Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.
Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.
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DOI：
10.3816/ccc.2005.n.030
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发表时间：
2005-09-01
影响因子：
3.4
通讯作者：
Strumberg, Dirk
中科院分区：
文献类型：
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作者：
Kupsch, Petra;Henning, Bernhard F;Strumberg, Dirk
背景：索拉非尼 (BAY 43-9006) 是一种多激酶抑制剂，已被证明可以通过靶向 Raf 激酶、血管内皮生长因子受体和血小板衍生生长因子受体来抑制肿瘤生长和肿瘤血管生成。在 I 期研究中，索拉非尼在晚期实体瘤患者中表现出单药活性，并在临床前研究中成功与奥沙利铂联合使用。这项 I 期研究调查了索拉非尼与奥沙利铂联合用药的安全性、药代动力学和疗效。 患者和方法：27 名难治性实体瘤患者被纳入初始剂量递增部分（队列 1、2A 和 2B），另外 10 名奥沙利铂难治性结直肠癌患者随后被纳入扩展部分（队列 3）。在 3 周周期的第 1 天给予奥沙利铂 130 mg/m2，从第 1 个周期的第 4 天开始以 200 mg 每天两次（队列 1）或 400 mg 每天两次（队列 2A、2B 和 3）连续口服索拉非尼。 结果：不良事件通常为轻度至中度，且未达到最大耐受剂量。常见的不良事件是腹泻（剂量递增部分的患者为52%，延伸部分的患者为20%）、感觉神经病变（44%和20%）和皮肤毒性（41%和80%）。未检测到索拉非尼和奥沙利铂之间的药代动力学相互作用。两名胃癌患者获得部分缓解。队列 1 和队列 2A/B 中 43% 的患者以及队列 3 中 78% 的患者病情稳定，持续时间 > 或 = 10 周。结论：连续口服索拉非尼 400 mg 每日两次与奥沙利铂安全联合，未检测到药物相互作用，并且在这项 I 期研究中显示出初步的抗肿瘤活性。建议将此剂量用于 II 期研究。
BACKGROUND: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin.PATIENTS AND METHODS: Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3).RESULTS: Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks.CONCLUSION: Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.