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Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly (Methusalem)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01502241
Recruitment Status : Completed
First Posted : December 30, 2011
Last Update Posted : December 30, 2011
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. Wolfgang Wick, Heidelberg University

Tracking Information
First Submitted Date  ICMJE December 24, 2011
First Posted Date  ICMJE December 30, 2011
Last Update Posted Date December 30, 2011
Study Start Date  ICMJE January 2005
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: December 29, 2011)
  • Event-free survival [ Time Frame: 12 months ]
    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).
  • Best response [ Time Frame: Within the first 8 months after surgery ]
    Response is assessed according MacDonald Criteria based on regular 3-monthly MRI.
  • Molecular prognostic or predictive biomarkers [ Time Frame: At 12 months ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly
Official Title  ICMJE 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)
Brief 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. 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Anaplastic Astrocytoma
Intervention  ICMJE
  • Drug: Temozolomide
    100 mg/m2 per day on seven out of fourteen days.
  • Radiation: Radiotherapy of the partial brain.
    60 Gy in 30 fractions à 2 Gy.
Study Arms  ICMJE
  • Active Comparator: Radiotherapy
    6 weeks standard partial brain treatment.
    Intervention: Radiation: Radiotherapy of the partial brain.
  • Experimental: Temozolomide
    Temozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007
    Intervention: Drug: Temozolomide
Publications * Wick 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 29, 2011)
412
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE November 2011
Actual Primary Completion Date November 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 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
  • 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

Exclusion Criteria:

  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 65 Years and older   (Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01502241
Other Study ID Numbers  ICMJE NOA-08
05-01 ( Registry Identifier: German Cancer Society )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Dr. Wolfgang Wick, Heidelberg University
Study Sponsor  ICMJE Heidelberg University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael Weller University of Zurich
Principal Investigator: Wolfgang Wick Heidelberg University
PRS Account Heidelberg University
Verification Date December 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP