Abstract Date: 5/1/2016
Viviane S. Tabar, MD
Ran Xu, MD
Antonio Omuro, MD (New York, NY)
This is the first report of the results of a Phase I trial of a Notch inhibitor(RO4929097) in combination with standard of care therapy in malignant gliomas(MG). The study is designed as a proof-of-concept and based on data developed in the lab using human tumor explants.
21 patients with newly-diagnosed MG received RO4929097 in three dosages (10, 15 and 20 mg) combined with temozolomide (TMZ) and radiotherapy (RT). Primary objectives were determining the maximum tolerated dose, toxicities and pharmacokinetics. The study design allowed for exploratory studies characterizing in human effects of RO4929097, including evaluation of tumor and brain drug penetration, neuro-imaging parameters and effects on the Notch pathway and cancer stem cells. Analyzed surgical specimens were differentially sampled from areas with and without blood-brain barrier disruption.
Treatment was well tolerated and no dose-limiting toxicities were observed. Immunohistochemistry of treated tumors showed a decrease in proliferation (Ki-67: 27.7% to 13.6%; n=7),and in expression of the notch receptor (NICD) by tumor cells (21.9% to 5.1%), and blood vessels (67.6% to 30.0%). Organotypic explant cultures of study patients revealed a decrease in proliferation, viability, and CD133+ cell population with treatment. Perfusion MRI demonstrated a significant decrease in relative plasma volume, from 9.34% to 3.92% after drug exposure (n=8).Upon recurrence, tumors exhibited a switch from Notch- to VEGF_dependent angiogenesis, suggesting a potential for combination therapy with anti-VEGF agents.
The combination of RO4929097 with TMZ and RT in newly-diagnosed malignant glioma is safe and well tolerated; the drug has variable blood brain barrier penetration with some evidence of target modulation, including inhibition of the Notch pathway and CSC population, and evidence of anti-angiogenesis. Lab data performed on fresh tumor tissue was predictive of treatment response.
Article ID: AA-35056