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

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.

Key Inclusion Criteria:

• Patients must be at least 18 years of age
• Pathologically documented breast cancer that:

• Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic
• 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.
• 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

• Disease progression on or after the last systemic therapy prior to starting study treatment
• 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