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: July 22, 2014
Last verified: December 2013

February 3, 2010
July 22, 2014
February 2010
January 2015   (final data collection date for primary outcome measure)
6-month PFS as assessed using MacDonald criteria and Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Standard MRI exams will be submitted to the ACRIN Imaging Core Laboratory for determination of progression-free survival by two readers. Images will be assessed using MacDonald criteria for progression versus response on 2D T1 and T2 weighted images. The primary measure of response will be by serial measures of the product of the two largest cross-sectional diameters. Progression (P): A > 25% increase in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period.
6-month progression-free survival rate [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01062425 on ClinicalTrials.gov Archive Site
  • OS as assessed using the Kaplan-Meier method [ Time Frame: From randomization to death due to any cause, assessed up to 2 years ] [ Designated as safety issue: No ]

    Differences between treatment arms will be tested in the log rank test. Multivariate analyses with the Cox proportional hazard model will be performed for OS and PFS with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.

    The covariates evaluated for the multivariate models are: assigned protocol treatment, MGMT methylation status, RPA risk class and other prognostic factors. Proportional hazard assumptions will be checked using different graphical or time-varying coefficients testing methods.

  • PFS as assessed using the Kaplan-Meier method [ Time Frame: From date of randomization to the date of first progression or death, assessed up to 2 years ] [ Designated as safety issue: No ]
    Differences between treatment arms will be tested in the log rank test. Multivariate analyses with the Cox proportional hazard model will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.
  • Incidence of treatment-related toxicity, compared between the cediranib + chemoradiation arm and the chemoradiation arm as assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and chi square testing [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    Hematological toxicities: grade 4 neutropenia (ANC including bands < 0.5 x 109/L); grade ≥ 3 thrombocytopenia. Renal toxicity: Serum creatinine > 2.0 x ULN. Hepatic Toxicity: ≥ grade 3 bilirubin elevation; ≥ grade 3 AST or ALT elevation for any duration. All other clinically significant CTCAE, v3.0
  • 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 is studying 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. 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 to chemoradiation treatment enhances treatment efficacy as measured by the 6-month progression-free survival rate.

II. To assess the association between overall survival and change in each of the following markers: Ktrans, gradient echo CBV, and [18F]FLT Ki and K1, from T0 to T1.

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 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.

VI. To assess the association between progression-free survival and change in each of the following markers: Ktrans, gradient echo CBV, and [18F]FLT Ki and K1 from T0 to T1.

VII. To assess the association between overall survival and change in each of the following markers: Ktrans, gradient echo CBV, and [18F]FLT Ki and K1 from T1 to T3.

VIII. To assess the association between progression-free survival and change in each of the following markers: Ktrans, gradient echo CBV, and [18F]FLT Ki and K1, from T1 to T3.

IX. To assess the association between overall and progression-free survival and the T0 values of each of the following markers: Ktrans, gradient echo CBV, and [18F]FLT Ki and K1.

X. To assess the relationship between [18F]FLT Ki and K1 and markers of tumor proliferation, both cross-sectionally and longitudinally.

XI. To evaluate the reproducibility of [18F]FLT Ki and K1 measurements. XII. To assess the association between overall and progression-free survival and the change in the "vascular normalization index" between T0 and T1.

OUTLINE: This is a multicenter study. Patients are stratified according to recursive partitioning analysis class (III vs IV vs V) and MGMT methylation status (methylated vs unmethylated vs invalid). 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 radiotherapy (intensity-modulated radiotherapy or 3-dimensional conformal radiotherapy) QD, 5 days a week, for 6 weeks and receive temozolomide PO QD and cediranib maleate PO QD for 6 weeks. Patients then receive cediranib maleate PO alone QD for 28 days. Patients then receive temozolomide PO QD for 5 days and cediranib maleate PO QD for 28 days. Treatment with temozolomide and cediranib maleate 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 radiotherapy (intensity-modulated radiotherapy or 3-dimensional conformal radiotherapy) QD, 5 days a week, for 6 weeks and receive temozolomide PO QD and placebo PO QD for 6 weeks. Patients then receive placebo PO alone QD for 28 days. Patients then receive temozolomide PO QD for 5 days and placebo PO QD for 28 days. Treatment with temozolomide and placebo repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Some patients undergo advanced imaging studies including magnetic resonance spectroscopy, dynamic contrast-enhanced MRI, dynamic susceptibility-contrast MRI, and/or 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography at baseline and periodically during study.

After completion of study therapy, 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
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Drug: cediranib maleate
    Given PO
    Other Names:
    • AZD2171
    • Recentin
  • Drug: temozolomide
    Given PO
    Other Names:
    • SCH 52365
    • Temodal
    • Temodar
    • TMZ
  • Other: placebo
    Given PO
    Other Name: PLCB
  • Radiation: intensity-modulated radiation therapy
    Given 5 days a week for 6 weeks
    Other Name: IMRT
  • Radiation: 3-dimensional conformal radiation therapy
    Given 5 days a week for 6 weeks
    Other Names:
    • 3D conformal radiation therapy
    • 3D-CRT
  • Procedure: magnetic resonance spectroscopic imaging
    Given at baseline and periodically during study
    Other Names:
    • 1H-nuclear magnetic resonance spectroscopic imaging
    • Proton Magnetic Resonance Spectroscopic Imaging
  • Procedure: dynamic contrast-enhanced magnetic resonance imaging
    Given at baseline and periodically during study
    Other Name: DCE-MRI
  • Other: fluorine F 18 fluorothymidine
    Given 18F-FLT PET at baseline and periodically during study
    Other Names:
    • 18F-FLT
    • 3'-deoxy-3'-[18F]fluorothymidine
    • fluorothymidine F-18
  • Procedure: positron emission tomography
    Given 18F-FLT PET at baseline and periodically during study
    Other Names:
    • FDG-PET
    • PET
    • PET scan
    • tomography, emission computed
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (cediranib maleate, temozolomide, radiotherapy)

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

    Some patients undergo advanced imaging studies including magnetic resonance spectroscopy, dynamic contrast-enhanced MRI, dynamic susceptibility-contrast MRI, and/or 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography at baseline and periodically during study.

    Interventions:
    • Drug: cediranib maleate
    • Drug: temozolomide
    • Radiation: intensity-modulated radiation therapy
    • Radiation: 3-dimensional conformal radiation therapy
    • Procedure: magnetic resonance spectroscopic imaging
    • Procedure: dynamic contrast-enhanced magnetic resonance imaging
    • Other: fluorine F 18 fluorothymidine
    • Procedure: positron emission tomography
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (temozolomide, radiotherapy)

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

    Some patients undergo advanced imaging studies including magnetic resonance spectroscopy, dynamic contrast-enhanced MRI, dynamic susceptibility-contrast MRI, and/or 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography at baseline and periodically during study.

    Interventions:
    • Drug: temozolomide
    • Other: placebo
    • Radiation: intensity-modulated radiation therapy
    • Radiation: 3-dimensional conformal radiation therapy
    • Procedure: magnetic resonance spectroscopic imaging
    • Procedure: dynamic contrast-enhanced magnetic resonance imaging
    • Other: fluorine F 18 fluorothymidine
    • Procedure: positron emission tomography
    • 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
283
Not Provided
January 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically confirmed glioblastoma or gliosarcoma (WHO grade IV)

    • Diagnosis must have been made by partial or complete surgical excision within the past 3-5 weeks

      • Cavitron ultrasonic aspirator-derived material or stereotactic biopsy not allowed
    • Tumor must have a supratentorial component
  • Must have ≥ 1 block of tumor tissue available for analysis of MGMT status

    • Tumor tissue must be of sufficient size for analysis of MGMT status, as determined by central pathology review
  • No recurrent or multifocal malignant gliomas
  • No metastases detected below the tentorium or beyond the cranial vault
  • Karnofsky performance status 70-100%
  • ANC ≥ 1,800/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed)
  • BUN ≤ 30 mg/dL
  • Creatinine ≤ 1.7 mg/dL
  • Urine protein:creatinine ratio ≤ 0.5 by urinalysis OR urine protein < 1,000 mg by 24-hour urine collection
  • Bilirubin ≤ 2.0 mg/dL
  • ALT and AST ≤ 3 times normal
  • PT/INR < 1.4 (unless on full-dose anticoagulation)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to undergo MRI or PET scan (i.e., no pacemaker or weight limitation) (for advanced imaging substudy)
  • Able to tolerate 2 IV lines, 1 in each arm (for advanced imaging substudy)
  • Systolic BP ≤ 140 mm Hg AND diastolic BP ≤ 90 mm Hg within the past 14 days (in the presence or absence of a stable regimen of anti-hypertensive therapy)
  • Mean QTc ≤ 500 msec (with Bazett's correction) on screening EKG
  • No familial long QT syndrome or other significant ECG abnormality within the past 14 days
  • No severe, active co-morbidity including, but not limited to, any of the following:

    • Unstable angina and/or congestive heart failure requiring hospitalization
    • Transmural myocardial infarction within the past 6 months
    • Recent myocardial infarction or ischemia as evidenced by S-T elevations of ≥ 2 mm on EKG within the past 14 days
    • NYHA class II-IV congestive heart failure requiring hospitalization within the past 12 months
    • Stroke, cerebral vascular accident, or transient ischemic attack within the past 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
    • Abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or significant traumatic injury within the past 28 days
    • Acute bacterial or fungal infection requiring IV antibiotics
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy
    • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

      • Laboratory tests for liver function and coagulation parameters not required
    • AIDS based upon current CDC definition

      • HIV testing not required
    • Active connective tissue disorders, such as lupus or scleroderma, that, in the opinion of the treating physician, may put the patient at high risk for radiation toxicity
    • Any other major medical illness or psychiatric impairment that, in the investigator's opinion, would prevent administration or completion of study therapy
  • No other invasive malignancy within the past 3 years except adequately treated nonmelanomatous skin cancer or curatively treated carcinoma in situ of the breast, oral cavity, or cervix
  • No prior allergic reaction to temozolomide
  • No prior allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib maleate
  • No prior allergic reactions attributed to compounds of similar chemical or biological composition to gadolinium or [18F]FLT contrast agents (for advanced imaging substudy)
  • See Disease Characteristics
  • Must have recovered from prior surgery, post-operative infection, and other complications
  • More than 28 days since prior major surgical procedure or open biopsy (other than craniotomy for tumor resection)
  • More than 30 days since prior and no concurrent treatment on other therapeutic clinical trials
  • At least 14 days since prior and no concurrent enzyme-inducing anti-epileptic drugs (EIAEDs)

    • Concurrent non-EIAEDs allowed
  • No prior chemotherapy or radiosensitizers for cancer of the head and neck region

    • Prior chemotherapy for a different cancer allowed
  • No prior temozolomide or cediranib maleate
  • No prior Gliadel wafers or any other intratumoral or intracavitary treatment
  • No prior radiotherapy to the head or neck (except for T1 glottic cancer) resulting in overlap of radiotherapy fields
  • No other concurrent VEGF inhibitors
  • Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin) allowed provided both of the following criteria are met:

    • 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) and patient is on a stable dose of oral anticoagulant or low molecular weight heparin
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
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Tracy Batchelor Radiation Therapy Oncology Group
National Cancer Institute (NCI)
December 2013

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