A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (DB-07)

A Phase 1b/2 Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore the Safety, Tolerability, and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd) in Combination With Other Anti-cancer Agents in Patients With HER2-positive Metastatic Breast Cancer (DESTINY-Breast07)

DESTINY-Breast07 will investigate the safety, tolerability, and anti-tumour activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in patients with HER2-positive Metastatic Breast Cancer

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab deruxtecan; Drug: Durvalumab; Drug: Pertuzumab; Drug: Paclitaxel; Drug: Tucatinib

Detailed Description

This study is modular in design allowing assessment of safety, tolerability and anti-tumour activity of T-DXd in combination with other anti-cancer agents. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the recommended Phase 2 dose (RP2D) determined in Part 1 will be used for the dose-expansion in Part 2.

The target population of interest in this study is patients with HER2-positive (as per ASCO/CAP 2018 guidelines) advanced/MBC inclusive of patients with active and stable brain metastases. Part 1 of each module will enroll patients with locally assessed HER2-positive advanced/MBC in second-line or later patients. Part 2 of each module will enroll patients with locally assessed HER2-positive breast cancer who have not received prior treatment for advanced/metastatic disease.

• Study Type: Interventional
• Enrollment (Actual): 244
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3000
    • Research Site
• Brazil
  • Barretos, Brazil, 14784-400
    • Research Site
  • Belo Horizonte, Brazil, 30150-274
    • Research Site
  • Natal, Brazil, 59075-740
    • Research Site
  • Porto Alegre, Brazil, 90610-000
    • Research Site
  • Porto Alegre, Brazil, 91350-200
    • Research Site
  • Rio de Janeiro, Brazil, 20560-120
    • Research Site
  • Sao Paulo, Brazil, 04029-000
    • Research Site
  • Sao Paulo, Brazil, 01317-001
    • Research Site
  • Sorocaba, Brazil, 18030-005
    • Research Site
• Canada
  • Quebec, Canada, G1S 4L8
    • Research Site
  • Toronto, Canada, M5G 2M9
    • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • Research Site
• France
  • Villejuif Cedex, France, 94805
    • Research Site
• Germany
  • München, Germany, 81675
    • Research Site
  • Würzburg, Germany, 97080
    • Research Site
• India
  • Delhi, India, 110085
    • Research Site
  • Gurgaon, India, 122001
    • Research Site
  • Madurai, India, 625107
    • Research Site
  • Mumbai, India, 400012
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Milan, Italy, 20141
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Rome, Italy, 168
    • Research Site
• Korea, Republic of
  • Busan-si, Korea, Republic of, 602-739
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 02841
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
• Poland
  • Bydgoszcz, Poland, 85-796
    • Research Site
  • Koszalin, Poland, 75-581
    • Research Site
  • Lublin, Poland, 20-090
    • Research Site
  • Łódź, Poland, 90-242
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow, Russian Federation, 111123
    • Research Site
  • Moscow, Russian Federation, 117997
    • Research Site
  • Moscow, Russian Federation, 121205
    • Research Site
  • Moscow, Russian Federation, 143423
    • Research Site
  • Moscow, Russian Federation, 105229
    • Research Site
  • Moscow, Russian Federation, 109240
    • Research Site
  • Saint Petersburg, Russian Federation, 195271
    • Research Site
  • Sankt-Peterburg, Russian Federation, 197758
    • Research Site
  • Sankt-Peterburg, Russian Federation, 196603
    • Research Site
• Spain
  • Barcelona, Spain, 08003
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08908
    • Research Site
  • Madrid, Spain, 28050
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
• Taiwan
  • Hualien, Taiwan, 970
    • Research Site
  • Tainan, Taiwan, 704
    • Research Site
  • Taipei, Taiwan, 235
    • Research Site
  • Taipei, Taiwan, 10449
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
  • Taipei, Taiwan, 10048
    • Research Site
  • Taipei City, Taiwan, 114
    • Research Site
  • Taoyuan City, Taiwan, 333
    • Research Site
• Turkey
  • Ankara, Turkey, 6100
    • Research Site
  • Edirne, Turkey, 22030
    • Research Site
  • Istanbul, Turkey, 34722
    • Research Site
  • Istanbul, Turkey, 34662
    • Research Site
  • Izmir, Turkey, 35100
    • Research Site
• United Kingdom
  • Buckhurst Hill, United Kingdom, IG9 5HX
    • Research Site
• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Research Site
    • Saint Petersburg, Florida, United States, 33705
      • Research Site
  • New York
    • Commack, New York, United States, 11725
      • Research Site
    • Harrison, New York, United States, 10604
      • Research Site
    • New York, New York, United States, 10016
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43219
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Research Site
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Research Site
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Patients must be at least 18 years of age

• Pathologically documented breast cancer that:

  1. Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic
  2. HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local assessment. The local HER2 result must be from a tumour sample obtained in the metastatic setting.
  3. Is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting
• Patient must have adequate tumor sample from the metastatic setting for biomarker assessment
• ECOG Performance Status of 0 or 1

• Part 1

  1. Disease progression on or after the last systemic therapy prior to starting study treatment
  2. At least 1 prior treatment line in metastatic setting required.

• Part 2 (Modules 0 - 5)

  a) No prior lines of therapy for advanced/MBC allowed

• Part 2 (Module 6 and 7) a) Zero or one prior lines of therapy for advanced/MBC allowed

CNS Inclusion

• Modules 0 - 5 Patients must have no brain metastases or stable brain metastases.
• Module 6 and 7 Patients must have untreated brain metastases not needing local therapy or previously treated brain metastases that have progressed since prior local therapy

Key Exclusion Criteria:

• Uncontrolled or significant cardiovascular disease
• Active or prior documented (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Spinal cord compression or a history of leptomeningeal carcinomatosis
• Prior treatment with immune checkpoint inhibitors
• Prior treatment with an ADC containing a topoisomerase I inhibitor
• Prior treatment with tucatinib

CNS Exclusion

• Modules 0 - 5: Has untreated brain metastasis
• Module 6 and 7: Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg dexamethasone or any brain lesion thought to require immediate local therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 1- T-DXd and Durvalumab; T-DXd and Durvalumab	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Durvalumab; Durvalumab: administered as an IV infusion; Other Names: MEDI4736
Experimental: Module 2- T-DXd and Pertuzumab; T-DXd and Pertuzumab	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Pertuzumab; Pertuzumab: administered as an IV infusion
Experimental: Module 0- T-DXd; T-DXd	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd
Experimental: Module 7 - T-DXd; T-DXd monotherapy in patients with active brain metastases (Part 2 Only)	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd
Experimental: Module 3- T-DXd and Paclitaxel; T-DXd and Paclitaxel (Arm not initiated in Part 2)	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Paclitaxel; Paclitaxel: administered as an IV infusion
Experimental: Module 4- T-DXd and Durvalumab and Paclitaxel; T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Durvalumab; Durvalumab: administered as an IV infusion; Other Names: MEDI4736; Drug: Paclitaxel; Paclitaxel: administered as an IV infusion
Experimental: Module 5 - T-DXd and Tucatanib; T-DXd and tucatinib (Arm not initiated in Part 2)	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Tucatinib; Tucatinib administered orally (tablet) twice daily; Other Names: ONT-380
Experimental: Module 6 - T-DXd and Tucatinib; T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated)	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Tucatinib; Tucatinib administered orally (tablet) twice daily; Other Names: ONT-380

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of adverse events (AEs)- Part 1	Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0	Up to follow-up period, approximately 53 months
Occurrence of serious adverse events (SAEs)- Part 1	Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0	Up to follow-up period, approximately 53 months
Occurrence of adverse events (AEs)- Part 2	Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0	Up to follow-up period, approximately 53 months
Occurrence of serious adverse events (SAEs)- Part 2	Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0	Up to follow-up period, approximately 53 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)- Part 1 and Part 2	ORR is defined as the proportion of patients who have a CR or PR, as determined by the Investigator at local site per RECIST 1.1.	Until progression, assessed up to approximately 53 months
Progression Free Survival (PFS)- Part 1 and Part 2	PFS is defined as time from the date of randomization until the date of progression as assessed by the Investigator at local site per RECIST 1.1, or death due to any cause.	Until progression, assessed up to approximately 53 months
Progression Free Survival 2 (PFS2)- Part 2	PFS2 is defined as time from the date of randomisation until the date of progression on next line treatment (the earliest of the progression event subsequent to first subsequent anticancer therapy) or death; second progression will be defined according to local standard clinical practice.	Assessed up to approximately 53 months
Duration of Response (DoR)- Part 2	DoR is defined as time from the date of first documented response until the date of documented progression or death in the absence of disease progression.	Until progression, assessed up to approximately 53 months
Overall Survival (OS)- Part 2	OS is defined as time from the date of randomisation until the date of death due to any cause.	Until death, assessed up to approximately 53 months
Serum Concentration of Trastuzumab Deruxtecan (T-DXd)	Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration	While on study drug up to study completion, approximately 53 months
Serum Concentration of Durvalumab	Determination of durvalumab concentration in serum at different time points after administration	While on study drug up to study completion, approximately 53 months
Serum Concentration of Pertuzumab	Determination of pertuzumab concentration in serum at different time points after administration	While on study drug up to study completion, approximately 53 months
Plasma Concentration of Paclitaxel	Determination of paclitaxel concentration in plasma at different time points after administration	While on study drug up to study completion, approximately 53 months
Plasma Concentration of Tucatinib	Determination of tucatinib concentration in plasma at different time points after administration	While on study drug up to study completion, approximately 53 months
Immunogenicity of trastuzumab deruxtecan	Percentage of patients who develop ADA for trastuzumab deruxtecan	Up to follow-up period, approximately 53 months
Immunogenicity of Durvalumab	Percentage of patients who develop ADA for durvalumab	Up to follow-up period, approximately 53 months
Immunogenicity of Pertuzumab	Percentage of patients who develop ADA for pertuzumab	Up to follow-up period, approximately 53 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo Company, Limited

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2020
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): July 2, 2025

Study Registration Dates

• First Submitted: August 31, 2020
• First Submitted That Met QC Criteria: August 31, 2020
• First Posted (Actual): September 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Breast Cancer; Brain Metastases; HER2-positive; DS-8201a; T-DXd; Trastuzumab Deruxtecan; DESTINY-Breast07; Anti-HER2 Antibody Drug Conjugate (ADC)
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immunoconjugates; Paclitaxel; Trastuzumab; Durvalumab; Pertuzumab; Tucatinib; Trastuzumab deruxtecan
• Other Study ID Numbers: D967JC00001; 2019-004531-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No