Piha-Paul Sarina A, Wheler Jennifer J, Fu Siqing, Levenback Charles, Lu Karen, Falchook Gerald S, Naing Aung, Hong David S, Tsimberidou Apostolia M, Kurzrock Razelle
Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX.
Oncotarget. 2014 Apr 15;5(7):1846-55. doi: 10.18632/oncotarget.1834.
Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.
We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.
Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.
Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study.
贝伐单抗和替西罗莫司是妇科肿瘤的有效药物。替西罗莫司可减弱缺氧诱导因子-1α水平的上调，这是抗血管生成药物的一种耐药机制，并且作用于PI3激酶/AKT/mTOR轴，该轴在这些肿瘤中通常存在异常。
我们分析了41例接受贝伐单抗和替西罗莫司I期研究治疗的妇科癌症患者的安全性和反应。
41名女性的中位年龄为60岁（范围33 - 80岁）；既往全身治疗的中位次数为4次（1 - 11次）。3级或4级治疗相关毒性包括：血小板减少（10%）、粘膜炎（2%）、高血压（2%）、高胆固醇血症（2%）、疲劳（7%）、天冬氨酸转氨酶升高（2%）和中性粒细胞减少（2%）。29名患者（71%）未出现大于2级的治疗相关毒性。两种药物均给予了FDA批准的全剂量（贝伐单抗15mg/kg静脉注射，每3周一次；替西罗莫司25mg静脉注射，每周一次），未出现剂量限制性毒性。8名患者（20%）疾病稳定（SD）> 6个月，7名患者（17%）部分缓解（PR）[总计 = 15/41例患者（37%）]。13例高级别浆液性组织学类型（卵巢或原发性腹膜）患者中有8例（62%）疾病稳定> 6个月/部分缓解。
贝伐单抗和替西罗莫司耐受性良好。37%的经过大量预处理的患者疾病稳定> 6个月/部分缓解，表明该联合用药值得进一步研究。
