On March 17, 2016 OncoMed Pharmaceuticals, Inc. (NASDAQ:OMED), a clinical-stage company developing novel anti-cancer stem cell and immuno-oncology therapeutics, reported dosing of the first patient in its Phase 1b clinical trial of OncoMed’s investigational agent demcizumab (anti-DLL4, OMP-21M18), with Merck’s anti-Programmed Cell Death 1 (PD1) therapy pembrolizumab (KEYTRUDA) (Press release, OncoMed, MAR 17, 2016, View Source [SID:1234509608]). Schedule your 30 min Free 1stOncology Demo! The combination of these agents may act as a double blockade for cancer-induced immune suppression with potential application to a number of solid tumor cancers.
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The Phase 1b clinical trial is enrolling patients with advanced or metastatic solid tumors to receive escalating dose cohorts of demcizumab plus an approved dose of pembrolizumab. Once an optimal combination dose is established, three expansion study cohorts will be enrolled in non-small cell lung cancer (NSCLC), anti-PD1 refractory solid tumors and castrate-resistant prostate cancer.
The primary objective of the trial is to determine the safety and tolerability of the demcizumab-pembrolizumab combination. The trial will also look at comparative pharmacokinetic profiles, incidence of antibodies against demcizumab or pembrolizumab, biomarker and immunological response, response rates and survival outcome in patients with advanced solid tumors, NSCLC, castrate-resistant prostate cancer and anti-PD1 antibody refractory cancers.
"We’ve designed the Phase 1b study to investigate the safety profile for the demcizumab and pembrolizumab combination and to look for signals of immunological, biomarker and anti-tumor activity in advanced solid tumors," said Jakob Dupont, M.D., OncoMed’s Chief Medical Officer. "Based on our preclinical studies, we believe demcizumab may have a distinctive immune modulatory effect of decreasing monocytic myeloid-derived suppressor cells, or MDSCs, within patient tumors. MDSCs are important cells that prevent a patient’s immune system from fighting their cancer, even in the setting of the new anti-PD1 treatments. In our preclinical studies, we have observed synergistic anti-tumor activity when combining anti-DLL4 and anti-PD1, which we attribute to their complementary mechanisms. We look forward to testing this novel combination in the clinic with the study investigators."
At the American Association of Cancer Research Annual Meeting in 2015, OncoMed reported on the impact of an anti-DLL4 and anti-PD1 on antitumor immune responses in preclinical studies. The combination of anti-DLL4 and anti-PD1 was found to have more potent antitumor and enhanced immuno-oncology activity than either agent alone. In addition to the synergistic anti-cancer immune responses observed, the combination of anti-DLL4 and anti-PD1 reduced tumor growth in re-implantation experiments, suggesting a more profound memory immune response was induced by the combination than either anti-DLL4 or anti-PD1 alone.
The Phase 1b combination study will be conducted at several sites in the U.S. and U.K., including Memorial Sloan Kettering Cancer Center, Columbia University, START Center for Cancer Care, University of Michigan Medical Center, Sarah Cannon Research Institute, University of California San Francisco, Rocky Mountain Cancer Centers and The Royal Marsden Hospital. Patients interested in participating in one of OncoMed’s clinical trials may learn more by calling 1-866-914-7347 or emailing [email protected].
About Demcizumab (anti-DLL4, OMP-21M18)
Demcizumab is a humanized monoclonal antibody targeting Delta-like Ligand 4 (DLL4), a key member of the Notch signaling pathway. Based on preclinical studies, demcizumab appears to have a multi-pronged mechanism of action: halting cancer stem cell growth and reducing cancer stem cell frequency, disrupting angiogenesis in the tumor and augmenting anti-tumor immune responses by decreasing tumor myeloid-derived suppressor cells (MDSCs).
In addition to the multi-arm demcizumab plus pembrolizumab Phase 1b clinical trial, demcizumab is currently being studied in two randomized Phase 2 clinical trials. The YOSEMITE trial is testing demcizumab with gemcitabine plus Abraxane versus gemcitabine plus Abraxane in first-line advanced pancreatic cancer patients. The DENALI trial is testing demcizumab with pemetrexed and carboplatin versus pemetrexed and carboplatin alone in first-line advanced non-small cell lung cancer patients. Demcizumab is part of OncoMed’s collaboration with Celgene Corporation.