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

Glioblastoma Clinical Trial

— Methusalem  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01502241
• Other study ID #: NOA-08
• Secondary ID: 05-01
• Status: Completed
• Phase: Phase 3
• First received: December 24, 2011
• Last updated: December 29, 2011
• Start date: January 2005
• Est. completion date: November 2011

Study information

• Verified date: December 2011
• Source: Heidelberg University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 412
• Est. completion date: November 2011
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 65 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Anaplastic Astrocytoma
• Astrocytoma
• Glioblastoma

Intervention

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.

Locations

Country	Name	City	State
Germany	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 Frankfurt	Frankfurt	Hessen
Germany	University of Freiburg	Freiburg
Germany	University of Hamburg	Hamburg
Germany	University of Hannover	Hannover
Germany	University of Hannover II	Hannover
Germany	University of Heidelberg	Heidelberg	Baden-Württemberg
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
Switzerland	University of Zurich	Zurich

Sponsors (1)

Lead Sponsor	Collaborator
Heidelberg University

Countries where clinical trial is conducted

Germany,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	12 months	No
Secondary	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).	12 months	Yes
Secondary	Best response	Response is assessed according MacDonald Criteria based on regular 3-monthly MRI.	Within the first 8 months after surgery	No
Secondary	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.	At 12 months	No