Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.
Phase I study of 17-allylamino-17 demethoxygeldanamycin, gemcitabine and/or cisplatin in patients with refractory solid tumors.
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DOI：
10.1007/s10637-009-9381-y
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发表时间：
2011-06
影响因子：
3.4
通讯作者：
Haluska, Paul
中科院分区：
文献类型：
--
作者：
Hubbard, Joleen;Erlichman, Charles;Toft, David O.;Qin, Rui;Stensgard, Bridget A.;Felten, Sara;Ten Eyck, Cynthia;Batzel, Gretchen;Ivy, S. Percy;Haluska, Paul
关键词：
测定17-AAG、吉西他滨和/或顺铂的最大耐受量(MTD)和剂量限制毒性(DLT)。检测外周血单个核细胞(PMBC)裂解物中Hsp90、Hsp70和ILK蛋白的水平，以评价17-AAG的作用。采用“3+3”设计的I期剂量递增试验在晚期实体肿瘤患者中进行。一旦确定吉西他滨+17-AAG+顺铂的MTD，就尝试用恒定剂量的吉西他滨和顺铂增加17-AAG的剂量。在发生显著的血液毒性后，修改了方案以评估三个队列：吉西他滨和17-AAG；17-AAG和顺铂；以及吉西他滨、17-AAG和顺铂，并修改了剂量。纳入的39名患者的毒性和反应是可评估的。A组17-AAG、吉西他滨和顺铂的MTD分别为154 mg/m2、750 mg/m2和40 mg/m2。在队列A中，在较高剂量水平上观察到DLT，包括中性粒细胞减少、高胆红素血症、脱水、GGT升高、低钠血症、恶心、呕吐和血小板减少。C组17-AAG和吉西他滨的MTD分别为154 mg/m2和750 mg/m2，观察到1个DLT(碱性磷酸酶升高)。在队列C中，血小板减少、发热和呼吸困难的DLT出现在较高剂量水平。其余的队列由于毒性而接近应计。6名患者出现部分反应。Hsp90平均水平较治疗前降低，Hsp70水平较治疗前升高。17-AAG联合吉西他滨和顺铂显示了抗肿瘤活性，但也出现了显著的血液学毒性。17-AAG联合吉西他滨是可以耐受的，并已证明在MTD中有活性。推荐的II期剂量定义为154 mg/m2的17-AAG和750 mg/m2的吉西他滨，目前正在卵巢癌和胰腺癌的II期研究中进行研究。对于含顺铂的联合用药，没有推荐的II期剂量。
To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of 17-AAG, gemcitabine and/or cisplatin. Levels of the proteins Hsp90, Hsp70 and ILK were measured in peripheral blood mononuclear cell (PMBC) lysates to assess the effects of 17-AAG. Phase I dose-escalating trial using a “3+3” design performed in patients with advanced solid tumors. Once the MTD of gemcitabine + 17-AAG + cisplatin was determined, dose escalation of 17-AAG with constant doses of gemcitabine and cisplatin was attempted. After significant hematologic toxicity occurred, the protocol was amended to evaluate three cohorts: gemcitabine and 17-AAG; 17-AAG and cisplatin; and gemcitabine, 17-AAG and cisplatin with modified dosing. The 39 patients enrolled were evaluable for toxicity and response. The MTD for cohort A was 154 mg/m2 of 17-AAG, 750 mg/m2 of gemcitabine, and 40 mg/m2 of cisplatin. In cohort A, DLTs were observed at the higher dose level and included neutropenia, hyperbilirubinemia, dehydration, GGT elevation, hyponatremia, nausea, vomiting, and thrombocytopenia. The MTD for cohort C was 154 mg/m2 of 17-AAG and 750 mg/m2 of gemcitabine, with one DLT observed (alkaline phosphatase elevation) observed. In cohort C, DLTs of thrombocytopenia, fever and dyspnea were seen at the higher dose level. The remaining cohorts were closed to accrual due to toxicity. Six patients experienced partial responses. Mean Hsp90 levels were decreased and levels of Hsp70 were increased compared to baseline. 17-AAG in combination with gemcitabine and cisplatin demonstrated antitumor activity, but significant hematologic toxicities were encountered. 17-AAG combined with gemcitabine is tolerable and has demonstrated evidence of activity at the MTD. The recommended phase II dose is defined as 154 mg/m2 of 17-AAG and 750 mg/m2 of gemcitabine, and is currently being investigated in phase II studies in ovarian and pancreatic cancers. There is no recommended phase II dose for the cisplatin-containing combinations.
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DOI：
10.1073/pnas.91.18.8324
发表时间：
1994-08-30
影响因子：
11.1
作者：
WHITESELL, L;MIMNAUGH, EG;NECKERS, LM
通讯作者：
NECKERS, LM
影响因子：
11.4
作者：
Zachos, G;Rainey, MD;Gillespie, DAF
通讯作者：
Gillespie, DAF
影响因子：
11.5
作者：
Nowakowski, Grzegorz S.;McCollum, Andrea K.;Erlichman, Charles
通讯作者：
Erlichman, Charles
影响因子：
3
作者：
SUPKO, JG;HICKMAN, RL;MALSPEIS, L
通讯作者：
MALSPEIS, L
影响因子：
11.5
作者：
Ramanathan, Ramesh K.;Egorin, Merrill J.;Belani, Chandra P.
通讯作者：
Belani, Chandra P.