Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study.
Phase I trial of GTI-2040, oxaliplatin, and capecitabine in the treatment of advanced metastatic solid tumors: a California Cancer Consortium Study.
复制标题
GTI-2040、奥沙利铂和卡培他滨治疗晚期转移性实体瘤的 I 期试验：加州癌症联盟研究。
DOI：
10.1007/s00280-009-0977-x
复制
发表时间：
2009
影响因子：
3
通讯作者：
Newman,EdwardM
中科院分区：
文献类型：
--
作者：
Shibata,StephenI;Doroshow,JamesH;Frankel,Paul;Synold,TimothyW;Yen,Yun;Gandara,DavidR;Lenz,Heinz-Josef;Chow,WarrenA;Leong,LucilleA;Lim,Dean;Margolin,KimA;Morgan,RobertJ;Somlo,George;Newman,EdwardM
背景GTI-2040是一种靶向核糖核苷酸还原酶M2 mRNA的20聚体反义寡核苷酸。它结合奥沙利铂和卡培他滨在I期临床试验中的晚期实体瘤患者的基础上，以前的研究表明增强化疗与核糖核苷酸还原酶inhibitors.MethodsPatients至少18岁的晚期不可治愈的实体瘤和正常的器官功能，以及Karnofsky性能状态≥60%的有资格。对于晚期疾病或辅助化疗后12个月内复发，需要既往接受过一次化疗方案。患者可能既往接受过氟尿嘧啶，包括卡培他滨，但未接受过奥沙利铂。治疗周期为21天。在每个周期中，GTI-2040以连续静脉输注方式给予14天，奥沙利铂以2小时静脉输注方式在第1天给予，卡培他滨口服，每天两次，持续14天。仅在周期1中，奥沙利铂和卡培他滨在第2天开始给药，以允许在有和无奥沙利铂和卡培他滨的情况下测量核糖核苷酸还原酶mRNA水平。使用标准的3 + 3设计在三名患者的群组中逐步增加剂量，直到建立最大耐受剂量，最大耐受剂量被定义为在以给定剂量水平治疗的六名患者中不超过一个第一周期剂量限制性毒性。奥沙利铂100 mg/m2，每21天1次。剂量限制性毒性为血液学毒性。在第7天和第14天获得的稳态GTI-2040药代动力学显示了先前报道的高患者间变异性。6名患者中有2名在最大耐受剂量下病情稳定，1名患者在较高剂量水平下有部分缓解，该患者患有重度预治疗的非小细胞肺癌。在样本数量有限的患者，有没有明确的减少核糖核苷酸还原酶表达在外周血单核细胞在treatment.ConclusionA组合的GTI-2040，卡培他滨和奥沙利铂在晚期实体瘤患者是可行的。
BackgroundGTI-2040 is a 20-mer antisense oligonucleotide targeting the mRNA of ribonucleotide reductase M2. It was combined with oxaliplatin and capecitabine in a phase I trial in patients with advance solid tumors based on previous studies demonstrating potentiation of chemotherapy with ribonucleotide reductase inhibitors.MethodsPatients at least 18 years of age with advanced incurable solid tumors and normal organ function as well as a Karnofsky performance status of ≥60% were eligible. One prior chemotherapy regimen for advanced disease or relapse within 12 months of adjuvant chemotherapy was required. Patients could have received prior fluoropyrimidines, including capecitabine, but not oxaliplatin. Treatment cycles were 21 days. In each cycle, GTI-2040 was given as a continuous intravenous infusion over 14 days, oxaliplatin as a 2-h intravenous infusion on day 1, and capecitabine orally twice a day for 14 days. In cycle 1 only, oxaliplatin and capecitabine were started on day 2 to allow ribonucleotide reductase mRNA levels to be measured with and without oxaliplatin and capecitabine. Doses were escalated in cohorts of three patients using a standard 3 + 3 design until the maximum tolerated dose was established, defined as no more than one first-cycle dose-limiting toxicity among six patients treated at a given dose level.ResultsThe maximum tolerated dose was estimated to be the combination of GTI-2040 3 mg/kg per day for 14 days, capecitabine 600 mg/m2twice daily for 14 days, and oxaliplatin 100 mg/m2every 21 days. Dose-limiting toxicities were hematologic. GTI-2040 pharmacokinetics, obtained at steady-state on days 7 and 14, showed the high inter-patient variability previously reported. Two of six patients had stable disease at the maximum tolerated dose and one patient, with heavily pre-treated non-small cell lung cancer, had a partial response at a higher dose level. In samples from a limited number of patients, there was no clear decrease in ribonucleotide reductase expression in peripheral blood mononuclear cells during treatment.ConclusionA combination of GTI-2040, capecitabine and oxaliplatin is feasible in patients with advanced solid tumors.