Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Cancer Biol Ther. 2009 Oct;8(19):1800-5. doi: 10.4161/cbt.8.19.9593.
Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active.
Twenty-nine heavily pretreated patients [median 3 [0-7]] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m(2) q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). A trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses.
Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m(2)), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. Patients were assessed for toxicity, pharmacokinetics and disease outcome.
The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m(2) q3weeks, respectively. The combination is tolerable and has potential antitumor activity.
羧基酰胺三唑（CAI）是一种钙内流抑制剂，具有抗血管生成和抗侵袭特性，并稳定肿瘤进展患者的病情。我们假设每日口服微粒化 CAI 联合每 3 周 q 紫杉醇治疗将具有良好的耐受性和活性。
29 名预处理过多的患者[中位数 3 [0-7]]入组了 5 个剂量水平。未观察到附加或累积毒性，且 III 级非血液学毒性罕见。中性粒细胞减少是最常见的血液学毒性，79%的患者出现这种情况，且随着紫杉醇剂量的增加，其严重程度呈上升趋势。最大耐受剂量（MTD）定义的推荐 II 期剂量为 CAI 每日 250mg 和紫杉醇 200mg/m2 q3 周。药代动力学分析显示，在所有剂量水平下，紫杉醇使 CAI 谷浓度增加了 100%以上（p<0.0001）。在部分缓解（PR；p=0.09）患者中发现 CAI 谷浓度的稳态有升高趋势。6 名患者有确认的 PR（24%；4-67 个周期，中位数为 10），2 名患者有轻微反应。
符合条件的实体瘤患者接受每日口服微粒化 CAI（150-250mg PO）和每 3 周静脉注射紫杉醇（175-250mg/m2），每种药物依次递增。CAI 在紫杉醇前一周开始给药，以便进行药代动力学分析。评估患者的毒性、药代动力学和疾病结果。
CAI 和紫杉醇联合应用的最大耐受剂量分别为每日 250mg 和每 3 周 200mg/m2。该联合方案具有良好的耐受性和潜在的抗肿瘤活性。
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