Study of Denikitug (GS-1811) Given Alone or With Nivolumab or Chemotherapy in Adults With Metastatic Gastric, Gastroesophageal Junction (GEJ), and Esophageal Adenocarcinomas

A Phase 2, Open-Label, Multicenter, Randomized Study to Evaluate Denikitug as Monotherapy or in Combination With Nivolumab or Chemotherapy in Participants With HER2-Negative, Unresectable, Recurrent, and/or Metastatic Gastric, Gastroesophageal Junction (GEJ), and Esophageal Adenocarcinomas

The goal of this clinical study is to learn more about the study drug, Denikitug (DEN, GS-1811), to evaluate the efficacy and safety of Denikitug Monotherapy and Denikitug-based combinations in in participants with human epidermal growth factor receptor 2 (HER2)-Negative, unresectable, recurrent, and/or metastatic, gastroesophageal junction (GEJ), and esophageal adenocarcinomas.

The primary objective of this study is to assess the effect of DEN as a monotherapy or in combination with nivolumab (NIVO) or ramucirumab (RAM) and paclitaxel (PAC) on objective response rate (ORR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST Version1.1).

Study Overview

• Status: Recruiting
• Conditions: Gastric Adenocarcinoma; Esophageal Adenocarcinoma; Gastroesophageal Junction; HER2-negative
• Intervention / Treatment: Drug: Denikitug; Drug: Nivolumab; Drug: Ramucirumab; Drug: Paclitaxel

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gilead Clinical Study Information Center; Phone Number: 1-833-445-3230 (GILEAD-0); Email: GileadClinicalTrials@gilead.com

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Recruiting
      • Chris O'Brien Lifehouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of locally advanced, unresectable, or metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinoma (EAC).
• Human epidermal growth factor receptor 2 (HER2)-negative status, as determined by local assessment using a validated immunohistochemistry assay, in situ hybridization or other amplification testing.

• 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:

  1. Platinum- and fluoropyrimidine-based chemotherapy.
  2. Therapy with an anti-programmed cell death protein 1 (PD1) or anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody (patients with PD-L1-positive tumors must have received prior PD-1/PD-L1-based therapy).
  3. Zolbetuximab or other Claudin-18 (CLDN18).2-targeted therapy, if indicated based on biomarker status.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Have adequate organ function.
• Male individuals and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use methods of contraception.

Key Exclusion Criteria:

• Active or history of autoimmune disease requiring systemic treatment within 2 years, inflammatory bowel disease (IBD) (Crohn's/ulcerative colitis), celiac disease, or noninfectious enteritis/colitis. (Physiologic hormone replacement not considered systemic treatment).
• History or current noninfectious pneumonitis/interstitial lung disease, including radiation-induced pneumonitis requiring steroids or active/recurrent pneumonitis of any etiology.
• Documented microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) disease by local polymerase chain reaction (PCR) (microsatellite status) and/or informed consent form (ICH) (mismatch repair (MMR)) assay
• (For Part 2 only) Has known history of peripheral neuropathy ≥ Grade 2 (per National Cancer Institute(NCI)-Common Tenninology Criteria for Adverse Events (CTCAE) Version 5.0).
• (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

• Prior treatment with DEN or other C-C chemokine receptor 8 (CCR8)-targeted agents.
• Prior Lonsurf (trifluridine-tipiracil) or paclitaxel (PAC)-based regimens in the first-line setting for advanced/metastatic gastroesophageal adenocarcinoma.
• Any systemic therapy (including investigational) targeting vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR) signaling pathways.
• Anticancer biologic within 4 weeks, orchemotherapy, targeted small molecule, or radiation therapy within 2 weeks prior to enrollment with unresolved adverse events (AE)s (Grade >2). (Observational study participants are eligible).
• Prior allogenic tissue/solid organ or stem cell transplantation. (Exception: corneal transplant not requiring systemic immunosuppression is allowed).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Arm A: DEN (Dose A) and NIVO; Participants will receive DEN Dose A as an IV infusion in combination with NIVO as an IV infusion.	Drug: Denikitug; Administered Intravenously; Other Names: GS-1811; Drug: Nivolumab; Administered Intravenously
Experimental: Part 1: Arm B: DEN (Dose B) and NIVO; Participants will receive DEN Dose B as an IV infusion in combination with NIVO as an IV infusion.	Drug: Denikitug; Administered Intravenously; Other Names: GS-1811; Drug: Nivolumab; Administered Intravenously
Experimental: Part 1: Arm C: DEN (Dose B); Participants will receive DEN Dose B as an IV infusion.	Drug: Denikitug; Administered Intravenously; Other Names: GS-1811
Experimental: Part 2: Arm D: Safety Run-in (SRI) Cohort; Participants will receive DEN in combination with ramucirumab (RAM) and paclitaxel (PAC). If dose for DEN is deemed safe during the SRI Cohort, the study will move forward into the Expansion Period.	Drug: Denikitug; Administered Intravenously; Other Names: GS-1811; Drug: Ramucirumab; Administered Intravenously; Drug: Paclitaxel; Administered Intravenously
Experimental: Part 2: Arm D: Expansion Cohort; If DEN dose is deemed safe in Arm D: SRI Cohort, participants will receive DEN at recommended dose as an IV infusion in combination with RAM and PAC.	Drug: Denikitug; Administered Intravenously; Other Names: GS-1811; Drug: Ramucirumab; Administered Intravenously; Drug: Paclitaxel; Administered Intravenously

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the percentage of participants who have achieved complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST Version 1.1.	Up to 4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	DOR is defined as the time of first response CR or PR as assessed by investigator, per RECIST Version 1.1 until the date of first documented progressive disease (PD) or death, whichever comes first.	Up to 4 years
Progression-Free Survival (PFS)	PFS is defined as the time from date of first dose until PD or death from any cause, whichever comes first as assessed by the investigator according to RECIST Version 1.1.	Up to 4 years
Overall Survival (OS)	OS is defined as the length of time from first dose until the date of death from any cause.	Up to 4 years
Percentage of Participants Experiencing Treatment-Emergent Adverse Event (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0		First dose date up to 120 days post last dose, up to 4 years.
Percentage of Participants Experiencing Clinical Laboratory Abnormalities According to the NCI CTCAE v5.0		First dose date up to 120 days post last dose, up to 4 years.
Pharmacokinetic (PK) Parameter: Serum concentration of DEN		Up to 4 years
PK Parameter: Cmax for Denikitug	Cmax is defined as the maximum observed concentration.	Up to 4 years
PK Parameter: AUCall for Denikitug	AUCall is defined as the cumulative areas under the curve for all time points.	Up to 4 years
Percentage of Participants who Developed Treatment-Emergent Antidrug Antibody (ADA) Against Denikitug		Up to 4 years

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Gilead Study Director, Gilead Sciences

Publications and helpful links

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: April 17, 2026
• First Submitted That Met QC Criteria: April 17, 2026
• First Posted (Actual): April 23, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Adenocarcinoma Of Esophagus; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Diterpenes; Nivolumab; Ramucirumab; Paclitaxel
• Other Study ID Numbers: GS-US-742-7757; 2025-524095-27 (Other Identifier: EU Trial (CTIS) Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No