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RecruitingInterventionalPhase 2

A Phase 1b/2 Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, and Antitumor Activity of Trastuzumab Deruxtecan (T-DXd) Monotherapy and Combinations in Adult Participants With HER2-expressing Gastric Cancer (DESTINY-Gastric-03)

NCT ID: NCT04379596Sponsor: AstraZenecaLast updated: 2026-06-11

Summary

DESTINY-Gastric03 will investigate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary antitumor activity of trastuzumab deruxtecan (T-DXd) alone or in combination with chemotherapy and/or immunotherapy in HER2-expressing advanced/metastatic gastric/gastroesophageal junction (GEJ) and esophageal adenocarcinoma patients. Study hypotheses: Combination of T-DXd with cytotoxic chemotherapy and/or immunotherapy administered to subjects at the recommended phase 2 dose will show manageable safety and tolerability and preliminary anti-tumor efficacy so as to permit further clinical testing. T-DXd in combination with cytotoxic chemotherapy or immune checkpoint inhibitor administered to HER2-expressing gastric, GEJ and esophageal cancer patients who have not received prior treatment for advanced/metastatic disease will show preliminary evidence of anti-tumour activity and the potential to become a therapeutic option for this patient population.

Arms & interventions

  • DrugFluorouracil (5-FU)

    5-FU: administered as an IV infusion

  • DrugCapecitabine

    Capecitabine: administered orally

  • BiologicalDurvalumab

    Durvalumab: administered as an IV infusion

  • DrugOxaliplatin

    Oxaliplatin: administered as an IV infusion

  • BiologicalTrastuzumab

    Trastuzumab: administered as an IV infusion

  • DrugTrastuzumab deruxtecan

    T-DXd: administered as an IV infusion

  • DrugCisplatin

    Cisplatin: administered as an IV infusion

  • BiologicalPembrolizumab

    Pembrolizumab: administered as an IV infusion

  • BiologicalVolrustomig

    Volrustomig: administered as an IV infusion

  • BiologicalRilvegostomig

    Rilvegostomig: administered as an IV infusion

Outcome measures

Primary

  • Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0

    Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0

    Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

  • Part 1: Ocurrence of dose-limiting toxicities (DLTs)

    Occurrence of dose limiting toxicities

    Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

  • Part 1: Changes from baseline in laboratory parameters

    Changes in laboratory parameters (every in appropriate units) compared to baseline results.

    Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

  • Part 1: Changes from baseline in vital signs

    Changes in vital signs results compared to baseline results.

    Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

  • Part 1: Changes from baseline in electrocardiogram (ECG) results

    Changes in ECG results compared to baseline results.

    Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.

  • Part 2, Part 3, Part 4 and Part 5: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR)

    Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

    Time frame: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months

Secondary

  • Part 1: Objective Response Rate (ORR)

    Time frame: Efficacy will be assessed at an average of approximately 12 months

  • Part 2, Part 3, Part 4 and Part 5: Occurrence of adverse events (AEs) and serious adverse events (SAEs)

    Time frame: Safety will be assessed up to follow-up period, approximately 24 months

  • Part 2, Part 3, Part 4 and Part 5: Changes from baseline in laboratory parameters

    Time frame: Safety will be assessed up to follow-up period, approximately 24 months

  • Part 2, Part 3, Part 4 and Part 5: Changes from baseline in vital signs

    Time frame: Safety will be assessed up to follow-up period, approximately 24 months

  • Part 2, Part 3 , Part 4 and Part 5: Changes from baseline in body weight

    Time frame: Safety will be assessed up to follow-up period, approximately 24 months

  • Part 2, Part 3, Part 4 and Part 5: Changes from baseline in electrocardiogram (ECG) results

    Time frame: Safety will be assessed up to follow-up period, approximately 24 months

  • Duration of Response (DoR)

    Time frame: Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months

  • Disease Control Rate (DCR)

    Time frame: Efficacy will be assessed at an average of approximately 12 months

  • Progression Free Survival (PFS)

    Time frame: Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months

  • Overall survival (OS)

    Time frame: Until death, efficacy (OS) will be assessed up to approximately 24 months

  • Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms

    Time frame: While on study drug up to study completion, approximately 24 months

  • Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab

    Time frame: While on study drug up to study completion, approximately 24 months

  • Presence of ADAs for T-DXD, durvalumab, volrustomig and rilvegostomig (in study arms including T-DXd and durvalumab, and T-DXd and volrustomig, and T-DXd and rilvegostomig respectively)

    Time frame: While on study drug up to study completion, approximately 24 months

  • Serum concentrations of volrustomig and rilvegostomig in study arms including T-DXd in combination with volrustomig and T-DXd in combination with rilvegostomig

    Time frame: While on study drug up to study completion, approximately 24 months

  • Comparison of ORR

    Time frame: While on study drug up to study completion, approximately 24 months

  • Comparison of DCR

    Time frame: While on study drug up to study completion, approximately 24 months

  • Comparison of DoR

    Time frame: While on study drug up to study completion, approximately 24 months

  • Comparison of PFS

    Time frame: While on study drug up to study completion, approximately 24 months

  • Comparison of OS

    Time frame: While on study drug up to study completion, approximately 24 months

Eligibility criteria

Sex: AllAge: 18 Years to 130 YearsHealthy volunteers: No
Inclusion criteria: 1. Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations 2. Disease Characteristics: 1. Locally advanced, unresectable, or metastatic disease based on most recent imaging 2. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results 3. For Part 3b,4b and Part 5, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results 3. For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2, Part 3, Part 4 and Part 5, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3 \[Arm 3A\] and Part 4 \[Arm 4A\]) or HER2-low (Part 3 \[Arm 3B\], Part 4 \[Arm 4B\] and Part 5)) status 4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1 5. Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function 6. If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study. Exclusion criteria: 1. Part 1 to 4: History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection. Part 5: evidence of active, uncontroled HIV, HBV or HCV infection. 2. Uncontrolled intercurrent illness. 3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening. 4. Lung-specific intercurrent clinically significant severe illnesses. 5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals. 6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). 7. Has spinal cord compression or clinically active central nervous system metastases.

Study locations (10)

Research Site

Santa Monica, California, 90404

Withdrawn

Research Site

Westwood, Kansas, 66205

Withdrawn

Research Site

Baltimore, Maryland, 21287

Recruiting

Research Site

Boston, Massachusetts, 02114

Withdrawn

Research Site

Boston, Massachusetts, 02215

Recruiting

Research Site

Ann Arbor, Michigan, 48109

Withdrawn

Research Site

New York, New York, 10065

Recruiting

Research Site

Durham, North Carolina, 27710

Withdrawn

Research Site

Houston, Texas, 77090

Recruiting

Research Site

Fairfax, Virginia, 22031

Withdrawn

References

  • Yu J, Mehta R. Biomarker-Driven Approach to the Treatment of Metastatic Gastric or Gastroesophageal Adenocarcinoma. J Natl Compr Canc Netw. 2025 May;23(5):e257036. doi: 10.6004/jnccn.2025.7036.(PubMed)