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

Eileen M O'Reilly, James Roach, Paul Miller, Kenneth H Yu, Catherine Tjan, Molly Rosano, Silva Krause, William Avery, Julie Wolf, Keith Flaherty, Darrell Nix, David P Ryan, Eileen M O'Reilly, James Roach, Paul Miller, Kenneth H Yu, Catherine Tjan, Molly Rosano, Silva Krause, William Avery, Julie Wolf, Keith Flaherty, Darrell Nix, David P Ryan

Abstract

Lessons learned: Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling.

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 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.

Trial registration: ClinicalTrials.gov NCT01621243.

© AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
Dose escalation and disposition in patients receiving at least one dose of necuparanib. Abbreviations: aPTT, activated partial thromboplastin time; DLT, dose‐limiting toxicity; Gem, gemcitabine; HGF, hepatocyte growth factor; LFTs, liver function tests; NabP, nab‐paclitaxel; Necu, necuparanib; PK, pharmacokinetics.
Figure 2.
Figure 2.
Concentration of necuparanib for patients with at least three measurable levels on day 1.
Figure 3.
Figure 3.
Activated partial thromboplastin time and prothrombin time in patients who received necuparanib in combination with nab‐paclitaxel and gemcitabine (cohorts 3–7). Abbreviations: aPTT, activated partial thromboplastin time; PT, prothrombin time.
Figure 4.
Figure 4.
Mean (standard deviation) serum hepatocyte growth factor levels by dose group Abbreviations: Gem, gemcitabine; HGF, hepatocyte growth factor; NabP, nab‐paclitaxel; necu, necuparanib.
Figure 5.
Figure 5.
Patient time on study for patients receiving necuparanib + gemcitabine (cohorts 1 and 2; A) or necuparanib + nab‐paclitaxel + gemcitabine (cohorts 3–7; B). Abbreviations: Gem, gemcitabine; NabP, nab‐paclitaxel; NE, not evaluable; Necu, necuparanib; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 6.
Figure 6.
Patient time on study for patients receiving necuparanib + gemcitabine (cohorts 1 and 2; A) or necuparanib + nab‐paclitaxel + gemcitabine (cohorts 3–7; B). Abbreviations: Gem, gemcitabine; NabP, nab‐paclitaxel; NE, not evaluable; Necu, necuparanib; PD, progressive disease; PR, partial response; SD, stable disease.

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