Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)

Official title

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)

Overview

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.

Interventions

• Drug Fluorouracil (5-FU)
  5-FU: administered as an IV infusion
• Drug Capecitabine
  Capecitabine: administered orally
• Biological Durvalumab
  Durvalumab: administered as an IV infusion
• Drug Oxaliplatin
  Oxaliplatin: administered as an IV infusion
• Biological Trastuzumab
  Trastuzumab: administered as an IV infusion
• Drug Trastuzumab deruxtecan
  T-DXd: administered as an IV infusion
• Drug Cisplatin
  Cisplatin: administered as an IV infusion
• Biological Pembrolizumab
  Pembrolizumab: administered as an IV infusion
• Biological Volrustomig
  Volrustomig: administered as an IV infusion
• Biological Rilvegostomig
  Rilvegostomig: administered as an IV infusion

Primary outcome measures

• Part 1: Occurrence of adverse events (AEs) and serious adverse events (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) [Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in laboratory parameters [Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in vital signs [Time frame: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in electrocardiogram (ECG) 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) [Time frame: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months]

Secondary outcome measures (12)

• 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]

Eligibility criteria

Inclusion criteria

• Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations
• Disease Characteristics:

• Locally advanced, unresectable, or metastatic disease based on most recent imaging
• 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
• 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
• 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
• Has measurable target disease assessed by the Investigator based on RECIST version 1.1
• Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function
• 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

• 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.
• Uncontrolled intercurrent illness.
• History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.
• Lung-specific intercurrent clinically significant severe illnesses.
• Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
• Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
• Has spinal cord compression or clinically active central nervous system metastases.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 15 centers

• Research Site — Chengdu
• Research Site — Guangzhou
• Research Site — Guiyang
• Research Site — Hangzhou
• Research Site — Hefei
• Research Site — Hefei
• Research Site — Shanghai
• Research Site — Shanghai
• … and 7 more centers

Brazil · 11 centers

• Research Site — Florianópolis
• Research Site — Londrina
• Research Site — Natal
• Research Site — Porto Alegre
• Research Site — Ribeirão Preto
• Research Site — Rio de Janeiro
• Research Site — Santa Maria
• Research Site — São Jose Do Rio Preto
• … and 3 more centers

United States · 10 centers

• Research Site — Santa Monica
• Research Site — Westwood
• Research Site — Baltimore
• Research Site — Boston
• Research Site — Boston
• Research Site — Ann Arbor
• Research Site — New York
• Research Site — Durham
• … and 2 more centers

Russia · 10 centers

• Research Site — Kostroma
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Moscow
• Research Site — Novosibirsk
• Research Site — Saint Petersburg
• Research Site — Saint Petersburg
• … and 2 more centers

Poland · 8 centers

• Research Site — Gdansk
• Research Site — Konin
• Research Site — Koszalin
• Research Site — Krakow
• Research Site — Lublin
• Research Site — Opole
• Research Site — Tomaszów Mazowiecki
• Research Site — Warsaw

Canada · 6 centers

• Research Site — Edmonton
• Research Site — Ottawa
• Research Site — Toronto
• Research Site — Toronto
• Research Site — Montreal
• Research Site — Québec

Germany · 6 centers

• Research Site — Frankfurt
• Research Site — Frankfurt
• Research Site — Hamburg
• Research Site — Leipzig
• Research Site — Mannheim
• Research Site — München

Italy · 6 centers

• Research Site — Milan
• Research Site — Milan
• Research Site — Naples
• Research Site — Padova
• Research Site — Roma
• Research Site — Verona

Taiwan · 6 centers

Center list to be confirmed — check the primary protocol.

South Korea · 5 centers

• Research Site — Seongnam-si
• … and 4 more centers

Spain · 5 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 5 centers

Center list to be confirmed — check the primary protocol.

Japan · 4 centers

• Research Site — Chūōku
• Research Site — Kashiwa
• Research Site — Kita-gun
• Research Site — Ota-shi

Netherlands · 3 centers

• Research Site — Amsterdam
• Research Site — Amsterdam
• Research Site — Utrecht

Publications

• 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. PMID 40341124

Identifiers

NCT: NCT04379596 · D967LC00001 · 2019-004483-22

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗