Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer
Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer
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DOI：
10.1200/jco.2004.02.106
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发表时间：
2004-06-01
影响因子：
45.3
通讯作者：
Logothetis, CJ
中科院分区：
文献类型：
--
作者：
Papandreou, CN;Daliani, DD;Logothetis, CJ
目的。目的：测定蛋白酶体抑制剂Bortezomib的剂量限制毒性和最大耐受量，每周静脉给药4次，每5周4次；采用血药浓度和全血20S蛋白酶体抑制(PI)法测定Bortezomib的药代动力学和药效学；毒性与Bortezomib剂量和20S R程度的相关性；初步确定Bortezomib在雄激素非依赖性前列腺癌(AIPCA)患者中的抗肿瘤活性。53例AIPCA患者128例接受了128个周期的硼替佐米治疗，剂量从0.13到2.0 mg/m(2)/剂量不等，采用谨慎的逐步升级方案和持续重新评估的方法。24例患者进行了药代动力学和药效学研究(1.45~2.0 mg/m(2))。观察到剂量相关的20S Pl，剂量限制性毒性为2.0 mg/m(2)(腹泻、低血压)，在剂量后1小时平均出现大于或等于75%20S Pl的毒性。其他副作用包括乏力、高血压、便秘、恶心和呕吐。在测试的窄剂量范围内，体表面积和Bortezomib清除量之间没有相关性。有证据表明，20s Pl大于或等于50%时，有生物学活性(血清前列腺特异性抗原和白细胞介素6水平下降)。2例AIPCa患者有前列腺特异性抗原反应，2例有淋巴结部分反应。在这个时间表中，硼替佐米的最大耐受量和推荐的II期剂量为1.6 mg/m(2)。在耐受剂量的Bortezomib中，AIPCA具有生物学活性(抑制核因子-kappa B相关标记)和抗肿瘤活性。该药应与化疗药物一起用于晚期前列腺癌的进一步研究。(C)2004年，由美国临床肿瘤学会提供。
Purpose. To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S R; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa).Patients and Methods. Fifty-three patients 128 with AIPCa received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2))Results. A dose-related 20S Pl was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of greater than or equal to75% 20S Pl. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at greater than or equal to50% 20S Pl. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes.Conclusion. The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer. (C) 2004 by American Society of Clinical Oncology.