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 R Litzow, Mrinal M 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

14 Citations (Scopus)

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

Fingerprint

Cytarabine
Acute Myeloid Leukemia
DNA Damage
Cell Cycle Checkpoints
MK-8776
Survival Rate
Survival
DNA

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. / Webster, Jonathan A.; Tibes, Raoul; Morris, Larry; Blackford, Amanda L.; Litzow, Mark R; Patnaik, Mrinal M; Rosner, Gary L.; Gojo, Ivana; Kinders, Robert; Wang, Lihua; Doyle, L. Austin; Huntoon, Catherine J.; Karnitz, Larry M; Kaufmann, Scott H; Karp, Judith E.; Smith, B. Douglas.

In: Leukemia Research, Vol. 61, 01.10.2017, p. 108-116.

Research output: Contribution to journalArticle

Webster, Jonathan A. ; Tibes, Raoul ; Morris, Larry ; Blackford, Amanda L. ; Litzow, Mark R ; Patnaik, Mrinal M ; Rosner, Gary L. ; Gojo, Ivana ; Kinders, Robert ; Wang, Lihua ; Doyle, L. Austin ; Huntoon, Catherine J. ; Karnitz, Larry M ; Kaufmann, Scott H ; Karp, Judith E. ; Smith, B. Douglas. / Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia. In: Leukemia Research. 2017 ; Vol. 61. pp. 108-116.
@article{f9bcf1dacaf84713ac9be08447a195cd,
title = "Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia",
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.",
keywords = "AML, Chk1, Cytarabine, Leukemia, MK-8776",
author = "Webster, {Jonathan A.} and Raoul Tibes and Larry Morris and Blackford, {Amanda L.} and Litzow, {Mark R} and Patnaik, {Mrinal M} and Rosner, {Gary L.} and Ivana Gojo and Robert Kinders and Lihua Wang and Doyle, {L. Austin} and Huntoon, {Catherine J.} and Karnitz, {Larry M} and Kaufmann, {Scott H} and Karp, {Judith E.} and Smith, {B. Douglas}",
year = "2017",
month = "10",
day = "1",
doi = "10.1016/j.leukres.2017.09.005",
language = "English (US)",
volume = "61",
pages = "108--116",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Randomized phase II trial of cytosine arabinoside with and without the CHK1 inhibitor MK-8776 in relapsed and refractory acute myeloid leukemia

AU - Webster, Jonathan A.

AU - Tibes, Raoul

AU - Morris, Larry

AU - Blackford, Amanda L.

AU - Litzow, Mark R

AU - Patnaik, Mrinal M

AU - Rosner, Gary L.

AU - Gojo, Ivana

AU - Kinders, Robert

AU - Wang, Lihua

AU - Doyle, L. Austin

AU - Huntoon, Catherine J.

AU - Karnitz, Larry M

AU - Kaufmann, Scott H

AU - Karp, Judith E.

AU - Smith, B. Douglas

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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.

AB - 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.

KW - AML

KW - Chk1

KW - Cytarabine

KW - Leukemia

KW - MK-8776

UR - http://www.scopus.com/inward/record.url?scp=85030104956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030104956&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2017.09.005

DO - 10.1016/j.leukres.2017.09.005

M3 - Article

C2 - 28957699

AN - SCOPUS:85030104956

VL - 61

SP - 108

EP - 116

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

ER -