A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors.
A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors.
复制标题
DOI：
10.1007/s10637-010-9563-7
复制
发表时间：
2012-04
影响因子：
3.4
通讯作者：
Shah, Manisha H.
中科院分区：
文献类型：
--
作者：
Ramaswamy, Bhuvaneswari;Phelps, Mitch A.;Baiocchi, Robert;Bekaii-Saab, Tanios;Ni, Wenjun;Lai, Ju-Ping;Wolfson, Anna;Lustberg, Mark E.;Wei, Lai;Wilkins, Deidre;Campbell, Angela;Arbogast, Daria;Doyle, Austin;Byrd, John C.;Grever, Michael R.;Shah, Manisha H.
基于在慢性淋巴细胞白血病（CLL）中使用药代动力学衍生的给药方案给予flavopiridol的有希望的活性和耐受性，我们在晚期实体瘤患者中使用该方案进行了I期研究。Flavopiridol作为30分钟的负荷剂量IV给药，然后每周4小时输注，持续4周，每6周重复一次。使用标准3+3 I期研究设计，在3例患者的队列中进行剂量递增。采集血样用于药代动力学和药效学研究。34例符合条件的晚期实体瘤患者共接受了208剂（中位数7，范围1-24）。总剂量范围为40 - 105 mg/m2。主要的剂量限制性毒性是细胞因子释放综合征（CKRS）。未观察到抗肿瘤反应。所有剂量的平均血浆峰浓度为1.65 ± 0.86 µM。浓度-时间曲线下面积（AUC 0-∞）范围为4.31 - 32.2 µM·hr，总体平均值为13.6 ± 7.0 µM·hr。血浆flavopiridol浓度和AUC随剂量成比例增加。细胞因子水平与临床结果之间没有相关性。在晚期实体瘤患者中，flavopiridol的最大耐受剂量为20 mg/m2推注，随后在4小时内输注20 mg/m2，每周给药，持续4周，以6周为周期。Flavopiridol PK显著不同，并且与使用类似给药方案的既往CLL研究相比，尽管预防性类固醇，在该患者组中观察到CKRS的频率更高。
Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors. Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies. Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1–24). Total doses ranged from 40 – 105 mg/m2. The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 µM. Area under the concentration-versus-time curve (AUC0–∞) ranged from 4.31 to 32.2 µM·hr with an overall mean of 13.6 ± 7.0 µM·hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes. The maximum-tolerated dose of flavopiridol is 20 mg/m2 bolus followed by 20 mg/m2 infusion over 4 hours given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.
登录
查看更多内容
影响因子：
20.3
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
通讯作者：
Grever, Michael R.
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
20.3
作者：
Parker, BW;Kaur, G;Senderowicz, AM
通讯作者：
Senderowicz, AM
DOI：
10.1158/1078-0432.ccr-09-1502
发表时间：
2009-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Rathkopf D;Dickson MA;Feldman DR;Carvajal RD;Shah MA;Wu N;Lefkowitz R;Gonen M;Cane LM;Dials HJ;Winkelmann JL;Bosl GJ;Schwartz GK
通讯作者：
Schwartz GK
影响因子：
2.6
作者：
Lin, TS;Howard, OM;Shipp, MA
通讯作者：
Shipp, MA