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Radiation Therapy Combined With Chemotherapy in Treating Patients With Anaplastic Astrocytoma or Mixed Gliomas

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: NCT00004259
Recruitment Status : Active, not recruiting
First Posted : January 27, 2003
Results First Posted : November 13, 2017
Last Update Posted : November 13, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

January 28, 2000
January 27, 2003
May 25, 2017
November 13, 2017
November 13, 2017
June 2000
February 1, 2015   (Final data collection date for primary outcome measure)
  • (Phase III) Overall Survival (OS) [ Time Frame: From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. ]
    Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact. Per the protocol, the pilot arms were not included in the Phase III analyses.
  • (Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms [ Time Frame: From start of treatment to 3 months ]
    Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the adverse event (AE). The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Dose limiting toxicity (DLT) was defined as grade 3+ pulmonary toxicity, grade 4+ thrombocytopenia (< 25,000 for 5 days), neutropenia (< 500/microl for 7 days), or neutropenia of any duration with fever requiring hospital admission after one dose reduction of 50% in BCNU. A 20% rate of grade 3+ pulmonary toxicities or a 40% rate of grade 4+ thrombocytopenia and neutropenia was considered unacceptable for a treatment arm combining RT, TMZ, and BCNU.
Not Provided
Complete list of historical versions of study NCT00004259 on ClinicalTrials.gov Archive Site
  • (Phase III) Time to Tumor Progression (TTP) [ Time Frame: From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. ]
    Three-year rate is reported. Progression is defined as a radiographic increase in size of the lesion by > 25%, recurrence of the study lesion, or the development of new lesions, confirmed by imaging. Time to tumor progression was estimated using the cumulative incidence function (CIF) on tumor progression, with death as a competing risk. Per the protocol, the pilot arms were not included in the Phase III analyses.
  • (Phase III) Number of Patients With Grade 3 or Higher Toxicity [ Time Frame: From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. ]
    Adverse events were graded using CTCAE v2.0. Grade refers to the severity of the AE. The CTCAE v2.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. The number of patients with grade or higher toxicity was calculated overall and for non-hematologic toxicity only. Per the protocol, the pilot arms were not included in the Phase III analyses.
  • (Phase III) Correlation of Molecular Analyses With Overall Survival and Time to Tumor Progression [ Time Frame: From randomization to date of death. Patients are followed until death. Analysis occurs after 155 deaths have been reported, estimated at 5.5 years from the study opening. ]
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Radiation Therapy Combined With Chemotherapy in Treating Patients With Anaplastic Astrocytoma or Mixed Gliomas
A Phase III Randomized Study (Phase I Closed) of Radiation Therapy and Temozolomide Versus Radiation Therapy and Nitrosourea for Anaplastic Astrocytoma And Mixed Anaplastic Oligoastrocytoma (Astrocytoma Dominant)

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy, such as temozolomide, carmustine, and lomustine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining radiation therapy with chemotherapy may kill more tumor cells.

PURPOSE: This randomized phase III trial is studying radiation therapy and temozolomide to see how well they work compared to radiation therapy and carmustine or lomustine in treating patients with anaplastic astrocytoma or mixed gliomas.

OBJECTIVES:

  • Compare the overall survival and time to tumor progression in patients with anaplastic astrocytoma or mixed gliomas treated with radiotherapy combined with temozolomide vs carmustine or lomustine vs temozolomide and carmustine (arm discontinued as of 8/15/02).
  • Compare the relative toxic effects of these regimens in these patients.
  • Correlate molecular analyses with overall survival and time to tumor progression in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (under 50 vs 50 and over), Karnofsky performance status (60-80% vs 90-100%), and prior surgery (biopsy only vs resection).

Phase I

  • Pilot Arms I and II: Prior to initiating the randomization to 1 of 3 treatment arms in phase III, Patients are accrued to Arm III regimen to determine tolerability.

Phase III

  • Patients are randomized to 1 of 2 treatment arms (3rd arm was dropped).

    • Arm I: Patients undergo radiotherapy 5 days a week for 6 weeks. Patients receive oral temozolomide on days 1-5 of the first week of radiotherapy. Chemotherapy repeats every 4 weeks for a total of 12 courses.
    • Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 1-2 hours on days 1-3 of the first week of radiotherapy and a second course on days 56-58. Chemotherapy repeats every 8 weeks for a total of 6 courses.
    • Arm III (dropped, did not open): Patients undergo radiotherapy as in arm I. Patients receive carmustine IV or lomustine IV over 3 hours on day 5 and oral temozolomide (2 hours after completion of carmustine or lomustine infusion) on days 1-5 of the first week of radiotherapy. Combination chemotherapy repeats every 8 weeks for 6 courses.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: Phase I: 30 patients; Phase III: 454 patients (227 per treatment arm) within 4 years.

Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Phase I (sequential) followed by phase III (parallel)
Masking: None (Open Label)
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Drug: BCNU 80mg/m2
    BCNU 80 mg/m2 will be administered as an intravenous infusion on days 1, 2, and 3 of the first week of radiotherapy and on days 56, 57, and 58, then every eight weeks for four more cycles for a total of 6 cycles (maximum BCNU dose 1440 mg/m2).
  • Drug: TMZ 200mg/m2
    200 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat every 28 days for a total of 12 cycles.
  • Radiation: radiation therapy
    1.8 Gy fractions (to isocenter), 1 fraction per day, 5 days per week to a dose of 59.4 Gy in 33 fractions.
  • Drug: CCNU
    CCNU at 130 mg/m2 orally every 8 weeks for a total of 6 cycles. Administered on day 1 of the first week of radiotherapy and on day 56, then administered every 8 weeks for four more cycles for a total of 6 cycles.
  • Drug: BCNU 150mg/m2
    BCNU 150 mg/m2 will be administered as an intravenous infusion on day 5 of radiotherapy, and it will be repeated every eight weeks for a total of six cycles (maximum total BCNU dose 900 mg/m2).
  • Drug: BCNU 200mg/m2
    BCNU 200 mg/m2 will be administered as an intravenous infusion on day 1 of radiotherapy and will be repeated every six weeks for a total of 6 cycles (maximum BCNU dose 1200 mg/m2).
  • Drug: TMZ 150mg/m2 six 6-week cycles
    150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 6-week cycles
  • Drug: TMZ 150mg/m2 six 8-week cycles
    150 mg/m2 orally on days 1-5 of the first week of radiotherapy. Repeat for a total of six 8-week cycles
  • Experimental: Radiation therapy + temozolomide (TMZ)
    Radiation therapy (RT) for 6 weeks concurrent with and followed by TMZ 200mg/m2 for twelve 28-day cycles
    Interventions:
    • Drug: TMZ 200mg/m2
    • Radiation: radiation therapy
  • Active Comparator: RT + BCNU/CCNU
    Radiation therapy for 6 weeks concurrent with and followed by BCNU 80mg/m2 or CCNU 130 mg/m2 for six 8-week cycles
    Interventions:
    • Drug: BCNU 80mg/m2
    • Radiation: radiation therapy
    • Drug: CCNU
  • Experimental: Pilot Arm #1: RT+TMZ+BCNU
    Radiation therapy for 6 weeks concurrent with and followed by BCNU 200mg/m2 and TMZ 150mg/m2 six 6-week cycles
    Interventions:
    • Radiation: radiation therapy
    • Drug: BCNU 200mg/m2
    • Drug: TMZ 150mg/m2 six 6-week cycles
  • Experimental: Pilot Arm #2: RT+TMZ+BCNU
    Radiation therapy for 6 weeks concurrent with and followed by BCNU 150mg/m2 and TMZ 150mg/m2 six 8-week cycles
    Interventions:
    • Radiation: radiation therapy
    • Drug: BCNU 150mg/m2
    • Drug: TMZ 150mg/m2 six 8-week cycles
Chang SM, Seiferheld W, Curran W, Share R, Atkins J, Choucair A, Kresl J, Thoron L, Cairncross G, Gilbert M, Bahary JP, Dolinskas C, Louis DN, Bushunow P, Buckner J, Barger G, Mehta M. Phase I study pilot arms of radiotherapy and carmustine with temozolomide for anaplastic astrocytoma (Radiation Therapy Oncology Group 9813): implications for studies testing initial treatment of brain tumors. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1122-6.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
230
Not Provided
February 1, 2015   (Final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Histologically proven unifocal anaplastic astrocytoma or mixed gliomas, including the following:

    • Anaplastic astrocytoma
    • Mixed oligodendroglial/astrocytic tumors

      • Oligodendroglial component must be no greater than 25%
  • No vascular proliferation and necrosis
  • Increased cellularity, pleomorphism, and nuclear atypia allowed
  • No tumor predominantly located in the posterior fossa (i.e., brainstem or cerebellum)
  • Patients with prior biopsy proven low grade astrocytoma who now have anaplastic astrocytoma and have had no prior radiotherapy or chemotherapy also eligible
  • Study therapy must begin within 6 weeks of diagnosis
  • No spinal cord tumors, spinal drop metastases, or metastases to noncontiguous meninges

    • Pathologic evidence of local meningeal infiltration by underlying tumor allowed

PATIENT CHARACTERISTICS:

Age:

  • 18 and over

Performance status:

  • Karnofsky 60-100%

Life expectancy:

  • At least 1 year

Hematopoietic:

  • Hemoglobin at least 10 g/dL
  • Absolute neutrophil count at least 1,500/mm^3
  • Platelet count at least 150,000/mm^3

Hepatic:

  • Bilirubin less than 2 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) less than 2 times ULN
  • Alkaline phosphatase less than 2 times ULN

Renal:

  • Blood urea nitrogen no greater than 25 mg/dL
  • Creatinine less than 1.5 times normal

Pulmonary:

  • No pre-existing lung disease that, in the investigator's opinion, would preclude administration of carmustine or lomustine or completion of therapy

Other:

  • No other major medical illness or psychiatric impairment that would preclude study compliance
  • No other malignancy within the past 5 years except nonmelanomatous skin cancer or carcinoma in situ of the cervix
  • No known hypersensitivity to 1 of the components of carmustine, lomustine, temozolomide, dacarbazine, or any other nitrosourea
  • No active infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

  • No prior biologic therapy

Chemotherapy:

  • See Disease Characteristics
  • No prior chemotherapy

Endocrine therapy:

  • Not specified

Radiotherapy:

  • See Disease Characteristics
  • No prior radiotherapy to brain or head and neck

Surgery:

  • Not specified

Other:

  • No other concurrent anticancer treatment for anaplastic astrocytoma until a recurrence is detected
Sexes Eligible for Study: All
18 Years to 120 Years   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
Canada
 
NCT00004259
RTOG-9813
CDR0000067512
ECOG-R9813
NCCTG-RTOG-9813
Yes
Not Provided
Not Provided
Radiation Therapy Oncology Group
Radiation Therapy Oncology Group
  • National Cancer Institute (NCI)
  • North Central Cancer Treatment Group
  • Eastern Cooperative Oncology Group
  • NRG Oncology
Study Chair: Susan M. Chang, MD University of California, San Francisco
Study Chair: Kurt A. Jaeckle, MD Mayo Clinic
Study Chair: Peter Bushunow, MD Lipson Cancer and Blood Center at Rochester General Hospital
Radiation Therapy Oncology Group
October 2017

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