背景:临床前模型表明抗血管生成疗法之间的协同作用,哺乳动物雷帕霉素靶蛋白(mTOR),和组蛋白去乙酰化酶抑制剂促进抗癌活性。
方法:该一期研究纳入了2012年4月至2018年之间的47名患者,并确定了安全性,最大耐受剂量(MTD),和剂量限制性毒性(DLT),当结合贝伐单抗,替西罗莫司,晚期癌症患者的丙戊酸。
结果:入选患者的中位年龄为56岁。对患者进行严重预处理,中位数为4行先前治疗。45名患者(95.7%)经历了一个或多个治疗相关的不良事件(TRAEs)。3级TRAEs为淋巴细胞减少症(14.9%),血小板减少症(8.5%),和粘膜炎(6.4%)。4级TRAE包括淋巴细胞减少(2.1%)和中枢神经系统脑血管缺血(2.1%)。六名患者在3级感染的10个剂量水平上发展了DLT,皮疹,粘膜炎,肠穿孔,脂肪酶升高,和4级脑血管缺血。MTD为剂量水平9(贝伐单抗5mg/kg第1天和第15天静脉内(IV)加替西罗莫司25mg第1、8、15和22天,每次口服(PO)和丙戊酸5mg/kg第1-7天和第15-21天)。3例患者的客观缓解率(ORR)为7.9%,确认部分缓解(PR)(腮腺各1例,卵巢,和阴道癌)。5例(13.1%)患者病情稳定(SD)≥+6个月。临床获益状态(CBR:PR+SD≥+6个月)为21%。
结论:贝伐单抗联合治疗,替西罗莫司,丙戊酸是可行的,但是有很多毒性,这将需要对未来的临床发展进行仔细的管理(ClinicalTrials.gov标识符:NCT01552434)。
BACKGROUND: Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity.
METHODS: This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab,
temsirolimus, and valproic acid in patients with advanced cancer.
RESULTS: Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus
temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%.
CONCLUSIONS: Combination therapy with bevacizumab,
temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).