Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)
Authors: Reardon David A. , Dietrich Jorg , Kaley Thomas , Gan Hui , Dunn Gavin P. , Cloughesy Timothy , Lim Michael , Clarke Jennifer , Park Andrew , Pan Linda , Lai Domenic W. , Karakunnel Joyson , Robbins Paul , Narwal Rajesh , Venhaus Ralph 
Published: May 2016

Abstract
Background: Programmed cell death ligand-1 (PD-L1) is widely expressed on antigen presenting cells (APC) and other immune cells. PD-L1 binds two important regulatory receptors on T-cells: programmed cell death-1 (PD-1) and CD80/B7. Targeting Programmed Death-1 (PD-1) and its ligand, PD-L1, have demonstrated promising anti-tumor activity among other challenging solid tumors and growing data implicates PD-1/PD-L1 signaling as a significant contributor to immunosuppression in glioblastoma (GBM). PD-1 is expressed by many GBM infiltrating lymphocytes while PD-L1 is expressed by 61-100% of GBM tumors. Furthermore, loss of the PTEN tumor suppressor gene, which occurs in 40-50% of GBM tumors, leads to increased transcription and expression of PD-L1 in GBM. These findings indicate that PD-L1 is an attractive and important therapeutic target in GBM. MEDI4736 (M), a human IgG1κ blocking monoclonal antibody against PD-L1, represents a compelling immune-mediated anti-tumor treatment for GBM.
Methods: Phase 2, multicenter, open-label study (NCT02336165) is evaluating the clinical efficacy and safety of M in GBM patients. Eligible patients include those who are newly diagnosed with unmethylated MGMT GBM scheduled for standard radiotherapy (Cohort A); Bevacizumab-naïve patients with recurrent GBM (Cohort B); and Bevacizumab-refractory patients with recurrent GBM (Cohort C). Cohort A patients will receive M at 10 mg/kg i.v. Q2W for up to 12 months beginning with standard radiotherapy. Cohort B will receive M at 10 mg/kg i.v. Q2W for up to 12 months as monotherapy. Cohort C will receive M at 10 mg/kg i.v. Q2W for up to 12 months in combination with continued bevacizumab at 10 mg/kg Q2W. Primary endpoints include overall survival (OS) at 12 months (cohort A), progression free survival rate at 6 months (PFS-6) (cohort B) and OS-6 (cohort C). Secondary endpoints are safety/tolerability, PFS, median OS, radiographic response, and quality of life (QoL) by EORTC QLQ-C30/BN20. Exploratory endpoints are patient neurologic function using the Neurologic Assessment in Neuro-Oncology (NANO) scale, as well as immuno-correlative biomarkers and pharmacokinetics.
Cohort A represents the first time MEDI4736 is being given in combination with radiation, so a 3+3 subject safety run-in is required by protocol. Subjects must clear a 10 week DLT observation period before enrollment opens to the remainder of the cohort. If 2 or more DLTs are noted within the first 6 patients, then the MEDI4736 dose will be de-escalated. Cohort C represents the first time MEDI4736 is being given in combination with bevacizumab, so a 3+3 subject safety run-in period similar to that for Cohort A is also required, but with a 6 week DLT observation period.
Study Status: All cohorts opened to enrollment in March 2015 with Cohorts A and C currently limited by the subject safety run-in period. As of 10 June 2015, the numbers of subjects enrolled by cohort are: Cohort A = 2, Cohort B = 26, Cohort C = 3. No DLTs have been reported, and clinical efficacy and safety data collection are ongoing.
Citation Format: David A. Reardon, Jorg Dietrich, Thomas Kaley, Hui Gan, Gavin P. Dunn, Timothy Cloughesy, Michael Lim, Jennifer Clarke, Andrew Park, Linda Pan, Domenic W. Lai, Joyson Karakunnel, Paul Robbins, Rajesh Narwal, Ralph Venhaus. Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM). [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A046.