Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma
Condition: Glioblastoma
MeSH terms: Glioblastoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Glioblastomas represent 40% of all tumors of the central nervous system (CNS) and are among
      the most lethal tumors. Temozolomide (TMZ) combined with radiotherapy was the first substance
      to significantly improve the overall survival (to 14.6 months) as compared to surgery and
      radiotherapy alone and increased the proportion of patients surviving more than 2 years to
      26%. TMZ showed the best efficacy in patients with a methylated O6-methylguanine-DNA
      methyltransferase (MGMT) promoter in part by eliminating stem cell-like tumor cells. Among
      patients with a methylated MGMT promoter, the median survival after treatment with combined
      radio-chemotherapy was 21.7 months, as compared to 15.3 months among those who were assigned
      to radiotherapy only. In the absence of methylation of the MGMT promoter, there was a smaller
      and statistically insignificant difference in survival between the treatment groups.

      Doxorubicin is one of the most effective substances in vitro against cells derived from
      glioblastoma. However, it has no significant effect in vivo due to poor blood-brain-barrier
      penetration. In a tumor model, tissue and CSF-concentrations of doxorubicin were
      substantially increased when sterically stabilized liposomes were used resulting in a
      comparable clinical response using approximately half of the dose of stabilized liposomes
      compared to conventional doxorubicin. A pegylated formulation (PEG-liposomal Doxorubicin)
      even further improved the penetration of the blood-brain barrier. Case series and two phase
      II-studies in patients with recurrent glioblastoma have shown modestly promising results for
      PEG-Dox.

      In this study, the investigators treated patients with recurrent glioblastoma with 20 mg/m2
      PEG-Dox on days 1 and 15 of each 28-day cycle. To determine the dose limiting toxicity of
      PEG-Dox combined with prolonged administration of TMZ, the investigators performed a phase I
      part ahead of the phase II study. To investigate, by means of a historical control analysis,
      if the addition of PEG-Dox to TMZ and radiotherapy improves the survival of patients, the
      investigators chose similar inclusion criteria and identical TMZ and radiotherapeutic regimes
      as in the EORTC26981/NCIC-CE.3 study.
    


Intervention name(s): Pegylated Liposomal Doxorubicine
Intervention type(s): Drug
Intervention description(s): In the dose escalation phase of the study, PEG-Dox is raised in steps of 5 mg/m2 in a 3-by-3 design, starting with 5 mg/m2 (group 1) up to 20 mg/m2 (group 4). In the phase II part of the study, the targeted dose of 20 mg/m2 is administered up to a cumulative dose of 550 mg/m2 or until tumor progression.
Other intervention name(s): Caelyx
Intervention MeSH terms: Doxorubicin; Liposomal doxorubicin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: glioblastoma; first-line; clinical trial; PEG-liposomal doxorubicin; temozolomide; radiotherapy; phase 1; phase 2