Trotabresib in Combination With Vinorelbine and Radiation Therapy for the Treatment of HER2+ Breast Cancer With Central Nervous System or Leptomeningeal Metastasis

PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) and recommended Phase II dose of trotabresib in combination with vinorelbine (VNR). (Phase I) II. To measure the progression free survival (PFS) from the date of first treatment of trotabresib to the date of first observation of progressive disease in both intracranial and extracranial sites in patients with brain metastases (BMs) and/or leptomeningeal disease (LMD). (Phase Ib \[Expansion\]) SECONDARY OBJECTIVES: I. To establish the safety of trotabresib in combination with VNR, measured by the number of patients with adverse events. (Phase I) II. To assess the tolerance and toxicity profile of trotabresib in combination with VNR following RT in HER2+ breast cancer patients with central nervous system (CNS) metastasis. (Phase Ib \[Expansion\]) II. To measure the overall survival (OS) from the date of first treatment to the date of death from any cause. (Phase Ib \[Expansion\]) III. To evaluate the response rate (RECIST v. 1.1 and RANO-BM criteria) in patients with measurable disease. (Phase Ib \[Expansion\]) EXPLORATORY OBJECTIVES: I. Disease monitoring using circulating tumor cells (CTCs) and circulating tumor DNA in peripheral blood and CSF. (Phase 1/1b) II. Expression of MZF1 and beta III tubulin in tumor tissue at baseline and during/after treatment when available. (Phase 1/1b) III. Evaluation of treatment response by metabolic positron emission tomography (PET) imaging using a novel 68Ga-HER2-nanobody (separate imaging protocol for select patients, pending future amendment to this trial for enrollment. (Phase 1/1b) IV. To estimate the concentrations of vinorelbine and trotabresib in central nervous system tissue (both in enhancing and non-enhancing parts). (Cohort S) OUTLINE: This is a phase I dose-escalation study of vinorelbine followed by a phase Ib dose expansion study. Patients are assigned to 1 of 2 cohorts. COHORT I: Patients central nervous system (CNS) metastases or leptomeningeal disease (LMD) undergo radiation therapy over 7 days in the absence of disease progression or unacceptable toxicity. Patients then receive trotabresib orally (PO) once daily (QD) on days 1-4 and vinorelbine intravenously (IV) over 6-10 minutes on days 4, 11, and 18 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT), and collection of blood samples throughout the trial. COHORT S (PRE-SURGICAL COHORT): Patients who undergo tumor resection receive trotabresib PO QD on days 1-4 and vinorelbine IV on day 4. Patients then undergo standard of care surgery. Patients may undergo radiation therapy after surgery per standard of care. Patients may then receive trotabresib PO QD on days 1-4 and vinorelbine IV over 6-10 minutes on days 4, 11, and 18 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo MRI, CT, and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 6 months for up to 1 year.