A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1)

• ClinicalTrials.gov Identifier: NCT03248492
• Recruitment Status: Active, not recruiting
• First Posted: August 14, 2017
• Results First Posted: February 17, 2020
• Last Update Posted: November 15, 2023
• Sponsor: Daiichi Sankyo
• Collaborators: AstraZeneca; Daiichi Sankyo Co., Ltd.
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: August 10, 2017
• First Posted Date: August 14, 2017
• Results First Submitted Date: January 17, 2020
• Results First Posted Date: February 17, 2020
• Last Update Posted Date: November 15, 2023
• Actual Study Start Date: August 25, 2017
• Actual Primary Completion Date: March 21, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 17, 2020)

Objective Response Rate as Confirmed by Independent Central Review Following Intravenous Administration of 5.4 mg/kg DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]

The number of participants with objective response was assessed every six weeks from Cycle 1 Day 1 through discontinuation of treatment, by independent central imaging facility review based on RECIST version 1.1.

Original Primary Outcome Measures (submitted: August 10, 2017)

Objective response rate (ORR) per imaging assessment [ Time Frame: within 22 months ]

Percentage of participants with objective response is assessed every six weeks from Cycle 1 Day 1 through disease progression, by independent central imaging facility review based on RECIST version 1.1

Current Secondary Outcome Measures (submitted: February 13, 2020)

• Objective Response Rate as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]
  The number of participants with objective response is assessed every six weeks from Cycle 1 Day 1 through discontinuation of treatment. Investigator-assessed objective response rate (ORR) was defined as the proportion of participants who achieved a best overall response of complete response or partial response based on local radiologists/investigators' tumor assessments.
• Best Overall Tumor Response as Confirmed By the Investigator Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]
  Best overall tumor response was defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) by the investigator based on RECIST v1.1. Participants who were non-evaluable (NE) are also reported.
• Disease Control Rate and Clinical Benefit Rate as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]
  Number of participants with controlled disease and who received clinical benefit from treatment as assessed by independent central review. DCR was defined as the proportion of participants who achieved a best overall response of complete response, partial response, or stable disease. CBR was defined as the proportion of participants who achieved a best overall response of complete response or partial response or more than 6 months of stable disease.
• Duration of Response (Complete Response or Partial Response) as Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]
  The estimated duration of confirmed response (complete response [CR] or partial response [PR]) was assessed by independent central review. Duration of response was defined as the time interval between the date of first documentation of objective response (CR or PR) and the date of the first objective documentation of disease progression or death due to any cause.
• Progression-Free Survival Estimate As Confirmed by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: at least 6 months after last participant enrolled received first dose up to 19 months (data cut off) ]
  The point estimate of progression-free survival (PFS) is reported. PFS was defined as the time interval between the date of randomization/registration and the first documentation of disease progression or death due to any cause.
• Percent Change From Baseline in Sum of Diameters Over Time as Determined by Independent Central Review Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Enrolled Analysis Set) [ Time Frame: Baseline up to Week 6, 12, 18, 24, 30, 36 post dose ]
  Best percent change in sum of diameters of measurable tumors was based on RECIST 1.1. The best percent change was defined as the percent change in the smallest sum of diameters from all post-baseline tumor assessments, taking as reference the baseline sum of diameters.
• Overall Summary of Treatment-emergent Adverse Events (TEAEs) Following Intravenous Administration of DS-8201a in Participants With Metastatic Breast Cancer (Safety Analysis Set) [ Time Frame: Day 0 to Day 47 post last dose ]
  TEAEs were assessed by severity and seriousness according to unique criteria. Severity described the intensity of an event and was graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Life-threatening consequences; urgent intervention indicated; and Grade 5: Death related to AE. Serious TEAEs were defined as any untoward medical occurrence that at any dose results in death, is life threatening, requires inpatient hospitalization, or causes prolongation of existing hospitalization.

Original Secondary Outcome Measures (submitted: August 10, 2017)

• Duration of response [ Time Frame: within 22 months ]
  Length of time response continued
• Best percent change in the sum of the longest diameters (SLD) of measurable tumors [ Time Frame: within 22 months ]
  The best percent change from baseline in the SLD will be provided by part/dose group
• Disease control rate (DCR) [ Time Frame: within 22 months ]
  Percentage of participants with controlled disease
• Clinical benefit rate (CBR) [ Time Frame: within 22 months ]
  Percentage of participants receiving clinical benefit from the treatment
• Progression-free survival [ Time Frame: within 22 months ]
  Percentage of participants still alive without the disease getting worse
• Overall survival (OS) [ Time Frame: at 22 months ]
  Percentage of participants still alive
• ORR assessed by the investigator based on RECIST version 1.1 [ Time Frame: within 22 months ]
  Percentage of participants with objective response as assessed by the investigator, based on RECIST version 1.1
• Maximum plasma/serum concentration (Cmax) [ Time Frame: within 21 days ]
  Categories: DS-8201a, total anti-HER2 antibody and MAAA-1181a
• Time to Cmax (Tmax) [ Time Frame: within 21 days ]
  Categories: DS-8201a, total anti-HER2 antibody and MAAA-1181a
• Area under the concentration-time curve (AUC) from dosing until the last quantifiable concentration (AUClast) [ Time Frame: within 21 days ]
  Categories: DS-8201a, total anti-HER2 antibody and MAAA-1181a
• AUC from the time of dosing until day 21 (AUC0-21d) [ Time Frame: at Day 21 ]
  Categories: DS-8201a, total anti-HER2 antibody and MAAA-1181a

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1)
• Official Title: A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1 (DESTINY-Breast01)
• Brief Summary: Some human epidermal growth factor receptor 2 (HER-2) breast cancer patients do not respond or become resistant to current treatment. DS-8201a is a new experimental product that is a combination of an antibody and a drug. It has not yet been approved for use. DS-8201a may slow down tumor growth. This might improve outcomes for these patients.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

HER2-positive patients will be classified into two groups: T-DM1 resistant/refractory (experimental) and T-DM1 intolerant (exploratory only).

Masking: None (Open Label)
Masking Description:

In Part 1, about 60 trastuzumab emtansine (T-DM1) resistant/refractory patients initially will be randomized into three treatment groups (low, medium and high doses) for Pharmacokinetics (PK), then about another 60 will be randomized into low and high doses to determine recommended dose (RD). After that, about 100 will receive the recommended dose in an open-label continuation stage (Part 2). About 10 TDM-1 intolerant patients will join the continuation stage as an exploratory only arm.

Primary Purpose: Treatment

• Condition: Breast Cancer

Intervention

Drug: DS-8201a

DS-8201a is sterile lyophilized powder reconstituted into a sterile aqueous solution (100 mg/5 mL) to be administered as low, medium and high intravenous (IV) doses for Part 1 of the trial. The dose for Part 2 will be determined based on results from Part 1.

Other Name: Experimental product

Study Arms

• Experimental: DS-8201a Low Dose
  T-DM1 resistant/refractory (R/R) patients in the low dose treatment group
  Intervention: Drug: DS-8201a
• Experimental: DS-8201a Medium Dose
  T-DM1 resistant/refractory (R/R) patients in the medium dose treatment group
  Intervention: Drug: DS-8201a
• Experimental: DS-8201a High Dose
  T-DM1 resistant/refractory (R/R) patients in the high dose treatment group
  Intervention: Drug: DS-8201a
• Exploratory Arm
  In Part 2b- Continuation Stage, about 10 T-DM1 Intolerant patients will receive the DS-8201a recommended dose (RD) as an exploratory arm
  Intervention: Drug: DS-8201a

Publications *

• Rugo HS, Bianchini G, Cortes J, Henning JW, Untch M. Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open. 2022 Aug;7(4):100553. doi: 10.1016/j.esmoop.2022.100553. Epub 2022 Aug 11.
• Bardia A, Harnden K, Mauro L, Pennisi A, Armitage M, Soliman H. Clinical Practices and Institutional Protocols on Prophylaxis, Monitoring, and Management of Selected Adverse Events Associated with Trastuzumab Deruxtecan. Oncologist. 2022 Aug 5;27(8):637-645. doi: 10.1093/oncolo/oyac107.
• Modi S. Trastuzumab deruxtecan in previously treated HER2-positive metastatic breast cancer: Plain language summary of the DESTINY-Breast01 study. Future Oncol. 2021 Sep 1;17(26):3415-3423. doi: 10.2217/fon-2021-0427. Epub 2021 Jul 15.
• Yin O, Iwata H, Lin CC, Tamura K, Watanabe J, Wada R, Kastrissios H, AbuTarif M, Garimella T, Lee C, Zhang L, Shahidi J, LaCreta F. Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan. Clin Pharmacol Ther. 2021 Oct;110(4):986-996. doi: 10.1002/cpt.2291. Epub 2021 Jun 10.
• Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J, Sohn J, Denduluri N, Perrin C, Aogi K, Tokunaga E, Im SA, Lee KS, Hurvitz SA, Cortes J, Lee C, Chen S, Zhang L, Shahidi J, Yver A, Krop I; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020 Feb 13;382(7):610-621. doi: 10.1056/NEJMoa1914510. Epub 2019 Dec 11.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 17, 2020): 253
• Original Estimated Enrollment (submitted: August 10, 2017): 230
• Estimated Study Completion Date: May 31, 2024
• Actual Primary Completion Date: March 21, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Men or women the age of majority in their country

• Has pathologically documented breast cancer that:

  1. is unresectable or metastatic
  2. has HER2 positive expression confirmed per protocol
• Has an adequate tumor sample
• Has at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• Has protocol-defined adequate cardiac, renal and hepatic function
• Agrees to follow protocol-defined method(s) of contraception

Exclusion Criteria:

• Has a medical history of myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia
• Has a corrected QT interval (QTc) prolongation to > 450 millisecond (ms) in males and > 470 ms in females
• Has a medical history of clinically significant lung disease
• Is suspected to have certain other protocol-defined diseases based on imaging at screening period

• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Italy, Japan, Korea, Republic of, Spain, United Kingdom, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT03248492
• Other Study ID Numbers: DS8201-A-U201; 2016-004986-18 ( EudraCT Number ); JapicCTI-173693(en) ( Registry Identifier: JapicCTI ); DESTINY-Breast01 ( Other Identifier: Daiichi Sankyo and AstraZeneca )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: 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/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Same as current

Collaborators

• AstraZeneca
• Daiichi Sankyo Co., Ltd.

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo

• PRS Account: Daiichi Sankyo
• Verification Date: November 2023