Trastuzumab Deruxtecan for Subjects With HER2-Positive Gastric Cancer or Gastro-Esophageal Junction Adenocarcinoma After Progression on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04)

Gastroesophageal Junction Adenocarcinoma Clinical Trial

Official title:

A Phase 3, Multicenter, 2-Arm Randomized, Open-Label Study of Trastuzumab Deruxtecan in Subjects With HER2-Positive Metastatic and/or Unresectable Gastric or Gastro-Esophageal Junction (GEJ) Adenocarcinoma Subjects Who Have Progressed on or After a Trastuzumab-Containing Regimen (DESTINY-Gastric04)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04704934
• Other study ID #: DS8201-A-U306
• Secondary ID: 2020-004559-34
• Status: Recruiting
• Phase: Phase 3
• Start date: May 21, 2021
• Est. completion date: February 1, 2026

Study information

• Verified date: May 2024
• Source: Daiichi Sankyo
• Contact: (EU & UK sites) Daiichi Sankyo Contact for Clinical Trial Inform
• Phone: 908-992-6400
• Email: CTRinfo[@]dsi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the efficacy and safety of trastuzumab deruxtecan (T-DXd) compared with ramucirumab and paclitaxel (Ram + PTX) in participants with HER2-positive gastric or gastro-esophageal junction (GEJ) adenocarcinoma who have progressed on or after a trastuzumab-containing regimen and have not received any additional systemic therapy.

Description:

This study will assess the efficacy and safety of T-DXd compared with Ram + PTX in participants with HER2-positive (defined as immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) gastric or GEJ adenocarcinoma (based on [American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines who have progressed on or after a trastuzumab-containing regimen and have not received any additional systemic therapy. Participants will be randomized 1:1 to either T-DXd or Ram + PTX treatment. The primary objective will assess overall survival. Secondary objectives will further assess progression-free survival, objective response rate, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of T-DXd.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 490
• Est. completion date: February 1, 2026
• Est. primary completion date: October 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults (according to local regulation) and able to provide informed consent for study participation.

• Pathologically documented gastric and GEJ adenocarcinoma that has been previously treated in the metastatic setting (unresectable, locally advanced, or metastatic disease).

• Progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen. Note: Prior neoadjuvant or adjuvant therapy with a trastuzumab-containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing neoadjuvant or adjuvant therapy. Prior neoadjuvant or adjuvant therapy that does not include trastuzumab will not be counted as a line of therapy regardless of the progression status of the subject.

• Locally or centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.

• Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening.

• Adequate bone marrow, renal, hepatic function, and blood clotting function within 14 days of randomization.

Exclusion Criteria:

• Use of anticancer therapy after trastuzumab-containing treatment

• Medical history of myocardial infarction (MI) within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV).

• Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate12-lead ECG.

• Has a history of (non-infectious) interstitial lung disease (ILD/pneumonitis) that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.

• Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of) pulmonary involvement at the time of Screening.

• Prior complete pneumonectomy.

• Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.

• Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.

• History of severe hypersensitivity reactions to either the T-DXd or inactive ingredients in T-DXd.

• History of severe hypersensitivity reactions to other monoclonal antibodies, including ramucirumab or to any of its excipients.

• Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.

• Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an unexplained fever >38.0°C during Screening visits or on the first scheduled day of dosing (at the discretion of the Investigator, participants with tumor fever may be enrolled), which in the Investigator's opinion might compromise the participant's participation in the study or affect the study outcome

• Clinically significant gastrointestinal disorder (eg, including hepatic disorders, bleeding, inflammation, occlusion, ileus, diarrhea Grade >1, jaundice, intestinal paralysis, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel obstruction) in the opinion of Investigator

• Has history of receiving live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention

Related Conditions & MeSH terms

• Adenocarcinoma
• Esophageal Neoplasms
• Gastric Cancer, Adenocarcinoma
• Gastroesophageal Junction Adenocarcinoma
• Stomach Neoplasms

Intervention

Drug:
• Trastuzumab deruxtecan
6.4 mg/kg IV infusion every 3 weeks on Day 1 of each 21-day cycle
• Ramucirumab
8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle
• Paclitaxel
80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle

Locations

Country	Name	City	State
Argentina	Fundacion Cenit	Buenos Aires
Argentina	Instituto Medico Especializado Alexander Fleming	Colegiales	Caba
Argentina	IONC Instituto Oncologico de Cordoba - Fundacion Richardet Longo	Nueva Cordoba	Cordoba
Argentina	Exelsus	San Miguel De Tucumán	Tucumán
Belgium	UCL St. Luc	Brussels
Belgium	Antwerp University Hospital	Edegem
Belgium	Pôle Hospitalier Jolimont	Haine-Saint-Paul
Belgium	UZ Leuven	Leuven
Brazil	PERSONAL - Oncologia de Precisao e Personalizada	Belo Horizonte
Brazil	Hospital Sirio Libanes	Brasilia
Brazil	ONCOSITE - Centro de Pesquisa Clinica em Oncologia LTDA	Ijui
Brazil	Hospital Ernesto Dornelles	Porto Alegre
Chile	Clinica San Carlos de Apoquindo	Santiago	Region Metropolitana
Chile	Fundacion Arturo Lopez Perez	Santiago	Region Metropolitana
Chile	SIM Centro de Investigacion Clinica	Temuco	Cautin
China	Beijing Cancer Hospital	Beijing
China	Peking Univ 3rd Hosp	Beijing
China	The 1st Hospital of Jilin Univ	Changchun
China	Zhongnan univ Xiangya hosp	Changshan	Hunan
China	Fujian Medical University - Fujian Provincial Cancer Hospital	Fuzhou	Fuijan
China	1Affiliated H of Sun Yat Sen U	Guangzhou	Guangdong
China	The Sixth Affiliated Hospital of Sun Yat-Sen University	Guangzhou	Guangdong
China	Sir Run Run Shaw Hospital	Hangzhou
China	Zhejiang Medical University - Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang
China	Anhui Provincial Hospital	Heifi	Anhui
China	Shandong Cancer Hospital & Institute	Jinan	Shandong
China	Linyi Cancer Hospital	Linyi
China	1 Affiliated H of Nanchang U	Nanchang
China	Jiangsu Province Hosp	Nanjing	Jiangsu
China	Fudan University - Shanghai Cancer Center	Shanghai
China	Shanghai First People's Hosp	Shanghai	Shanghai
China	Zhongshan Hosp Fudan Univ	Shanghai	Shanghai
China	1st Hosp of China Medical Univ	Shenyang	Liaoning
China	Liaoning Cancer Hospital	Shenyang	Liaoning
China	Hebei Medical Univ 4th Hosp	Shijiazhuang	Hebei
China	Xinjiang Medical University - Cancer Hospital	Urumqi	Xinjiang
China	Xiamen University - The First Affiliated Hospital	Xiamen	Fujian
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
France	CHU Besançon	Besancon
France	CHRU	Brest
France	Centre Oscar Lambret	Lille
France	Centre Leon Berard	Lyon Cedex 08
France	Hopital de la Timone	Marseille
France	Institut de Recherche en Cancerologie de Montpellier IRCM	Montpellier
France	Hopital Europeen G. Pompidou	Paris
France	Hopital Saint Antoine	Paris
France	L Institut Mutualiste Montsouris	Paris
France	Centre Hospitalier Universitaire CHU de Rennes - Hopital de Pontchaillou	Rennes
France	Pharmacie ICLN	Saint-Priest-en-Jarez
France	Gustave Roussy, étage -1.	Villejuif
Germany	Charité-Unimedizin Berlin	Berlin
Germany	Uniklinikum Carl-Gustav-Carus	Dresden Sachsen
Germany	Evang. Klin. Essen-Mitte gGmbH	Essen
Germany	Ins. für klinische onk. Forschung	Frankfurt Am Main Hessen
Germany	Asklepios Tumorzentrum Altona	Hamburg
Germany	Häm-Onk. Praxis Eppendorf	Hamburg
Germany	Uni zu Koln-Unikl. Koln	Kln Nordrhein-westfalen
Germany	Universitares Krebszentrum	Leipzig
Hong Kong	Pamela Youde Nethersole Eastern Hospital	Chai Wan
Hong Kong	Princess Margaret Hospital	Hong Kong
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	The Chinese University of Hong Kong (CUHK) - Prince of Wales Hospital (PWH) - Vascular and Interventional Radiology Foundation (VIRF) Clinical Science Centre	Hong Kong
Hungary	Magyar Honvedseg Egeszs. K	Budapest
Hungary	Debreceni Egyetem Klinikai	Debrecen
Hungary	Tolna M. Balassa Janos Korhaz	Szekszard
Ireland	Cork University Hospital	Cork
Ireland	Beaumont Hospital	Dublin
Ireland	St James's Hospital	Dublin
Ireland	Tallaght University Hospital	Dublin
Israel	Soroka Univ Medical CTR	Be'er-Sheva Southern
Israel	Davidoff Center	Petach Tikva
Israel	The Chaim Sheba Medical Center	Ramat Gan
Italy	AOU Pisana	Barone
Italy	IRCC-FPO Candiolo	Candiolo
Italy	AOU Mater Domini	Catanzaro
Italy	Istituto Europeo di Oncologia S.r.L Divisione di Oncologia Medica Gastrointestinale e Tumori Neuroendocrini	Milan
Italy	Ospedale Niguarda	Milan
Italy	Istituto Nazionale dei Tumori	Milano
Italy	San Raffaele Hospital	Milano
Italy	Azienda Ospedaliero-Universitaria di Modena	Modena
Italy	Aou Vanvitelli	Napoli
Italy	Istituto Oncologico Veneto	Padua
Italy	Azienda Ospedaliero-Universitaria Pisana	Pisa
Japan	National Cancer Center Hospital	Chuo Ku
Japan	Osaka International Cancer Institute	Chuo Ku
Japan	Gifu University Hospital	Gifu
Japan	National Cancer Center Hospital East	Kashiwa
Japan	Kobe City Medical Center General Hospital	Kobe
Japan	Kochi Health Sciences Center	Kochi
Japan	The Cancer Institute Hospital of JFCR	Koto-Ku
Japan	National Hospital Organization Shikoku Cancer Center	Matsuyama
Japan	Aichi Cancer Center Hospital	Nagoya-shi	Aichia
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Kindai University Hospital	Osaka-sayama
Japan	Osaka University Hospital	Suita
Korea, Republic of	Kyungpook Nat Uni Chilgok Hos	Daegu
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun
Korea, Republic of	Seoul Nati Univ Bundang Hosp	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chonbuk National University Hospital - Jeonbuk Regional Cancer Center	Seoul
Korea, Republic of	Korea Univ Anam Hosp	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St. Marys Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Poland	Sklodowska-Curie Inst Oncology	Warszawa
Poland	Uniwersytecki Szpital Kliniczny im.Mikulicza-Radeckiego	Wroclaw
Portugal	Hospital Sra da Oliveira	Creixomil E Mariz
Portugal	Instituto Portugues De Oncologia Do Porto Francisco Gentil, E.P.E.	Porto
Portugal	C Hosp Tras Montes Alto Douro	Vila Real
Romania	S.C. Oncopremium-Team SRL	Baia Mare
Romania	Institutul Oncologic Prof. Dr. Alexandru Trestiorean Bucuresti IOB	Bucharest
Romania	S.C. Medisprof SRL	Cluj-Napoca
Romania	Centrul de Oncologie Sf. Nectarie	Craiova
Russian Federation	SBIH Chelyabinsk Regional Clinical Centre of Oncology and Nuclear Medicine	Chelyabinsk
Russian Federation	City Clinical Oncology Dispensary	Saint-Petersburg
Russian Federation	Private Medical Institution "Euromedservice"	St.Petersburg
Russian Federation	Republican Clinical Oncology Dispensary	Ufa
Singapore	National Cancer Centre Singapore	Singapore
Singapore	National Univ Cancer Inst SGP	Singapore
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Germans Trias i Pujol	Barcelona
Spain	Hospital Vall d'Hebron	Barcelona
Spain	H. Gregorio Maranon	Madrid
Spain	Hosp Univ Ramón y Cajal	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital de Navarra	Pamplona
Spain	Hospital Clinico Universitario de Santiago de Compostela	Santiago de Compostela
Spain	H. Clinico U. de Valencia	Valencia
Taiwan	CGMF-Kaohsiung Branch	Kaohsiung
Taiwan	KMUH	Kaohsiung
Taiwan	China Medical Univ Hosp	Taichung
Taiwan	National Cheng Kung Univ Hosp	Tainan
Taiwan	MacKay Memorial Hospital	Taipei
Taiwan	National Taiwan University Hospital NTUH	Taipei
Taiwan	Taipei Veterans General Hosp	Taipei
Taiwan	CGMF-Linkou Branch	Taoyuan
Turkey	SBU Adana Sehir Hastanesi	Adana
Turkey	Trakya Universitesi Balkan	Edirne
Turkey	Suleyman Yalcin Seh. Hast.	Istanbul
Turkey	Inonu Uni. Turgut Ozal Tip	Malatya
Ukraine	MedicalCenter ASKLEPION LLC	Kyiv
Ukraine	National Cancer Institute	Kyiv
Ukraine	LLC "Oncolife"	Zaporizhzhia
United Kingdom	Queens University Belfast - Centre for Cancer Research and Cell Biology CCRCB	Belfast
United Kingdom	University Hospitals Birmingham UHB NHS Foundation Trust - Queen Elizabeth Hospital Birmingham QEHB	Birmingham
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Velindre NHS Trust - Velindre Cancer Centre VCC	Cardiff
United Kingdom	Ninewells Hospital	Dundee
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	The Clatterbridge Cancer Centre NHS Foundation Trust	Liverpool
United Kingdom	Royal Marsden NHS	London
United Kingdom	UCLH Trust	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	University of Oxford, The Churchill Hospital	Oxford
United Kingdom	Royal Marsden Sutton	Sutton
United Kingdom	Leeds Teaching Hospitals NHS Trust	West Yorkshire

Sponsors (2)

Lead Sponsor	Collaborator
Daiichi Sankyo	AstraZeneca

Countries where clinical trial is conducted

Argentina,  Belgium,  Brazil,  Chile,  China,  France,  Germany,  Hong Kong,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Poland,  Portugal,  Romania,  Russian Federation,  Singapore,  Spain,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel	Overall survival (OS) is defined as the time from date of randomization until death from any cause.	Time from date of randomization until death (due to any cause), up to approximately 36 months
Secondary	Progression-free Survival in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel	Progression-free survival (PFS) is defined as the time from date of randomization until first objective radiographic tumor progression or death from any cause, based on Investigator assessment.	Time from date of randomization until first objective radiographic disease progression or death (due to any cause) whichever occurs first, up to approximately 36 months
Secondary	Objective Response Rate in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel	Objective response rate (ORR) is defined as the proportion of participants who achieve a best response of complete response (CR) or partial response (PR) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria as assessed by Investigator.	From start of treatment to date of documented disease progression, up to approximately 36 months
Secondary	Duration of Response in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel	Duration of response (DoR) is defined time from the initial response (CR or PR) until documented tumor progression or death from any cause and based on Investigator assessment.	Time from initial response (CR or PR) to date of documented disease progression or death (due to any cause) whichever occurs first, up to approximately 36 months
Secondary	Disease Control Rate in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel	Disease control rate (DCR) is defined as the proportion of participants who achieved CR, PR, or stable disease (SD) for a minimum of 6 weeks during study treatment, based on Investigator assessment.	From start of treatment to date of documented disease progression, up to approximately 36 months
Secondary	Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI), and Physical Examination Findings	Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.	From time subjects signs informed consent form up to 40 days after last study dose
Secondary	Serum Concentrations for Trastuzumab Deruxtecan, total anti-HER2 antibody, and Active Metabolite MAAA-1181a		Cycles 1-4 and subsequent cycles on Day 1 pre- and post-infusion (each cycle is 28 days)
Secondary	Percentage of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline)	The immunogenicity of trastuzumab deruxtecan will be assessed.	Cycles 1, 2, and 4 on Day 1 pre-infusion, then every 4 cycles on Day 1 pre-infusion, 40 day follow up until death, withdrawal of consent, or lost to follow up whichever occurs first (each cycle is 28 days)
Secondary	Percentage of Participants Who Have Treatment-emergent ADAs	The immunogenicity of trastuzumab deruxtecan will be assessed.	Cycles 1, 2, and 4 on Day 1 pre-infusion, then every 4 cycles on Day 1 pre-infusion, 40 day follow up until death, withdrawal of consent, or lost to follow up whichever occurs first (each cycle is 28 days)