A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer (DB-08)

A Phase 1b Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd) in Combination With Other Anti-cancer Agents in Patients With Metastatic HER2-low Breast Cancer (DESTINY-Breast08)

DESTINY-Breast 08 will investigate the safety, tolerability, PK and preliminary anti-tumour activity of T-DXd in combination with other therapies in patients with Metastatic HER2-low Advanced or Metastatic Breast Cancer

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab deruxtecan; Drug: Capecitabine; Drug: Durvalumab; Drug: Paclitaxel; Drug: Capivasertib; Drug: Anastrozole; Drug: Fulvestrant

Detailed Description

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

The target population of interest in this study is patients with HER2-low (IHC 1+ or IHC 2+/ISH -) (as per ASCO/CAP 2018 guidelines) advanced/MBC. Part 1 of each module will enroll patients with locally confirmed HER2-low advanced/MBC in second-line or later (≥ 2L) settings

Part 2 of each module will enroll patients with HER2-low MBC who have either not received prior treatment, or received only 1 prior treatment (depending on the module-specific exclusion criteria) for advanced/metastatic disease

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • East Melbourne, Australia, 3002
    • Research Site
  • Westmead, Australia, 2145
    • Research Site
• Belgium
  • Edegem, Belgium, 2650
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Ottignies, Belgium, 1340
    • Research Site
• Brazil
  • Goiania, Brazil, 74605-070
    • Research Site
  • Porto Alegre, Brazil, 90035-003
    • Research Site
  • Porto Alegre, Brazil, 90110-270
    • Research Site
  • Sao Paulo, Brazil, 04543-000
    • Research Site
  • São Paulo, Brazil, 03102-002
    • Research Site
• Canada
  • Quebec, Canada, G1J 1Z4
    • Research Site
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • Research Site
• France
  • Villejuif Cedex, France, 94805
    • Research Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
• Mexico
  • Monterrey, Mexico, 64710
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow, Russian Federation, 143442
    • Research Site
  • Saint Petersburg, Russian Federation, 199226
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan, 82445
    • Research Site
  • Taichung, Taiwan, 40443
    • Research Site
  • Taipei, Taiwan, 100
    • Research Site
  • Taipei, Taiwan, 235
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
  • Taipei City, Taiwan, 114
    • Research Site
  • Taoyuan, Taiwan, 333
    • Research Site
• United States
  • New York
    • Commack, New York, United States, 11725
      • Research Site
    • Harrison, New York, United States, 10604
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
    • Uniondale, New York, United States, 11553
      • Research Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Research Site
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Research Site
    • Germantown, Tennessee, United States, 38138
      • Research Site
  • Texas
    • Fort Worth, Texas, United States, 76104
      • 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

• Male or female patients who have pathologically documented breast cancer that:

  1. Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay
  2. Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) or ER and PgR negative (ER and PgR <1%) per ASCO/CAP guidelines in the metastatic setting
• Patient must have adequate tumor sample for biomarker assessment
• ECOG Performance Status of 0 or 1

For patients with HR+ disease:

Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required.

Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3.

For patients with HR- disease:

Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5.

Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5.

Key Exclusion Criteria:

• Uncontrolled intercurrent illness
• Uncontrolled or siginificant cardiovascular disease
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Lung-specific intercurrent clinically significant illnesses
• Has spinal cord compression or clinically active central nervous system metastases
• Active primary immunodeficiency
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Prior treatment with ADC that comprises of an exatecan derivative that is a topoisomerase I inhibitor.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Module 1: T-DXd + capecitabine; T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Capecitabine; Capecitabine: administered orally
Experimental: Module 2: T-DXd + durvalumab + paclitaxel; T-DXd: 5.4 mg/kg Q3W, intravenous use Durvalumab: 1120 mg Q3W, intravenous use Paclitaxel: 80 mg/m2 QW in 3-week cycles, intravenous use	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; Other Names: Taxol A
Experimental: Module 3: T-DXd + capivasertib; T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Capivasertib; Capivasertib: administered orally; Other Names: AZD5363
Experimental: Module 4: T-DXd + anastrozole; T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Anastrozole; Anastrozole: administered orally; Other Names: Anastrozol
Experimental: Module 5: T-DXd + fulvestrant; T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use	Drug: Trastuzumab deruxtecan; T-DXd: administered as an IV infusion; Other Names: DS-8201a, T-DXd; Drug: Fulvestrant; Fulvestrant: administered as an IM injection

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 24 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 24 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 24 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 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)- Part 2	ORR defined as the proportion of patients who have a confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1	Until progression, assessed up to approximately 24 months
Progression Free Survival (PFS)- Part 2	PFS defined as time from the date of first dose until the date of progression as determined by the investigator at local site per RECIST 1.1, or death due to any cause	Until progression or death, assessed up to approximately 24 months
Duration of Response (DoR)- Part 2	DoR defined as time from the date of first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression	Until progression or death, assessed up to approximately 24 months
Overall Survival (OS)- Part 2	OS defined as time from the date of first dose until the date of death by any cause	Until death, assessed up to approximately 24 months
Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a	Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration	While on study drug up to study completion, approximately 24 months
Immunogenicity of trastuzumab deruxtecan	Percentage of patients who develop ADA for trastuzumab deruxtecan	Up to follow-up period, approximately 24 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 24 months
Immunogenicity of durvalumab	Percentage of patients who develop ADAs for durvalumab	Up to follow-up period, approximately 24 months

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo Co., Ltd.; Daiichi Sankyo Company, Limited
• Investigators: Principal Investigator: Komal Jhaveri, MD, FACP, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• AstraZeneca Breast Cancer Study Locator website - To learn which AstraZeneca breast cancer clinical trials are looking for participants with specific diagnosis, stage, and treatment history.

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2020
• Primary Completion (Actual): August 16, 2023
• Study Completion (Estimated): November 28, 2025

Study Registration Dates

• First Submitted: September 15, 2020
• First Submitted That Met QC Criteria: September 15, 2020
• First Posted (Actual): September 21, 2020

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Breast Cancer; HER2-negative; DS-8201a; T-DXd; Trastuzumab Deruxtecan; Anti-HER2 Antibody Drug Conjugate (ADC); HER2-low; DESTINY-Breast08; Triple-negative breast cancer (TNBC)
• 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; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Estrogen Receptor Antagonists; Immunoconjugates; Paclitaxel; Trastuzumab; Capecitabine; Fulvestrant; Durvalumab; Anastrozole; Trastuzumab deruxtecan
• Other Study ID Numbers: D967JC00002; 2020-002797-27 (EudraCT Number); 2023-505690-33-00 (Other Identifier: EU CT 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