Radiation Therapy (RT) and Temozolomide (TMZ) in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
European Organisation for Research and Treatment of Cancer - EORTC
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT00304031
First received: March 15, 2006
Last updated: March 28, 2014
Last verified: March 2014

March 15, 2006
March 28, 2014
January 2006
February 2011   (final data collection date for primary outcome measure)
Overall Survival (OS) [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00304031 on ClinicalTrials.gov Archive Site
  • Progression-free Survival (PFS) [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
  • Comparison of OS and PFS in Patients With Unmethylated MGMT [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
  • Comparison of OS and PFS in Patients With Methylated MGMT [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
  • Correlation of Tumor MGMT Gene Methylation Status With Treatment Response [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: From start of treatment to end of follow-up ] [ Designated as safety issue: Yes ]
  • Correlation of PFS With OS at 6 Months [ Time Frame: From randomization to date of progression, death or last follow-up. Analysis occurs after 647 deaths have been reported. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
Not Provided
 
Radiation Therapy (RT) and Temozolomide (TMZ) in Treating Patients With Newly Diagnosed Glioblastoma or Gliosarcoma
Phase III Trial Comparing Conventional Adjuvant Temozolomide With Dose-Intensive Temozolomide in Patients With Newly Diagnosed Glioblastoma

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide may kill more tumor cells. It is not yet known which schedule of temozolomide when given together with radiation therapy is more effective in treating glioblastoma or gliosarcoma.

PURPOSE: This randomized phase III trial is studying two different schedules of temozolomide to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed glioblastoma or gliosarcoma.

OBJECTIVES:

Primary

  • Determine if dose-intensifying (increasing the "dose-density") the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by overall survival of patients with newly diagnosed glioblastoma or gliosarcoma.

Secondary

  • Determine if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.
  • Determine in patients with unmethylated MGMT (O6-methylguanine-DNA methyltransferase) if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
  • Determine in patients with methylated MGMT if dose-intensifying the adjuvant temozolomide component of the chemoradiation treatment enhances treatment efficacy (overall and progression-free survival) compared with patients receiving conventional temozolomide dosing.
  • Determine if there is an association between tumor MGMT gene methylation status and treatment response.
  • Compare and record the toxicities of the conventional and dose-intense chemotherapy regimens.
  • Evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to recursive partitioning analysis class (III vs IV vs V), MGMT gene methylation status (methylated vs nonmethylated vs indeterminate), and radiotherapy criteria used (standard vs revised European).

Patients undergo radiotherapy daily, 5 days per week for 6 weeks. Patients also receive oral temozolomide daily during radiotherapy. Patients are then randomized to 1 of 2 treatment arms. Randomized treatment begins approximately 4 weeks after completion of radiotherapy.

  • Arm I: Patients receive oral temozolomide on days 1-5.
  • Arm II: Patients receive oral temozolomide on days 1-21. In both arms, treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.

After completion of study treatment, patients are followed every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: This study requires 750 patients randomized to the two treatment arms.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: Concurrent temozolomide
    Daily oral temozolomide (75 mg/m2) up to 49 doses.
  • Radiation: Concurrent radiation therapy
    60 Gy in 2 Gy fractions
  • Drug: 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle
    Oral temozolomide on days 1-5 of a 28-day cycle. Dose starts at 150mg/m2 for first cycle, increases to 200mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.
  • Drug: 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle
    Oral temozolomide on days 1-21 of a 28-day cycle. Dose starts at 75mg/m2 for first cycle, increases to 100mg/m2 for subsequent cycles if no unacceptable toxicity. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease may receive up to 6 more courses of temozolomide.
  • Active Comparator: Conventional adjuvant TMZ
    Concurrent radiation therapy with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle.
    Interventions:
    • Drug: Concurrent temozolomide
    • Radiation: Concurrent radiation therapy
    • Drug: 100mg/m2 adjuvant temozolomide days 1 to 5 of 28 day cycle
  • Experimental: Dose-dense adjuvant TMZ
    Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Starting four weeks after completion of RT, 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle.
    Interventions:
    • Drug: Concurrent temozolomide
    • Radiation: Concurrent radiation therapy
    • Drug: 75mg/m2 adjuvant temozolomide days 1-21 of 28 day cycle
  • No adjuvant TMZ (not randomized )
    Concurrent radiation therapy (RT) with concurrent temozolomide (75 mg/m2) up to 49 doses. Not randomized to either adjuvant TMZ arm.
    Interventions:
    • Drug: Concurrent temozolomide
    • Radiation: Concurrent radiation therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
1173
Not Provided
February 2011   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Histologically proven glioblastoma or gliosarcoma

    • Diagnosis must be made by open biopsy or tumor resection

      • Diagnosis by stereotactic biopsy not allowed
    • Tumor must have supratentorial component
    • Contrast-enhanced MRI or CT scan (if MRI is not available) of the brain must be performed preoperatively and postoperatively prior to initiation of radiotherapy, within 28 days prior to study entry

      • If pre- and postoperative contrast-enhanced CT scans are obtained, must be of sufficient quality
  • Meets 1 of the following recursive positioning analysis classifications:

    • Class III

      • Age < 50 years and Karnofsky performance status (KPS) 90-100%
    • Class IV, meeting 1 of the following criteria:

      • Age < 50 years and KPS < 90%
      • Age ≥ 50 years and KPS 70-100% and underwent prior partial or total tumor resection with no worse than minor neurofunction impairment
    • Class V, meeting 1 of the following criteria:

      • Age ≥ 50 years and KPS 70-100% and underwent prior partial or total tumor resection with worse than minor neurofunction impairment
      • Age ≥ 50 years and KPS 70-100% and underwent prior tumor biopsy only
      • Age ≥ 50 years and KPS < 70%
  • Underwent most recent brain tumor surgery within the past 5 weeks
  • No recurrent or multifocal malignant gliomas
  • At least 1 block of tissue available for analysis of MGMT gene methylation status
  • No metastases detected below the tentorium or beyond the cranial vault

PATIENT CHARACTERISTICS:

  • KPS 60-100%
  • Absolute neutrophil count ≥ 1,500 cells/mm^3
  • Platelet count ≥ 100,000 cells/mm^3
  • Hemoglobin ≥ 10 g/dL (transfusion or other intervention allowed)
  • BUN (blood urea nitrogen) ≤ 25 mg/dL
  • Creatinine ≤ 1.7 mg/dL
  • Bilirubin ≤ 2.0 mg/dL
  • AST (aspartate aminotransferase ) and ALT (alanine amino transferase) ≤ 3 times normal
  • Negative pregnancy test
  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • No prior invasive malignancy (except for nonmelanomatous skin cancer) unless patient is disease free for ≥ 3 years (e.g., carcinoma in situ of the breast, oral cavity, or cervix allowed)
  • No severe, active comorbidity, including any of the following:

    • Unstable angina and/or congestive heart failure requiring hospitalization
    • Transmural myocardial infarction within the last 6 months
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    • Known hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
    • Known AIDS based upon current CDC (Center for Disease Control) definition
    • Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy
    • Active connective tissue disorders, such as lupus or scleredema that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity
  • No prior allergic reaction to temozolomide

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from the effects of surgery, postoperative infection, and other complications prior to study entry
  • No prior chemotherapy or radiosensitizers (including polifeprosan 20 with carmustine implant [Gliadel wafers] or any other intratumoral or intracavitary treatment) for cancers of the head and neck region

    • Prior chemotherapy for a different cancer is allowed
  • No prior radiotherapy to the head or neck (except for T1 glottic cancer) that would result in an overlap of radiation fields
  • No treatment on other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study
  • No concurrent prophylactic growth factors
  • No other concurrent investigational drugs
  • No concurrent surgical procedures for tumor debulking
  • No other concurrent chemotherapy, immunotherapy, or biologic therapy
  • No additional concurrent stereotactic boost radiotherapy
  • No concurrent intensity-modulated radiotherapy
  • Concurrent steroids allowed provided dose is stable or decreasing in the past 5 days
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States,   Canada
 
NCT00304031
RTOG-0525, CDR0000465183, EORTC-26052, EORTC-22053, NCI-2009-00731
Yes
Radiation Therapy Oncology Group
Radiation Therapy Oncology Group
  • National Cancer Institute (NCI)
  • European Organisation for Research and Treatment of Cancer - EORTC
Principal Investigator: Mark R. Gilbert, MD M.D. Anderson Cancer Center
Study Chair: Minesh P. Mehta, MD University of Wisconsin, Madison
Study Chair: Roger Stupp, MD Centre Hospitalier Universitaire Vaudois
Radiation Therapy Oncology Group
March 2014

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