Cediranib, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma - Full Text View

Sponsor:	Massachusetts General Hospital
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00662506

Purpose

RATIONALE: Cediranib 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. 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. Giving cediranib together with temozolomide and radiation therapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of cediranib to see how well it works when given together with temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma.

Condition	Intervention	Phase
Brain and Central Nervous System Tumors	Drug: cediranib maleate Drug: temozolomide Genetic: proteomic profiling Other: immunoenzyme technique Other: immunohistochemistry staining method Other: laboratory biomarker analysis Procedure: adjuvant therapy Procedure: diffusion tensor imaging Procedure: diffusion-weighted magnetic resonance imaging Procedure: dynamic contrast-enhanced magnetic resonance imaging Radiation: fludeoxyglucose F 18 Radiation: intensity-modulated radiation therapy	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment
Official Title:	A Phase Ib/II Study of AZD2171 in Combination With Daily Temozolomide and Radiation in Patients With Newly Diagnosed Glioblastoma Not Taking Enzyme-Inducing Anti-Epileptic Drugs

Resource links provided by NLM:

Genetics Home Reference related topics: pyridoxal 5'-phosphate-dependent epilepsy

MedlinePlus related topics: Cancer MRI Scans

Drug Information available for: Fluorodeoxyglucose F18 Temozolomide Cediranib

U.S. FDA Resources

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

Primary Outcome Measures:

Safety profile and optimal dose of cediranib during chemoradiotherapy [ Designated as safety issue: Yes ]
Progression-free survival [ Designated as safety issue: No ]

Secondary Outcome Measures:

MRI parameters [ Designated as safety issue: No ]
Blood biomarkers [ Designated as safety issue: No ]
Tumor biomarkers [ Designated as safety issue: No ]

Estimated Enrollment:	80
Study Start Date:	April 2008
Estimated Primary Completion Date:	April 2013 (Final data collection date for primary outcome measure)

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Detailed Description:

OBJECTIVES:

Primary

To determine the safety profile and optimal dose of cediranib (15 mg or 20 mg or 30 mg) when given in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. (Phase I)
To determine median progression-free survival of patients with newly diagnosed glioblastoma treated with this regimen. (Phase II)

Secondary

To determine the radiographic response proportion in patients with measurable disease treated with this regimen. (Phase II)
To determine the median overall survival of patients treated with this regimen. (Phase II)
To determine the "vascular normalization" window in these patients by the application of serial, non-invasive, MRI parameters. (Phase II)
To measure the glucose metabolism changes in a subset of patients by performing fludeoxyglucose F 18 positron emission tomography (FDG-PET) studies. (Phase II)
To measure circulating endothelial and progenitor cells and plasma levels of VEGF-A; VEGF-B; VEGF-C; VEGF-D; sVEGFR1, sVEGFR2, bFGF, PlGF, PDGF-AA; PDGF-AB; PDGF-BB; SDF1α; tumstatin; thrombospondin-1; interleukin-8; collagen IV sICAM1, and sVCAM1 as markers for response to cediranib in these patients. (Phase II)
To correlate treatment outcomes with pre-cediranib tumor specimens (with respect to cell proliferation, apoptosis, and microvascular density [MVD], basement membrane and pericyte coverage, and angiopoietin-1 and -2 expression) to determine whether these immunohistochemical analyses can be predictive of the response to cediranib. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of cediranib followed by a phase II study. Patients begin study treatment within 21-42 days after craniotomy or 14-21 days after sterotactic biopsy.

Phase Ib:
- Chemoradiotherapy: Patients receive oral cediranib once daily and oral temozolomide once daily for 6 weeks. Within 2-6 hours of dosing, patients undergo concurrent intensity-modulated radiotherapy (IMRT) once daily, 5 days a week for 6 weeks.
- Cediranib monotherapy: Patients receive oral cediranib once daily for 4 weeks (weeks 7-10).
- Cediranib and temozolomide monthly therapy: Patients receive oral cediranib once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and 31.
- Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).
Phase II:
- Chemoradiotherapy: Patients receive oral cediranib at the recommended phase II dose determined in phase Ib, oral temozolomide, and undergo concurrent IMRT as in phase Ib (weeks 1-6).
- Cediranib monotherapy: Patients receive oral cediranib (at the recommended phase II dose determined in phase Ib) once daily for 4 weeks (weeks 7-10).
- Cediranib and temozolomide monthly therapy: Patients receive oral cediranib (at the recommended phase II dose determined in phase Ib) once daily for 24 weeks (weeks 11-34) and temozolomide once daily, 5 days a week in weeks 11, 15, 19, 23, 27, and 31.
- Cediranib monotherapy: Patients receive a fixed-dose of cediranib once daily for 24 weeks (weeks 35-58).

Patients undergo blood and urine sample collection at baseline and periodically during study. Blood samples are measured for tumstatin, as well as other well established biomarkers, including VEGF-A, -D, sVEGFR1, sVEGFR2, sICAM1, sVCAM1, PlGF, PDGF-AA, PDGF-AB, PDGF-BB, thrombospondin-1, and IL-8 by electrochemiluminescence detection. Circulating endothelial cell (CEC) assays are evaluated to assess the kinetics of CECs and progenitor cells prior to and during antiangiogenic therapy with cediranib and chemoradiotherapy. Urine samples are collected for proteomic analyses to evaluate serial change of growth factors such as VEGF and PlGF and of matrix metalloproteinases in response to treatment with cediranib. Archival tumor tissue is collected for analysis of tumor microvascular density, basement membrane and pericyte coverage, angiopoietin-1 and -2 expression, tumor cell proliferation, and apoptosis by immunostaining methods and immunoenzyme techniques.

Patients also undergo dynamic contrast enhanced (DCE)-MRI and T2-weighted or perfusion-weighted MRI at baseline and periodically during study to monitor antiangiogenic effect on tumor vasculature through parameters reflecting both tumor perfusion and permeability; and diffusion tensor imaging to measure degree of water diffusion and fractional anisotrophy. A subset of patients undergo fludeoxyglucose F 18 positron emission tomography (FDG-PET) periodically to monitor antiangiogenic effects on glucose utilization.

After completion of study treatment, patients are followed periodically for 1 year.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed glioblastoma
- Newly diagnosed disease
Scheduled to receive standard post-surgical (i.e., biopsy or resection) temozolomide and radiotherapy
Must have residual, contrast-enhancing tumor (≥ 1 centimeter in ≥ 1 dimension)
Patients must be maintained on a stable corticosteroid regimen for 5 days prior to their baseline scan and for 5 days prior to their first vascular MRI; the dose of steroids should remain the same during the baseline vascular MRIs
Archival tumor tissue available for molecular analysis
No intratumoral hemorrhage or peritumoral hemorrhage by MRI

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Leukocytes ≥ 3,000/mcl
Absolute neutrophil count ≥ 1,500/mcL
Platelet count ≥ 100,000/mcL
Hemoglobin ≥ 8 g/dL
Total bilirubin normal
AST/ALT ≤ 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Proteinuria ≤ 1+ on two consecutive dipsticks ≥ 7 days apart
Mini-mental status examination score ≥ 15
Must be able to tolerate MRI and must consent to participate in additional Vascular Imaging Procedures per protocol
- CT scans cannot be substituted for MRI
Mean QTc ≤ 500 msec (with Bazett's correction) by electrocardiogram
No concurrent malignancy except curatively treated basal cell or squamous cell carcinoma skin cancer or carcinoma in situ of the cervix or breast
- Patients with prior malignancies must be disease-free for ≥ 5 years
No history of familial long QT syndrome or other significant ECG abnormality
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib
No uncontrolled intercurrent illness including, but not limited to, any of the following:
- Hypertension (e.g., blood pressure > 140/90 mm Hg)
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situations that would preclude study compliance
No known coagulopathy that increases risk of bleeding
No history of clinically significant hemorrhages in the past
No New York Heart Association class III-IV heart disease
No condition requiring concurrent drugs or biologics with proarrhythmic potential

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
No prior chemotherapy, radiotherapy, or any experimental therapy for this disease
No prior IV bevacizumab for any other medical condition
No prior carmustine implant (Gliadel Wafer)
No prior brachytherapy or radiosurgery for this disease
More than 30 days since prior and no other concurrent investigational agents or participation in an investigational therapeutic trial
At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs (EIAEDs)
- Concurrent non-EIAEDs allowed
No concurrent CYP450-inducing anticonvulsants
No concurrent anticoagulants (e.g., dalteparin, warfarin, or low-molecular weight heparin)
- If patients require warfarin or other anticoagulants (e.g., low-molecular weight heparin) while on study, then patient may continue treatment
No concurrent combination antiretroviral therapy for HIV-positive patients
No concurrent VEGF inhibitors
No concurrent pentamidine
No concurrent herbal or nontraditional medications
No other concurrent chemotherapy agents, investigational agents, or biologic therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00662506

Locations

United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Patrick Y. Wen, MD 617-632-2166 patrick_wen@dfci.harvard.edu
Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114
Contact: Clinical Trials Office - Massachusetts General Hospital 877-726-5130

Sponsors and Collaborators

Massachusetts General Hospital

National Cancer Institute (NCI)

Investigators

Study Chair:

Tracy Batchelor, MD, MPH

Massachusetts General Hospital

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Massachusetts General Hospital ( Tracy Batchelor )
Study ID Numbers:	CDR0000593717, MGH-07-344
Study First Received:	April 18, 2008
Last Updated:	June 16, 2009
ClinicalTrials.gov Identifier:	NCT00662506 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

adult giant cell glioblastoma
adult glioblastoma
adult gliosarcoma

Additional relevant MeSH terms:

Glioblastoma
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Astrocytoma
Antineoplastic Agents
Nervous System Diseases
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Temozolomide
Pharmacologic Actions
Neuroectodermal Tumors

Neoplasms
Neoplasms by Site
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Antineoplastic Agents, Alkylating
Glioma
Neoplasms, Neuroepithelial
Alkylating Agents
Nervous System Neoplasms
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 25, 2009