title: 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.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu-Chittenden
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Meenu
authors.initials: M
authors.lastname: Jain
authors.affiliation: Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland.
authors.forename: Parag
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Dhaval
authors.initials: D
authors.lastname: Patel
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Aufforth
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Neychev
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Samira
authors.initials: S
authors.lastname: Sadowski
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sudheer K
authors.initials: SK
authors.lastname: Gara
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Bharat H
authors.initials: BH
authors.lastname: Joshi
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Candice
authors.initials: C
authors.lastname: Cottle-Delisle
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Merkel
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lily
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.affiliation: Tumor Vaccines and Biotechnology Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D036002:ADP Ribose Transferases; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000628:therapy; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000473:pathology* / Q000628:therapy; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001427:Bacterial Toxins; D005098:Exotoxins; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D018793:Interleukin-13; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019233:Retreatment; D016896:Treatment Outcome; D037521:Virulence Factors; D055815:Young Adult; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
keywords: IL-13-PE; Phase I; maximum-tolerated dose; metastatic adrenocortical carcinoma; pharmacokinetics; systemic administration