PHASE-I CLINICAL-STUDY OF THE RECOMBINANT ONCOTOXIN TP40 IN SUPERFICIAL BLADDER-CANCER

Transforming growth factor alpha-Pseudomonas exotoxin-40 (TP40) is a h ybrid fusion protein that selectively binds to cancer cells that expre ss the epidermal growth factor receptor, TP40 is then internalized and kills these cells by virtue of its Pseudomonas exotoxin-derived domai ns, We studied the safety and short-term antitumor activity of intrave sical TP40 in 43 patients with refractory superficial bladder cancer, These patients had resected T-a/T-1 disease (n = 19), visible T-a or T -1 lesions (n = 11), or carcinoma in situ (n = 13), Patients were trea ted with increasing dose levels of TP40 at 0.15, 0.3, 0.6, 1.2, 2.4, 4 .8, or 9.6 mg/week for 6 weeks and evaluated by comparing pretreatment and posttreatment cystoscopic examinations, cytology, and histopathol ogy, All TP40 doses were well tolerated, No evidence of antitumor acti vity was seen in any of the patients with T-a or T-1 lesions, However, 8 of 9 patients with evaluable carcinoma in situ were judged by histo pathology of multiple biopsy specimens to exhibit clinical improvement following TP40 therapy, In most of these responsive patients, cystosc opic examination supported the histopathological findings, although cy tology of urine and bladder washings persistently demonstrated maligna nt cells, Therefore, TP40 appears to be a well-tolerated biological ag ent that may prove to have utility in treating carcinoma in situ of th e bladder.