A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies.
A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies.
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DOI：
10.1158/1078-0432.ccr-11-0666
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发表时间：
2011-11-01
期刊：
影响因子：
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通讯作者：
Kurzrock R
中科院分区：
文献类型：
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作者：
Moroney JW;Schlumbrecht MP;Helgason T;Coleman RL;Moulder S;Naing A;Bodurka DC;Janku F;Hong DS;Kurzrock R
脂质体多柔比星（D）和贝伐单抗（A）是妇科和乳腺恶性肿瘤的活性单药，其耐药机制相同：上调缺氧诱导因子（HIF-1α）。因此，我们在D和A（DAT）中加入了抑制HIF-1α的替西罗莫司（T）。试验目的是评估安全性、初步疗效和确定生物学反应相关性。周期长度为21天，第1天IV D、A和T;第8天和第15天T（3+3剂量68递增设计，扩展队列）。进行PIK 3CA、BRAF、KRAS的突变测定和PTEN缺失的免疫组织化学。本报告详细介绍了74例妇科和乳腺恶性肿瘤患者，他们在研究中接受了至少一剂药物。中位患者年龄：52，（27-79）;既往治疗方案：4，（1-11）。缓解：1例（1.4%）完全缓解（CR），14例（18.9%）部分缓解（PR），13例（17.6%）疾病稳定（SD）≥ 6个月（总计= 37.9%）。最常见的1级毒性是疲劳（27%）和贫血（20.2%）。显著的3/4级毒性：血小板减少症（9.5%）、粘膜炎（6.7%）和肠穿孔（2.7%）。在25/59（42.3%）的测试患者中鉴定出PIK 3CA突变或PTEN缺失。其中，9例（36%）达到CR/PR，4例（16%）SD ≥ 6个月（CR+PR+SD ≥ 6个月= 52%）。DAT耐受性良好，副作用可控。观察到的反应值得进一步评价。值得注意的是，突变分析显示PI 3 K通路畸变的应答者百分比较高。
Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: up-regulation of hypoxia inducible factor (HIF-1α). We therefore added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy and identification of biologic response correlates. Cycle length was 21 days, with IV D, A and T on day 1; T on days 8 and 15 (3+3 dose68 escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS and immunhistochemistry for PTEN loss were performed. This report details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52, (27-79); prior regimens: 4, (1–11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%) and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25/59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with PI3K pathway aberrations.