Lessons learned: Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models.Because of toxicity and lack of efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma.
Background: Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC.
Methods: Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study.
Results: The study was terminated early because of high incidence of dose-limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235-six with clear cell and four with non-clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d.
Cohort: DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease.
Conclusion: BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease.
作者总结
经验
• 本研究结果强调了PI3K/mTOR双重抑制在临床环境中的额外毒性, 而在临床前模型中并未预见到这种毒性。
• 鉴于当前配方BEZ235具有毒性又缺乏有效性, 不应在肾细胞癌患者中开展进一步研究。
摘要
背景. 哺乳动物雷帕霉素靶蛋白复合物1 (mTORC1) 变构抑制剂获批用于治疗晚期肾细胞癌 (RCC)。临床前模型提示对磷脂酰肌醇3激酶 (PI3K) 和mTOR激酶的双重抑制可能产生更好的抗癌作用。本研究旨在确定强效PI3K和mTOR抑制剂BEZ235在晚期RCC患者中的安全性。
方法. 本研究对象为标准治疗失败的晚期RCC患者, 每日两次给予剂量递增的BEZ235微囊制剂治疗, 直至发生疾病进展或不可接受的毒性事件。主要终点为确定最大耐受剂量 (MTD) 以及决定II期研究的建议剂量。
结果. 本研究因剂量限制毒性 (DLT) 发生率高而提早终止。10例患者接受了BEZ235治疗, 其中6例为透明细胞癌亚型, 4例为非透明细胞癌亚型。5例患者发生DLT, 包括起始400 mg BID组的2/2例患者、200 mg BID组的1/6例患者, 以及300 mg BID组的2/2例患者。DLT包括疲劳、皮疹、恶心与呕吐、腹泻、黏膜炎、纳差以及味觉异常。5例患者可评价治疗反应, 其中2例患者的最佳治疗反应为疾病稳定, 3例发生疾病进展。
结论. BEZ235每日两次给药方案导致了明显的毒性, 并且未观察到客观缓解, 不建议在晚期RCC患者中对该化合物开展进一步研究。The Oncologist 2016;21:787–788d
Trial registration: ClinicalTrials.gov NCT01453595.
©AlphaMed Press; the data published online to support this summary is the property of the authors.