Mita Monica M, Rowinsky Eric K, Forero Leonardo, Eckhart S Gail, Izbicka Elzbieta, Weiss Geoffrey R, Beeram Muralidhar, Mita Alain C, de Bono Johann S, Tolcher Anthony W, Hammond Lisa A, Simmons Paul, Berg Kristin, Takimoto Chris, Patnaik Amita
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
Cancer Chemother Pharmacol. 2007 Feb;59(2):165-74. doi: 10.1007/s00280-006-0255-0. Epub 2006 May 31.
This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination.
Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib.
Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months.
The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.
本II期研究评估了小分子血管内皮生长因子（VEGF）受体-2酪氨酸激酶抑制剂司马沙尼与沙利度胺联合应用于转移性黑色素瘤患者的疗效、耐受性、药代动力学（PK）和药效学（PD）特征。
既往至少一种生物和/或化疗方案治疗失败的转移性黑色素瘤患者，接受递增剂量的沙利度胺联合固定剂量的司马沙尼治疗。
12例患者入组，接受44个疗程的司马沙尼治疗，静脉注射固定剂量145mg/m²，每周两次，联合沙利度胺，沙利度胺起始剂量为每日200mg，根据患者耐受情况进行剂量递增。在第一个疗程中，司马沙尼在沙利度胺前1天开始给药，以便评估司马沙尼单独用药时（第1疗程）以及与沙利度胺联合用药时（第2疗程）的药代动力学。主要毒性包括深静脉血栓形成、头痛和下肢水肿。在可评估反应的10例患者中，观察到1例持续20个月的完全缓解和1例持续12个月的部分缓解。此外，4例患者疾病稳定持续2至10个月。司马沙尼的药代动力学特征表现为药物暴露参数与单药II期研究中观察到的参数相当，表明不存在主要的药物相互作用。第1疗程中司马沙尼的最大血浆浓度值为1.2 - 3.8μg/ml，第2疗程为1.1 - 3.9μg/ml。平均终末半衰期为1.3（±0.31）小时。生物学研究显示，在研究中持续超过4个月的患者治疗后血清VEGF浓度升高。
司马沙尼与沙利度胺联合应用可行，且在既往治疗失败的转移性黑色素瘤患者中显示出抗肿瘤活性。对于晚期黑色素瘤和其他恶性肿瘤患者，可能有必要进一步评估针对多种血管生成途径的治疗策略。
