Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma

Glioblastoma Clinical Trial

Official title:

RNOP-09: Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma - a Phase II Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00944801
• Other study ID #: RNOP-09
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: July 17, 2009
• Last updated: July 21, 2009
• Start date: July 2002
• Est. completion date: May 2009

Study information

• Verified date: July 2009
• Source: University of Regensburg
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: May 2009
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• newly diagnosed glioblastoma

• centrally confirmed histology

• Karnofsky performance score (KPS) > 70%

• stable corticosteroids within 2 weeks before inclusion

• leucocytes > 3/ul, thrombocytes > 100/ul, Hb > 10 g/dl

• additional standard criteria

Exclusion Criteria:

• other tumor in history

• pretreatment with radiotherapy to the brain

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Glioblastoma

Intervention

Drug:
• Pegylated Liposomal Doxorubicine
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.

Locations

Country	Name	City	State
Germany	University of Regensburg, Department of Neurology	Regensburg

Sponsors (2)

Lead Sponsor	Collaborator
University of Regensburg	Essex Pharma (Schering-Plough) Germany

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	progression free survival probability at 12 months to detect an improvement of the PFS-12 of 15.6% as compared to EORTC26981/NCIC-CE.3 combination arm (PFS-12: 26.9%)		12 months after inclusion of last patient	No
Secondary	PFS-24, mOS, OS-12, OS-24, mTTP, response rate, rate of stabilizations , and toxicity profile		12 months after inclusion of last patient	Yes