Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Clin Cancer Res. 2010 Nov 1;16(21):5288-95. doi: 10.1158/1078-0432.CCR-10-0700. Epub 2010 Sep 20.
Folate receptor α expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. Farletuzumab, a humanized monoclonal antibody against folate receptor α, has shown antitumor activity and favorable toxicity in preclinical evaluation. This phase I, dose-escalation study was conducted to determine the safety of weekly i.v. farletuzumab and establish the maximum tolerated dose (MTD).
Patients with platinum-refractory or platinum-resistant epithelial ovarian cancer received farletuzumab (12.5-400 mg/m(2)) on days 1, 8, 15, and 22 of a 5-week cycle. Intrapatient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related adverse event of grade 3 or higher, and the MTD was the highest dose at which one or none of six patients experienced a DLT. Disease progression was recorded using Response Evaluation Criteria in Solid Tumors criteria and serum CA-125.
Twenty-five heavily pretreated patients were included in the safety, efficacy, and pharmacokinetic analyses. No DLTs or MTDs were encountered, and dose escalation was continued to farletuzumab 400 mg/m(2). C(max) and AUC(0-24) (area under the serum concentration-time curve) increased in an approximately dose-proportional manner, and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. Stable disease by Response Evaluation Criteria in Solid Tumors was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles.
In this phase I study, farletuzumab administered as an i.v. infusion at doses of 12.5 to 400 mg/m(2) was generally safe and well tolerated in the management of heavily pretreated patients with epithelial ovarian cancer.
叶酸受体α在正常成人组织中表达受到严格限制，但在多种人类癌症类型中上调，包括上皮性卵巢癌。Farletuzumab 是一种针对叶酸受体α的人源化单克隆抗体，在临床前评估中显示出抗肿瘤活性和良好的毒性。本研究进行了一项 I 期、剂量递增研究，旨在确定每周静脉注射 farletuzumab 的安全性，并确定最大耐受剂量（MTD）。
铂类耐药或铂类难治性上皮性卵巢癌患者接受 farletuzumab（12.5-400mg/m²）治疗，方案为每 5 周周期的第 1、8、15 和 22 天给药。不允许患者内剂量递增。剂量限制性毒性（DLT）定义为与治疗相关的 3 级或更高级别的不良事件，MTD 为 6 名患者中 1 名或无 1 名患者发生 DLT 的最高剂量。使用实体瘤反应评估标准和血清 CA-125 记录疾病进展情况。
25 名预处理较多的患者纳入安全性、疗效和药代动力学分析。未发生 DLT 或 MTD，继续增加 farletuzumab 剂量至 400mg/m²。C（max）和 AUC（0-24）（血清浓度-时间曲线下面积）呈近似剂量比例增加，核成像子研究证实了肿瘤靶向性。无客观缓解。9 名（36%）患者出现实体瘤疗效评价标准稳定疾病，4 名患者血清 CA-125 降低。3 名患者继续接受治疗，共完成 3 个周期。
在这项 I 期研究中，静脉注射 farletuzumab 剂量为 12.5 至 400mg/m²，在治疗预处理较多的上皮性卵巢癌患者中，一般安全且耐受良好。
