Phase Ib study of PTC299, a novel oral inhibitor of tumor VEGF expression, in patients with advanced cancer.

Abstract

3041 Background: PTC299 is a novel, oral investigational drug designed to inhibit tumor expression of VEGF and other angiogenic cytokines. PTC299–administered alone or in combination with taxanes–has shown antitumor activity in multiple xenograft models of human cancers. Methods: A phase Ib study comprised 3 stages, each using a classic 3+3 design. In stage 1, monotherapy was given 4 weeks on and 2 weeks off using body-weight-adjusted BID dosing. In stage 2, monotherapy was given continuously with unit BID or TID dosing. In stage 3, PTC299 was given with docetaxel, 75 mg/m2. Treatment was given until disease progression. Safety, PK, and activity were assessed. Results: The study enrolled 27 subjects (9 males, 18 females) with median [range] age 59 [31-75] years, ECOG PS 0 (n=16) or 1 (n=11), 13 tumor types, and median [range] of prior therapies of 3 [0-8] to receive PTC299 in stage 1 (n=12), stage 2 (n=6), or stage 3 (n=9). Median [range] of time on treatment has been 10 [3-61+] weeks. No MTD was observed through the highest dose levels: stage 1, 1.2 mg/kg BID; stage 2, 120 mg TID; and stage 3, 100 mg TID. Adverse events were infrequent, usually grade 1, and not generally considered PTC299-related. No hypertension was observed. PTC299 PK were generally dose proportional, with rapid appearance of drug in plasma, Tmax of ∼4 hours, and an effective t1/2 of ∼12 hours. From day 1 to day 28 (stage 1) or day 42 (stage 2), PTC299 showed a ∼2-fold accumulation when dosed continuously. Trough plasma concentrations exceeded values associated with maximal preclinical antitumor activity. Decreases in circulating angiogenic VEGF and inflammatory cytokines (IL-6) were seen. Patients with thyroid cancer (n=2), chondrosarcoma (n=1), and head and neck cancers (n=3) remain on study with stable disease for 14+, 2.8+, 8+, 5.6+, 3.7+, and 2.6+ months respectively. Patients with other advanced cancers (n=5) completed the study with stable disease for 3.5-12 months. Conclusions: PTC299 monotherapy or combination therapy with docetaxel is generally well tolerated, achieves target plasma concentrations, and shows evidence of pharmacodynamic and clinical activity. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PTC Therapeutics PTC Therapeutics