A Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma and Correlation of Baseline Serum-Soluble Intracellular Adhesion Molecule-1 with Outcome
A Phase II Trial of Fosbretabulin in Advanced Anaplastic Thyroid Carcinoma and Correlation of Baseline Serum-Soluble Intracellular Adhesion Molecule-1 with Outcome
复制标题
DOI：
10.1089/thy.2008.0321
复制
发表时间：
2009-03-01
期刊：
影响因子：
6.6
通讯作者：
Remick, Scot C.
中科院分区：
文献类型：
--
作者：
Mooney, Colin J.;Nagaiah, Govardhanan;Remick, Scot C.
背景资料：Fosbretabulin是一种新型血管破坏剂，对甲状腺未分化癌（ATC）细胞系、异种移植物具有抗肿瘤活性，并且在I期试验中具有可证实的疗效。这项II期研究确定了fosbretabulin在晚期ATC患者中的疗效和安全性，以及fosbretabulin是否通过使中位生存期加倍而改变ATC的自然史。第二个目的是评估血清可溶性细胞内粘附分子-1（sICAM）的预后价值。方法：26例患者在28天周期的第1、8和15天接受10分钟静脉输注45 mg/m2的非布他布林。在基线、前两个周期和治疗结束时测定sICAM水平。治疗持续到疾病progress.Results：Fosbretabulin是耐受性良好，3级毒性观察9例（35%），4级毒性1例（4%）。4例患者的QTc延长延迟治疗，导致1例患者停止治疗。中位生存期为4.7个月，分别有34%和23%的患者在6个月和12个月时存活。7例患者的中位疾病稳定持续时间为12.3个月（范围：4.4-37.9个月）。在24例患者中测量了基线血清sICAM水平，中位数为253.5 ng/mL。在基线sICAM水平的三分位数之间，无事件生存率存在显著差异（p < 0.009）。结论：在本试验中，使用单药磷他布林没有观察到客观反应，并且我们没有观察到生存率加倍作为我们的主要终点。这是有史以来对ATC进行的最大规模的前瞻性试验之一。Fosbretabulin在晚期ATC患者中具有可接受的安全性特征，三分之一的患者存活超过6个月。尽管样本量小，但低基线sICAM水平可预测无事件生存。sICAM作为治疗性生物标志物的进一步前瞻性验证和探索与磷他布林的联合治疗方案是必要的。
Background: Fosbretabulin is a novel vascular-disrupting agent that has antitumor activity against anaplastic thyroid cancer (ATC) cell lines, xenografts, and demonstrable efficacy in a phase I trial. This phase II study determined the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM).Methods: Twenty-six patients received fosbretabulin 45 mg/m(2) as a 10-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and end of therapy. Treatment was continued until disease progression.Results: Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four causing one to stop treatment. Median survival was 4.7 months with 34% and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4-37.9 months). Baseline serum sICAM levels were measured in 24 patients with a median 253.5 ng/mL. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (p < 0.009).Conclusions: There were no objective responses seen with single-agent fosbretabulin as administered in this trial, and we did not observe a doubling of survival as our primary endpoint. This is among the largest prospective trials ever conducted for ATC. Fosbretabulin has an acceptable safety profile in patients with advanced ATC, and one-third survived more than 6 months. Despite a small sample size, low baseline sICAM levels were predictive of event-free survival. Further prospective validation of sICAM as a therapeutic biomarker and exploring combination regimens with fosbretabulin are warranted.