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

Cancer Medicine

Yi Liu-Chittenden³  Meenu Jain³  Parag Kumar¹  Dhaval Patel³  Rachel Aufforth³  Vladimir Neychev³  Samira Sadowski³  Sudheer K. Gara³  Bharat H. Joshi²  Candice Cottle-Delisle³  Roxanne Merkel³  Lily Yang³  Markku Miettinen⁴  Raj K. Puri² 

[1] Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland;Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland;Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

关键词: IL‐13‐PE;    maximum‐tolerated dose;    metastatic adrenocortical carcinoma;    pharmacokinetics;    Phase I;    systemic administration;   

DOI  :  10.1002/cam4.449

来源: Wiley

【 摘 要 】

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 1–2 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 (C_max) 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.

【 授权许可】

CC BY   
© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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