Temozolomide and Radiation Therapy With or Without Cediranib Maleate in Treating Patients With Newly Diagnosed Glioblastoma

Adult Glioblastoma Clinical Trial

Official title:

Randomized, Phase II, Double-Blind, Placebo-Controlled Trial of Conventional Chemoradiation and Adjuvant Temozolomide Plus Cediranib Versus Conventional Chemoradiation and Adjuvant Temozolomide Plus Placebo in Patients With Newly Diagnosed Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01062425
• Other study ID #: NCI-2011-02012
• Secondary ID: NCI-2011-02012CD
• Status: Completed
• Phase: Phase 2
• Start date: February 26, 2010
• Est. completion date: May 20, 2022

Study information

• Verified date: May 2022
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies temozolomide, radiation therapy, and cediranib maleate to see how well they work compared with temozolomide, radiation therapy, and a placebo in treating patients with newly diagnosed glioblastoma (a type of brain tumor). 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. Radiation therapy uses high energy x-rays to kill tumor cells. Cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether temozolomide and radiation therapy are more effective when given with or without cediranib maleate in treating glioblastoma.

Description:

PRIMARY OBJECTIVES:

I. To determine if the addition of cediranib (cediranib maleate) to chemoradiation treatment enhances treatment efficacy as measured by the 6-month progression-free survival rate.

SECONDARY OBJECTIVES:

I. To determine if the addition of cediranib to chemoradiation treatment enhances treatment efficacy as measured by overall survival.

II. To determine if the addition of cediranib to chemoradiation treatment enhances treatment efficacy as measured by progression-free survival.

III. To determine if there is an association between tumor O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) gene methylation status and treatment response and outcome.

IV. To compare and record the toxicities of the cediranib + chemoradiation arm versus the chemoradiation arm.

V. To evaluate whether 6-month progression-free survival is associated with overall survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cediranib maleate orally (PO) once daily (QD) for 3 days. Patients then undergo radiation therapy (intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy) QD, 5 days a week, for 6 weeks and receive temozolomide PO QD and cediranib maleate PO QD for 6 weeks. Patients then receive temozolomide PO QD alone on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD for 3 days. Patients then undergo radiation therapy (intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy) QD, 5 days a week, for 6 weeks and receive temozolomide PO QD and placebo PO QD for 6 weeks. Patients then receive temozolomide PO QD alone on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 261
• Est. completion date: May 20, 2022
• Est. primary completion date: December 6, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or gliosarcoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration

• Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient size for analysis of MGMT status

• Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged

• Cavitron ultrasonic aspirator (CUSA)-derived material is not allowed; fresh frozen tumor tissue acquisition is encouraged

• Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis

• The tumor tissue must be sent as soon as possible to maximize the likelihood of eligibility; tumor tissue may not be submitted later than 28 days after the surgical procedure, because tissue analysis will not be able to be performed in time for treatment to commence by the mandatory 6-week post-surgery outer limit; submission of tissue earlier than 28 days post-surgery is highly recommended

• The tumor must have a supratentorial component

• History/physical examination, including neurologic examination, within 14 days prior to step 2 registration

• The patient must have recovered from the effects of surgery, post-operative infection, and other complications before step 2 registration

• A diagnostic contrast-enhanced magnetic resonance imaging (MRI) of the brain must be performed preoperatively and postoperatively prior to step 1 registration; the postoperative scan must be performed within 28 days prior to step 1 registration

• Documentation of steroid doses/concurrent medications within 14 days prior to step 2 registration

• Karnofsky performance status >= 70 within 14 days prior to step 2 registration

• Complete blood count (CBC)/differential obtained within 14 days prior to step 2 registration on study, with adequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) >= 1,800 cells/mm^3

• Platelets >= 100,000 cells/mm^3

• Hemoglobin >=10.0 g/dl (Note: The use of transfusion or other intervention to achieve hemoglobin (Hgb) >= 10.0 g/dl is acceptable)

• Adequate renal function, as defined below:

• Blood urea nitrogen (BUN) =< 30 mg/dl within 14 days prior to step 2 registration

• Creatinine =< 1.7 mg/dl within 14 days prior to step 2 registration

• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x normal range within 14 days prior to step 2 registration

• Systolic blood pressure =< 140 mm Hg AND diastolic pressure =< 90 mm Hg within 14 days prior to step 2 registration in the presence or absence of a stable regimen of anti-hypertensive therapy

• Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on warfarin confirmed by testing within 1 week of step 2 registration

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria:

• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin

• Patient must provide study specific informed consent prior to step 1 registration

• Women of childbearing potential and male participants must practice adequate contraception

• For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

• Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for >= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible)

• Recurrent or multifocal malignant gliomas

• Metastases detected below the tentorium or beyond the cranial vault

• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide or cediranib); prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted

• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization

• Transmural myocardial infarction within the last 6 months

• Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days of step 2 registration

• New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration

• History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for tumor resection

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol

• Active connective tissue disorders, such as lupus or scleroderma, which in the opinion of the treating physician may put the patient at high risk for radiation toxicity

• Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

• Pregnant or lactating women

• Prior allergic reaction to temozolomide

• Patients treated on any other therapeutic clinical protocols within 30 days prior to step 1 registration or during participation in the study

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib

• Mean QTc >500 msec (with Bazett's correction) in screening electrocardiogram or history of familial long QT syndrome or other significant ECG abnormality noted within 14 days of treatment

• Patients receiving concurrent vascular endothelial growth factor (VEGF) inhibitors are prohibited from participating in this study

• Patients must not be on enzyme-inducing anti-epileptic drugs (EIAED); patients may be on non-enzyme inducing anti-epileptic drugs (NEIAED) or may not be taking any anti-epileptic drugs; in patients who have previously been on EIAED there must be at least a 14 day period since the last dose of an EIAED before the first dose of cediranib

Related Conditions & MeSH terms

• Adult Glioblastoma
• Adult Gliosarcoma
• Glioblastoma
• Gliosarcoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3-dimensional conformal radiotherapy

Drug:
• Cediranib Maleate
Given PO

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Placebo Administration
Given PO

Drug:
• Temozolomide
Given PO

Locations

Country	Name	City	State
United States	Jefferson Abington Hospital	Abington	Pennsylvania
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Health System - Barberton Campus	Barberton	Ohio
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	The Kirklin Clinic at Acton Road	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical Center	Cincinnati	Ohio
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	University of Texas Medical Branch	Galveston	Texas
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Queen's Medical Center	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Sparrow Hospital	Lansing	Michigan
United States	Baptist Health Lexington	Lexington	Kentucky
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Yale University	New Haven	Connecticut
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	AdventHealth Orlando	Orlando	Florida
United States	Bay Medical Center	Panama City	Florida
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Lake Huron Medical Center	Port Huron	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	University Hospitals Portage Medical Center	Ravenna	Ohio
United States	University of Rochester	Rochester	New York
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	UH Seidman Cancer Center at Salem Regional Medical Center	Salem	Ohio
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Sparta Cancer Treatment Center	Sparta	New Jersey
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Carle Cancer Center	Urbana	Illinois
United States	Compass Oncology Vancouver	Vancouver	Washington
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Reading Hospital	West Reading	Pennsylvania
United States	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Cancer Treatment Center	Wooster	Ohio
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology, Radiation Therapy Oncology Group

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	6-month Progression-free Survival Rate	Six-month progression-free survival is the rate of patients who have NOT progressed at six months, where progressive disease is defined as any of the following: = 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. Progression will be determined by central review of MRI exams, assessed using MacDonald criteria for progression versus response on 2D T1 and T2 weighted images.	From randomization to 6 months.
Secondary	Overall Survival (OS)	OS will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested using the log rank test. Multivariate analyses with the Cox proportional hazard model for OS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.	From randomization to time of death due to any cause. Patients are followed until death. Analysis occurs after all patients have been potentially followed for six months.
Secondary	Progression-free Survival (PFS)	Progression-free survival time is defined as time from randomization to date of first progression or death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive without progression are censored at the date of last contact. Progression is defined as any of the following: = 25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration.	From randomization to time of first progression or death due to any cause. Patients are followed until death. Analysis occurs after all patients have been potentially followed for six months.
Secondary	Incidence of Grade 3+ Toxicities	The number of patients with reported grade 3 and higher treatment-related toxicities as assessed by Common Terminology Criteria for Adverse Events version 4.0	From randomization to six months.