Department of Medical Oncology and Cancer Genomics Netherlands, Erasmus MC Cancer Institute, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Br J Cancer. 2014 Feb 18;110(4):888-93. doi: 10.1038/bjc.2013.798. Epub 2013 Dec 24.
The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1-3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m(-2) per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m(-2) per cycle, every 3 weeks) is 800 mg daily.
血管内皮生长因子受体（VEGFR）通路在实体恶性肿瘤中起着关键作用，可能参与化疗耐药。帕唑帕尼，一种针对 VEGFR1-3 等受体的抑制剂，作为单一药物具有活性，并具有增强化疗抗肿瘤活性的吸引力。我们进行了帕唑帕尼联合两种不同伊立替康方案的剂量发现和药代动力学（PK）/药效学研究。
在 3+3+3 设计中，接受高级实体肿瘤的患者接受口服帕唑帕尼联合伊立替康递增剂量，伊立替康连续 3 天给药或每天 3 小时静脉推注 3 天（每个周期 9 g/m2，每 3 周一次）。获得伊立替康和帕唑帕尼的药代动力学数据。监测胎盘衍生生长因子（PlGF）、血管内皮生长因子-A（VEGF-A）、可溶性 VEGFR2（sVEGFR2）和循环内皮细胞的血浆水平作为生物标志物。
共纳入 61 例患者。连续伊立替康输注联合帕唑帕尼至 1000mg/天似乎是安全的，而联合推注伊立替康输注则因各种不良事件而毒性太大。观察到伊立替康依赖性帕唑帕尼暴露下降。联合伊立替康后，观察到 PlGF 和 VEGF-A 增加，同时 sVEGFR2 水平下降，与帕唑帕尼介导的 VEGFR2 抑制一致。
与推注伊立替康相比，连续输注伊立替康可安全联合帕唑帕尼。伊立替康联合用药导致帕唑帕尼暴露降低，但不影响帕唑帕尼的生物学效应。进一步研究中，联合连续 3 天伊立替康（每个周期 9 g/m2，每 3 周一次）推荐的帕唑帕尼剂量为 800mg/天。
