Phase 2 Randomized Open‑Label Study of Denikitug Monotherapy vs Combination Therapy in HER2‑negative Unresectable Metastatic Gastric/GEJ/Esophageal Adenocarcinoma

Trial ID: 2025-524095-27-00
Protocol: GS-US-742-7757
Sponsor: Gilead Sciences Inc.

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Diseases & Conditions

Oesophageal adenocarcinoma

Objectives

The primary objective is to evaluate the effect of denikitug as monotherapy or in combination with nivolumab or ramucirumab plus paclitaxel on objective response rate (ORR) as assessed by the investigator according to RECIST Version 1.1. This endpoint directly measures antitumor activity and is pivotal for determining clinical benefit in HER2‑negative, unresectable, recurrent, and/or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinomas.

Secondary objectives include:

Assessment of duration of response (DOR) and progression‑free survival (PFS) under the same treatment arms, providing insight into the durability of disease control.
Evaluation of overall survival (OS) to determine impact on patient longevity.
Characterization of safety and tolerability for denikitug alone and in combination regimens.
Investigation of pharmacokinetics (PK) and immunogenicity to inform dosing and potential immune reactions.

Participants

The trial enrolled 75 participants, comprising both male and female adults aged 18 years and older, all of whom had histologically confirmed locally advanced, unresectable, or metastatic gastric, gastro‑esophageal junction, or esophageal adenocarcinomas that were HER2-negative. Eligible individuals demonstrated an Eastern Cooperative Oncology Group performance status of 0–1, a life expectancy of at least three months, and measurable disease per RECIST 1.1 criteria. All participants had experienced disease progression following first‑line systemic therapy, which included platinum‑ and fluoropyrimidine‑based chemotherapy and, where applicable, prior anti‑PD‑1/PD‑L1 therapy. Inclusion required adequate organ function, availability of recent tumor tissue for analysis, and, for those of childbearing potential, adherence to prescribed contraception. The cohort represented a generally healthy adult population with acceptable functional status, suitable for evaluating the investigational regimen.

Plans and Procedures

The study is a Phase 2, open‑label, multicenter, randomized trial evaluating denikitug administered as monotherapy or in combination with nivolumab, ramucirumab, and paclitaxel in adults with HER2‑negative, unresectable, recurrent, or metastatic gastric, gastroesophageal junction, and esophageal adenocarcinomas. Participants undergo a screening visit to confirm eligibility, including assessment of organ function, performance status, and availability of tumor tissue; upon meeting all inclusion criteria, they are randomized to one of the treatment arms. Treatment is delivered intravenously according to the assigned regimen, and participants return for scheduled follow‑up visits at regular intervals for safety monitoring, pharmacokinetic sampling, and tumor imaging to assess response per RECIST Version 1.1. The primary efficacy endpoint is objective response rate, defined as the proportion of patients achieving complete or partial response. Secondary endpoints include duration of response, progression‑free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Participants remain in the study until the end‑of‑study visit, which occurs after the last scheduled assessment or earlier if disease progression, unacceptable toxicity, withdrawal of consent, or a decision by the investigator or sponsor mandates discontinuation. The overall trial timeline spans from the anticipated recruitment start on 6 April 2026 to an estimated completion date of 8 May 2028, with each participant expected to be involved for the duration of treatment and follow‑up, typically up to 12 months or until one of the early termination criteria is met.

Treatment

GS‑1811 150 mg/vial concentrate for solution for infusion contains a humanised IgG1 monoclonal antibody directed against CCR8. The product is supplied as a sterile solution for infusion and is administered intravenously. Dosing is defined in the study protocol and is given as an intravenous infusion on the scheduled treatment days.

Denikitug is provided as a solution for infusion for intravenous administration. The investigational agent is delivered by intravenous infusion according to the protocol‑specified schedule, with each dose administered on the designated treatment day.

Nivolumab (OPDIVO) 10 mg/mL concentrate for solution for infusion is a comparator immunotherapy supplied as a sterile solution for infusion. It is administered intravenously, with dosing and infusion frequency determined by the study protocol.

Ramucirumab (Cyramza) 10 mg/mL concentrate for solution for infusion is a comparator anti‑angiogenic agent supplied as a sterile solution for infusion. It is given by intravenous infusion according to the dosing schedule outlined in the protocol.

Paclitaxel albumin‑bound (Abraxane) 5 mg/mL powder for dispersion for infusion is a comparator chemotherapy provided as a powder that is reconstituted for intravenous infusion. Administration follows the protocol‑defined dosing intervals.

All study treatments are administered on the days specified in the protocol, typically at the beginning of each treatment cycle. Dosing schedules are recorded in the case report form, and participant compliance is monitored through infusion logs, drug accountability records, and periodic review of administration times.

Efficacy

Efficacy will be evaluated primarily by the objective response rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR) as determined by the investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Secondary efficacy assessments include duration of response (DOR), measured from the date of first documented CR or PR until the first occurrence of progressive disease (PD) or death; progression‑free survival (PFS), calculated from the date of first dose to PD or death from any cause; and overall survival (OS), defined as the time from first dose to death from any cause. Additional secondary measures comprise the incidence and severity of treatment‑emergent adverse events, serum concentrations of denikitug with pharmacokinetic parameters (e.g., Cmax, AUCall), and the proportion of participants developing anti‑drug antibodies.

Inclusion and Exclusion Criteria

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Inclusion Criteria

General G1. Participants assigned male or female at birth, 18 years of age or older (for sites in the Republic of Korea, see Appendix 11.11.2), able to understand and give written informed consent and comply with treatment and follow-up.
G2. Participants assigned male or female at birth who are of childbearing potential and engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.5.
Medical History/Physical Characteristics MH1. Histologically or cytologically confirmed diagnosis of locally advanced, unresectable, or metastatic gastric, GEJ, or EACs.
MH2. HER2-negative status, as determined by local assessment using a validated immunohistochemistry assay, in situ hybridization or other amplification testing.
MH3. Has had disease progression during or after first line of systemic therapy for advanced or metastatic gastric, GEJ, or EACs, which must have included at least one of the following: Platinum- and fluoropyrimidine-based chemotherapy. Therapy with an anti-PD1 or anti-PD-L1 mAb (patients with PD-L1-positive tumors must have received prior PD-1/PD-L1-based therapy). Zolbetuximab or other CLDN18.2-targeted therapy, if indicated and approved/available in the country where the participant is enrolled based on biomarker status.
MH4. Documented PD by computed tomography (CT) or magnetic resonance imaging (MRI) during or after the most recent therapy per RECIST Version 1.1 criteria by investigator assessment.
MH5. Measurable disease by CT or MRI as per RECIST Version 1.1 criteria by investigator assessment (see Appendix 11.8.1). Note: Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
MH6. ECOG performance status score of 0-1 (see Appendix 11.7).
Laboratory Assessments LA1. Negative serum pregnancy test at screening and enrollment (see Appendix 11.5).
LA2. Have adequate organ function as indicated by the screening laboratory values listed in the protocol. In addition to the Laboratory Assessments Inclusion Criteria listed above that are applicable to Part 1 and Part 2 the following additional criteria are only applicable to Part 2:
LA3. (Part 2 only) Have adequate organ function as indicated by the following screening laboratory values.
Other Inclusion Criteria OI1. Life expectancy of at least 3 months.
OI2. Able and willing to participate and comply with all study requirements and provide signed and dated informed consent prior to the initiation of any study procedures.
OI3. Availability of tumor tissue from an archival (obtained ideally within 12 months prior to enrollment) or fresh biopsy in the form of a formalin-fixed paraffin-embedded block (preferably) or at least 15 freshly sectioned, unstained slides. If < 15 unstained slides are available, and it is not clinically feasible to obtain a new biopsy, the participant may still be eligible upon consultation with the sponsor medical monitor.

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Exclusion Criteria

Medical Conditions/History MC1. Participants with plans to breastfeed during the study period and 4 months following the last dose of study intervention
MC2. Known hypersensitivity to the study intervention, its metabolites, or formulation excipient.
MC3. Active second malignancy. Participants with a history of malignancy who have been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or participants with surgically cured tumors with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) may be enrolled.
MC4. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are prescribed 10 mg/day or less of prednisone or its equivalent. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
MC5. Meet any of the following criteria for cardiovascular disease: Symptomatic cardiac or cerebrovascular disease; cerebral vascular accident/stroke/myocardial infarction or unstable angina pectoris or any other deep arterial thromboembolic events within 6 months of enrollment. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication). New York Heart Association Class II or greater congestive heart failure or known left ventricular ejection fraction (LVEF) less than 40%.
MC6. Have active serious infection requiring antibiotics. Note: Prophylactic antibiotic treatment is allowed.
MC7. History of autoimmune disease or active autoimmune disease that has required systemic treatment within 2 years prior to the start of study treatment (eg, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs), any history of noninfectious enteritis or colitis requiring treatment with corticosteroids, or any history of inflammatory bowel disease (including Crohn’s disease or ulcerative colitis) or Celiac disease. Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment as listed above.
MC8. History of (noninfectious) pneumonitis/interstitial lung disease or current pneumonitis/interstitial lung disease, including: Radiation-induced pneumonitis requiring systemic steroids Active or recurrent pneumonitis of any etiology
MC9. History of GI perforation, permanent ileostomy, abdominal abscess or fistula within 6 months, active or uncontrolled GI bleeding within 4 weeks, or any condition associated with significant risk of bleeding or perforation (eg, untreated varices, tumor erosion, recent GI surgery).
MC10. Have a documented histological diagnosis of squamous cell carcinoma of the esophagus or any other non-adenocarcinoma histological subtype (eg, small-cell/neuroendocrine carcinoma, gastric lymphoma, GI stromal tumor, carcinoid).
MC11. Have documented MSI-H or dMMR disease by local assessment using a validated polymerase chain reaction (PCR) (microsatellite status) and/or immunohistochemistry (mismatch repair [MMR]) assay.
MC12. Prior treatment discontinuation due to imAEs on immunotherapy, and/or any history of Grade 3 or higher diarrhea or colitis-related to prior immunotherapy. In addition to the Medical Conditions/History Exclusion Criteria listed above that are applicable to Part 1 and Part 2 the following additional criteria are only applicable to Part 2:
MC13. (For Part 2 only) Serious nonhealing wound, nonhealing ulcer or nonhealing bone fracture within 28 days prior to enrollment.
MC14. (For Part 2 only) Has uncontrolled arterial hypertension ≥ 150/≥ 90 mm Hg despite standard medical management.
MC15. (For Part 2 only) Has known history of peripheral neuropathy ≥ Grade 2 (per NCI-CTCAE Version 5.0).
MC16. (For Part 2 only) Deep venous thromboembolic event within 28 days prior to enrollment.
MC17. (For Part 2 only) Known coagulopathy that increases the risk of bleeding, bleeding diatheses. Any other Grade 3 or higher hemorrhage/bleeding event within 28 days prior to enrollment.
Prior/Concurrent Therapy or Clinical Study Experience PT1. Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.3.2.
PT2. Use of other investigational drugs (drugs not marketed for any indication) within 4 weeks of enrollment.
PT3. Prior treatment with: DEN or other CCR8-targeted agents. Lonsurf (trifluridine-tipiracil) or PAC-based regimens in the first-line setting for advanced or metastatic gastroesophageal adenocarcinoma. Any systemic therapy (including investigational agents) targeting vascular endothelial growth factors (VEGF) or the vascular endothelial growth factor receptor (VEGFR) signaling pathways. Anticancer biologic agent within 4 weeks prior to enrollment or have had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to enrollment and have not recovered (ie, Grade 2 or less) from AEs from prior anticancer therapy at the time of enrollment. Participants in observational studies are eligible. Allogenic tissue/solid organ transplantation, including allogeneic stem cell transplantation. Exception: prior corneal transplant without requirement for systemic immunosuppressive agents is allowed.
PT4. Have a diagnosis of immunodeficiency or are receiving chronic systemic steroid therapy (with dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to enrollment. Intermittent use of topical, inhalational, intranasal, and intraocular steroids is permitted.
PT5. Have not recovered (ie, Grade 2 or less) from active/unresolved AEs. Note: participants with Grade 2 or less neuropathy or alopecia are an exception to this criterion and may be enrolled. Note: if participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. In addition to the Prior/Concurrent Therapy or Clinical Study Experience Exclusion Criteria listed above that are applicable to Part 1 and Part 2, the following criteria are only applicable to Part 2:
PT6. (For Part 2 only) Prior treatment with systemic therapy with other anti-angiogenic drugs.
PT7. (For Part 2 only) Receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters defined in the inclusion criteria are met.
PT8. (For Part 2 only) Receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs, eg, indomethacin, ibuprofen, naproxen or similar agents) or other anti-platelet agents (eg, clopidogrel, ticlopidine, dipyridamole, anagrelide). Aspirin use at doses up to 325 mg/day is permitted.
Diagnostic Assessments DA1. Have known history of HIV-1 or HIV-2 with uncontrolled viral load or requiring medications that may interfere with metabolism of DEN and/or the other study drugs.
DA2. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In participants with a history of HBV or HCV, participants with detectable viral loads will be excluded. Participants who test positive for hepatitis B surface antigen (HBsAg) will be excluded. Participants who test positive for antibody against hepatitis B core antigen (anti-HBc) will require HBV DNA by quantitative PCR for confirmation of active disease. Participants who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease. Participants with a known history of HCV or a positive HCV antibody test will not require an HCV antibody assessment at screening and will only require HCV RNA by quantitative PCR for confirmation of active disease.
Other Exclusion Criteria OE1. Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation, prevent completion of study procedures and follow-up examinations, or poses an undue risk to the participant.
OE2. Use of any live attenuated vaccines against infectious diseases within 4 weeks (28 days) prior to enrollment.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Yet Recruiting	06 Apr 2026	19
Spain	Not Yet Recruiting	06 Apr 2026	26

Sites & Investigators

Research sites

Hospital Vall d’Hebron Centre Hospitalier Universitaire De Lille Centre Leon Berard Institut Gustave Roussy

Investigators

Roberto P.Clélia C.Anthony T.Rosine G.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Treatment Duration	EU MP Number
OPDIVO 10 mg/mL concentrate for solution for infusion.	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD2941372
Abraxane 5 mg/ml powder for dispersion for infusion.	Comparator	POWDER FOR DISPERSION FOR INFUSION	INTRAVENOUS	1	PRD9254301
OPDIVO 10 mg/mL concentrate for solution for infusion.	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD2941375
GS-1811	Test	SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD13555170
OPDIVO 10 mg/mL concentrate for solution for infusion.	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION.	INTRAVENOUS	1	PRD9332410
Cyramza 10 mg/ml concentrate for solution for infusion	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD1961195
GS-1811 150 mg/vial concentrate for solution for infusion	Test	SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD10169228
OPDIVO 10 mg/mL concentrate for solution for infusion.	Comparator	CONCENTRATE FOR SOLUTION FOR INFUSION	INTRAVENOUS	1	PRD6183485