Originally published as JCO Early Release 10.1200/JCO.2008.19.5677 on February 23 2009

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Phase I Trial of AEG35156 Administered as a 7-Day and 3-Day Continuous Intravenous Infusion in Patients With Advanced Refractory Cancer

From the Christie Hospital National Health Service Foundation Trust; Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester; Department of Oncology, University of Cambridge, Addenbrookes Hospital, Cambridge; Drug Development Office, Cancer Research UK, London, England; Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, Scotland; and Aegera Therapeutics Inc, Montreal, Québec, Canada.

Corresponding author: Malcolm Ranson, PhD, MBChB, Department of Medical Oncology, University of Manchester, Christie Hospital National Health Service Foundation Trust, Wilmslow Rd, Manchester, M20 4BX, England; e-mail: malcolm.ranson{at}christie.nhs.uk.

Purpose To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors.

Patients and Methods This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m²/d and continued until consistent dose-limiting toxicity (DLT) was observed.

Results Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m²/d for the 7DI regimen and 213 mg/m²/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity.

Conclusion In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non–small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.

Supported by Cancer Research UK, London, United Kingdom. E.D. was funded by a Cancer Research UK Studentship (Grant No. C237/A7819). K.C. was partly funded by Aegera Therapeutics and a Cancer Research UK Studentship (Grant No. C96/A4743).

Presented in part at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006 Atlanta, GA; and the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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