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A humanized monoclonal antibody directed against the N-terminal epitope of Notch ligand DLL4 (delta-like 4) with potential antineoplastic activity. Demcizumab binds to the membrane-binding portion of DLL4 and prevents its interaction with Notch-1 and Notch-4 receptors, thereby inhibiting Notch-mediated signaling and gene transcription, which may impede tumor angiogenesis. Activation of Notch receptors by DLL4 stimulates proteolytic cleavage of the Notch intracellular domain (NICD); after cleavage, NICD is translocated into the nucleus and mediates the transcriptional regulation of a variety of genes involved in vascular development. The expression of DLL4 is highly restricted to the vascular endothelium. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)
OncoMed’s Demcizumab Phase 1b Clinical Trials Show Encouraging Safety and Anti-Tumor Activity at ESMO
MADRID and REDWOOD CITY, Calif, Sept. 28, 2014 (GLOBE NEWSWIRE) —
OncoMed Pharmaceuticals, Inc. (Nasdaq:OMED), a clinical-stage company developing novel therapeutics that target cancer stem cells (CSCs), or tumor-initiating cells, 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.
“As we advance to Phase 2 clinical trials of demcizumab, we have successfully identified strategies that result in both favorable tolerability and compelling response rates,” said Jakob Dupont, M.D., OncoMed’s Chief Medical Officer. “To date, sixty-four patients have been enrolled and treated on the demcizumab truncated dosing schedule that will be used in our randomized Phase 2 studies. The majority of these patients have now been followed for greater than 100 days without any moderate-to-severe cardiopulmonary toxicities and a number of patients remain on treatment.”
“Based on the data generated from our Phase 1b studies in pancreatic and non-small cell lung cancer we have identified a dosing regimen with impressive anti-tumor activity and an acceptable safety profile. We have confidence that these data enable the advancement of both programs into planned randomized Phase 2 studies in pancreatic cancer and NSCLC. Results from our Phase 1b demcizumab program not only signal the potential safety and anti-tumor activity for this drug, but also provide encouragement for the potential of an anti-cancer stem cell hypothesis,” said Paul J. Hastings, Chairman and Chief Executive Officer.
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 Oncológico 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).
Demcizumab Phase 1b in NSCLC
Demcizumab in combination with pemetrexed and carboplatin was generally well tolerated in 39 chemotherapy-naïve NSCLC patients evaluable for safety in the Phase 1b clinical study. Nausea, fatigue and hypertension were the most common demcizumab-related toxicities. The addition of carboplatin and pemetrexed did not appear to impact demcizumab pharmacokinetics. Of 33 patients evaluable for efficacy, one (3%) had a complete response, 15 (45%) had a partial response and 13 (39%) had stable disease per RECST criteria. The overall clinical benefit rate was 88 percent. Median progression-free survival was not reached as of July 25, 2014 for the patients treated with the Phase 2 regimen. Eight patients treated with demcizumab once every three weeks at doses of 5mg/kg or 7.5mg/kg plus pemetrexed and carboplatin on-study and in some cases continued administration of protocol defined chemotherapy off-study have remained progression free for greater than 300 days.
The Phase 1b implemented truncated dosing of demcizumab along with cardiac monitoring using BNP and echocardiography following the occurrence of reversible cardiopulmonary toxicity in earlier studies. The combination of truncated dosing and cardiac monitoring appears to prevent the onset of late cardiopulmonary toxicity. Of note, the truncated dosing schedule did not appear to impact drug efficacy: among the 14 evaluable patients, who received demcizumab on a truncated dosing schedule, one had a complete response, seven had a partial response, five achieved stable disease and one had progressive disease resulting in an overall clinical benefit rate in this subset of patients of 93 percent.
Truncated demcizumab dosing at 5mg/kg once every three weeks is ongoing with three patients at this dose level still on therapy as of the data cut off of July 25, 2014. The company expects to initiate a large international randomized Phase 2 clinical trial of demcizumab with carboplatin and pemetrexed in first-line non-squamous NSCLC by the end of the year. The planned demcizumab dose for the Phase 2 study will be 5mg/kg once every three weeks.
Data from the Phase 1b study of demcizumab in NSCLC were presented on September 27 in a poster titled: “A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab (DEM), Pemetrexed (PEM) & Carboplatin (CARBO) in Patients with First-line Non-Squamous NSCLC” (#1240P).
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage company focused on discovering and developing novel therapeutics targeting cancer stem cells (CSCs). OncoMed has five anti-cancer product candidates in clinical development, including demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), anti-Notch1 (OMP-52M51), vantictumab (anti-FZD7, OMP-18R5), and ipafricept (FZD8-Fc, OMP-54F28), which target key cancer stem cell signaling pathways including Notch and Wnt. OncoMed has two other antibodies in preclinical development, anti-DLL4/anti-VEGF bispecific (OMP-305B83) and anti-RSPO3 (OMP-131R10), with Investigational New Drug filings planned for late 2014 or early 2015. OncoMed is also pursuing discovery of additional novel anti-CSC and cancer immunotherapy product candidates. OncoMed has formed strategic alliances with Celgene Corporation, Bayer Pharma AG and GlaxoSmithKline (GSK). Additional information can be found at the company’s website: www.oncomed.com.
To the extent that statements contained in this press release are not descriptions of historical facts regarding OncoMed Pharmaceuticals, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including OncoMed’s expectations regarding the advancement of demcizumab into randomized Phase 2 clinical trials in NSCLC and pancreatic cancer; the timing of Phase 2 clinical trials for demcizumab; the tolerability of demcizumab at efficacious doses; the ability of OncoMed’s dosing and cardiac monitoring strategies to mitigate demcizumab-related toxicities while maintaining efficacy; the potential of demcizumab to significantly impact treatment and the clinical outcome of patients with cancer, especially pancreatic cancer or NSCLC; the potential of anti-cancer stem cell therapeutics; and the timing of Investigational New Drug filings for OncoMed’s anti-DLL4/anti-VEGF bispecific and anti-RSPO3 antibodies. Such forward-looking statements involve substantial risks and uncertainties that could cause OncoMed’s clinical development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainties inherent in the preclinical and clinical development process; the risks and uncertainties of the regulatory approval process; OncoMed’s dependence on its collaboration partners, including Celgene, GSK and Bayer, for the funding of its partnered programs; OncoMed’s ability to raise additional capital to support the development of its unpartnered programs; OncoMed’s dependence on the development and marketing efforts of its partners for the commercial success of its partnered product candidates; OncoMed’s reliance on third parties to conduct certain preclinical studies and all of its clinical trials; OncoMed’s reliance on single source third-party contract manufacturing organizations to manufacture and supply its product candidates; OncoMed’s ability to validate, develop and obtain regulatory approval for companion diagnostics; OncoMed’s ability to achieve market acceptance and commercial success of its product candidates once regulatory approval is achieved; OncoMed’s ability to discover, develop and commercialize additional product candidates; the ability of competitors to discover, develop or commercialize competing products more quickly or more successfully; OncoMed’s dependence on its Chairman and Chief Executive Officer, its Chief Scientific Officer, its Chief Medical Officer and other key executives; risk of third party claims alleging infringement of patents and proprietary rights or seeking to invalidate OncoMed’s patents or proprietary rights; and the ability of OncoMed’s proprietary rights to protect its technologies and product candidates. OncoMed undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to OncoMed’s business in general, see OncoMed’s Annual Report on Form 10-K for the fiscal year ended December 31, 2013, filed with the Securities and Exchange Commission (SEC) on March 18, 2014, OncoMed’s Quarterly Report on Form 10-Q for the fiscal quarter ended March 31, 2014, filed with the SEC on May 8, 2014, and OncoMed’s Quarterly Report on Form 10-Q for the fiscal quarter ended June 30, 2014, filed with the SEC on August 7, 2014.
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