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

Brain and Central Nervous System Tumors Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00004259
• Other study ID #: RTOG-9813
• Secondary ID: CDR0000067512ECO
• Status: Completed
• Phase: Phase 3
• Start date: June 2000
• Est. completion date: May 14, 2018

Study information

• Verified date: August 2019
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 230
• Est. completion date: May 14, 2018
• Est. primary completion date: February 1, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Astrocytoma
• Brain and Central Nervous System Tumors
• Central Nervous System Neoplasms
• Nervous System Neoplasms

Intervention

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).
• 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.
• 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).
• 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).
• 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
• 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

Locations

Country	Name	City	State
United States	Akron City Hospital	Akron	Ohio
United States	McFarland Clinic, PC	Ames	Iowa
United States	Theda Care Cancer Institute	Appleton	Wisconsin
United States	Mission Hospitals - Memorial Campus	Asheville	North Carolina
United States	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Deaconess Billings Clinic - Downtown	Billings	Montana
United States	St. Joseph Medical Center	Bloomington	Illinois
United States	Lynn Regional Cancer Center at Boca Raton Community Hospital - Main Center	Boca Raton	Florida
United States	Graham Hospital	Canton	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas
United States	Enloe Cancer Center at Enloe Medical Center	Chico	California
United States	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio
United States	Case Comprehensive Cancer Center	Cleveland	Ohio
United States	John B. Amos Cancer Center	Columbus	Georgia
United States	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas
United States	CCOP - Duluth	Duluth	Minnesota
United States	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas
United States	Eureka Community Hospital	Eureka	Illinois
United States	North Bay Cancer Center	Fairfield	California
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Galesburg Clinic	Galesburg	Illinois
United States	Galesburg Cottage Hospital	Galesburg	Illinois
United States	InterCommunity Cancer Center of Western Illinois	Galesburg	Illinois
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Mason District Hospital	Havana	Illinois
United States	Hopedale Medical Complex	Hopedale	Illinois
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	Florida Oncology Associates at Southside Cancer Center	Jacksonville	Florida
United States	Integrated Community Oncology Network	Jacksonville Beach	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Good Samaritan Cancer Center at Good Samaritan Hospital	Kearney	Nebraska
United States	Kewanee Hospital	Kewanee	Illinois
United States	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Southwest Medical Center	Liberal	Kansas
United States	McDonough District Hospital	Macomb	Illinois
United States	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin
United States	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey
United States	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin
United States	Mobile Infirmary Medical Center	Mobile	Alabama
United States	Cancer Center of Kansas, PA - Newton	Newton	Kansas
United States	BroMenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center	Normal	Illinois
United States	Methodist Cancer Center at Methodist Hospital - Omaha	Omaha	Nebraska
United States	Florida Oncology Associates	Orange Park	Florida
United States	Community Hospital of Ottawa	Ottawa	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois
United States	Florida Cancer Center - Palatka	Palatka	Florida
United States	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas
United States	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois Valley Community Hospital	Peru	Illinois
United States	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania
United States	Arizona Oncology Services Foundation	Phoenix	Arizona
United States	Allegheny Cancer Center at Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas
United States	Perry Memorial Hospital	Princeton	Illinois
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Reading Hospital and Medical Center	Reading	Pennsylvania
United States	Lipson Cancer and Blood Center at Rochester General Hospital	Rochester	New York
United States	Flagler Cancer Center	Saint Augustine	Florida
United States	Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford	Salem	Ohio
United States	Cancer Center of Kansas, PA - Salina	Salina	Kansas
United States	Latter Day Saints Hospital	Salt Lake City	Utah
United States	Guthrie Cancer Center at Guthrie Clinic Sayre	Sayre	Pennsylvania
United States	St. Margaret's Hospital	Spring Valley	Illinois
United States	Valley Cancer Center	Spring Valley	Illinois
United States	St. John's Regional Health Center	Springfield	Missouri
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	Cotton-O'Neil Cancer Center	Topeka	Kansas
United States	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma
United States	Solano Radiation Oncology Center	Vacaville	California
United States	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey
United States	Fox Chase Virtua Health Cancer Program at Virtua West Jersey	Voorhees	New Jersey
United States	University of Wisconcin Cancer Center at Aspirus Wausau Hospital	Wausau	Wisconsin
United States	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas
United States	Associates in Womens Health, PA - North Review	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas
United States	CCOP - Wichita	Wichita	Kansas
United States	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas
United States	Cancer Treatment Center	Wooster	Ohio

Sponsors (5)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	Eastern Cooperative Oncology Group, National Cancer Institute (NCI), North Central Cancer Treatment Group, NRG Oncology

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 temozolom — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	(Phase III) Overall Survival (OS)	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.	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.
Primary	(Phase I) Number of Subjects With Dose Limiting Toxicities (DLT) on the Two Pilot Arms	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.	From start of treatment to 3 months
Secondary	(Phase III) Time to Tumor Progression (TTP)	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.	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.
Secondary	(Phase III) Number of Patients With Grade 3 or Higher Toxicity	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.	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.
Secondary	(Phase III) Survival Time by MGMT Status	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. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.	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.
Secondary	(Phase III) Progression-free Survival by MGMT Status	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. Progression-free survival time is defined as time from randomization to date of progression or 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. Tumor tissue samples were analyzed for methylation status of methyl guanine methyl transferase (MGMT), classified as methylated vs. unmethylated.	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.