNA test results are eligible.
– Subject has an active autoimmune disease that has required systemic treatment within the past 2 years.
– Subject has active infection requiring systemic therapy that has not completely resolved within 14 days prior to start of study treatment.
– Subject has significant cardiovascular disease, including any of the following:
a. 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 or hypertensive crisis within 6 months prior to administration of first dose of study drug.
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 (Subject with rate controlled atrial fibrillation for > 1 month prior to first dose of study drugs are eligible)
– Subject has known active central nervous system metastases and/or carcinomatous meningitis.
– 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 the start of study treatment.
a. Subject is without complete recovery from a major surgical procedure 14 days prior to the first dose of study treatment.
– Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgment.
– Subject has another malignancy for which treatment is required per investigator’s clinical judgment.
– 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 in the opinion of the investigator.