A Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX 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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of zolbetuximab plus capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX (as first-line treatment) as measured by Progression Free Survival (PFS). This study will also evaluate efficacy, physical function, safety, and tolerability of zolbetuximab, as well as its effects on quality of life. Pharmacokinetics (PK) of zolbetuximab and the immunogenicity profile of zolbetuximab will be evaluated as well.

Detailed Description
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The study consists of the following periods: screening; treatment; post-treatment follow up, safety follow up, long term and survival follow-up.

Official Title
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A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX 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

Conditions
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Locally Advanced Unresectable Gastroesophageal Junction (GEJ) Adenocarcinoma or Cancer, Locally Advanced Unresectable Gastric Adenocarcinoma or Cancer, Metastatic Gastric Adenocarcinoma or Cancer, Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma

Intervention / Treatment
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* Drug: zolbetuximab
* Drug: oxaliplatin
* Drug: capecitabine
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: Not a woman of childbearing potential (WOCBP) OR WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for 9 months after the final administration of oxaliplatin 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 treatment administration. Female subject must not donate ova starting at screening and throughout the study period, and for 9 months after the final administration of oxaliplatin and 6 months after the final administration of all other study drugs. A male subject with female partner(s) of childbearing potential: must agree to use contraception during the treatment period and for 6 months after the final study treatment administration. A male subject must not donate sperm during the treatment period and for 6 months after the final study treatment 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 treatment 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 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 or 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 the case of multiple sample collections within this period, the most recent sample collection with available results should be used to determine eligibility. Hemoglobin (Hb) ≥ 9 g/dl. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb ≥ 9 g/dL. Absolute Neutrophil Count (ANC) ≥ 1.5x10^9/L Platelets ≥ 100x10^9/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/international normalized ratio (PT/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, immunotherapy or other systemic anticancer therapies as long as it was completed at least 6 months 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 treatment with herbal medications or other treatments that have known antitumor activity within 28 days prior to randomization. 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 CAPOX. Subject has known dihydropyrimidine dehydrogenase (DPD) 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 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 (CNS) 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 co-morbid 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (zolbetuximab plus CAPOX)<br>Participants will receive a loading dose of zolbetuximab at Cycle 1 Day 1 followed by a lower dose in subsequent cycles every 3 weeks. Additionally, participants will receive CAPOX (capecitabine/oxaliplatin) treatment until IRC confirmed disease progression or a total of 8 treatments (each cycle is defined as 3 weeks = approximately 21 days). Oxaliplatin is administered on day 1 of each cycle, whereas capecitabine is taken twice daily on days 1 through 14. After a maximum of 8 treatments of Oxaplatin, subjects may continue to receive capecitabine twice daily on days 1 through 14 of each cycle at the investigator's discretion until the subject meets study treatment discontinuation criteria. | Drug: zolbetuximab<br>* Zolbetuximab will be administered as a minimum 2-hour IV infusion.<br>* Other names: IMAB362;Drug: oxaliplatin<br>* Oxaliplatin will be administered as a 2-hour IV infusion.<br>Drug: capecitabine<br>* Capecitabine will be administered orally twice daily (bid).<br>|
| Placebo Comparator: Arm B (Placebo plus CAPOX)<br>Participants will receive placebo starting at Cycle 1 Day 1 and every 3 weeks thereafter. Additionally, participants will receive CAPOX (capecitabine/oxaliplatin) treatment until IRC confirmed disease progression or a total of 8 treatments (each cycle is defined as 3 weeks = approximately 21 days). Oxaliplatin is administered on day 1 of each cycle, whereas capecitabine is taken twice daily on days 1 through 14. After a maximum of 8 treatments of Oxaplatin, subjects may continue to receive capecitabine twice daily on days 1 through 14 of each cycle at the investigator's discretion until the subject meets study treatment discontinuation criteria. | Drug: oxaliplatin<br>* Oxaliplatin will be administered as a 2-hour IV infusion.<br>Drug: capecitabine<br>* Capecitabine will be administered orally twice daily (bid).<br>Drug: placebo<br>* Placebo will be administered as a minimum 2-hour IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from the date of randomization until the date of radiological progressive disease (per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by Independent Review Committee (IRC)) or death from any cause, whichever is earliest. | up to 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from the date of randomization until the date of death from any cause. | up to 23 months | 
| Time to confirmed deterioration (TTCD) in participant-reported physical functioning and Global Health Status/Quality of Life (GHS/QoL) | TTCD is measured by EORTC QLQ-C30 and QLQ-OG25 plus STO22 Belching subscale and defined as time to first confirmed deterioration; that is, time from randomization to first clinically meaningful deterioration that is confirmed at the next scheduled visit. | Up to 16 months | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants who have a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by Independent Review Committee (IRC) per RECIST 1.1. | up to 13 months | 
| Duration Of Response (DOR) | DOR, defined as the time from the date of the first response (CR/PR) until the date of progressive disease as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest. | up to 13 months | 
| Safety and tolerability assessed by adverse events (AEs) | An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | up to 16 months | 
| Number of participants with laboratory assessments abnormalities and or adverse events | Number of participants with potentially clinically significant laboratory values. | up to 14 months | 
| Number of participants with vital signs abnormalities and or adverse events | Number of participants with potentially clinically significant vital sign values. | up to 14 months | 
| Number of participants with electrocardiograms (ECG) abnormalities and or adverse events | Number of participants with potentially clinically significant ECG values. | up to 14 months | 
| Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events | Number of participants with potentially clinically significant ECOG performance status values. ECOG grades 0-5, where 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair and 5 = Dead. | up to 13 months | 
| Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC-QLQ-C30) | EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change. | up to 16 months | 
| Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Oesophago-Gastric Module 25 (QLQ-OG25) questionnaire plus EORTC-QLQ-STO22 Belching subscale | The EORTC-QLQ-OG25 instrument evaluates Gastric and Gastroesophageal Junction (GEJ) cancer-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion. It is a 25-item questionnaire. Participants rate items on a four-point scale, with 1 as not at all and 4 as very much. To ensure relevant symptoms are adequately covered two questions from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach (EORTC-QLQ-STO22) instrument related to belching and bile or acid coming in your mouth will be asked following the OG25 questionnaire. Participants rate items on a 4 point scale, with 1 as not at all and 4 as very much. The total and subscale scores from the OG25 and item scores from the STO22 items will be reported. | up to 16 months | 
| Health Related Quality of Life (HRQoL) measured by the Global Pain (GP) questionnaire | The GP instrument is a single assessment of overall pain where 0 equals no pain and 10 equals extreme pain. Low pain scores are considered a better outcome than a high pain score. | up to 16 months | 
| Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire | The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples. | up to 16 months | 
| Pharmacokinetics (PK) of zolbetuximab: Concentration Immediately Prior to Dosing at multiple dosing (Ctrough) | Ctrough will be derived from the PK serum samples collected. | up to 16 months | 
| Number of anti-drug antibody (ADA) Positive Participants | Immunogenicity will be measured by the number of participants that are ADA positive. | up to 16 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLDN 18.2, gastroesophageal junction cancer, adenocarcinoma, IMAB362, oxaliplatin, HER2, claudiximab, capecitabine, gastric cancer, HER2 Negative, zolbetuximab