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