Comparison of Two Dosing Regimens of Temozolomide in Patients With Progressive or Recurrent Glioblastoma (DIRECTOR)

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

For patients with progressive or recurrent glioblastoma there is no standard therapy. One strategy is re-exposure to temozolomide in a higher dose. This increase in dosing can be done by 2 regimens. Aim of this study is to compare these 2 dosing regimens concerning toxicity. In study arm A patients receive temozolomide for one week, followed by a week without temozolomide. In study arm B patients receive temozolomide for three weeks, followed by a week without temozolomide. The regimen that is less toxic will be selected for further evaluations.

Study Overview

• Status: Completed
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Temozolomide in both arms; Drug: Temozolomide in both arms

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Landesnervenklinik Wagner-Jauregg
  • Wien, Austria, 1090
    • Medical University Vienna, Department of Internal Medicine I
• Germany
  • Berlin, Germany, 13353
    • Charite, Department of Neurosurgery
  • Bochum, Germany, 44892
    • Knappschaftskrankenhaus, Department of Neurology
  • Bonn, Germany, 53105
    • University Hospital Bonn, Department of Neurology
  • Düsseldorf, Germany, 40001
    • University Hospital Düsseldorf
  • Frankfurt, Germany, 60528
    • Klinikum der Johann-Wolfgang von Goethe-Universität, Dr. Senckenbergisches Institut für Neuroonkologie, Zentrum für Neurologie und Neurochirurgie
  • Freiburg, Germany, 79106
    • University Hospital Freiburg
  • Heidelberg, Germany, 69120
    • University Hospital Heidelberg, Department of Neurooncology
  • Homburg/ Saar, Germany, 66421
    • Saarland University, Department of Neurosurgery
  • Köln, Germany, 50937
    • Klinik für Allgemeine Neurochirurgie
  • Leipzig, Germany, 04103
    • Klinik und Poliklinik für Neurochirurgie
  • Munich, Germany, 81377
    • Ludwig Maximilians University of Munich , Grosshadern Hospital, Department of Neurosurgery
  • Regensburg, Germany, 93053
    • University of Regensburg, Department of Neurology
• Switzerland
  • Lausanne, Switzerland
    • Centre Hospitalier Universitaire Vaudois and University of Lausanne
  • CH
    • Zurich, CH, Switzerland, 8091
      • University Hospital Zurich, Department of Neurology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Progressive or recurrent glioblastoma documented by MRI no earlier than 180 days after first surgery for glioblastoma and no earlier than 90 days after completion of radiotherapy.
• Histological diagnosis of glioblastoma
• Tissue available for the determination of MGMT promoter methylation in the primary tumor or from the recurrent tumor if a patient undergoes a surgical procedure at recurrence prior to study entry.
• Prior treatment with temozolomide administered concomitantly with radiotherapy and at least for two cycles (5/28) as an adjuvant treatment
• Informed consent
• Age 18-80 years
• Karnofsky performance score > 50%
• Neutrophil counts > 1 500/µl
• Platelet counts > 100 000/µl
• Hemoglobin > 10 g/dl
• Serum creatinin < 1.5-fold upper normal range
• ASAT or ALAT < 3-fold upper normal range unless attributed to anticonvulsants
• Alkaline phosphatase < 3-fold upper normal range
• Women with childbearing potential must have a negative serum pregnancy test ≤14 days prior to study enrollment
• Willingness to apply contraception according to local requirements (as stated in patient information)

Exclusion Criteria:

• 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.
• Treatment with any chemotherapy other than temozolomide according to the schedule of the EORTC NCIC trial (Stupp et al. N Engl J Med 2005;352:987-996) except that an adjuvant starting dose of 200 mg/m2 and more than 6 cycles of adjuvant temozolomide are allowed
• Prior systemic or local treatment with DNA-damaging agents, tyrosine kinase inhibitors or anti-angiogenic agents for any cancer
• Allergy to or other intolerability of temozolomide
• Unable to undergo MRI
• 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
• HIV infection
• Pregnancy
• Breast feeding
• Treatment within in any other clinical trial parallel to the treatment phase of the current study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: one week on one week off; One week on temozolomide is followed by a week without temozolomide.	Drug: Temozolomide in both arms; initial dose 120 mg/m2 in arm A; Other Names: Temodal; Drug: Temozolomide in both arms; initial dose 80 mg/m2 in arm B; Other Names: Temodal
Experimental: three weeks on, one week off; Temozolomide is given over 3 weeks, followed by a week without temozolomide.	Drug: Temozolomide in both arms; initial dose 120 mg/m2 in arm A; Other Names: Temodal; Drug: Temozolomide in both arms; initial dose 80 mg/m2 in arm B; Other Names: Temodal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Median time to treatment failure. Treatment failure is reached (i) upon tumor progression as outlined in protocol (ii) if treatment has to be terminated due to toxicity or (iii) if the patient dies for any reason.	up to one year

Secondary Outcome Measures

Outcome Measure	Time Frame
progression free survival	up to two years

Collaborators and Investigators

• Sponsor: Prof. Dr. Wolfgang Wick
• Collaborators: Essex Pharma GmbH
• Investigators: Study Chair: Michael Weller, Prof. Dr., University of Zurich

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: July 16, 2009
• First Submitted That Met QC Criteria: July 16, 2009
• First Posted (Estimate): July 17, 2009

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: August 13, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: temozolomide; progressive or recurrent glioblastoma; dose intensification; comparison of two dosing regimens
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: DIRECTOR; 2008-006871-60 (EudraCT Number); ISRCTN68738654 (Registry Identifier: controlled-trials)