Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer
Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer
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DOI：
10.1200/jco.2005.02.2194
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发表时间：
2006-01-01
影响因子：
45.3
通讯作者：
Raymond, E
中科院分区：
文献类型：
--
作者：
Faivre, S;Delbaldo, C;Raymond, E
目的建立舒尼替尼的安全性、药动学和推荐剂量。舒尼替尼是一种具有抗血管生成和抗肿瘤作用的多靶点酪氨酸激酶抑制剂。患者和方法舒尼替尼口服4周，每6周1次。结果28例患者接受的剂量范围为15 ~ 59 mg/m2。（范围为50 mg/隔日至150 mg/d）。在最大耐受剂量≥ 75 mg/d时报告的剂量限制性毒性为可逆的3级疲劳、3级高血压和2级大疱性皮肤毒性。因此，推荐剂量为50 mg/d。在该剂量下，主要不良反应为口腔疼痛、水肿和血小板减少。在剂量>= 50 mg/d时观察到毛发变色和皮肤变黄。药代动力学数据表明，可以实现>= 50 ng/mL的潜在活性目标血浆浓度，具有中度患者间变异性和与每日单次给药相容的长半衰期。在3例肾细胞癌、1例神经内分泌肿瘤、1例间质肿瘤和1例未知原发性腺癌患者中观察到6例客观缓解。结论舒尼替尼在50 mg/d剂量下（给药4周，停药2周），毒性可控制。抗肿瘤活性支持在肾细胞癌、胃肠道肿瘤、神经内分泌肿瘤和间质瘤患者中进行进一步研究。未来的研究可能会考虑包括前瞻性成像技术，如高频超声监测肿瘤密度。
Purpose To establish the safety, pharmacokinetics, and recommended dose of sunitinib, a novel oral multitargeting tyrosine kinase inhibitor with antiangiogenic and antitumor properties, in patients with advanced malignancies.Patients and Methods Sunitinib was given orally for 4 weeks every 6 weeks.Results Twenty-eight patients received doses ranging from 15 to 59 mg/m(2) (ranging from 50 mg every other day to 150 mg/d). Dose-limiting toxicities reported at the maximum-tolerated doses >= 75 mg/d were reversible grade 3 fatigue, grade 3 hypertension, and grade 2 bullous skin toxicity. Therefore, the recommended dose was 50 mg/d. At this dose, the main adverse effects were sore mouth, edema, and thrombocytopenia. Hair discoloration and yellow coloration of the skin were observed at doses >= 50 mg/d. Pharmacokinetic data indicate that potentially active target plasma concentrations >= 50 ng/mL can be achieved with moderate interpatient variability and a long half-life compatible with a single daily dosing. Six objective responses were observed in three renal cell carcinomas, one neuroendocrine tumor, one stromal tumor, and one unknown primary adenocarcinoma patient. At higher doses ( >= 75 mg/d), tumor responses were often associated with reduced intratumoral vascularization and central tumor necrosis, eventually resulting in organ perforation or fistula.Conclusion At the dose of 50 mg/d (4 weeks on, 2 weeks off), sunitinib displays manageable toxicity. Antitumor activity supports further studies in patients with renal cell carcinoma, gastrointestinal, neurcendocrine, and stromal tumors. Future studies may consider including prospective imaging techniques such as high frequency ultrasound to monitor tumor density.