title: Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias.
abstract: OBJECTIVE
  Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776.
  
  
  METHODS
  Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose.
  
  
  RESULTS
  Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage.
  
  
  CONCLUSIONS
  These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517.
authors.affiliation: Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland 21287, USA. jkarp2@jhmi.edu
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Brian M
authors.initials: BM
authors.lastname: Thomas
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Greer
authors.forename: Christopher
authors.initials: C
authors.lastname: Sorge
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Kevin
authors.initials: K
authors.lastname: Peterson
authors.forename: Paula
authors.initials: P
authors.lastname: Schneider
authors.forename: Karen
authors.initials: K
authors.lastname: Mackey
authors.forename: Tomoko
authors.initials: T
authors.lastname: Freshwater
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Gladstone
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Showel
authors.forename: Sabine
authors.initials: S
authors.lastname: Loechner
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Horowitz
authors.forename: Randi
authors.initials: R
authors.lastname: Isaacs
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D003561:Cytarabine / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C468783:H2AX protein, human; D006657:Histones; C559815:MK-8776; D011720:Pyrazoles; D011743:Pyrimidines; D003561:Cytarabine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1