Mross Klaus, Drevs Joachim, Müller Marianne, Medinger Michael, Marmé Dieter, Hennig Jürgen, Morgan Bruno, Lebwohl David, Masson Eric, Ho Yu-Yun, Günther Clemens, Laurent Dirk, Unger Clemens
Tumour Biology Center at the Albert-Ludwigs-University Freiburg, Breisacher Strasse 117, D-79106 Freiburg i. Br., Germany.
Eur J Cancer. 2005 Jun;41(9):1291-9. doi: 10.1016/j.ejca.2005.03.005.
The family of VEGF receptors are important mediators of angiogenesis, which is essential for tumour growth and metastasis. PTK/ZK is a multiple VEGF receptor inhibitor that blocks the activity of all known VEGF receptor tyrosine kinases. This phase I/II trial evaluated the safety, pharmacokinetics and efficacy of PTK/ZK in patients with liver metastases from solid tumours. Patients were administered oral PTK/ZK monotherapy once daily at doses of 300-1200 mg/day in 28-day cycles until unacceptable toxicity or tumour progression occurred. Twenty-seven patients were enrolled and treatment with PTK/ZK was generally well tolerated. The most frequently reported adverse events were fatigue, nausea, dizziness, and vomiting (mostly National Cancer Institute Common Toxicity Criteria grade 1 or 2). The area under the concentration-time curve (AUC) of PTK/ZK increased between 300 and 1000 mg/day with no further increase from 1000 to 1200 mg/day; the AUC decreased by 50% between day 1 and day 15. The DCE-MRI showed a statistically significant early reduction of tumour blood supply (measured as Ki) at day 2 at doses > or = 750 mg/day. Disease progression was significantly correlated with percent change from baseline Ki. Thirteen patients had stable disease for at least two cycles (56 days). Median overall survival was 11.8 months (95% CI = 6.6, 17.1 months). Long-term therapy with PTK/ZK demonstrated predictable pharmacokinetics, was safe and feasible in patients with metastatic disease, and showed promising clinical activity. The minimum biologically active dose was established at 750 mg/day whereas the recommended dose for phase III studies is 1200 mg/day.
血管内皮生长因子（VEGF）受体家族是血管生成的重要介质，而血管生成对肿瘤生长和转移至关重要。PTK/ZK是一种多VEGF受体抑制剂，可阻断所有已知VEGF受体酪氨酸激酶的活性。这项I/II期试验评估了PTK/ZK在实体瘤肝转移患者中的安全性、药代动力学和疗效。患者接受口服PTK/ZK单药治疗，每日一次，剂量为300 - 1200毫克/天，每28天为一个周期，直至出现不可接受的毒性或肿瘤进展。27名患者入组，PTK/ZK治疗总体耐受性良好。最常报告的不良事件是疲劳、恶心、头晕和呕吐（大多为美国国立癌症研究所常见毒性标准1级或2级）。PTK/ZK的浓度 - 时间曲线下面积（AUC）在300至1000毫克/天之间增加，从1000至1200毫克/天不再进一步增加；AUC在第1天至第15天下降了50%。动态对比增强磁共振成像（DCE - MRI）显示，在剂量≥750毫克/天的情况下，第2天肿瘤血供（以Ki衡量）出现统计学显著的早期减少。疾病进展与基线Ki的变化百分比显著相关。13名患者疾病稳定至少两个周期（56天）。中位总生存期为11.8个月（95%可信区间 = 6.6，17.1个月）。PTK/ZK的长期治疗显示出可预测的药代动力学，对转移性疾病患者安全可行，并显示出有前景的临床活性。确定的最低生物活性剂量为750毫克/天，而III期研究的推荐剂量为1200毫克/天。
