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A Phase 3 Study of ASP2138 Plus Drug Combination in Adults with HER2‑Negative, CLDN18.2‑Positive Advanced Gastric Cancer (First‑Line Treatment)

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults with gastric or gastroesophageal junction adenocarcinoma that cannot be removed by surgery or has spread to other parts of the body. All participants have tumors that are HER2‑negative and Claudin 18.2‑positive. The investigational drug being tested is called ASP2138, which is given together with standard chemotherapy regimens known as CAPOX or mFOLFOX6, and with the immunotherapy medicine pembrolizumab. A comparison group receives the same chemotherapy but receives a placebo instead of the new drug, and may or may not receive pembrolizumab. The chemotherapy backbone includes medicines such as oxaliplatin, fluorouracil, capecitabine, and folinic acid, which are given by IV infusion or taken as oral tablets, while the placebo is provided as an IV infusion of either glucose or sodium chloride.

The purpose of the study is to determine whether adding the new drug to the usual treatment improves outcomes for patients with this type of cancer. Participants receive a series of treatment cycles in which the medicines are administered through a vein (infusion) or taken by mouth, followed by regular clinic visits where doctors check vital signs, perform blood tests, and conduct imaging scans to see how the disease is responding. Throughout the study, patients are asked to report any side effects they experience, and their overall quality of life is assessed with questionnaires. The trial continues until the disease progresses, side effects become unmanageable, or the study period ends.

The research process

The trial runs in 6 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and Treatment Assignment

    After enrollment, you are randomly assigned to one of two study arms. One arm receives ASP2138 together with chemotherapy and pembrolizumab. The other arm receives a matching placebo together with chemotherapy and either pembrolizumab or its placebo. The study is double‑blind, so you will not know which specific medications you receive.

  2. Step 2

    First Infusion Cycle

    On the first day of the treatment cycle you attend the clinic for intravenous infusions. The infusion bag contains the study drug (ASP2138 or its placebo such as glucose or sodium chloride) and the chemotherapy agents oxaliplatin, fluorouracil, and folinic acid. A separate infusion of pembrolizumab or its matching placebo is also administered. Each infusion is given as a single dose per the study protocol.

  3. Step 3

    Oral Medication Period

    If the chemotherapy regimen includes capecitabine, you will take capecitabine tablets by mouth. The tablets are taken as directed, usually at regular intervals each day during the cycle, according to the study instructions.

  4. Step 4

    Subsequent Treatment Cycles

    The same set of infusions and oral medication is repeated for each subsequent treatment cycle. You will return to the clinic at the scheduled intervals to receive the infusions of the study drug or placebo, chemotherapy, and pembrolizumab or its placebo. Treatment continues until the investigator decides to stop it because of disease progression, unacceptable side effects, or completion of the planned number of cycles.

  5. Step 5

    Safety and Response Assessments

    During the trial you undergo regular safety evaluations, including blood tests, vital‑sign measurements, electrocardiograms (ECG), and performance‑status checks. Imaging studies are performed to assess tumor response according to RECIST criteria. You will also complete questionnaires about symptoms and quality of life.

  6. Step 6

    End of Treatment and Follow‑Up

    After the final treatment cycle you continue with scheduled follow‑up visits. These visits include the same safety assessments and imaging studies to monitor long‑term outcomes and any delayed effects of the study medications.

Who can join the trial?

15 criteria

  • Be at least 18 years old when you sign the consent form.
  • Your tumor must be HER2‑negative (tests show HER2 protein level is low or absent).
  • Your tumor must test positive for CLDN18.2 (a specific protein found on some cancer cells).
  • You need a valid result for PD‑L1 testing. If your tumor has a condition called microsatellite instability‑high or is mismatch repair deficient, you can still join as long as the PD‑L1 test shows a score of 1 or higher.
  • Your overall health score, called ECOG performance status, must be 0 or 1 (meaning you are fully active or able to do light work).
  • Recent lab tests (taken within the last 14 days) must be normal, and if you receive a blood transfusion, your hemoglobin level measured at least 24 hours later must be at least 9 g/dL.
  • You must agree not to be in another interventional study while taking part in this study.
  • You must provide a special preserved tumor sample called FFPE (formalin‑fixed, paraffin‑embedded) for testing.
  • Your stomach or gastro‑esophageal junction cancer must be confirmed by a tissue exam (either under a microscope or by cell analysis).
  • Imaging tests (like scans) must show that the cancer is locally advanced and cannot be removed by surgery, or that it has spread to other parts of the body, confirmed within 28 days before joining.
  • The doctor must believe you have a life expectancy of at least 12 weeks.
  • If you are female, you must not be pregnant, must not be breastfeeding, and must follow specific birth‑control rules (including using reliable contraception or having a negative pregnancy test) for the study period and for a set time after the last treatment.
  • If you are male, you must agree to use contraception with any partner who could become pregnant, use condoms or remain abstinent during the study, and not donate sperm for a period after the last treatment.
  • You must sign an informed consent form agreeing to all study requirements.
  • Your cancer must be measurable on scans according to the RECIST V1.1 criteria, with imaging done within 28 days before randomization.

Who cannot join the trial?

31 criteria

  • Having a stomach or gastro‑esophageal junction cancer that is not an adenocarcinoma (for example, a mixed‑type or other kind of cancer).
  • Having an active infection that needs medicines (systemic therapy) and that has not completely cleared at least 7 days before you would start the study.
  • Being infected with HIV unless your immune‑cell count (CD4+ T‑cell count) is 350 cells/µL or higher and you have not had an AIDS‑defining infection in the past year.
  • Testing positive for tuberculosis (TB) or having an active TB infection.
  • Having an active hepatitis B (positive surface antigen) or hepatitis C infection.
  • Having received chemotherapy or immunotherapy for this cancer before, except for a very limited amount (no more than one cycle of specific drugs) and only if it was given at least 6 months ago with disease progression.
  • Taking strong immune‑suppressing medicines, including systemic corticosteroids, within 7 days before the study (small replacement doses are allowed).
  • Having had a major operation within the last 28 days and not fully recovered from it.
  • Having received a drug that targets CLDN18.2 within the last 28 days (or five drug half‑lives) or having had severe (grade 3 or higher) stomach or intestinal side effects from such a drug.
  • Having had radiation treatment (radiotherapy) for this cancer within the last 14 days and not recovered from any related side effects (a 7‑day gap is allowed for short palliative radiation).
  • Having active cancer spread to the brain or spinal fluid (CNS metastases or carcinomatous meningitis). Treated brain metastases are allowed only if they have been stable on scans for at least 4 weeks and you have not needed steroids for at least 14 days.
  • Having a psychiatric condition or social situation that would make it difficult for you to follow the study requirements.
  • Having a hole or abnormal connection in the gastrointestinal tract (GI perforation or fistula), untreated stomach ulcers, a recent arterial clot (within 6 months), a recent major vein clot (within 3 months), or significant stomach or intestinal bleeding.
  • Having a complete or partial blockage of the stomach outlet that causes persistent vomiting.
  • Having existing nerve damage in the arms or legs that is worse than mild (greater than grade 1 peripheral neuropathy).
  • Having high blood pressure (hypertension) that is not well controlled.
  • Having serious heart or blood‑vessel problems, such as severe heart failure, recent heart attack, unstable chest pain, recent heart procedures, stroke, a hypertensive crisis, a prolonged heart‑beat interval (QTc > 450 ms for men, > 470 ms for women), a history of long QT syndrome, or serious irregular heart rhythms needing medication.
  • Having an immune‑deficiency disorder or an autoimmune disease that required strong medicines (like disease‑modifying agents, corticosteroids, or other immune‑suppressants) in the past 2 years.
  • Having previously received drugs that block the PD‑1, PD‑L1, or PD‑L2 pathways (or similar immune‑targeting drugs) unless they were given only around the time of surgery.
  • Receiving a live or live‑attenuated vaccine within the past 30 days.
  • Having taken the antiviral medicines brivudine, sorivudine, or similar drugs within 28 days (or five half‑lives) before the study.
  • Having taken any other experimental (investigational) medication within 28 days (or five half‑lives) before the study.
  • Being known to have a complete deficiency of the enzyme DPD (which affects how certain chemotherapy drugs are processed).
  • Having any other medical condition that the doctor believes would make the study unsafe or unsuitable for you.
  • Having had a severe allergic reaction or known intolerance to any of the study drugs.
  • Having had another type of cancer within the past 3 years, except for certain skin cancers, low‑risk prostate cancer under watchful waiting, or carcinoma in situ that has been fully removed.
  • Having pernicious anemia or other anemia caused by a lack of vitamin B12.
  • Having a history of non‑infectious lung inflammation (pneumonitis) that needed steroids, current lung inflammation, or any interstitial lung disease.
  • Having an uncontrolled bleeding disorder (coagulopathy) or taking blood‑thinning medication that makes your INR (a blood‑clotting test) higher than 2.
  • Having a recent serious bleeding problem (grade 2 or higher bleeding) within the past 28 days.
  • Having any other uncontrolled illness that could interfere with the study.
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Investigated drugs

  • Pembrolizumab

    is an immunotherapy drug that helps the body’s immune system see and attack cancer cells. In this study it is given through an IV to see if it improves outcomes when used with chemotherapy.

  • ASP2138

    is an experimental medicine being tested for the first time in this trial. It is given by IV infusion and is thought to work together with chemotherapy and immunotherapy to help stop tumor growth.

  • Oxaliplatin

    is a chemotherapy drug that damages the DNA inside cancer cells, making it hard for them to grow and divide. It is given by IV as part of the standard chemotherapy regimens used in the trial.

  • Fluorouracil (5‑FU)

    is a chemotherapy medicine that interferes with the building blocks cancer cells need to make new DNA. It is given by IV infusion and is a key part of the chemotherapy combinations used in the study.

  • Capecitabine

    is an oral chemotherapy pill that the body changes into fluorouracil after it is swallowed. It allows patients to take part of their chemotherapy at home rather than through an IV.

  • Calcium folinate (folinic acid)

    is a medication given together with fluorouracil. It helps protect normal cells from some side effects and can make the chemotherapy work better.

What is already known about the treatment

  • Glucose

    Given by infusion as a simple sugar solution, it is used in this trial as a placebo with no expected effect on the cancer; glucose is a well‑known substance that provides energy to cells and is widely described in medical literature; it has no therapeutic indication for tumor treatment; it works by raising blood sugar levels temporarily; it is classified as a carbohydrate solution.

  • Sodium Chloride

    Administered by infusion as a salt solution, it serves as a placebo in the study and does not treat the disease; sodium chloride is a common medical fluid used to maintain fluid balance and is well documented; it has no therapeutic role in cancer; it works by supplying sodium and chloride ions to the bloodstream; it is classified as an electrolyte solution.

  • Oxaliplatin

    Delivered as an infusion solution for intravenous use, this chemotherapy drug is approved for treating gastric and colorectal cancers and is extensively studied in the literature; its main use is to stop tumor growth; it works by attaching to DNA and preventing cancer cells from copying their genetic material; it belongs to the class of platinum‑based antineoplastic agents.

  • Fluorouracil

    Given by infusion as a solution for injection, fluorouracil is an established chemotherapy medicine for gastric, colorectal and other cancers; it is a standard part of cancer treatment regimens; it works by mimicking a building block of DNA and blocking the cancer cell’s ability to make new DNA; it is classified as an antimetabolite chemotherapy agent.

  • Capecitabine

    Taken orally as a film‑coated tablet, capecitabine is an approved chemotherapy drug for breast, colorectal and gastric cancers; it is used to shrink or slow tumor growth; once inside the body it is converted to fluorouracil, which then interferes with DNA production in cancer cells; it is classified as a pro‑drug antimetabolite.

  • Folinic Acid

    Administered by infusion, folinic acid (calcium folinate) is used in cancer therapy to enhance the effect of fluorouracil and reduce side‑effects; it is a recognized supportive medication in oncology; it works by helping normal cells make DNA, which protects them while fluorouracil attacks cancer cells; it belongs to the vitamin‑derived rescue agents class.

Investigated diseases

Locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma - This cancer originates in the lining of the stomach or the junction where the esophagus meets the stomach. It grows to a size or location that cannot be removed by surgery, or it spreads beyond the original site to distant organs. The tumor may invade nearby tissues, lymph nodes, and can send cancer cells through the bloodstream to places such as the liver, lungs, or peritoneum. Over time the primary mass can enlarge and new metastatic lesions may appear, indicating disease progression. As the disease advances, patients may experience increasing gastrointestinal symptoms and general discomfort.
Trial detailsLast updated 25 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-524557-14-00Protocol code2138-CL-0301Estimated enrolment468 patientsSponsorAstellas Pharma Global Development Inc.

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