Department of Medical Physics, University of Wisconsin-Madison, Wisconsin, USA.
University of Wisconsin Carbone Cancer Center, 600 Highland Avenue, Madison, WI, 53792, USA.
Cancer Chemother Pharmacol. 2018 Aug;82(2):211-219. doi: 10.1007/s00280-018-3599-3. Epub 2018 May 25.
A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.
Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.
14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUV decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUV decreased - 44% (p = 0.03).
The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.
在 VEGFR-TKI 治疗中断期间同步进行细胞周期特异性化疗的序贯方法可能会提高这种联合治疗的治疗指数。在这项研究中，我们研究了多西他赛与新型 VEGFR-TKI X-82 序贯联合使用的安全性/耐受性和药效学作用。
晚期实体恶性肿瘤患者接受 X-82 每日一次（第 1-14 天），第 15-20 天治疗中断，第 21 天给予多西他赛的 21 天治疗周期。随机分为低剂量 X-82（200mg）或高剂量 X-82（400mg）组，比例为 1:1。患者计划进行四次 3'-去氧-3'-F-氟胸苷（FLT）PET/CT 扫描，以评估肿瘤细胞增殖的变化。总结肿瘤的 PET 标准化摄取值（SUV），并使用混合效应模型评估变化。
14 名患者入组并接受中位数为 3.5 个周期（范围 0-12）的治疗。高剂量组（50%）的 3 名患者和低剂量组（38%）的 3 名患者在研究期间经历了至少一次 3 级不良事件（感染、血细胞减少、电解质异常和血管并发症）。有 4 名患者的 13 个转移性肿瘤进行了 FLT PET/CT 扫描。在第 1 周期 X-82 暴露期间，肿瘤 SUV 下降了 -11%（p=0.04）。在多西他赛给药和第 2 周期 X-82 暴露期间，肿瘤 SUV 下降了 -44%（p=0.03）。
X-82 和多西他赛的序贯联合使用是安全的，并导致 FLT 摄取减少。此外，第 2 周期（X-82 加多西他赛）中 FLT 摄取的减少大于第 1 周期（X-82 单独），表明序贯化疗增强了治疗的药效学作用。
