Clinical trial NCT01062425: Temozolomide and Radiation Therapy With or Without Cediranib Maleate in Treating Patients With Newly Diagnosed Glioblastoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Glioblastoma
Adult Gliosarcoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: NRG Oncology
name: Radiation Therapy Oncology Group
First posted: 2010-02-04
Enrollment: 261
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 6-month Progression-free Survival Rate
timeFrame: From randomization to 6 months.
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 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.
measure: Progression-free Survival (PFS)
timeFrame: 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.
measure: Incidence of Grade 3+ Toxicities
timeFrame: From randomization to six months.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Birmingham
country: United States
facility: The Kirklin Clinic at Acton Road
state: Alabama
city: Scottsdale
country: United States
facility: Arizona Oncology Services Foundation
state: Arizona
city: Tucson
country: United States
facility: Banner University Medical Center - Tucson
state: Arizona
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: Saint Joseph Hospital - Orange
state: California
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Panama City
country: United States
facility: Bay Medical Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Honolulu
country: United States
facility: Queen's Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Honolulu
country: United States
facility: The Cancer Center of Hawaii-Liliha
state: Hawaii
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Fort Wayne
country: United States
facility: Radiation Oncology Associates PC
state: Indiana
city: Fort Wayne
country: United States
facility: Parkview Hospital Randallia
state: Indiana
city: Indianapolis
country: United States
facility: IU Health Methodist Hospital
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Prairie Village
country: United States
facility: Kansas City NCI Community Oncology Research Program
state: Kansas
city: Lexington
country: United States
facility: Baptist Health Lexington
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Scarborough
country: United States
facility: Maine Medical Center- Scarborough Campus
state: Maine
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Clinton Township
country: United States
facility: Henry Ford Macomb Hospital-Clinton Township
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Detroit
country: United States
facility: Ascension Saint John Hospital
state: Michigan
city: Flint
country: United States
facility: Genesys Regional Medical Center-West Flint Campus
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Lansing
country: United States
facility: Sparrow Hospital
state: Michigan
city: Pontiac
country: United States
facility: Saint Joseph Mercy Oakland
state: Michigan
city: Port Huron
country: United States
facility: Lake Huron Medical Center
state: Michigan
city: Saginaw
country: United States
facility: Ascension Saint Mary's Hospital
state: Michigan
city: Warren
country: United States
facility: Saint John Macomb-Oakland Hospital
state: Michigan
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Sparta
country: United States
facility: Sparta Cancer Treatment Center
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Novant Health Forsyth Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Summa Health System - Akron Campus
state: Ohio
city: Akron
country: United States
facility: Cleveland Clinic Akron General
state: Ohio
city: Barberton
country: United States
facility: Summa Health System - Barberton Campus
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Center-UC Medical Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Ravenna
country: United States
facility: University Hospitals Portage Medical Center
state: Ohio
city: Salem
country: United States
facility: UH Seidman Cancer Center at Salem Regional Medical Center
state: Ohio
city: West Chester
country: United States
facility: University of Cincinnati Cancer Center-West Chester
state: Ohio
city: Wooster
country: United States
facility: Cancer Treatment Center
state: Ohio
city: Tulsa
country: United States
facility: Natalie Warren Bryant Cancer Center at Saint Francis
state: Oklahoma
city: Clackamas
country: United States
facility: Clackamas Radiation Oncology Center
state: Oregon
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital and Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Abington
country: United States
facility: Jefferson Abington Hospital
state: Pennsylvania
city: Bethlehem
country: United States
facility: Saint Luke's University Hospital-Bethlehem Campus
state: Pennsylvania
city: Bryn Mawr
country: United States
facility: Bryn Mawr Hospital
state: Pennsylvania
city: Dunmore
country: United States
facility: Northeast Radiation Oncology Center
state: Pennsylvania
city: Greensburg
country: United States
facility: UPMC Cancer Centers - Arnold Palmer Pavilion
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Paoli
country: United States
facility: Paoli Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Washington
country: United States
facility: UPMC Washington Hospital Radiation Oncology
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Spartanburg
country: United States
facility: Spartanburg Medical Center
state: South Carolina
city: Rapid City
country: United States
facility: Rapid City Regional Hospital
state: South Dakota
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital Center
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Saint George
country: United States
facility: Saint George Regional Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists-Salt Lake City
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center - Montlake
state: Washington
city: Vancouver
country: United States
facility: Compass Oncology Vancouver
state: Washington
city: Wheeling
country: United States
facility: Wheeling Hospital/Schiffler Cancer Center
state: West Virginia
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Wausau
country: United States
facility: Aspirus Regional Cancer Center
state: Wisconsin
Study officials:
affiliation: NRG Oncology
name: Tracy T Batchelor
role: PRINCIPAL_INVESTIGATOR
References: