A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia

Ivana Gojo, Jan H. Beumer, Keith W. Pratz, Michael A. McDevitt, Maria R. Baer, Amanda L. Blackford, B. Douglas Smith, Steven D. Gore, Hetty E. Carraway, Margaret M. Showel, Mark J. Levis, Amy E. Dezern, Douglas E. Gladstone, Jiuping Jay Ji, Lihua Wang, Robert J. Kinders, Marie Pouquet, Ismail Ali-Walbi, Michelle A. Rudek, Weijie Poh & 5 others James G. Herman, Larry M. Karnitz, Scott H. Kaufmann, Alice Chen, Judith E. Karp

Research output: Contribution to journalArticle

Abstract

Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. Experimental Design: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m2 daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted.

LanguageEnglish (US)
Pages697-706
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number3
DOIs
StatePublished - Feb 1 2017

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temozolomide
Acute Myeloid Leukemia
Methylation
Phosphorylation
Polymers
Poly Adenosine Diphosphate Ribose
Fanconi Anemia
Stomatitis
Esophagitis
Poly(ADP-ribose) Polymerase Inhibitors
veliparib
DNA Damage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia. / Gojo, Ivana; Beumer, Jan H.; Pratz, Keith W.; McDevitt, Michael A.; Baer, Maria R.; Blackford, Amanda L.; Smith, B. Douglas; Gore, Steven D.; Carraway, Hetty E.; Showel, Margaret M.; Levis, Mark J.; Dezern, Amy E.; Gladstone, Douglas E.; Ji, Jiuping Jay; Wang, Lihua; Kinders, Robert J.; Pouquet, Marie; Ali-Walbi, Ismail; Rudek, Michelle A.; Poh, Weijie; Herman, James G.; Karnitz, Larry M.; Kaufmann, Scott H.; Chen, Alice; Karp, Judith E.

In: Clinical Cancer Research, Vol. 23, No. 3, 01.02.2017, p. 697-706.

Research output: Contribution to journalArticle

Gojo, I, Beumer, JH, Pratz, KW, McDevitt, MA, Baer, MR, Blackford, AL, Smith, BD, Gore, SD, Carraway, HE, Showel, MM, Levis, MJ, Dezern, AE, Gladstone, DE, Ji, JJ, Wang, L, Kinders, RJ, Pouquet, M, Ali-Walbi, I, Rudek, MA, Poh, W, Herman, JG, Karnitz, LM, Kaufmann, SH, Chen, A & Karp, JE 2017, 'A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia' Clinical Cancer Research, vol. 23, no. 3, pp. 697-706. https://doi.org/10.1158/1078-0432.CCR-16-0984
Gojo, Ivana ; Beumer, Jan H. ; Pratz, Keith W. ; McDevitt, Michael A. ; Baer, Maria R. ; Blackford, Amanda L. ; Smith, B. Douglas ; Gore, Steven D. ; Carraway, Hetty E. ; Showel, Margaret M. ; Levis, Mark J. ; Dezern, Amy E. ; Gladstone, Douglas E. ; Ji, Jiuping Jay ; Wang, Lihua ; Kinders, Robert J. ; Pouquet, Marie ; Ali-Walbi, Ismail ; Rudek, Michelle A. ; Poh, Weijie ; Herman, James G. ; Karnitz, Larry M. ; Kaufmann, Scott H. ; Chen, Alice ; Karp, Judith E. / A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 3. pp. 697-706.
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T1 - A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia

AU - Gojo, Ivana

AU - Beumer, Jan H.

AU - Pratz, Keith W.

AU - McDevitt, Michael A.

AU - Baer, Maria R.

AU - Blackford, Amanda L.

AU - Smith, B. Douglas

AU - Gore, Steven D.

AU - Carraway, Hetty E.

AU - Showel, Margaret M.

AU - Levis, Mark J.

AU - Dezern, Amy E.

AU - Gladstone, Douglas E.

AU - Ji, Jiuping Jay

AU - Wang, Lihua

AU - Kinders, Robert J.

AU - Pouquet, Marie

AU - Ali-Walbi, Ismail

AU - Rudek, Michelle A.

AU - Poh, Weijie

AU - Herman, James G.

AU - Karnitz, Larry M.

AU - Kaufmann, Scott H.

AU - Chen, Alice

AU - Karp, Judith E.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Purpose: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. Experimental Design: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m2 daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. Results: Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted.

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