A phase I trial of AEG35156 (XIAP antisense) administered as 2-hour intravenous infusions in patients with advanced tumours

Abstract

3541 Background: The X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein. AEG35156 is a 2nd generation antisense oligonucleotide to human XIAP that enhances cancer cell apoptosis preclinically as a single agent and in combination with chemotherapeutics. Methods: The primary objective was to establish the maximum tolerated dose of AEG35156 given as a 2-hour infusion once weekly following 3 daily loading doses in week 1. Other objectives were to evaluate AEG35156 pharmacokinetics, XIAP inhibition, circulating apoptosis biomarkers and document anti-tumour activity. Results: Twenty-nine adult patients (16 M; 13 F) have been registered. Twenty-three have completed at least one 3-week treatment cycle at doses ranging from 60 to 500mg AEG35156. Treatment has been generally well tolerated, the most common toxicities have been grade I chills/pyrexia, rapidly reversible increases in aPTT at the end of infusion and mild transaminitis. One patient at 240mg had a silent myocardial infarction probably related to prophylactic aspirin withdrawal prior to starting protocol therapy. Three DLTs were observed at AEG35156 350mg: Grade 3 chills/lethargy (mesothelioma), grade 3 transaminitis (colon), transient grade 3 chills/tumour lysis syndrome/transaminitis (small lymphocytic lymphoma). A less intensive dosing protocol was deemed appropriate for future NHL patients and a protocol amendment excluding NHL patients from this study and permitting resumption in patients with solid tumors and including premedication with dexamethasone / acetaminophen was implemented. Dosing at AEG35156 500mg has been completed with no DLTs and the study is ongoing at 650mg. Pharmacokinetics were dose-proportional and linear from 60 to 500mg AEG35156. Mean plasma Cmax at 500mg was 55μg/mL. Decreases in XIAP mRNA have been observed in PBMCs at dose levels ≥240mg and increased levels of circulating biomarkers of apoptosis have been observed in some patients. One patient with NHL who received only a single infusion had rapid clearance of circulating tumour cells and reduction in nodal disease. Conclusions: AEG35156 can be safely delivered by 2-hour infusions and preliminary evidence of XIAP mRNA knockdown and antitumour activity in lymphoma has been observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Aegera Therapeutics Inc. Aegera Therapeutics Inc. Aegera Therapeutics Inc. Aegera Therapeutics Inc.