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

Publication ,  Journal Article
Mason, WP; Belanger, K; Nicholas, G; Vallières, I; Mathieu, D; Kavan, P; Desjardins, A; Omuro, A; Reymond, D
Published in: J Neurooncol
April 2012

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/m(2)/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/m(2)/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.

Duke Scholars

Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

April 2012

Volume

107

Issue

2

Start / End Page

343 / 349

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Kaplan-Meier Estimate
  • Infusions, Intraventricular
  • Humans
  • Glioblastoma
 

Citation

APA
Chicago
ICMJE
MLA
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Mason, W. P., Belanger, K., Nicholas, G., Vallières, I., Mathieu, D., Kavan, P., … Reymond, D. (2012). A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. J Neurooncol, 107(2), 343–349. https://doi.org/10.1007/s11060-011-0747-6
Mason, Warren P., Karl Belanger, Garth Nicholas, Isabelle Vallières, David Mathieu, Petr Kavan, Annick Desjardins, Antonio Omuro, and Didier Reymond. “A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression.J Neurooncol 107, no. 2 (April 2012): 343–49. https://doi.org/10.1007/s11060-011-0747-6.
Mason WP, Belanger K, Nicholas G, Vallières I, Mathieu D, Kavan P, et al. A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. J Neurooncol. 2012 Apr;107(2):343–9.
Mason, Warren P., et al. “A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression.J Neurooncol, vol. 107, no. 2, Apr. 2012, pp. 343–49. Pubmed, doi:10.1007/s11060-011-0747-6.
Mason WP, Belanger K, Nicholas G, Vallières I, Mathieu D, Kavan P, Desjardins A, Omuro A, Reymond D. A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. J Neurooncol. 2012 Apr;107(2):343–349.
Journal cover image

Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

April 2012

Volume

107

Issue

2

Start / End Page

343 / 349

Location

United States

Related Subject Headings

  • Tandem Mass Spectrometry
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Middle Aged
  • Male
  • Magnetic Resonance Imaging
  • Kaplan-Meier Estimate
  • Infusions, Intraventricular
  • Humans
  • Glioblastoma