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)

Study Overview
=================
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.

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 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.

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)

Conditions
-----------------
Gastric Cancer, Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Trastuzumab deruxtecan
* Drug: Ramucirumab
* Drug: Paclitaxel


Participation Criteria
=================
Eligibility 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. 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab deruxtecan<br>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<br>* 6.4 mg/kg IV infusion every 3 weeks on Day 1 of each 21-day cycle<br>* Other names: ENHERTU®;|
| Active Comparator: Ramucirumab + paclitaxel<br>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<br>* 8 mg/kg IV infusion on Days 1 and 15 of a 28-day cycle<br>* Other names: CYRAMZA®;Drug: Paclitaxel<br>* 80 mg/m^2 IV infusion on Days 1, 8, and 15 of a 28-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
T-DXd, DS-8201a, Ramucirumab, Paclitaxel, Gastric Cancer, Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Trastuzumab deruxtecan