Phase I portion of the phase I-II study of the X-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).

Abstract

e14519 Background: The X-linked Inhibitor of Apoptosis (XIAP) inhibits caspases 3, 7 and 9 which are proteases responsible for apoptotic cell death. XIAP has been shown to be highly expressed in HCC and is a potential therapeutic target. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA which lowers the apoptotic threshold of cancer cells and also accumulates in the liver. We report on the Phase I portion of a study which determined the recommended dose of AEG35156 administered in combination with sorafenib in patients with advanced HCC. Methods: Patients with histologically or clinically diagnosed HCC satisfying AASLD Criteria who had failed or were unsuitable for curative therapy were enrolled. The initial dose of AEG35156 was 100 mg administered by 2-hour infusion once weekly and escalated to 200 and 300 mg in the second and third cohorts. Three patients were initially entered at each dose level with additional patients added at the recommended dose. All patients received standard daily sorafenib at 400 mg BID. One cycle of therapy was 21 days. Dose-limiting toxicity was defined in cycle 1 as patients with any drug related grade 4 neutropenia or thrombocytopenia lasting > 7 days, febrile neutropenia or any grade 3 or 4 major organ toxicity except alopecia or nausea/vomiting. Results: A total of 13 patients were recruited with 3 patients treated in each of the first two cohorts and 7 patients treated with 300 mg of AEG35156. All patients were hepatitis B positive, 12/13 were male with an age range of 35 to 66, 10/13 patients had stage IVB disease and 12 were Child-Pugh A with one B. No DLT was observed. Common toxicities included hand foot skin reaction, fatigue, diarrhea, and anorexia. Encouraging signs of clinical efficacy were seen at AEG35156 doses ≥ 200 mg. Conclusions: AEG35156 is well tolerated in combination with sorafenib in patients with advanced HCC. The phase II portion of this study is ongoing with 48 patients being randomized (2:1) to receive either AEG35156 at 300 mg in combination with sorafenib or sorafenib alone. Efficacy will be evaluated based on progression-free survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aegera Therapeutics Aegera Therapeutics