Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 22, No 14S (July 15 Supplement), 2004: 6593
© 2004 American Society of Clinical Oncology

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Abstract

Results from a phase I study of intraventricular administration of rituximab in patients with recurrent lymphomatous meningitis

UCSF, San Francisco, CA; Memorial Sloan Kettering Cancer Center, New York, NY; Genentech, South San Francisco, CA

6593

Background: CNS complications of non-Hodgkin's lymphoma (NHL) remain an important cause of morbidity and death in patients with intermediate or high-grade disease. We previously conducted an analysis of the safety and pharmacokinetics of intrathecal Rituximab administration in nonhuman primates (Rubenstein et al; Blood 2003). These results constitute the basis for the current phase I study of intraventricular Rituximab administration. Methods: Six patients with recurrent or refractory CD20 + leptomeningeal NHL were treated at UCSF or at MSKCC. Nine planned injections of Rituximab at 10 mg and at 25 mg dose levels were administered through an Ommaya reservoir over a 5 week period. Matched CSF and serum levels of Rituximab were measured at baseline, 1, 2, 4, 8, 24 and 96 hours. To define early transcriptional events caused by Rituximab, gene expression profile analysis was conducted on B-lymphoma cells purified from CSF at baseline, 1, 2, and 4 hours post-Rituximab administration. Results: Our preliminary results suggest that intraventricular administration of Rituximab was well-tolerated. Toxicities observed include mild leukoencephalopathy and paresthesias, each occurring in one patient. Pharmacokinetic parameters were similar to those defined in nonhuman primates. High peak drug levels were obtained within the ventricles with evidence for rapid craniospinal axis distribution; Rituximab was reproducibly detectable within the lumbar sac at 4 hours. Administration of Rituximab by LP in resulted in a 5-fold increase in intraventricular concentration at 90 minutes. Cytologic responses were immediately detected in 4 patients. One patient had complete resolution of parenchymal as well as leptomeningeal NHL and marked improvement in ocular NHL. Gene expression profile analysis provided evidence for the activation of an apoptotic pathway after Rituximab exposure. Conclusions: Intraventricular Rituximab administration represents a novel means of treatment of CNS involvement of NHL. Efficacy and safety data are promising but additional studies and follow-up are required to evaluate this route of administration.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech

Abstract presentation from the 2004 ASCO Annual Meeting