Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer
Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer
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DOI：
10.1093/annonc/mdh052
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发表时间：
2004-02-01
影响因子：
50.5
通讯作者：
Raymond, E
中科院分区：
文献类型：
--
作者：
Monnerat, C;Henriksson, R;Raymond, E
背景：PKC412 （n -苯甲酰-staurosporine）是一种蛋白激酶C的口服抑制剂，具有抑制细胞周期和抗血管生成的特性。这项剂量发现I期研究旨在确定PKC412与顺铂-吉西他滨联合时的最大耐受剂量（MTD）。患者和方法：在非小细胞肺癌患者中，每天递增剂量的PKC412，顺铂100mg /m(2)在第2天，吉西他滨1000mg /m(2)在第1、8和15天。剂量递增是基于改进的连续重新评估方法。结果：分配到四个队列的23例患者接受PKC412，剂量范围为25至150mg /天，可评估。3级腹泻发生在3/4的患者在周期1，使我们定义150mg /天为MTD。基于多个周期的MTD被重新定义为100mg /天，因为3/7的患者在重复周期后出现2-3级恶心/呕吐导致停药。因此，下一个较低的剂量50mg /天被认为是第11期试验的推荐剂量。在8例患者的33个疗程中，毒性包括1-2级腹泻（12.5%）和虚弱（50%），只有1例患者在该剂量水平下出现3级头痛。3例患者出现部分缓解。结论：本研究结果表明，在晚期非小细胞肺癌患者中，50mg /天剂量的PKC412可以安全地加入顺铂和吉西他滨。
Background: PKC412 (N-benzoyl-staurosporine), an oral inhibitor of protein kinase C, is capable of cell cycle inhibition and is endowed with anti-angiogenic properties. This dose-finding phase I study was designed to establish the maximum tolerated dose (MTD) of PKC412 when combined with cisplatin-gemcitabine.Patients and methods: Escalating doses of PKC412 were given every day of a 4 week cycle with cisplatin 100 mg/m(2) on day 2 and gemcitabine 1000 mg/m(2) on days 1, 8 and 15 in patients with non-small-cell lung cancer. Dose escalation was based on a modified continuous reassessment method.Results: Twenty-three patients, assigned to four cohorts receiving PKC412 at a dose ranging from 25 to 150 mg/day were evaluable. Grade 3 diarrhea occurring in 3/4 patients at cycle I led us to define 150 mg/day as the MTD. The MTD based on multiple cycles was redefined as 100 mg/day, since prolonged grade 2-3 nausea/ vomiting leading to treatment discontinuation occurred in 3/7 patients after repeated cycles. The next lower dose tested of 50 mg/day was therefore considered as the recommended dose for phase 11 trials. Among 33 cycles in eight patients, toxicity consisted of grade 1-2 diarrhea (12.5%) and asthenia (50%) with only one patient experiencing grade 3 headache at this dose level. A partial response was observed in three patients.Conclusions: The results of the present study indicate that PKC412 at a dose of 50 mg/day can be safely added to cisplatin and gemcitabine in patients with advanced non-small-cell lung cancer.