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

Primary Purpose

Glioblastoma

Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Pegylated Liposomal Doxorubicine
Sponsored by
University of Regensburg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring glioblastoma, first-line, clinical trial, PEG-liposomal doxorubicin, temozolomide, radiotherapy, phase 1, phase 2

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Regensburg, Department of Neurology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pegylated Liposomal Doxorubicin

Arm Description

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.

Outcomes

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%)

Secondary Outcome Measures

PFS-24, mOS, OS-12, OS-24, mTTP, response rate, rate of stabilizations , and toxicity profile

Full Information

First Posted
July 17, 2009
Last Updated
July 21, 2009
Sponsor
University of Regensburg
Collaborators
Essex Pharma Germany
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1. Study Identification

Unique Protocol Identification Number
NCT00944801
Brief Title
Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma
Official Title
RNOP-09: Pegylated Liposomal Doxorubicine and Prolonged Temozolomide in Addition to Radiotherapy in Newly Diagnosed Glioblastoma - a Phase II Study
Study Type
Interventional

2. Study Status

Record Verification Date
July 2009
Overall Recruitment Status
Completed
Study Start Date
July 2002 (undefined)
Primary Completion Date
May 2009 (Actual)
Study Completion Date
May 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
University of Regensburg
Collaborators
Essex Pharma Germany

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma
Keywords
glioblastoma, first-line, clinical trial, PEG-liposomal doxorubicin, temozolomide, radiotherapy, phase 1, phase 2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pegylated Liposomal Doxorubicin
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Pegylated Liposomal Doxorubicine
Other Intervention Name(s)
Caelyx
Intervention Description
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.
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ulrich Bogdahn, MD, Prof.
Organizational Affiliation
Department of Neurology, University of Regensburg
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Regensburg, Department of Neurology
City
Regensburg
ZIP/Postal Code
93053
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
19725960
Citation
Beier CP, Schmid C, Gorlia T, Kleinletzenberger C, Beier D, Grauer O, Steinbrecher A, Hirschmann B, Brawanski A, Dietmaier C, Jauch-Worley T, Kolbl O, Pietsch T, Proescholdt M, Rummele P, Muigg A, Stockhammer G, Hegi M, Bogdahn U, Hau P. RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study. BMC Cancer. 2009 Sep 2;9:308. doi: 10.1186/1471-2407-9-308.
Results Reference
derived

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

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