A Study to Assess the Antitumor Activity, Safety, Pharmacokinetics and Biomarkers of Zolbetuximab (IMAB362) in Participants With Claudin (CLDN) 18.2 Positive, Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma
A Phase 2 Study of Zolbetuximab (IMAB362) as Monotherapy, or in Combination With mFOLFOX6 and in Combination With Pembrolizumab in Subjects With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma Whose Tumors Have High or Intermediate Claudin (CLDN) 18.2 Expression
The purpose of this study is to determine the Objective Response Rate (ORR) of zolbetuzimab as a single agent as assessed by an independent central reader. This study will also assess the ORR and Progression Free Survival (PFS) of zolbetuximab in combination with mFOLFOX6 and in combination with pembrolizumab, assess the safety and tolerability, assess the effects on CLDN18.2 expression and assess the immunogenicity and immunomodulatory effects of zolbetuximab as a single agent and in combination with mFOLFOX6 and in combination with pembrolizumab. This study will also evaluate the pharmacokinetics (PK) of zolbetuximab, oxaliplatin, fluorouracil (5-FU), and pembrolizumab, evaluate health-Related Quality of Life (HRQoL), evaluate the Disease Control Rate (DCR), Duration of Response (DOR), PFS of zolbetuximab as a single agent, in combination with mFOLFOX6 and in combination with pembrolizumab based on both investigator and independent central reader assessment, assess Overall Survival (OS) of zolbetuximab as a single agent and in combination with pembrolizumab.
18 Years and up
Accepting Healthy Volunteers?
- Female subject eligible to participate if she is not pregnant 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 gastric or GEJ adenocarcinoma.
- Subject has radiographically-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 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
NOTE: This criterion is not applicable for subjects in Cohort 3A. Cohorts 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 of study treatment. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
- Subject's tumor sample has CLDN18.2 expression (defined as moderate to strong membranous staining by central IHC testing) as follows:
Cohorts 1A, 2 and 3B: CLDN18.2 ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing. Cohort 3A: Subject's tumor expresses CLDN18.2 ≥ 50% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
- Cohorts 1A and 3A Only:
Subject has disease progression on or after at least 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.
- Cohort 2 Only:
- Subject has not received prior systemic anti-cancer therapy for their advanced disease (subject may have received neoadjuvant and/or fluorouracil-containing adjuvant chemotherapy as long as it has been completed ≥ 6 months before the first dose of study treatment).
- Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing.
- Cohorts 1A, 2 and 3B:
- Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment.
- Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period.
- Subject agrees not to participate in another interventional study while on treatment.
- 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 the first dose of study treatment. In case of multiple laboratory data within this period, the most recent data should be used.
- Hemoglobin (Hgb) ≥ 9 g/dL (transfusion is allowed, but post-transfusion Hgb [24 hours or later following transfusion] must be ≥ 9 /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)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN in subjects without liver metastases (≤ 5 x ULN if liver metastases are present)
- Estimated creatinine clearance ≥ 30 mL
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
- Cohorts 3A and 3B Only: No prior checkpoint inhibitor therapy.
- Cohort 3B Only:
- Subject has disease progression on 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.
- Subject has a tumor that is PD-L1 positive defined as a CPS ≥ 1 based on immunohistochemical staining with the Dako 22C3 PDL1 assay based on local or central testing.
- Subject has had 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 or contraindication to any component 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 systemic corticosteroids 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) receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast use are allowed.
- 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 preclude the subject from participation.
- Subject has history of central nervous system metastases and/or carcinomatous meningitis 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.
NOTE: Screening for these infections should be conducted per local requirements.
- 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 hepatitis C (HCV) serology, but negative HCV RNA test results are eligible.
- Subjects treated for HCV with undetectable viral load results are eligible.
- Subject has had within 6 months prior to first dose of study treatment any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure.
- Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study treatment.
- Subject has active autoimmune disease that has required systemic treatment in the past 3 months prior to the start of study treatment.
- Subject has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the subject unsuitable for study participation.
- Subject has had a major surgical procedure ≤ 28 days before start of study treatment.
- Subject is without complete recovery from a major surgical procedure ≤ 14 days before start of study treatment.
- Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days (Cohort 1) and ≤ 28 days (Cohort 2) prior to start of study treatment and has NOT any related toxicity.
- Subject has another malignancy, for which treatment is required.
- Cohort 2 Only, subject has any of the following:
- Prior severe allergic reaction or intolerance to any component of mFOLFOX6 chemotherapeutics in this study
- Known dihydropyrimidine dehydrogenase deficiency
- Known peripheral neuropathy > Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the subject ineligible).
- Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving.
- History of clinically significant ventricular arrhymias (i.e. sustained ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)
- QTc interval >450 msec for male subjects; QTc interval >470 for female subjects
- History or family history of congenital long QT syndrome
- Cardiac arrhymias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to first dose of study treatment are eligible)
- Cohort 3A and 3B Only, subject has any of the following:
- Subjects with ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or gastrointestinal ulcerative disease, or other uncontrolled or clinically significant medical disorders.
- Subjects with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed.
- Subject has known history of serious hypersensitivity reaction to a known ingredient of pembrolizumab.
- Cohort 3B Only: Subject with known microsatellite instability-high or mismatch repair deficient tumors.