Vanhoefer Udo, Tewes Mitra, Rojo Federico, Dirsch Olaf, Schleucher Norbert, Rosen Oliver, Tillner Joachim, Kovar Andreas, Braun Ada H, Trarbach Tanja, Seeber Siegfried, Harstrick Andreas, Baselga José
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.
J Clin Oncol. 2004 Jan 1;22(1):175-84. doi: 10.1200/JCO.2004.05.114.
To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR).
This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity.
Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000. Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity.
Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.
研究人源化抗表皮生长因子受体单克隆抗体EMD72000在表达表皮生长因子受体（EGFR）的实体瘤患者中的安全性和耐受性，并探索其药代动力学和药效学特征。
这是一项EMD72000针对晚期、EGFR阳性、无法接受任何既定化疗或放疗的实体恶性肿瘤患者的I期剂量递增试验。EMD72000每周给药一次，不进行常规预处理，直至疾病进展或出现不可接受的毒性。
22名患者接受了五种不同剂量水平（400至2000mg/周）的EMD72000治疗。美国国立癌症研究所通用毒性标准3级头痛和首次输注后出现的发热在2000mg/周时为剂量限制性毒性；因此，最大耐受剂量为1600mg/周。未观察到其他严重副作用，尤其是未观察到过敏反应或腹泻。痤疮样皮肤反应是最常见的毒性反应，但程度较轻，11名患者（50%）为1级，3名患者（14%）为2级。药代动力学分析显示EMD72000具有可预测的药代动力学特征。对系列皮肤活检的药效学研究表明，EMD72000有效消除了EGFR介导的细胞信号传导（例如，降低了EGFR和丝裂原活化蛋白激酶的磷酸化），而总EGFR蛋白无变化。所有剂量水平均实现了客观缓解（23%；95%CI，8%至45%）和疾病稳定（27%；95%CI，11%至50%），且缓解患者接受治疗长达18个月而无累积毒性。
EMD72000治疗耐受性良好，并在EGFR表达肿瘤的重度预处理患者中显示出活性证据。所研究剂量的EMD72000显著抑制下游EGFR依赖性过程。
