Su Jack M, Thompson Patrick, Adesina Adekunle, Li Xiao-Nan, Kilburn Lindsay, Onar-Thomas Arzu, Kocak Mehmet, Chyla Brenda, McKeegan Evelyn, Warren Katherine E, Goldman Stewart, Pollack Ian F, Fouladi Maryam, Chen Alice, Giranda Vincent, Boyett James, Kun Larry, Blaney Susan M
Texas Children's Cancer Center, Baylor College of Medicine (J.M.S., P.T., A.A., X-N.L., S.M.B.); Children's National Medical Center (L.K.); St. Jude Children's Research Hospital (A.O-T., J.B., L.K.); University of Tennessee Health Science Center (M.K.); AbbVie Pharmaceuticals (B.C., E.M., V.G.); National Cancer Institute, Pediatric Oncology Branch (K.E.W.); Children's Hospital of Chicago (S.G.); Children's Hospital of Pittsburgh (I.F.P.); Cincinnati Children's Hospital Medical Center (M.F.); Cancer Therapy Evaluation Program, National Cancer Institute (A.C.).
Neuro Oncol. 2014 Dec;16(12):1661-8. doi: 10.1093/neuonc/nou103. Epub 2014 Jun 7.
A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to (i) estimate the maximum tolerated doses (MTDs) or recommended phase II doses (RP2Ds) of veliparib and TMZ; (ii) describe the toxicities of this regimen; and (iii) evaluate the plasma pharmacokinetic parameters and extent of PARP inhibition in peripheral blood mononuclear cells (PBMCs) following veliparib.
TMZ was given once daily and veliparib twice daily for 5 days every 28 days. Veliparib concentrations and poly(ADP-ribose) (PAR) levels in PBMCs were measured on days 1 and 4. Analysis of pharmacokinetic and PBMC PAR levels were performed twice during study conduct to rationally guide dose modifications and to determine biologically optimal MTD/RP2D.
Twenty-nine evaluable patients were enrolled. Myelosuppression (grade 4 neutropenia and thrombocytopenia) were dose limiting. The RP2Ds are veliparib 25 mg/m(2) b.i.d. and TMZ 135 mg/m(2)/d. Only 2 out of 12 patients treated at RP2Ds experienced dose-limiting toxicities. Although no objective response was observed, 4 patients had stable disease >6 months in duration, including 1 with glioblastoma multiforme and 1 with ependymoma. At the RP2D of veliparib, pediatric pharmacokinetic parameters were similar to those in adults.
Veliparib and TMZ at the RP2D were well tolerated in children with recurrent brain tumors. A phase I/II trial to evaluate the tolerability and efficacy of veliparib, TMZ, and radiation in children with newly diagnosed brainstem gliomas is in progress.
开展了一项针对复发性脑肿瘤患儿的I期试验，研究口服聚（ADP - 核糖）聚合酶（PARP）抑制剂维利帕尼（ABT - 888）与替莫唑胺（TMZ）联合使用的情况，目的是：（i）评估维利帕尼和替莫唑胺的最大耐受剂量（MTD）或推荐的II期剂量（RP2D）；（ii）描述该治疗方案的毒性；（iii）评估维利帕尼给药后外周血单核细胞（PBMC）中的血浆药代动力学参数及PARP抑制程度。
替莫唑胺每日给药一次，维利帕尼每日给药两次，每28天给药5天。在第1天和第4天测量PBMC中的维利帕尼浓度和聚（ADP - 核糖）（PAR）水平。在研究过程中对药代动力学和PBMC PAR水平进行了两次分析，以合理指导剂量调整并确定生物学上最佳的MTD/RP2D。
共纳入29例可评估患者。骨髓抑制（4级中性粒细胞减少和血小板减少）为剂量限制性毒性。RP2D为维利帕尼25mg/m²，每日两次，替莫唑胺135mg/m²/天。在RP2D剂量下接受治疗的12例患者中只有2例出现剂量限制性毒性。虽然未观察到客观缓解，但有4例患者疾病稳定超过6个月，其中1例为多形性胶质母细胞瘤，1例为室管膜瘤。在维利帕尼的RP2D剂量下，儿童药代动力学参数与成人相似。
复发性脑肿瘤患儿对RP2D剂量的维利帕尼和替莫唑胺耐受性良好。一项评估维利帕尼、替莫唑胺及放疗对新诊断脑干胶质瘤患儿的耐受性和疗效的I/II期试验正在进行中。
