DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing Gastric Cancer [DESTINY-Gastric01]

Phase 2

Completed

• Conditions: Neoplasm, Gastrointestinal
• Interventions: Drug: Physician's Choice; Drug: DS-8201a

• Registration Number: NCT03329690
• Lead Sponsor: Daiichi Sankyo Co., Ltd.

Brief Summary

The primary purpose of this trial is to compare the efficacy and safety of DS-8201a and physician's choice treatment in HER2-overexpressing advanced gastric or gastroesophageal junction adenocarcinoma patients who have progressed on two prior treatment regimens including fluoropyrimidine agent, platinum agent, and trastuzumab.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-10-30
• Study First Submitted QC: 2017-10-30
• Study Start: 2017-11-02
• Study First Posted: 2017-11-06
• Primary Completion: 2019-11-08
• Results First Submitted: 2020-11-03
• Results First Submitted QC: 2020-11-03
• Results First Posted: 2020-11-27
• Study Completion: 2020-12-11
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-17
• Last Update Posted: 2022-03-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 233

Inclusion Criteria

1. Has a pathologically documented locally advanced or metastatic adenocarcinoma of gastric or gastroesophageal junction
2. Progression on and after at least 2 prior regimens
3. Has an adequate tumor sample
4. Has measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

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Exclusion Criteria

1. Has a medical history of myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia

2. Has a QTc prolongation to > 450 millisecond (ms) in males and > 470 ms in females

3. Has a medical history of clinically significant lung disease

4. Is suspected to have certain other protocol-defined diseases based on imaging at screening period

5. Has history of any disease, metastatic condition, drug/medication use or other condition that might, per protocol or in the opinion of the investigator, compromise:

   1. safety or well-being of the participant or offspring
   2. safety of study staff
   3. analysis of results

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Parallel: Physician's Choice	Physician's Choice	Participants with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) advanced gastric or gastroesophageal junction adenocarcinoma, whose disease has progressed on two prior regimens, will receive monotherapy prescribed by the physician before enrollment.
Parallel: DS-8201a	DS-8201a	Participants with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) advanced gastric or gastroesophageal junction adenocarcinoma, whose disease has progressed on two prior regimens, will receive DS-8201a once every 3 weeks.
Exploratory: Naïve HER2 IHC 2+/ISH-	DS-8201a	A maximum of 20 non-randomized participants with HER2 IHC 2+/ISH- advanced gastric or gastroesophageal junction adenocarcinoma will receive DS-8201a once every three weeks.
Exploratory: Naïve HER2 IHC 1+	DS-8201a	A maximum of 20 non-randomized patients with HER2 IHC 1+ advanced gastric or gastroesophageal junction adenocarcinoma will receive DS-8201a once every 3 weeks.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Best Overall Response Based on Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	Baseline to date of first documented objective response, up to 36 months postdose	The best overall response is the best overall response (BOR) recorded from the start of the study treatment until the end of treatment and includes complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) and not evaluable (NE) as assessed by independent central imaging review (ICR) based on RECIST version 1.1. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Unconfirmed BOR (not confirmed by ICR) and confirmed BOR (confirmed by ICR) are reported.
Percentage of Participants With Objective Response Rate Based on Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	Baseline to date of first documented objective response (CR or PR), up to 36 months postdose	The Objective Response Rate (ORR) is the percentage of participants who achieved a best overall response of Complete Response (CR) or Partial Response (PR), assessed by independent central imaging review (ICR) based on RECIST version 1.1. CR was defined as a disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions. Unconfirmed ORR (not confirmed by ICR) and confirmed ORR (confirmed by ICR) are reported.

Secondary Outcome Measures

Name	Time	Method
Overall Survival Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	From the date of randomization to the date of death (due to any cause), up to 36 months postdose	Duration of survival follow-up (months) was defined as the date of last contact - date of randomization/ registration + 1.Overall Survival (OS) was defined as the time from the date of randomization (the date of the registration for the Exploratory Cohorts) to the date of death due to any cause.
Disease Control Rate With and Without Confirmation by Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	Baseline to date of first documented objective response (CR, PR, and SD), up to 36 months postdose	Disease control rate (DCR) was defined as the sum of complete response (CR) rate, partial response (PR) rate, and stable disease (SD) rate. As per RECIST v1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions.
Time to Treatment Failure Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Full Analysis Set)	From date of randomization to first documentation of PD, death due to any cause, or treatment discontinuation (whichever comes first), up to 36 months postdose	Time to treatment failure (TTF) was defined as the time from the date of randomization (the date of the registration for Exploratory Cohorts) to the earliest date of the first objective documentation of progressive disease (PD), death due to any cause, or treatment discontinuation.
Progression-Free Survival Based on Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	From the date of randomization to the first documented disease progression or date of death (whichever occurs first), up to 36 months postdose	Progression-free survival (PFS) was defined as the time from the date of randomization (the date of the registration for the Exploratory Cohorts) to the earliest date of the first objective documentation of progressive disease (PD) or death due to any cause. PD was defined as at least a 20% increase in the sum of diameters of target lesions.
Duration of Response Based on Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Full Analysis Set)	From the date of first objective response (CR or PR) to the date of first documentation of PD or death (whichever occurs first), up to 36 months postdose	Duration of Response (DOR) was defined as the time from the date of the first documentation of objective response (complete response \[CR\] or partial response \[PR\]) to the date of the first objective documentation of progressive disease (PD) or death due to any cause. DoR was measured for responding subjects (PR or CR) only.
Objective Response Rate and Best Overall Response Based on Independent Central Review Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Intent-to-Treat Analysis Set)	From randomization to first documented objective response, up to 36 months postdose	The Objective Response Rate (ORR) is the percentage of participants who achieved a best overall response of Complete Response (CR) or Partial Response (PR), assessed by Independent Central Review (ICR) based on RECIST version 1.1. The best overall response is the best overall response (BOR) recorded from the start of the study treatment until the end of treatment and includes CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE) as assessed by Investigator based on RECIST version 1.1. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (at least a 20% increase in the sum of diameters of target lesions). Confirmed ORR and BOR (confirmed by ICR) are reported.
Pharmacokinetic Parameter of Maximum Observed Serum Concentration (Cmax) and Trough Serum Concentration (Ctrough) of DS-8201a and Total Anti-HER2 Antibody Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. The maximum serum concentration (Cmax) and the trough serum concentration (Ctrough) of DS-8201a were assessed. These serum PK parameters for DS-8201a and total anti-HER2 antibody were estimated in each participant using standard noncompartmental methods.
Pharmacokinetic Parameter of Maximum Observed Serum Concentration (Cmax) and Trough Serum Concentration (Ctrough) of MAAA-1181 Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. The maximum serum concentration (Cmax) and the trough serum concentration (Ctrough) of DS-8201a were assessed. These serum PK parameters for MAAA-1181a were estimated in each participant using standard noncompartmental methods.
Pharmacokinetic Parameters of Area Under the Concentration Versus-Time Curve of DS-8201a and Total Anti-HER2 Antibody Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. Area under the concentration versus time curve (AUC) from Time 0 to the Last Quantifiable Concentration (AUClast) and Area Under the Concentration versus-Time Curve up to 21 days (AUC21d) are reported. These serum PK parameters for DS-8201a and total anti-HER2 antibody were estimated in each participant using standard noncompartmental methods.
Pharmacokinetic Parameter Terminal Elimination Half-life (t1/2) of DS-8201a, Total Anti-HER2 Antibody and MAAA-1181 Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. Terminal elimination half-life (t1/2) of DS-8201a was assessed. This serum PK parameter for DS-8201a, total anti-HER2 antibody, and MAAA-1181a were estimated in each participant using standard noncompartmental methods.
Summary of Most Common Treatment-Emergent Adverse Events (TEAEs) ≥20% of Any Grade by Preferred Term Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Safety Analysis Set)	Baseline up to 47 days after last dose, up to 36 months postdose	A treatment-emergent adverse event (TEAE) is defined as an adverse event that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the initiating the study drug until 47 days after last dose of the study drug.
Objective Response Rate and Best Overall Response Based on Investigator Assessment Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (Response Evaluable Set)	From randomization to first documented objective response, up to 36 months postdose	The Objective Response Rate (ORR) is the percentage of participants who achieved a best overall response of Complete Response (CR) or Partial Response (PR), assessed by Investigator based on RECIST version 1.1. The best overall response is the best overall response (BOR) recorded from the start of the study treatment until the end of treatment and includes CR, PR, stable disease (SD), progressive disease (PD) and not evaluable (NE) as assessed by Investigator based on RECIST version 1.1. CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (at least a 20% increase in the sum of diameters of target lesions). Unconfirmed ORR and BOR (not confirmed by Investigator) and confirmed ORR and BOR (confirmed by Investigator) are reported.
Pharmacokinetic Parameters of Area Under the Concentration Versus-Time Curve of MAAA-1181 Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. Area under the concentration versus time curve (AUC) from Time 0 to the Last Quantifiable Concentration (AUClast) and Area Under the Concentration versus-Time Curve up to 21 days (AUC21d) are reported. These serum PK parameters for MAAA-1181a were estimated in each participant using standard noncompartmental methods.
Pharmacokinetic Parameter of Time to Maximum Serum Concentration (Tmax) of DS-8201a, Total Anti-HER2 Antibody and MAAA-1181 Following Treatment With DS-8201a	Cycle 1 and 3, Day 1: predose, 4 hours (h), 7h postdose; Day 8, Day 15, and Day 22 postdose; Cycle 2, Day 1 and Day 22 postdose; Cycle 4, 6, and 8, Day 1 postdose (each cycle is 21 days)	Blood samples for DS-8201a pharmacokinetic (PK) analysis were obtained at the specified timepoints. The time to maximum serum concentration (Tmax) of DS-8201a was assessed. This serum PK parameter for DS-8201a, total anti-HER2 antibody, and MAAA-1181a were estimated in each participant using standard noncompartmental methods.
Overall Summary of Treatment-emergent Adverse Events (TEAEs) Following Treatment With DS-8201a in Participants With HER2-Expressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma. (Safety Analysis Set)	Baseline up to 47 days after last dose, up to 36 months postdose	A treatment-emergent adverse event (TEAE) is defined as an adverse event that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the initiating the study drug until 47 days after last dose of the study drug. Serious adverse events (SAEs) with an onset or worsening 48 days or more after the last dose of study drug, if considered related to the study treatment, are also TEAEs.

Trial Locations

Locations (66)

Hirosaki University Hospital; 🇯🇵 Hirosaki, Aomori, Japan

National Hospital Organization Shikoku Cancer Center; 🇯🇵 Matsuyama, Ehime, Japan

Japan Community Health Care Organization Kyushu Hospital; 🇯🇵 Kitakyushu, Fukuoka, Japan

Kure Medical Center; 🇯🇵 Kure, Hiroshima, Japan

Kansai Rosai Hospital; 🇯🇵 Amagasaki, Hyogo, Japan

Ibaraki Prefectural Central Hospital; 🇯🇵 Kasama, Ibaraki, Japan

Toyonaka Municipal Hospital; 🇯🇵 Toyonaka, Osaka, Japan

Showa University Koto Toyosu Hospital; 🇯🇵 Koto-Ku, Tokyo, Japan

Kochi Health Sciences Center; 🇯🇵 Kochi, Japan

Hokkaido University Hospital; 🇯🇵 Sapporo, Hokkaido, Japan

Hyogo Cancer Center; 🇯🇵 Akashi, Hyogo, Japan

Miyagi Cancer Center; 🇯🇵 Natori, Miyagi, Japan

Hiroshima City Asa Citizens Hospital; 🇯🇵 Hiroshima, Japan

Kanazawa University Hospital; 🇯🇵 Kanazawa, Ishikawa, Japan

Kagawa University Hospital; 🇯🇵 Kita, Kagawa, Japan

Chiba Cancer Center; 🇯🇵 Chiba, Japan

Toranomon Hospital; 🇯🇵 Minato-Ku, Tokyo, Japan

St. Marianna University School of Medicine Hospital; 🇯🇵 Kawasaki, Kanagawa, Japan

The Kitasato Institute Kitasato University Hospital; 🇯🇵 Sagamihara, Kanagawa, Japan

National Cancer Center Hospital; 🇯🇵 Chuo Ku, Tokyo, Japan

Gifu University Hospital; 🇯🇵 Gifu, Japan

Hiroshima Prefectural Hospital; 🇯🇵 Hiroshima, Japan

Osaka General Medical Center; 🇯🇵 Osaka, Japan

Niigata Cancer Center Hospital; 🇯🇵 Niigata, Japan

Chungbuk National University Hospital; 🇰🇷 Cheongju-si, Chungcheongbuk-do, Korea, Republic of

Seoul National University Bundang Hospital; 🇰🇷 Seongnam, Korea, Republic of

Korea University Guro Hospital; 🇰🇷 Seoul, Korea, Republic of

Kyushu University Hospital; 🇯🇵 Fukuoka, Japan

Osaki Citizen Hospital; 🇯🇵 Osaki, Miyagi, Japan

Inje University Haeundae Paik Hospital; 🇰🇷 Busan, Korea, Republic of

National Cancer Center Hospital East; 🇯🇵 Kashiwa, Chiba, Japan

Tokyo Metropolitan Komagome Hospital; 🇯🇵 Bunkyō-Ku, Tokyo, Japan

Gunma Prefectural Cancer Center; 🇯🇵 Ōta, Gunma, Japan

Yokohama City University Medical Center; 🇯🇵 Yokohama, Kanagawa, Japan

Tochigi Cancer Center; 🇯🇵 Utsunomiya, Tochigi, Japan

Kanagawa Cancer Center; 🇯🇵 Yokohama, Kanagawa, Japan

Japanese Red Cross Kyoto Daini Hospital; 🇯🇵 Kamigyō-ku, Kyoto, Japan

Shizuoka Cancer Center; 🇯🇵 Shizuoka, Japan

Chonbuk National University Hospital; 🇰🇷 Jeonju, Korea, Republic of

Yonsei Cancer Center, Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Asan Medical Center; 🇰🇷 Seoul, Korea, Republic of

Aichi Cancer Center Hospital; 🇯🇵 Nagoya, Aichi, Japan

Kobe City Medical Center General Hospital; 🇯🇵 Kobe, Hyogo, Japan

Iwate Medical University Hospital; 🇯🇵 Shiwa-gun, Iwate, Japan

Osaka University Hospital; 🇯🇵 Suita, Osaka, Japan

The Cancer Institute Hospital of Japanese Foundation for Cancer Research; 🇯🇵 Koto-Ku, Tokyo, Japan

Fukui Prefectural Hospital; 🇯🇵 Fukui, Japan

National Hospital Organization Kyushu Cancer Center; 🇯🇵 Fukuoka, Japan

Okayama University Hospital; 🇯🇵 Okayama, Japan

Local Incorporated Administrative Agency Osaka City Hospital Organization Osaka City General Hospital; 🇯🇵 Osaka, Japan

Osaka International Cancer Institute; 🇯🇵 Osaka, Japan

Kindai University Hospital; 🇯🇵 Osaka, Japan

Saitama Cancer Center; 🇯🇵 Saitama, Japan

Shizuoka General Hospital; 🇯🇵 Shizuoka, Japan

National Cancer Center; 🇰🇷 Ilsan, Gyeonggi-do, Korea, Republic of

Dong-A University Hospital; 🇰🇷 Busan, Korea, Republic of

Keio University Hospital; 🇯🇵 Tokyo, Japan

Chonnam National University Hwasun Hospital; 🇰🇷 Gwangju, Korea, Republic of

Kyungpook National University Chilgok Hospital; 🇰🇷 Daegu, Korea, Republic of

Gachon University Gil Medical Center; 🇰🇷 Incheon, Korea, Republic of

Korea University Anam Hospital; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

Gangnam Severance Hospital; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Chung-Ang University Hospital; 🇰🇷 Seoul, Korea, Republic of

The Catholic University of Korea, Seoul St. Mary's Hospital; 🇰🇷 Seoul, Korea, Republic of