A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05)

• ClinicalTrials.gov Identifier: NCT04622319
• Recruitment Status: Recruiting
• First Posted: November 9, 2020
• Last Update Posted: February 3, 2023
• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: AstraZeneca; NSABP Foundation Inc; German Breast Group; Spanish Breast Cancer Research Group (SOLTI)
• Information provided by (Responsible Party): Daiichi Sankyo, Inc.

Tracking Information

• First Submitted Date: November 2, 2020
• First Posted Date: November 9, 2020
• Last Update Posted Date: February 3, 2023
• Actual Study Start Date: December 4, 2020
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 6, 2020): Invasive Disease-free Survival (IDFS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Randomization to date of invasive local, axillary or distant recurrence, invasive contralateral breast cancer or death from any cause (whichever occurs first), up to approximately 81 months postdose ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 6, 2020)

• Disease-free Survival (DFS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Randomization to date of the first occurrence of an IDFS event including second primary non-breast cancer event or contralateral or ipsilateral ductal carcinoma in situ (whichever occurs first), up to approximately 81 months postdose ]
• Overall Survival (OS) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Randomization to date of death from any cause, up to approximately 81 months postdose ]
• Distant Recurrence-free Interval (DRFI) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Randomization to date of distant recurrence, up to approximately 81 months postdose ]
• Brain Metastases-free Interval (BMFI) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Randomization to date of brain metastasis, up to approximately 81 months postdose ]
• Percentage of Treatment-emergent Adverse Events in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) Compared With Trastuzumab Emtansine (T-DM1) Treatment [ Time Frame: Baseline up to approximately 81 months postdose ]
• Serum Concentrations of Trastuzumab Deruxtecan (T-DXd), total anti-HER2 antibody, and Active Metabolite MAAA-1181a [ Time Frame: Pre-dose on Day 1 of Cycles 1, 4 and 10 and within 15 minutes post-dose on Day 1 of Cycles 1 and 4 (each cycle is 21 days) ]
• Percentage of Participants Positive for Treatment-emergent Anti-drug Antibodies (ADAs) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) [ Time Frame: Baseline up to approximately 81 months postdose ]

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05)
• Official Title: A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in Participants With High-Risk HER2-Positive Primary Breast Cancer Who Have Residual Invasive Disease in Breast or Axillary Lymph Nodes Following Neoadjuvant Therapy (DESTINY-Breast05)
• Brief Summary: Patients with HER2-positive primary breast cancer (BC) who do not achieve complete response after appropriate neoadjuvant therapy are at higher risk of disease recurrence. More effective treatment options are needed for this patient population. This study will examine the efficacy and safety of trastuzumab deruxtecan (T-DXd) compared with trastuzumab emtansine (T-DM1) in high-risk patients with residual invasive breast cancer following neoadjuvant therapy.

Detailed Description

This study will examine trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2-positive primary BC who have residual invasive disease in breast or axillary lymph nodes with higher risk of recurrence, which includes patients who were inoperable at disease presentation or had pathological node-positive status after neoadjuvant therapy.

The primary objective is to compare invasive disease-free survival (IDFS) between T-DXd and T-DM1 treatment arms in this population. The key secondary objective of the study is to evaluate disease-free survival (DFS).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• HER2-Positive Primary Breast Cancer
• Residual Invasive Breast Cancer

Intervention

• Drug: DS-8201a
  Administered initially as an intravenous (IV) infusion at a dose of 5.4 mg/kg on Day 1 of each 21-day cycle
  Other Name: Trastuzumab deruxtecan (T-DXd)
• Drug: T-DM1
  Administered initially as an intravenous (IV) infusion at a dose of 3.6 mg/kg on Day 1 of each 21-day cycle
  Other Name: Trastuzumab emtansine (T-DM1)

Study Arms

• Experimental: Trastuzumab deruxtecan (T-DXd)
  Participants who will be randomized to receive trastuzumab deruxtecan (T-DXd) at a starting dose of 5.4 mg/kg.
  Intervention: Drug: DS-8201a
• Active Comparator: Trastuzumab ematansine (T-DM1)
  Participants who will be randomized to receive trastuzumab ematansine (T-DM1) at a starting dose of 3.6 mg/kg.
  Intervention: Drug: T-DM1

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 6, 2020): 1600
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 1, 2027
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Adults ≥18 years old (local regulatory requirements will apply if the legal age of consent for study participation is >18 years old)

• Pathologically documented HER2-positive breast cancer (BC):

  • HER2-positive expression defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) confirmed prior to study randomization
• Histologically confirmed invasive breast carcinoma
• Clinical stage at disease presentation: T1-4, N0-3, M0; patients presenting with T1N0 tumors are not eligible

• Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the following high-risk criteria:

  • Inoperable breast cancer at presentation (prior to neoadjuvant therapy), defined as clinical stages T4, N0-3, M0 or T1-3, N2-3, M0
  • Operable at presentation, defined as clinical stages T1-3,N0-1,M0, with axillary node positive disease (ypN1-3) following neoadjuvant therapy

• Completion of neoadjuvant systemic chemotherapy, including taxane and HER2-directed treatment prior to surgery

  • Systemic therapy must consist of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab (± pertuzumab) and at least 9 weeks of taxane based chemotherapy. Patients may have received an anthracycline as part of neoadjuvant therapy in addition to taxane chemotherapy.
• Adequate excision as confirmed per medical records: surgical removal of all clinically evident disease in the breast and lymph nodes.
• An interval of no more than 12 weeks between the date of last surgery and the date of randomization.
• Known hormone receptor (HR) status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR positive status defined by either positive estrogen receptor (ER) and/or positive progesterone receptor (PR) status. HR-negative status defined by both known negative ER and known negative PR.
• Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening.
• Has adequate organ function within 14 days before randomization.

Key Exclusion Criteria:

• Stage IV (metastatic) BC
• History of any prior (ipsi- or contralateral) breast cancer except lobular carcinoma in situ (LCIS)
• Evidence of clinically evident gross residual or recurrent disease following neoadjuvant therapy and surgery
• Prior treatment with T-DXd, T-DM1 or other anti-HER2 antibody-drug conjugate (ADC)

• History of exposure to the following cumulative doses of anthracyclines:

  • Doxorubicin > 240 mg/m^2
  • Epirubicin or Liposomal Doxorubicin-Hydrochloride > 480 mg/m^2
  • For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
• History of other malignancy within the last 5 years except for appropriately treated CIS of the cervix, nonmelanoma skin carcinoma, Stage I melanoma skin carcinoma, Stage I uterine cancer, or other appropriately treated non-breast malignancies
• History of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids and/or has ILD/pneumonitis noted on computed tomography (CT) scan of the chest at Screening (asymptomatic interstitial changes confined to recent radiation therapy fields are not excluded)
• Known pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months prior to randomization, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease).
• Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior lobectomy or pneumonectomy
• Medical history of myocardial infarction (MI) within 6 months before randomization, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), troponin levels consistent with MI as defined according to the manufacturer 28 days prior to randomization

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: 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

• Listed Location Countries: Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Czechia, Denmark, France, Germany, Greece, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Peru, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04622319
• Other Study ID Numbers: DS8201-A-U305; 2020-003982-20 ( EudraCT Number ); DESTINY-Breast05 ( Other Identifier: Daiichi Sankyo and AstraZeneca ); NSABP B-60 ( Other Identifier: National Surgical Adjuvant Breast and Bowel Project (NSABP) ); GBG-103 ( Other Identifier: German Breast Group (GBG) ); SOLTI-2001 ( Other Identifier: Spanish Breast Cancer Research Group (SOLTI) )
• Has Data Monitoring Committee: Yes

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: Informed Consent Form (ICF)
• 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, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Daiichi Sankyo, Inc.
• Original Study Sponsor: Same as current

Collaborators

• AstraZeneca
• NSABP Foundation Inc
• German Breast Group
• Spanish Breast Cancer Research Group (SOLTI)

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo, Inc.

• PRS Account: Daiichi Sankyo, Inc.
• Verification Date: February 2023