First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma A Phase 2b Randomized Clinical Trial
First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma A Phase 2b Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2015.3101
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发表时间：
2015-12-01
期刊：
影响因子：
28.4
通讯作者：
Levitt, Daniel J.
中科院分区：
文献类型：
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作者：
Chawla, Sant P.;Papai, Zsuzsanna;Levitt, Daniel J.
晚期软组织肉瘤的标准治疗几十年来没有实质性改变，患者预后仍然很差。Aldoxorubicin是一种新的白蛋白结合阿霉素前体药物，在1期临床研究中显示出对晚期软组织肉瘤的临床活性。目的评价aldoxorubicin与阿霉素治疗晚期软组织肉瘤的疗效和安全性。设计、环境和参与者：国际、多中心、2b期、开放标签、随机研究，在一般社区实践、私人实践或机构实践中进行。在2012年8月至2013年12月期间，筛选了140例既往未经治疗的局部晚期、不可切除或转移性软组织肉瘤患者。干预：将患者随机（2：1）分为aldoxorubicin 350 mg/m2（相当于阿霉素260 mg/m2的剂量）或doxorubicin 75 mg/m2组，每3周一次，共6个周期。次要终点为6个月无进展生存期、总生存期、肿瘤缓解率和安全性。所有疗效终点均由独立和当地的review. Results进行评估，共有126例患者被随机分配，123例接受aldoxorubicin（n = 83）或阿霉素（n = 40）。患者年龄中位数（范围）为54.0岁（21-77岁）; 42例（34%）患有平滑肌肉瘤。通过独立审查，与阿霉素相比，aldoxorubicin组的中位无进展生存期显著改善（5.6 [95%CI，3.0-8.1] vs 2.7 [95%CI，1.6-4.3]个月; P =.02），6个月无进展生存率也是如此（46%和23%; P =.02）。aldoxorubicin组的中位总生存期为15.8（95%CI，13.0至不可用）个月，阿霉素组为14.3（95%CI，8.6-20.6）个月（P = 0.21）。通过独立审查，aldoxorubicin组的总体肿瘤缓解率（根据实体瘤缓解评价标准，第1.1版）高于多柔比星组（25%[20例患者，均部分缓解] vs 0%）。使用阿霉素时，3级或4级中性粒细胞减少症的发生率高于使用阿霉素时（24例[29%] vs 5例[12%]），但3级或4级发热性中性粒细胞减少症的发生率并不高（12例[14%] vs 7例[18%]）。没有观察到急性心脏毒性作用，无论是治疗，虽然左心室射血分数小于50%发生在3的40例患者接受阿霉素。结论和相关性单剂aldoxorubicin治疗显示优于阿霉素的上级疗效，延长无进展生存期和改善6个月的无进展生存率和肿瘤反应。Aldoxorubicin治疗显示出可管理的不良反应，没有意外事件，也没有急性心脏毒性的证据。需要进一步研究aldoxorubicin治疗晚期软组织肉瘤。
IMPORTANCE Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies.OBJECTIVE To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, ormetastatic soft-tissue sarcoma were screened. INTERVENTIONS Randomization (2: 1) to aldoxorubicin 350mg/m(2) (dose equivalent to doxorubicin 260mg/m(2)) or doxorubicin 75mg/m2, administered once every 3 weeks for up to 6 cycles.MAIN OUTCOMES AND MEASURES Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review.RESULTS A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P =.02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P =.02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P =.21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25%[20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin.CONCLUSIONS AND RELEVANCE Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted.