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About
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 (with or without Nivolumab) 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 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT). This study will also evaluate the pharmacokinetics (PK) of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT) and PK of oxaliplatin, fluorouracil (5-FU), and pembrolizumab in combination with zolbetuximab, 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 (with or without Nivolumab) 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 mFOLFOX6 and nivolumab and in combination with FLOT.
Full description
This is a study to assess the antitumor activity of zolbetuximab, an Immunoglobulin (IgG1) chimeric monoclonal antibody directed against CLDN18.2, in subjects with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma and locoregional gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive. For each cohort, the study consists of the following periods: pre-screening; screening; treatment; and follow-up for disease progression (or post-treatment follow-up for disease recurrence, which will be conducted for Cohort 5). In addition, there will be a survival follow-up period for Cohorts 1A, 4B, and 5 participants only. Tolerability of zolbetuximab in combination with pembrolizumab in Japanese participant(s) will be evaluated in Cohort 3A DLT assessment. Tolerability of zolbetuximab in combination with mFOLFOX6 and nivolumab in Japanese subject(s) will be evaluated in Cohort 4B, if Japanese subjects are not enrolled in the Cohort 4A DLT assessment.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Female subject eligible to participate if she is not pregnant and at least one of the following conditions applies:
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 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs.
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.
Cohorts 1-4: Subject has radiographically-confirmed, locally advanced, unresectable or 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 strong membranous staining as determined by central IHC testing.
Subject agrees to not 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 central laboratory data within this period, the most recent data should be used.
Specific to Cohort 1A:
Specific to Cohort 2:
Specific to Cohort 3A:
Specific to Cohort 4A and 4B:
Specific to Cohort 4B Only:
Specific to Cohort 5 Only:
Exclusion criteria
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.
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.
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 within 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 psychiatric illness or social situations that would preclude study compliance.
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
Cohort 2, 4 and 5 Only, subject has any of the following:
Cohorts 3A, 4A and 4B Only, subject has any of the following:
Cohort 4B Only: Subjects has microsatellite instability-high or mismatch repair deficient tumors.
Cohort 5 Only, subject has either of the following:
Primary purpose
Allocation
Interventional model
Masking
143 participants in 5 patient groups
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Central trial contact
Astellas Pharma Global Development
Data sourced from clinicaltrials.gov
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