PTC299, a Novel Regulator of Tumor VEGF Expression, Is Well Tolerated and Achieves Target Plasma Concentrations: Dose-Ranging Results of a Phase 1b Study in Women with Metastatic Breast Cancer.
Authors: Knight D. , Tiersten A. , Miao H. , Llorente M. , Elfring G. , Novik Y. , Speyer J. , Volm M. , Miller L. 
Published: December 2010

Background: Current anti-angiogenic drugs interfere with the vascular endothelial growth factor (VEGF) signaling pathway. PTC299 is an orally delivered, small-molecule investigational drug designed to inhibit the expression of VEGF and other angiogenic cytokines within tumors. PTC299 also induces a parallel interruption of tumor cell division at the G1/S phase of the cell cycle, offering several potential mechanisms of action. In multiple models of human cancers grown as xenografts in mice, including breast cancer, single-agent PTC299 decreases tumor and plasma VEGF levels and results in significant tumor regression or delay of tumor growth. Data from Phase 1a testing in healthy volunteers supported initiation of this Phase 1b, 2-stage, open-label, dose-ranging, escalating-dose, safety, pharmacokinetic (PK), and pharmacodynamic study evaluating PTC299 monotherapy and PTC299 combination therapy with hormonal agents in adult women with metastatic breast cancer.Materials and Methods: In Stage 1, patients have received PTC299 monotherapy in repeated 6-week cycles, each comprising a 4-week course of PTC299 administered on a twice daily (BID) schedule, followed by a 2-week washout period. The study was designed to enroll 3 successive cohorts of 3 to 6 patients at progressively higher dose levels of 0.3 mg/kg/dose BID, 0.6 mg/kg/dose BID, or 1.2 mg/kg/dose BID, with treatment given until disease progression or unacceptable toxicity. Safety, PK, and antitumor activity have been assessed.Results: Stage 1 enrolled 9 subjects (3 at each dose level) with a median [range] of 53 [31-76] years old and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (n=1) or 1 (n=8). Patients were extensively pretreated with hormonal (patient n=3), chemotherapy (n=9), and/or antiangiogenic agents (n=6). No dose-limiting toxicity was observed. Adverse events have generally been infrequent, low-grade, and do not appear to be PTC299-related. No hypertension, bleeding, thromboembolism, or proteinuria has been seen. Drug plasma concentrations have exceeded the maximally active plasma trough level identified in nude mouse xenograft models. Disease stabilization through multiple cycles (∼6 months and ∼4.5 months, respectively) has been observed in 2 subjects at the highest PTC299 dose level (1.2 mg/kg/dose BID). In these subjects, improvements in tumor-related markers of angiogenesis/inflammation have been observed.Discussion: PTC299 may offer safety, efficacy, and convenience advantages relative to current anti-angiogenic drugs. In Stage 1 of this Phase 1b study, PTC299 has been well tolerated, has achieved target plasma concentrations, and has shown suggestions of antitumor and pharmacodynamic activity. Accrual to Stage 2, in which subjects receive PTC299 combination therapy with hormonal agents, is ongoing.Supported by a translational breast cancer research grant award from the Congressionally Directed Medical Research Programs of the Department of Defense

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6092.