ACTR-51. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/MTOR INHIBITOR GDC-0084 GIVEN TO GLIOBLASTOMA (GBM) PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER STATUS

Abstract

BACKGROUND GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR) efficacious in GBM models driven by activation of the PI3K pathway. GDC-0084 crosses the blood-brain barrier (BBB) and achieves a brain / plasma ratio of approximately 1.0 in three animal species. GDC-0084 was given as once daily oral dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012; {type:clinical-trial,attrs:{text:NCT01547546,term_id:NCT01547546}}NCT01547546) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established Class I PI3K/mTOR inhibitor class-effects. GDC-0084 was rapidly absorbed and demonstrated linear- and dose-proportional increases in exposure. The MTD was determined to be 45 mg once daily, with 7/8 patients receiving this dose having drug exposures consistent with anti-tumor activity in pre-clinical models. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that GDC-0084 crossed the BBB, with a uniform distribution throughout the brain. The current phase 2 study will investigate the efficacy and safety of GDC 0084 in patients with newly diagnosed GBM, with unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status.