First human dose study evaluating safety and pharmacokinetics of LY2181308, an antisense oligonucleotide designed to inhibit survivin

Abstract

Listen

Translate article

3518 Background: Survivin is a member of the inhibitors of apoptosis proteins (IAP) family, which are generally expressed in tumor but not in normal differentiated cells. LY2181308, a novel 2’-O-methoxymethyl modified anti-sense oligonucleotide (2-MOE-ASO), is a specific inhibitor of survivin mRNA. Methods: Patients who had exhausted all effective anti-tumor therapies were enrolled in this study consisting of 3 parts. Part A consisted of 1-patient cohorts and a dose escalation of 100% to the anticipated biological effective dose range; Part B enrolled 3-patient cohorts with pre- and post-dosing tumor biopsies to determine PD effects including intra-tumoral ASO and survivin using immunocytochemistry and branched chain DNA analysis for survivin mRNA; Part C consisted of an expansion cohort with pre- and post-dosing biopsies. The treatment schedule consisted of 3 consecutive daily 3-hour intravenous (iv) loading doses followed by weekly iv maintenance doses. Results: 24 patients were enrolled in the study all of whom were evaluable for safety and PK up to the 1000 mg dose. The maximum tolerated dose was 750 mg. The PK was consistent with other 2-MOE-ASOs. LY2181308 was rapidly distributed into tissues with 90% of the plasma exposure cleared through tissue distribution within 24 hours. Plasma profiles were adequately described by the pre-clinical three-exponential disposition PK model. The half-lives of these disposition phases were 30 to 60 minutes, 2 to 3 hours and 15 to 25 days, respectively. LY2181308 plasma clearance was approximately 2.66 L/h (geomean with coefficient of variation <30%) corresponding to a mean exposure of about 280–300 μg.h/mL and a mean Cmax of about 61 μg/mL (CV 23 %) following a 750 mg dose. The most frequent adverse events were a transient prolongation of aPTT (not associated with bleeding) and flu-like symptoms. The vast majority of the events observed up to 750 mg were mild to moderate according to the CTCAE severity grading. No drug-related CTCAE grade 3 and 4 was observed at the 750 mg dose. Conclusions: LY2181308 showed a safety and PK profile consistent with previously described 2- MOE-ASOs. Based on the favourable toxicity profile of LY2181308, further single agent and combination studies are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly