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
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
Zolbetuximab is being studied in people with cancer in and around the stomach or where the food pipe (esophagus) joins the stomach, called 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 stomach 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 people taking part in those countries will leave this study and receive licensed zolbetuximab.
The main aim(s) of the study is(are) to determine the efficacy of zolbetuximab combined with chemotherapy compared to a placebo combined with chemotherapy in treating adults with Claudin 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.
Adults with locally advanced unresectable or metastatic 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 one of the 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. The chemotherapy is called CAPOX (capecitabine and oxaliplatin) and will be given as an infusion and also as tablets. People will have 1 infusion of either zolbetuximab or placebo together with oxaliplatin chemotherapy in 3-week (21-day) cycles. People will also take 1 tablet of capecitabine (chemotherapy) twice a day for the first 2 weeks (14 days) of each cycle. People may receive zolbetuximab or placebo until their cancer worsens, they cannot tolerate the treatment, or they need to start another cancer treatment. People will receive CAPOX for up to about 6 months (8 treatment cycles). After the 6 months, people may receive capecitabine chemotherapy only, 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 treatment. The study doctors will check if people had any medical problems from 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 within 7 days after they stop their study treatment. People will be asked about any medical problems and will have a health check. People who start treatment with licensed zolbetuximab will not need to attend the clinic for further visits and will receive standard of care health checks. People who continue study treatment will visit the clinic at 1 and 3 months after they stop their study treatment. They will continue to have scans every 9 or 12 weeks to check for any changes in their cancer. They 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 treatment or not.
After the marketing approval in Japan on 26 Mar 2024, this study continued as "post marketing clinical study" in Japan. In the rest of the countries which participated in this study, this study continued as clinical study.
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:
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:
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. (Unique to China: Subject has a known HER2-negative gastric or GEJ tumor.)
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.
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.
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:
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 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.
Houston, Texas 77030, United States
Northwood, Argentina
Haebrin, China
Neo Faliro, Piraeus, Greece
Rio Patras, Greece
Kita-gun, Japan
Jeollanam-do, South Korea
Tianan, Taiwan
Laksi, Thailand
Muang, Thailand
Muang, Thailand
Pathumwan, Thailand
Atakum, Turkey (Türkiye)