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.

Keywords: Gemcitabine; Low-molecular-weight heparin; Metastatic pancreatic cancer; Nab-paclitaxel; Necuparanib.

Conflict of interest statement

Conflict of interest statement E.M. O.’R. received research funding to MSK: Momenta Pharmaceuticals, Genentech, Roche, BMS, Celgene, MabVax Therapeutics, ActaBiologica, Parker Institute, AstraZeneca, Silenseed. She is a consulting/advisory to Cytomx, BioLineRx, Targovax, Celgene, Bayer, Loxo, Polaris, Merck, AstraZenica to Consulting/advisory. D.M. received research funding from Oncolytics and Merck and is a consultant/advisory to Amgen, Bayer, BMS, Eisai, EMD Serono, Exelexis, Genentech. T.B.S. is a consultant to Imugene, Immuneering, Bayer, Genentech, Incyte, Ipsen, Exelexis, Lilly, Astra-Zeneca, Merck and Array. M.R., J.M.R.: Momenta Pharmaceuticals (former employee). K.T.F. is Board of Directors at Clovis Oncology, Strata Oncology, Vivid Biosciences, Checkmate Pharmaceuticals; he is also in Corporate Advisory Board of X4 Pharmaceuticals, PIC Therapeutics, Scientific Advisory Board of Sanofi, Amgen, Asana, Adaptimmune, Fount, Aeglea, Shattuck Labs, Tolero, Apricity, Oncoceutics, Fog Pharma, Neon, Tvardi, xCures, Monopteros, Vibliome, and he is Consultant for Novartis, Genentech, BMS, Merck, Takeda, Verastem, Boston Biomedical, Pierre Fabre, Debiopharm. D.R.: Equity: MPM Capital, Acworth Pharmaceuticals, is on Advisory Board of MPM Capital, Oncorus, Gritstone Oncology, Maverick Therapeutics. Publishing: Johns Hopkins University Press, Uptodate McGraw Hill. All other authors have no competing interests.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:

CONSORT Flow Diagram

Figure 2:

Kaplan-Meier Overall Survival Curve

Figure 3:

Kaplan-Meier Progression-Free Survival Curve