PTC299 is a novel, orally bioavailable, small-molecule drug designed to control tumor growth by selectively inhibiting tumor vascular endothelial growth factor (VEGF) protein expression at the post-transcriptional level. In vitro studies in cultured tumor cells demonstrate that PTC299 impairs VEGF production in multiple tumor types. In vivo studies in preclinical animal models of human tumor show that PTC299 reduces tumor and plasma VEGF concentrations, decreases tumor microvessel density, substantially impedes tumor progression, and prolongs survival in mice bearing intracranial human glioblastoma multiforme (GBM). Evaluation of drug disposition has indicated that PTC299 penetrates the blood-brain barrier. Safety pharmacology and toxicology studies and Phase 1 studies in healthy volunteers and patients with cancer have indicated that PTC299 is generally well tolerated at the dose levels to be used in the proposed study outlined below. This grant application describes a Phase 2, open-label, efficacy, safety and pharmacodynamic study. Adult patients with recurrent GBM will receive PTC299 in repeated 4-week cycles comprising daily oral PTC299 administration of 100mg/dose on a 2 times per day schedule. Treatment will be administered until tumor progression. The primary objective will be to assess 6-month progression-free-survival (PFS-6) in patients receiving PTC299 therapy. Enrollment will occur in a single stage in which 30 subjects will be recruited. The study will test the null hypothesis that the PFS-6 rate is <10% against the alternative that it is >35% at a significance level of <0.05 and power of >0.90. If >7 subjects achieve a PFS-6, the null hypothesis will be rejected. Secondary objectives will include determination of objective response rates, progression-free-survival;evaluation of tumor blood flow;measurement of concentrations of circulating angiogenic factors;measurement of changes in angiogenic markers present in glioma-derived circulating exosomes;and characterization of health-related quality-of-life. The safety, pharmacokinetic, and compliance profile of PTC299 will also be assessed. GBM is a highly angiogenic and fatal malignancy that relies upon VEGF overexpression to maintain tumor growth. Anti-VEGF therapy offers promise in ameliorating the clinical manifestations of this disease. PTC299's development represents a unique translational research approach, transforming a decade of research in 2 areas - tumor angiogenesis and post-transcriptional control - into a targeted, practical-to-deliver, oral therapy intended to control tumor growth while offering safety, dosing flexibility, and convenience for patients. Development of PTC299 in GBM and other tumor types represents the first effort to validate the concept of modulating post-transcriptional control mechanisms with an orally bioavailable small molecule as a means to treat human disease. Successful achievement of study goals would support a registration-directed development program that could lead to regulatory approval of PTC299 in patients with recurrent GBM.

Public Health Relevance

There are no approved therapies for patients with recurrent glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults. The goal of the planned clinical trial is to evaluate the anti-tumor activity and safety of PTC299. The intent is to generate adequate data to support the launch of a larger, placebo-controlled study and ultimately to obtain FDA approval of PTC299 for the treatment of recurrent GBM, thereby addressing a major unmet medical need.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (01))
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Needleman, Katherine
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Ptc Therapeutics, Inc.
South Plainfield
United States
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