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

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
4. Patient must have adequate tumor sample from the metastatic setting for biomarker assessment
5. 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

1. Modules 0 - 5 Patients must have no brain metastases or stable brain metastases.
2. 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:

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

CNS Exclusion

1. Modules 0 - 5: Has untreated brain metastasis
2. 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