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

• ClinicalTrials.gov Identifier: NCT04556773
• Recruitment Status: Active, not recruiting
• First Posted: September 21, 2020
• Last Update Posted: March 16, 2023
• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo Co., Ltd.; Daiichi Sankyo Company, Limited
• Information provided by (Responsible Party): AstraZeneca

Study Description

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 139 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)
• Actual Study Start Date: December 17, 2020
• Estimated Primary Completion Date: August 10, 2023
• Estimated Study Completion Date: August 10, 2023

Arms and Interventions

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; Other Name: 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 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; Other Name: 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 Name: DS-8201a, T-DXd; Drug: Fulvestrant; Fulvestrant: administered as an IM injection

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Locations

United States, New York

Research Site

Commack, New York, United States, 11725

Research Site

Harrison, New York, United States, 10604

Research Site

New York, New York, United States, 10029

Research Site

New York, New York, United States, 10065

Research Site

Uniondale, New York, United States, 11553

United States, North Carolina

Research Site

Chapel Hill, North Carolina, United States, 27514

United States, Tennessee

Research Site

Chattanooga, Tennessee, United States, 37404

Research Site

Germantown, Tennessee, United States, 38138

United States, Texas

Research Site

Fort Worth, Texas, United States, 76104

Australia

Research Site

East Melbourne, Australia, 3002

Research Site

Westmead, Australia, 2145

Belgium

Research Site

Edegem, Belgium, 2650

Research Site

Leuven, Belgium, 3000

Research Site

Ottignies, Belgium, 1340

Brazil

Research Site

Florianópolis, Brazil, 88034-000

Research Site

Goiania, Brazil, 74605-070

Research Site

Porto Alegre, Brazil, 90035-003

Research Site

Porto Alegre, Brazil, 90110-270

Research Site

Sao Paulo, Brazil, 01317-001

Research Site

Sao Paulo, Brazil, 04543-000

Research Site

São Paulo, Brazil, 03102-002

Research Site

São Paulo, Brazil, 04538-132

Canada, British Columbia

Research Site

Kelowna, British Columbia, Canada, V1Y 5L3

Canada

Research Site

Quebec, Canada, G1J 1Z4

France

Research Site

Villejuif Cedex, France, 94805

Korea, Republic of

Research Site

Seoul, Korea, Republic of, 03080

Research Site

Seoul, Korea, Republic of, 03722

Research Site

Seoul, Korea, Republic of, 05505

Research Site

Seoul, Korea, Republic of, 06351

Mexico

Research Site

Monterrey, Mexico, 64710

Russian Federation

Research Site

Moscow, Russian Federation, 115478

Research Site

Moscow, Russian Federation, 143442

Research Site

Saint Petersburg, Russian Federation, 199226

Taiwan

Research Site

Kaohsiung, Taiwan, 82445

Research Site

Taichung, Taiwan, 40443

Research Site

Taipei City, Taiwan, 114

Research Site

Taipei, Taiwan, 100

Research Site

Taipei, Taiwan, 11217

Research Site

Taipei, Taiwan, 235

Research Site

Taoyuan, Taiwan, 333

Sponsors and Collaborators

AstraZeneca

Daiichi Sankyo Co., Ltd.

Daiichi Sankyo Company, Limited

Investigators

• Principal Investigator: Komal Jhaveri, MD, FACP; Memorial Sloan Kettering Cancer Center

More Information

Additional Information:

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. 

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04556773
• Other Study ID Numbers: D967JC00002
• First Posted: September 21, 2020
• Last Update Posted: March 16, 2023
• Last Verified: March 2023

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

• 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:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Paclitaxel; Capecitabine; Trastuzumab; Durvalumab; Fulvestrant; Anastrozole; Trastuzumab deruxtecan; 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