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Cancer medicine

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


PMID 25767039

Abstract

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-13Rα2) expressions in their tumors. IL-13-PE at dose of 1-2xa0μg/kg was administered intravenously (IV) on day 1, 3, and 5 in a 4-week cycle. Six patients received 1xa0μg/kg and two patients received 2xa0μg/kg of IL-13-PE. Dose-limiting toxicity was observed at 2xa0μg/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 21.0xa0ng/mL, and the terminal half-life of IL-13-PE was 30-39xa0min. 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 14-28xa0days of initial treatment. Of the five patients treated at MTD and assessed for response, one patient had stable disease for 5.5xa0months before disease progression; the others progressed within 1-2xa0months. In conclusion, systemic IV administration of IL-13-PE is safe at 1xa0μg/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.