Circulating VEGF levels as a biomarker to clinical benefit to PTC299, the first inhibitor of VEGF synthesis.

Abstract

e13588 Background: Solid tumor growth is dependent on angiogenesis, a process mediated primarily by vascular endothelial growth factor (VEGF). Currently approved anti-angiogenic agents sequester VEGF or block activation of VEGF receptors. Despite extensive investigations, no reliable biomarkers have been identified for these agents. PTC299 is an investigational oral small molecule that differs from existing therapies by inhibiting VEGF synthesis at the translational level while conserving physiologic VEGF expression. Methods: A phase 1b clinical trial is evaluating PTC299 monotherapy (36 pts) or in combination with docetaxel (10 pts) from 0.3 mg/kg to 600 mg bid in patients with advanced incurable cancer. Serum VEGF was assessed at baseline and during therapy. The maximum on‑treatment reduction in VEGF at any post-baseline visit was used for a stratified analysis. Decreases in VEGF, defined as <10% (low) and ≥10% (high), identified the strata. Duration of therapy was used as a surrogate for stable disease in a Kaplan‑Meier analysis. Results: The study enrolled 46 patients (20 males; 26 females; median age: 62 years). Patients with lower VEGF reductions while on therapy (<10%, n=12) had a median duration of stable disease of 5.3 weeks while patients with greater maximal VEGF reductions (≥10%, n=31) had significantly longer stable disease (median 12.0 weeks, log-rank p<0.001). VEGF decreases were greater in patients with higher baseline values. No Grade 3 or 4 hypertension, bleeding, or proteinuria occurred. One patient had an acute liver injury. Conclusions: Reductions in circulating VEGF are associated with prolonged duration of anti-angiogenic therapy and stable disease. Results are consistent with preclinical experiments and support the hypothesis that PTC299 does not affect physiologic VEGF but inhibits pathologic VEGF. In this study, oral administration of PTC299 as monotherapy or in combination with docetaxel therapy has been generally well tolerated at all doses tested.