Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias

Judith E. Karp, Brian M. Thomas, Jacqueline M. Greer, Christopher Sorge, Steven D. Gore, Keith W. Pratz, B. Douglas Smith, Karen S. Flatten, Kevin Peterson, Paula Schneider, Karen Mackey, Tomoko Freshwater, Mark J. Levis, Michael A. McDevitt, Hetty E. Carraway, Douglas E. Gladstone, Margaret M. Showel, Sabine Loechner, David A. Parry, Jo Ann HorowitzRandi Isaacs, Scott H. Kaufmann

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

Purpose: 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. Experimental Design: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m2 over 72 hours (667 mg/m2/24 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/m2/dose. Results: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmarplantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m2). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m2 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/m2, 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/m2) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT #00907517.

Original languageEnglish (US)
Pages (from-to)6723-6731
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number24
DOIs
StatePublished - Dec 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Karp, J. E., Thomas, B. M., Greer, J. M., Sorge, C., Gore, S. D., Pratz, K. W., Smith, B. D., Flatten, K. S., Peterson, K., Schneider, P., Mackey, K., Freshwater, T., Levis, M. J., McDevitt, M. A., Carraway, H. E., Gladstone, D. E., Showel, M. M., Loechner, S., Parry, D. A., ... Kaufmann, S. H. (2012). Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. Clinical Cancer Research, 18(24), 6723-6731. https://doi.org/10.1158/1078-0432.CCR-12-2442