Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma
Randomized trial of the combination of lomeguatrib and temozolomide compared with temozolomide alone in chemotherapy naive patients with metastatic cutaneous melanoma
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DOI：
10.1200/jco.2007.10.8217
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发表时间：
2007-06-20
影响因子：
45.3
通讯作者：
Middleton, Mark R.
中科院分区：
文献类型：
--
作者：
Ranson, Malcolm;Hersey, Peter;Middleton, Mark R.
目的评价洛美佳曲 (LM)（一种 O-6-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 灭活剂）与替莫唑胺 (TMZ)、单独使用 TMZ 以及单独使用 TMZ 治疗疾病进展后 LM/TMZ 组合治疗晚期黑色素瘤患者的肿瘤反应、药效学效果和安全性。在每个 28 天治疗周期的第 1 至 5 天接受 40 至 80 mg LM 和 125 mg/m(2) TMZ 或 200 mg/m(2) TMZ。口服药物最多六个治疗周期。仅接受 TMZ 治疗的患者如果身体状况足以接受治疗，则在疾病进展时接受 LM/TMZ。 结果 纳入了 104 名患者，每个试验组有 52 名患者。 27 名接受 TMZ 治疗的患者在 TMZ 治疗病情进展后接受了 LM/TMZ 治疗。出乎意料的是，肿瘤活检分析显示 LM/TMZ 40 mg/d LM 后 MGMT 快速恢复。因此，LM 剂量逐渐增加至 60 mg/d，然后是 80 mg/d。 LM/TMZ 的肿瘤缓解率为 13.5%，单独 TMZ 的肿瘤缓解率为 17.3%。没有患者对 LM/TMZ 产生反应并通过 TMZ 取得进展。 LM/TMZ 至疾病进展的中位时间为 65.5 天，TMZ 为 68 天。尽管血液学和胃肠道不良事件很常见，但所有治疗均耐受良好。 LM/TMZ 联合治疗组中观察到血液学不良事件发生率较高。结论 LM 和 TMZ 在当前给药方案中的疗效与单独 TMZ 的疗效相似。为了维持肿瘤中 MGMT 的消耗，LM 的剂量需要持续超过 TMZ 的剂量。
PurposeTo evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O-6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma.Patients and MethodsPatients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m(2) TMZ or 200 mg/m(2) TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment.ResultsOne hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm.ConclusionThe efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.