Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme
Phase II study of lonidamine and diazepam in the treatment of recurrent glioblastoma multiforme
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DOI：
10.1023/a:1023756707900
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发表时间：
2003-05-01
影响因子：
3.9
通讯作者：
Delattre, JY
中科院分区：
文献类型：
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作者：
Oudard, S;Carpentier, A;Delattre, JY
复发性多形性胶质母细胞瘤（GBM）对大多数治疗努力具有抗性，反应率低，存活期很少超过6个月。没有标准的化疗方案和新的治疗approaches. We报告了一个开放标签，非对照，多中心的II期临床试验氯尼达明（LND）和地西泮在16例GBM首次复发和Karnofsky性能状态大于或等于70。治疗方案包括LND 450 mg/天和地西泮15 mg/天，口服，每28天为一周期，直至疾病进展或出现不可接受的毒性。患者接受中位3个周期（范围，1-12）。未观察到完全或部分缓解。因此，根据研究设计，未入组额外患者，试验关闭。然而，观察到7个稳定（50%）。中位进展时间为8周（范围：5-19周）。复发后的中位总生存期为15周（范围：14-61周）。除嗜睡外，未观察到3-4级毒性，且无治疗相关死亡。9例患者因嗜睡（III级）而降低地西泮剂量。LND和地西泮的组合耐受性良好。LND和地西泮作用于参与细胞能量代谢的两个不同的线粒体位点，可能对肿瘤生长产生细胞抑制作用，如稳定患者的高百分比所示。在使用的给药方案下，LND-地西泮未显示完全或部分缓解。LND加地西泮可能是有趣的辅助设置或与化疗作用于不同的目标，并增加治疗指数。
Recurrent glioblastoma multiforme (GBM) is resistant to most therapeutic endeavours, with low response rates and survival rarely exceeding 6 months. There are no standard chemotherapeutic regimens and new therapeutic approaches have to be found. We report an open-label, uncontrolled, multicentre phase II trial of lonidamine (LND) and diazepam in 16 patients with GBM at first relapse and a Karnofsky performance status greater than or equal to70. The treatment regimen consisted of LND 450 mg/day and diazepam 15 mg/day orally of every 28-day cycle until progression or unacceptable toxicity. Patients received a median of three cycles (range, 1-12). No complete or partial response was observed. Therefore, according to the design of the study, no additional patients were enrolled and the trial was closed. Nevertheless, seven stabilizations (50%) were observed. Median time to progression was 8 weeks (range, 5-19 weeks). Median overall survival from recurrence was 15 weeks (range, 14-61 weeks). No grade 3-4 toxicity, except somnolence, was observed and there were no therapy-related deaths. Dose reduction for diazepam due to somnolence (grade III) was performed in 9 patients. The combination of LND and diazepam is well tolerated. LND and diazepam, acting on two distinct mitochondrial sites involved in cellular energy metabolism, may exert a cytostatic effect on tumour growth as shown by the high percentage of stable patients. The LND-diazepam at the used dosing schedule did not show a complete or partial response. LND plus diazepam may be interesting in the adjuvant setting or associated to chemotherapy to act on different targets and increase the therapeutic index.