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

NCT00944801 | Completed Phase 1 DMC

• 1 other identifier: RNOP-09
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioblastoma

Keywords

glioblastoma; first-line; clinical trial; PEG-liposomal doxorubicin; temozolomide; radiotherapy; phase 1; phase 2

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (1)

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

  12 months after inclusion of last patient

Study Arms (1)

Pegylated Liposomal Doxorubicin

EXPERIMENTAL

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

Interventions

Pegylated Liposomal Doxorubicine DRUG

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.

Also known as: Caelyx

Pegylated Liposomal Doxorubicin

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• newly diagnosed glioblastoma
• centrally confirmed histology
• Karnofsky performance score (KPS) \> 70%
• leucocytes \> 3/ul, thrombocytes \> 100/ul, Hb \> 10 g/dl
• additional standard criteria

You may not qualify if:

• other tumor in history
• pretreatment with radiotherapy to the brain

Sponsors & Collaborators

• University of Regensburg: lead
• Essex Pharma Germany: collaborator

Study Sites (1)

University of Regensburg, Department of Neurology

Regensburg, 93053, Germany

Location

Related Publications (1)

• 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.

  PMID: 19725960 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

liposomal doxorubicin

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Ulrich Bogdahn, MD, Prof.

  Department of Neurology, University of Regensburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: July 17, 2009
• First Posted: July 23, 2009
• Study Start: July 1, 2002
• Primary Completion: May 1, 2009
• Study Completion: May 1, 2009
• Last Updated: July 23, 2009

Record last verified: 2009-07

Locations

DE (1)