• Clin Cancer Res · Feb 2017

    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, James G Herman, Larry M Karnitz, Scott H Kaufmann, Alice Chen, and Judith E Karp.
    • Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland. igojo1@jhmi.edu.
    • Clin Cancer Res. 2017 Feb 1; 23 (3): 697-706.

    PurposeIn 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 DesignPatients 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.ResultsForty-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.ConclusionsVeliparib 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. Clin Cancer Res; 23(3); 697-706. ©2016 AACR.©2016 American Association for Cancer Research.

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