A Study to Compare Zolbetuximab (IMAB362) and Chemotherapy With Placebo and Chemotherapy in Adults With Gastric Cancer.

Phase 3Active Not RecruitingNCT03504397

Astellas Pharma Global Development, Inc.565 enrolled

Overview

Zolbetuximab is being studied in people with cancer in and around the stomach or where the food pipe (esophagus) joins the stomach, called gastroesophageal junction (GEJ) 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 the Claudin 18.2 protein in their tumor, which switches on the body's immune system to attack the tumor. There is an unmet medical need to treat people with advanced stomach cancer or GEJ cancer. This study will give more information about how well zolbetuximab works when given with chemotherapy in adults with advanced stomach cancer or GEJ cancer. In this study, adults with advanced stomach cancer or GEJ cancer will either be given zolbetuximab with chemotherapy or a placebo with chemotherapy. A placebo looks like zolbetuximab but doesn't have any medicine in it. Zolbetuximab with chemotherapy has already been approved to treat gastric cancer and GEJ cancer in some countries. This study is being done in countries where zolbetuximab has not yet been approved for use. If zolbetuximab becomes approved for use in those countries taking part in this study, the study doctor will switch study treatment in those countries to the licensed zolbetuximab. If this happens, people taking part in those countries will leave this study and receive licensed zolbetuximab. The main aim of the study is to check if zolbetuximab and chemotherapy can prevent or delay the worsening of people's gastric cancer and GEJ cancer compared to placebo and chemotherapy. Adults with advanced stomach cancer or GEJ cancer can take part. 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. A tumor sample of their cancer will also have the Claudin 18.2 protein. They may have been previously treated with certain standard therapies, but have not been treated with chemotherapy for their cancer. 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, or have a specific heart condition, or infections. The study treatments are either zolbetuximab with chemotherapy, or placebo with chemotherapy. People who take part will receive just 1 of the study treatments by chance. Study treatment will be double-blinded. That means that the people in the study and the study doctors will not know who takes which of the study treatments. Study treatment will be given in cycles. The study treatment is given to people slowly through a tube into a vein. This is called an infusion. People will have 4 infusions in 6-week (42-day) cycles as follows: * Zolbetuximab or placebo - 2 infusions in a cycle. * Chemotherapy (called modified FOLFOX6 or mFOLFOX6) - 3 infusions in a cycle. The first infusion is combined with zolbetuximab or placebo on day 1 of each cycle. People may receive zolbetuximab or placebo until their cancer worsens, they cannot tolerate the study treatment, or they need to start another cancer treatment. People will receive mFOLFOX6 for up to 6 months (4 study treatment cycles). After the 6 months people may receive chemotherapy containing folinic acid and fluorouracil instead of mFOLFOX6. People may receive folinic acid and fluorouracil chemotherapy for more than 6 months, or until their cancer worsens, they cannot tolerate the study treatment, or they need to start another cancer treatment. People will visit the clinic on certain days during their study treatment. The study doctors will check if people had any medical problems from taking zolbetuximab or the other study treatments. Also, people in the study will have health checks. On some visits they will have scans to check for any changes in their cancer. People will have the option of giving a tumor sample after their study treatment has finished. People will visit the clinic after they stop their study treatment. People who start treatment with licensed zolbetuximab or mFOLFOX6 outside of this study will not need to visit the clinic. People will be asked about any medical problems and will have a health check. People will visit the clinic at 1 month after they stop their study treatment. People will continue to have scans every 9 or 12 weeks to check for any changes in their cancer. People will have telephone health checks 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 study treatment or not.

Interventions

zolbetuximabDRUG

Participants received an IV infusion (as a minimum of 2-hour infusion) of zolbetuximab at a loading dose of 800 mg/m\^2 on C1D1 followed by subsequent doses of 600 mg/m\^2 every 3 weeks starting from C1D22 until participant meets study treatment discontinuation criteria. Each cycle was approximately 42 days.

placeboDRUG

Participants received an IV infusion (as a minimum of 2-hour infusion) of placebo matched to zolbetuximab on C1D1 followed by subsequent doses every 3 weeks starting from C1D22 until participant met study treatment discontinuation criteria. Each cycle was approximately 42 days.

oxaliplatinDRUG

Participants received up to 12 treatments of oxaliplatin administered 85 mg/m\^2 IV infusion over 2 hours) on Days 1, 15 and 29 of each cycle.. A maximum of 12 doses of oxaliplatin was permitted. Each cycle was approximately 42 days.

folinic acidDRUG

Participants received up to 12 treatments of folinic acid administered 400 mg/m\^2 IV infusion over 2 hours 4 or more cycles on Days 1, 15 and 29 of each cycle. participants could continue to receive folinic acid on Days 1, 15 and 29 of each cycle at the investigator's discretion or until the participant met the study treatment discontinuation criteria. Each cycle was approximately 42 days.

fluorouracilDRUG

Participants received up to 12 treatments of 5-fluorouracil over 4 or more cycles administered by IV bolus 400 mg/m\^2 over 5 to 15 minutes followed by 2400mg/m\^2 over 46-48 hours continuous IV infusion every 2 weeks for 4 cycles. Participants could continue to receive 5-fluorouracil on Days 1, 15 and 29 of each cycle at the investigator's discretion or until the participant met the study treatment discontinuation criteria. Each cycle was approximately 42 days.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Female subject eligible to participate if she is not pregnant (negative serum pregnancy test at screening; female subjects with elevated serum beta human chorionic gonadotropin and a demonstrated non-pregnant status through additional testing are eligible) 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 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 drug 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 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 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 immunohistochemistry (IHC) testing. * Subject has a HER2-Negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative gastric or GEJ tumor.) * 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 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 (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb ≥ 9 g/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) 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 (PT)/international normalized ratio (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 may have received treatment with herbal medications that have known antitumor activity \> 28 days 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 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 mFOLFOX6. * Subject has known dihydropyrimidine dehydrogenase 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 would 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 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 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.

Outcomes

Primary Outcomes

Progression Free Survival (PFS)

PFS was defined as the time from the date of randomization until the date of radiological progressive disease (PD) (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 by independent review committee \[IRC\]) or death from any cause, whichever was earliest. PD was defined as development of new, or progression of existing metastases to the primary cancer under the study. Kaplan -Meier (KM) estimates was used.

Time frame: From date of randomization until the date of first documented radiological progression or date of death from any cause, whichever occurred first (up to 62 months and 18 days)

Secondary Outcomes

Overall Survival (OS)

OS was defined as the time from the date of randomization until the date of death from any cause. Kaplan-Meier estimates was used.