Additional identifiers
EudraCT number
2008-006871-60
ClinicalTrials.gov number
NCT00941460
Protocol/serial number
2008-006871-60
Study information
Scientific title
Dose-intensified rechallenge with temozolomide, one week on one week off versus three weeks on one week off in patients with progressive or recurrent glioblastoma: a prospective, multicentre, multinational, randomised, parallel-group, open, phase II trial
Acronym
Director
Study hypothesis
The primary objective of this study is to show the superiority of arm A (one week on temozolomide one week off) versus arm B (three weeks on temozolomide one week off) in terms of time to treatment failure.
On 05/01/2010 this record was updated to include further information on the site locations; this information can be found in the interventions section of this record under the above update date. At this time, the anticipated start date of this trial was also updated to the date of first participant recruitment. The initial anticipated start date of this trial was 16/03/2009.
Ethics approval
The Ethics Committee of the Medical Faculty of Heidelberg (Ethikkommission der Medizinischen Fakultät Heidelberg), 18/06/2009, ref: AFmu-050/2009
Study design
Prospective multicentre multinational randomised parallel-group open phase II trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Progressive or recurrent glioblastoma
Intervention
In treatment arm A, patients will be treated with an initial dose of 120 mg/m^2 unless there was grade III or IV myelotoxicity with conventional temozolomide (5/28) previously. These patients will be started at 90 mg/m^2. Temozolomide will be given orally on days 1 - 7 and 15 - 21. The dose will be modified if necessary.
In treatment arm B, patients will start with an initial dose of 80 mg/m^2 unless there was significant myelotoxicity with conventional temozolomide (5/28) previously. These patients will be started at 60 mg/m^2. Temozolomide will be given orally on days 1 - 21. The dose will be modified if necessary.
1 year of treatment; follow-up until death or for one year.
Site location and principal investigator information added as of 05/01/2010:
University Hospital Zurich (Switzerland)
Department of Neurology
Zurich, Switzerland
Site PI: Prof Dr M Weller
Email: michael.weller@usz.ch
University Hospital Complex of Vaud (Centre Hospitalier Universitaire Vaudois [CHUV]) (Switzerland)
University of Lausanne
Lausanne, Switzerland
Site PI: Prof Dr R Stupp
Email: roger.stupp@chuv.hospvd.ch
Charité - University Medicine Berlin (Charité - Universitätsmedizin Berlin) (Germany)
Department of Neurosurgery
Berlin, Germany
Site PI: Prof Dr P Vajkoczy
Email: peter.vajkoczy@charite.de
University Hospital Bonn (Universitätsklinikum Bonn) (Germany)
Department of Neurology
Bonn, Germany
Site PI: Prof Dr U Herrlinger
Email: ulrich.herrlinger@ukb.uni-bonn.de
The Miners' Hospital Bochum-Langendreer (Knappschaftskrankenhaus Bochum-Langendreer) (Germany)
Department of Neurology
Bochum, Germany
Site PI: Prof Dr U Schlegel
Email: uwe.schlegel@kk-bochum.de
Johann Wolfgang Goethe University Hospital (Klinikum der Johann-Wolfgang von Goethe-Universität) (Germany)
Dr Senckenbergisches Institut für Neuroonkologie
Zentrum für Neurologie und Neurochirurgie
Frankfurt am Main, Germany
Site PI: Prof Dr J Steinbach
Email: joachim.steinbach@med.uni-frankfurt.de
Saarland University Hospital (Universitätsklinikum des Saarlandes) (Germany)
Department of Neurosurgery
Homburg/Saar, Germany
Site PI: PD Dr R Ketter Homburg
Email: ncrket@uks.eu
University Hospital Heidelberg (Universitätsklinikum Heidelberg) (Germany)
Department of Neuro-oncology
Heidelberg, Germany
Site PI: Prof Dr med W Wick
Email: wolfgang.wick@med.uni-heidelberg.de
University of Leipzig (Germany)
Klinik und Poliklinik für Neurochirurgie
Leipzig, Germany
Site PI: Prof Dr J Meixensberger
Email: meix@medizin.uni-leipzig.de
Ludwig Maximilians University of Munich (Germany)
Grosshadern Hospital
Department of Neurosurgery
München, Germany
Site PI: Prof Dr J Tonn
Email: joerg.christian.tonn@med.uni-muenchen.de
University of Regensburg (Germany)
Department of Neurology
Regensburg, Germany
Site PI: PD Dr P Hau
Email: peter.hau@medbo.de
Medical University Vienna (Austria)
Department of Internal Medicine I
Vienna, Austria
Site PI: Prof Dr C Marosi
Email: christine.marosi@meduniwien.ac.at
State Mental Hospital of Wagner-Jauregg (Landesnervenklinik Wagner-Jauregg) (Austria)
Linz, Austria
Site PI: Dr J Pichler
Email: josef.pichler@gespag.at
Site location and principal investigator information added as of 05/10/2011:
University Hospital Düsseldorf (Universitätsklinikum Düsseldorf, Neurochirurgische Klinik, Abt. Hirntumorchirurgie)
Düsseldorf, Germany
Site PI: Prof. Dr. med. Michael Sabel
Email: sabel@uni-duesseldorf.de
University Hospital Freiburg (Universitätsklinikum Freiburg, Stereotaktische Neurochirurgie)
Freiburg, Germany
Site PI: Prof. Dr. med. Guido Nikkhah
Email: stereo@uniklinik-freiburg.de
University Hospital Cologne (Universitätsklinikum Köln, Klinik für allgemeine Neurochirurgie)
Köln, Germany
Site PI: Prof. Dr. med. Roland Goldbrunner
Email: roland.goldbrunner@uk-koeln.de
Updated 05/07/2012: the trial was stopped due to a slower than anticipated recruitment rate.
Updated 14/08/2014: the study is completed now and the publication is currently in preparation.
Intervention type
Drug
Phase
Phase II
Drug names
Temozolomide
Primary outcome measures
Median time to treatment failure. Treatment failure is reached:
1. Upon tumour progression, measured every 8 weeks during treatment, every 3 months during follow-up
2. If treatment has to be terminated due to toxicity, measured at every contact between investigator and patient (according to protocol: weekly during first cycle, then every 4 weeks; during follow-up every 3 months)
3. If the patient dies for any reason
Secondary outcome measures
1. Progression-free survival (PFS), measured every 8 weeks during treatment, every 3 months during follow-up
2. Overall survival, measured every 8 weeks during treatment, every 3 months during follow-up
3. Objective responses (complete response [CR] and partial response [PR]), measured every 8 weeks during treatment, every 3 months during follow-up
4. Outcome (PFS-6, PFS, survival, best response) relative to MGMT promoter methylation in recurrent tumour, measured every 8 weeks during treatment, every 3 months during follow-up
5. Outcome relative to duration of prior treatment (e.g. number of completed 5/28 cycles after radiation therapy)
6. Outcome relative to interval from completion of prior TMZ chemotherapy treatment (less than 3 months versus greater than 3 months)
7. Toxicity including lymphocytes, CD4 T cell and regulatory T cell counts, measured every 8 weeks during treatment, every 3 months during follow-up
8. Expression of the mismatch repair genes MLH-1, MSH-2, MSH-6 and PMS2 in tumour tissue determined by immunohistochemistry
9. Changes in MGMT status in recurrent disease relative to initial tumour tissue if applicable, measured weekly during first cycle, then every 8 weeks; during follow-up every 3 months
10. Changes in MGMT activity in peripheral blood during ongoing therapy will be assessed during the first cycle at days 1, 8, 15, 22, then MGMT activity will be investigated every 8 weeks; during follow-up every 3 months
11. Quality of life determined by EORTC QoL-Brain 20 Neurotoxicity determined by MRI, measured every 8 weeks during treatment, every 3 months during follow-up
12. Neurotoxicity determined by Mini-Mental State Examination (MMSE), MRI and NeuroCogFx neuropsychological examination, measured every 4 weeks during treatment, every 3 months during follow-up
13. Outcome relative to extent of resection (gross total resection versus resection with residual contrast-enhancing tumour versus biopsy)
14. Screening for aberrant MGMT promoter methylation in peripheral blood, measured weekly during first cycle, then every 8 weeks; during follow-up every 3 months
Overall trial start date
23/09/2009
Overall trial end date
16/03/2013
Reason abandoned
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 05/10/2011:
1. Progressive or recurrent glioblastoma documented by magnetic resonance imaging (MRI) no earlier than 180 days after first surgery for glioblastoma and no earlier than 90 days after completion of radiotherapy
2. Histological diagnosis of glioblastoma
3. Tissue available for the determination of MGMT promoter methylation in the primary tumor or from the recurrent tumor of a patient undergoes a surgical procedure at recurrence prior to study entry
4. Prior treatment with temozolomide administered concomitantly with radiotherapy and at least for two cycles (5/28) as an adjuvant treatment
5. Informed consent
6. Aged 18 - 80 years, either sex
7. Karnofsky performance score greater than 50%
8. Neutrophil counts greater than 1,500/µl
9. Platelet counts greater than 100,000/µl
10. Haemoglobin greater than 10 g/dl
11. Serum creatinine less than 1.5-fold upper normal range
12. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) less than three-fold upper normal range unless attributed to anticonvulsants
13. Alkaline phosphatase less than three-fold upper normal range
14. Women with childbearing potential must have a negative serum pregnancy test less than or equal to 14 days prior to study enrolment
Added 05/10/2011:
15. Willingness to apply contraception according to local requirements (as stated in patient information)
Previous inclusion criteria:
3. Tissue available for the determination of MGMT gene promoter methylation in the recurrent tumour
All other points remained unchanged.
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
166 (105 actually recruited)
Participant exclusion criteria
1. Progressive or recurrent glioblastoma documented by MRI earlier than 180 days after first surgery for glioblastoma and earlier than 90 days after completion of radiotherapy
2. Treatment with any chemotherapy other than temozolomide according to the schedule of the EORTC NCIC trial except that an adjuvant starting dose of 200 mg/m^2 and more than six cycles of adjuvant temozolomide are allowed
3. Prior systemic or local treatment with deoxyribonucleic acid (DNA)-damaging agents, tyrosine kinase inhibitors or anti-angiogenic agents for any cancer
4. Allergy to or other intolerability of temozolomide
5. Unable to undergo MRI
6. Past medical history of diseases with poor prognosis, e.g. severe coronary heart disease, severe diabetes, immune deficiency, residual deficits after stroke, severe mental retardation
7. Human immunodeficiency virus (HIV) infection
8. Pregnancy
9. Breast feeding
10. Treatment within in any other clinical trial parallel to the treatment phase of the current study
Recruitment start date
23/09/2009
Recruitment end date
16/03/2013
Locations
Countries of recruitment
Austria, Germany, Switzerland
Trial participating centre
University Hospital Heidelberg
Heidelberg
69120
Germany
Sponsor information
Organisation
University Hospital Heidelberg (Universitätsklinikum Heidelberg) (Germany)
Sponsor details
Karl-Ruprechts-University Heidelberg
Im Neuenheimer Feld 400
Heidelberg
69115
Germany
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Industry
Funder name
Essex Pharma GmbH (Germany)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary