DS-8201a for trEatment of aBc, BRain Mets, And Her2[+] Disease

Inclusion Criteria

• Signed Informed Consent Form (ICF) prior to participation in any study-related activities.
• Male or female patients ≥ 18 years at the time of signing ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 for Cohorts 1 to 4 and 0-2 for cohort 5.
• Life expectancy ≥ 12 weeks.
• Histologically confirmed invasive breast cancer based on local testing on the most recent analyzed biopsy of the following breast cancer (BC) subtypes per 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria:
• Cohort 1 and 3: HER2 positive status
• Cohort 4: HER2-low expressing status
• Cohort 2 and 5: both HER2 positive and HER2-low expressing status

Note 1: According to the 2018 ASCO-CAP guidelines, HER2- positive status is defined as HER2 immunohistochemistry (IHC) 3+, in situ hybridization (ISH) ≥ 2.0, or average HER2 copy number ≥ 6.0 signals. HER2-low expressing status defined as IHC 2+ / ISH-negative or IHC 1+ (ISH-negative or untested).

Note 2: Central confirmation of HER2 is not required for study entry. However, tissue blocks, or slides, must be submitted to confirm BC subtype by a Sponsor-designated central laboratory retrospectively.

• Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
• At least one brain lesion needed to be measurable (≥10 mm on T1-weighted, gadolinium-enhanced MRI) (study cohorts 2 to 4) or leptomeningeal carcinomatosis (LMC) with positive cerebrospinal fluid (CSF) cytology (study cohort 5).
• Study cohort 1: History of BM that are non-progressing after WBRT and/or SRS and or surgery.
• Study cohort 2: Presence of asymptomatic BM without clinical requirement for local intervention (WBRT and/or SRS and/or surgery).
• Study cohorts 3 and 4: Evidence of new and/or progressive BM following previous WBRT and/or SRS and/or surgery.
• Study cohort 5: Evidence of LMC with positive CSF cytology.
• Previous treatments:
• For HER2-positive patients have been previously treated with a taxane and at least one HER2-targeted therapy in the advanced scenario.
• For HER2-low-expressing patients that also are endocrine receptor negative must have been previously treated with at least one chemotherapy regimen. If endocrine receptor positive, patients must have been previously treated with at least one chemotherapy and one endocrine regimen in the metastatic setting.
• Patients must agree to collection of blood samples at the time of inclusion, at cycle 2 of treatment, and upon progression or study termination.

Note: In study cohort 5: Patients must agree to perform spinal taps or must be willing to have an Ommaya reservoir placed for CSF assessment, at baseline, every three weeks for 12 weeks (corresponding to the first 5 cycles of treatment) and every six weeks thereafter.

• Willingness and ability to provide tumor biopsy (if feasible) from metastatic lesions or breast primary tumor both at the time of the inclusion and after disease progression in order to perform exploratory studies.

Note: If feasible, patients should provide a tissue sample at baseline from metastases amenable to biopsy (at sites of locoregional recurrence [skin, chest wall, breast or lymph nodes], or distant recurrence [bone, liver, lung or abdomen]) or as alternative from breast primary tumor, that will be obtained between progression to the prior regimen and inclusion in the study. Patients for whom tissue sample cannot be obtained (e.g., non-measurable disease, inaccessible tumor or subject safety concern) may submit an archived metastatic tumor specimen only upon agreement from the Sponsor. If feasible, an additional tissue sample should be collected at the end of treatment visit for patients who discontinue treatment due to disease progression.

• Patients should have left ventricular ejection fraction (LVEF) ≥ 50% by e