Abstract OT2-06-01: Phase I/II study of T-DM1 alone versus T-DM1 and metronomic temozolomide in secondary prevention of HER2-Positive breast cancer brain metastases following stereotactic radiosurgery
Authors: Zimmer AS , Gril B , Steinberg S , Smart D , Gilbert M , Armstrong T , Xiao L , Houston N , Biassou N , Brastianos P , Carter S , Lyden DC , Lipkowitz S , Steeg P 
Published: February 2018

Abstract
Background: Brain metastases occur in up to 25-40% of HER2+ breast cancer patients. Standard treatment is limited to surgery or stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT), with high levels of recurrence or progression, limiting survival and quality of life in most patients. Our group has demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases in murine models of breast cancer. Based on these findings, we propose a secondary-prevention clinical trial.
Trial Design: Phase I/II open label study. Phase I will follow a standard 3+3 design: T-DM1 3.6 mg/kg IV every 21 days plus TMZ 30, 40 or 50 mg/m2 daily. Phase II: randomization T-DM1 3.6 mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D). Patients will undergo radiology guided lumbar puncture at baseline and after 6 weeks of treatment (C3D1) for correlative studies, brain MRI, systemic restaging CTs, and questionnaires for evaluation of symptoms and quality of life (MDASI-BT and PROMIS®) every 6 weeks.
Eligibility: HER2+ breast cancer with ≤3 brain metastases, treated with SRS and/or resection ≤6 weeks before enrollment, no leptomeningeal metastases, no previous WBRT, able to complete brain MRI with contrast evaluations, willing to undergo lumbar puncture, ECOG ≤2 and adequate organ and marrow function. HBV, HCV or HIV-positive patients are ineligible.
Specific Aims: Phase I: to identify the maximum tolerated dose (MTD) of TMZ combined with T-DM1. Phase II: to determine if the combination regimen of T-DM1 and TMZ improves the recurrence-free incidence from distant new brain metastases at one year as compared to T-DM1 alone. Biomarkers, including cell free DNA sequencing from CSF, serum and tumor block, serum markers for neuroinflammation, and patient reported outcomes, will be analyzed in an exploratory fashion.
Statistical Methods: Phase I, MTD will be identified based on the dose level at which 0 or 1 patient in 6 has a DLT. Phase II, to test whether TMZ will increase RFS from 50% to 65% at 12 months. RFS Kaplan-Meier curves will be created for each of the randomized arms and compared using a one-tailed log-rank test, with a one-sided 0.10 significance level of interest to be detected. Patients will be stratified for number of brain lesions and status of systemic metastases (controlled or not).
Target Accrual: 49 evaluable patients per arm (total 98), plus 9 to 18 patients during phase I. Trial will open in Summer 2017, at NIH in Bethesda, MD.
Contact Information: Principal Investigator: Alexandra S Zimmer, MD alexandra.zimmer@nih.gov
Citation Format: Zimmer AS, Gril B, Steinberg S, Smart D, Gilbert M, Armstrong T, Xiao L, Houston N, Biassou N, Brastianos P, Carter S, Lyden DC, Lipkowitz S, Steeg P. Phase I/II study of T-DM1 alone versus T-DM1 and metronomic temozolomide in secondary prevention of HER2-Positive breast cancer brain metastases following stereotactic radiosurgery [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-01.