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

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 (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.

• Authors: Yi Liu-Chittenden, Meenu Jain, Parag Kumar, Dhaval Patel, Rachel Aufforth, Vladimir Neychev, Samira Sadowski, Sudheer K Gara, Bharat H Joshi, Candice Cottle-Delisle, Roxanne Merkel, Lily Yang, Markku Miettinen, Raj K Puri, Electron Kebebew
• Journal: Cancer medicine (Cancer Med) Vol. 4 Issue 7 Pg. 1060-8 (Jul 2015) ISSN: 2045-7634 [Electronic] United States
• PMID: 25767039 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Neutralizing
• Antineoplastic Agents
• Bacterial Toxins
• Exotoxins
• Interleukin-13
• Recombinant Fusion Proteins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A

Topics

• ADP Ribose Transferases
• Adolescent
• Adrenal Cortex Neoplasms (drug therapy, pathology, therapy)
• Adrenocortical Carcinoma (drug therapy, pathology, therapy)
• Adult
• Aged
• Antibodies, Neutralizing (blood)
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Bacterial Toxins
• Exotoxins
• Female
• Humans
• Infusions, Intravenous
• Interleukin-13
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Metastasis
• Recombinant Fusion Proteins (administration & dosage, adverse effects, pharmacokinetics)
• Retreatment
• Treatment Outcome
• Virulence Factors
• Young Adult