Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

Abstract

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

• Authors: John H Sampson, Gamal Akabani, Gary E Archer, Darell D Bigner, Mitchel S Berger, Allan H Friedman, Henry S Friedman, James E Herndon 2nd, Sandeep Kunwar, Steve Marcus, Roger E McLendon, Alison Paolino, Kara Penne, James Provenzale, Jennifer Quinn, David A Reardon, Jeremy Rich, Timothy Stenzel, Sandra Tourt-Uhlig, Carol Wikstrand, Terence Wong, Roger Williams, Fan Yuan, Michael R Zalutsky, Ira Pastan
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 65 Issue 1 Pg. 27-35 (Oct 2003) ISSN: 0167-594X [Print] United States
• PMID: 14649883 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Exotoxins
• Recombinant Fusion Proteins
• Transforming Growth Factor alpha

Topics

• Adult
• Aged
• Brain Neoplasms (drug therapy, mortality)
• Drug Evaluation, Preclinical
• Exotoxins (administration & dosage)
• Female
• Glioblastoma (drug therapy, mortality)
• Humans
• Infusions, Parenteral
• Male
• Maximum Tolerated Dose
• Middle Aged
• Pseudomonas aeruginosa (chemistry)
• Recombinant Fusion Proteins (administration & dosage)
• Survival Rate
• Transforming Growth Factor alpha (administration & dosage)
• Treatment Outcome