Advani S H, Achrekar S D, Doval D C, Raghunadharao D, Wilhelm F E, Acharya M
Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, India.
Indian J Cancer. 2014 Jan-Mar;51(1):40-4. doi: 10.4103/0019-509X.134617.
Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies.
To determine the safety, dose-limiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD).
Phase 1, open-label, dose-escalation study in men and women ≥18 years of age.
An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD).
All data summaries were descriptive. PK parameters were estimated using compartmental analysis.
25 patients (16 male, 9 female, 26-66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days.
2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.
瑞戈非尼是一种强效多激酶抑制剂，可选择性诱导癌细胞有丝分裂停滞和凋亡，对正常细胞无毒，目前正被开发用于治疗实体瘤和血液系统恶性肿瘤。
确定在晚期实体瘤或血液系统恶性肿瘤患者中，每周两次、每次2、4或8小时持续静脉输注瑞戈非尼，共3周，每4周为一个周期，其安全性、剂量限制性毒性和临床活性；并确认推荐的2期剂量（RPTD）的安全性和耐受性。
1期开放标签剂量递增研究，纳入年龄≥18岁的男性和女性。
剂量递增阶段优化了3200mg瑞戈非尼的输注持续时间（2、4或8小时），每周两次，每4周周期中的3周；扩展阶段确定最大耐受剂量（MTD）。
所有数据汇总均为描述性。使用房室分析估计药代动力学参数。
25例患者（16例男性，9例女性，26 - 66岁，均为亚洲人）接受了瑞戈非尼治疗，16例在剂量递增阶段；9例在扩展阶段。确定MTD为3200mg，4小时输注，2400mg，4小时被宣布为RPTD。14例可评估患者中，5例最佳反应为疾病稳定，平均（范围）为90（43 - 108）天。
确定2400mg瑞戈非尼，4小时输注为RPTD。5例患者疾病稳定持续6 - 16周。
