Safety and tolerance of multiple weekly intracavitary injections of I-chlorotoxin (TM-601): Preliminary results of a prospective clinical trial in patients with recurrent glioblastoma multiforme
J. B. Fiveash, L. B. Nabors, A. N. Mamelak, N. G. Avgeropoulos, B. L. Guthrie, N. W. Salomon, J. Portnow and R. D. Bucholz

University of Alabama at Birmingham, Birmingham, AL; Cedars-Sinai Medical Center, Los Angeles, CA; Florida Hospital, Orlando, FL; Transmolecular, Inc., Cambridge, MA; Saint Louis University, Saint Louis, MO. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, No 18S (June 20 Supplement), 2006: 1555

Background: I-chlorotoxin is a peptide originally derived from scorpion venom that will specifically bind to tumor cells targeting lamellipodia and produces a variety of secondary messenger effects through phosphatidyl inositol signaling. Preclinical studies suggest it is both a radiation and chemotherapy sensitizer. A previous phase I/II clinical trial defined the distribution and dosimetry of single injection intracavitary 131I-chlorotoxin and suggested clinical activity in patients with recurrent glioma. Methods: 15 patients with recurrent GBM after prior treatment (radiation therapy), were enrolled in this sequential, multiple-dose escalation study with re-resection and implantation of a ventricular access device (VAD) into the resection cavity. Dose limiting toxicity was defined as any grade 3 or greater toxicity judged probably related to study drug and occurring within 7–11 days of the last dose. Dosing cohorts of 3–5 patients were entered at each of the listed dose levels designed to maintain a constant drug specific activity. Results: One subject did not complete treatment due to thrombocytopenia possibly related to a VAD infection necessitating removal of the VAD following the initial dose of study drug. Eight serious adverse events (SAEs) were observed in 15 patients after study drug administration. These included seizure, cerebral edema, and gait disturbances. None were judged to be both unexpected and related to study drug. No dose limiting toxicity was observed. Two subjects experienced Grade 1/2 CTC 3.0 neutropenia. Conclusions: The safety profile of weekly intracavitary injections of I-chlorotoxin was acceptable. Dose limiting toxicity was not reached at the final planned dose level D (6 x 40 mCi/0.8 mg peptide, total 240 mCi), which is the maximum practical dose. Accrual to the randomized phase II portion of this trial comparing three vs. six weekly injections began 12/2005.

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