The Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO 80045, USA.
Clin Cancer Res. 2013 Jul 1;19(13):3649-58. doi: 10.1158/1078-0432.CCR-12-3166. Epub 2013 May 9.
Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies.
Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized.
Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas.
This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies.
瑞达福罗默（MK-8669，AP23573）是一种有效的和选择性的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂。在临床前，瑞达福罗默在体外显示出对多种人类肿瘤的抗增殖活性，在体内肿瘤异种移植模型中也显示出活性，与其他抗癌药物联合使用时具有相加或协同作用。抗肿瘤活性已在成人中得到证实。这项 I 期研究旨在确定瑞达福罗默在患有难治性恶性肿瘤的儿科患者中的安全性、药理学、生物学和毒性特征。
年龄在 1 至 18 岁的晚期实体肿瘤的合格儿童被纳入 3+3 剂量递增设计，以确定瑞达福罗默的安全性、耐受性和最大耐受剂量（MTD）/剂量限制性毒性（DLT）。对毒性、药代动力学和药效学进行了特征描述。
15 名患者接受了治疗。在测试的任何剂量水平均未观察到 DLT；因此，未确定 MTD。大多数不良事件为轻度至中度；最常见的 3 级和 4 级不良事件为血液学毒性，包括血小板减少症和贫血。非血液学不良事件主要为电解质紊乱。在儿童中观察到的瑞达福罗默药代动力学特征与先前在成人中显示的特征一致。药效学证实，所测试的剂量范围具有药理/药效学活性。40%的患者达到了稳定的疾病状态，包括 6 名中枢神经系统肿瘤患者中的 4 名和 8 名肉瘤患者中的 2 名。
这项儿科首例研究表明，第二代 mTOR 抑制剂瑞达福罗默在接受过多重预处理的患有难治性实体肿瘤的儿童中具有良好的耐受性。在测试的剂量范围内未观察到 DLTs。瑞达福罗默可能成为儿科恶性肿瘤的治疗选择。
