A phase II and pharmacodynamic trial of RO4929097 for patients with recurrent/progressive glioblastoma.

Abstract

Listen

Translate article

TPS135 Background: Patients with recurrent glioblastoma (rGBM) have a 6-month progression-free survival (PFS6) of only 10-15%. Cancer stem-like cells (CSCs) are a subset of cells that are capable of self renewal and differentiation within a tumor. These properties are felt to be a major cause of resistance to chemotherapy and radiotherapy. Furthermore, CSCs promote tumor angiogenesis. Therefore, CSCs are an attractive target for therapy of GBM. Proliferation of CSCs occurs via several pathways. One of the major signaling pathways is Notch. Elevation of Notch signaling imparts a tumor growth advantage by keeping tumor cells in a stem cell-like proliferative state. Expression of Notch is critical for survival and proliferation of human gliomas. Gamma secretase (GS) cleaves the Notch receptor as part of normal Notch function and is thus a critical enzyme in the Notch pathway. Therefore, disruption of the Notch pathway by inhibition of GS is a logical treatment strategy for patients with GBM. RO4929097 is an oral small molecule inhibitor of GS. This phase II and pharmacodynamic study will assess the efficacy of RO4929097 against rGBM and will include biomarker assays on freshly resected GBM samples from patients receiving this agent. Methods: Two groups of adults with contrast-enhancing rGBMs and no prior GS inhibitor treatment will be eligible: Group A - 40 non-surgical patients who will receive RO4929097, 20 mg 3 days on/4 days off with a primary endpoint of PFS6 on a standard phase II design; and Group B- 20 patients who will receive drug before and after resection of rGBM. Group B patients must have tumor > 2.5 cm in diameter. These patients will receive drug pre-op: 10 mg/d x 6 days; and post-op: 20 mg 3 days on/4 days off until progression. Fresh tumor from Group B patients will be assayed for neurosphere generation, expression levels of Notch pathway components and downstream targets and survival of mice bearing fresh tumor tissue. The goal is to achieve a 25% reduction of neurosphere generation when compared to a contemporaneous group of rGBM patients. If successful, these studies will provide proof of principle that CSC-targeted drug therapy can cross the blood tumor barrier and can alter the molecular and functional aspects of CSCs.