In a Phase I/II study of Trabedersen (OT-101), a phosphorothioate antisense specific for human TGF- β2 mRNA, patients with advanced pancreatic cancer (PAC) treated in the 2nd-line and beyond exhibited improved overall survival (OS) when OT-101 was followed with chemotherapy. Here, we examined the association between plasma levels of cyto-/chemokines and OS outcomes to identify potential biomarkers for improved OS.
37 PAC patients were treated with continuous IV infusion in escalating doses of 2 treatment schedules (7-days-on, 7-days-off and 4-days-on, 10-days-off). Plasma levels of 31 cyto-/chemokines were measured at 8 separate time points over 3 cycles of OT-101 treatment (140 mg/m2/day, 4-days-on, 10-days-off). Standardized maximum levels of individual cyto-/chemokines on Day 2 were subtracted from levels on Day 5 of each cycle of treatment and correlated with log10 transformed OS values. Feedback interactions with PK parameters were also investigated utilizing an ANCOVA model.
A median OS of 14.5 months and 2.6 months was observed for 2nd-line patients treated with and without subsequent chemotherapies, respectively (p = 0.0009). Increasing difference of IL-8 levels at Day 2 vs Day 5 was positively correlated with OS (R2 = 0.58, P = 0.0066). Stratifying for patients with and without chemo, R2 increased to 0.99 and 0.77 respectively. Similar results were observed for IL-15, with R2 = 0.93 in patients with chemo and R2 = 0.50 in those without. ANCOVA models for two PK parameters exhibited significant model fits (F3,7 = 7.89, P = 0.012 for Simulated Vz Mean; F3,7 = 8.18, P = 0.011 for Simulated Cl Mean) and the interaction effects resulted in lower p-values for the correlation of OS vs IL-8 levels.
Increasing peak levels of IL-8 and IL-15 response on Day 2 of OT-101 treatment correlated with OS in PAC patients. This correlation with OS was evident regardless of subsequent chemotherapy or not indicating spikes in IL-8 and IL-15 as potential biomarkers for OT-101.
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L. Hwang, W. Wang, S. Qazi, K. Ng, O. D’cruz, V. Trieu: Employee