Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer
Phase I and II study of exisulind in combination with capecitabine in patients with metastatic breast cancer
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DOI：
10.1200/jco.2003.02.114
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发表时间：
2003-09-15
影响因子：
45.3
通讯作者：
Hortobagyi, GN
中科院分区：
文献类型：
--
作者：
Pusztai, L;Zhen, JH;Hortobagyi, GN
目的：研究exisulind联合卡培他滨治疗35例转移性乳腺癌（MBC）患者的安全性和临床活性。患者和方法：所有患者既往均接受过蒽环类和紫杉烷类化疗。研究探索了两种剂量水平，125和250 mg口服作为连续每日治疗，与卡培他滨2000 mg/m(2)联合使用，在21天的周期中持续14天。在I期研究中，剂量限制性毒性为手足综合征和腹泻。第11期试验选择125 mg bid剂量。结果：最常见的2 - 3级非血液学不良事件是手足综合征（57%）和疲劳（48%）。最常见的2至3级实验室异常是粒细胞减少症。未发生死亡、意外不良事件或累积毒性。31例可评估缓解的患者中有1例完全缓解，4例部分缓解（客观缓解率为16%）。中位反应持续时间为31周；3例患者病情稳定时间超过26周。总体临床获益（完全缓解、部分缓解或病情稳定26周）为23%。14个标本用于免疫组化评估磷酸二酯酶-5同工酶（PDE-5）和PDE-2的表达，PDE-5是exisulind的靶标。80%的肿瘤在侵袭性癌细胞中有一定程度的PDE-5表达，其中35%的肿瘤呈中度或强染色。78%的肿瘤显示PDE-2中度或强烈染色。肿瘤反应与染色强度之间无明显关联。结论：Exisulind（口服125 mg）联合卡培他滨在重度预处理的MBC患者中具有良好的耐受性，其抗癌活性与单用卡培他滨相似。(C) 2003年由美国临床肿瘤学会出版。
Purpose : We studied the safety and clinical activity of exisulind in combination with capecitabine in 35 patients with metastatic breast cancer (MBC).Patients and Methods: All patients had received previous anthracycline and taxane chemotherapies. Two dose levels of exisulind were explored, 125 and 250 mg orally bid as continuous daily therapy, concomitant with capecitabine 2,000 mg/m(2) for 14 days in 21-day cycles. In the phase I study, the dose-limiting toxicities were hand-foot syndrome and diarrhea. The 125-mg bid dose was selected for phase 11 testing.Results: The most common nonhematologic grade 2 to 3 adverse events were hand-foot syndrome (57%) and fatigue (48%). The most frequent grade 2 to 3 laboratory abnormality was granulocytopenia. No death, unexpected adverse events, or cumulative toxicity were encountered. One complete and four partial responses were achieved (objective response rate, 16%) in the 31 patients assessable for response. The median duration of response was 31 weeks; three patients experienced stable disease longer than 26 weeks. Overall clinical benefit (complete response, partial response, or stable disease > 26 weeks) was 23%. Fourteen specimens were available for immunohistochemical assessment of phosphodiesterase-5 isoenzyme (PDE-5) and PDE-2 expression, which are the targets of exisulind. Eighty percent of tumors showed some expression of PDE-5 in the invasive cancer cells including 35% that showed moderate or strong staining. PDE-2 showed moderate or strong staining in 78% of tumors. There was no apparent association between tumor response and staining intensity.Conclusion: Exisulind (125 mg orally bid) in combination with capecitabine is well tolerated and the combination has anticancer activity similar to that of capecitabine alone in heavily pretreated patients with MBC. (C) 2003 by American Society of Clinical Oncology.