title: Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder.
abstract: Superficial transitional cell carcinoma (STCC) of the bladder is usually managed with intravesical bacille Calmette-Guerin. Recombinant human interleukin-12 (rhIL-12) is a heterodimeric cytokine that induces T-cell and natural killer cell proliferation/activation and production of IFNgamma. It has demonstrated preclinical in vivo bladder antitumor activity and no systemic toxicity. This phase 1 study evaluated intravesical rhIL-12 administration in patients with STCC (Tis, Ta, or T1) who had failed at least one prior intravesical therapy or had at least two recurrences of low-grade tumors. Eligible patients had adequate hematologic, renal, and hepatic function and Karnofsky performance status at least 70%. Cohorts of three patients received 5, 20, 50, 100, and 200 microg rhIL-12 (treated n = 15). Each patient received intravesical rhIL-12 weekly for 6 weeks, with a 2-hour bladder dwell. No patient experienced moderate, severe, or life-threatening systemic toxicity. Treatment-related adverse events included dysuria, urinary frequency, urinary urgency, asthenia, pain, hematuria, bladder spasms, and chills. Specific AE incidences were not dose-related. Among 12 patients without visible pretreatment lesions, 7 remained disease-free and 5 experienced recurrence of STCC within the 4-week follow-up period. Three patients with pretreatment Tis or Ta/T1 lesions had persistent disease at posttreatment follow-up. No patients with persistent tumor manifested antitumor response to rhIL-12. Two-hour dwell urine samples and 24- to 30-hour postdose serum samples showed negligible induction of IFNgamma. In summary, intravesical rhIL-12 was well tolerated by patients with recurrent STCC but showed no clinically relevant evidence of antitumor or immunologic effects.
authors.affiliation: The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA. GEOFFREY.WEISS@med.va.gov
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Weiss
authors.forename: Michael A
authors.initials: MA
authors.lastname: O'Donnell
authors.forename: Kevin
authors.initials: K
authors.lastname: Loughlin
authors.forename: Kristilyn
authors.initials: K
authors.lastname: Zonno
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Laliberte
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Sherman
mesh_terms: D000283:Administration, Intravesical; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D002455:Cell Division; D015331:Cohort Studies; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12