Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: Phase I results Journal Article
| Authors: | O’Reilly, E. M.; Roach, J.; Miller, P.; Yu, K. H.; Tjan, C.; Rosano, M.; Krause, S.; Avery, W.; Wolf, J.; Flaherty, K.; Nix, D.; Ryan, D. P. |
| Article Title: | Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: Phase I results |
| Abstract: | Background. Necuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab-paclitaxel in patients with metastatic pancreatic cancer. Methods. Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined. Results. Thirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab- paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplas-tin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTDand selected for further assessment in phase II. Conclusion. Acceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated. © AlphaMed Press 2017. |
| Journal Title: | The Oncologist |
| Volume: | 22 |
| Issue: | 12 |
| ISSN: | 1083-7159 |
| Publisher: | Oxford University Press |
| Date Published: | 2017-12-01 |
| Start Page: | 1429 |
| End Page: | 1430, e130-e139 |
| Language: | English |
| DOI: | 10.1634/theoncologist.2017-0472 |
| PROVIDER: | scopus |
| PMCID: | PMC5728039 |
| PUBMED: | 29158367 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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