Trastuzumab Deruxtecan Plus Nivolumab Plus Capecitabine Plus Oxaliplatin for HER2 Low Gastric and Gastroesophageal Junction Adenocarcinoma (T-DXd_HER2Low)

An Open Label Phase 1b/2 Study to Evaluate Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) Plus Nivolumab Plus Capecitabine Plus Oxaliplatin for Patients With HER2-Low Gastric and Gastroesophageal Junction Adenocarcinoma

To evaluate the safety and tolerability of the combination therapy of T-DXd, nivolumab, and chemotherapy in patients with untreated HER2-low gastric or gastroesophageal junction adenocarcinoma, and to determine the recommended dose. Subsequently, the efficacy and safety at the recommended dose will be assessed.

Study Overview

• Status: Completed
• Conditions: Gastric Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: T-DXd; Drug: Nivolumab; Drug: Capecitabine; Drug: Oxaliplatin

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba
    • Kashiwa, Chiba, Japan, 277-8577
      • National Cancer Center Hospital East

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Historical confirmation of adenocarcinoma of the gastric, gastroesophageal junction, or esophagus is considered by the investigator or subinvestigator to be unresectable advanced or recurrent.
2. HER2 low expression: IHC1+, or IHC2+ and ISH negative [FISH or DISH method] in HER2 test of the primary lesion or metastatic lesion.
3. Having one or more measurable disease as specified in RECIST Guideline version 1.1.
4. Systemic treatment is untreated (local radiation and surgical treatment is acceptable).
5. Age at the date of informed consent is 20 years or older.
6. ECOG Performance status (PS) of 0 or 1.
7. Has LVEF >= 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment.
8. Has a corrected QT interval (QTc) =< 470 ms in females, or QTc =< 450 ms in males based on a 12-lead ECG screening within 28 days before enrollment (allowed on the same day of the week). [Fridericia's correction is recommended]
9. The most recent laboratory value within 14 days before enrollment meets all of the following. (Examinations on the same day of the week 2 weeks prior to the date of enrollment are allowed.) (1)Absolute Neutrophil count =< 1,500/mm3 (2)Hemoglobin =< 9.0 g/dL (3)Platelet count =< 100,000/mm3 (4)Total bilirubin =< 1.5 mg/dL (5)AST(GOT) =< 100 IU/L =< 200 IU/L in the presence of hepatic involvement (6)ALT(GPT) =< 100 IU/L =< 200 IU/L in the presence of hepatic involvement (7)Creatinine =< 1.5 mg/dL (8)PT(INR) < 1.8 and aPTT < 60 seconds

10. Has adequate treatment washout period before enrollment (allowed on the same day of the week), defined as:

    i. Surgery with general anesthesia: >= 4 weeks ii. Radiotherapy: >= 4 weeks (including palliative stereotactic body radiation therapy to the chest; palliative stereotactic body radiation therapy to other than the chest >= 2 weeks; abdominal vertebral bodies should be included in the abdomen).

    iii. Chloroquine and hydroxychloroquine: >= 15 days

11. No blood transfusion was performed within 7 days before registration. (Transfusions on the same day of the week prior to the day of enrollment are allowed.)
12. Female of childbearing potential have a negative pregnancy test within 7 days before enrollment (allowed on the same day of the week). Male and Female of childbearing potential agree to contraception for a period (4 months for male and 7 months for Female) from informed consent to the last dose of study drug.
13. Written informed consent of participation in the study has been obtained from the patient.

Exclusion Criteria:

1. Has a prior chemotherapy for unresectable advanced or recurrent gastric/esophagogastric junction/esophageal adenocarcinoma. (Note: Patients are eligible if they have received prior preoperative or postoperative adjuvant therapy. However, treatment must have been completed at least 6 months prior to enrollment and progression must have occurred at least 6 months after completion of treatment).
2. Metastases to the central nervous system have been identified. (Only if CNS involvement is clinically suspected, cerebral CT scanning or MRI confirmation is mandatory at the time of screening.).

3. Has a medical history of myocardial infarction or congestive heart failure (New York Heart Association Classes II-IV) within 6 months before enrollment, corresponding to the **troponin levels diagnosed as myocardial infarction as defined by the *manufacturer within 28 days before enrollment (allowed on the same day), unstable angina, or any serious arrhythmia requiring treatment.

   *: Manufacturer refers to a testing company used by a study implementation institution.

   **: Enrollment is allowed if a subject exceeds ULN, if the subject is examined and myocardial infarction can be excluded.

4. Active cancer that requires aggressive treatment, such as chemotherapy or operation
5. Has serious (hospitalized) complications (intestinal palsy, intestinal obstruction, pulmonary fibrosis, diabetes mellitus that is difficult to control, heart failure, myocardial infarction, unstable angina, renal failure, liver failure, psychiatric disorders, cerebrovascular disorders, etc.)

6. Grade 1 or residual adverse effects of prior therapy that have not resolved to baseline (excluding hair loss).

   Note:Participants with Grade2 chronic toxicity (Defined as no worse than Grade 2 for at least 3 months prior to enrollment and manageable with standard therapy) who are considered by the investigator to have treatment-related toxicity are eligible for enrollment.

   • Chemotherapy-Induced Neuropathy
   • Malaise
7. Has history of gastrointestinal perforation and/or gastrointestinal fistula within 6 months before enrollment.

8. Has any of the following infections:

   • HBs antigen positive
   • HBs antibody or HBc antibody and HBV-DNA positive
   • Active hepatitis C (e.g., if HCV RNA is detected qualitatively) Patients who are HBsAg positive but who have achieved HBV DNA level < 1.3 log IU/mL (2.1 log copies/mL) after treatment with antiviral drugs such as NAs, are eligible for the study.
9. HIV infection has been documented.

10. Lung diseases are defined as:

    • Has a history of non-infectious interstitial lung disease or pneumonitis that required treatment, has interstitial lung disease or pneumonitis, or these lung diseases cannot be ruled out by radiographic examination before enrollment.
    • Severe pulmonary impairment (e.g., pulmonary embolism within 3 months prior to enrollment, serious bronchial asthma, severe COPD, restrictive pulmonary disease, or pleural effusion).
    • Lung-related autoimmune or connective tissue or inflammatory diseases (e.g., rheumatoid arthritis, Sjogren's syndrome, or sarcoidosis) with clinically severe pulmonary risks.
    • Has history of pneumonectomy.
11. Has history of concomitant autoimmune disease or chronic or recurrent autoimmune disease.
12. Administration of systemic adrenocortical hormones (except prophylactic administration for tests or allergic reactions, and temporary use for the purpose of reducing edema associated with radiotherapy) or immunosuppressants is required, or has received these treatments within 14 days before enrollment in the study.
13. Has unhealed wounds, ulcers, or fractures.
14. If you have uncontrolled acute systemic infection that requires Infusion intravenous antibiotic, antiviral, or antifungal drug.
15. If you have received a live attenuated vaccine (mRNA vaccine or replication-defective adenovirus vaccine is not regarded as live attenuated vaccine) within 30 days before the initial administration.
16. If patients are a pregnancy or breastfeeding patient.
17. Patients who do not take appropriate contraceptive measures during the study and contraceptive period
18. Severe hypersensitivity to the active ingredient or additive of the study drug has been confirmed.
19. Has history/complications of severe hypersensitivity reactions to other monoclonal antibodies.
20. Unwilling or unable to comply with any of implementation matters stipulated in the study implementation protocol or any of the instructions of the physician.
21. The investigator or sub investigator considered it ineligible for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T-DXd plus Nivolumab, Capecitabine	Drug: T-DXd; T-DXd (4.4mg/kg, intravenous, q3w); Drug: Nivolumab; Nivolumab (360 mg, intravenous, q3w); Drug: Capecitabine; Capecitabine (750mg/m2 twice daily, days 1-14, orally); Drug: Oxaliplatin; Oxaliplatin (70mg/m2, intravenous, q3w)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of DLTs in Phase Ib part	The incidence of DLTs in each cohort will be calculated for the DLT evaluable population.	3 weeks
ORR in Phase II part	The ORR is defined as the proportion of participants whose best overall response, as assessed by the principal investigator or sub-investigator according to the RECIST guidelines version 1.1, is either CR or PR.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DoR)	The duration is defined as the period from the date on which a complete response (CR) or partial response (PR) was first confirmed based on the overall response according to the RECIST Guidelines version 1.1, up to the earlier of the date on which disease progression (PD based on imaging) was determined or the date of death from any cause.	1 year
Disease Control Rate (DCR)	The DCR is defined as the proportion of participants whose best overall response according to the RECIST guidelines version 1.1 was CR or PR, or whose SD persisted for 6 weeks or longer.	1 year
Progression-Free Survival (PFS)	The period is calculated from the date of registration until the earlier of the date of confirmed progression or the date of death from any cause.	1 year
Overall Survival (OS)	The period is calculated from the date of registration until the date of death from any cause.	1 year
Incidence of adverse events	The treatment-emergent AEs will be summarized by CTCAE v5.0	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
HER2 expression at central review	Analysis of efficacy in cases confirmed to have low HER2 expression at central review (ORR, PFS, DoR, DCR, OS)	1 year
Evaluation of tumor tissue biomarkers by immunohistochemistry/in situ hybridization and RNA sequencing in the PhIb and PhII cohorts	This outcome measure relates to an ancillary biomarker research study conducted as part of the main trial. Exploratory assessment of tumor tissue biomarkers will be performed using archived FFPE tumor specimens, including PD-L1, CD8, CD4, EBER-ISH, MMR protein expression, CLDN18.2, EGFR, FGFR, and MET expression by immunohistochemistry and/or in situ hybridization, and gene expression profiling by RNA sequencing.	1 year

Collaborators and Investigators

• Sponsor: National Cancer Center Hospital East
• Investigators: Principal Investigator: Kohei Shitara, MD, National Cancer Center Hospital East

Study record dates

Study Major Dates

• Study Start (Actual): December 20, 2023
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: April 6, 2026
• First Submitted That Met QC Criteria: April 10, 2026
• First Posted (Actual): April 14, 2026

Study Record Updates

• Last Update Posted (Actual): April 14, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Gastric Cancer; DS-8201a; T-DXd; Trastuzumab Deruxtecan; HER2-Low
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; Oxaliplatin; Nivolumab
• Other Study ID Numbers: EPOC2203

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