Abstract P5-19-17: Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC)
Authors: Gutierrez Maya , Mouret Fourme Emmanuelle , Le Rhun Emilie , Tredan Olivier , Dieras Veronique , Tresca Patricia , Mefti Fawzia , Turbiez Isabelle , Taillibert Sophie , Desvignes Céline , Paintaud Gilles 
Published: May 2015

Abstract
Metastatic breast cancer (MBC) is the leading non hematologic cause of leptomeningeal metastases (LM), associated with a poor prognosis. Amongst breast cancer (BC) subtypes, HER2+ tumors present a high LM incidence. Intravenous (IV) trastuzumab (T) has improved survival of MBC patients but better control of central nervous system (CNS) disease is needed. The main physiopathological hypothesis for intracranial recurrences is the low level of T in cerebrospinal fluid (CSF) due to his high molecular weight (148kD). Intraventricular (via Ommaya port) or intrathecal (IT) T administration would permit LM progression control through high therapeutic T concentrations in the CSF. This prospective trial, sponsored by Institut Curie, was the first Phase I-II study to investigate the safety and efficacy of IT T administration for HER2+ LM in BC. The final results of the Phase I cohort are reported herein. Methods: LM diagnosis was based on either CSF with HER2+ cytology or clinical/MRI imagings of meningitis. Adequate organs functions for all patients were required. The T IT (or via Ommaya port) injections were given on weekly basis during 8 weeks. We used a Fibonacci dose escalation design, 4 dose levels (DL) (30-150mg). The objectives of this phase I were to investigate the maximum tolerated dose (MTD) and the recommend dose (DR) of T. A pharmacokinetic (PK) data analysis was performed. We targeted a concentration in the CSF close to the residual serum concentration (30µg/mL) achieved with standard IV schedule.
Results: Starting May 2011, 19 patients were included, with 16 evaluable for toxicity (three had not received the treatment) treated in 4 DL (30-150mg). Twelve patients were evaluable for PK and 210 samples T concentrations available (103 in the LCR and 107 in the serum). The MTD was not reached and the treatment appears to have been well tolerated by the patients. Neither Grade ≥3 toxicity nor neurological toxicity related to IT T was observed. The T target-concentration in the CSF was reached at DL4 and the recommended T dose for the Phase II trial is 150 mg. Five patients have experimented a evident clinical benefit and received more than 8 weekly injections with an average of 23 [12-40]. Extended data on clinical outcome and PK will be presented. Conclusion: Intraventricular or IT injections appears to be safe at the dose of 150 mg and possibly effective. The Phase II study will investigate the efficacy of the recommended dose on neurological progression-free survival at 2 months in 19 patients. This trial was performed with Roche funding.
Citation Format: Maya Gutierrez, Emmanuelle Mouret Fourme, Emilie Le Rhun, Olivier Tredan, Veronique Dieras, Patricia Tresca, Fawzia Mefti, Isabelle Turbiez, Sophie Taillibert, Céline Desvignes, Gilles Paintaud. Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-17.