title: 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.affiliation: Division of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA. samps001@mc.duke.edu
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Gamal
authors.initials: G
authors.lastname: Akabani
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kunwar
authors.forename: Steve
authors.initials: S
authors.lastname: Marcus
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Alison
authors.initials: A
authors.lastname: Paolino
authors.forename: Kara
authors.initials: K
authors.lastname: Penne
authors.forename: James
authors.initials: J
authors.lastname: Provenzale
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quinn
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Jeremy
authors.initials: J
authors.lastname: Rich
authors.forename: Timothy
authors.initials: T
authors.lastname: Stenzel
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: Carol
authors.initials: C
authors.lastname: Wikstrand
authors.forename: Terence
authors.initials: T
authors.lastname: Wong
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: Fan
authors.initials: F
authors.lastname: Yuan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D004353:Drug Evaluation, Preclinical; D005098:Exotoxins / Q000008:administration & dosage*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D015996:Survival Rate; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha