Date: 2017-04-10
Type of
information: Halting of the trial
phase: 2
Announcement: halting of the trial
Company: OncoMed Pharmaceuticals (USA - CA) Celgene (USA - NJ)
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.
Disease: first-line metastatic pancreatic cancer
Therapeutic
area: Cancer - Oncology
Country: Australia, Belgium, Canada, Spain, UK, USA
Trial
details:
- The double-blind, placebo-controlled Phase 2 "YOSEMITE" clinical trial is designed to compare the efficacy and safety of demcizumab combined with standard of care Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in patients with first-line metastatic pancreatic cancer. The Phase 2 dose of demcizumab was 3.5 mg/kg every two weeks for up to 70 days. The primary endpoint of the trial is progression-free survival. Secondary endpoints include overall survival, response rate, duration of response, safety, immunogenicity and pharmacokinetics. Patients enrolled in the YOSEMITE Phase 2 were randomized into one of three study arms receiving 1) standard of care plus one course of demcizumab, 2) standard of care plus demcizumab followed by a second course of demcizumab after a 98-day wash-out period or 3) standard of care plus placebo. (NCT02289898)
Latest
news:
- • On April 10, 2017, OncoMed Pharmaceuticals reported top-line results from the company's Phase 2 YOSEMITE clinical trial of demcizumab in combination with Abraxane® plus gemcitabine in previously untreated patients with metastatic pancreatic cancer. The trial was designed to assess the efficacy and safety of demcizumab plus standard-of-care chemotherapy in first-line metastatic pancreatic cancer with the primary endpoint of progression-free survival and a secondary endpoint of overall survival. The trial did not meet the primary endpoint of progression-free survival. Additionally, the interim median overall survival analysis did not show a benefit for demcizumab in combination with Abraxane plus gemcitabine compared to the Abraxane, gemcitabine plus placebo arm in patients with first-line metastatic pancreatic cancer. Based on the lack of benefit over standard-of-care, Peregrine Pharmaceuticals will be discontinuing the trial. The company will also discontinue any additional enrollment in the other ongoing demcizumab trials and conduct analyses of the data from those trials as planned.
Summary of Key Findings
Progression-Free Survival: The median progression-free survival (mPFS) was essentially the same across all arms of the study. For patients receiving demcizumab (either one or two truncated courses) in combination with Abraxane plus gemcitabine the mPFS was 5.5 months compared to a mPFS of 5.5 months for those in the Abraxane, gemcitabine plus placebo group (HR=0.93). In addition, no significant differences were observed when the individual treatment arms were compared to the Abraxane, gemcitabine plus placebo arm: in patients receiving a single truncated course of demcizumab the mPFS was 5.4 months (HR=1.03), and the mPFS was 5.5 months (HR=0.83) in patients receiving two truncated courses of demcizumab.
Interim Overall Survival: The interim median overall survival (mOS) for patients receiving either one or two truncated courses of demcizumab in combination with Abraxane plus gemcitabine (n =136) was 13.2 months, while a mOS was not reached for the Abraxane, gemcitabine plus placebo arm (HR=1.02). No significant differences were observed when the individual treatment arms were compared: an interim mOS of 10.6 months was observed with a single course of demcizumab (n=71) (HR=1.2) and an interim mOS of 13.3 months was seen among patients receiving two courses of demcizumab (n=65) (HR=0.87). These results are based on an analysis that occurred at the 125th PFS event at which time there were 75 deaths.
Response and Clinical Benefit Rates: Overall response rate (defined as complete responses and partial responses) was 33.1% (45 of 136 patients) in the combined demcizumab, Abraxane plus gemcitabine groups and 41.2% (28 of 68 patients) in the Abraxane, gemcitabine plus placebo group. The overall clinical benefit rate (defined as complete responses, partial responses and stable disease) was slightly higher in the pooled demcizumab arms at 74.3% (101 of 136 patients) compared to 70.6% (48 of 68 patients) in the Abraxane, gemcitabine plus placebo group. Response was measured using the RECIST 1.1 criteria and is based on unconfirmed investigator assessment.
Safety and tolerability: Demcizumab, Abraxane plus gemcitabine were generally well tolerated with nausea, diarrhea, anemia and fatigue being the most common reported toxicities. The incidence of Grade 3 or greater heart failure, pulmonary hypertension and bleeding were (3.7% vs. 0%), (0.7% vs 0%) and (8.1% vs. 1.5%) in the pooled demcizumab, Abraxane plus gemcitabine arms and the Abraxane, gemcitabine plus placebo arm, respectively.
• On September 1, 2016, OncoMed Pharmaceuticals announced the completion of patient enrollment of 207 patients in the randomized Phase 2 "YOSEMITE" clinical trial of demcizumab (anti-DLL4, OMP-21M18) for the treatment of first-line metastatic pancreatic cancer. Topline results are expected in the first half of 2017.
In OncoMed's Phase 1b clinical trial of demcizumab truncated dosing and Abraxane plus gemcitabine, 14 of 28 (50%) patients evaluable for response achieved partial responses (unconfirmed) and another 11 (39%) achieved stable disease. Among 32 patients evaluable for survival in the Phase 1b, median progression-free survival was 7.1 months and median overall survival was 12.7 months for the patients who received one truncated 70-day course of demcizumab with Abraxane plus gemcitabine. The combination of demcizumab and Abraxane plus gemcitabine was generally well tolerated with fatigue, nausea and vomiting being the most common drug related toxicities. Final results from OncoMed's Phase 1b trial of demcizumab were presented at the 2016 Gastrointestinal Cancers Symposium.
- • On April 22, 2015, OncoMed Pharmaceuticals announced that dosing has begun in the randomized Phase 2 clinical trial of demcizumab (anti-DLL4, OMP-21M18) in patients with first-line metastatic pancreatic cancer. The double-blind, placebo-controlled Phase 2 "YOSEMITE" clinical trial is designed to compare the efficacy and safety of demcizumab combined with standard of care Abraxane® (paclitaxel protein-bound particles for injectable suspension) (albumin bound) plus gemcitabine in patients with first-line metastatic pancreatic cancer. Approximately 200 patients will be randomized into one of three study arms. Patients in Arm 1 will receive Abraxane plus gemcitabine (standard of care) plus placebo. Patients in Arm 2 will receive standard of care plus one course of demcizumab 3.5 mg/kg every two weeks for 70 days. Patients in Arm 3 will receive standard of care plus a second course of demcizumab following a 100-day wash out period. The Phase 2 trial is being conducted at approximately 50 centers in the U.S., Canada, Europe and Australia.
- OncoMed is eligible to achieve a $70 million milestone from Celgene for successful completion of an interim safety analysis associated with the two randomized demcizumab Phase 2 trials (the YOSEMITE study and the DENALI non-small cell lung cancer trial). The safety analysis will be performed by an independent data safety monitoring board (DSMB) using pre-specified safety criteria agreed to in the collaboration agreement and is expected to occur in late 2015/early 2016.
Is
general: Yes
