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
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Clin Cancer Res. 2017 Feb 1;23(3):697-706. doi: 10.1158/1078-0432.CCR-16-0984. Epub 2016 Aug 8.
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.
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 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.
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 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.
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. Clin Cancer Res; 23(3); 697-706. ©2016 AACR.
在临床前研究中，聚（ADP - 核糖）聚合酶（PARP）抑制剂维利帕尼通过增强DNA损伤来增强替莫唑胺的抗白血病作用。因此，我们开展了一项1期研究，在复发、难治性急性髓系白血病（AML）或由侵袭性髓系恶性肿瘤引起的AML患者中使用剂量递增的维利帕尼联合替莫唑胺。
患者每28至56天接受一次维利帕尼[第1周期第1天每天一次20 - 200 mg，第4 - 12天每天两次（第2周期及以后为第1 - 8天）]和替莫唑胺[第1周期第3 - 9天每天150 - 200 mg/m²（第2周期及以后为第1 - 5天）]。评估了维利帕尼的药代动力学和药效学[抑制聚（ADP - 核糖）聚合物（PAR）形成和诱导H2AX磷酸化的能力]。还检测了O6 - 甲基鸟嘌呤 - DNA甲基转移酶（MGMT）和PARP1蛋白的预处理水平、MGMT启动子的甲基化以及范可尼贫血通路的完整性。
48例患者在7个剂量水平接受治疗。剂量限制性毒性为持续超过7天的口腔黏膜炎和食管炎。最大耐受剂量（MTD）为维利帕尼每日两次150 mg联合替莫唑胺每日200 mg/m²。完全缓解（CR）率为17%（48例患者中的8例）。维利帕尼的暴露量以及对PAR聚合物形成的抑制呈剂量依赖性增加。在缓解者中观察到维利帕尼诱导的CD34细胞中H2AX磷酸化增加。4例MGMT启动子甲基化患者中有3例实现CR。
维利帕尼联合替莫唑胺耐受性良好，对晚期AML有活性。对该方案以及治疗诱导的H2AX磷酸化和MGMT甲基化作为潜在反应预测指标进行进一步评估似乎是必要的。《临床癌症研究》；23(3)；697 - 706。©2016美国癌症研究协会。
