Investigational New Drugs

, Volume 33, Issue 2, pp 349–356 | Cite as

Phase I study of XL281 (BMS-908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors

  • Mark A. Dickson
  • Michael S. Gordon
  • Gerald Edelman
  • Johanna C. Bendell
  • Ragini R. Kudchadkar
  • Patricia M. LoRusso
  • Stuart H. Johnston
  • Douglas O. Clary
  • Gary K. Schwartz


Background XL281 is a potent and selective inhibitor of wild-type and mutant RAF kinases with anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may confer sensitivity to RAF kinase inhibitors. Methods We performed a phase I study of XL281 in patients with advanced solid tumors. Patients were enrolled in successive cohorts of XL281 orally once daily in 28-day cycles. Twice daily dosing, different formulations, and the effect of food and famotidine were also studied. At the MTD expanded cohorts with defined mutations were treated. Results In total, 160 patients were treated. The MTD on the QD schedule was 150 mg. The most common toxicities were diarrhea, nausea, and fatigue. Plasma Cmax and AUC increased with dose. Famotidine resulted in lower AUC while food had no effect. Two patients had partial responses by RECIST: One with papillary thyroid cancer with NRAS mutation and one with uveal melanoma. Another nine patients had tumor decrease of >10 % but did not meet RECIST criteria for PR. Matched tumors pairs from 33 patients showed evidence of RAF inhibition with significant decreases in pERK, pMEK and pAKT. Conclusions XL281 was generally well tolerated and the MTD was established at 150 mg/day. Partial responses and clinical benefit were observed in several patients. Tumor biopsies demonstrated effective target inhibition.


Phase I Trials Kinase inhibitors Pharmacokinetics and pharmacodynamics 


Conflict of interest

Two authors (D.O.C. and S.H.J.) are paid employees of the sponsor. All other authors declare no potential conflicts of interest.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


The study was sponsored by Exelixis.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mark A. Dickson
    • 1
    • 2
  • Michael S. Gordon
    • 3
  • Gerald Edelman
    • 4
  • Johanna C. Bendell
    • 5
  • Ragini R. Kudchadkar
    • 6
  • Patricia M. LoRusso
    • 7
  • Stuart H. Johnston
    • 8
  • Douglas O. Clary
    • 8
  • Gary K. Schwartz
    • 9
  1. 1.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Weill Cornell Medical CollegeNew YorkUSA
  3. 3.Pinnacle Oncology HematologyScottsdaleUSA
  4. 4.Mary Crowley Cancer Research CenterDallasUSA
  5. 5.Sarah Cannon Research InstituteNashvilleUSA
  6. 6.Emory UniversityAtlantaUSA
  7. 7.Yale UniversityNew HavenUSA
  8. 8.Exelixis Inc.South San FranciscoUSA
  9. 9.Columbia University Medical CenterNew YorkUSA

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