Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago phase II consortium study
Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago phase II consortium study
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DOI：
10.1200/jco.2004.07.165
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发表时间：
2004-01-01
影响因子：
45.3
通讯作者：
Stadler, WM
中科院分区：
文献类型：
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作者：
Davis, NB;Taber, DA;Stadler, WM
目的确定蛋白酶体抑制剂PS-341在IV期肾细胞癌患者中的反应率、疾病进展时间和毒性。患者与方法sp -341静脉滴注1.5 mg/m(2)，每周2次，每21天1次，连续2周。在没有3至4级毒性的情况下，剂量增加到1.7 mg/m(2)。三个周期后进行了重新评估。为了评估蛋白酶体的抑制作用，患者被随机分配在PS-341第一次给药前或第三个周期后进行肿瘤核心活检。此外，在相同的时间间隔内采集全血。结果入选患者23例；21个可评估反应。2例患者从未接受治疗（1例患者拒绝治疗，1例患者肿瘤不足以进行活检）。18名患者完成了至少3个疗程的治疗；3例患者在两个周期后出现疾病进展。4级毒性反应为关节痛、腹泻和呕吐。3级毒性包括血小板减少伴出血、贫血、发热性中性粒细胞减少、胃肠道毒性、疼痛、疲劳、神经病变（单感觉、混合感觉运动）和电解质紊乱。7例患者发生1 ~ 2级神经病变。发生血栓形成1例，胸腔积液1例。只看到一个客观的反应。蛋白酶体活性通过特定凝乳胰蛋白酶活性（SpA）和凝乳胰蛋白酶/胰蛋白酶活性（ChT:T）测定。PS-341后，平均全血SpA和ChT:T下降（P = 0.07, P = 0.09）。11日,分别)。结论PS-341在转移性肾细胞癌中的临床活性尚缺乏证据。活检和全血样本数量不足，无法得出关于肿瘤内蛋白酶体抑制的结论。不建议在这种疾病情况下进行进一步的评估。
PurposeDetermine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer.Patients and MethodsPS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals.ResultsTwenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively).ConclusionEvidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.