Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points
Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points
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DOI：
10.1158/1078-0432.ccr-04-2566
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发表时间：
2005-08-15
影响因子：
11.5
通讯作者：
Erlichman, C
中科院分区：
文献类型：
--
作者：
Bible, KC;Lensing, JL;Erlichman, C
目的：Flavopiridol，细胞周期蛋白依赖性激酶抑制剂，转录抑制剂和DNA相互作用剂，与顺铂或卡铂相结合，以建立毒性，评估药代动力学，并检查其对患者癌症和患者外周血单核细胞（PBMC）中选定的多肽水平的影响。第1阶段：顺铂固定在30 mg/m2，并逐步增加flavopiridol。II期：Flavopiridol固定在I期最大耐受剂量（MTD），顺铂递增。第三阶段：flavopiridol固定在第一阶段MTD与递增carboplatin.Results：39例患者接受了136个周期的化疗。仅11%的患者出现中性粒细胞减少。3级flavopiridol/CDDP毒性为恶心（30%）、呕吐（19%）、腹泻（15%）、脱水（15%）和中性粒细胞减少（10%）。Flavopiridol联合卡铂导致意外的高毒性和1例治疗相关死亡。34%的治疗患者病情稳定（>3个月），但无客观缓解。II期MTD为60 mg/m2顺铂和100 mg/m2/24小时flavopiridol。如所给出的，CDDP没有改变flavopiridol的药代动力学。Flavopiridol可诱导患者PBMC中p53和pSTAT 3水平升高，但对cyclin D1、phosphoRNA聚合酶II和Mcl-1无影响。结论：Flavopiridol与顺铂联合治疗肿瘤是安全的。Flavopiridol/卡铂治疗患者的意外毒性减弱了这种替代组合的热情。对患者PBMC中多肽水平的分析表明，flavopiridol可能影响其体内已知的体外分子靶点中的一些，但不是全部。
Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC).Experimental Design: Therapy was given every 3 weeks. Stage 1: cisplatin was fixed at 30 mg/m(2) with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin.Results: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m(2) cisplatin and 100 mg/m(2) /24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1.Conclusions: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.