Propper D J, McDonald A C, Man A, Thavasu P, Balkwill F, Braybrooke J P, Caponigro F, Graf P, Dutreix C, Blackie R, Kaye S B, Ganesan T S, Talbot D C, Harris A L, Twelves C
Cancer Research Campaign Department of Medical Oncology, Beatson Oncology Centre, Glasgow, UK.
J Clin Oncol. 2001 Mar 1;19(5):1485-92. doi: 10.1200/JCO.2001.19.5.1485.
N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days.
Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles.
The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L.
PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.
N-苯甲酰基星形孢菌素（PKC412）是一种蛋白激酶C抑制剂，在实验室模型中具有抗肿瘤活性。我们确定了每日口服PKC412并重复28天周期的毒性。
32例晚期实体癌患者接受了7个剂量水平（每日12.5至300毫克）的治疗，共68个周期。
最常见的与治疗相关的毒性反应为恶心、呕吐、疲劳和腹泻。在两个最高剂量水平（225和300毫克/天），16例患者中有15例出现恶心/呕吐（常见毒性标准[CTC]，第1版），16例中有9例为2级，16例中有3例为3级；16例患者中有6例出现CTC 2级腹泻。治疗1个月后，接受剂量≥100毫克/天的患者循环淋巴细胞计数（P<.02）和单核细胞计数（P<.01）显著降低。然而，只有2例患者出现骨髓抑制（均为2级）。2例进行性胆管癌患者中，1例病情稳定持续4.5个月，1例部分缓解持续4个月。PKC412剂量与曲线下面积（0至24小时）和最大血浆浓度之间存在线性关系，患者间差异显著。估计中位消除半衰期为1.6天（范围为0.9至4.0天），并检测到一种中位半衰期为36天的代谢物。前三个剂量组（150至300毫克）的PKC412稳态血浆水平是细胞对PKC412的50%抑制浓度（0.2至0.7微摩尔/升）的5至10倍。
PKC412可通过长期口服治疗安全给药，150毫克/天适用于II期研究。药代动力学和缺乏传统毒性表明，可能还需要药效学措施来优化药物剂量和给药方案。
