McKeage M J, Von Pawel J, Reck M, Jameson M B, Rosenthal M A, Sullivan R, Gibbs D, Mainwaring P N, Serke M, Lafitte J-J, Chouaid C, Freitag L, Quoix E
University of Auckland, 85 Park Road, Grafton, Private Bag 92019, Auckland 1142, New Zealand.
Br J Cancer. 2008 Dec 16;99(12):2006-12. doi: 10.1038/sj.bjc.6604808.
ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive </=6 cycles of carboplatin area under the plasma concentration-time curve 6 mg ml(-1) min and paclitaxel 175 mg m(-2) (CP, n=36) or standard therapy plus ASA404 1200 mg m(-2) (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.
ASA404（5,6 - 二甲基呫吨酮 - 4 - 乙酸或DMXAA）是一种小分子肿瘤血管破坏剂（肿瘤血管破坏剂）。这项随机II期研究评估了ASA404联合卡铂和紫杉醇的标准疗法，用于治疗组织学确诊的IIIb期或IV期非小细胞肺癌（NSCLC）且此前未接受过化疗的患者。患者被随机分为接受血浆浓度 - 时间曲线下面积为6mg ml(-1)·min的卡铂和175mg m(-2)的紫杉醇共≤6个周期（CP组，n = 36），或标准疗法加1200mg m(-2)的ASA404（ASA404 - CP组，n = 37）。添加ASA404后，总卡铂或游离卡铂以及紫杉醇的全身暴露量变化不大。两组的安全性特征相似且可控，大多数不良反应归因于标准疗法。与标准疗法组相比，ASA404联合组的肿瘤缓解率（31%对22%）、肿瘤进展的中位时间（5.4个月对4.4个月）和中位生存期（14.0个月对8.8个月，风险比0.73，95%CI 0.39，1.38）均有所改善。总之，本研究证实了ASA404与卡铂和紫杉醇联合用于先前未治疗的晚期NSCLC患者的可行性，显示出可控的安全性特征且无不良药代动力学相互作用。结果表明，ASA404可能有益，但这需要在更大规模的试验中进行评估。
