@article{91b7d3323a4e4445b1189b4c460d3e0d,
title = "A phase 1 study of the PARP inhibitor veliparib in combination with temozolomide in acute myeloid leukemia",
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.",
author = "Ivana Gojo and Beumer, {Jan H.} and Pratz, {Keith W.} and McDevitt, {Michael A.} and Baer, {Maria R.} and Blackford, {Amanda L.} and Smith, {B. Douglas} and Gore, {Steven D.} and Carraway, {Hetty E.} and Showel, {Margaret M.} and Levis, {Mark J.} and Dezern, {Amy E.} and Gladstone, {Douglas E.} and Ji, {Jiuping Jay} and Lihua Wang and Kinders, {Robert J.} and Marie Pouquet and Ismail Ali-Walbi and Rudek, {Michelle A.} and Weijie Poh and Herman, {James G.} and Karnitz, {Larry M.} and Kaufmann, {Scott H.} and Alice Chen and Karp, {Judith E.}",
note = "Funding Information: We are grateful to the patients who participated in this study and the nurses and physicians who cared for them. We would like to thank Robert G. Fenton for contribution to study design, Karen Flatten, Kevin Peterson, Paula Schneider, and Cathy Huntoon for technical assistance with the correlative studies, and research nurses Jackie Greer and Stephanie Fleckinger for their effort on this study. This work is supported by NIH grants U01CA070095, U01CA099168, UM1CA186690, UM1CA186691, and N01CM5701716. The project described was also supported by the Cancer Pharmacokinetics and Pharmacodynamics Facility at University of Pittsburgh Cancer Institute (P30CA047904) and the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 TR 001079). Frederick National Laboratory support was provided by NCI, NIH, under contract no. HHSN261200800001E. Merck and Co., Inc. provided temozolomide for this study. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright}2016 AACR.",
year = "2017",
month = feb,
day = "1",
doi = "10.1158/1078-0432.CCR-16-0984",
language = "English (US)",
volume = "23",
pages = "697--706",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "3",
}