Department of Medicine,Royal Marsden Hospital, NHS Foundation Trust, Surrey and London, UK.
Ann Oncol. 2012 Apr;23(4):942-7. doi: 10.1093/annonc/mdr317. Epub 2011 Jul 12.
Targeting platelet-derived growth factor receptor-β (PDGFR-β) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-β inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC).
Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly. Imatinib 400 mg od was given for 7 days (day minus 2-5) each cycle.
Twenty-seven patients received 168 cycles in total. Median age was 61 years (44-74 years). Dose-limiting toxicities occurred in two of two patients at DL5 (G4 thrombocytopenia, G3 lethargy), defined as the maximum tolerated dose and one of six patients at DL4 (G3 lethargy). DL4 was expanded. There were 2 of 27 partial responses and 14 of 27 stable disease [disease control 52%, 95% confidence interval (CI) 32% to 71%]. Median progression-free survival and overall survival were 4.6 (95% CI 2.1-7.0) and 5.6 months (95% CI 2.5-8.7), respectively.
In gemcitabine-refractory PC, gemcitabine (1000 mg/m(2)) and oxaliplatin (85 mg/m(2)) can be safely combined with imatinib given on a 7 days on and 7 days off intermittent schedule.
靶向血小板衍生生长因子受体-β（PDGFR-β）是一种降低肿瘤相关间质液压力、增强细胞毒性药物摄取和降低化疗耐药性的潜在策略。本研究旨在确定吉西他滨联合奥沙利铂治疗晚期吉西他滨耐药性胰腺癌（PC）患者时，联合使用伊马替尼（一种有效的 PDGFR-β抑制剂）的安全剂量。
采用 3+3 剂量递增设计，体能状态为 0 或 1 的患者进入 5 个连续剂量水平（DL）的吉西他滨[第 1 天，400mg（DL1）至 1000mg/m²（DL4）]和奥沙利铂[第 2 天，85mg/m²（DL1-4）和 100mg/m²（DL5）]，每两周一次。伊马替尼 400mg 每天一次，每个周期连用 7 天（第-2 天至第 5 天）。
27 例患者共接受 168 个周期治疗。中位年龄为 61 岁（44-74 岁）。DL5 时 2 例患者出现剂量限制毒性（G4 血小板减少症，G3 乏力），定义为最大耐受剂量；DL4 时 6 例患者中 1 例出现剂量限制毒性（G3 乏力）。DL4 进行了扩展。27 例患者中 2 例有部分缓解，14 例有稳定疾病[疾病控制率为 52%（95%CI 32%至 71%）]。中位无进展生存期和总生存期分别为 4.6 个月（95%CI 2.1-7.0）和 5.6 个月（95%CI 2.5-8.7）。
在吉西他滨耐药性 PC 中，吉西他滨（1000mg/m²）和奥沙利铂（85mg/m²）可安全联合伊马替尼，按 7 天用药和 7 天停药的间歇方案给药。
