Kieran Mark W, Supko Jeffrey G, Wallace Dana, Fruscio Robert, Poussaint Tina Young, Phillips Peter, Pollack Ian, Packer Roger, Boyett James M, Blaney Susan, Banerjee Anu, Geyer Russ, Friedman Henry, Goldman Stewart, Kun Larry E, Macdonald Tobey
Pediatric Neuro-Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Pediatr Blood Cancer. 2009 Feb;52(2):169-76. doi: 10.1002/pbc.21873.
SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.
SU5416是一种新型的小分子酪氨酸激酶抑制剂，可作用于血管内皮生长因子受体1和2。开展了一项I期剂量递增研究，根据是否同时使用酶诱导抗惊厥药物进行分层（II层为同时使用，I层为未使用），以评估最大耐受剂量（MTD），并描述SU5416在难治性脑肿瘤儿科患者中的毒性特征。I层从110 mg/m²开始独立进行剂量递增，而II层从48 mg/m²开始。33例符合条件的患者在I层（n = 23）和II层（n = 10）接受治疗。肿瘤类型包括23例胶质瘤、4例神经肿瘤、4例室管膜瘤和2例脉络丛癌。I层的MTD最初估计为110 mg/m²。在排除短暂性AST升高后，对方案进行了修订以确定MTD。MTD的重新评估从145 mg/m²剂量水平开始，但由于申办方停止了SU5416的研发，试验在完成前提前结束。最严重的药物相关毒性为3级肝酶异常、关节痛和幻觉。同时给予酶诱导抗惊厥药物对SU5416的血浆药代动力学没有显著影响。I层19例患者的SU5416总体清除率、表观分布容积和终末相半衰期的平均值分别为26.1±12.5 l/hr/m²、41.9±21.4 l/m²和1.11±0.41小时。SU5416在儿童中的血浆药代动力学与先前在成年癌症患者中报道的结果相似。在I层16例患者中的4例观察到疾病稳定期延长。
