Aspeslagh Sandrine, Awada Ahmad, S Matos-Pita Arturo, Aftimos Philippe, Bahleda Ratislav, Varga Andréa, Soria Jean-Charles
aJules Bordet Institute, Brussels, Belgium bGustave Roussy, Paris-Saclay University, Drug Development Department (DITEP), Villejuif, France cPharma Mar, S.A., Avenida de los Reyes, 1, Polígono Industrial La Mina-Norte, 28770 Colmenar Viejo, Madrid, Spain.
Anticancer Drugs. 2016 Nov;27(10):1021-7. doi: 10.1097/CAD.0000000000000409.
This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.
这项I期试验评估了海洋来源的环缩肽普利地辛与贝伐单抗联合用药在晚期癌症患者中的毒性特征和最大耐受剂量。13名患者入组，接受三种剂量水平的普利地辛治疗（2.8mg/m²，n = 3；3.8mg/m²，n = 4；4.8mg/m²，n = 6），同时给予固定剂量的贝伐单抗（10mg/kg）。两种药物均在28天周期的第1天和第15天静脉给药。所有13名患者均可进行安全性和毒性评估。在接受测试的最大剂量（普利地辛4.8mg/m²和贝伐单抗10mg/kg）治疗的6名患者中，有2名出现剂量限制性毒性，包括3级疲劳、3级肌痛，以及2例2/3级丙氨酸转氨酶升高持续超过7天或导致后续周期延迟超过2周（各1例）。普利地辛与贝伐单抗联合用药的推荐剂量为：普利地辛3.8mg/m²，贝伐单抗1·mg/kg，每2周一次。最常见的治疗相关不良事件为恶心、呕吐、疲劳、鼻出血和头痛。相关血液学毒性极小。未观察到客观疾病缓解；然而，在4例患有结直肠癌、肾癌和宫颈癌的患者中观察到疾病稳定（>3个月）。普利地辛与贝伐单抗联合用药是可行的。疾病稳定是获得的最佳反应。
