Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
Clin Cancer Res. 2012 Oct 1;18(19):5489-98. doi: 10.1158/1078-0432.CCR-12-0507. Epub 2012 Jul 26.
We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.
The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a "3+3" design, cohorts of three to six patients received paclitaxel (175 mg/m(2)) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.
Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42-82) with a median of 2 prior regimens (range: 0-6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3-4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS(6-month) actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.
Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity.
我们进行了一项Ⅰ期研究，评估达沙替尼（一种口服 SRC 家族酪氨酸激酶抑制剂）联合紫杉醇和卡铂治疗晚期和复发性上皮性卵巢癌的疗效。
主要目的是确定最大耐受剂量（MTD）。次要目标包括评估毒性、反应率（RR）、药代动力学和药效动力学。采用“3+3”设计，每 3 周给予紫杉醇（175mg/m²）和卡铂（AUC 6），同时给予递增剂量的达沙替尼（每日 100、120 和 150mg），共 3 至 6 例患者为一组，随后进行 8 例扩展组。
2007 年 6 月至 2009 年 12 月期间共纳入 20 例患者。中位年龄为 61 岁（范围：42-82），中位既往治疗方案数为 2（范围：0-6），71%的患者为铂敏感疾病。每组 3 至 6 例患者，扩展组 8 例。在治疗的前两个周期观察药代动力学。100mg 达沙替尼组观察到 1 例剂量限制性毒性（3 级肌痛）。所有周期中其他毒性包括中性粒细胞减少症（95%为 3-4 级；150mg 剂量组为 91%）、血小板减少症（35%为 3-4 级）和乏力（10%为 3 级）。RR 为 40%（3 例完全缓解，15%；5 例部分缓解，25%），10 例（50%）患者疾病稳定，2 例患者无法评估。6 个月无进展生存（PFS）的实际估计值为 86%。中位 PFS 和 OS 分别为 7.8 和 16.2 个月。
由于随后周期骨髓抑制发生率较高，达沙替尼的推荐Ⅱ期剂量为每日 150mg，联合紫杉醇和卡铂。该联合方案安全有效。
