A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia

作者：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

来源：Clinical Cancer Research, 2017, 23(3): 697-706.

DOI：10.1158/1078-0432.CCR-16-0984

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/m(2) 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/m(2) 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.

• 出版日期2017-2