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

Phase 1

Active, not recruiting

• Conditions: Metastatic Breast Cancer
• Interventions: Drug: Trastuzumab deruxtecan; Drug: Durvalumab; Drug: Fulvestrant; Drug: Capecitabine; Drug: Capivasertib; Drug: Anastrozole; Drug: Paclitaxel

• Registration Number: NCT04556773
• Lead Sponsor: 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

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

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2020-09-15
• Study First Submitted QC: 2020-09-15
• Study First Posted: 2020-09-21
• Study Start: 2020-12-17
• Primary Completion: 2023-08-16
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-22
• Last Update Posted: 2024-11-25
• Study Completion: 2025-11-28

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 138

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Module 2: T-DXd + durvalumab + paclitaxel	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
Module 1: T-DXd + capecitabine	Trastuzumab deruxtecan	T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use
Module 4: T-DXd + anastrozole	Trastuzumab deruxtecan	T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral
Module 2: T-DXd + durvalumab + paclitaxel	Durvalumab	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
Module 5: T-DXd + fulvestrant	Fulvestrant	T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use
Module 1: T-DXd + capecitabine	Capecitabine	T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use
Module 2: T-DXd + durvalumab + paclitaxel	Trastuzumab deruxtecan	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
Module 3: T-DXd + capivasertib	Trastuzumab deruxtecan	T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use
Module 3: T-DXd + capivasertib	Capivasertib	T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use
Module 4: T-DXd + anastrozole	Anastrozole	T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral
Module 5: T-DXd + fulvestrant	Trastuzumab deruxtecan	T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use

Primary Outcome Measures

Name	Time	Method
Occurrence of serious adverse events (SAEs)- Part 1	Up to follow-up period, approximately 24 months	Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of serious adverse events (SAEs)- Part 2	Up to follow-up period, approximately 24 months	Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0
Occurrence of adverse events (AEs)- Part 2	Up to follow-up period, approximately 24 months	Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0
Occurrence of adverse events (AEs)- Part 1	Up to follow-up period, approximately 24 months	Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0

Secondary Outcome Measures

Name	Time	Method
Immunogenicity of durvalumab	Up to follow-up period, approximately 24 months	Percentage of patients who develop ADAs for durvalumab
Objective Response Rate (ORR)- Part 2	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
Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a	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
Duration of Response (DoR)- Part 2	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
Progression Free Survival (PFS)- Part 2	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
Overall Survival (OS)- Part 2	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 durvalumab	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 trastuzumab deruxtecan	Up to follow-up period, approximately 24 months	Percentage of patients who develop ADA for trastuzumab deruxtecan

Trial Locations

Locations (1)

Research Site; 🇨🇳 Taoyuan, Taiwan