Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors.
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DOI：
10.1158/1078-0432.ccr-09-1502
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Schwartz GK
中科院分区：
文献类型：
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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
Flavopiridol是一种细胞周期蛋白依赖性激酶抑制剂，与化疗联合应用具有良好的临床疗效。临床前数据表明，flavopiridol增强奥沙利铂（OX）和氟尿嘧啶（5 FU）诱导的细胞凋亡的序列依赖性方式。我们进行了一项Flavopiridol + FOLFOX（亚叶酸、5 FU和OX）治疗晚期实体瘤的I期试验。基于序列依赖性生长抑制，在5 FU之前每两周与OX一起施用Flavopiridol。评价Flavopiridol药代动力学和p53状态。48例患者在研究中接受治疗。随着OX（85 mg/m2）和5 FU（2400 mg/m2）剂量递增，剂量限制性毒性（DLT）包括低钠血症、血小板减少症和中性粒细胞减少症。随后减少5 FU以允许flavopiridol的剂量递增。flavopiridol剂量递增的DLT为恶心、呕吐和中性粒细胞减少。最大耐受剂量（MTD）为flavopiridol 70 mg/m2，奥沙利铂85 mg/m2，5 FU 1800 mg/m2持续输注48小时。在铂难治性生殖细胞肿瘤（GCT）中观察到临床活性：9例可评价患者中有3例（33%）在影像学上显示部分缓解，10例患者中有7例（70%）血清肿瘤标志物下降。在胰腺、胃和汗腺肿瘤中也观察到缓解。Flavopiridol药代动力学具有显著的患者间变异性。在MTD时，肿瘤样品对于应答者是p53突变体（>30%阳性细胞），对于非应答者是p53野生型。Flavopiridol联合FOLFOX是一种安全且可耐受的方案。在肿瘤类型中观察到有希望的临床活性。在铂难治性GCT人群中的令人鼓舞的结果促使了一项II期试验，该试验目前正在开放招募。
Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin (OX)- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and OX) for advanced solid tumors. Flavopiridol was administered every two weeks with OX before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. Forty-eight patients were treated on study. With dose escalation of OX (85 mg/m2) and 5FU (2400 mg/m2), dose-limiting toxicities (DLT) included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. DLTs with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose (MTD) was flavopiridol 70 mg/m2, oxaliplatin 85 mg/m2, and 5FU 1800 mg/m2 continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors (GCTs): 3 out of 9 (33%) evaluable patients demonstrated a partial response on imaging, and 7 out of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the MTD, tumor samples were p53 mutant (>30% positive cells) for responders and p53 wild-type for non-responders. Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory GCT population has prompted a phase II trial which is currently open for accrual.