Clinical Trials

Date: 2016-01-22

Type of information: Presentation of results at a congress

phase: 1b

Announcement: presentation of results at the Gastrointestinal Cancers Symposium

Company: OncoMed Pharmaceuticals (USA - CA)

Product: demcizumab

Action mechanism: monoclonal antibody. 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. A Phase 1 trial combining demcizumab with the anti-PD1 antibody pembrolizumab in solid tumor patients is planned to initiate in early 2016.  

Disease: pancreatic cancer

Therapeutic area: Cancer - Oncology

Country:

Trial details:

Latest news:

• • On January 22, 2016, OncoMed Pharmaceuticals announced updated survival data from the Phase 1b clinical trial of demcizumab (anti-DLL4, OMP-21M18) at the Gastrointestinal Cancers Symposium. The Phase 1b dose-escalation and expansion study assessed the safety, biomarker, and anti-tumor activity of demcizumab and gemcitabine plus Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) in 32 previously untreated patients with advanced pancreatic cancer. Demcizumab in combination with chemotherapy had an acceptable safety profile. The updated Kaplan-Meier estimated median progression-free survival was 7.1 months and median overall survival was 12.7 months for the patients who received the demcizumab-gemcitabine-Abraxane combination. Current standard-of-care treatment for advanced pancreatic cancer with gemcitabine and Abraxane, based on Phase 3 data, has median progression-free survival of 5.5 months and median overall survival of 8.5 months. A randomized Phase 2 "YOSEMITE" trial in first-line pancreatic cancer patients with metastatic disease is currently being conducted at more than 50 centers in the U.S., Canada, Europe and Australia. Approximately 200 patients will be randomized into one of three study arms. Patients in Arm 1 will receive standard-of-care gemcitabine plus Abraxane plus placebo. Patients in Arm 2 patients will receive standard of care plus one course of demcizumab 3.5 mg/kg every two weeks for six doses (70 days). Patients in Arm 3 will receive standard of care with demcizumab for two courses. OncoMed expects to complete enrollment of the Phase 2 trial in 2016 and data from this trial is anticipated in early 2017. Additional Phase 1b Results: In total 56 subjects were enrolled in this Phase 1b trial. The first 24 subjects received the double of demcizumab and gemcitabine and after a protocol amendment 32 subjects received demcizumab (in a truncated fashion) with the new standard of care of gemcitabine plus Abraxane. Fourteen of the 28 (50%) evaluable patients who received the demcizumab-gemcitabine-Abraxane combination had a RECIST partial response (unconfirmed) and 11 achieved stable disease, resulting in a clinical benefit rate of 89 percent. Demcizumab and gemcitabine plus Abraxane were generally well tolerated with fatigue, nausea and vomiting being the most common drug related toxicities. Truncated demcizumab therapy (i.e. 70 days of therapy) appears to prevent the onset of late cardiopulmonary toxicity, as none of the 32 patients treated in this manner developed heart failure or pulmonary hypertension. Pharmacodynamic analyses demonstrated clear down regulation of Notch pathway gene expression at the Phase 2 dose of demcizumab. These data are being presented in a poster titled "A Phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) and gemcitabine (GEM) +/- nab-paclitaxel in patients with pancreatic cancer" (Abstract 341), during Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract. Results presented provide eight months of additional follow-up on survival benefit.
• • On June 1, 2015, at the 2015 ASCO Annual Meeting, OncoMed Pharmaceuticals presented data from its Phase 1b clinical trials of demcizumab (anti-DLL4, OMP-21M18) in advanced pancreatic patients who have not received prior treatment for locally advanced or metastatic disease. Demcizumab, when combined with standard of care Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine resulted in a 50 percent response rate, progression-free survival of nine months and overall survival of ten months in an all-comer patient population. A total of 56 patients with advanced pancreatic cancer were enrolled in the open-label, multi-center Phase 1b trial of demcizumab. Thirty-two patients received demcizumab administered in a truncated manner in combination with standard-of-care Abraxane® plus gemcitabine after the Phase 1b protocol was amended to reflect this updated standard-of-care in pancreatic cancer. Of 28 patients evaluable for efficacy who received the three drug combination, partial responses were seen in 14 patients (50%) and 11 patients (39%) achieved stable disease as measured by RECIST criteria, resulting in an 89 percent overall clinical benefit rate in this all-comer patient population. Median progression-free survival was 9.0 months and median overall survival was 10.1 months for those patients who received the demcizumab-Abraxane-gemcitabine combination. Current standard-of-care treatment for advanced pancreatic cancer with Abraxane plus gemcitabine has median progression-free survival of 5.5 months and median overall survival of 8.5 months. Biomarker analysis of surrogate makers in whole blood cells demonstrated target engagement of demcizumab that down regulated Notch pathway gene expression at all doses (2.5 to 5mg/kg) and up regulated genes associated with angiogenesis. These results are consistent with the mechanism of action observed for demcizumab in preclinical experiments and also support the selection of the demcizumab Phase 2 dose in pancreas cancer of 3.5mg/kg every two weeks. Patient tumor samples were also evaluated for additional potential predictive markers of demcizumab's activity. These markers will be further explored in the randomized Phase 2 trial.
• Demcizumab in combination with gemcitabine and Abraxane was generally well tolerated, with fatigue, nausea and vomiting being the most common drug-related toxicities. Truncated demcizumab therapy (in which demcizumab is dosed for 70 days) appears to prevent the onset of late reversible cardiopulmonary toxicity. Among the 32 patients treated with truncated demcizumab in this study no moderate-to-severe cardiovascular toxicities occurred.
• These data were presented at the 2015 ASCO Annual Meeting in a poster titled "A Phase 1b study of the anti-cancer stem cell agent demcizumab (DEM) & gemcitabine (GEM) +/- paclitaxel protein bound particles (nab-paclitaxel) in patients with pancreatic cancer" (Abstract #4118) by Manuel Hidalgo, MD, Vice Director of Translational Research Clinical Research Programme Director Head of Gastrointestinal Cancer CRU Centro Nacional de Investigaciones Oncológicas (CNIO) (Spanish National Cancer Research Centre).
• OncoMed is currently enrolling patients in a randomized Phase 2 demcizumab trial (YOSEMITE) in patients with metastatic pancreatic cancer. Approximately 200 patients will be randomized into one of three study arms. Patients in Arm 1 will receive standard of care gemcitabine plus Abraxane plus placebo. Patients in Arm 2 patients will receive standard of care plus one course of demcizumab 3.5 mg/kg every two weeks for six doses (70 days). Patients in Arm 3 will receive standard of care with demcizumab for two courses. The Phase 2 trial is being conducted at approximately 50 centers in the U.S., Canada, Europe and Australia.
• • On September 28, 2014, OncoMed Pharmaceuticals presented safety and efficacy data from two Phase 1b clinical trials of demcizumab (anti-DLL4, OMP-21M18) in pancreatic cancer and non-small cell lung cancer (NSCLC) at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain.
• Results from the Phase 1b studies demonstrate that demcizumab, in combination with standard-of-care chemotherapy, is well tolerated, especially in patients where the company's risk mitigation, monitoring and truncated dosing strategies have been employed. Encouraging tumor response rates were presented at ESMO from a study of demcizumab with gemcitabine or gemcitabine plus Abraxane® (paclitaxel protein-bound particles for injectible suspension) (albumin bound) in patients with first-line pancreatic cancer, and from the study of demcizumab plus pemetrexed and carboplatin for the first-line treatment of Stage III/IV NSCLC. OncoMed's Phase 1b studies identified the demcizumab dosing schedules for the company's planned randomized Phase 2 proof-of-concept trials.
• Demcizumab Phase 1b in Pancreatic Cancer: In 47 pancreatic cancer patients evaluable for safety, the combination of demcizumab and gemcitabine, with or without nab-paclitaxel, was generally well tolerated. Fatigue, nausea and vomiting were the most common drug related toxicities. Among 22 evaluable patients who received the demcizumab + gemcitabine + nab-paclitaxel combination, nine (41%) achieved partial responses and 10 had stable disease as measured by RECIST criteria, resulting in an overall clinical benefit rate of 86 percent. Median progression-free survival for the demcizumab + nab paclitaxel + gemcitabine combination has not yet been reached at the Phase 2 dose. Six patients were still undergoing treatment at the final dose tested of 3.5mg/kg as of July 15, 2014.
• OncoMed implemented a truncated dosing schedule for demcizumab following an observation of reversible cardiopulmonary toxicities in earlier studies. Additionally, all patients are being followed with cardiac monitoring using B-type natriuretic peptide (BNP) (an early indicator of cardiotoxicity) and echocardiography. Cardioprotective medications, such as angiotensin-converting enzyme inhibitors, were administered to patients with rising BNPs. The truncated dosing and cardiac monitoring strategies appear to have mitigated the risks of cardiopulmonary toxicity. None of the 26 pancreatic cancer patients treated in this manner have developed moderate-to-severe heart failure or pulmonary hypertension. OncoMed's Phase 1b clinical study of demcizumab in pancreatic cancer patients has completed enrollment. By the end of this year, the company currently plans to initiate a large international randomized Phase 2 clinical trial utilizing the truncated 3.5mg/kg dose of demcizumab every two weeks. The truncated dosing and cardiac monitoring strategies will be further evaluated in the randomized Phase 2 study for pancreatic cancer. Data from OncoMed's Phase 1b clinical study of demcizumab in pancreatic cancer patients were presented by Dr. Manuel Hidalgo, M.D., Ph.D., Director of the Centro Integral Oncologico Clara Campal (CIOCC), START Madrid and lead investigator for the Phase 1b demcizumab clinical study, in the "Gastrointestinal tumours, non-colorectal" discussion session in a poster titled: "A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab (DEM) & Gemcitabine (GEM) +/- Paclitaxel Protein Bound Particles (nab-paclitaxel) in Patients with Pancreatic Cancer" (#616PD).

Is general: Yes