T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases Following Stereotactic Radiosurgery

Summary

Participation Requirements

Description

Background: Breast cancer is the most common cancer in women. In the HER2+ subtype, brain metastases can occur in up to 25-40% of patients. The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). Currently, ind...

Background: Breast cancer is the most common cancer in women. In the HER2+ subtype, brain metastases can occur in up to 25-40% of patients. The standard therapy for brain metastases continues to be surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). Currently, independently of localized or systemic treatment modality, once brain metastases are established, options for treatment are limited, and the disease almost invariably progresses, limiting not only survival but also quality of life in most patients. Preclinical literature suggests the hypothesis that preventing the formation of a metastasis by a drug may be more efficacious than attempting to shrink an established lesion. Our group has shown in vitro and in vivo in animal models injected with a brain tropic MGMT+ cell line, that even in very low doses temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases. We propose a secondary-prevention clinical trial with oral TMZ given to HER2+ breast cancer patients with brain metastases after recent local treatment (SRS or surgical resection) in combination with the anti-HER2 agent T-DM1 for systemic control of disease. Objectives: Phase I (run in): to identify the maximum tolerated dose (MTD) of TMZ when used in combination with T-DM1. Phase II: to determine if the combination regimen of T-DM1 and temozolomide improves the freedom from distant new brain metastases following stereotactic radiosurgery or surgical resection in HER2-positive breast cancer brain metastases, as compared to T-DM1 alone guided by one-year results as an important benchmark for measuring improvement. Eligibility: Phase I: Histologically confirmed HER2+ breast cancer. ECOG performance status 0-2 and adequate organ and marrow function. Brain metastases, treated within 12 weeks of study entry with SRS, resection or WBRT. Patients with leptomeningeal metastatic disease are ineligible. Patients that are unable to complete a brain MRI with contrast are ineligible. Patients with breast tissue expanders must have those removed before enrollment. HBV, HCV or HIV-positive patients are ineligible. Patient with impaired cardiac function or clinically significant cardiac disease are ineligible. Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period, and will be taken off protocol. Phase II: Histologically confirmed HER2+ breast cancer. ECOG performance status 0-2 and adequate organ and marrow function. 1-10 brain metastases, by contrast MRI, treated within 12 weeks of study entry with SRS and/or resection. Patients with leptomeningeal metastatic disease are ineligible. Patients with history of WBRT are ineligible. Patients that are unable to complete a brain MRI with contrast are ineligible. Patients with breast tissue expanders must have those removed before enrollment. HBV, HCV or HIV-positive patients are ineligible. Patient with impaired cardiac function or clinically significant cardiac disease are ineligible. Corticosteroids will be allowed at enrollment and during the first month of treatment with T-DM1 after SRS, up to a dose of no more than 10mg of dexamethasone daily or equivalent. Patients that need to continue corticosteroids after the initial month will not be allowed to increase the dose after that period, and will be taken off protocol. Design: This is a Phase I/II open label study that will evaluate the potential benefit of TMZ in prevention of new brain metastases in patients with limited brain metastases from HER2+ breast cancer, previously treated with SRS or surgical resection of brain metastases. All patients will receive the standard second-line therapy for HER2+ metastatic breast cancer: T-DM1. During phase II patients will be randomized between T-DM1 plus TMZ versus T-DM1 alone. Phase I run in: T-DM1 3.6 mg/kg IV every 21 days plus TMZ 30, 40 or 50 mg/m^2 daily. Phase II: T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D). Phase I will follow a standard 3+3 design. Thus, with 3 dose levels, up to 18 patients may be included in the initial safety evaluation. In the phase II portion of the trial, a total of 49 evaluable subjects per arm (98 total) will need to be randomized over a 3-year period and followed for an additional 2 years from the date of entry of the last patient, with occurrence of 79 total relapses in both arms combined, in order to have 80% power to compare the curves.

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