Article

Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer.

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, UK.
Journal of Clinical Oncology (impact factor: 18.37). 03/2009; 27(10):1660-6. DOI:10.1200/JCO.2008.19.5677 pp.1660-6
Source: PubMed

ABSTRACT 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.
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/m(2)/d and continued until consistent dose-limiting toxicity (DLT) was observed.
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/m(2)/d for the 7DI regimen and < or = 213 mg/m(2)/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.
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.

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Keywords

3DI schedule
 
4 adverse events
 
7 days
 
abnormal laboratory values
 
acute myeloid leukemia
 
AEG35156 chemotherapy combinations
 
antitumor activity
 
breast cancer
 
Circulating biomarkers
 
consistent dose-limiting toxicity
 
dramatic decrease
 
hepatic enzymes
 
maximum-tolerated dose
 
maximum-tolerated doses
 
non-small-cell lung cancer
 
Phase I/II trials
 
predictable toxicities
 
refractory malignant tumors
 
second-generation antisense
 
XIAP mRNA levels