PTC299 for Treatment of Neurofibromatosis Type 2

A Phase 2 Study to Assess the Efficacy, Safety, and Pharmacodynamic Activity of PTC299 in Patients With Neurofibromatosis Type 2

Formation of new blood vessels (angiogenesis) is important for tumor growth in neurofibromatosis type 2 (NF2). It is known that tumors make a protein called vascular endothelial growth factor (VEGF) and there are higher levels of VEGF in the tumors and blood of many patients with NF2. VEGF stimulates the formation of blood vessels that supply the tumor with nutrients and oxygen. PTC299 is an oral drug that has been shown to decrease production of VEGF in animal models of human cancer. In these animal models, oral PTC299 administration decreases VEGF levels in the tumor and in the bloodstream, decreases blood vessel numbers in the tumor, and significantly slows or halts tumor growth. Safety studies in research animals indicate good tolerability at doses and drug levels that are higher than those planned for the clinical studies. Results from Phase 1a studies in healthy volunteers indicate that PTC299 achieves levels of PTC299 in the bloodstream that are known to be active in animal models of human tumor. This Phase 2 study is designed to test the hypothesis that PTC299 will be tolerable and will show evidence of VEGF reduction, antitumor activity, and hearing improvement when administered orally to patients with NF2.

The study will be conducted in 2 stages. In Stage 1 of the study, 11 patients will receive daily treatment with PTC299 administered at 100 mg/dose twice per day for up to 1 year or until tumor progression. If no subject responds with tumor shrinkage or an improvement in hearing, then the study will be stopped. If ≥1 out of 11 subjects respond, then the study will proceed to Stage 2 to enroll an additional 14 subjects for a total of 25 subjects.

PTC299 will be administered orally at 100 mg/dose twice per day for up to 1 year or until tumor progression

To assess the effects of PTC299 on pure tone thresholds, brainstem auditory evoked responses (BAERs), and otoacoustic emissions (OAEs) in patients with NF2

Inclusion Criteria: Age ≥18 years Diagnosis of NF2 Presence of vestibular schwannomas Evidence of progressive increase in vestibular schwannoma size or worsening hearing loss due to vestibular schwannoma Adequate functional status (Karnofsky Performance Score ≥60) Adequate bone marrow, liver, kidney function If sexually active, willingness to use effective barrier or medical contraception For women of childbearing potential, no pregnancy or breast-feeding Discontinuation of other therapies (except corticosteroids) for the treatment of NF2 and resolution of any acute toxic effects of prior therapies Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions Willingness to provide informed consent Exclusion Criteria: Uncontrolled hypertension, major bleeding, HIV infection, or recent acute cardiovascular event Prior exposure to another anti-angiogenic therapy (eg, bevacizumab, sunitinib)