INTRAVENTRICULAR IMMUNOTOXIN THERAPY FOR LEPTOMENINGEAL NEOPLASIA

OBJECTIVE: The goals of this clinical trial of intraventricular 454A12 -rRA therapy were to identify dose-limiting toxicities, to evaluate th e pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intr aventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454 A12-rRA is a conjugate of a monoclonal antibody against the human tran sferrin receptor and recombinant ricin A chain, the enzymatically acti ve subunit of the protein toxin ricin. Patients were treated with sing le doses of 454A12-rRA ranging from 1.2 to 1200 mu g. RESULTS: The ear ly phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (C SF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than t he clearance of coinjected technetium-99m-diethylenetriamine penta-ace tic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degr adation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling t he concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 mu g of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 mu g caused a CSF inflammatory response that was associated with t ransient headache, vomiting, and altered mental status, This acute syn drome was responsive to steroids and CSF drainage. No systemic toxicit y was detected. In four of the eight patients, a greater than 50% redu ction of tumor cell counts in the lumbar CSF occurred within 5 to 7 da ys after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance ima ging evidence of tumor progression was demonstrated in seven of the ei ght patients after treatment. CONCLUSION: Tumoricidal concentrations o f the immunotoxin 454A12-rRA can be attained safely in the CSF of pati ents with leptomeningeal tumor spread.