Abstract B2: Results of a phase 1b study of PTC299, a novel oral inhibitor of tumor VEGF expression, in patients with advanced cancer

Background: PTC299 is a novel, orally bioavailable, small molecule designed to inhibit the expression of tumor‐derived VEGF and other angiogenic cytokines. In multiple xenograft models of human cancers, single‐agent PTC299 decreases tumor and plasma VEGF levels and induces significant tumor regression or growth delay. Methods: A Phase 1b study has been initiated with 3 stages, each using a classic 3+3 design. In Stages 1 and 2, patients received PTC299 monotherapy in repeated 6‐week cycles (Stage 1: 4 weeks on and 2 weeks off therapy with body‐weight‐adjusted BID dosing; Stage 2: continuous therapy with unit BID or TID dosing). In Stage 3, unit dosing PTC299 is administered with docetaxel. In all stages, treatment was given until disease progression or unacceptable toxicity. Safety, PK, PD activity, and antitumor activity have been assessed. Results: The study has enrolled 18 subjects (6 males, 12 females) with median [range] age 61 [31–81] years, ECOG performance status of 0 (n=10) or 1 (n=8), 9 different tumor types, and median [range] of prior therapies of 3 [0–8] to receive PTC299 in Stage 1 (n=12) and Stage 2 (n=6). Median [range] of time on treatment has been 2 [1–7] cycles. No maximum tolerated dose (MTD) has been established through the highest dose levels tested: Stage 1, 1.2 mg/kg/dose BID and Stage 2, 100 mg/dose TID. Adverse events have been infrequent, usually Grade 1, and have not generally been considered PTC299‐related. No hypertension has been observed. PTC299 pharmacokinetics is generally dose proportional, with rapid appearance of drug in plasma, T max of ∼4 hours, and an effective t 1/2 of ∼12 hours. From Day 1 to Day 28 in Stage 1 (Day 42 in Stage 2), there has been an increase in plasma concentrations at all dose levels, indicating accumulation (∼2 fold) when PTC299 is dosed continuously. PTC299 trough plasma concentrations have exceeded values of 0.5–1.0 g/mL associated with maximal activity in mouse xenograft models. PTC299 treatment has been associated with reductions in circulating angiogenic/inflammatory cytokines. Five of eighteen (28%) patients with thyroid cancer, melanoma, basal cell carcinoma, and chondrosarcoma (2) have remained on study with stable disease for 11+, 4.5, 5, 6+, and 4.5+ months respectively. A patient with papillary thyroid cancer has had a sustained tumor marker decrease of >50% lasting for >7 months. Discussion: Single‐agent PTC299 has been well tolerated, has achieved target plasma concentrations, and has shown evidence of pharmacodynamic and clinical activity. Accrual to Stage 3 with docetaxel has been initiated. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B2.