City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
Clin Cancer Res. 2013 Apr 1;19(7):1884-93. doi: 10.1158/1078-0432.CCR-12-0652. Epub 2013 Feb 12.
Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis.
Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m(2) twice daily (DL1 and DL2) or 1,000 mg/m(2) twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis.
Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m(2) twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed.
Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m(2) twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.
达沙替尼是一种 SRC 家族激酶抑制剂，在晚期乳腺癌中有一定的活性。我们旨在评估达沙替尼联合卡培他滨的毒性和最大耐受剂量（MTD），估计疗效，并探讨对血管生成的影响。
剂量水平（DL）为达沙替尼 50mg 每日两次（DL1）、70mg 每日两次（DL2 和 DL3）或 100mg 每日一次（DL3a）；卡培他滨在 21 天周期的第 1 至 14 天使用，剂量为 825mg/m2 每日两次（DL1 和 DL2）或 1000mg/m2 每日两次[DL3 和 DL3a（MTD）]。DL3a 扩展用于评估安全性/疗效。采集血浆样本进行生物标志物分析。
31 名和 21 名患者分别在递增和扩展阶段接受治疗。60%的肿瘤为激素受体阳性。最常见的不良反应（AE）为任何级别恶心（58%）、手足综合征（44%）、腹泻（33%）、疲劳（33%）、呕吐（31%）和乏力（31%）。最常见的 3/4 级 AE 为手足综合征（12%）、腹泻（8%）、疲劳（8%）、胸腔积液（8%）和呕吐（6%）。MTD 定义为 DL3a（卡培他滨 1000mg/m2 每日两次和达沙替尼 100mg 每日一次）。在接受 DL3a 治疗的 25 名可评价反应的患者中，确认部分缓解的比例为 24%，稳定疾病的比例为另外 32%；中位无进展生存期为 14.4 周。观察到血浆 VEGF-A 显著下降，VEGFR-2 和胶原-IV 显著增加。
达沙替尼 100mg 每日一次联合卡培他滨 1000mg/m2 每日两次，在 56%的可评价反应患者中耐受性良好，并与临床获益相关。生物标志物变化与抗血管生成作用一致。
