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癌症常见磷脂酰肌醇-3-激酶（PI3K）信号传导途径活化。在临床前模型中，口服泛PI3K抑制剂布帕利西（布帕尼西）可抑制人类癌症增殖。布帕利西的西方和日本成人晚期实体肿瘤研究确定了每天100mg的推荐剂量，并得到可接受的安全性和有效性证据。 2016年11月，国际抗癌研究所（IIAR）官方期刊《抗癌研究》正式发表广东省人民医院广东省医学科学院广东省肺癌研究所吴一龙、中山大学肿瘤防治中心中山大学附属肿瘤医院张力、法国诺华、美国诺华、瑞士诺华、中国医学科学院北京协和医学院肿瘤医院国家癌症中心徐兵河等学者的剂量递增/扩展Ⅰ期研究报告，确定了中国晚期实体肿瘤患者每日一次口服单药布帕利西的最大耐受剂量（MTD）。 本研究共32例患者（原发肿瘤部位：肺部15例，乳腺10例，头颈部7例），其中26例曾接受过≥2线抗肿瘤治疗，予布帕利西每天80mg（15例）或100mg（17例）。 结果发现，5例患者出现剂量限制性毒性：3级抑郁1例、2级高血糖症3例、3级高血糖症1例。 最常见的布帕利西相关不良事件为高血糖（18例，56%）、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高9例（28%）以及焦虑（6例）。最常见的布帕利西相关3/4级不良事件：高血糖（3例，9%）、ALT和AST升高（2例，6%）、γ-谷氨酰转肽酶增加（2例，6%）。 最佳疗效为疾病稳定（SD）10例（31%）。 因此，本研究确定中国晚期实体肿瘤患者的布帕利西MTD为每天100mg。本研究的安全性、有效性和药代动力学数据，与既往西方和日本人群的报告相似。 Anticancer Res. 2016 Nov;36(11):6185-6194. Phase I Study of the Pan-PI3K Inhibitor Buparlisib in Adult Chinese Patients with Advanced Solid Tumors. Wu YL, Zhang LI, Trandafir L, Dong T, Duval V, Hazell K, Xu B. Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China; Sun Yat-Sen University Cancer Center, Guangzhou, P.R. China; Novartis Pharma S.A.S., Paris, France; Novartis Pharmaceutical Corporation, East Hanover, NJ, U.S.A; Novartis Pharma AG, Basel, Switzerland; National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China. BACKGROUND/AIM: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is frequently activated in cancer. Buparlisib (BKM120), an oral pan-PI3K inhibitor, inhibits proliferation of human cancer in preclinical models. Studies of buparlisib in Western and Japanese adults with advanced solid tumors established a recommended dose of 100 mg/day and showed an acceptable safety profile and evidence of efficacy. This phase I dose-escalation/expansion study aimed to establish the maximum tolerated dose (MTD) of single-agent, once daily oral buparlisib in Chinese patients with advanced solid tumors. MATERIALS AND METHODS: Patients (n=32; primary tumor site: lung (n=15), breast (n=10) or head and neck (n=7); ≥2 prior lines of antineoplastic therapy (n=26)) received 80 mg (n=15) or 100 mg (n=17) daily buparlisib. RESULTS: Five patients experienced dose-limiting toxicities: grade (G)3 depression (n=1), G2 hyperglycemia (n=3) and G3 hyperglycemia (n=1). Most frequent buparlisib-related adverse events were hyperglycemia (n=18; 56%), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increase (n=9; 28%), as well as anxiety (n=6; 19%); most common buparlisib-related G3/4 adverse events: hyperglycemia (n=3; 9%), ALT and AST increase (n=2; 6%), as well as gamma-glutamyltransferase increase (n=2; 6%). Best response was stable disease (SD) in 10 patients (31%). CONCLUSION: The MTD of buparlisib was declared as 100 mg/day. Safety, efficacy and pharmacokinetic data from this study were similar to those previously reported in Western and Japanese populations. KEYWORDS: Buparlisib; breast cancer; head and neck cancer; lung cancer; phosphatidylinositol-3-kinase PMID: 27793950 |
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