Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naive patients with advanced non-small-cell lung cancer
Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-naive patients with advanced non-small-cell lung cancer
复制标题
DOI：
10.1023/a:1008319923516
复制
发表时间：
2000-07-01
影响因子：
50.5
通讯作者：
Goldhirsch, A
中科院分区：
文献类型：
--
作者：
De Pas, T;de Braud, F;Goldhirsch, A
背景。吉西他滨 (GEM) 和紫杉醇 (TAX) 是治疗非小细胞肺癌 (NSCLC) 的活性、非交叉耐药性药物。我们进行了一项 I 期研究，以确定晚期 NSCLC 初治患者每周给予的 GEM 和 TAX 的最大耐受剂量 (MTD)、抗肿瘤活性和药代动力学。患者和方法：在第 1、8、15 天每 4 周逐渐增加 GEM (800-2000 mg/m(2)) 和 TAX (60-100 mg/m(2)) 的剂量，以达到治疗目的。 35名晚期非小细胞肺癌患者。在三个较高剂量水平下评估 TAX 和 GEM 的血浆药代动力学。 结果：在没有 MTD 的情况下，剂量递增被终止，因为累积毒性增加导致剂量调整或治疗延迟在 6 和 7 水平（TAX 100 mg/m(2) 分别加 GEM 1750 和 2000 mg/m(2)）。血液学毒性包括 3% 的周期出现 4 级中性粒细胞减少症，一个周期出现 3 级血小板减少症，三个周期出现发热性中性粒细胞减少症。最大非血液学毒性分别为 8% 和 5% 周期的 3 级血清转氨酶升高和 2 级神经感觉毒性。在两个较高剂量水平下，观察到 GEM 的非线性药代动力学，且 C-max 和 AUG 存在显着变化。没有药代动力学相互作用的报道。在所有剂量水平上均出现了目标缓解，30 名可评估患者的总体缓解率为 43%（95% 置信区间 (95% CI)：25.5%-62.6%）。结论：每周给药 GEM 和 TAX 的耐受性非常好，并且在 NSCLC 中显示出有希望的抗肿瘤活性。考虑到 GEM 的累积毒性和药代动力学特征，建议 II 期研究的 GEM 剂量为 1500 mg/m(2)，TAX 剂量为 100 mg/m2。
Background. Gemcitabine (GEM) and paclitaxel (TAX) are active, non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performed a phase I study to determine the maximum-tolerated dose (MTD), antitumor activity and pharmacokinetics of GEM and TAX given weekly in chemo-naive patients with advanced NSCLC.Patients and methods: Escalating doses of GEM (800-2000 mg/m(2)) and TAX (60-100 mg/m(2)) were administered on days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasma pharmacokinetics of TAX and GEM was assessed at the three higher dose-levels.Results: Dose-escalation was discontinued in absence of MTD because of increased cumulative toxicity leading to dose modification or treatment delay at levels 6 and 7 (TAX 100 mg/m(2) plus GEM 1750 and, respectively, 2000 mg/m(2)). Hematological toxicity included grade 4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycle and febrile neutropenia in three cycles. Maximal non-hemathological toxicity was grade 3 elevation in serum transaminases and grade 2 neuro-sensory toxicity in 8% and 5% of cycles, respectively. At the two higher dose-levels a non-linear pharmacokinetics of GEM was observed with a remarkable variability of C-max and AUG. No pharmacokinetic interactions were reported. Objectives responses were seen at all dose levels, with an overall response rate of 43% (95% confidence interval (95% CI): 25.5%-62.6%) in 30 evaluable patients.Conclusions: The weekly administration of GEM and TAX is very well tolerated, and has shown promising antitumor activity in NSCLC. In view of the cumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500 mg/m(2) of GEM and 100 mg/m2 of TAX are recommended for phase II studies.