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

Официальное название

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)

Обзор

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.

Вмешательства

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

Первичные конечные точки

• Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0 [Срок оценки: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Ocurrence of dose-limiting toxicities (DLTs) [Срок оценки: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in laboratory parameters [Срок оценки: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in vital signs [Срок оценки: Safety will be assessed up to the follow-up period, approximately 24 months.]
• Part 1: Changes from baseline in electrocardiogram (ECG) results [Срок оценки: 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) [Срок оценки: (Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months]

Вторичные конечные точки (12)

• Part 1: Objective Response Rate (ORR) [Срок оценки: 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) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: Safety will be assessed up to follow-up period, approximately 24 months]
• Duration of Response (DoR) [Срок оценки: Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months]
• Disease Control Rate (DCR) [Срок оценки: Efficacy will be assessed at an average of approximately 12 months]
• Progression Free Survival (PFS) [Срок оценки: Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months]
• Overall survival (OS) [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: While on study drug up to study completion, approximately 24 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 15 центров

• Research Site — Чэнду
• Research Site — Гуанчжоу
• Research Site — Guiyang
• Research Site — Ханчжоу
• Research Site — Хэфэй
• Research Site — Хэфэй
• Research Site — Шанхай
• Research Site — Шанхай
• … и ещё 7 центров

Бразилия · 11 центров

• 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
• … и ещё 3 центра

США · 10 центров

• Research Site — Santa Monica
• Research Site — Westwood
• Research Site — Baltimore
• Research Site — Boston
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• Research Site — Ann Arbor
• Research Site — New York
• Research Site — Durham
• … и ещё 2 центра

Россия · 10 центров

• Research Site — Kostroma
• Research Site — Moscow
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• Research Site — Novosibirsk
• Research Site — Saint Petersburg
• Research Site — Saint Petersburg
• … и ещё 2 центра

Польша · 8 центров

• Research Site — Gdansk
• Research Site — Konin
• Research Site — Koszalin
• Research Site — Krakow
• Research Site — Lublin
• Research Site — Opole
• Research Site — Tomaszów Mazowiecki
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Канада · 6 центров

• Research Site — Edmonton
• Research Site — Ottawa
• Research Site — Toronto
• Research Site — Toronto
• Research Site — Montreal
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Германия · 6 центров

• Research Site — Frankfurt
• Research Site — Frankfurt
• Research Site — Hamburg
• Research Site — Leipzig
• Research Site — Mannheim
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Италия · 6 центров

• Research Site — Milan
• Research Site — Milan
• Research Site — Naples
• Research Site — Padova
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Тайвань · 6 центров

Список центров уточняется — проверьте первичный протокол.

South Korea · 5 центров

• Research Site — Seongnam-si
• … и ещё 4 центра

Испания · 5 центров

Список центров уточняется — проверьте первичный протокол.

Великобритания · 5 центров

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Япония · 4 центра

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

Нидерланды · 3 центра

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

Публикации

• 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

Идентификаторы

NCT: NCT04379596 · D967LC00001 · 2019-004483-22

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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