S0001 RT and Carmustine With or Without O6BG in Patients With New Glioblastoma Multiforme or Gliosarcoma - Full Text View

Sponsor:	Southwest Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by (Responsible Party):	Southwest Oncology Group
ClinicalTrials.gov Identifier:	NCT00017147

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. O6-benzylguanine may help carmustine kill more tumor cells by making tumor cells more sensitive to the drug. It is not yet known whether radiation therapy and carmustine are more effective with or without O6-benzylguanine.

PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy plus carmustine with or without O6-benzylguanine in treating patients who have newly diagnosed glioblastoma multiforme or gliosarcoma.

Condition	Intervention	Phase
Malignant Neoplasms of Eye, Brain and Other Parts of Central Nervous System	Drug: carmustine Radiation: radiation therapy Drug: O6-Benzylguanine	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase III Study of Radiation Therapy (RT) and O6-Benzylguanine (O6-BG) Plus BCNU Versus RT and BCNU Alone for Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma

Resource links provided by NLM:

Genetics Home Reference related topics: retinoblastoma

MedlinePlus related topics: Cancer Eye Cancer

Drug Information available for: O(6)-Benzylguanine Carmustine

U.S. FDA Resources

Further study details as provided by Southwest Oncology Group:

Primary Outcome Measures:

Survival [ Time Frame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Progression-free survival [ Time Frame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 ] [ Designated as safety issue: No ]
Time to treatment failure [ Time Frame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5 ] [ Designated as safety issue: No ]
Toxicity [ Time Frame: assessed weekly for 42 weeks ] [ Designated as safety issue: Yes ]

Enrollment:	183
Study Start Date:	September 2001
Estimated Study Completion Date:	January 2012
Primary Completion Date:	May 2006 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: O6-BG + BCNU + Radiation Therapy O6-BG: 120 mg/m^2 IV over 1 hour on day 1 of each cycle BCNU: 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose. Radiation Therapy: 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.	Drug: carmustine 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG. 200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm. Radiation: radiation therapy 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions. Drug: O6-Benzylguanine 120 mg/m^2 IV over 1 hour on day 1 of each cycle Other Name: O6-BG
Active Comparator: BCNU + Radiation Therapy	Drug: carmustine 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG. 200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm. Radiation: radiation therapy 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.

Arms

Assigned Interventions

Experimental: O6-BG + BCNU + Radiation Therapy

O6-BG: 120 mg/m^2 IV over 1 hour on day 1 of each cycle BCNU: 40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose. Radiation Therapy: 5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.

Drug: carmustine

40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG.

200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm.

Radiation: radiation therapy

5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.

Drug: O6-Benzylguanine

120 mg/m^2 IV over 1 hour on day 1 of each cycle

Other Name: O6-BG

Active Comparator: BCNU + Radiation Therapy

Drug: carmustine

40 mg/m^2 IV over 1 hour on day 1 of each cycle 6 hours after O6-BG dose for experimental arm with O6=BG.

200 mg/m^2 IV over 1 hour on day 2 of each cycle for the active comparator arm.

Radiation: radiation therapy

5 days/week using one fraction per day and a dose of 180 cGy per fraction. Initial target volume is dose of 5040 cGy in 28 fractions with boost target volume of 1080 cGy in 6 fractions.

Detailed Description:

OBJECTIVES:

Compare the overall survival, failure-free survival, and progression-free survival of patients with newly diagnosed glioblastoma multiforme or gliosarcoma treated with radiotherapy and carmustine with or without O6-benzylguanine.
Compare the frequency and severity of toxic effects of these regimens in these patients.
Correlate the survival of these patients with the expression of O6-alkylguanine-DNA alkyltransferase.

OUTLINE: This is a randomized study. Patients are stratified according to age (under 50 vs 50 and over), prior surgery (biopsy only vs resection), and Zubrod performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients undergo radiotherapy daily 5 days a week over 7 weeks for a total of 34 fractions. Patients also receive chemotherapy comprising O6-benzylguanine IV over 1 hour followed 6 hours later by carmustine IV over 1 hour on day 1 of radiotherapy. Chemotherapy repeats every 6 weeks for a maximum of 7 courses in the absence of disease progression or unacceptable toxicity.
Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV as in arm I.

Patients are followed at week 48, every 4 months for 1 year, and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 375 patients will be accrued for this study within 5 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed glioblastoma multiforme or gliosarcoma
- Biopsy or surgical resection within the past 28 days
  - MRI* with gadolinium performed before registration
  - Patients who undergo a simple biopsy only require preoperative MRI* with gadolinium
No more than 2 noncontiguous tumor sites based on T2-weighted MRI (in 3 dimensions)*
No prior radiotherapy-delivered cephalad to the interspace between the seventh cervical and the first thoracic vertebral body NOTE: *If an MRI is not medically feasible, patients may have a CT scan with contrast

PATIENT CHARACTERISTICS:

Age:

18 and over

Performance status:

Zubrod 0-2

Life expectancy:

Not specified

Hematopoietic:

Absolute neutrophil count at least 3,000/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 8 g/dL

Hepatic:

Bilirubin no greater than 2 times upper limit of normal (ULN)
SGOT/SGPT no greater than 2 times ULN
Alkaline phosphatase no greater than 2 times ULN
PT/PTT no greater than 1.2 times ULN

Renal:

Not specified

Cardiac:

No severe cardiac disease, including any of the following:
- Uncontrolled arrhythmias or conduction defects
- Major problems with edema (e.g., residual swelling in the legs from deep vein thrombosis)
- Recent coronary artery disease
- Poorly controlled hypertension (i.e., diastolic blood pressure greater than 110 mm Hg and/or systolic blood pressure greater than 180 mm Hg)

Pulmonary:

DLCO at least 70% of predicted
No severe pulmonary disease

Other:

HIV negative
No severe Cushing's syndrome
No known allergies to any of the study drugs
No major psychiatric illness
No poorly controlled diabetes complicated by steroid treatment
No other medical illness that cannot be adequately controlled or that would preclude study participation
No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission
Not pregnant or nursing
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Not specified

Chemotherapy:

No prior chemotherapy
No other concurrent antitumor chemotherapy

Endocrine therapy:

No concurrent hormonal therapy except postmenopausal estrogen replacement therapy
Corticosteroids at stable or decreasing dose for tumor edema allowed

Radiotherapy:

See Disease Characteristics
No prior radiotherapy
No other concurrent radiotherapy (including intensity-modulated radiotherapy) to the index lesion(s)

Surgery:

See Disease Characteristics
No concurrent antitumor surgery

Other:

No other concurrent investigational drugs
No other concurrent antineoplastic drugs or therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00017147

Show 163 Study Locations

Sponsors and Collaborators

Southwest Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:	Deborah T. Blumenthal, MD	University of Utah
Study Chair:	Alexander M. Spence, MD	University of Washington
Study Chair:	Keith J. Stelzer, MD, PhD	Celilo Cancer Center at Mid-Columbia Medical Center

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Blumenthal DT, Wade M, Rankin CJ, et al.: MGMT methylation in newly-diagnosed glioblastoma multiforme (GBM): from the S0001 phase III study of radiation therapy (RT) and O6-benzylguanine, (O6BG) plus BCNU versus RT and BCNU alone for newly diagnosed GBM. [Abstract] J Clin Oncol 24 (Suppl 18): A-1512, 2006.

Quezado M, Ronchetti R, Rapkiewicz A, Santi M, Blumenthal DT, Rushing EJ. Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM. Clin Neuropathol. 2005 Jul-Aug;24(4):163-9.

Responsible Party:	Southwest Oncology Group
ClinicalTrials.gov Identifier:	NCT00017147 History of Changes
Other Study ID Numbers:	CDR0000068656, S0001, U10CA032102
Study First Received:	June 6, 2001
Last Updated:	January 12, 2012
Health Authority:	United States: Federal Government; United States: Food and Drug Administration

Keywords provided by Southwest Oncology Group:

adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma

Additional relevant MeSH terms:

Neoplasms
Eye Neoplasms
Glioblastoma
Gliosarcoma
Neoplasms by Site
Eye Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Carmustine
O(6)-benzylguanine
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on February 09, 2012