This clinical trial studies treatment for gastric cancer and gastroesophageal junction adenocarcinoma that cannot be surgically removed or has spread to other parts of the body. The study tests a combination of medications including zolbetuximab, pembrolizumab, and chemotherapy drugs (capecitabine, oxaliplatin, fluorouracil, and folinic acid). The purpose is to evaluate whether adding zolbetuximab to pembrolizumab and chemotherapy works better than chemotherapy and pembrolizumab alone as a first treatment.
The study involves people whose tumors test negative for a protein called HER2 but positive for two other proteins called CLDN18.2 and PD-L1. During the study, participants will receive either zolbetuximab or a placebo along with pembrolizumab and chemotherapy through intravenous infusions. Some chemotherapy medications will be given as tablets to take by mouth.
Researchers will track how long participants live, whether their cancer grows or spreads, and how their tumors respond to treatment. They will also monitor participants for any side effects from the treatment combination. The study will check blood samples to measure drug levels and test for the body’s immune response to the medications.
1Initial treatment phase
You will receive a combination of medications through different methods:
– Zolbetuximab (Vyloy) given through an intravenous infusion
– Pembrolizumab (Keytruda) given through an intravenous infusion
– One of two chemotherapy combinations:
2Chemotherapy option 1 (CAPOX)
CAPOX combination includes:
– Oxaliplatin given through an infusion
– Capecitabine taken as oral medication
3Chemotherapy option 2 (mFOLFOX6)
mFOLFOX6 combination includes:
– Oxaliplatin given through an infusion
– Fluorouracil given through intravenous injection or infusion
– Folinic acid given through an infusion
4Monitoring phase
Regular assessments will include:
– Evaluation of how the cancer responds to treatment
– Physical examinations
– Blood tests
– Heart monitoring (ECG)
– Checking for side effects of the treatment
5Treatment duration
The study will continue until:
– The cancer shows signs of progression
– Unacceptable side effects occur
– The planned end date of the study (January 2030)
Your doctor will regularly evaluate if continuing the treatment is beneficial for you
Who Can Join the Study?
Must be at least 18 years old to sign the consent form
Must have a tumor that tests positive for PD-L1 (a protein that helps control immune system responses)
Must have confirmed gastric or gastroesophageal adenocarcinoma (cancer of the stomach or where the stomach meets the esophagus)
Must have advanced cancer that cannot be surgically removed or has spread to other parts of the body, confirmed by imaging within 28 days before study start
Must have cancer that can be measured by imaging scans. If there is only one measurable tumor and previous radiation therapy, the tumor must either be outside the treated area or show growth after radiation
Must have good physical function status (ECOG score of 0 or 1), meaning able to perform daily activities with minimal assistance
Must have a life expectancy of at least 12 weeks as determined by the doctor
Must be able to receive treatment with mFOLFOX6 or CAPOX (types of chemotherapy) and pembrolizumab (an immunotherapy drug)
Must have a tumor that is HER2-negative (does not have high levels of a specific protein called HER2)
Must have a tumor that is positive for CLDN18.2 (a specific protein found in some stomach cancers)
Who Cannot Join the Study?
Known allergy or sensitivity to any of the study medications or their components
Previous treatment with chemotherapy for advanced or metastatic (cancer that has spread to other parts of the body) gastric cancer
Active autoimmune disease (condition where your immune system attacks healthy cells) requiring systemic treatment
Presence of brain metastases (cancer spread to the brain) that are untreated or unstable
History of other cancers within the last 5 years, except for successfully treated non-melanoma skin cancer or cervical cancer in situ
Significant heart conditions including heart failure, uncontrolled high blood pressure, or recent heart attack
Active hepatitis B or hepatitis C infection
Active tuberculosis infection
Pregnant or breastfeeding women
Unable to swallow oral medications
Major surgery within 4 weeks before starting the study treatment
Participation in another clinical trial within 4 weeks before starting this study
Any condition that, in the opinion of the study doctor, would make participation unsafe
Zolbetuximab is an antibody medication that targets a specific protein called Claudin 18.2, which is found on the surface of some stomach and gastroesophageal junction cancer cells. It works by helping the immune system recognize and attack cancer cells.
Pembrolizumab is an immunotherapy medication that helps the body’s immune system detect and fight cancer cells. It works by blocking a protein called PD-L1 that cancer cells use to hide from the immune system.
CAPOX is a combination chemotherapy treatment that includes two medications: capecitabine and oxaliplatin. These medications work together to kill cancer cells or stop them from growing.
mFOLFOX6 is another combination chemotherapy treatment that includes several medications: fluorouracil, leucovorin, and oxaliplatin. These medications work together in different ways to kill cancer cells or prevent them from multiplying.
Gastric Adenocarcinoma – A type of stomach cancer that begins in the glandular cells of the stomach lining. These cells normally produce mucus and other fluids that help with digestion. The disease typically develops slowly over many years, starting with changes in the stomach’s inner lining. As the cancer grows, it can spread deeper into the stomach walls and potentially to other parts of the body.
Gastric Cancer – A disease where abnormal cells form in the tissues of the stomach. It usually starts in the mucus-producing cells that line the stomach. The condition can develop in any part of the stomach and can spread throughout the stomach and to other organs. Early stages may have minimal symptoms, while the disease progresses gradually over time.
Gastroesophageal Junction Adenocarcinoma – A cancer that forms in the area where the esophagus joins the stomach. This type of cancer develops in the glandular tissue near the junction of these two organs. The disease begins in the cells that make and release mucus and other fluids. As it progresses, it can affect both the lower esophagus and upper portion of the stomach.
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