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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 : Not yet recruiting
First Posted : September 21, 2020
Last Update Posted : September 21, 2020
Sponsor:
Collaborator:
Daiichi Sankyo Company, Limited
Information provided by (Responsible Party):
AstraZeneca

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

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Trastuzumab deruxtecan Drug: Durvalumab Drug: Paclitaxel Drug: Capivasertib Drug: Anastrozole Drug: Fulvestrant Drug: Capecitabine Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 185 participants
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
Official Title: 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)
Estimated Study Start Date : November 27, 2020
Estimated Primary Completion Date : December 23, 2022
Estimated Study Completion Date : December 23, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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 Name: 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 Name: DS-8201a, T-DXd

Drug: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Paclitaxel
Paclitaxel: administered as an IV infusion

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 Name: DS-8201a, T-DXd

Drug: Capivasertib
Capivasertib: administered orally
Other Name: 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 Name: DS-8201a, T-DXd

Drug: Anastrozole
Anastrozole: administered orally

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 Name: DS-8201a, T-DXd

Drug: Fulvestrant
Fulvestrant: administered as an IM injection




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Immunogenicity of trastuzumab deruxtecan [ Time Frame: Up to follow-up period, approximately 24 months ]
    Percentage of patients who develop ADA for trastuzumab deruxtecan

  7. 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

  8. Immunogenicity of durvalumab [ Time Frame: Up to follow-up period, approximately 24 months ]
    Percentage of patients who develop ADAs for durvalumab



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04556773


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Sponsors and Collaborators
AstraZeneca
Daiichi Sankyo Company, Limited
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04556773    
Other Study ID Numbers: D967JC00002
First Posted: September 21, 2020    Key Record Dates
Last Update Posted: September 21, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
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
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Breast Cancer
HER2-negative
HER2-low
Trastuzumab Deruxtecan
T-DXd
DS-8201a
DESTINY-Breast08
Anti-HER2 Antibody Drug Conjugate (ADC)
Triple-negative breast cancer (TNBC)
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Capecitabine
Trastuzumab
Durvalumab
Fulvestrant
Anastrozole
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Immunological
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors