Clinical Trials

Date: 2016-03-17

Type of information: Treatment of the first patient

phase: 1b

Announcement: treatment of the first patient

Company: OncoMed Pharmaceuticals (USA - CA) Celgene (USA - NJ)

Product: demcizumab and pembrolizumab

Action mechanism:

• monoclonal antibody/immune checkpoint inhibitor. Demcizumab (anti-DLL4, OMP-21M18), is a monoclonal antibody optimized to block the key Notch signaling pathway in cancer stem cells. Specifically, demcizumab selectively targets Delta-like ligand 4 (DLL4), an activator of the Notch signaling pathway—a pathway known to be important in cancer stem cells and cancer. Blocking DLL4 has been shown in preclinical studies to result in broad-spectrum anti-tumor activity via multiple mechanisms, including disrupting angiogenesis, inhibiting cancer stem cell growth, and promoting cell differentiation, and potentially immune activation. Demcizumab is part of OncoMed’s collaboration with Celgene. 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. A Phase 1b/2 trial of demcizumab and paclitaxel in patients with platinum-resistant ovarian cancer is also ongoing.
• Keytruda® (pembrolizumab - MK-3475) is an highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA. In October 2014, the FDA has gralso anted Breakthrough Therapy Designation to Keytruda® (pembrolizumab) for the treatment of patients with Epidermal Growth Factor Receptor (EGFR) mutation-negative, and Anaplastic Lymphoma Kinase (ALK) rearrangement-negative non-small cell lung cancer (NSCLC) whose disease has progressed on or following platinum-based chemotherapy. In November 2015, the FDA has granted Breakthrough Therapy Designation to Keytruda® for the treatment of patients with microsatellite instability high (MSI-H) metastatic colorectal cancer. Keytruda® is the first approved drug that blocks the PD-1 cellular pathway.
• 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.

Disease: locally advanced or metastatic solid tumors

Therapeutic area: Cancer - Oncology

Country: UK, USA

Trial details:

• The purpose of this study is to test the efficacy and safety of an experimental drug, demcizumab, when given in combination with pembrolizumab. Demcizumab is a humanized monoclonal antibody and was developed to target cancer stem cells. Demcizumab may block the growth of cancer stem cells, the remaining cancer cells, and it may also impair the productive growth of new blood vessels, which tumors need to grow and spread. This study is sponsored by OncoMed Pharmaceuticals. (NCT02722954)

Latest news:

• • On March 17, 2016, OncoMed Pharmaceuticals announced dosing of the first patient in its Phase 1b clinical trial of OncoMed's investigational agent demcizumab (anti-DLL4, OMP-21M18), with Merck&Co's anti-Programmed Cell Death 1 (PD1) therapy pembrolizumab (Keytruda®). 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. 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. The 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.

Is general: Yes