Department of Gynecologic Oncology and Reproductive Medicine, M D Anderson Cancer Center, Houston, TX 77030, USA.
Lancet Oncol. 2011 Nov;12(12):1109-17. doi: 10.1016/S1470-2045(11)70244-3. Epub 2011 Oct 10.
Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population.
For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501.
From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%).
Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted.
US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation.
生物靶向治疗被认为是提高卵巢癌女性患者治疗效果的可行策略。我们评估了阿柏西普联合多西紫杉醇在该人群中的安全性、耐受性、药代动力学、相关循环和影像学衍生生物标志物以及临床活性。
在这项 1 期（药代动力学）研究中，符合条件的患者具有可测量的、复发性或持续性上皮性卵巢癌、原发性腹膜癌或输卵管癌，且最多接受过两种先前的化疗方案。阿柏西普以 2、4 或 6mg/kg 的三个剂量水平静脉给药（每 21 天一次），以确定 2 期研究的最大耐受剂量。在单药阿柏西普（周期 0）和联合多西紫杉醇（75mg/m2）静脉给药的先导期进行药代动力学评估和动态成像。2 期研究的入组标准与 1 期相同。患者以两阶段设计入组，静脉注射阿柏西普 6mg/kg 和多西紫杉醇 75mg/m2，每 3 周一次。主要终点是根据实体瘤反应评价标准 1.0 评估的客观缓解率（ORR）。该试验已完成入组，所有患者现已停止研究。该试验在 ClinicalTrials.gov 注册，编号为 NCT00436501。
从 1 期研究中发现，阿柏西普和多西紫杉醇的推荐 2 期剂量分别为 6mg/kg 和 75mg/m2。观察到三个剂量水平的无结合阿柏西普的对数线性药代动力学。未观察到剂量限制毒性。46 名可评估患者入组 2 期试验；33 名患者对铂类耐药（15 名耐药），13 名患者对铂类敏感。确认的 ORR 为 54%（46 例中有 25 例；11 例患者完全缓解，14 例患者部分缓解）。超过 2 名患者（5%）观察到 3-4 级毒性：中性粒细胞减少症 37 例（80%）；白细胞减少症 25 例（54%）；乏力 23 例（50%）；呼吸困难 10 例（22%）；和口腔炎 3 例（7%）。与阿柏西普相关的特定不良反应为 5 例（11%）1-2 级高血压，1 例（2%）2 级蛋白尿。
报告的剂量和方案下，阿柏西普联合多西紫杉醇可安全给药，并与显著的抗肿瘤活性相关。这些发现表明，有必要进一步在卵巢癌中开发这种联合用药。
美国国立癌症研究所、美国国防部、赛诺菲-安万特、妇科癌症基金会、马库斯基金会和英联邦基金会。
