Clinical Trials

Date: 2015-04-16

Type of information: Presentation of results at a congress

phase: 1b

Announcement: presentation of results at the European Lung Cancer Conference

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.

Disease: non-small cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country:

Trial details:

Latest news:

• • On April 16, 2015, OncoMed Pharmaceuticals presented new data from the Phase 1b clinical trial of demcizumab (anti-DLL4, OMP-21M18) in patients with first-line advanced non-small cell lung cancer (NSCLC) at the European Lung Cancer Conference. The Phase 1b trial studied several doses of demcizumab (2.5, 5, and 7.5 mg/kg) in combination with carboplatin and pemetrexed (Alimta®) every three weeks. Twenty-three subjects received continuous dosing of demcizumab with up to six cycles of pemetrexed and carboplatin followed by demcizumab maintenance. Twenty-three subjects received a truncated dosing schedule of demcizumab for four doses with pemetrexed and carboplatin, followed by pemetrexed maintenance. Of 40 patients evaluable for efficacy, the overall RECIST response rate was 50 percent (1 complete response and 19 partial responses) and an additional 15 patients had a best response of stable disease, yielding a clinical benefit rate of 88 percent.
• Median progression-free survival (PFS) based on Kaplan-Meier estimates was 5.3 months and 5.8 months for the continuous and truncated cohorts, respectively. A worst-case analysis (to ensure that Kaplan-Meier estimates are not impacted by selective reporting) showed a median overall survival (OS) of 6.3 months for the continuous demcizumab cohort, and a median OS of 8.1 months for the truncated dose patients. Prolonged PFS and OS were observed for a subset of patients treated with continuous demcizumab. This was apparent by the plateau at the tail end of the Kaplan Meier curve. Specifically, of the 23 patients in the continuous dosing group, ten survived more than 300 days. In these 10 patients who survived more than 300 days, there was a cumulative 21.8 years of patient follow-up beyond those 300 days, and among these ten patients, only two patient deaths occurred as of the February 26, 2015 data cut off. Survival data from patients treated with the truncated demcizumab dose regimen is less mature, although the Kaplan-Meier curves, as of the February cut-off date, show a similar trajectory.
• Safety and Tolerability and Biomarker Data: The regimen of demcizumab, pemetrexed and carboplatin was generally well-tolerated with fatigue, nausea and manageable hypertension being the most common demcizumab-related toxicities. Two cases of reversible Grade 3 pulmonary hypertension and heart failure occurred earlier in the trial in patients treated with continuous demcizumab for greater than 160 days. Subsequent patients were treated with a truncated risk mitigating demcizumab regimen (i.e., 63 days of treatment). The truncated demcizumab treatment and patient monitoring with BNP and ECHO appears to prevent the onset of late cardiopulmonary toxicity. There were no incidents of moderate-to-severe cardiopulmonary toxicity events observed using the truncated dosing regimen. The Phase 2 dose of demcizumab at 5mg/kg every three weeks administered on a truncated dosing schedule was selected. Pharmacodynamic analyses of gene expression of patient samples demonstrated clear modulation of the Notch pathway that lasted up to 77 days after the last dose of study drug.
• These data were presented at the European Lung Cancer Conference by Dr. Dupont on behalf of the demcizumab NSCLC study investigators in a poster titled "A Phase 1b study of anti-DLL4 (delta-like ligand 4) antibody demcizumab (DEM) with pemetrexed (PEM) and carboplatin (CARBO) in patients with 1st-line non-squamous NSCLC".
• • On September 29, 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(R) (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 NSCLC Demcizumab in combination with pemetrexed and carboplatin was generally well tolerated in 39 chemotherapy-naive 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).

Is general: Yes