A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus
A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus
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DOI：
10.1158/1078-0432.ccr-06-0910
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发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
van Dongen, Guus A. M. S.
中科院分区：
文献类型：
--
作者：
Tijink, Bernard M.;Buter, Jan;van Dongen, Guus A. M. S.
目的：评估bivatuzumab mertansine的安全性、药代动力学、最大耐受剂量和初步疗效。Bivatuzumab是一种针对CD44v6的人源化单克隆抗体，此前在I期放射免疫治疗试验中似乎是安全的，而偶联美坦辛是一种有效的美坦辛衍生物。实验设计：头颈部或食道的无法治愈的鳞状细胞癌患者均符合条件。比瓦妥珠单抗每周静脉输注，连续3周。只要毒性未达到2级，每个剂量级计划治疗1例患者；否则，三名患者必须接受治疗，直到出现剂量限制性毒性。起始剂量为20mg /m(2)，随后剂量逐步增加至20mg /m2。无疾病进展且未出现剂量限制性毒性的患者符合重复疗程的条件。在整个治疗期间采集血清样本，以确定比瓦妥珠单抗mertansine的药代动力学特性，并评估人抗比瓦妥珠单抗mertansine抗体反应。结果：7名患者接受了总计23周剂量的比瓦珠单抗mertansine治疗。1名100mg /m2和1名120mg /m2剂量的患者在治疗期间病情稳定，但也出现了1级皮肤毒性（脱屑）。其中一人接受了第二次治疗。在本研究中达到的最高剂量水平（140 mg/m2）下，一名患者在两次输注后发生中毒性表皮坏死松解并死亡。皮肤角质形成细胞发生大量凋亡，而皮肤毒性只有对症治疗。在考虑到本例中毒性表皮坏死松解和其他试验中观察到的皮肤相关不良事件后，对整个I期项目（4项临床试验，70例患者）治疗的所有患者的风险-收益评估结果为阴性。因此，该共轭物的开发停止了。药代动力学变量的个体间变异性较低，BIWI - 1暴露量随剂量成比例增加。未观察到抗比伐单抗mertansine反应。结论：比瓦妥珠单抗mertansine的主要毒性作用是针对皮肤，很可能是由于CD44v6在该组织中的表达。大多数皮肤反应是可逆的；然而，发生了一起致命的药物相关不良事件。在达到最大耐受剂量之前停止临床开发。
Purpose: To assess safety, pharmacokinetics, maximum tolerated dose, and preliminary efficacy of bivatuzumab mertansine. Bivatuzumab is a humanized monoclonal antibody directed against CD44v6, which previously seemed to be safe in phase I radioimmunotherapy trials, whereas the conjugated mertansine is a potent maytansine derivative.Experimental Design: Patients with incurable squamous cell carcinoma of the head and neck or esophagus were eligible. Bivatuzumab was given weekly for 3 consecutive weeks by i.v. infusion. One patient was planned to be treated at each dose tier as long as toxicity did not reach grade 2; otherwise, three patients had to be treated until dose-limiting toxicity occurred. Starting dose was 20 mg/m(2) and dose was subsequently escalated in steps of 20 mg/m2. Patients without disease progression and not experiencing dose-limiting toxicity were eligible for repeated courses. Blood serum samples were taken throughout the treatment period to determine the pharmacokinetic properties of bivatuzumab mertansine and to assess the human anti - bivatuzumab mertansine antibody response.Results: Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m2 and one at the 120 mg/m2 level experienced stable disease during treatment phase but also developed grade 1 skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m2), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The risk-benefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials. Therefore, development of the conjugate was discontinued. Interindividual variability in pharmacokinetic variables was low and exposure to BIWI 1 increased proportionally with dose. No anti - bivatuzumab mertansine reactions were observed.Conclusion: The main toxicity of bivatuzumab mertansine was directed against the skin, most probably due to CD44v6 expression in this tissue. The majority of skin reactions was reversible; however, one fatal drug-related adverse event had occurred. Clinical development was discontinued before reaching maximum tolerated dose.