Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma

Purpose: The purpose is to determine dose-limiting toxicity, pharmacokinetics, pharmacodynamics, and immunobiology after i.p. injections of recombinant human IL-12 (rhIL-12). Experimental Design: rhIL-12 was administered to 29 previously treated patients with peritoneal carcinomatosis from Müllerian carcinomas, gastrointestinal tract carcinomas and peritoneal mesothelioma in a Phase I trial. rhIL-12 doses were increased from 3 to 600 ng/kg. Three or more patients at each level received weekly i.p. injections of rhIL-12. Results: Dose-limiting toxicity (elevated transaminase) occurred in 2 of 4 patients at the 600 ng/kg dose. More frequent toxicities included fever, fatigue, abdominal pain, nausea, and catheter-related infections. Ten patients received 300 ng/kg with acceptable frequency and severity of side effects. Two patients (one with ovarian cancer and one with mesothelioma) had no remaining disease at laparoscopy. Eight patients had stable disease and 19 progressive disease. At 300 ng/kg i.p., IL-12 was cleared from peritoneal fluid in a biphasic manner with a terminal-phase half-life of 18.7 h; peritoneal fluid levels of IL-12 5 min after i.p. injection were 100-200 pg/ml, and serum levels reached ∼10 pg/ml between 24 and 36 h. IL-1-α, IL-2, IL-10, tumor necrosis factor α, and IFN-γ, were determined in serum and peritoneal fluid. IFN-γ, IL-10, and tumor necrosis factor α were detected most frequently. Immunobiological effects included peritoneal tumor cell apoptosis, decreased tumor cell expression of basic fibroblast growth factor and vascular endothelial growth factor, elevated IFN-γ, and IFN-inducible protein 10 transcripts in peritoneal exudate cells, and increased proportions of peritoneal CD3⁺ relative to CD14⁺ cells. Conclusions: rhIL-12 at 300 ng/kg by weekly i.p. injection is biologically active and adequately tolerated for Phase II studies.