title: Phase I trial of AEG35156 administered as a 7-day and 3-day continuous intravenous infusion in patients with advanced refractory cancer.
abstract: OBJECTIVE
  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.
  
  
  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/m(2)/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/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Dean
authors.forename: Duncan
authors.initials: D
authors.lastname: Jodrell
authors.forename: Kate
authors.initials: K
authors.lastname: Connolly
authors.forename: Sarah
authors.initials: S
authors.lastname: Danson
authors.forename: Jacques
authors.initials: J
authors.lastname: Jolivet
authors.forename: Jon
authors.initials: J
authors.lastname: Durkin
authors.forename: Stephen
authors.initials: S
authors.lastname: Morris
authors.forename: Debra
authors.initials: D
authors.lastname: Jowle
authors.forename: Tim
authors.initials: T
authors.lastname: Ward
authors.forename: Jeff
authors.initials: J
authors.lastname: Cummings
authors.forename: Gemma
authors.initials: G
authors.lastname: Dickinson
authors.forename: Leon
authors.initials: L
authors.lastname: Aarons
authors.forename: Eric
authors.initials: E
authors.lastname: Lacasse
authors.forename: Lesley
authors.initials: L
authors.lastname: Robson
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000187:drug effects / Q000235:genetics
chemical_list: C498209:AEG 35156; D000970:Antineoplastic Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human