Phase i trial of AEG35156 an antisense oligonucleotide to xiap plus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma

OBJECTIVES:: 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 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 given on days 1, 8, and 15 every 28 days. AEG35156 plus gemcitabine failed to show significant clinical activity in advanced PDA.