Lassman Andrew B, Pugh Stephanie L, Gilbert Mark R, Aldape Kenneth D, Geinoz Sandrine, Beumer Jan H, Christner Susan M, Komaki Ritsuko, DeAngelis Lisa M, Gaur Rakesh, Youssef Emad, Wagner Henry, Won Minhee, Mehta Minesh P
Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York (A.B.L. current); Memorial Sloan Kettering Cancer Center, New York, New York (A.B.L. during accrual, L.M.D.); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (S.L.P., S.G., M.W); The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G., K.D.A. during accrual; R.K.); Neuro-Oncology Branch, National Cancer Institute/National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (M.R.G. current); University of Toronto and Princess Margaret Cancer Centre, Toronto, Canada (K.D.A. current); Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (J.H.B., S.M.C.); Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy Pittsburgh, Pennsylvania (J.H.B.); NCI Community Oncology Research Program - Kansas City, Prairie Village, Kansas (R.G.); Arizona Oncology Services Foundation, Tucson, Arizona (E.Y.); Penn State University and The Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.W.); University of Maryland Medical Systems, Baltimore, Maryland (M.P.M.).
Neuro Oncol. 2015 Jul;17(7):992-8. doi: 10.1093/neuonc/nov011. Epub 2015 Mar 10.
We conducted a phase II trial to evaluate the efficacy of dasatinib, a multitargeted tyrosine kinase inhibitor, for adults with recurrent glioblastoma (GBM).
Eligibility requirements were Karnofsky performance status ≥ 60%; no concurrent hepatic enzyme-inducing anticonvulsants; prior treatment with surgery, radiotherapy, and temozolomide exclusively; and activation or overexpression of ≥ 2 putative dasatinib targets in GBM (ie, SRC, c-KIT, EPHA2, and PDGFR). Using a 2-stage design, 77 eligible participants (27 in stage 1, if favorable, and then 50 in stage 2) were needed to detect an absolute improvement in the proportion of patients either alive and progression-free patients at 6 months (6mPFS) or responding (any duration) from a historical 11% to 25%.
A high rate of ineligibility (27%) to stage 1 precluded a powered assessment of efficacy, but there was also infrequent treatment-related toxicity at 100 mg twice daily. Therefore, the study was redesigned to allow intrapatient escalation by 50 mg daily every cycle as tolerated (stage 1B) before determining whether to proceed to stage 2. Escalation was tolerable in 10 of 17 (59%) participants evaluable for that endpoint; however, among all eligible patients (stages 1 and 1B, n = 50), there were no radiographic responses, median overall survival was 7.9 months, median PFS was 1.7 months, and the 6mPFS rate was 6%. The clinical benefit was insufficient to correlate tested biomarkers with efficacy. The trial was closed without proceeding to stage 2.
Intraparticipant dose escalation was feasible, but dasatinib was ineffective in recurrent GBM. Clinical trials.gov identified. NCT00423735 (available at http://clinicaltrials.gov/ct2/show/NCT00423735).
我们开展了一项II期试验，以评估多靶点酪氨酸激酶抑制剂达沙替尼对复发性胶质母细胞瘤（GBM）成年患者的疗效。
入选标准为卡氏评分≥60%；无同时使用诱导肝酶的抗惊厥药物；此前仅接受过手术、放疗和替莫唑胺治疗；以及GBM中≥2个假定的达沙替尼靶点激活或过表达（即SRC、c-KIT、EPHA2和PDGFR）。采用两阶段设计，需要77名符合条件的参与者（第1阶段27名，若结果良好则第2阶段50名）来检测患者6个月时存活且无进展（6mPFS）或有反应（任何持续时间）的比例从历史对照的11%绝对提高至25%。
第1阶段的高不合格率（27%）排除了进行有效疗效评估的可能，但每日两次100 mg剂量时与治疗相关的毒性也很少见。因此，该研究重新设计为在决定是否进入第2阶段之前，允许每个周期根据耐受情况将患者剂量每日增加50 mg（1B阶段）。对于该终点可评估的17名参与者中有10名（59%）的剂量增加是可耐受的；然而，在所有符合条件的患者（1期和1B期，n = 50）中，没有影像学反应，中位总生存期为7.9个月，中位无进展生存期为1.7个月，6mPFS率为6%。临床获益不足，无法将检测的生物标志物与疗效相关联。该试验未进入第2阶段即结束。
患者内剂量递增是可行的，但达沙替尼对复发性GBM无效。已在ClinicalTrials.gov注册。NCT00423735（可在http://clinicaltrials.gov/ct2/show/NCT00423735获取）。
