Thomas A L, Trarbach T, Bartel C, Laurent D, Henry A, Poethig M, Wang J, Masson E, Steward W, Vanhoefer U, Wiedenmann B
Department of Oncology, University of Leicester, Leicester Royal Infirmary, Leicester, UK.
Ann Oncol. 2007 Apr;18(4):782-8. doi: 10.1093/annonc/mdl469. Epub 2007 Jan 11.
This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity.
Thirty-five patients received escalating doses of PTK/ZK (range 500-2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage.
Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months.
The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.
本开放标签的IB期研究旨在确定口服每日一次的PTK787/ZK 222584（PTK/ZK）联合奥沙利铂/5-氟尿嘧啶（5-FU）/亚叶酸钙（FOLFOX4）化疗用于晚期结直肠癌患者的安全性/毒性特征及推荐剂量。次要目标是评估完整的药代动力学并收集抗肿瘤活性的初步证据。
35例患者持续接受递增剂量的PTK/ZK（范围为每日500 - 2000 mg）。在第1天和第2天给予同步FOLFOX4化疗，并每14天重复一次。持续增加PTK/ZK的剂量，直至确定最大耐受剂量（MTD），然后以MTD剂量纳入更多患者。
PTK/ZK的平均治疗持续时间为9.5个月。MTD为每日1250 mg，最常见的剂量限制性毒性（DLT）为头晕。高血压（23%，3级）和中性粒细胞减少（37%，3 + 4级）是最常见的3级或4级不良事件。药代动力学分析未发现PTK/ZK与5-FU、亚叶酸钙和奥沙利铂联合使用期间存在相互作用的证据。中位无进展生存期为11.4个月。
在该患者群体中，PTK/ZK联合FOLFOX4的MTD为每日1250 mg。该联合方案可行且安全，并且与显著的药代动力学相互作用无关。
