Scientific Publications by FDA Staff

Cancer Med 2015 Jul;4(7):1060-8

Phase I trial of systemic intravenous infusion of interleukin-13-Pseudomonas exotoxin in patients with metastatic adrenocortical carcinoma.

Liu-Chittenden Y, Jain M, Kumar P, Patel D, Aufforth R, Neychev V, Sadowski S, Gara SK, Joshi BH, Cottle-Delisle C, Merkel R, Yang L, Miettinen M, Puri RK, Kebebew E

Adrenocortical carcinoma (ACC) is a rare but lethal malignancy without effective current therapy for metastatic disease. IL-13-PE is a recombinant cytotoxin consisting of human interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin A (PE). The main objectives of this Phase I dose-escalation trial were to assess the maximum-tolerated dose (MTD), safety, and pharmacokinetics (PK) of IL-13-PE in patients with metastatic ACC. Eligible patients had confirmed IL-13 receptor alpha 2 (IL-13Ra2) expressions in their tumors. IL-13-PE at dose of 1-2 µg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1 µg/kg and two patients received 2 µg/kg of IL-13-PE. Dose-limiting toxicity was observed at 2 µg/kg, at which patients exhibited thrombocytopenia and renal insufficiency without requiring dialysis. PK analysis demonstrated that at MTD, the mean maximum serum concentration (Cmax ) of IL-13-PE was 21.0 ng/mL, and the terminal half-life of IL-13-PE was 30-39 min. Two (25%) of the eight patients had baseline neutralizing antibodies against PE. Three (75%) of the remaining four tested patients developed neutralizing antibodies against IL-13-PE within 14-28 days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5 months before disease progression; the others progressed within 1-2 months. In conclusion, systemic IV administration of IL-13-PE is safe at 1 µg/kg. All tested patients developed high levels of neutralizing antibodies during IL-13-PE treatment. Use of strategies for immunodepletion before IL-13-PE treatment should be considered in future trials.