Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
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DOI：
10.1158/0008-5472.can-11-1227
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发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Doroshow JH
中科院分区：
文献类型：
--
作者：
Kummar S;Chen A;Ji J;Zhang Y;Reid JM;Ames M;Jia L;Weil M;Speranza G;Murgo AJ;Kinders R;Wang L;Parchment RE;Carter J;Stotler H;Rubinstein L;Hollingshead M;Melillo G;Pommier Y;Bonner W;Tomaszewski JE;Doroshow JH
进行了ABT-888（veliparib）（一种聚（ADP-核糖）聚合酶（PARP抑制剂））与拓扑异构酶I靶向药物拓扑替康组合的I期试验，以确定该组合在难治性实体瘤和淋巴瘤患者中的最大耐受剂量（MTD）、安全性、药代动力学和药效学。评价了静脉内拓扑替康联合ABT-888（10 mg）每日两次（BID）口服给药的不同方案和剂量。评估血浆和尿液药代动力学，并测量肿瘤和外周血单核细胞（PBMC）中聚（ADP-核糖）（PAR）和DNA损伤标记物γ H2 AX的水平。24例患者入组。显著的骨髓抑制限制了ABT-888与标准剂量的托泊替康联合给药的能力，需要降低剂量。使用携带人肿瘤异种移植物的无胸腺小鼠的临床前研究也告知了时间表变化。MTD确定为21天周期的第1-5天，拓扑替康0.6 mg/m2/天和ABT-888 10 mg BID。托泊替康未改变ABT-888的药代动力学。在3对肿瘤活检样本中观察到PAR水平降低超过75%;在23例可测量水平的患者中，19例患者的PBMC中观察到PAR水平降低超过50%。在接受ABT-888和托泊替康的患者中观察到循环肿瘤细胞（CTC）和PBMC中γ H2 AX应答增加。我们证明了PARP抑制剂ABT-888与拓扑异构酶I抑制剂拓扑替康在PBMC、肿瘤和CTC中的机制相互作用。该试验的结果表明，PARP抑制可以调节临床中修复拓扑异构酶I介导的DNA损伤的能力。
A phase I trial of ABT-888 (veliparib), a poly(ADP-ribose) polymerase (PARP inhibitor), in combination with topotecan, a topoisomerase I–targeted agent, was performed to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed, and levels of poly(ADP-ribose) (PAR) and the DNA-damage marker, γH2AX, were measured in tumor and peripheral blood mononuclear cells (PBMCs). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to co-administer ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/day and ABT-888 10 mg BID on days 1–5 of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We demonstrate a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I–mediated DNA damage in the clinic.