Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: Evidence for activity in non-small-cell lung cancer
Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: Evidence for activity in non-small-cell lung cancer
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DOI：
10.1200/jco.2002.04.006
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发表时间：
2002-11-15
影响因子：
45.3
通讯作者：
Hong, WK
中科院分区：
文献类型：
--
作者：
Herbst, RS;Madden, TL;Hong, WK
目的：临床前研究表明抗血管生成剂 TNP-470 与细胞毒疗法具有协同作用。 TNP-470 与紫杉醇一起给予患有实体瘤的成人，以确定联合方案的安全性和最佳剂量，并评估药代动力学相互作用。 患者和方法：32 名患者按时间顺序入组到两个治疗组之一。 A 组涉及固定的 TNP-470 剂量和递增剂量的紫杉醇，B 组涉及固定的紫杉醇剂量和递增剂量的 TNP-470。评估紫杉醇和TNP-470的药代动力学和毒性。结果：TNP-470每周3次60 mg/m(2)给药和紫杉醇225 mg/m(2)每3周超过3小时给药的组合被定义为最大耐受剂量和最佳剂量。骨髓抑制与单独使用紫杉醇所预期的相似。观察到轻度至中度神经认知障碍；然而，根据研究前和研究后的神经精神测试结果确定，大多数变化是亚临床的和可逆的。观察到该组合的紫杉醇清除率临床上无显着降低。所有患者的中位生存期为 14.1 个月。据报道，32 名患者中的 8 名 (25%) 和 16 名 NSCLC 患者中的 6 名 (38%) 出现部分缓解，其中 60% 的患者之前接受过化疗。结论：TNP-470 和紫杉醇的组合（每种均为单药剂量）似乎耐受性良好，两种药物之间的药代动力学相互作用最小。有必要对 TNP-470 与化疗方案在 NSCLC 和其他实体瘤中的进一步研究。
Purpose: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions.Patients and Methods: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity.Results: The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy.Conclusion: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.