Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. Wolfgang Wick, University of Heidelberg
ClinicalTrials.gov Identifier:
NCT01502241
First received: December 24, 2011
Last updated: December 29, 2011
Last verified: December 2011
  Purpose

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.


Condition Intervention Phase
Glioblastoma
Anaplastic Astrocytoma
Drug: Temozolomide
Radiation: Radiotherapy of the partial brain.
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Heidelberg University:

Primary Outcome Measures:
  • Overall survival [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Event-free survival [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    Response is assessed according MacDonald Criteria based on regular 3-monthly MRI.

  • Molecular prognostic or predictive biomarkers [ Time Frame: At 12 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 412
Study Start Date: January 2005
Study Completion Date: November 2011
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Radiotherapy
6 weeks standard partial brain treatment.
Radiation: Radiotherapy of the partial brain.
60 Gy in 30 fractions à 2 Gy.
Experimental: Temozolomide
Temozolomide in a one week on/one week off schedule per Wick et al. 2004 and A. Wick et al. 2007
Drug: Temozolomide
100 mg/m2 per day on seven out of fourteen days.

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.

  Eligibility

Ages Eligible for Study:   65 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01502241

Locations
Germany
University of Heidelberg
Heidelberg, Baden-Württemberg, Germany, 69120
University of Frankfurt
Frankfurt, Hessen, Germany, 60528
Charite Berlin
Berlin, Germany
University of Bochum
Bochum, Germany
University of Bonn
Bonn, Germany
University of Dresden
Dresden, Germany
University of Düsseldorf
Düsseldorf, Germany
University of Erlangen
Erlangen, Germany
University of Essen
Essen, Germany
University of Freiburg
Freiburg, Germany
University of Hamburg
Hamburg, Germany
University of Hannover
Hannover, Germany
University of Hannover II
Hannover, Germany
University of Homburg
Homburg, Germany
University of Kiel
Kiel, Germany
University of Leipzig
Leipzig, Germany
University of Mainz
Mainz, Germany
University of Heidelberg
Mannheim, Germany
University of Marburg
Marburg, Germany
University of Regensburg
Regensburg, Germany
University of Tübingen
Tübingen, Germany
University of Ulm
Ulm, Germany
Switzerland
University of Zurich
Zurich, Switzerland, 8091
Sponsors and Collaborators
Heidelberg University
Investigators
Study Director: Michael Weller University of Zurich
Principal Investigator: Wolfgang Wick Heidelberg University
  More Information

No publications provided by Heidelberg University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Prof. Dr. Wolfgang Wick, Chairman and Director Neurooncology, University of Heidelberg
ClinicalTrials.gov Identifier: NCT01502241     History of Changes
Other Study ID Numbers: NOA-08, 05-01
Study First Received: December 24, 2011
Last Updated: December 29, 2011
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Heidelberg University:
elderly
brain tumors
MGMT
chemotherapy
Newly diagnosed
patients > 65 years

Additional relevant MeSH terms:
Astrocytoma
Glioblastoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014