A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer

Phase 1

Active, not recruiting

• Conditions: Metastatic Breast Cancer
• Interventions: Drug: Trastuzumab deruxtecan; Drug: Tucatinib; Drug: Durvalumab; Drug: Pertuzumab; Drug: Paclitaxel

• Registration Number: NCT04538742
• Lead Sponsor: AstraZeneca

Brief Summary

DESTINY-Breast07 will investigate the safety, tolerability, and anti-tumour activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in patients with HER2-positive Metastatic Breast Cancer

Detailed Description

This study is modular in design allowing assessment of safety, tolerability and anti-tumour activity of T-DXd in combination with other anti-cancer agents. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the recommended Phase 2 dose (RP2D) determined in Part 1 will be used for the dose-expansion in Part 2.

The target population of interest in this study is patients with HER2-positive (as per ASCO/CAP 2018 guidelines) advanced/MBC inclusive of patients with active and stable brain metastases. Part 1 of each module will enroll patients with locally assessed HER2-positive advanced/MBC in second-line or later patients. Part 2 of each module will enroll patients with locally assessed HER2-positive breast cancer who have not received prior treatment 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: 2020-08-31
• Study First Submitted QC: 2020-08-31
• Study First Posted: 2020-09-04
• Study Start: 2020-12-28
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-11
• Last Update Posted: 2024-12-13
• Primary Completion: 2025-01-31
• Study Completion: 2025-01-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 245

Inclusion Criteria

• Patients must be at least 18 years of age

• Pathologically documented breast cancer that:

  1. Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic
  2. HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local assessment. The local HER2 result must be from a tumour sample obtained in the metastatic setting.
  3. Is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting

• Patient must have adequate tumor sample from the metastatic setting for biomarker assessment

• ECOG Performance Status of 0 or 1

• Part 1

  1. Disease progression on or after the last systemic therapy prior to starting study treatment
  2. At least 1 prior treatment line in metastatic setting required.

• Part 2 (Modules 0 - 5)

  a) No prior lines of therapy for advanced/MBC allowed

• Part 2 (Module 6 and 7) a) Zero or one prior lines of therapy for advanced/MBC allowed

CNS Inclusion

• Modules 0 - 5 Patients must have no brain metastases or stable brain metastases.
• Module 6 and 7 Patients must have untreated brain metastases not needing local therapy or previously treated brain metastases that have progressed since prior local therapy

Key

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Exclusion Criteria

• Uncontrolled or significant cardiovascular disease
• Active or prior documented (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Spinal cord compression or a history of leptomeningeal carcinomatosis
• Prior treatment with immune checkpoint inhibitors
• Prior treatment with an ADC containing a topoisomerase I inhibitor
• Prior treatment with tucatinib

CNS Exclusion

• Modules 0 - 5: Has untreated brain metastasis
• Module 6 and 7: Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg dexamethasone or any brain lesion thought to require immediate local therapy

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Module 5 - T-DXd and Tucatanib	Tucatinib	T-DXd and tucatinib (Arm not initiated in Part 2)
Module 1- T-DXd and Durvalumab	Trastuzumab deruxtecan	T-DXd and Durvalumab
Module 1- T-DXd and Durvalumab	Durvalumab	T-DXd and Durvalumab
Module 2- T-DXd and Pertuzumab	Trastuzumab deruxtecan	T-DXd and Pertuzumab
Module 2- T-DXd and Pertuzumab	Pertuzumab	T-DXd and Pertuzumab
Module 3- T-DXd and Paclitaxel	Paclitaxel	T-DXd and Paclitaxel (Arm not initiated in Part 2)
Module 4- T-DXd and Durvalumab and Paclitaxel	Trastuzumab deruxtecan	T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)
Module 4- T-DXd and Durvalumab and Paclitaxel	Durvalumab	T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)
Module 4- T-DXd and Durvalumab and Paclitaxel	Paclitaxel	T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)
Module 0- T-DXd	Trastuzumab deruxtecan	T-DXd
Module 5 - T-DXd and Tucatanib	Trastuzumab deruxtecan	T-DXd and tucatinib (Arm not initiated in Part 2)
Module 6 - T-DXd and Tucatinib	Trastuzumab deruxtecan	T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated)
Module 7 - T-DXd	Trastuzumab deruxtecan	T-DXd monotherapy in patients with active brain metastases (Part 2 Only)
Module 3- T-DXd and Paclitaxel	Trastuzumab deruxtecan	T-DXd and Paclitaxel (Arm not initiated in Part 2)
Module 6 - T-DXd and Tucatinib	Tucatinib	T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated)

Primary Outcome Measures

Name	Time	Method
Occurrence of adverse events (AEs)- Part 1	Up to follow-up period, approximately 53 months	Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of serious adverse events (SAEs)- Part 1	Up to follow-up period, approximately 53 months	Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0
Occurrence of adverse events (AEs)- Part 2	Up to follow-up period, approximately 53 months	Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0
Occurrence of serious adverse events (SAEs)- Part 2	Up to follow-up period, approximately 53 months	Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival 2 (PFS2)- Part 2	Assessed up to approximately 53 months	PFS2 is defined as time from the date of randomisation until the date of progression on next line treatment (the earliest of the progression event subsequent to first subsequent anticancer therapy) or death; second progression will be defined according to local standard clinical practice.
Serum Concentration of Trastuzumab Deruxtecan (T-DXd)	While on study drug up to study completion, approximately 53 months	Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration
Serum Concentration of Durvalumab	While on study drug up to study completion, approximately 53 months	Determination of durvalumab concentration in serum at different time points after administration
Serum Concentration of Pertuzumab	While on study drug up to study completion, approximately 53 months	Determination of pertuzumab concentration in serum at different time points after administration
Plasma Concentration of Paclitaxel	While on study drug up to study completion, approximately 53 months	Determination of paclitaxel concentration in plasma at different time points after administration
Progression Free Survival (PFS)- Part 1 and Part 2	Until progression, assessed up to approximately 53 months	PFS is defined as time from the date of randomization until the date of progression as assessed by the Investigator at local site per RECIST 1.1, or death due to any cause.
Duration of Response (DoR)- Part 2	Until progression, assessed up to approximately 53 months	DoR is defined as time from the date of first documented response until the date of documented progression or death in the absence of disease progression.
Overall Survival (OS)- Part 2	Until death, assessed up to approximately 53 months	OS is defined as time from the date of randomisation until the date of death due to any cause.
Immunogenicity of Pertuzumab	Up to follow-up period, approximately 53 months	Percentage of patients who develop ADA for pertuzumab
Objective Response Rate (ORR)- Part 1 and Part 2	Until progression, assessed up to approximately 53 months	ORR is defined as the proportion of patients who have a CR or PR, as determined by the Investigator at local site per RECIST 1.1.
Immunogenicity of trastuzumab deruxtecan	Up to follow-up period, approximately 53 months	Percentage of patients who develop ADA for trastuzumab deruxtecan
Immunogenicity of Durvalumab	Up to follow-up period, approximately 53 months	Percentage of patients who develop ADA for durvalumab
Plasma Concentration of Tucatinib	While on study drug up to study completion, approximately 53 months	Determination of tucatinib concentration in plasma at different time points after administration

Trial Locations

Locations (1)

Research Site; 🇬🇧 Buckhurst Hill, United Kingdom