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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04556773
Recruitment Status : Recruiting
First Posted : September 21, 2020
Last Update Posted : November 28, 2022
Sponsor:
Collaborators:
Daiichi Sankyo Co., Ltd.
Daiichi Sankyo Company, Limited
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE September 15, 2020
First Posted Date  ICMJE September 21, 2020
Last Update Posted Date November 28, 2022
Actual Study Start Date  ICMJE December 17, 2020
Estimated Primary Completion Date January 26, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
  • Occurrence of adverse events (AEs)- Part 1 [ Time Frame: Up to follow-up period, approximately 24 months ]
    Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0
  • Occurrence of serious adverse events (SAEs)- Part 1 [ Time Frame: Up to follow-up period, approximately 24 months ]
    Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0
  • Occurrence of adverse events (AEs)- Part 2 [ Time Frame: Up to follow-up period, approximately 24 months ]
    Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0
  • Occurrence of serious adverse events (SAEs)- Part 2 [ Time Frame: Up to follow-up period, approximately 24 months ]
    Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2020)
  • Objective Response Rate (ORR)- Part 2 [ Time Frame: Until progression, assessed up to approximately 24 months ]
    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
  • Progression Free Survival (PFS)- Part 2 [ Time Frame: Until progression or death, assessed up to approximately 24 months ]
    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
  • Duration of Response (DoR)- Part 2 [ Time Frame: Until progression or death, assessed up to approximately 24 months ]
    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
  • Overall Survival (OS)- Part 2 [ Time Frame: Until death, assessed up to approximately 24 months ]
    OS defined as time from the date of first dose until the date of death by any cause
  • Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a [ Time Frame: While on study drug up to study completion, approximately 24 months ]
    Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration
  • Immunogenicity of trastuzumab deruxtecan [ Time Frame: Up to follow-up period, approximately 24 months ]
    Percentage of patients who develop ADA for trastuzumab deruxtecan
  • Serum Concentration of durvalumab [ Time Frame: While on study drug up to study completion, approximately 24 months ]
    Determination of durvalumab concentration in serum at different time points after administration
  • Immunogenicity of durvalumab [ Time Frame: Up to follow-up period, approximately 24 months ]
    Percentage of patients who develop ADAs for durvalumab
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer
Official Title  ICMJE 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)
Brief Summary 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
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study will initially consist of 5 treatment modules, each of which includes T-DXd in combination with other anti-cancer agents. Each module 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 recommended Phase 2 dose (RP2D) for the combination, either as determined in Part 1 or from another clinical study if appropriate. For each module, patients will be centrally assigned to one of the open modules, as per the module specific criteria.

In addition to safety and tolerability, this study will also assess ORR, PFS, DoR, and OS for each treatment combination.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Breast Cancer
Intervention  ICMJE
  • Drug: Trastuzumab deruxtecan
    T-DXd: administered as an IV infusion
    Other Name: DS-8201a, T-DXd
  • Drug: Durvalumab
    Durvalumab: administered as an IV infusion
    Other Name: MEDI4736
  • Drug: Paclitaxel
    Paclitaxel: administered as an IV infusion
    Other Name: Taxol A
  • Drug: Capivasertib
    Capivasertib: administered orally
    Other Name: AZD5363
  • Drug: Anastrozole
    Anastrozole: administered orally
    Other Name: Anastrozol
  • Drug: Fulvestrant
    Fulvestrant: administered as an IM injection
  • Drug: Capecitabine
    Capecitabine: administered orally
Study Arms  ICMJE
  • 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
    Interventions:
    • Drug: Trastuzumab deruxtecan
    • Drug: Capecitabine
  • 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
    Interventions:
    • Drug: Trastuzumab deruxtecan
    • Drug: Durvalumab
    • Drug: Paclitaxel
  • Experimental: Module 3: T-DXd + capivasertib
    T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use
    Interventions:
    • Drug: Trastuzumab deruxtecan
    • Drug: Capivasertib
  • Experimental: Module 4: T-DXd + anastrozole
    T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral
    Interventions:
    • Drug: Trastuzumab deruxtecan
    • Drug: Anastrozole
  • Experimental: Module 5: T-DXd + fulvestrant
    T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use
    Interventions:
    • Drug: Trastuzumab deruxtecan
    • Drug: Fulvestrant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 5, 2022)
182
Original Estimated Enrollment  ICMJE
 (submitted: September 15, 2020)
185
Estimated Study Completion Date  ICMJE January 26, 2024
Estimated Primary Completion Date January 26, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: AZ Breast Cancer Study Navigators +1-877-400-4656 AstraZeneca@CareboxHealth.com
Listed Location Countries  ICMJE Australia,   Belgium,   Brazil,   Canada,   France,   Korea, Republic of,   Mexico,   Russian Federation,   Taiwan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04556773
Other Study ID Numbers  ICMJE D967JC00002
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  ICMJE
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
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.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Daiichi Sankyo Co., Ltd.
  • Daiichi Sankyo Company, Limited
Investigators  ICMJE
Principal Investigator: Komal Jhaveri, MD, FACP Memorial Sloan Kettering Cancer Center
PRS Account AstraZeneca
Verification Date November 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP