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: December 6, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Drug: cediranib maleate
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
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Estimated Enrollment: 283
Study Start Date: February 2010
Estimated Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Drug: cediranib maleate
Given PO
Other Names:
  • AZD2171
  • Recentin
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
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 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.

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

  Show Detailed Description

  Eligibility

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

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01062425

  Show 102 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Tracy Batchelor Radiation Therapy Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01062425     History of Changes
Other Study ID Numbers: NCI-2011-02012, NCI-2011-02012, CDR0000665163, RTOG-0837, RTOG-0837, U10CA021661
Study First Received: February 3, 2010
Last Updated: December 6, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Maleic acid
Temozolomide
Dacarbazine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents, Alkylating
Alkylating Agents
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014