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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)

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ClinicalTrials.gov Identifier: NCT04704934
Recruitment Status : Recruiting
First Posted : January 12, 2021
Last Update Posted : April 19, 2022
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Brief 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.

Condition or disease Intervention/treatment Phase
Gastric Cancer, Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Drug: Trastuzumab deruxtecan Drug: Ramucirumab Drug: Paclitaxel Phase 3

Detailed 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 and confirmed by central assessment of tumor tissue) 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 490 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : May 21, 2021
Estimated Primary Completion Date : April 15, 2024
Estimated Study Completion Date : November 15, 2024


Arm Intervention/treatment
Experimental: Trastuzumab deruxtecan
Participants who will be randomized to receive a 6.4 mg/kg intravenous (IV) dose of trastuzumab deruxtecan once every 3 weeks on Day 1 of each 21-day cycle.
Drug: Trastuzumab deruxtecan
6.4 mg/kg IV infusion every 3 weeks on Day 1 of each 21-day cycle
Other Names:
  • T-DXd
  • DS-8201a
  • ENHERTU®

Active Comparator: Ramucirumab + paclitaxel
Participants who will be randomized to receive a 8 mg/kg IV dose of ramucirumab on Days 1 and 15 in combination with 80 mg/m^2 IV dose of paclitaxel on Days 1, 8, and 15 of a 28-day cycle.
Drug: Ramucirumab
8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle
Other Name: CYRAMZA®

Drug: Paclitaxel
80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle




Primary Outcome Measures :
  1. Overall Survival in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel [ Time Frame: Time from date of randomization until death (due to any cause), up to approximately 36 months ]
    Overall survival (OS) is defined as the time from date of randomization until death from any cause.


Secondary Outcome Measures :
  1. Progression-free Survival in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel [ Time Frame: 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 ]
    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.

  2. Objective Response Rate in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel [ Time Frame: From start of treatment to date of documented disease progression, up to approximately 36 months ]
    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.

  3. Duration of Response in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel [ Time Frame: 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 ]
    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.

  4. Disease Control Rate in Participants Who Were Administered Trastuzumab Deruxtecan Compared With Ramucirumab in Combination With Paclitaxel [ Time Frame: From start of treatment to date of documented disease progression, up to approximately 36 months ]
    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.

  5. Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI), and Physical Examination Findings [ Time Frame: From time subjects signs informed consent form up to 40 days after last study dose ]
    Adverse events will be graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0.

  6. Serum Concentrations for Trastuzumab Deruxtecan, total anti-HER2 antibody, and Active Metabolite MAAA-1181a [ Time Frame: Cycles 1-4 and subsequent cycles on Day 1 pre- and post-infusion (each cycle is 28 days) ]
  7. Percentage of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) [ Time Frame: Cycles 1, 2, and 4 on Day 1 pre-infusion, then every 4 cycles on Day 1 pre-infusion, end of treatment, 40 day follow up, and long-term follow up until death, withdrawal of consent, or lost to follow up whichever occurs first (each cycle is 28 days) ]
    The immunogenicity of trastuzumab deruxtecan will be assessed.

  8. Percentage of Participants Who Have Treatment-emergent ADAs [ Time Frame: Cycles 1, 2, and 4 on Day 1 pre-infusion, then every 4 cycles on Day 1 pre-infusion, end of treatment, 40 day follow up, and long-term follow up until death, withdrawal of consent, or lost to follow up whichever occurs first (each cycle is 28 days) ]
    The immunogenicity of trastuzumab deruxtecan will be assessed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  • 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, and hepatic 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04704934


Contacts
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Contact: (EU & UK sites) Daiichi Sankyo Contact for Clinical Trial Information 908-992-6400 CTRinfo@dsi.com
Contact: (Asia sites) Daiichi Sankyo Contact for Clinical Trial Information +81-3-6225-1111(M-F 9-5 JST) dsclinicaltrial@daiichisankyo.co.jp

Locations
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Sponsors and Collaborators
Daiichi Sankyo, Inc.
AstraZeneca
Investigators
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Study Director: Global Clinical Leader Daiichi Sankyo, Inc.
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Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT04704934    
Other Study ID Numbers: DS8201-A-U306
2020-004559-34 ( EudraCT Number )
First Posted: January 12, 2021    Key Record Dates
Last Update Posted: April 19, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daiichi Sankyo, Inc.:
Gastric Cancer, Adenocarcinoma
Gastroesophageal Junction Adenocarcinoma
Trastuzumab deruxtecan
T-DXd
DS-8201a
Ramucirumab
Paclitaxel
Additional relevant MeSH terms:
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Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Head and Neck Neoplasms
Esophageal Diseases
Paclitaxel
Trastuzumab
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological