Phase I clinical data on Anti-Notch2/3 was featured earlier this week in an oral plenary session at the24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland. Additional clinical biomarker data were presented in a poster session. Demcizumab (OncoMed Pharmaceuticals, Inc)Phase Ib clinical data in non-small cell lung cancer patients were also featured in a separate poster session.

The oral presentationby the principal Investigator David C. Smith, M.D.,Professor of Medicine and Urology and the University of Michigan Cancer Centerevaluated the OMP-59R5 (OncoMed Pharmaceuticals, Inc) administered intravenously to patients with advance solid tumors.

Cancer Stem Cells
OMP-59R5 is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Initially discovered by screening a phage display library against the Notch2 receptor, the antibody binds to a conserved epitope on Notch2 and Notch3. Preclinical studies have demonstrated that OMP-59R5 exhibits two mechanisms of action. The firstmechanism downregulates Notch pathway signaling confirming that OMP-59R5 appears to have anti-Cancer Stem cells or anti-CSC effects.CSCs, the subpopulation of cells in a tumor responsible for driving growth and metastasis of the tumor.

CSCsarealso known as tumor-initiating cells, exhibit certain properties which include the capacity to divide and give rise to new CSCs via a process called self-renewal and the capacity to differentiate or change into the other cells that form the bulk of the tumor. Common cancer drugs target bulk tumor cells but have limited impact on CSCs, thereby providing a path for recurrence of the tumor.

The second mechanismshows that OMP-59R5 affects pericytes, impacting stromal and tumor microenvironment. The program is currently in Phase Ib/II in first-line advanced pancreatic cancer patients.

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Clinical trial
In clinical trial (n=39 patients), OMP-59R5 was generally well tolerated, with diarrhea as the main treatment-related and dose-related adverse event. Maximum tolerated doses (MTDs) have been established at doses of 2.5mg/kg weekly and 7.5mg/kg every three weeks.

The results showed that an every two week dosing schedule,also under investigation,prolonged stable diseasenoted in multiple tumor types, including adenoid cystic carcinoma, liposarcoma, Kaposi?s sarcoma, rectal cancer, and triple-negative breast cancer. Based on these data, researchers at OncoMed have advanced Anti-Notch2/3 into an ongoing Phase Ib/II ALPINE trial (Antibody therapy in first-Line Pancreatic cancer Investigating anti-Notch Efficacy and safety) in first-line advanced pancreatic cancer patients.

Pharmacodynamic modulation
In addition, the company presented a poster (Abstract #314, Poster #64) describing the results of a comprehensive biomarker analysis in the Anti-Notch2/3 PhaseI study, which demonstrated pharmacodynamic (PD) modulation of the Notch pathway in patients with advanced solid tumors.

Principal Investigator Anthony W. Tolcher, M.D., FRCP and colleagues of The START Center for Cancer Care, San Antonio, TX concluded that the PD effects of OMP-59R5 on Notch targets, stem cell pathways in surrogate tissues, and in tumor tissue on serial biopsy were clearly established in this first-in-human study at doses equal to or greater than 1mg/kg every other week.

In an unrelated interim Phase Ib trial of demcizumab (Anti-DLL4, OMP-21M18), a humanized monoclonal antibody that inhibits Delta Like Ligand 4, or DLL4, in the Notch signaling pathway, clinical data in non-small cell lung cancer was presented in a poster session (Abstract #598, Poster #169) at the meeting. Principal Investigator Mark McKeage M.D. of the University of Auckland, Auckland, New Zealand and colleagues reported that in 17 evaluable patients, treatment of demcizumab plus pemetrexed and carboplatin resulted in disease control(partial response plus stable disease by RECIST) in 94% (16 of 17) of patients, including a 44% RECIST partial response rate. Additionally, two patients treated with 5mg/kg every three weeks remain progression free for greater than 16 months. The trial showed that demcizumab was well tolerated, with fatigue and hypertension being the most common drug-related toxicities.

?Both demcizumab and Anti-Notch2/3 appear to have tolerable safety profiles, and we are encouraged by the efficacy and biomarker results to date,? noted Jakob Dupont, MD, OncoMed?s Chief Medical Officer. Paul Hastings, President and Chief Executive Officer of OncoMed, added, ?We are excited to present clinical data on two of our anti-cancer stem cell investigational product candidates at the EORTC-AACR-NCI meeting, and we look forward to advancing both of these product candidates further in clinical development.?

Manufacturing agreement
Last month, Lonza Group Ltd, a global leader in biological manufacturing and OncoMed Pharmaceuticals, Inc, agreed that Lonza will developand manufactureOncoMed?s pipeline of anti-cancer stem cell therapeutics. Under the agreement, Lonza will produce material at its mammalian manufacturing facility in Slough, UK. The multi-product GS System? License provides access to Lonza?s GS Gene Expression System? and Version 8 Media and Feeds Manufacturing Platform.

For more information:
– A First-in-Human Phase I Study to Evaluate the Fully Human Monoclonal Antibody OMP-59R5 (anti-Notch2/3) Administered Intravenously to Patients with Advance Solid Tumors? (abstract #28)

Clinical trials
NCT01277146 – A Dose Escalation Study of OMP-59R5 in Subjects With Solid Tumors
NCT01647828 – A Phase 1b/2 Study of OMP-59R5 in Combination With Gemcitabine in Subjects With Previously Untreated Stage IV Pancreatic Cancer (ALPINE)
NCT00744562 – A Phase 1 Dose Escalation Study of OMP-21M18 in Subjects With Solid Tumors
NCT01189968 – A Study of Carboplatin and Pemetrexed Plus OMP-21M18 in Subjects With Non-Squamous Non-Small Cell Lung Cancer
NCT01189942 – A Study of FOLFIRI Plus OMP-21M18 as 1st or 2nd-line Treatment in Subjects With Metastatic Colorectal Cancer
NCT01189929 – A Study of Gemcitabine Plus OMP-21M18 as 1st-line Treatment in Subjects With Pancreatic Cancer

Photo 1: David C. Smith, M.D., Professor of Medicine and Urology. Photo Credit: University of Michigan Cancer CenterPhoto 2: Anthony W. Tolcher, M.D., FRCP. Photo Credit.The START Center for Cancer Care, San Antonio, TX.Photo 3: Mark McKeage M.D. The University of Auckland, Auckland, New Zealand.

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