title: Phase I trial of AEG35156 an antisense oligonucleotide to XIAP plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma.
abstract: OBJECTIVE
  AEG35156 is an antisense oligonucleotide (ASO) that targets the X-linked inhibitor of apoptosis mRNA. Preclinical studies showed potent activity of AEG35156 in combination with gemcitabine in pancreatic ductal adenocarcinoma (PDA). A phase I study was conducted to establish the maximum-tolerated dose, safety, and antitumor activity of AEG35156 plus gemcitabine in metastatic PDA.
  
  
  METHODS
  Fourteen patients with metastatic PDA were enrolled. Nine patients were treated at 350 mg IV and 5 patients at 500 mg IV of AEG35156, 3 weeks on/1 week off of a 28-day cycle. Gemcitabine was administered at 1000 mg/m(2) IV over 30 minutes immediately after AEG35156 in both groups. Because of perceived neurotoxicity dose deescalation to 350 mg was recommended.
  
  
  RESULTS
  All 14 patients were evaluable for tolerability and toxicity. Toxicities include neutropenia (grade 3/4, 6 patients), thrombocytopenia (grade 3, 2 patients), peripheral neuropathy (grade 3, 2 patients), fatigue (grade 3, 4 patients), ascites (grade 3, 2 patients), and nausea/vomiting (grade 4, 2 patients). Five patients (45%) experienced stable disease with a median progression-free survival of 58 days (95% CI, 52-107 d).
  
  
  CONCLUSIONS
  The maximum-tolerated dose is AEG35156 500 mg plus gemcitabine 1000 mg/m(2) given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA.
authors.affiliation: Arizona Cancer Center, Tucson, AZ 85724, USA. dmahadevan@azcc.arizona.edu
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.forename: Pavani
authors.initials: P
authors.lastname: Chalasani
authors.forename: Diane
authors.initials: D
authors.lastname: Rensvold
authors.forename: Sandy
authors.initials: S
authors.lastname: Kurtin
authors.forename: Chris
authors.initials: C
authors.lastname: Pretzinger
authors.forename: Jacques
authors.initials: J
authors.lastname: Jolivet
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009841:Oligonucleotides / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015996:Survival Rate; D016896:Treatment Outcome; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: C498209:AEG 35156; D000964:Antimetabolites, Antineoplastic; D009841:Oligonucleotides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine