口服集落刺激因子1受体抑制剂PLX3397治疗复发性胶质母细胞瘤：常春藤基金会早期临床试验联盟II期研究
Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study.
作者信息
Butowski Nicholas, Colman Howard, De Groot John F, Omuro Antonio M, Nayak Lakshmi, Wen Patrick Y, Cloughesy Timothy F, Marimuthu Adhirai, Haidar Sam, Perry Arie, Huse Jason, Phillips Joanna, West Brian L, Nolop Keith B, Hsu Henry H, Ligon Keith L, Molinaro Annette M, Prados Michael
机构信息
University of California at San Francisco, San Francisco, California (N.B., A.P., J.P., A.M.M, M.P.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.F.D.G.); Department of Neurology, Memorial Sloan Kettering Cancer Hospital, New York, New York (A.M.O.); Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts (L.N., P.Y.W., S.H., K.L.L.); UCLA Medical Center, Los Angeles, California (T.F.C.); Plexxikon Inc., Berkeley, California (A.M., B.L.W., K.B.N., H.H.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (K.L.L.); Department of Pathology, Memorial Sloan Kettering Cancer Hospital, New York, New York (J.H.).
出版信息
Neuro Oncol. 2016 Apr;18(4):557-64. doi: 10.1093/neuonc/nov245. Epub 2015 Oct 8.
BACKGROUND
The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development.
METHODS
We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.
RESULTS
A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values.
CONCLUSION
PLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
背景
集落刺激因子1受体（CSF1R）配体，即CSF1和白细胞介素-34，以及KIT配体干细胞因子，在胶质母细胞瘤（GB）中表达。小胶质细胞、巨噬细胞、血管和肿瘤细胞也表达CSF1R，小胶质细胞的清除可降低肿瘤负荷和侵袭能力。PLX3397是一种口服小分子药物，可选择性抑制CSF1R和KIT，在模型系统中可穿透血脑屏障，是临床开发的一种新方法。
方法
我们对复发性GB患者进行了一项II期研究。主要终点是6个月无进展生存期（PFS6）。次要终点包括总生存缓解率、安全性以及血浆/肿瘤组织药代动力学。探索性终点包括血液和肿瘤组织中药物效应的药效学指标。
结果
共纳入37例患者，其中13例在计划手术切除前接受治疗（队列1），24例未接受手术治疗（队列2）。PLX3397的口服剂量为每日1000 mg，耐受性良好。PFS6的主要疗效终点仅为8.6%，无客观缓解。药代动力学终点显示，血浆中最大浓度（Cmax）中位数为8090 ng/mL，达到Cmax的时间为2小时。药物暴露7天后获得的肿瘤组织显示，药物水平中位数为5500 ng/g。药效学变化包括与治疗前基线值相比，血浆中集落刺激因子1增加，CD14（dim）/CD16+单核细胞减少。
结论
PLX3397耐受性良好，易于穿过血肿瘤屏障，但未显示出疗效。正在进行更多研究，测试联合策略和潜在生物标志物，以识别更有可能产生反应的患者。
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