Bilen Mehmet Asim, Fu Siqing, Falchook Gerald S, Ng Chaan S, Wheler Jennifer J, Abdelrahim Maen, Erguvan-Dogan Basak, Hong David S, Tsimberidou Apostolia M, Kurzrock Razelle, Naing Aung
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Chemother Pharmacol. 2015 Apr;75(4):869-74. doi: 10.1007/s00280-015-2695-x. Epub 2015 Feb 10.
The objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide.
In this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase.
Twenty-six patients with advanced cancer (14 men/12 women), median age of 56 years (range 38-70 years), and a median number of two prior therapies (range 0-12) were enrolled. The most common toxicities were fatigue, rash, neutropenia, thrombocytopenia, and change in mental status. Dose-limiting toxic (DLT) effects were grade III confusion (n = 3), somnolence (n = 1), and gait disturbance (n = 1). The MTD was reached at VPA 30 mg/kg and lenalidomide 25 mg. Although only two of the 12 patients from the dose-expansion phase had DLT during the first cycle at the MTD, during subsequent cycles the majority of patients required dose reduction of VPA to 5-20 mg/kg because of fatigue and drowsiness. No significant tumor reductions were noticed in patients with ACC, but seven of these patients had stable disease over four cycles. Of non-ACC patients, one patient with melanoma and one patient with parathyroid carcinoma had stable disease for six cycles and eight cycles, respectively.
Lenalidomide combined with VPA was well tolerated. We recommend starting VPA at 5 mg/kg and titrating upward to 20 mg/kg. No significant tumor reductions were noticed in patients with ACC.
本研究的目的是评估丙戊酸（VPA）和来那度胺的耐受性和疗效。
在这项3+3设计研究中，VPA按7天用药、7天停药的日程每日给药，来那度胺每日给药28天。由于在剂量递增阶段观察到反应，另外12例腺样囊性癌（ACC）患者在剂量扩展阶段接受了最大耐受剂量（MTD）。
入组了26例晚期癌症患者（14例男性/12例女性），中位年龄56岁（范围38 - 70岁），既往治疗的中位次数为2次（范围0 - 12次）。最常见的毒性反应为疲劳、皮疹、中性粒细胞减少、血小板减少和精神状态改变。剂量限制性毒性（DLT）效应为3级意识模糊（n = 3）、嗜睡（n = 1）和步态障碍（n = 1）。VPA 30 mg/kg和来那度胺25 mg时达到MTD。尽管剂量扩展阶段的12例患者中只有2例在MTD的第一个周期出现DLT，但在随后的周期中，大多数患者因疲劳和嗜睡需要将VPA剂量减至5 - 20 mg/kg。ACC患者未观察到明显的肿瘤缩小，但其中7例患者在4个周期内病情稳定。在非ACC患者中，1例黑色素瘤患者和1例甲状旁腺癌患者分别在6个周期和8个周期内病情稳定。
来那度胺联合VPA耐受性良好。我们建议VPA起始剂量为5 mg/kg，并向上滴定至20 mg/kg。ACC患者未观察到明显的肿瘤缩小。
