Neoplasms

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Neoplasms, Second Primary

Breast Diseases

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Vinorelbine

Tubulin Modulators

Antimitotic Agents

Patients CNS metastases or LMD undergo radiation therapy over 7 days in the absence of disease progression or unacceptable toxicity. Patients 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.

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.

Biospecimen Collection

Computed Tomography

Magnetic Resonance Imaging

Radiation Therapy

Resection

Trotabresib

Roger Stupp, MD

This phase I/Ib trial tests the safety, side effects, and best dose of vinorelbine when given in combination with trotabresib in treating patients with HER2 positive breast cancer that has spread to the central nervous system or leptomeninges (metastasis). Cancer cells that make too much HER2 may grow more quickly and are more likely to spread to other parts of the body as metastases, including the central nervous system. Trotabresib is part of a family of drugs called BET inhibitors. Trotabresib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vinorelbine is in a class of medications called vinca alkaloids. It works by slowing or stopping the growth of cancer cells in your body. Giving trotabresib and vinorelbine may increase in the anti-cancer activity of vinorelbine when used in combination with radiation (radiotherapy).

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.

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

A Phase I/Ib Trial of Trotabresib (BMS-986378), an Oral BET Inhibitor) in Combination With Vinorelbine and Radiation Therapy in HER2+ Breast Cancer Patients With Central Nervous System Metastasis and Leptomeningeal Disease (CA076-1008)

To assess the toxicity profile of vinorelbine and trotabresib this endpoint will collect and report the frequency of adverse events by type, severity (grade), timing, and attribution to vinorelbine and trotabresib, according the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Toxicities will be summarized by maximum grade and patients with and without leptomeningeal spread will be evaluated separately.

To assess the toxicity profile of VNR and trotabresib this endpoint will collect and report the frequency of adverse events by type, severity (grade), timing, and attribution to VNR and trotabresib, according the NCI-CTCAE version 5.0. Toxicities will be summarized by maximum grade.

Median PFS will be calculated based on the Kaplan-Meier estimates of PFS. PFS data will be collected from the initiation of trial therapy (C1D1) until the patient experiences disease progression, initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause (whichever is sooner). If disease progression or death from any cause is not observed prior to initiating subsequent anti-cancer therapy or completing study participation, the PFS will be censored as the last available disease assessment.

Medium OS (mOS) will be calculated based on the Kaplan-Meier estimates of OS. OS data will be collected from the initiation of trial therapy (C1D1) until the patient completes study follow up participation, experiences death from any cause or is documented as lost to follow up per institutional standard (whichever is sooner). If death from any cause is not observed prior to completing study participation, the OS will be censored as the time of the last available documentation of survival status. Last available documentation of survival status is defined as the date of death or the latest of the following times: treatment discontinuation date, last dosing administration date, last disease assessment date, or the last follow-up date when the patient was known to be alive.

will calculate the proportion of treated patients who experience an objective response \[confirmed complete response (CR) or confirmed partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.11 and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Confirmation of response should be conducted via imaging ≥ 28 days after the response was first documented. The date of first response for either CR or PR will be used for the calculation of ORR. ORR data will be collected from the initiation of trial therapy (C1D1) until the response has been confirmed, the patient experiences disease progression, initiates subsequent anti-cancer therapy, or completes study participation (whichever occurs first). Will also determine the objective response rate specifically for intracranial/central nervous system (CNS) disease, disease sites with and without radiotherapy, and extracranial disease.

Spots Global Cancer Trial Database for trotabresib

Every month we try and update this database with for trotabresib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for trotabresib

Every month we try and update this database with for trotabresib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for trotabresib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.