Department of Oncology, APHP - Saint-Louis Hospital, Paris, France.
Br J Cancer. 2011 Nov 22;105(11):1640-5. doi: 10.1038/bjc.2011.440. Epub 2011 Oct 25.
BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1-3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1-3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients.
This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m(-2), every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity.
Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ≥50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone.
Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m(-2) of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.
BIBF 1120 是一种口服、强效的酪氨酸激酶抑制剂，可同时靶向血管内皮生长因子受体 1-3、血小板衍生生长因子受体 α 和 β、成纤维细胞生长因子受体 1-3，以及 FLT3 和 Src。目前，该分子正处于二线非小细胞肺癌和一线卵巢癌患者的 III 期开发阶段。
本研究为 I 期剂量递增研究，评估了连续每日 BIBF 1120 联合标准剂量多西他赛（75mg/m2，每 3 周一次）和泼尼松（5mg，每日两次）治疗转移性、初治、激素难治性前列腺癌（HRPC）患者的安全性和最大耐受剂量。次要目的是评估 BIBF 1120 和多西他赛的药代动力学（PK）特征，并初步评估抗肿瘤活性。
患者接受 BIBF 1120 100mg BID（n=3）、150mg BID（n=3）、200mg BID（n=3）和 250mg BID（n=12）治疗。最常见的药物相关不良事件是腹泻（71.4%）、乏力（61.9%）、恶心（28.6%）、呕吐（28.6%）和脱发（23.8%）。最大耐受剂量为 BIBF 1120 250mg BID。在该剂量水平下，12 名患者中有 6 名出现了可逆的 3/4 级肝酶升高。在 19 名可评估的患者中，13 名（68.4%）患者的前列腺血清抗原水平从基线水平下降了≥50%，在 6 名可测量病变的患者中，1 名患者根据实体瘤反应评价标准（RECIST）达到部分缓解。药代动力学分析显示，BIBF 1120 与多西他赛/泼尼松之间无相互作用。
基于总体安全性，BIBF 1120 200mg BID 为 BIBF 1120 与标准剂量 75mg/m2 多西他赛和泼尼松联合治疗的推荐剂量，该联合方案可能进一步在 HRPC 患者中进行研究。该联合方案耐受性良好，初步显示出疗效，并且没有提示 BIBF 1120 与多西他赛之间的 PK 相互作用。
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