GlioblastomaPhase 3MethusalemNCT01502241
Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly
A Phase 3 study testing Temozolomide and Radiotherapy of the partial brain. in people with Glioblastoma and Anaplastic Astrocytoma, run by Heidelberg University at 23 sites in 2 countries.
Trial summary
The study aims to optimize the treatment of elderly subjects (> 65) with anaplastic astrocytoma and glioblastoma. Current treatment policies tend to be no more than palliative. There is no consensus as to how radical the surgery should be. Read more about this study
- Who is it for?
- Ages 65 years and older
- Conditions the study is for
- Glioblastoma, Anaplastic Astrocytoma
- What is being tested?
- Temozolomide and Radiotherapy of the partial brain.
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 412 participants
- Where
- 23 sitesin 2 countries
- Study dates
- Jan 2005to Nov 2011
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 years and older
- All sexes
- No healthy volunteers
- Older adult
Who may be able to join
- Histologically confirmed supratentorial anaplastic astrocytoma or glioblastoma
- Age > 65
- Karnofsky performance score > 60%
- Neutrophilic granulocyte count > 1500/µl
- Platelet count > 100 000/µl
- Hemoglobin > 10 g/dl
Show all 12Show fewer
- Serum creatinine < 1.5 times the lab's upper normal limit
- AST or ALT < 3 times the lab's upper normal limit
- Alkaline phosphatase < 3 times the lab's upper normal limit
- No previous systemic chemotherapy
- No previous radiotherapy to the brain
- Written consent
Who cannot join
- Serious medical or neurological condition with a poor prognosis
- HIV infection
- Second cancer requiring radiotherapy or chemotherapy (contact the study coordinat if necessary)
- Hypersensitivity to temozolomide
- Conditions associated with regular vomiting that might affect oral administration of the drugs
- Psychological, familial, social or geographical circumstances with major implications for compliance with the study visit schedule
- Patient was taking part in other intervention studies within a month of starting this study
Trial locations and contacts
23 sites in 2 countries.
23 sites in 2 countries
Germany22 sites
Charite Berlin
Berlin
University of Bochum
Bochum
University of Bonn
Bonn
University of Dresden
Dresden
University of Düsseldorf
Düsseldorf
University of Erlangen
Erlangen
University of Essen
Essen
University of Frankfurt
Frankfurt am Main, Hesse, 60528
University of Freiburg
Freiburg im Breisgau
University of Hamburg
Hamburg
University of Hannover II
Hanover
University of Hannover
Hanover
University of Heidelberg
Heidelberg, Baden-Wurttemberg, 69120
University of Homburg
Homburg
University of Kiel
Kiel
University of Leipzig
Leipzig
University of Mainz
Mainz
University of Heidelberg
Mannheim
University of Marburg
Marburg
University of Regensburg
Regensburg
University of Tübingen
Tübingen
University of Ulm
Ulm
About this study
Official title: Temozolomid (One Week on/One Week Off) Versus Strahlentherapie in Der Primärtherapie Anaplastischer Astrozytome Und Glioblastome Bei älteren Patienten: Eine Randomisierte Phase III-Studie (Methvsalem)
The study aims to optimize the treatment of elderly subjects (> 65) with anaplastic astrocytoma and glioblastoma. Current treatment policies tend to be no more than palliative. There is no consensus as to how radical the surgery should be. Involved-field radiotherapy is the treatment most likely to be accepted apart from supportive and palliative measures. The role of chemotherapy is barely defined. Study data available to date does not suggest that this patient population would benefit from combined radiochemotherapy. The aim of the study is to verify the hypothesis that first-line chemotherapy with one week on/one week off temozolomide is not inferior to extended-field radiotherapy in the first-line treatment of anaplastic astrocytoma and glioblastoma in the elderly (> 65 age group). The primary endpoint is median survival, as life expectancy is limited to several months. Secondary endpoints are response rates in both arms (CR, PR, MacDonald et al. 1990), median progression-free survival, 1-year and 2-year survival rates, definition of MGMT as molecular genetic prognostic or predictive markers, and quality of life. Theoretically, it should be possible to preserve quality of life in the first-line chemotherapy arm of the study.
Read the detailed description
This study is a prospective, randomized Phase III intervention study. Following histological documentation of the diagnosis by biopsy or resection of an anaplastic astrocytoma or glioblastoma, patients will be randomized either to receive postoperative extended-field radiotherapy (arm A) or to receive postoperative chemotherapy with temozolomide (arm B). Randomization will be done for all sites at the CRO, Alcedis GmbH.
For patients intending to participate in the study, the procedure is as follows:
- Request a reference neuropathological review from the brain tumor reference center in Bonn (Prof. Dr. G. Reifenberger) through the local neuropathology department. This review need not be present at randomization because anaplastic astrocytoma and glioblastoma cases are eligible
- Contact: Prof. Dr. W. Wick, Dep. Neurooncology, National Center for Tumor Diseases and Neurology Clinic, University of Heidelberg, wolfgang.wick@med.uni-heidelberg.de or CRO: Alcedis, Giessen at Alcedis GmbH, I. Helm, Winchester Str. 2, 35394 Gießen, Tel.: 0641 944360, Fax: 0641 94436 70, E-mail: ihe@alcedis.de
- Provide written confirmation that the patient signed the ethics committee-approved consent form
- Submit the registration form and a copy of the EORTC-QLQ given in Annexes
In subjects with progressive or recurrent disease, the investigating site will verify whether specific tumor treatment is justified. If yes, chemotherapy with temozolomide is recommended in arm A, possibly after further surgery. Subjects in arm B will receive radiotherapy, possible after further surgery. As all-cause mortality is the primary endpoint, all therapeutic measures following first-line therapy should be documented.
If study treatment is discontinued (first-line therapy) because of progressive disease or if progression occurs after completion of study treatment, the pertinent images should be submitted to the reference center for neuroradiology in Tübingen for reference review.
The treatment modalities employed in the study are chemotherapeutic and radiotherapeutic procedures licensed in the Federal Republic of Germany for use in human subjects. Temozolomide is currently licensed for treating subjects with recurrent disease and since 2006 in newly diagnosed glioblastoma together with radiotherapy. The time allotted for the individual treatment sections is 6 weeks for radiotherapy, while chemotherapy will be continued until progression or unacceptable adverse effects occur. The precise chemotherapy sequence is shown in the protocol. The criteria for withdrawal from the study are defined in in the protocol. Four years is the period scheduled for recruiting all patients.
- Conditions
- Glioblastoma, Anaplastic Astrocytoma
- Being tested
- Temozolomide, Radiotherapy of the partial brain.
- Keywords
- elderly, brain tumors, MGMT, chemotherapy, Newly diagnosed, patients > 65 years
- Medical subject headings
- Glioblastoma, Astrocytoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TemozolomideDrug
100 mg/m2 per day on seven out of fourteen days.
Radiotherapy of the partial brain.Radiation
60 Gy in 30 fractions à 2 Gy.
| Study group | Role | What they receive |
|---|---|---|
| Radiotherapy | Active comparator | 6 weeks standard partial brain treatment. Receives: Radiation: Radiotherapy of the partial brain. |
| Temozolomide | Experimental | Temozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007 Receives: Drug: Temozolomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall survival
The primary endpoint was overall survival, measured in days from surgery to death for any reason. Patients alive at the day of the last contact were censored.
Measured: 12 months
Secondary outcomes (3)
Event-free survival
Secondary efficacy end points included EFS. EFS was defined as time from surgery to first progression for patients with progression respectively to death for patients without progression. Patients without progression or death were censored at the day of the last contact. Univariate analysis of OS and EFS used Kaplan-Meier estimates21 and a Cox proportional hazard model for evaluating Hazard Ratios (HR) with 95%-confidence intervals and median OS and EFS with 95%-confidence intervals (CI).
Measured: 12 months
Best response
Response is assessed according MacDonald Criteria based on regular 3-monthly MRI.
Measured: Within the first 8 months after surgery
Molecular prognostic or predictive biomarkers
Tumor tissue, fresh or paraffine-embedded, or DNA/RNA/proteins from tissue are analyzed for the status of known molecular parameters, e.g. MGMT, for a prognostic or predictive role. Further, newly discovered molecular parameters are assessed for their potential to predict outcome.
Measured: At 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Dec 2011 (estimated)
- Study startJan 2005
- Primary completionNov 2010
- Study completionNov 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 412 participants (actual)
Sponsor and investigators
- Lead sponsor
- Heidelberg University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Dr. Wolfgang Wick, Heidelberg University
- Investigators
- Michael Weller, Study director, University of ZurichWolfgang Wick, Principal investigator, Heidelberg University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01502241
- Sponsor's protocol ID
- NOA-08
- Other IDs
- 05-01
- Acronym
- Methusalem
- Status last verified
- Dec 2011
- First submitted
- 24 Dec 2011
- Last updated
- 30 Dec 2011
- Results posted
- No
- Data monitoring committee
- No
Publications
Wick A, Kessler T, Platten M, Meisner C, Bamberg M, Herrlinger U, Felsberg J, Weyerbrock A, Papsdorf K, Steinbach JP, Sabel M, Vesper J, Debus J, Meixensberger J, Ketter R, Hertler C, Mayer-Steinacker R, Weisang S, Bolting H, Reuss D, Reifenberger G, Sahm F, von Deimling A, Weller M, Wick W. Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma. Neuro Oncol. 2020 Aug 17;22(8):1162-1172. doi: 10.1093/neuonc/noaa033.
PubMed 32064499Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. doi: 10.1016/S1470-2045(12)70164-X. Epub 2012 May 10.
PubMed 22578793
Study at a glance
From the registry record, last updated by the sponsor on 30 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Temozolomid (One Week on/One Week Off) Versus Strahlentherapie in Der Primärtherapie Anaplastischer Astrozytome Und Glioblastome Bei älteren Patienten: Eine Randomisierte Phase III-Studie (Methvsalem)
- ClinicalTrials.gov ID
- NCT01502241
- Acronym / sponsor ID
- Methusalem / NOA-08
- Conditions
- Glioblastoma, Anaplastic Astrocytoma
- Keywords
- elderly, brain tumors, MGMT, chemotherapy, Newly diagnosed, patients > 65 years
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 412 participants (actual)
- Lead sponsor
- Heidelberg UniversityUniversity, hospital or other
- Study start
- Jan 2005
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2011 (actual)
- First posted
- 30 Dec 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study aims to optimize the treatment of elderly subjects (> 65) with anaplastic astrocytoma and glioblastoma. Current treatment policies tend to be no more than palliative. There is no consensus as to how radical the surgery should be. Involved-field radiotherapy is the treatment most likely to be accepted apart from supportive and palliative measures. The role of chemotherapy is barely defined. Study data available to date does not suggest that this patient population would benefit from combined radiochemotherapy. The aim of the study is to verify the hypothesis that first-line chemotherapy with one week on/one week off temozolomide is not inferior to extended-field radiotherapy in the first-line treatment of anaplastic astrocytoma and glioblastoma in the elderly (> 65 age group). The primary endpoint is median survival, as life expectancy is limited to several months. Secondary endpoints are response rates in both arms (CR, PR, MacDonald et al. 1990), median progression-free survival, 1-year and 2-year survival rates, definition of MGMT as molecular genetic prognostic or predictive markers, and quality of life. Theoretically, it should be possible to preserve quality of life in the first-line chemotherapy arm of the study.
Detailed description
This study is a prospective, randomized Phase III intervention study. Following histological documentation of the diagnosis by biopsy or resection of an anaplastic astrocytoma or glioblastoma, patients will be randomized either to receive postoperative extended-field radiotherapy (arm A) or to receive postoperative chemotherapy with temozolomide (arm B). Randomization will be done for all sites at the CRO, Alcedis GmbH.
For patients intending to participate in the study, the procedure is as follows:
- Request a reference neuropathological review from the brain tumor reference center in Bonn (Prof. Dr. G. Reifenberger) through the local neuropathology department. This review need not be present at randomization because anaplastic astrocytoma and glioblastoma cases are eligible
- Contact: Prof. Dr. W. Wick, Dep. Neurooncology, National Center for Tumor Diseases and Neurology Clinic, University of Heidelberg, wolfgang.wick@med.uni-heidelberg.de or CRO: Alcedis, Giessen at Alcedis GmbH, I. Helm, Winchester Str. 2, 35394 Gießen, Tel.: 0641 944360, Fax: 0641 94436 70, E-mail: ihe@alcedis.de
- Provide written confirmation that the patient signed the ethics committee-approved consent form
- Submit the registration form and a copy of the EORTC-QLQ given in Annexes
In subjects with progressive or recurrent disease, the investigating site will verify whether specific tumor treatment is justified. If yes, chemotherapy with temozolomide is recommended in arm A, possibly after further surgery. Subjects in arm B will receive radiotherapy, possible after further surgery. As all-cause mortality is the primary endpoint, all therapeutic measures following first-line therapy should be documented.
If study treatment is discontinued (first-line therapy) because of progressive disease or if progression occurs after completion of study treatment, the pertinent images should be submitted to the reference center for neuroradiology in Tübingen for reference review.
The treatment modalities employed in the study are chemotherapeutic and radiotherapeutic procedures licensed in the Federal Republic of Germany for use in human subjects. Temozolomide is currently licensed for treating subjects with recurrent disease and since 2006 in newly diagnosed glioblastoma together with radiotherapy. The time allotted for the individual treatment sections is 6 weeks for radiotherapy, while chemotherapy will be continued until progression or unacceptable adverse effects occur. The precise chemotherapy sequence is shown in the protocol. The criteria for withdrawal from the study are defined in in the protocol. Four years is the period scheduled for recruiting all patients.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Radiotherapy | Active comparator | Radiation: Radiotherapy of the partial brain.6 weeks standard partial brain treatment. |
| Temozolomide | Experimental | Drug: TemozolomideTemozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007 |
Who may qualify
- Ages
- 65 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
Key inclusion criteria (12 listed)
- Histologically confirmed supratentorial anaplastic astrocytoma or glioblastoma
- Age > 65
- Karnofsky performance score > 60%
- Neutrophilic granulocyte count > 1500/µl
- Platelet count > 100 000/µl
Key exclusion criteria (7 listed)
- Serious medical or neurological condition with a poor prognosis
- HIV infection
- Second cancer requiring radiotherapy or chemotherapy (contact the study coordinat if necessary)
- Hypersensitivity to temozolomide
- Conditions associated with regular vomiting that might affect oral administration of the drugs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Temozolomide100 mg/m2 per day on seven out of fourteen days. | Drug | Temozolomide |
| Radiotherapy of the partial brain.60 Gy in 30 fractions à 2 Gy. | Radiation | Radiotherapy |
Primary outcome
Overall survival
Time frame: 12 months
The primary endpoint was overall survival, measured in days from surgery to death for any reason. Patients alive at the day of the last contact were censored.
3 secondary outcomes
Event-free survival
Time frame: 12 months
Best response
Time frame: Within the first 8 months after surgery
Molecular prognostic or predictive biomarkers
Time frame: At 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Dec 2011.
- Derived from this study: PubMed 32064499Wick A, Kessler T, Platten M, Meisner C, Bamberg M, Herrlinger U, Felsberg J, Weyerbrock A, Papsdorf K, Steinbach JP, Sabel M, Vesper J, Debus J, Meixensberger J, Ketter R, Hertler C, Mayer-Steinacker R, Weisang S, Bolting H, Reuss D, Reifenberger G, Sahm F, von Deimling A, Weller M, Wick W. Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma. Neuro Oncol. 2020 Aug 17;22(8):1162-1172. doi: 10.1093/neuonc/noaa033.
- Derived from this study: PubMed 22578793Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012 Jul;13(7):707-15. doi: 10.1016/S1470-2045(12)70164-X. Epub 2012 May 10.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Weller study director
University of Zurich
Wolfgang Wick principal investigator
Heidelberg University
23 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Temozolomide and Radiotherapy of the partial brain. in people with Glioblastoma and Anaplastic Astrocytoma, run by Heidelberg University at 23 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in Germany, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Overall survival (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01502241, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2011.