Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia

Jonathan A. Webster, Raoul Tibes, Larry Morris, Amanda L. Blackford, Mark Litzow, Mrinal Patnaik, Gary L. Rosner, Ivana Gojo, Robert Kinders, Lihua Wang, L. Austin Doyle, Catherine J. Huntoon, Larry M. Karnitz, Scott H. Kaufmann, Judith E. Karp, B. Douglas Smith

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Purpose Cytosine arabinoside (AraC) remains the backbone of most treatment regimens for acute myeloid leukemia (AML). Incorporation of AraC into DNA activates checkpoint kinase 1 (Chk1), leading to cell-cycle arrest and diminished AraC cytotoxicity, which can be reversed by the selective Chk1 inhibitor MK-8776. Building on a Phase I trial, we conducted a phase II trial comparing timed sequential AraC with or without MK-8776. Methods Patients with relapsed or primary refractory AML were randomized 1:1 to receive either AraC with MK-8776 (Arm A); or AraC alone (Arm B). Results 32 patients were treated: 14 assigned to Arm A and 18 to Arm B. There were 5 (36%) complete responses (CR/CRi) and 1 (7%) partial response (PR) in Arm A, and 8 (44%) CR/CRis and 1 (6%) PR in Arm B. Median survival did not differ significantly between the two groups (5.9 months in Arm A vs. 4.5 months in Arm B). MK-8776 led to a robust increase in DNA damage in circulating leukemic blasts as measured by increased γ-H2AX (16.9% ± 6.1% prior and 36.4% ± 6.8% at one hour after MK-8776 infusion, p = 0.016). Conclusion Response rates and survival were similar between the two groups in spite of evidence that MK-8776 augmented DNA damage in circulating leukemic blasts. Better than expected results in the control arm using timed sequential AraC and truncated patient enrollment may have limited the ability to detect clinical benefit from the combination.

Original languageEnglish (US)
Pages (from-to)108-116
Number of pages9
JournalLeukemia Research
Volume61
DOIs
StatePublished - Oct 1 2017

Keywords

  • AML
  • Chk1
  • Cytarabine
  • Leukemia
  • MK-8776

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Webster, J. A., Tibes, R., Morris, L., Blackford, A. L., Litzow, M., Patnaik, M., Rosner, G. L., Gojo, I., Kinders, R., Wang, L., Doyle, L. A., Huntoon, C. J., Karnitz, L. M., Kaufmann, S. H., Karp, J. E., & Smith, B. D. (2017). Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. Leukemia Research, 61, 108-116. https://doi.org/10.1016/j.leukres.2017.09.005