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.
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.
Sampson
John H
JH
Division of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA. samps001@mc.duke.edu
Akabani
Gamal
G
Archer
Gary E
GE
Bigner
Darell D
DD
Berger
Mitchel S
MS
Friedman
Allan H
AH
Friedman
Henry S
HS
Herndon
James E
JE
Kunwar
Sandeep
S
Marcus
Steve
S
McLendon
Roger E
RE
Paolino
Alison
A
Penne
Kara
K
Provenzale
James
J
Quinn
Jennifer
J
Reardon
David A
DA
Rich
Jeremy
J
Stenzel
Timothy
T
Tourt-Uhlig
Sandra
S
Wikstrand
Carol
C
Wong
Terence
T
Williams
Roger
R
Yuan
Fan
F
Zalutsky
Michael R
MR
Pastan
Ira
I
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
D005098:Exotoxins; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha