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Study of denikitug alone or with drug combination in adults with HER2‑negative metastatic gastric, gastroesophageal junction and esophageal adenocarcinoma

Fast replyRegistered drugNo placebo
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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 HER2-negative, unresectable, recurrent, and/or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinomas. These are cancers that start in the stomach or the area where the stomach meets the esophagus and have spread or cannot be removed by surgery. The treatment being tested is a new drug called denikitug, given by intravenous infusion, either alone or together with the immune‑system drug nivolumab or with a combination of the blood‑vessel targeting drug ramucirumab and the chemotherapy drug paclitaxel.

The purpose of the study is to see how well these approaches shrink or control the tumors. Participants are randomly assigned to one of the treatment groups and receive a series of infusion visits over several weeks, with regular check‑ups to look at tumor size and overall health.

During the study, doctors will measure the objective response rate, which means the proportion of patients whose tumors get smaller or disappear, and will also watch for any side effects or changes in blood tests. The schedule includes clinic visits for the infusions, imaging scans to view the tumors, and laboratory tests to ensure safety.

The research process

The trial runs in 9 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Enrollment and assignment to treatment group

    After you agree to join the study, you are placed into one of the study arms. the arms may include denikitug alone, denikitug together with nivolumab, or denikitug combined with ramucirumab and paclitaxel.

  2. Step 2

    Baseline assessments

    Before the first dose, you undergo a series of tests that may include a physical exam, blood work, and imaging scans to document the current status of your disease.

    These results serve as the reference point for later comparisons.

  3. Step 3

    First intravenous infusion

    The first dose of the assigned medication(s) is given by intravenous (iv) infusion, which means the drug is delivered slowly through a needle placed in a vein.

    If you are in the combination arm, each drug (denikitug, nivolumab, ramucirumab, paclitaxel) is administered separately but during the same visit according to the study schedule.

  4. Step 4

    Subsequent treatment cycles

    You receive additional iv infusions of the assigned drug(s) at regular intervals that are defined by the study protocol.

    The exact frequency (for example, every two weeks) and the total number of cycles are determined by the protocol and may continue until disease progression, unacceptable side effects, or completion of the planned treatment period.

  5. Step 5

    Routine monitoring visits

    During the treatment period, you attend scheduled visits for safety checks, blood tests, and imaging studies.

    These visits help the study team evaluate how the disease is responding and whether any side effects are occurring.

  6. Step 6

    Assessment of response

    The study uses standard imaging criteria (recist version 1.1) to determine whether your tumor shows a complete response, partial response, stable disease, or progression.

    The results are recorded by the investigator and used to calculate the primary outcome of the trial.

  7. Step 7

    Treatment discontinuation

    Treatment may be stopped if the disease progresses, if serious side effects develop, or after the predetermined number of cycles has been completed.

    The decision is made according to the study protocol and your health status.

  8. Step 8

    End‑of‑treatment evaluation

    Once treatment ends, you undergo a final set of assessments similar to the baseline tests to document the overall effect of the therapy.

  9. Step 9

    Post‑treatment follow‑up

    After the last dose, you are followed for a period of time to monitor long‑term outcomes such as overall survival and any delayed side effects.

    Follow‑up visits occur at intervals specified in the study protocol.

Who can join the trial?

13 criteria

  • Be assigned male or female at birth, be at least 18 years old, and be able to understand and sign a written consent form and follow the study procedures.
  • Have adequate organ function as shown by the required laboratory test results at the screening visit.
  • Have a life expectancy of at least 3 months as judged by the doctor.
  • Be willing and able to follow all study requirements and sign the consent form before any study activities begin.
  • Provide a sample of tumor tissue that is either stored from a previous biopsy (ideally taken within the past 12 months) or a fresh biopsy, in the form of a formalin‑fixed paraffin‑embedded block or at least 15 unstained microscope slides; if fewer slides are available, the study team may still consider you after review.
  • If you are of childbearing potential and have heterosexual intercourse, you must agree to use the study‑specified method of contraception to prevent pregnancy during the trial.
  • Have a confirmed diagnosis (by looking at cells under a microscope) of locally advanced, unresectable, or metastatic gastric, gastro‑esophageal junction (GEJ), or esophageal adenocarcinoma.
  • Have a HER2‑negative tumor, meaning the cancer cells do not show excess HER2 protein or gene amplification as tested by a validated lab method such as immunohistochemistry or in‑situ hybridization.
  • Have experienced disease progression after the first line of systemic therapy for advanced or metastatic disease, which must have included at least one of the following: chemotherapy that contains platinum and fluoropyrimidine drugs, therapy with an anti‑PD‑1 or anti‑PD‑L1 antibody (if the tumor was PD‑L1‑positive), or a CLDN18.2‑targeted drug such as zolbetuximab if it was available and appropriate.
  • Show documented progressive disease on a CT (computed tomography) or MRI (magnetic resonance imaging) scan performed during or after the most recent therapy, using the RECIST Version 1.1 criteria (a standard way doctors measure tumor changes).
  • Have measurable disease on a CT or MRI scan according to RECIST Version 1.1, meaning the tumor lesions can be accurately measured; lesions in areas that were previously irradiated are allowed if they have shown progression.
  • Have an ECOG performance status score of 0‑1, indicating you are fully active (0) or restricted in physically strenuous activity but able to do light work (1).
  • For women of childbearing potential, have a negative pregnancy test at both screening and enrollment.

Who cannot join the trial?

33 criteria

  • Planning to breastfeed during the study and for four months after the last dose.
  • Having a type of cancer that is not an adenocarcinoma (for example, squamous cell cancer, small‑cell, neuroendocrine, lymphoma, stromal tumor, or carcinoid).
  • Having MSI‑H or dMMR disease – a specific genetic abnormality detected by special lab tests (PCR or immunohistochemistry).
  • Previous severe side effects from immunotherapy, such as grade 3 or higher diarrhea or inflammation of the colon (colitis).
  • Serious non‑healing wound, ulcer, or bone fracture within the past 28 days (applies to part 2 of the study).
  • Uncontrolled high blood pressure (≥150 mm Hg systolic or ≥90 mm Hg diastolic) despite medication (part 2 only).
  • Peripheral neuropathy (nerve damage) that is grade 2 or higher (part 2 only).
  • Recent blood clot (deep‑vein thrombosis) within the past 28 days (part 2 only).
  • Bleeding disorders or any serious bleeding event (grade 3 or higher) within the past 28 days (part 2 only).
  • Use of prohibited medications listed in the study protocol.
  • Use of other investigational (non‑approved) drugs within four weeks before enrollment.
  • Allergic reaction (hypersensitivity) to the study drug, its breakdown products, or any ingredient in the formulation.
  • Previous treatment with denikitug (DEN) or other CCR8‑targeted agents.
  • Previous first‑line use of Lonsurf (trifluridine‑tipiracil) or paclitaxel‑based chemotherapy for advanced stomach or esophageal cancer.
  • Prior therapy that targets VEGF or VEGFR pathways (drugs that block blood‑vessel growth signals).
  • Recent anticancer therapy (including chemotherapy, targeted drugs, or radiation) within two weeks before enrollment, or not fully recovered (more than grade 2 side effects) from such therapy.
  • Allogenic organ or stem‑cell transplant (except a prior corneal transplant without systemic immune‑suppressing drugs).
  • Immunodeficiency or use of strong systemic steroids (more than 10 mg prednisone daily) or other immune‑suppressing medicines within seven days before enrollment.
  • Unresolved side effects from previous treatment that are worse than grade 2 (except mild nerve damage or hair loss).
  • Prior use of other anti‑angiogenic drugs (medicines that block new blood‑vessel formation) – part 2 only.
  • Therapeutic anticoagulation (blood‑thinning medication such as warfarin or low‑molecular‑weight heparin) – part 2 only.
  • Chronic use of non‑steroidal anti‑inflammatory drugs (NSAIDs) or anti‑platelet agents (e.g., ibuprofen, naproxen, clopidogrel) – part 2 only; low‑dose aspirin up to 325 mg/day is allowed.
  • Uncontrolled HIV infection (high viral load or medicines that would interfere with study drugs).
  • Active hepatitis B or hepatitis C infection (detectable virus in the blood).
  • Other serious medical or psychiatric conditions that could interfere with the study or put the patient at high risk.
  • Use of live attenuated vaccines (weakened‑virus vaccines) within four weeks before enrollment.
  • Active second cancer (another cancer that is currently present, unless it was completely treated and disease‑free for at least three years).
  • Active cancer spread to the brain or central nervous system (including carcinomatous meningitis); stable, previously treated brain metastases are allowed only if stable for at least four weeks and on low‑dose steroids.
  • Significant heart or blood‑vessel disease, such as recent heart attack, stroke, unstable chest pain, serious heart rhythm problems, heart failure (class II or higher), or left‑ventricular ejection fraction below 40%.
  • Active serious infection that requires antibiotics.
  • Autoimmune disease that needed systemic treatment (like steroids or immune‑suppressing drugs) within the past two years, or inflammatory bowel disease (Crohn’s disease, ulcerative colitis) or celiac disease requiring such treatment.
  • Pneumonitis or interstitial lung disease (lung inflammation or scarring), whether caused by radiation or other reasons.
  • Recent gastrointestinal problems such as a perforated gut, permanent ileostomy, abdominal abscess, fistula (abnormal connection), uncontrolled GI bleeding, or conditions that greatly increase bleeding or perforation risk (e.g., untreated varices, tumor erosion, recent GI surgery).
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Investigated drugs

  • GS-1811

    is an investigational medicine that contains a human‑engineered antibody designed to block a protein called CCR8. By attaching to CCR8, the antibody may help the immune system recognize and attack cancer cells. In this study it is given through an IV infusion.

  • Denikitug

    is the experimental drug being tested as a single treatment or together with other medicines. It is a specially designed protein that aims to stimulate the body’s immune response against tumor cells. Patients receive it by IV infusion.

  • Nivolumab

    (brand name Opdivo) is an approved cancer medicine that belongs to a class called checkpoint inhibitors. It works by blocking the PD‑1 pathway, which can release the brakes on immune cells so they can better attack cancer. In the trial it is given by IV infusion, either alone or together with denikitug.

  • Ramucirumab

    (brand name Cyramza) is a drug that targets a protein called VEGFR‑2, which helps tumors form new blood vessels. By blocking this protein, ramucirumab can slow the growth of blood vessels that feed the cancer. It is administered through an IV infusion and used in combination with denikitug and chemotherapy in the study.

  • Paclitaxel albumin‑bound

    (brand name Abraxane) is a form of chemotherapy that uses tiny particles of the drug paclitaxel attached to albumin, a protein that helps carry the medicine into cancer cells. It works by stopping cancer cells from dividing. In the trial it is given by IV infusion together with denikitug and ramucirumab.

What is already known about the treatment

  • Denikitug

    This investigational drug is administered as an intravenous infusion of a sterile solution. It is a humanised IgG1 monoclonal antibody that binds to the CCR8 receptor on certain immune cells, helping to modify the tumor‑immune environment. It is being studied for HER2‑negative, unresectable or metastatic gastric, gastroesophageal junction and esophageal adenocarcinomas. It belongs to the class of immune‑modulating monoclonal antibodies.

  • Nivolumab

    This medication is given by intravenous infusion of a clear solution. It is an approved drug that blocks the PD‑1 protein on T‑cells, allowing the immune system to recognize and attack cancer cells. It is used for several advanced cancers, including the gastric and esophageal cancers studied in this trial. It is classified as a checkpoint inhibitor immunotherapy.

  • Ramucirumab

    This drug is delivered as an intravenous infusion of a sterile solution. It is an approved monoclonal antibody that blocks the VEGFR‑2 receptor, preventing new blood vessels from feeding the tumor. It is indicated for advanced stomach, gastro‑esophageal and other solid tumors, and is combined with chemotherapy in this study. It belongs to the class of anti‑angiogenic antibodies.

  • Paclitaxel albumin‑bound

    This medication is given as an intravenous infusion after reconstitution of a powder for dispersion. It is an approved chemotherapy that stabilises microtubules, which stops cancer cells from dividing. It is used for a variety of solid tumours, including gastric and esophageal cancers, and is part of the combination regimen in this trial. It is classified as a taxane‑type anticancer agent.

Investigated diseases

HER2-negative unresectable recurrent or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinoma - It is a type of cancer that starts in the glandular cells lining the stomach, the area where the stomach meets the esophagus, or the lower part of the esophagus. The tumor can grow into surrounding tissues and spread to nearby lymph nodes. Because it cannot be removed surgically, it may continue to enlarge and cause symptoms such as difficulty swallowing or stomach pain. Cancer cells can also travel through the bloodstream to distant organs, leading to recurrence or metastasis. Over time, the disease often progresses from a localized growth to widespread involvement.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-524095-27-00Protocol codeGS-US-742-7757Estimated enrolment120 patientsSponsorGilead Sciences Inc.

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