367TiP - Phase 1 Dose Escalation and Cohort Expansion Study of the Safety of Intrathecal Trastuzumab in Her2 Positive Parenchymal Brain Metastatic Breast Cancer: Trial Protocol

Abstract

ABSTRACT Background: The brain is described frequently as the first site of relapse in women with HER2 positive breast cancer treated with trastuzumab. Strategies for better control of brain metastases and outcome improvement are lacking. Intrathecal trastuzumab (IT) was safely performed in cynomolgus monkeys and is being investigated in early trials for meningeal carcinomatosis. Case reports showed clinical benefit and radiological response in HER2 positive parenchymal brain metastatic breast cancer (bMBC) patients. The primary objectives of this study are to determine safety and tolerability of IT. The secondary objectives are to establish IT pharmacokinetic (PK) profile and to measure its preliminary anti-tumor activity. Trial design: Open label single-arm interventional study, non-randomized, phase 1 study, using a “3 + 3” design followed by expansion cohorts. Patients will be treated in cohorts of 3-6 based on standard phase I dose escalation parameters requiring 0/3 or 1/6 patients per cohort to have a DLT before dose escalation. Dosing is as follows: cohort 50 mg IT, cohort 100 mg IT, cohort 150 mg IT. An Ommaya reservoir for IT will be placed surgically. Patients will be treated every 3 weeks concurrently with standard systemic therapy, after local treatment: surgery/stereostatic surgery and/or WBRT. Expansion cohorts will be stratified for each modality of previous local treatment. Safety will be assessed by incidence of DLT, establishment of the MTD, RP2D and schedule. Tolerability will be assessed by incidence of Adverse Events according to the CTCAE v4.0. Trastuzumab PK profile will be determined in CSF and plasma during dose escalation and expansion cohort. Preliminary IT anti-tumor activity will be determined by radiological response assessed by brain MRI using RECIST 1.1 criteria; biological response, accessed by CSF cytology; time to neurological progression, assessed with EORTC QOL QLCQ- 30 and time to progression via Kaplan-Meier curves. This study will be the first to determine the recommended dose for IT in HER2 positive parenchymal bMBC and may support development of future phase II/III clinical trials. Disclosure: All authors have declared no conflicts of interest.