Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.
Phase II study of temozolomide (TMZ) and everolimus (RAD001) therapy for metastatic melanoma: a North Central Cancer Treatment Group study, N0675.
复制标题
DOI：
10.1097/coc.0b013e31827b45d4
复制
发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Markovic SN
中科院分区：
文献类型：
--
作者：
Dronca RS;Allred JB;Perez DG;Nevala WK;Lieser EA;Thompson M;Maples WJ;Creagan ET;Pockaj BA;Kaur JS;Moore TD;Marchello BT;Markovic SN
哺乳动物雷帕霉素靶蛋白（mTOR）通路在恶性黑色素瘤和原位病变中被激活，而不是良性痣。PI 3 K-Akt-mTOR信号传导的抑制涉及黑素瘤细胞对烷化剂[替莫唑胺（TMZ）]的敏化和肿瘤血管生成的抑制。我们进行了一项单臂II期多机构合作组研究，以评估TMZ和雷帕霉素衍生物依维莫司联合治疗转移性不可切除的恶性黑色素瘤患者的抗肿瘤活性和安全性。患者接受10 mg/d的RAD 001治疗5/7天（即50 mg/ wk），并接受200 mg/m2/d的TMZ治疗5天，每个周期。在前39例合格患者中，17例PFS-9成功，阳性试验的预定阈值为18/39例患者。总体而言，48例患者中有21例在9周时无进展，无事件生存率为44%（95%置信区间，29%-59%）。中位无进展生存期为2.4个月，中位总生存期为8.6个月。4例患者达到部分缓解;缓解的中位持续时间为15.1个月。未观察到完全缓解。治疗总体耐受性良好，仅1例患者因毒性（高脂血症）停止治疗。TMZ和RAD 001的组合耐受性良好，但未能达到/超过我们在转移性黑色素瘤患者中有希望的临床活性的研究阈值。
Mammalian target of rapamycin (mTOR) pathway is activated in malignant melanoma and in situ lesions as opposed to benign nevi. Inhibition of PI3K-Akt-mTOR signaling is implicated in sensitization of melanoma cells to alkylating agents [temozolomide (TMZ)] and inhibition of tumor angiogenesis. We conducted a single-arm phase II multi-institution cooperative group study to assess the antitumor activity and safety profile of the combination of TMZ and the rapamycin derivative everolimus in patients with metastatic unresectable malignant melanoma. Patients received 10 mg/d of RAD001 for 5 of 7 days (ie, 50 mg/ wk) and 200 mg/m2/d of TMZ for 5 days each cycle. Of the first 39 eligible patients, 17 were PFS-9 successes, for a predetermined threshold of 18/39 patients for a positive trial. Overall, 21 of 48 patients were progression free at 9 weeks, for an event-free survival rate of 44% (95% confidence interval, 29%–59%). The median progression-free survival was 2.4 months and the median overall survival was 8.6 months. Four patients achieved a partial response; the median duration of response was 15.1 months. No complete remissions were observed. Treatment was in general well tolerated with only 1 patient discontinuing therapy due to toxicity (hyperlipidemia). The combination of TMZ and RAD001 was well tolerated but failed to meet/exceed our study threshold for promising clinical activity in patients with metastatic melanoma.