Pharmacodynamic (PD) evaluation of LY2181308 in patients with metastatic malignancies

Abstract

3507 Background: Survivin is an inhibitor of apoptosis and its overexpression in cancer has been associated with poor survival. LY2181308 (LY), a novel modified antisense oligonucleotide is a specific inhibitor of survivin. The safety and PK profile of LY from this first-in-human study was presented at ASCO 2008. We now present the PD data from this trial. Methods: Patients with advanced or metastatic malignancies who had failed previous anti-tumor treatments were enrolled. Three consecutive IV loading doses given over 3 hours were followed by weekly maintenance doses. Pre- and post-dosing biopsies were mandated to test for evidence of modification of the target at doses where a PD effect was expected. Biopsies were taken 48 hours after the last loading dose by CT-guided fine needle biopsy. Tumor tissue was paraffin-embedded for immunohistochemistry (IHC) and survivin gene expression. Given the finite amount of biopsy material, the quantification of survivin protein was prioritized. In addition, at one site, pre- and post-dosing endobronchial sampling was conducted in NSCLC patients, with the aim of quantifying levels of native survivin protein, and assessing changes in cell cycle profile in freshly isolated tumor cells using FACS analysis. Results: Out of the 34 patients enrolled, 22 patients had a pre- and posttreatment biopsy. Results from IHC indicated that survivin expression was reduced in the nucleus and cytoplasm in 11/17 and 5/14 evaluable pairs, respectively. LY was detected in neoplastic and non-neoplastic tumor cells in 5/16 and 15/16 evaluable pairs respectively. Gene expression analysis indicated a reduction in survivin expression by 20% to 50% in 11/15 evaluable pairs. Analysis of the fresh tumor material from endobronchial sampling revealed that 2 out of 3 patients with NSCLC had a near-complete elimination of survivin-positive cells accompanied by an increase in the fraction of cells with a sub-G1 DNA content, consistent with cell death. Conclusions: In this study, we were able to demonstrate the presence of the ASO in tumor tissue and confirm a reduction in survivin protein and gene expression. These findings demonstrate the proof of principle of antitumor activity of LY and provide the rationale for phase II studies. [Table: see text]

Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin

“…Gene expression analysis indicated a reduction in survivin expression of 20-50% in 11 of 15 evaluable pairs. Analysis of fresh tumor from endobronchial sampling revealed that 2 of 3 NSCLC patients had a near-complete elimination of survivin-positive cells accompanied by an increase in the fraction of cells with a sub-G1 DNA content, consistent with cell death [ 106 ]. Furthermore, a human micro-dosing imaging PK study of an ASO with LY2181308 using carbon-11 radiolabeled LY2181308 ([ 11 C]LY2181308) was conducted.…”

Oligonucleotide-Based Drug Development: Considerations for Clinical Pharmacology and Immunogenicity

“…18 –20 Various studies have demonstrated the antisense effect of ASOs and the effective reduction of target expression. 13,19,21 Pharmacologic effects of ASOs are certainly related directly to drug concentrations in the target organ. Studies have shown that ASO plasma concentrations in the postdistribution phase correlate with target tissue concentrations and can serve as a surrogate measure of target tissue concentrations for further correlation analysis with PD endpoint.…”

“…These issues relate to the achievement of effective intracellular concentrations and the relationship of intracellular concentrations to the drug plasma levels, PD response, clinical efficacy, and safety. 21,25,26…”