αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma

Eur J Cancer. 2013 Jun;49(9):2161-9. doi: 10.1016/j.ejca.2013.02.033. Epub 2013 Apr 6.

Abstract

Background: Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway.

Patients and methods: Patients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome.

Results: For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS.

Conclusion: Association of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Biomarkers / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy*
  • Combined Modality Therapy
  • Drug Administration Schedule
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Focal Adhesion Kinase 1 / metabolism
  • Glioblastoma / metabolism
  • Glioblastoma / therapy*
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Male
  • Middle Aged
  • Protein-Serine-Threonine Kinases / metabolism
  • Quinolones / administration & dosage*
  • Quinolones / adverse effects
  • Radiation-Sensitizing Agents / administration & dosage*
  • Radiation-Sensitizing Agents / adverse effects
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptors, Vitronectin / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers
  • Integrin alphaVbeta3
  • Quinolones
  • Radiation-Sensitizing Agents
  • Receptors, Vitronectin
  • integrin alphaVbeta5
  • Fibroblast Growth Factor 2
  • integrin-linked kinase
  • Receptor, Fibroblast Growth Factor, Type 1
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • Protein-Serine-Threonine Kinases
  • tipifarnib