A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer (DB-07)

AstraZeneca

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Metastatic Breast Cancer

Treatments: Drug: Tucatinib; Drug: Durvalumab; Drug: Trastuzumab deruxtecan; Drug: Paclitaxel; Drug: Pertuzumab

Study type: Interventional

Funder types: Industry; Other

Identifiers

NCT04538742

2023-505309-18-00 (Registry Identifier)

2019-004531-22 (EudraCT Number)

D967JC00001

Details and patient eligibility

About

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

Full 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.

Enrollment: 245 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key 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 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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245 participants in 8 patient groups

Module 1- T-DXd and Durvalumab

Experimental group

Description:

T-DXd and Durvalumab

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Durvalumab

Module 2- T-DXd and Pertuzumab

Experimental group

Description:

T-DXd and Pertuzumab

Treatment:

Drug: Pertuzumab

Drug: Trastuzumab deruxtecan

Module 3- T-DXd and Paclitaxel

Experimental group

Description:

T-DXd and Paclitaxel (Arm not initiated in Part 2)

Treatment:

Drug: Paclitaxel

Drug: Trastuzumab deruxtecan

Module 4- T-DXd and Durvalumab and Paclitaxel

Experimental group

Description:

T-DXd and Durvalumab and Paclitaxel (Arm not initiated in Part 1 and Part 2)

Treatment:

Drug: Paclitaxel

Drug: Trastuzumab deruxtecan

Drug: Durvalumab

Module 0- T-DXd

Experimental group

Description:

T-DXd

Treatment:

Drug: Trastuzumab deruxtecan

Module 5 - T-DXd and Tucatanib

Experimental group

Description:

T-DXd and tucatinib (Arm not initiated in Part 2)

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Tucatinib

Module 6 - T-DXd and Tucatinib

Experimental group

Description:

T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) (Arm not initiated)

Treatment:

Drug: Trastuzumab deruxtecan

Drug: Tucatinib

Module 7 - T-DXd

Experimental group

Description:

T-DXd monotherapy in patients with active brain metastases (Part 2 Only)

Treatment:

Drug: Trastuzumab deruxtecan