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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01062425
First received: February 3, 2010
Last updated: February 4, 2015
Last verified: December 2014

February 3, 2010
February 4, 2015
February 2010
January 2015   (final data collection date for primary outcome measure)
Progression-free survival (PFS) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
The difference in PFS rates between the two treatments will be tested using Z test for two proportions. PFS will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested in the log rank test. Multivariate analyses with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.
6-month progression-free survival rate [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01062425 on ClinicalTrials.gov Archive Site
  • Overall survival (OS) [ Time Frame: From randomization to death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    OS will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested in 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.
  • PFS [ Time Frame: From date of randomization to the date of first progression or death, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]
    The difference in PFS rates between the two treatments will be tested using Z test for two proportions. PFS will be estimated using the Kaplan-Meier method and differences between treatment arms will be tested in the log rank test. Multivariate analyses with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.
  • Incidence of grade 3+ toxicities, as assessed using Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Differences in observed severities of toxicities (grade 3+) between groups will be tested using a chi square test.
  • MGMT methylation status [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Statistical analysis will also be performed to identify the effect of MGMT methylation status on overall and progression-free survival.
  • Overall survival (OS) [ Designated as safety issue: No ]
  • Progression-free survival (PFS) [ Designated as safety issue: No ]
  • Treatment-related toxicity as measured by NCI CTCAE v4.0 [ Designated as safety issue: Yes ]
  • Association between OS and change in markers [ Designated as safety issue: No ]
  • Association between PFS and change in markers [ Designated as safety issue: No ]
  • Association between OS and PFS and the T0 value of markers [ Designated as safety issue: No ]
  • Relationship between [18F]FLT Ki and K1 and markers of tumor proliferation, both cross-sectionally and longitudinally [ Designated as safety issue: No ]
  • Reproducibility of [18F]FLT Ki and K1 measurements [ Designated as safety issue: No ]
  • Association between OS and PFS and the change in the "vascular normalization index" between T0 and T1 [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Temozolomide and Radiation Therapy With or Without Cediranib Maleate in Treating Patients With Newly Diagnosed Glioblastoma
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

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Drug: Cediranib Maleate
    Given PO
    Other Names:
    • AZD2171
    • Recentin
  • Drug: Temozolomide
    Given PO
    Other Name: TMZ
  • Other: Placebo
    Given PO
    Other Name: PLCB
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo intensity-modulated radiation therapy
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Radiation: 3-Dimensional Conformal Radiation Therapy
    Undergo 3-dimensional conformal radiotherapy
    Other Names:
    • 3D-CRT
    • Conformal Therapy
    • Radiation Conformal Therapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Experimental: Arm I (cediranib maleate, temozolomide, radiation therapy)
    Patients receive cediranib maleate PO once 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.
    Interventions:
    • Drug: Cediranib Maleate
    • Drug: Temozolomide
    • Radiation: Intensity-Modulated Radiation Therapy
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Other: Laboratory Biomarker Analysis
  • Active Comparator: Arm II (placebo, temozolomide, radiation therapy)
    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.
    Interventions:
    • Drug: Temozolomide
    • Other: Placebo
    • Radiation: Intensity-Modulated Radiation Therapy
    • Radiation: 3-Dimensional Conformal Radiation Therapy
    • Other: Laboratory Biomarker Analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
261
Not Provided
January 2015   (final data collection date for primary outcome measure)

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
    • CUSA (Cavitron ultrasonic aspirator)-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
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01062425
NCI-2011-02012, NCI-2011-02012, CDR0000665163, RTOG 0837, RTOG-0837, U10CA021661, U10CA180868
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Tracy Batchelor NRG Oncology
National Cancer Institute (NCI)
December 2014

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