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

Tracking Information

• First Submitted Date: September 15, 2020
• First Posted Date: September 21, 2020
• Last Update Posted Date: March 16, 2023
• Actual Study Start Date: December 17, 2020
• Estimated Primary Completion Date: August 10, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer
• 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)
• 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: Interventional
• Study Phase: Phase 1

Study Design

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: Metastatic Breast Cancer

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 15, 2023): 139
• Original Estimated Enrollment (submitted: September 15, 2020): 185
• Estimated Study Completion Date: August 10, 2023
• Estimated Primary Completion Date: August 10, 2023 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Brazil, Canada, France, Korea, Republic of, Mexico, Russian Federation, Taiwan, United States

Administrative Information

• NCT Number: NCT04556773
• Other Study ID Numbers: 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

• 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: AstraZeneca
• Original Study Sponsor: Same as current

Collaborators

• Daiichi Sankyo Co., Ltd.
• Daiichi Sankyo Company, Limited

Investigators

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

• PRS Account: AstraZeneca
• Verification Date: March 2023