Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Victoria 8006, Australia.
Cancer Chemother Pharmacol. 2013 Feb;71(2):321-30. doi: 10.1007/s00280-012-2009-5. Epub 2012 Oct 30.
Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities.
Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily.
Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib.
MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR.
通过降低肿瘤间质液压力来抑制血小板衍生生长因子受体 (PDGFR)，可能会提高化疗的疗效。伊马替尼以治疗相关剂量抑制 PDGFR 激酶活性。这项 I 期研究旨在评估伊马替尼联合 mFOLFOX6-贝伐单抗在晚期结直肠癌患者中的最大耐受剂量 (MTD)，并确定药代动力学 (PK) 相互作用和毒性。
符合条件的患者具有可测量的疾病和足够的器官功能。在第 14 天，患者开始每天服用伊马替尼加贝伐单抗（5mg/kg/2 周）。两周后（第 1 天），患者还接受了 12 个周期的全剂量 mFOLFOX6-贝伐单抗治疗。采集血样进行 PK 分析。在最初的 6 周内定义了 DLTs。标准的伊马替尼剂量递增，有 3 个患者队列：计划剂量水平 (DL)：DL1：400mg；DL2：600mg；DL3：800mg 每天。
共招募了 10 名患者。DL1 有 3 名患者，DL2 有 7 名患者。在 DL2 中，6 名患者中有 3 名观察到 DLTs：发热性中性粒细胞减少症（2）；3 级感染和 4 级中性粒细胞减少症（1）。中性粒细胞减少症是最常见的不良事件：总体上超过 60%的患者出现 3/4 级。在 DL2 患者中，伊马替尼清除率在化疗后降低（P<0.05）。奥沙利铂和 5-FU 的 PK 不受伊马替尼影响。
伊马替尼的 MTD 为 400mg 加全剂量 mFOLFOX-贝伐单抗。伊马替尼的剂量递增受到中性粒细胞减少症的限制。由于伊马替尼可以在抑制 PDGFR 的水平上给药，因此需要进一步研究。
