The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: A california cancer consortium phase I study
The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: A california cancer consortium phase I study
复制标题
DOI：
10.1097/jto.0b013e31815e8b88
复制
发表时间：
2008-01-01
影响因子：
20.4
通讯作者：
Gandara, Anddavid R.
中科院分区：
文献类型：
--
作者：
Davies, Angela M.;Ruel, Christopher;Gandara, Anddavid R.
简介：硼替佐米是一种小分子蛋白酶体抑制剂，在非小细胞肺癌（NSCLC）患者中具有单药活性，在临床前研究中与吉西他滨具有协同作用。吉西他滨联合卡铂是晚期NSCLC的公认一线治疗。我们进行了一项I期研究，吉西他滨和卡铂联合硼替佐米。方法：硼替佐米给药的第1，4，8和11天，吉西他滨后的第1天和第8天，和卡铂的第1天，21天的周期。评估了三种递增剂量水平：硼替佐米1.0 mg/m2/吉西他滨800 mg/m2、硼替佐米1.0 mg/m2/吉西他滨1000 mg/m2和硼替佐米1.3 mg/m2/吉西他滨1000 mg/m2，联合卡铂AUC 5.0。中位年龄为59岁（范围34-74岁），23例患者为IV期。16例患者的Karnofsky评分为80%。剂量限制性毒性为3级血小板减少伴出血和发热性中性粒细胞减少伴4级血小板减少和3级低钠血症。最大耐受剂量定义为硼替佐米1.0 mg/m2、吉西他滨1000 mg/m2和卡铂AUC 5.0。最常见的3/4级毒性是血小板减少症（很少与出血相关）和中性粒细胞减少症。26例患者中有9例（35%）达到部分缓解，8例患者病情稳定。结论：硼替佐米1.0 mg/m2、吉西他滨1000 mg/m2和卡铂AUC 5.0联合治疗NSCLC显示出可控制的毒性和令人鼓舞的活性。该方案用于II期研究。
Introduction: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib.Methods: Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m(2)/gemcitabine 800 mg/m(2), bortezomib 1.0 mg/m(2)/gemcitabine 1000 mg/m(2), and bortezomib 1.3 mg/m(2)/gemcitabine 1000 mg/m(2), in combination with carboplatin AUC 5.0.Results: Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34-74), and 23 patients were stage IV. The Karnofsky performance score was 80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m(2), gemcitabine 1000 mg/m(2), and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease.Conclusions: The combination of bortezomib 1.0 mg/m(2), gemcitabine 1000 mg/m(2), and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.