Phase I/II study of atrasentan, an endothelin a receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer
Phase I/II study of atrasentan, an endothelin a receptor antagonist, in combination with paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer
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DOI：
10.1158/1078-0432.ccr-07-1508
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发表时间：
2008-03-01
影响因子：
11.5
通讯作者：
Bepler, Gerold
中科院分区：
文献类型：
--
作者：
Chiappori, Alberto A.;Haura, Eric;Bepler, Gerold
目的：内皮素及其细胞膜受体（ETAR和ETBR）参与肿瘤的发生。Atrasentan是一种有效的选择性ETAR拮抗剂，对肿瘤增殖、细胞凋亡和血管生成有直接作用。本研究旨在评估阿特拉森坦对紫杉醇药代动力学的影响，并确定阿特拉森坦联合紫杉醇卡铂的安全性和有效性。实验设计：入选IIIB期（恶性胸腔积液）和IV期非小细胞肺癌的化疗患者。毒性和反应分别采用美国国家癌症研究所共同毒性标准2.0版和实体瘤标准中的反应评价标准来确定。治疗包括紫杉醇（225 mg/m(2)）和卡铂（曲线下面积，6），每3周第1天给药。从第1周期的第4天开始，连续给予固定剂量的每日10mg阿特拉西坦口服。在前10例患者的前两个周期（阿特拉森治疗前和治疗后）计算紫杉醇清除率。结果：所有44例患者的生存、毒性和反应均可评估。阿特拉森坦治疗前后的平均紫杉醇清除率无显著变化（平均+/- SD分别为21.2 +/- 4.5 L/h和21.3 +/- 4.9 L/h） （P = 0.434）。3/4级毒性>= 10%为淋巴细胞减少（22.7%）、中性粒细胞减少（20.5%）、呼吸困难（11.4%）和高血糖（11.4%）。缓解率为18.2%，无进展生存期为4.2个月，中位生存期为10.6个月，1年生存率为43%。结论：阿特拉森坦联合紫杉醇-卡铂是安全且耐受性良好的，无明显的紫杉醇-阿特拉森坦药动学相互作用。晚期非小细胞肺癌的疗效和生存率与单独化疗的研究相当。
Purpose: Endothelins and their cell membrane receptors (ETAR and ETBR) are implicated in neoplastic pathogenesis. Atrasentan, a potent, selective ETAR antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis. This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin.Experimental Design: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non-small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute Common Toxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m(2)) and carboplatin (area under the curve, 6) administered on day l every 3 weeks. A fixed 10 mg daily oral dose of atrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre- and post-atrasentan) in the first 10 patients.Results: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean +/- SD, 21.2 +/- 4.5 L/h versus 21.3 +/- 4.9 L/h) for pre- and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities >= 10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%.Conclusion: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non - small cell lung cancer were comparable with studies of chemotherapy alone.