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

July 21, 2009 updated by: University of Regensburg

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

63

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Regensburg, Germany, 93053
        • University of Regensburg, Department of Neurology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pegylated Liposomal Doxorubicin
Radiotherapy is planned with dedicated computed tomography and three-dimensional planning systems and delivered to the gross tumor volume with a 2 to 3 cm margin for the clinical target volume. After a 4-week break, patients receive adjuvant TMZ 150 to 200 mg/m2 day 1 to 5 in 28 days until tumor progression or up to at least 12 cycles. 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.
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.
Other Names:
  • Caelyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
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%)
Time Frame: 12 months after inclusion of last patient
12 months after inclusion of last patient

Secondary Outcome Measures

Outcome Measure
Time Frame
PFS-24, mOS, OS-12, OS-24, mTTP, response rate, rate of stabilizations , and toxicity profile
Time Frame: 12 months after inclusion of last patient
12 months after inclusion of last patient

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Regensburg

Collaborators

Essex Pharma Germany

Investigators

  • Principal Investigator: Ulrich Bogdahn, MD, Prof., Department of Neurology, University of Regensburg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2002

Primary Completion (Actual)

May 1, 2009

Study Completion (Actual)

May 1, 2009

Study Registration Dates

First Submitted

July 17, 2009

First Submitted That Met QC Criteria

July 21, 2009

First Posted (Estimate)

July 23, 2009

Study Record Updates

Last Update Posted (Estimate)

July 23, 2009

Last Update Submitted That Met QC Criteria

July 21, 2009

Last Verified

July 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RNOP-09

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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