title: Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma.
abstract: Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: A
authors.initials: A
authors.lastname: Rakhit
authors.forename: L H
authors.initials: LH
authors.lastname: Schwartz
authors.forename: T
authors.initials: T
authors.lastname: Olencki
authors.forename: T M
authors.initials: TM
authors.lastname: Malone
authors.forename: K
authors.initials: K
authors.lastname: Sandstrom
authors.forename: R
authors.initials: R
authors.lastname: Nadeau
authors.forename: H
authors.initials: H
authors.lastname: Parmar
authors.forename: R
authors.initials: R
authors.lastname: Bukowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12