A Study of Zolbetuximab (IMAB362) in Adults With Gastric Cancer

NCT ID: NCT03505320

Last Updated: 2025-10-20

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 143 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-29
• Study Completion Date: 2027-05-31

Brief Summary

Zolbetuximab is being studied as a treatment for people with cancer in and around the stomach or cancer where the food pipe (esophagus) joins the stomach (gastroesophageal junction cancer). Most people with this type of cancer have a protein called Claudin 18.2 in their tumor. Zolbetuximab is thought to work by attaching to Claudin 18.2 in their tumor. This switches on the body's immune system to attack the tumor.

There is an unmet medical need to treat people with advanced cancer in and around the stomach or gastroesophageal junction cancer. This study will provide more information on zolbetuximab given by itself and in combination with other treatments in adults with advanced stomach or gastroesophageal junction cancer. The study is currently ongoing globally. People in this study will either be treated with zolbetuximab by itself, with zolbetuximab and chemotherapy, with zolbetuximab and a medicine called pembrolizumab, or zolbetuximab with chemotherapy and a medicine called nivolumab.

This study is ongoing, but enrollment in any of the treatment options has been completed. In addition, at this stage of the study, treatment in some of these treatment options has completed.

The main aim of this study is to check how well zolbetuximab controls tumors when given by itself.

Adults with cancer in and around the stomach or gastroesophageal junction cancer can take part. Their cancer is locally advanced unresectable or metastatic and has the CLDN18.2 marker in a tumor sample. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery.

Metastatic means the cancer has spread to other parts of the body. They may have been previously treated with standard therapies. People cannot take part if they need to take medicines to suppress their immune system, have blockages or bleeding in their gut, have specific uncontrollable cancers such as symptomatic or untreated cancers in the nervous system, have a specific heart condition or infections.

There are different treatments in the study. People who take part will receive just 1 of the treatments.

Treatment will be given in cycles. The treatment is given through a vein; this is called an infusion. Some people with advanced disease will have 1 infusion in 3 week (21-day) cycles. Some people will have several infusions in 6 week (42-day) cycles. Some people with cancer in and around the stomach or gastroesophageal junction who have surgery for their cancer will have a few infusions in 2-week (14-day) cycles. This will happen before and after they have surgery for their cancer.

People may receive chemotherapy for up to 6 months. Some people enrolled to received zolbetuximab and pembrolizumab, may have received pembrolizumab for up to 2 years.

People will visit the clinic on certain days during their treatment; there may be extra visits during the first cycle of treatment. The study doctors will check if people had any medical problems from zolbetuximab and the other study treatments. Also, people in the study will have a health check including blood tests. On some visits they will also have scans to check for any changes in their cancer. Tumor samples will be taken at certain visits with the option of giving a tumor sample after treatment has finished.

People will visit the clinic after they stop treatment. They will be asked about any medical problems and will have a health check including blood tests. After the clinic visits end some people will have a telephone health check every 3 months. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.

Detailed 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.

Conditions

Pharmacokinetics of Zolbetuximab; Gastric Cancer; Gastro-esophageal Junction (GEJ) Cancer; Pharmacokinetics of Oxaliplatin; Pharmacokinetics of Fluorouracil Bolus (5-FU)

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

zolbetuximab (Cohort 1A)

Participants will be treated with zolbetuximab on a 21-day cycle in which zolbetuximab will be administered as a single agent every 3 weeks until disease progression, toxicity requiring cessation, start of another anti-cancer treatment or other treatment discontinuation criteria are met.

Group Type: EXPERIMENTAL

zolbetuximab

Intervention Type: DRUG

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

mFOLFOX6 plus zolbetuximab (Cohort 2)

Participants will be treated with zolbetuximab and mFOLFOX6 on a 42-day cycle in which zolbetuximab is administered on days 1 and 22, and mFOLFOX6 is administered on days 1, 15 and 29; however, for the first cycle, zolbetuximab will be administered on day 3 (instead of day 1) to allow for pharmacokinetic collection. Participants will receive up to 12 mFOLFOX6 treatments (4 cycles). Beginning at cycle 5, participants may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab for the remainder of the study per investigator's discretion. mFOLFOX6 treatment includes oxaliplatin: intravenous \[IV\] infusion, leucovorin: IV infusion, fluorouracil bolus: IV bolus, fluorouracil infusion: continuous IV infusion.

Group Type: EXPERIMENTAL

zolbetuximab

Intervention Type: DRUG

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

oxaliplatin

Intervention Type: DRUG

Oxaliplatin will be administered as a 2-hour IV infusion.

leucovorin

Intervention Type: DRUG

Leucovorin will be administered as a 2-hour IV infusion.

fluorouracil

Intervention Type: DRUG

Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.

folinic acid

Intervention Type: DRUG

Folnic acid will be administered as a 2-hour IV infusion.

Pembrolizumab plus zolbetuximab (Cohort 3A)

Participants will be treated with zolbetuximab and pembrolizumab on a 21-day cycle. Loading dose of zolbetuximab will be administered at cycle 1, day 1 followed by maintenance dose of zolbetuximab once every 3 weeks (Q3W). Pembrolizumab will be administered to 3 to 6 subjects at a intravenously on day 1 of every 21-day cycle and will be infused 1 hour after the zolbetuximab infusion is completed. Tolerability and safety of zolbetuximab in combination with pembrolizumab will be evaluated during the 3-week dose-limiting toxicity (DLT) assessment period. If this cycle 1 dose is not tolerable, a lower dose of zolbetuximab in combination with pembrolizumab will subsequently be evaluated.

Group Type: EXPERIMENTAL

zolbetuximab

Intervention Type: DRUG

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab will be administered intravenously over 30 minutes.

Zolbetuximab in combination with mFOLFOX6 and nivolumab (Cohort 4A/4B)

Participants will be treated with zolbetuximab and mFOLFOX6, nivolumab on a 42-day cycle. Cohort 4A: Loading dose of zolbetuximab in combination with nivolumab and mFOLFOX6 on cycle 1 day 1, followed by zolbetuximab in combination with nivolumab and mFOLFOX6 q2w \[days 15 and 29\] (1 cycle = 6 weeks). Tolerability and safety of zolbetuximab in combination with nivolumab, mFOLFOX6 will be evaluated during the 3-week DLT assessment period. If cycle 1 dose is not tolerable, a lower dose of dose zolbetuximab in combination with nivolumab and mFOLFOX6 will be subsequently evaluated. Cohort 4B: Subjects will be treated with the combination of zolbetuximab, mFOLFOX6 and nivolumab at the dose deemed tolerable in Cohort 4A. Subjects will receive up to 12 mFOLFOX6 treatments (4 cycles). For Cohorts 4A and 4B, beginning at cycle 5, subjects may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab and nivolumab for the remainder of the study per investigator's discretion.

Group Type: EXPERIMENTAL

zolbetuximab

Intervention Type: DRUG

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

oxaliplatin

Intervention Type: DRUG

Oxaliplatin will be administered as a 2-hour IV infusion.

leucovorin

Intervention Type: DRUG

Leucovorin will be administered as a 2-hour IV infusion.

fluorouracil

Intervention Type: DRUG

Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.

folinic acid

Intervention Type: DRUG

Folnic acid will be administered as a 2-hour IV infusion.

nivolumab

Intervention Type: DRUG

Nivolumab will be administered intravenously according to institutional standards.

Zolbetuximab in combination with FLOT (Cohort 5)

Participants will be treated with zolbetuximab & FLOT for a total of eight 2-week cycles. 4 cycles preoperatively & 4 cycles postoperatively 6-12 weeks after surgery.

Preoperative: Participants will receive zolbetuximab loading dose on cycle 1 day 1, followed by FLOT on cycle 1 day 2. For cycles 2-4, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 & FLOT on day 2.

Post operative: Participants will receive zolbetuximab loading dose on cycle 5 day 1, followed by FLOT on cycle 5 day 2. For cycles 6-8, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 and FLOT on day 2. For participants who experience a DLT during preoperative treatment on the loading dose, the postoperative loading dose may be lowered.

Group Type: EXPERIMENTAL

zolbetuximab

Intervention Type: DRUG

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

oxaliplatin

Intervention Type: DRUG

Oxaliplatin will be administered as a 2-hour IV infusion.

leucovorin

Intervention Type: DRUG

Leucovorin will be administered as a 2-hour IV infusion.

fluorouracil

Intervention Type: DRUG

Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.

folinic acid

Intervention Type: DRUG

Folnic acid will be administered as a 2-hour IV infusion.

Docetaxel

Intervention Type: DRUG

Docetaxel will be administered as a 1-hour IV infusion.

Interventions

zolbetuximab

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

Intervention Type: DRUG

oxaliplatin

Oxaliplatin will be administered as a 2-hour IV infusion.

Intervention Type: DRUG

leucovorin

Leucovorin will be administered as a 2-hour IV infusion.

Intervention Type: DRUG

fluorouracil

Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.

Intervention Type: DRUG

Pembrolizumab

Pembrolizumab will be administered intravenously over 30 minutes.

Intervention Type: DRUG

folinic acid

Folnic acid will be administered as a 2-hour IV infusion.

Intervention Type: DRUG

nivolumab

Nivolumab will be administered intravenously according to institutional standards.

Intervention Type: DRUG

Docetaxel

Docetaxel will be administered as a 1-hour IV infusion.

Intervention Type: DRUG

Other Intervention Names

IMAB362

Eligibility Criteria

Inclusion Criteria

• 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 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs.
• 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.

• Hemoglobin (Hgb) ≥ 9 g/dL (transfusion is allowed, but post-transfusion Hgb [24 hours or later following transfusion] must be ≥ 9 g/dL)
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
• Platelets ≥ 100 × 10^9/L
• Albumin ≥ 2.5 g/dL
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN in subjects without liver metastases (≤ 5 × ULN if liver metastases are present)
• Cohorts 1-4: Estimated creatinine clearance ≥ 30 mL/min
• Cohort 5: Serum creatinine ≤ 1.5 × ULN, or estimated creatinine clearance ≥ 50 mL/min for subjects with serum creatinine levels > 1.5 × ULN
• Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × ULN (except for subjects receiving anticoagulation therapy)

Specific to Cohort 1A:

• Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. 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 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 and all associated side effects have resolved to grade 1 or less.
• 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 as indicated in the Schedule of Assessments.

Specific to Cohort 2:

• Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. 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 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.
• 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 as indicated in the Schedule of Assessments.

Specific to Cohort 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 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.
• Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4A and 4B:

• Subject has radiologically evaluable disease.
• Subject has not received prior systemic anti-cancer therapy for their advanced disease.
• Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing.
• Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4B Only:

• 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.

Specific to Cohort 5 Only:

• Subject has new histologically confirmed primary gastric or GEJ adenocarcinoma that is amenable to curative resection.
• Subject has locoregional, resectable gastric or GEJ adenocarcinoma. GEJ may include type I-III Siewert classification. Clinical stage will be determined by endoscopic ultrasound (EUS) and/or CT or MRI. Diagnostic laparoscopy may be used as per institutional guidelines and clinical practices.
• Subject meets one of the following criteria of locoregional disease by clinical TNM staging:
• GEJ: cT2,N0 (high risk-lesions: ≥ 3 cm, poorly differentiated), cT1b-cT2,N+ or cT3-cT4a,Any N.
• Gastric: T2 to T4a, and/or N1-3,M0.
• Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing

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

• Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days (Cohorts 1 and 3A) and ≤ 28 days (Cohorts 2 and 4A or 4B) prior to start of study treatment and has NOT recovered from any related toxicity.
• Subject has another malignancy, for which treatment is required.
• Cohort 2, 4 and 5 Only, subject has any of the following:

• Prior severe allergic reaction or intolerance to any component of mFOLFOX6 or FLOT chemotherapeutics in this study
• Known dihydropyrimidine dehydrogenase deficiency (DPD).
• 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 arrhythmias.
• 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 (Subjects with rate controlled atrial fibrillation for > 1 month prior to first dose of study treatment are eligible).
• Cohorts 3A, 4A and 4B Only, subject has any of the following:

• Ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or gastrointestinal ulcerative disease, or solid organ or stem cell transplant (for Cohort 4) or other uncontrolled or clinically significant medical disorders.
• 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.
• Known history of serious hypersensitivity reaction to a known ingredient of pembrolizumab or nivolumab.
• Cohort 4B Only: Subjects has microsatellite instability-high or mismatch repair deficient tumors.
• Cohort 5 Only, subject has either of the following:

• Subject cannot undergo curative resection per the investigator's judgment
• Subject meets the following criterion of locoregional disease by clinical TNM staging: cT1N0.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Astellas Pharma Global Development, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Global Medical Lead

Role: STUDY_DIRECTOR

Astellas Pharma Global Development, Inc.

Locations

The Angeles Clinic and Research Institute

Los Angeles, California, United States

UCLA Medical Center

Santa Monica, California, United States

University of Chicago

Chicago, Illinois, United States

Mass General / North Shore Can

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Weill Cornell Medical College

New York, New York, United States

Site FR33003

Pessac, Nouvelle-Aquitaine, France

Site FR33002

Poitiers, Nouvelle-Aquitaine, France

Site FR33001

Brest, , France

Site FR33004

Paris, , France

Site IT39005

Milan, , Italy

Site IT39002

Napoli, , Italy

Site IT39004

Padua, , Italy

Site IT39003

Pisa, , Italy

Site JP81001

Chiba, , Japan

Site JP81002

Tokyo, , Japan

Site JP81003

Tokyo, , Japan

Site KR82002

Seongnam-si, , South Korea

Site KR82001

Seoul, , South Korea

Site TW88601

Taichung, , Taiwan

Site TW88602

Tainan City, , Taiwan

Countries

United States; France; Italy; Japan; South Korea; Taiwan

Other Identifiers

2017-002566-50

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

jRCT2080225325

Identifier Type: REGISTRY

Identifier Source: secondary_id

2024-511649-21-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

8951-CL-0103

Identifier Type: -

Identifier Source: org_study_id