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Targeted Oncology

, Volume 12, Issue 1, pp 97–109 | Cite as

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

  • Jean-Luc Van LaethemEmail author
  • 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
Original Research Article

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.

Keywords

Gemcitabine Objective Response Rate KRAS Mutation Disease Control Rate Advanced Pancreatic Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank Tanja Torbica, PhD, at Complete HealthVizion for assistance in the preparation and revision of the draft manuscript, based on detailed discussion and feedback from all the authors.

Compliance with Ethical Standards

Funding

This study was supported by Bayer HealthCare Pharmaceuticals, Inc. John Bridgewater is partly supported by the UCLH/UCL Biomedical Research Centre.

Conflict of Interest

HR has performed a consulting or advisory role for Boehringer Ingelheim, Bayer, GlaxoSmithKline, Bristol-Myers Squibb, Roche, and Sanofi-Aventis. JJ has performed a consulting or advisory role for Eli Lilly, Pfizer, AstraZeneca, and Celgene; participated in a speaker bureau for Roche; received research funding from GlaxoSmithKline, Roche, and Novartis; and received travel, accommodation, and other expenses from Boehringer Ingelheim. MH has received honoraria from Celgene, research funding from Roche and Boehringer Ingelheim, and travel, accommodation, and other expenses from Celgene and Boehringer Ingelheim. MP has received honoraria and research funding from Bayer. PR has received honoraria from Roche, Sirtex, Bayer, and Celgene; performed a consulting or advisory role for Roche, Sirtex, Sanofi-Aventis, Celgene, Baxter, Merck Serono, and Daiichi Sankyo; received research funding from Sanofi-Aventis, Bayer, Roche, and Merrimack; and received travel, accommodation, and other expenses from Roche, Merck Serono, Celgene, and Sanofi-Aventis. JB is partly supported by the UCLH/UCL Biomedical Research Centre. He has performed a consulting or advisory role for Roche, Merck Serono, and AstraZeneca, and has received travel, accommodation, and other expenses from Merck Serono and the European Society for Medical Oncology. BM has received honoraria from, and has performed a consulting or advisory role for, Bayer. SC has performed a consulting or advisory role for Roche, Sanofi-Aventis, and Celgene. PM has received honoraria from Ipsen, Bayer, and Celgene, and has received research funding from Ipsen. DVB has received travel, accommodation, and other expenses from Amgen. MG, KR, AS, and HS are employees of Bayer Pharma AG. VLG is an employee of Bayer S.p.A. PRa is an employee of Bayer HealthCare Pharmaceuticals, Inc. and has stock or other ownership interests in Bayer HealthCare Pharmaceuticals, Inc. MT and BHC are employees of Bayer HealthCare Pharmaceuticals, Inc. J-LVL, UMM, CW, PS, AZ, WS, and SD have no conflicts of interest to declare.

Supplementary material

11523_2016_469_MOESM1_ESM.docx (553 kb)
ESM 1 (DOCX 553 kb)

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Jean-Luc Van Laethem
    • 1
    Email author
  • Hanno Riess
    • 2
  • Jacek Jassem
    • 3
  • Michael Haas
    • 4
  • Uwe M. Martens
    • 5
  • Colin Weekes
    • 6
  • Marc Peeters
    • 7
  • Paul Ross
    • 8
  • John Bridgewater
    • 9
  • Bohuslav Melichar
    • 10
  • Stefano Cascinu
    • 11
  • Piotr Saramak
    • 12
  • Patrick Michl
    • 13
    • 14
  • David Van Brummelen
    • 15
  • Alberto Zaniboni
    • 16
  • Wollf Schmiegel
    • 17
  • Svein Dueland
    • 18
  • Marius Giurescu
    • 19
  • Vittorio L. Garosi
    • 20
  • Katrin Roth
    • 19
  • Anke Schulz
    • 19
  • Henrik Seidel
    • 19
  • Prabhu Rajagopalan
    • 21
  • Michael Teufel
    • 21
  • Barrett H. Childs
    • 21
  1. 1.Department of GastroenterologyErasme University HospitalBrusselsBelgium
  2. 2.Medical Department, Division of Hematology, Oncology and Tumor ImmunologyCharity Hospital, Virchow-Klinikum CampusBerlinGermany
  3. 3.Department of Oncology and RadiotherapyMedical University of GdanskGdanskPoland
  4. 4.Department of Hematology and OncologyUniversity of Munich Medical CenterMunichGermany
  5. 5.Department of Hematology and OncologyCancer Center Heilbronn-FrankenHeilbronnGermany
  6. 6.Division of Medical OncologyUniversity of Colorado Cancer CenterAuroraUSA
  7. 7.Department of OncologyAntwerp University HospitalEdegemBelgium
  8. 8.Department of Medical OncologyGuy’s & St Thomas’ HospitalLondonUK
  9. 9.Department of OncologyUCL Cancer InstituteLondonUK
  10. 10.Department of OncologyPalacky University Medical School and University Hospital OlomoucOlomoucCzech Republic
  11. 11.Department of Medical Oncology, A.O.U. United HospitalsPolytechnic University of MarcheAnconaItaly
  12. 12.Department of Oncological GastroenterologyMaria Skłodowska-Curie Memorial Cancer CenterWarsawPoland
  13. 13.Department of Gastroenterology, Endocrinology, Metabolism and InfectiologyUniversity Hospital of Giessen and MarburgMarburgGermany
  14. 14.Universitätsklinikum Halle - University Hospital Halle (Saale)Halle (Saale)Germany
  15. 15.Department of RadiotherapyUZ BrusselsBrusselsBelgium
  16. 16.Department of Medical OncologyPoliambulanza Foundation Hospital InstituteBresciaItaly
  17. 17.Department of Gastroenterology and HepatologyMedical University Hospital BochumBochumGermany
  18. 18.Department of OncologyOslo University Radium HospitalOsloNorway
  19. 19.Bayer Pharma AGBerlinGermany
  20. 20.Bayer S.p.A.MilanItaly
  21. 21.Bayer HealthCare Pharmaceuticals, Inc.WhippanyUSA

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