Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma Journal Article
| Authors: | O'Reilly, E. M.; Barone, D.; Mahalingam, D.; Bekaii-Saab, T.; Shao, S. H.; Wolf, J.; Rosano, M.; Krause, S.; Richards, D. A.; Yu, K. H.; Roach, J. M.; Flaherty, K. T.; Ryan, D. P. |
| Article Title: | Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma |
| Abstract: | Background: Necuparanib, a rationally engineered low-molecular-weight heparin, combined with gemcitabine/nab-paclitaxel showed an encouraging safety and oncologic signal in a phase Ib trial. This randomised multicentre phase II trial evaluates the addition of necuparanib or placebo to gemcitabine/nab-paclitaxel in untreated metastatic pancreatic ductal adenocarcinoma (PDAC). Patients and methods: Eligibility included 18 years, histologically or cytologically confirmed metastatic PDAC, measurable disease and Eastern Co-Operative Oncology Group performance status of 0–1. Patients were randomly assigned to necuparanib (5 mg/kg subcutaneous injection once daily) or placebo (subcutaneous injection once daily) and gemcitabine/nab-paclitaxel on days 1, 8 and 15 of 28-day cycles. The primary end-point was median overall survival (OS), and secondary end-points included median progression-free survival, response rates and safety. Results: One-hundred ten patients were randomised, 62 to necuparanib arm and 58 to placebo arm. The futility boundary was crossed at a planned interim analysis, and the study was terminated by the Data Safety Monitoring Board. The median OS was 10.71 months (95% confidence interval [CI]: 7.95–11.96) for necuparanib arm and 9.99 months (95% CI: 7.85–12.85) for placebo arm (hazard ratio: 1.12, 95% CI: 0.66–1.89, P-value: 0.671). The necuparanib arm had a higher incidence of haematologic toxicity relative to placebo patients (83% and 70%). Conclusion: The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243 © 2020 Elsevier Ltd |
| Keywords: | adult; cancer survival; controlled study; treatment response; aged; major clinical study; overall survival; fatigue; neutropenia; cancer combination chemotherapy; diarrhea; drug efficacy; drug safety; drug withdrawal; hypophosphatemia; side effect; gemcitabine; paclitaxel; metastasis; progression free survival; multiple cycle treatment; phase 2 clinical trial; sensory neuropathy; anemia; bleeding; randomized controlled trial; thrombocytopenia; cohort analysis; deep vein thrombosis; abdominal pain; alanine aminotransferase blood level; aspartate aminotransferase blood level; febrile neutropenia; lymphocytopenia; pneumonia; lung embolism; alanine aminotransferase; aspartate aminotransferase; hypokalemia; hyponatremia; add on therapy; multicenter study; vein thrombosis; thrombosis; antibody response; peripheral edema; pancreas adenocarcinoma; pleura effusion; hyperbilirubinemia; hematoma; pericardial effusion; epistaxis; brain hemorrhage; chemotherapy-induced peripheral neuropathy; skin bleeding; heparin induced thrombocytopenia; rectum hemorrhage; nab-paclitaxel; hypertransaminasemia; low-molecular-weight heparin; activated partial thromboplastin time; human; male; female; priority journal; article; median survival time; peripheral vein; necuparanib; metastatic pancreatic cancer; chemotherapy induced nausea; injection site bleeding |
| Journal Title: | European Journal of Cancer |
| Volume: | 132 |
| ISSN: | 0959-8049 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-06-01 |
| Start Page: | 112 |
| End Page: | 121 |
| Language: | English |
| DOI: | 10.1016/j.ejca.2020.03.005 |
| PROVIDER: | scopus |
| PUBMED: | 32361265 |
| PMCID: | PMC8133644 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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