A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

被引:0
作者
Warren P. Mason
Karl Belanger
Garth Nicholas
Isabelle Vallières
David Mathieu
Petr Kavan
Annick Desjardins
Antonio Omuro
Didier Reymond
机构
[1] Princess Margaret Hospital,Hôpital Notre Dame
[2] CHUM,Hôtel
[3] Ottawa Hospital Regional Cancer Center,Dieu de Québec
[4] CHUQ,Hôpital Fleurimont
[5] CHUS,Royal Victoria Hospital
[6] MUHC,undefined
[7] Duke University Medical Center,undefined
[8] Memorial Sloan Kettering Cancer Center,undefined
[9] Thallion Pharmaceuticals Inc.,undefined
来源
Journal of Neuro-Oncology | 2012年 / 107卷
关键词
Glioblastoma; Anticancer agent; Raf-1; Ras-MAPK signaling pathway; TLN-4601;
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摘要
This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the Ras-MAPK signaling pathway, and in animal models crosses the blood–brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN-4601 was administered at a dose of 480 mg/m2/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf-1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m2/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule.
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页码:343 / 349
页数:6
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