First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.
First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.
复制标题
奥拉帕尼治疗难治性实体瘤儿科患者的首个 1 期临床研究。
作者：
Takagi M;Ogawa C;Iehara T;Aoki-Nogami Y;Ishibashi E;Imai M;Kimura T;Nagata M;Yasuhara M;Masutani M;Yoshimura K;Tomizawa D;Ogawa A;Yonemori K;Morishita A;Miyamoto S;Takita J;Kihara T;Nobori K;Hasebe K;Miya F;Ikeda S;Shioda Y;Matsumot
高风险、难治性、复发性或转移性实体瘤患者的生存率仍然很低。一个聚（ADP-核糖）聚合酶（PARP）抑制剂可能是有效的治疗儿科实体瘤有缺陷的homologous recombination.MethodsThis开放标签，多中心1期临床试验评估的安全性，耐受性和疗效奥拉帕尼，PARP抑制剂，在儿科患者难治性实体瘤推荐剂量2期试验。采用标准3 + 3剂量递增设计，每天口服奥拉帕尼（62.5、125和187.5 mg/m2，每日两次）（1个周期= 28天）。3-18岁复发性儿科实体瘤患者符合条件。药代动力学和药效学analysesperformed.Results15例患者入组并接受奥拉帕尼单药治疗，这是耐受性良好。推荐的II期每日给药剂量为187.5 mg/m2，每日两次。药代动力学与剂量成比例。儿童中187.5 mg/m2每日两次给药0 - 12 h的浓度-时间曲线下面积和血浆峰浓度与200 mg每日两次队列中获得的既往数据相当，但低于成人中300 mg每日两次队列的数据。药效学研究表明对PARP活性有实质性抑制作用。在肾母细胞瘤和神经母细胞瘤患者中观察到两个部分反应。ConclusionsThis报告是第一个临床试验，描述使用PARP抑制剂作为单一疗法在儿童。Olaparib耐受性良好，在DNA损伤反应缺陷的儿科肿瘤中观察到初步的抗肿瘤反应。Lay summaryThis Phase 1 trial evaluated efficacy and safety of olaparib in patients with refractory children solid tumors.Olaparib耐受性良好，在2/15例患者中达到客观反应。DNA损伤反应在近一半的晚期神经母细胞瘤患者中减弱，结果支持进一步研究奥拉帕尼作为DNA损伤反应或修复缺陷型儿科癌症的新治疗方法。
BackgroundThe survival of patients with high‐risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP‐ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination.MethodsThis open‐label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose‐escalation design. Patients aged 3–18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed.ResultsFifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2twice daily. Pharmacokinetics were dose proportional. The area under the concentration‐time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2twice daily in children were comparable to previous data obtained in a 200‐mg, twice‐daily cohort and lower than those in the 300‐mg twice‐daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma.ConclusionsThis report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response‐defective pediatric tumors.Lay summaryThis Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors.Olaparib was well tolerated, achieving objective response in 2/15 patients.The DNA damage response was attenuated in nearly one‐half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor.The results support further investigation of olaparib as a new treatment for DNA damage‐response or repair‐defective pediatric cancers.