Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
J Neurooncol. 2012 Nov;110(2):257-64. doi: 10.1007/s11060-012-0964-7. Epub 2012 Aug 30.
Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m(2) in a standard "3+3" design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m(2) cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m(2) cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m(2) with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.
长春瑞滨（MPC-6827）是一种微管蛋白不稳定药物，在大脑中能达到高浓度。长春瑞滨破坏异种移植物中新形成的血管。我们确定了长春瑞滨联合卡铂治疗复发性多形性胶质母细胞瘤（GBM）患者的安全性和耐受性。在标准的“3+3”设计中，测试了长春瑞滨的三个预先选定剂量：2.1、2.7 和 3.3mg/m(2)。长春瑞滨在 2.1mg/m(2)组的 6 周周期的每两周一次给药，或在随后的周期中每 3 周一次给药 4 周周期的 3 周。卡铂以每 2 周的曲线下面积（AUC）剂量 4 静脉给药，用于 2.1mg/m(2)组，或在随后的周期中每个 4 周周期的第 1 天给药。19 名患有首次或第二次复发的 GBM 的患者入组。4 名患者（21%）经历了 3 级或更高级别的长春瑞滨或卡铂相关不良事件，包括感觉迟钝、脑缺血、贫血和血小板减少症。长春瑞滨的平均血浆半衰期为 3.2 小时（SD=0.82）。根据 Macdonald 标准，有 2 名患者至少达到部分缓解。其中一名患者在开始使用长春瑞滨超过 24 个月后仍无进展且停止治疗。5 名患者疾病稳定。所有患者的中位无进展生存期（PFS）为 8 周，6 个月的 PFS 率为 21%。在复发性/难治性 GBM 患者中，长春瑞滨的先前确定的单药最大耐受剂量 3.3mg/m(2)与卡铂联合使用，该组合安全且耐受良好。在这个血管丰富的肿瘤患者人群中，没有观察到脑出血。
