Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results

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 gemcitabinenab-paclitaxel in patients with metastatic pancreatic cancer. Methods. Patients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m(2) gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m(2) 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 thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and 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.