PMID- 26252788
OWN - NLM
STAT- MEDLINE
DCOM- 20160408
LR  - 20220613
IS  - 2044-5385 (Electronic)
IS  - 2044-5385 (Linking)
VI  - 5
IP  - 8
DP  - 2015 Aug 7
TI  - A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor 
      fedratinib (SAR302503) in patients with myelofibrosis.
PG  - e335
LID - 10.1038/bcj.2015.63 [doi]
AB  - In this phase 2 open-label randomized study, 31 patients with intermediate-2 or 
      high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in 
      consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end 
      point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response 
      rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% 
      (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, 
      improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 
      weeks, 68% of patients remained on fedratinib and 16% had discontinued because of 
      adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), 
      diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of 
      reversible hepatic failure and one case of Wernicke's encephalopathy (after 
      analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but 
      no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, 
      adjusted for multiple comparisons) of 28 cytokines was observed, many of which 
      correlated with spleen reduction. These data confirm the clinical activity of 
      fedratinib in MF. After the analysis cutoff date, additional reports of 
      Wernicke's encephalopathy in other fedratinib trials led to discontinuation of 
      the sponsored clinical development program.
FAU - Pardanani, A
AU  - Pardanani A
AD  - Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
FAU - Tefferi, A
AU  - Tefferi A
AD  - Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
FAU - Jamieson, C
AU  - Jamieson C
AD  - Department of Medicine, UCSD Moores Cancer Centre, University of California San 
      Diego, La Jolla, CA, USA.
FAU - Gabrail, N Y
AU  - Gabrail NY
AD  - Gabrail Cancer Center, Canton, OH, USA.
FAU - Lebedinsky, C
AU  - Lebedinsky C
AD  - Sanofi Oncology, Sanofi, Cambridge, MA, USA.
FAU - Gao, G
AU  - Gao G
AD  - Sanofi Oncology, Sanofi, Cambridge, MA, USA.
FAU - Liu, F
AU  - Liu F
AD  - Sanofi Oncology, Sanofi, Cambridge, MA, USA.
FAU - Xu, C
AU  - Xu C
AD  - Sanofi Oncology, Sanofi, Cambridge, MA, USA.
FAU - Cao, H
AU  - Cao H
AD  - Sanofi Oncology, Sanofi, Cambridge, MA, USA.
FAU - Talpaz, M
AU  - Talpaz M
AD  - Division of Hematology-Oncology, Department of Internal Medicine, Comprehensive 
      Cancer Center, The University of Michigan Hospital and Health Systems, Ann Arbor, 
      MI, USA.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150807
PL  - United States
TA  - Blood Cancer J
JT  - Blood cancer journal
JID - 101568469
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cytokines)
RN  - 0 (Pyrrolidines)
RN  - 0 (Sulfonamides)
RN  - 6L1XP550I6 (fedratinib)
RN  - EC 2.7.10.2 (JAK2 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Cytokines/blood
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gene Frequency
MH  - Humans
MH  - Janus Kinase 2/antagonists & inhibitors/genetics
MH  - Male
MH  - Middle Aged
MH  - Mutation, Missense
MH  - Primary Myelofibrosis/blood/*drug therapy/genetics
MH  - Pyrrolidines/adverse effects/pharmacokinetics/*therapeutic use
MH  - Spleen/drug effects
MH  - Sulfonamides/adverse effects/pharmacokinetics/*therapeutic use
MH  - Treatment Outcome
PMC - PMC4558588
EDAT- 2015/08/08 06:00
MHDA- 2016/04/09 06:00
PMCR- 2015/08/01
CRDT- 2015/08/08 06:00
PHST- 2015/07/01 00:00 [received]
PHST- 2015/07/09 00:00 [accepted]
PHST- 2015/08/08 06:00 [entrez]
PHST- 2015/08/08 06:00 [pubmed]
PHST- 2016/04/09 06:00 [medline]
PHST- 2015/08/01 00:00 [pmc-release]
AID - bcj201563 [pii]
AID - 10.1038/bcj.2015.63 [doi]
PST - epublish
SO  - Blood Cancer J. 2015 Aug 7;5(8):e335. doi: 10.1038/bcj.2015.63.