A Phase I Study of Flavopiridol in Combination With Gemcitabine and Irinotecan in Patients With Metastatic Cancer
A Phase I Study of Flavopiridol in Combination With Gemcitabine and Irinotecan in Patients With Metastatic Cancer
复制标题
DOI：
10.1097/coc.0b013e3181b2043f
复制
发表时间：
2010-08-01
影响因子：
2.6
通讯作者：
Rabinowitz, Ian
中科院分区：
文献类型：
--
作者：
Fekrazad, Houman M.;Verschraegen, Claire F.;Rabinowitz, Ian
背景：Flavopiridol（HMR 1275）是一种人工合成的黄酮类化合物，通过抑制细胞周期蛋白依赖性激酶抑制剂而具有抗肿瘤活性。Flavopiridol与化疗以顺序依赖的方式协同作用。Flavopiridol单药I期研究的主要不良事件是分泌性腹泻、中性粒细胞减少、血栓形成和疲劳。晚期实体瘤患者在第1天接受吉西他滨800 mg/m2和伊立替康80 mg/m2治疗，随后在第2天接受flavopiridol治疗，起始剂量为30 mg/m2，每个剂量水平递增15 mg/m2，对前6名患者在第8天和第9天重复（3周周期），然后对其余患者在第15天和第16天重复（4周周期）。该协议已被修改为无法重新给药后1 week.Results：14名女性和7名男性晚期实体瘤入组。中位年龄为51岁，既往化疗的中位次数为3（0-9）。在第一个方案治疗的6例受试者中，观察到中性粒细胞减少性脓毒症（1例患者）、3级腹泻（1例患者）和中性粒细胞减少症（2例患者）阻止第8天再次治疗。Flavopiridol的II期推荐剂量为45 mg/m2，联合伊立替康和吉西他滨，每2周一次。剂量限制性毒性为电解质失衡伴疲劳（1例患者），肾衰竭和呼吸困难伴缺氧（各1例患者），分别见于45和60 mg/m2剂量。最常见的副作用是疲劳（81%），恶心（71%），腹泻（67%），短暂性骨髓抑制（43%）和呕吐（24%）。结论：每2周给药一次，II期推荐剂量45 mg/m2的flavopiridol联合伊立替康（80 mg/m2）和吉西他滨（800 mg/m2）耐受性良好。
Background: Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue.Patients and Methods: Patients with advanced solid tumors were treated with gemcitabine 800 mg/m(2) and irinotecan 80 mg/m(2) on day 1, followed by flavopiridol, starting dose of 30 mg/m(2) on day 2 with increment of 15 mg/m(2) per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week.Results: Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0-9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m(2) in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m(2) doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%).Conclusions: The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m(2) of flavopiridol in combination with irinotecan (80 mg/m(2)) and gemcitabine (800 mg/m(2)).