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羧甲酰胺三唑用于复发性上皮性卵巢癌患者的II期试验。

Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer.

作者信息

Hussain Mahrukh M, Kotz Herbert, Minasian Lori, Premkumar Ahalya, Sarosy Gisele, Reed Eddie, Zhai Suoping, Steinberg Seth M, Raggio Miranda, Oliver Vyta Kulpa, Figg William D, Kohn Elise C

机构信息

Medical Oncology Clinical Research Unit, Medical Ovarian Cancer Clinic and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1500, USA.

出版信息

J Clin Oncol. 2003 Dec 1;21(23):4356-63. doi: 10.1200/JCO.2003.04.136.

DOI:10.1200/JCO.2003.04.136
PMID:14645425
Abstract

PURPOSE

Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer.

PATIENTS AND METHODS

Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured.

RESULTS

Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed.

CONCLUSION

CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.

摘要

目的

羧酰胺三唑(CAI)是一种非电压门控钙通道和钙通道介导信号通路的细胞生长抑制剂。它可抑制血管生成、肿瘤生长、侵袭和转移。我们推测CAI能使复发卵巢癌患者病情稳定持续≥6个月。

患者与方法

符合条件的患者为上皮性卵巢癌患者,终末器官功能良好,疾病可测量,且既往接受过三种或更少治疗方案。采用药代动力学给药方法每日口服CAI,以维持血浆浓度在2至4μg/mL之间。每8周进行一次影像学检查以评估反应。阳性结果包括疾病稳定或改善持续≥6个月。检测血浆血管内皮生长因子(VEGF)、白细胞介素(IL)-8和基质金属蛋白酶(MMP)-2。

结果

36例患者可进行主要终点分析评估,38例可进行毒性评估。44%的患者既往接受过三种治疗方案,超过50%的患者有四个或更多病灶部位,48%的患者有肝转移。33例患者在第一个周期内达到目标浓度范围。11例患者(31%)达到≥6个月的结局终点,其中1例部分缓解(8个月),3例轻微缓解(8、12 +和13个月)。疾病进展的中位时间为3.6个月(范围1.6至13.3个月)。CAI耐受性良好,大多为1至2级毒性。3级事件包括疲劳(5%)、呕吐(2%)、中性粒细胞减少性发热(2%)和中性粒细胞减少(2%)。无4级不良事件。未观察到VEGF、IL-8和MMP-2与CAI浓度或临床结局之间存在关联。

结论

CAI是一种有潜力的药物,可进一步研究其对复发卵巢癌的病情稳定作用。鉴于其毒性有限,它可能作为该疾病的维持治疗药物发挥作用。

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