Phase I trial of intravenous IL-4 pseudomonas exotoxin protein (NBI-3001) in patients with advanced solid tumors that express the IL-4 receptor.
NBI-3001 is a novel immunotoxin of attenuated Pseudomonas exotoxin fused to circularly permutated IL-4, which has shown some antitumor effects in glioblastoma multiforme with intratumoral administration. The authors evaluated the safety and tolerability of NBI-3001 administered intravenously in a dose-escalation design to patients with renal cell and non-small cell lung carcinoma whose tumors showed at least 10% IL-4 receptor expression. Cohorts of three to six patients were treated at dose levels of 0.008, 0.016, and 0.027 mg/m2 daily x 5 days every 28 days. Neutralizing antibody (NAB) titers, plasma levels of NBI-3001, and patient tolerability were monitored sequentially. 14 patients received a total of 36 cycles of NBI-3001 (range 1-6). No dose-limiting toxicities were noted at dose levels 0.008 and 0.016 mg/m2. At 0.027 mg/m2, two patients developed self-limiting, grade 3 or 4 transaminase elevation during cycle 1. NAB titers of more than 1:100 were detected in five of the seven patients treated with at least two cycles; the median titer after cycle 1 and the median maximum titer in subsequent cycles were 1:50 and approximately 1:1,710, respectively. No objective tumor responses were noted. Eight of 12 evaluable patients with renal cell carcinoma had stable disease; four patients had disease progression. High NAB titers resulted in four patients being withdrawn from the study. The dose-limiting toxicity for intravenous NBI-3001 was transaminase elevation at 0.027 mg/m2. NBI-3001 at 0.016 mg/m2 was well tolerated. Low circulating levels of NBI-3001, coupled with rising NAB titers, may have contributed to the lack of response in tumors that express IL-4R.
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA. lgarland@azcc.arizona.edu
Linda
L
Garland
Barbara
B
Gitlitz
Scot
S
Ebbinghaus
Henry
H
Pan
Hans
H
de Haan
Raj K
RK
Puri
Daniel
D
Von Hoff
Robert
R
Figlin
D000368:Aged; D000917:Antibody Formation / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D005098:Exotoxins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015847:Interleukin-4 / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019948:Receptors, Interleukin-4 / Q000032:analysis*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D019948:Receptors, Interleukin-4; C479467:interleukin-4-Pseudomonas exotoxin; D015847:Interleukin-4