Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Gynecol Oncol. 2012 Oct;127(1):70-4. doi: 10.1016/j.ygyno.2012.06.009. Epub 2012 Jun 16.
Preclinical data suggest an important role for the sarcoma proto-oncogene tyrosine kinase (SRC) in the oncogenesis of epithelial ovarian cancer (EOC) or primary peritoneal carcinoma (PPC). The Gynecologic Oncology Group (GOG) conducted a Phase II trial to evaluate the efficacy and safety of dasatinib, an oral SRC-family inhibitor in EOC/PPC, and explored biomarkers for possible association with clinical outcome.
Eligible women had measurable, recurrent or persistent EOC/PPC and had received one or two prior regimens which must have contained a platinum and a taxane. Patients were treated with 100mg orally daily of dasatinib continuously until progression of disease or adverse effects prevented further treatment. Primary endpoints were progression-free survival (PFS)≥6months and response rate. Serial plasma samples were assayed for multiple biomarkers. Circulating free DNA was quantified as were circulating tumor and endothelial cells.
Thirty-five (35) patients were enrolled in a two-stage sequential design. Of the 34 eligible and evaluable patients, 20.6% (90% confidence interval: 10.1%, 35.2%) had a PFS≥6months; there were no objective responses. Grade 3-4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. Lack of clinical activity limited any correlation of biomarkers with outcome.
Dasatinib has minimal activity as a single-agent in patients with recurrent EOC/PPC.
临床前数据表明肉瘤原癌基因酪氨酸激酶（SRC）在卵巢上皮癌（EOC）或原发性腹膜癌（PPC）的发生中起着重要作用。妇科肿瘤学组（GOG）进行了一项 II 期临床试验，以评估口服 SRC 家族抑制剂 dasatinib 在 EOC/PPC 中的疗效和安全性，并探索可能与临床结果相关的生物标志物。
符合条件的女性患有可测量的、复发性或持续性 EOC/PPC，并且已经接受了一种或两种以前的治疗方案，这些方案必须包含铂类药物和紫杉烷类药物。患者每天口服 100mg dasatinib 连续治疗，直至疾病进展或不良反应导致无法进一步治疗。主要终点是无进展生存期（PFS）≥6 个月和缓解率。对连续的血浆样本进行了多种生物标志物的检测。检测了循环游离 DNA、循环肿瘤细胞和内皮细胞。
在两阶段顺序设计中招募了 35 名（35 名）患者。在 34 名符合条件和可评估的患者中，有 20.6%（90%置信区间：10.1%，35.2%）的患者 PFS≥6 个月；没有客观缓解。3-4 级毒性为胃肠道（主要为恶心和呕吐；n=4）、肺部（呼吸困难和/或胸腔积液；n=4）和疼痛（n=5），以及贫血、不适、失眠、皮疹和中枢神经系统出血等罕见情况。缺乏临床活性限制了生物标志物与结果的任何相关性。
dasatinib 作为单一药物在复发性 EOC/PPC 患者中活性有限。
