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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gilead Sciences Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-06-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Gilead Sciences Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Efficacy

To assess the effect of denikitug (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 Version 1.1 (RECIST Version 1.1).

Secondary objectives 4

1. To assess the effect of DEN as monotherapy and in combination with NIVO or RAM and PAC on duration of response (DOR) and progression-free survival (PFS) as assessed by the investigator according to RECIST Version 1.1.
2. To assess the effect of DEN as a monotherapy and in combination with NIVO or RAM and PAC on overall survival (OS).
3. To evaluate the safety and tolerability of DEN as monotherapy and in combination with NIVO or RAM and PAC.
4. To evaluate pharmacokinetics (PK) and immunogenicity of DEN as monotherapy and in combination with NIVO or RAM and PAC.

Conditions and MedDRA coding

HER2-negative, unresectable, recurrent, and/or metastatic gastric, GEJ, and esophageal adenocarcinomas

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 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.
2. 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.
3. Medical History/Physical Characteristics MH1. Histologically or cytologically confirmed diagnosis of locally advanced, unresectable, or metastatic gastric, GEJ, or EACs.
4. MH2. HER2-negative status, as determined by local assessment using a validated immunohistochemistry assay, in situ hybridization or other amplification testing.
5. 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.
6. 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.
7. 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.
8. MH6. ECOG performance status score of 0-1 (see Appendix 11.7).
9. Laboratory Assessments LA1. Negative serum pregnancy test at screening and enrollment (see Appendix 11.5).
10. 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:
11. LA3. (Part 2 only) Have adequate organ function as indicated by the following screening laboratory values.
12. Other Inclusion Criteria OI1. Life expectancy of at least 3 months.
13. 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.
14. 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.

Exclusion criteria 29

1. Medical Conditions/History MC1. Participants with plans to breastfeed during the study period and 4 months following the last dose of study intervention
2. MC2. Known hypersensitivity to the study intervention, its metabolites, or formulation excipient.
3. 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.
4. 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.
5. 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%.
6. MC6. Have active serious infection requiring antibiotics. Note: Prophylactic antibiotic treatment is allowed.
7. 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.
8. 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
9. 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).
10. 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).
11. 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.
12. 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:
13. MC13. (For Part 2 only) Serious nonhealing wound, nonhealing ulcer or nonhealing bone fracture within 28 days prior to enrollment.
14. MC14. (For Part 2 only) Has uncontrolled arterial hypertension ≥ 150/≥ 90 mm Hg despite standard medical management.
15. MC15. (For Part 2 only) Has known history of peripheral neuropathy ≥ Grade 2 (per NCI-CTCAE Version 5.0).
16. MC16. (For Part 2 only) Deep venous thromboembolic event within 28 days prior to enrollment.
17. 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.
18. 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.
19. PT2. Use of other investigational drugs (drugs not marketed for any indication) within 4 weeks of enrollment.
20. 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.
21. 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.
22. 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:
23. PT6. (For Part 2 only) Prior treatment with systemic therapy with other anti-angiogenic drugs.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. OE2. Use of any live attenuated vaccines against infectious diseases within 4 weeks (28 days) prior to enrollment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 6

1. DOR is measured from 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.
2. PFS is 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.
3. OS is length of time from first dose until the date of death from any cause.
4. The incidence, severity, seriousness, and relatedness of treatment-emergent adverse events (TEAEs) and incidence and severity of clinical laboratory abnormalities graded according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
5. Serum concentration of DEN and estimated PK parameters (eg, Cmax, AUCall).
6. Percentage of treatment-emergent antidrug (DEN) antibody (ADA)-positive and ADA-negative participants.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gilead Sciences Inc.

Sponsor organisation

Gilead Sciences Inc.

Address

333 Lakeside Drive

City

Foster City

Postcode

94404-1147

Country

United States

Scientific contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Public contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Third parties 4

Locations

2 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 70 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications