Department of Medical Oncology, Erasmus University Medical Center Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands.
Br J Cancer. 2010 Jun 8;102(12):1699-706. doi: 10.1038/sj.bjc.6605696. Epub 2010 May 18.
This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide.
Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m(-2) for 3 days or 6 g m(-2) for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.
With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed.
With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.
本研究旨在确定舒尼替尼联合两种不同伊氟鸟苷输注方案的最大耐受剂量（MTD）。
纳入标准为晚期实体瘤、一般状况评分良好、器官功能良好且无标准治疗方法的患者。舒尼替尼持续每日一次、按递增剂量分组给药，联合伊氟鸟苷，9 g/m²连续 3 天或 6 g/m²连续 5 天，每 3 周给药一次。进行药代动力学（PK）和药效学（PD）评估。
在生长因子支持下，32 例入组患者中舒尼替尼联合任一伊氟鸟苷方案的 MTD 为 12.5 mg。中性粒细胞减少相关的不良反应为剂量限制毒性。舒尼替尼不影响伊氟鸟苷的 PK。伊氟鸟苷显著降低了舒尼替尼的暴露量，并增加了其代谢物 SU12662 的暴露量。PD 参数无一致变化。
在生长因子支持下，舒尼替尼联合两种伊氟鸟苷方案的 MTD 为 12.5 mg。由于 CYP3A 诱导，伊氟鸟苷降低了舒尼替尼的血药水平。由于 PK 相互作用无法解释可以与伊氟鸟苷联合应用的相对较低剂量的舒尼替尼，因此可能存在毒性协同作用。这种情况是否也适用于抗肿瘤活性，需要进一步探讨。
