Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA.
VA Palo Alto Health Care System, 3801 Miranda Avenue, 111-ONC, Palo Alto, CA, 94304-1290, USA.
Cancer Chemother Pharmacol. 2018 Sep;82(3):541-550. doi: 10.1007/s00280-018-3646-0. Epub 2018 Jul 20.
To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.
Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine C, and AUC. Patients remained on study until progressive disease or unacceptable AEs.
In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.
For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
评估 XL647 的安全性、耐受性和药代动力学，并确定每日一次口服 XL647 的最大耐受剂量（MTD），采用间歇性或连续性给药方案。
患有晚期实体恶性肿瘤的患者被纳入连续队列，接受递增剂量的口服每日一次 XL647，采用两种不同的给药方案：每 14 天周期的连续 5 天（研究 XL647-001）或连续 28 天周期（研究 XL647-002）。进行 PK 采样以确定 C 和 AUC。患者继续接受研究，直到疾病进展或不可接受的 AE。
在 XL647-001 中，9 个剂量水平共纳入 42 名患者。最常见的药物相关 AE 是腹泻、恶心、皮疹和疲劳。将 4.68mg/kg 队列扩展至 6 名患者，未发生进一步的剂量限制性毒性（DLT），这被认为是 MTD。在 XL647-002 中，5 个剂量水平共纳入 31 名患者。300mg 时 1/6 患者发生 3 级肺炎，被宣布为 MTD。最常见的 AE 包括 1/2 级皮疹、腹泻、疲劳、味觉障碍和 QTc 延长。XL647 后，药效学血浆标志物水平没有一致变化，根据这个有限的数据集无法得出结论。
对于口服 XL647，当每 14 天周期的连续 5 天给予 4.68mg/kg 或 350mg 固定剂量，以及每日一次连续给予时，剂量为 300mg，被认为是 MTD。在达到 MTD 的剂量下，XL647 耐受性良好。
