Objective: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity.
Methods: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms.
Results: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment.
Conclusion: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.