Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma
Phase II trial of flavopiridol, a cyclin dependent kinase inhibitor, in untreated metastatic malignant melanoma
复制标题
DOI：
10.1023/b:drug.0000026258.02846.1c
复制
发表时间：
2004-08-01
影响因子：
3.4
通讯作者：
Eisenhauer, EA
中科院分区：
文献类型：
--
作者：
Burdette-Radoux, S;Tozer, RG;Eisenhauer, EA
目的：检测细胞周期蛋白依赖性激酶（cdk）抑制剂flavopiridol在恶性黑色素瘤中的活性，恶性黑色素瘤是一种细胞周期蛋白依赖性激酶系统经常异常的疾病。患者和方法：患者有组织学证实，一维可测量的恶性黑色素瘤，无法治愈的标准治疗。允许既往辅助免疫治疗，但患者未接受其他晚期疾病治疗。Flavopiridol的剂量为50 mg/m2，IV给药，每日1小时，每3周给药3天。每2个周期评估患者的缓解情况。结果：17例患者随访时间超过5个月。在16例可评价缓解的患者中未记录客观缓解。7例患者（44%）在2个周期后病情稳定，中位时间为2.8个月（范围1.8-9.2）。最常见的治疗相关非血液学毒性为腹泻（82%）、恶心（47%）、疲乏（41%）、厌食（35%）和呕吐（29%）。除腹泻（3例患者3级，1例患者4级）、恶心（1例患者3级）和肿瘤疼痛（1例患者3级）外，大多数治疗相关毒性均为轻度。血液学毒性极轻微，均未恶化至2级。88%的患者接受了大于或等于90%计划剂量强度的治疗; 2例患者因胃肠道（GI）毒性而降低剂量。结论：Flavopiridol在本研究中使用的剂量方案下耐受性良好，具有可接受的（主要是GI）毒性特征。尽管16例患者中有7例病情稳定，持续时间为1.8至9.2个月，但根据客观缓解标准，没有证据表明恶性黑色素瘤具有显著的临床活性。
Purpose: To test the activity of the cyclin dependent kinase (cdk) inhibitor flavopiridol in malignant melanoma, a disease with frequent abnormalities of the cyclin dependent kinase system. Patients and methods: Patients had histologically proven, unidimensionally measurable malignant melanoma, incurable by standard therapy. Prior adjuvant immunotherapy was allowed, but patients were otherwise untreated for advanced disease. Flavopiridol was administered at a dose of 50 mg/m(2) IV over 1 hour daily x 3 days every 3 weeks. Patients were assessed for response every 2 cycles. Results: 17 patients were accrued over 5 months. No objective responses were documented in the 16 patients evaluable for response. Seven patients (44%) had stable disease after 2 cycles, with a median of 2.8 months (range 1.8-9.2). The most common treatment-related non-hematologic toxicities were diarrhea (82%), nausea (47%), fatigue (41%), anorexia (35%) and vomiting (29%). Most treatment-related toxicities were mild, except for diarrhea (grade 3 in 3 patients, grade 4 in 1 patient), nausea (grade 3 in 1 patient) and tumor pain (grade 3 in 1 patient). Hematologic toxicities were minimal, none worse than grade 2. Eighty-eight percent of patients received greater than or equal to90% planned dose intensity; 2 patients had dose reductions for gastrointestinal (GI) toxicity. Conclusions: Flavopiridol is well tolerated at the dose regimen used in this study, with an acceptable (primarily GI) toxicity profile. Although 7 of the 16 patients had stable disease ranging from 1.8 to 9.2 months in duration, there was no evidence of significant clinical activity in malignant melanoma by objective response criteria.