The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, 195 Little Albany St., New Brunswick, NJ 08901, USA.
Invest New Drugs. 2012 Feb;30(1):258-65. doi: 10.1007/s10637-010-9504-5. Epub 2010 Aug 10.
In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib.
Imatinib was administered at 400 mg daily on days 1-5, 8-12 and 15-19. Gemcitabine was started at 600 mg/m(2) at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m(2) on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients.
Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m(2) on days 3 and 10 for gemcitabine, 30 mg/ m(2) on day 10 for docetaxel, and 400 mg daily on days 1-5 and 8-12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles.
An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control.
在 I 期研究中，吉西他滨联合伊马替尼的联合治疗具有广泛的抗肿瘤活性且耐受性良好。本 I 期试验评估了多西他赛、吉西他滨和伊马替尼的三联疗法。
伊马替尼每天 400mg，第 1-5 天、第 8-12 天及第 15-19 天用药；第 3 天和第 10 天，吉西他滨起始剂量为 600mg/m²，以 10mg/min 的速度给药，第 10 天给予多西他赛 30mg/m²，每 21 天为一个周期。在选定的患者中进行弥散和动态对比增强磁共振成像（MRI）检查。
这项经机构审查委员会批准的研究共纳入了 20 例复发/难治性实体瘤患者。患者的平均年龄为 64 岁，平均 ECOG PS 为 1 分。两名患者接受了弥散/灌注 MRI 检查。在剂量水平 1 时发生了 2 例 3 级血液学毒性后，方案被修订为减少伊马替尼的剂量。吉西他滨的 MTD 为第 3 天及第 10 天 600mg/m²，第 10 天多西他赛 30mg/m²，第 1-5 天及第 8-12 天伊马替尼 400mg 每日用药。一个周期后出现的剂量限制毒性为中性粒细胞减少性发热，以及胸腔和心包积液。在 MTD 下，1 例间皮瘤患者和 1 例非小细胞肺癌（NSCLC）患者的最佳缓解为 6 个周期的疾病稳定，1 例 NSCLC 患者的最佳缓解为 4 个周期的疾病稳定。
本三联疗法的 MTD 出乎意料地较低。我们的研究结果表明，药物相互作用放大了毒性，而肿瘤控制改善的证据很少。
