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| 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 |
| ISRCTN | ISRCTN68738654 |
| ClinicalTrials.gov identifier | |
| Public 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 |
| 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 |
| Serial number at source | 2008-006871-60 |
| 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.
As of 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. |
| Lay summary | Not provided at time of registration |
| Ethics approval | Added 09/07/2009: The Ethics Committee of the Medical Faculty of Heidelberg (Ethikkommission der Medizinischen Fakultät Heidelberg) approved on the 18th June 2009 (ref: AFmu-050/2009) |
| Study design | Prospective multicentre multinational randomised parallel-group open phase II trial |
| Countries of recruitment | Austria, Germany, Switzerland |
| Disease/condition/study domain | Progressive or recurrent glioblastoma |
| Participants - 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 3-fold upper normal range unless attributed to anticonvulsants 13. Alkaline phosphatase less than 3-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. |
| Participants - 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 6 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 |
| Anticipated start date | 23/09/2009 |
| Anticipated end date | 16/03/2013 |
| Status of trial | Ongoing |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | 166 |
| Interventions |
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 |
| Primary outcome measure(s) |
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 measure(s) |
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. Outome 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 |
| Sources of funding | Essex Pharma GmbH (Germany) |
| Trial website | |
| Publications | |
| Contact name | Prof Wolfgang Wick |
| Address |
University Hospital Heidelberg
Karl-Ruprechts-University Heidelberg Vossstr. 2/ Geb. 4410 |
| City/town | Heidelberg |
| Zip/Postcode | 69120 |
| Country | Germany |
| Sponsor | University Hospital Heidelberg (Universitätsklinikum Heidelberg) (Germany) |
| Address |
Karl-Ruprechts-University Heidelberg
Im Neuenheimer Feld 400 |
| City/town | Heidelberg |
| Zip/Postcode | 69115 |
| Country | Germany |
| Sponsor website: | http://www.med.uni-heidelberg.de/ |
| Date applied | 23/02/2009 |
| Last edited | 06/10/2011 |
| Date ISRCTN assigned | 23/04/2009 |
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| © 2012 ISRCTN unless otherwise stated. | |
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