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
DOI	https://doi.org/10.1186/ISRCTN68738654
ClinicalTrials.gov (NCT)	NCT00941460
Clinical Trials Information System (CTIS)	2008-006871-60
Protocol serial number	2008-006871-60
Sponsor	University Hospital Heidelberg (Universitätsklinikum Heidelberg) (Germany)
Funder	Essex Pharma GmbH (Germany)

Submission date: 23/02/2009
Registration date: 23/04/2009
Last edited: 07/02/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Wolfgang Wick
Scientific

University Hospital Heidelberg
Karl-Ruprechts-University Heidelberg
Vossstr. 2/ Geb. 4410
Heidelberg
69120
Germany

Study information

Primary study design	Interventional
Study design	Prospective multicentre multinational randomised parallel-group open phase II trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
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
Study acronym	Director
Study objectives	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(s)	The Ethics Committee of the Medical Faculty of Heidelberg (Ethikkommission der Medizinischen Fakultät Heidelberg), 18/06/2009, ref: AFmu-050/2009
Health condition(s) or problem(s) studied	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 / device / biological / vaccine name(s)	Temozolomide
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
Key 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. 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
Completion date	16/03/2013

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	166
Key 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.
Key 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
Date of first enrolment	23/09/2009
Date of final enrolment	16/03/2013

Locations

Countries of recruitment

Austria
Germany
Switzerland

Study participating centre

University Hospital Heidelberg

Heidelberg
69120
Germany

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/05/2015		Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

07/02/2019: Publication reference added.