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Clinical Trials of Cancer Immunotherapies

Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)

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 and Ralph Venhaus
David A. Reardon
1Dana-Farber Cancer Institute, Boston, MA,
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Jorg Dietrich
2Massachusetts General Hospital, Boston, MA,
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Thomas Kaley
3Memorial Sloan Kettering Cancer Center, New York, NY,
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Hui Gan
4Austin Hospital, Melbourne, Australia,
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Gavin P. Dunn
5Washington University, St. Louis, MO,
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Timothy Cloughesy
6Ronald Reagan UCLA Medical Center, Los Angeles, CA,
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Michael Lim
7Johns Hopkins Hospital, Baltimore, MD,
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Jennifer Clarke
8University of California, San Francisco, CA,
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Andrew Park
9Ludwig Institute for Cancer Research, New York, NY,
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Linda Pan
9Ludwig Institute for Cancer Research, New York, NY,
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Domenic W. Lai
10MedImmune, Gaithersburg, MD.
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Joyson Karakunnel
10MedImmune, Gaithersburg, MD.
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Paul Robbins
10MedImmune, Gaithersburg, MD.
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Rajesh Narwal
10MedImmune, Gaithersburg, MD.
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Ralph Venhaus
9Ludwig Institute for Cancer Research, New York, NY,
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DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A046 Published January 2016
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Abstracts: CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY

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.

  • ©2016 American Association for Cancer Research.
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Cancer Immunology Research: 4 (1 Supplement)
January 2016
Volume 4, Issue 1 Supplement
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Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)
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 and Ralph Venhaus
Cancer Immunol Res January 1 2016 (4) (1 Supplement) A046; DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A046

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Abstract A046: Phase 2 study to evaluate the clinical efficacy and safety of MEDI4736 in patients with glioblastoma (GBM)
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 and Ralph Venhaus
Cancer Immunol Res January 1 2016 (4) (1 Supplement) A046; DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A046
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