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

This study has been completed.
Sponsor:
Collaborator:
Essex Pharma (Schering-Plough) Germany
Information provided by:
University of Regensburg
ClinicalTrials.gov Identifier:
NCT00944801
First received: July 17, 2009
Last updated: July 21, 2009
Last verified: July 2009
  Purpose

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.


Condition Intervention Phase
Glioblastoma
Drug: Pegylated Liposomal Doxorubicine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: RNOP-09: Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma - a Phase II Study

Resource links provided by NLM:


Further study details as provided by University of Regensburg:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Enrollment: 63
Study Start Date: July 2002
Study Completion Date: May 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Caelyx

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00944801

Locations
Germany
University of Regensburg, Department of Neurology
Regensburg, Germany, 93053
Sponsors and Collaborators
University of Regensburg
Essex Pharma (Schering-Plough) Germany
Investigators
Principal Investigator: Ulrich Bogdahn, MD, Prof. Department of Neurology, University of Regensburg
  More Information

No publications provided by University of Regensburg

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ulrich Bogdahn, Prof. Dr. med., Department of Neurology, University of Regensburg
ClinicalTrials.gov Identifier: NCT00944801     History of Changes
Other Study ID Numbers: RNOP-09
Study First Received: July 17, 2009
Last Updated: July 21, 2009
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Regensburg:
glioblastoma
first-line
clinical trial
PEG-liposomal doxorubicin
temozolomide
radiotherapy
phase 1
phase 2

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Liposomal doxorubicin
Doxorubicin
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014