title: Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes.
abstract: OBJECTIVE
  The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma.
  
  
  METHODS
  Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks.
  
  
  RESULTS
  Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%.
  
  
  CONCLUSIONS
  SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. ayounes@mdanderson.org
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
authors.forename: Jorge
authors.initials: J
authors.lastname: Romaguera
authors.forename: Michelle
authors.initials: M
authors.lastname: Fanale
authors.forename: Peter
authors.initials: P
authors.lastname: McLaughlin
authors.forename: Frederick
authors.initials: F
authors.lastname: Hagemeister
authors.forename: Amanda
authors.initials: A
authors.lastname: Copeland
authors.forename: Sattva
authors.initials: S
authors.lastname: Neelapu
authors.forename: Larry
authors.initials: L
authors.lastname: Kwak
authors.forename: Jatin
authors.initials: J
authors.lastname: Shah
authors.forename: Silvana
authors.initials: S
authors.lastname: de Castro Faria
authors.forename: Stefan
authors.initials: S
authors.lastname: Hart
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wood
authors.forename: Ramesh
authors.initials: R
authors.lastname: Jayaraman
authors.forename: Kantharaj
authors.initials: K
authors.lastname: Ethirajulu
authors.forename: Joy
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001952:Bridged-Ring Compounds / Q000008:administration & dosage* / Q000009:adverse effects*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects*; D012008:Recurrence; D055815:Young Adult
chemical_list: C561234:11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; D001952:Bridged-Ring Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053614:Janus Kinase 2