Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed.
OBJECTIVE
Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator of transcription pathway in the pathogenesis and clinical course of pancreatic cancer.


METHODS
In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation.


RESULTS
In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).


CONCLUSIONS
Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE. herbert.hurwitz@duke.edu.
Herbert I
HI
Hurwitz
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Nikhil
N
Uppal
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Stephanie A
SA
Wagner
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Johanna C
JC
Bendell
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
J Thaddeus
JT
Beck
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Seaborn M
SM
Wade
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
John J
JJ
Nemunaitis
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Philip J
PJ
Stella
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
J Marc
JM
Pipas
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Zev A
ZA
Wainberg
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Robert
R
Manges
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
William M
WM
Garrett
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Deborah S
DS
Hunter
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Jason
J
Clark
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Lance
L
Leopold
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Victor
V
Sandor
Herbert I. Hurwitz, Duke University Medical Center, Durham, NC; Nikhil Uppal, New York University Langone Arena Oncology, Lake Success, NY; Stephanie A. Wagner, Indiana University Melvin and Bren Simon Cancer Center; Robert Manges, Investigative Clinical Research of Indiana, Indianapolis, IN; Johanna C. Bendell, Sarah Cannon Research Institute, Nashville, TN; J. Thaddeus Beck, Highlands Oncology Group, Fayetteville, AR; Seaborn M. Wade III, Virginia Cancer Institute, Richmond, VA; John J. Nemunaitis, Mary Crowley Medical Research Center, Dallas, TX; Philip J. Stella, St Joseph Mercy Health System, Alexander Cancer Care Center, Ann Arbor, MI; J. Marc Pipas, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center, Lebanon, NH; Zev A. Wainberg, University of California, Los Angeles, Los Angeles, CA; and William M. Garrett, Deborah S. Hunter, Jason Clark, Lance Leopold, Victor Sandor, and Richard S. Levy, Incyte Corporation, Wilmington, DE.
Richard S
RS
Levy
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine / Q000008:administration & dosage; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines; D015996:Survival Rate; D000093542:Gemcitabine
D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D003841:Deoxycytidine; D000069287:Capecitabine; C540383:ruxolitinib; D000093542:Gemcitabine