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Targeted Oncology
Published in: Targeted Oncology 1/2017

01-02-2017 | Original Research Article

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Authors: Jean-Luc Van Laethem, Hanno Riess, Jacek Jassem, Michael Haas, Uwe M. Martens, Colin Weekes, Marc Peeters, Paul Ross, John Bridgewater, Bohuslav Melichar, Stefano Cascinu, Piotr Saramak, Patrick Michl, David Van Brummelen, Alberto Zaniboni, Wollf Schmiegel, Svein Dueland, Marius Giurescu, Vittorio L. Garosi, Katrin Roth, Anke Schulz, Henrik Seidel, Prabhu Rajagopalan, Michael Teufel, Barrett H. Childs

Published in: Targeted Oncology | Issue 1/2017

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Abstract

Background

Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.

Methods

Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.

Results

Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).

Conclusion

Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.
Appendix
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Metadata
Title
Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer
Authors
Jean-Luc Van Laethem
Hanno Riess
Jacek Jassem
Michael Haas
Uwe M. Martens
Colin Weekes
Marc Peeters
Paul Ross
John Bridgewater
Bohuslav Melichar
Stefano Cascinu
Piotr Saramak
Patrick Michl
David Van Brummelen
Alberto Zaniboni
Wollf Schmiegel
Svein Dueland
Marius Giurescu
Vittorio L. Garosi
Katrin Roth
Anke Schulz
Henrik Seidel
Prabhu Rajagopalan
Michael Teufel
Barrett H. Childs
Publication date
01-02-2017
Publisher
Springer International Publishing
Published in
Targeted Oncology / Issue 1/2017
Print ISSN: 1776-2596
Electronic ISSN: 1776-260X
DOI
https://doi.org/10.1007/s11523-016-0469-y

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