Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas

• Published in: Neurosurgery Vol. 85; no. 4; pp. E641 - E649
• Main Authors: Patil, Chirag G, Walker, David G, Miller, Dennis M, Butte, Pramod, Morrison, Beth, Kittle, David S, Hansen, Stacey J, Nufer, Kaitlin L, Byrnes-Blake, Kelly A, Yamada, Miko, Lin, Lynlee L, Pham, Kim, Perry, Jeff, Parrish-Novak, Julia, Ishak, Laura, Prow, Tarl, Black, Keith, Mamelak, Adam N
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2019; Copyright by the Congress of Neurological Surgeons; Wolters Kluwer Health, Inc
• Subjects: Adult; Aged; Brain cancer; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - metabolism; Brain Neoplasms - surgery; Brain tumors; Dose-Response Relationship, Drug; Female; Fluorescence; Fluorescent Dyes - administration & dosage; Fluorescent Dyes - pharmacokinetics; Glioma; Glioma - diagnostic imaging; Glioma - metabolism; Glioma - surgery; Gliomas; Humans; Indocyanine Green - administration & dosage; Indocyanine Green - analogs & derivatives; Indocyanine Green - pharmacokinetics; Injections, Intravenous; Male; Medical diagnosis; Middle Aged; Neoplasm Recurrence, Local - diagnostic imaging; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - surgery; Neurosurgery; Optical Imaging - methods; Pharmacokinetics; Scorpion Venoms - administration & dosage; Scorpion Venoms - pharmacokinetics; Surgery; Tumors; Australia; Fluorescent dyes; Brain neoplasms; Craniotomy; Glioma; Cystine-knot miniproteins
• ISSN: 0148-396X; 1524-4040; 1524-4040
• DOI: 10.1093/neuros/nyz125

Abstract BACKGROUND Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. OBJECTIVE To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. METHODS Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. RESULTS A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. CONCLUSION These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas. Graphical Abstract Graphical Abstract