Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, Sacramento, CA 95817, USA.
Invest New Drugs. 2012 Oct;30(5):2001-7. doi: 10.1007/s10637-011-9761-y. Epub 2011 Oct 21.
To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies.
An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3.
Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia.
Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.
确定多靶点激酶抑制剂索拉非尼在晚期预处理实体恶性肿瘤患者中是否可以进行个体内剂量递增。
在这项前瞻性试验中，采用了起始剂量为 400mg 每日两次的个体内剂量递增方案。如果没有 3 级及以上不良事件，则在第二个周期将剂量递增至 600mg 每日两次，在第三个周期递增至 800mg 每日两次。如果在第一个周期中出现 3 级及以上不良事件，则在第二个周期将剂量减至 400mg 每日一次。如果在第二个周期中没有出现 3 级及以上不良事件，则允许在第三个周期重新递增剂量。主要终点是耐受剂量递增至 600mg 每日两次的患者比例，以及耐受剂量重新递增至 400mg 每日两次的患者比例。
共纳入 50 名患有各种实体瘤且中位治疗线数为 3 线的合格患者。11 名患者（22%）耐受了主要剂量递增或重新递增。仅有 14 名患者（28%）在不改变剂量或停止治疗的情况下完成了第一个周期。有 7 名患者（57%）耐受了主要剂量递增至第二个周期。有 4 名患者（80%）耐受了剂量重新递增至第三个周期。递增失败的原因包括肿瘤进展（42%）和不良事件（26%）。常见的 3 级及以上不良事件包括手足皮肤反应、高血压和低磷血症。
在预处理的实体瘤患者中，个体内剂量递增和/或重新递增索拉非尼是不可行的。索拉非尼的剂量递增仍然是一种研究方法。
