A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients.
A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients.
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DOI：
10.1158/1078-0432.ccr-14-3220
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发表时间：
2015-08-15
期刊：
影响因子：
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通讯作者：
Wen PY
中科院分区：
文献类型：
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作者：
Lee EQ;Kaley TJ;Duda DG;Schiff D;Lassman AB;Wong ET;Mikkelsen T;Purow BW;Muzikansky A;Ancukiewicz M;Huse JT;Ramkissoon S;Drappatz J;Norden AD;Beroukhim R;Weiss SE;Alexander BM;McCluskey CS;Gerard M;Smith KH;Jain RK;Batchelor TT;Ligon KL;Wen PY
凡德他尼是一种KDR（VEGFR 2）、EGFR和RET的酪氨酸激酶抑制剂，可增强对化疗和放疗的敏感性。我们在新诊断的胶质母细胞瘤（GBM）患者中进行了一项放射（RT）和替莫唑胺联合或不联合凡德他尼的随机、非比较、II期研究。我们计划将总共114例新诊断的GBM患者以2：1的比例随机分配至标准RT和替莫唑胺组，其中76例患者接受或38例患者不接受每日100 mg凡德他尼。年龄≥ 18岁、Karnofsky体力状态（KPS）≥ 60且未接受酶诱导抗癫痫药治疗的患者合格。主要终点是从随机分组之日起的中位总生存期（OS）。次要终点包括中位无进展生存期（PFS）、12个月PFS和安全性。相关研究包括药代动力学以及组织和血清生物标志物分析。基于中期分析的结果，研究因无效而提前终止。我们入组了106例患者（RT/替莫唑胺组36例，凡德他尼/RT/替莫唑胺组70例）。RT/替莫唑胺组的中位OS为15.9个月[95%置信区间（CI），11.0-22.5个月]，凡德他尼/RT/替莫唑胺组为16.6个月（95% CI，14.9-20.1个月）（对数秩P = 0.75）。在新诊断的GBM或神经胶质肉瘤患者的标准放化疗中添加每日100 mg剂量的凡德他尼与潜在的药效学生物标志物变化相关，并且耐受性良好。然而，与平行对照组相比，该方案未显著延长OS，导致研究提前终止。
Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary end-point was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0–22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9–20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study.