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

NCT06137651 | Withdrawn Phase 1 DMC FDA Drug

• 4 other identifiers: NU 22C02NCI-2023-08757STU00220214P30CA060553
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Breast Carcinoma; Metastatic Malignant Neoplasm in the Brain; Metastatic Malignant Neoplasm in the Leptomeninges

Outcome Measures

Primary Outcomes (2)

• Dose limiting toxicities (Phase I)

  Up to 28 days after treatment

• Incidence of adverse events (Phase Ib)

  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.

  Up to 30 days after last dose

Secondary Outcomes (4)

• Incidence of adverse events (Phase I)

  Up to 30 days after last dose

• Progression-free survival (PFS) (Phase Ib)

  Time that elapses between the initiation of trial therapy (cycle 1 day 1 [C1D1]) and the day of first documented disease progression or death from any cause for all evaluable patients, assessed up to 1 year

• Overall survival (OS) (Phase Ib)

  Time that elapses between the initiation of trial therapy (C1D1) and the date of death from any cause for all evaluable patients, assessed up to 1 year

• Objective response rate (ORR) (Phase Ib)

  Time that elapses between the initiation of trial therapy (C1D1) and the date of death from any cause for all evaluable patients, assessed up to 1 year

Study Arms (2)

Cohort I (radiation therapy, trotabresib, vinorelbine)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Radiation: Radiation Therapy; Drug: Trotabresib; Drug: Vinorelbine

Cohort S (surgery, trotabresib, vinorelbine)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Radiation: Radiation Therapy; Procedure: Resection; Drug: Trotabresib; Drug: Vinorelbine

Interventions

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Computed Tomography PROCEDURE

Undergo CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Radiation Therapy RADIATION

Undergo radiation therapy

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Resection PROCEDURE

Undergo surgery

Also known as: Surgical Resection

Cohort S (surgery, trotabresib, vinorelbine)

Trotabresib DRUG

Given PO

Also known as: 4-(2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one, BET Inhibitor CC-90010, CC 90010, CC-90010, CC90010

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Vinorelbine DRUG

Given IV

Also known as: Dihydroxydeoxynorvinkaleukoblastine

Cohort I (radiation therapy, trotabresib, vinorelbine); Cohort S (surgery, trotabresib, vinorelbine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed diagnosis of HER2+ breast cancer. Patients may be immunohistochemistry (IHC) 3+ and/or fluorescence in situ hybridization (FISH) positive for HER2. IHC 2+ HER2 patients are eligible with reflex FISH-positive testing with the ratio ≥ 2.0. Alternatively, circulating tumor DNA testing positive for HER2 mutation is accepted for eligibility
• Patients must have newly diagnosed or progressive brain and/or leptomeningeal metastases, and a change in management and of treatment regimen is indicated. There is no limit on the number and types of prior systemic or intrathecal therapies
• Subjects must have an estimated life expectancy ≥ 3 months
• At registration, patients must have an interval of at least 2 weeks after the end of prior cytotoxic chemotherapy or immunotherapy or previous RT, one week from prior targeted small molecule drug treatment, interval of ≥ 4 weeks from prior bevacizumab or nitrosourea. At treatment start of trotabresib, there must be an interval of ≥ 4 weeks since last cytotoxic chemotherapy (6 weeks for prior nitrosourea) or immunotherapy
• Note: Anti-HER2 directed treatment is allowed to continue, however, should be switched to trastuzumab before initiation of trotabresib. No washout period is required
• Patients must be age ≥ 18 years on the day of signing consent
• Patients must exhibit Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Leukocytes (WBC) ≥ 3,000/mcL or absolute neutrophil count (ANC) ≥ 1,500/mcL (within 14 days prior to registration)
• Hemoglobin (Hgb) ≥ 10 g/dL (within 14 days prior to registration)
• Platelets (PLT) ≥ 75,000/mcL (within 14 days prior to registration)
• Total bilirubin \< 1.5 x upper limit of normal (ULN) (except patient with documented Gilbert's syndrome, ≤ 5 x ULN) (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 3 x institutional ULN (within 14 days prior to registration)
• Creatinine \< 1.5x upper limit of normal (ULN) (within 14 days prior to registration)
• Patients must be able to swallow oral medication
• Patients who are currently participating in or have participated in a study of an investigational agent or device must have discontinued the use of the investigational drug or device ≥ 4 weeks from registration on this study

You may not qualify if:

• Patients who are on escalating doses of corticosteroids
• Note: Patients must be on a stable or decreasing dose of corticosteroids equivalent to dexamethasone ≤ 8mg averaged over the last 7 days to be eligible for the study
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to trotabresib and vinorelbine (VNR)
• Patients who have a known additional malignancy that is progressing or requires active treatment
• Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Patients who have impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• LVEF \< 45% as determined from review of any standard of care echocardiograms (ECHOs) multigated acquisition scans/(MUGAs) completed in the past 2 years
• Complete left bundle branch or bifascicular block (verified by review of medical records)
• Congenital long QT syndrome (verified by review of medical records)
• Persistent or clinically meaningful ventricular arrhythmias or atrial fibrillation (verified by review of medical records)
• Fridericia's correction formula (QTcF) ≥ 480 msec on screening electrocardiogram (ECG)
• Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting therapy (verified by review of medical records)
• Patients who require ongoing treatment with chronic, therapeutic dosing of anti-coagulants (ex. warfarin, low molecular weight heparin, Factor Xa inhibitors, thrombin antagonists)
• Note: Low dose low molecular weight heparin for catheter maintenance and for prophylactic use are permitted if medically indicated
• Patients who have a history of bleeding diathesis

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms; Meningeal Carcinomatosis

Interventions

Specimen Handling; Magnetic Resonance Spectroscopy; Radiotherapy; Radiation; Vinorelbine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Meningeal Neoplasms

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Therapeutics; Physical Phenomena; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Roger Stupp, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2023
• First Posted: November 18, 2023
• Study Start: December 31, 2023
• Primary Completion: March 27, 2024
• Study Completion: March 27, 2024
• Last Updated: April 1, 2024

Record last verified: 2024-03

Locations

US (1)