Cediranib, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma

NCT ID: NCT00662506

Last Updated: 2023-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 46 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2014-04-30

Brief Summary

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. 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.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety profile and optimal dose of AZD2171 (cediranib) (15mg or 20mg or 30mg) in combination with temozolomide and radiation in patients with newly diagnosed glioblastoma (Phase Ib) II. To determine median progression-free survival of patients with newly diagnosed glioblastoma treated with AZD2171 in combination with temozolomide and radiation (Phase II)

SECONDARY OBJECTIVES:

I. To determine the radiographic response proportion in newly diagnosed glioblastoma patients with measurable disease. (Phase II) II. To determine the median overall survival. (Phase II) III. To determine the "vascular normalization" window in newly diagnosed glioblastoma patients by the application of serial, non-invasive, MRI parameters. (Phase II) IV. To measure the glucose metabolism changes in a subset of newly diagnosed glioblastoma patients by performing FDG PET studies. (Phase II) V. Measurement of 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, sVCAM1 as markers for response to AZD2171 in newly diagnosed glioblastoma patients. (Phase II) VI. Correlation of treatment outcomes with pre-AZD2171 tumor specimens with respect to cell proliferation, apoptosis, microvascular density (MVD), basement membrane and pericyte coverage, angiopoietin-1 and -2 expression to determine whether these immunohistochemical analyses can be predictive of the response to AZD2171. (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 stereotactic biopsy.

PHASE Ib:

CHEMORADIOTHERAPY: Patients receive cediranib orally (PO) 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 cediranib PO once daily for 4 weeks (weeks 7-10). Cediranib and temozolomide monthly therapy: Patients receive cediranib PO 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 cediranib PO at the recommended phase II dose determined in phase Ib, temozolomide PO, and undergo concurrent IMRT as in phase Ib (weeks 1-6). Cediranib monotherapy: Patients receive cediranib PO (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 cediranib PO (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 anisotropy. 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.

Conditions

Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (enzyme inhibitor therapy, chemotherapy, IMRT)

See Detailed Description

Group Type: EXPERIMENTAL

Cediranib Maleate

Intervention Type: DRUG

Given PO

Diffusion Tensor Imaging

Intervention Type: PROCEDURE

Undergo DTI

Diffusion Weighted Imaging

Intervention Type: PROCEDURE

Undergo T1 weighted DCE-MRI

Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo DCE-MRI

Fludeoxyglucose F-18

Intervention Type: RADIATION

Undergo 18 FDG PET

Intensity-Modulated Radiation Therapy

Intervention Type: RADIATION

Undergo IMRT

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Perfusion Magnetic Resonance Imaging

Intervention Type: PROCEDURE

Undergo PWI

Positron Emission Tomography

Intervention Type: PROCEDURE

Undergo 18 F FDG-PET

Temozolomide

Intervention Type: DRUG

Given PO

Interventions

Cediranib Maleate

Given PO

Intervention Type: DRUG

Diffusion Tensor Imaging

Undergo DTI

Intervention Type: PROCEDURE

Diffusion Weighted Imaging

Undergo T1 weighted DCE-MRI

Intervention Type: PROCEDURE

Dynamic Contrast-Enhanced Magnetic Resonance Imaging

Undergo DCE-MRI

Intervention Type: PROCEDURE

Fludeoxyglucose F-18

Undergo 18 FDG PET

Intervention Type: RADIATION

Intensity-Modulated Radiation Therapy

Undergo IMRT

Intervention Type: RADIATION

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Perfusion Magnetic Resonance Imaging

Undergo PWI

Intervention Type: PROCEDURE

Positron Emission Tomography

Undergo 18 F FDG-PET

Intervention Type: PROCEDURE

Temozolomide

Given PO

Intervention Type: DRUG

Other Intervention Names

AZD2171; AZD2171 Maleate; Recentin; DTI; Diffusion Weighted MRI; Diffusion-Weighted Magnetic Resonance Imaging; Diffusion-Weighted MR Imaging; Diffusion-Weighted MRI; DWI; DWI MRI; DWI-MRI; MR Diffusion-Weighted Imaging; DCE MRI; DCE-MRI; DYNAMIC CONTRAST ENHANCED MRI; 18FDG; FDG; fludeoxyglucose F 18; Fludeoxyglucose F18; Fluorine-18 2-Fluoro-2-deoxy-D-Glucose; Fluorodeoxyglucose F18; IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; magnetic resonance perfusion imaging; Medical Imaging, Positron Emission Tomography; PET; PET SCAN; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac

Eligibility Criteria

Inclusion Criteria

• 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
• 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
• No other concurrent chemotherapy agents, investigational agents, or biologic therapy
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elizabeth R Gerstner, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

Countries

United States

References

Hoebel KV, Bridge CP, Ahmed S, Akintola O, Chung C, Huang RY, Johnson JM, Kim A, Ly KI, Chang K, Patel J, Pinho M, Batchelor TT, Rosen BR, Gerstner ER, Kalpathy-Cramer J. Expert-centered Evaluation of Deep Learning Algorithms for Brain Tumor Segmentation. Radiol Artif Intell. 2024 Jan;6(1):e220231. doi: 10.1148/ryai.220231.

Reference Type: DERIVED

PMID: 38197800 (View on PubMed)

Hoebel KV, Patel JB, Beers AL, Chang K, Singh P, Brown JM, Pinho MC, Batchelor TT, Gerstner ER, Rosen BR, Kalpathy-Cramer J. Radiomics Repeatability Pitfalls in a Scan-Rescan MRI Study of Glioblastoma. Radiol Artif Intell. 2020 Dec 16;3(1):e190199. doi: 10.1148/ryai.2020190199. eCollection 2021 Jan.

Reference Type: DERIVED

PMID: 33842889 (View on PubMed)

Emblem KE, Farrar CT, Gerstner ER, Batchelor TT, Borra RJ, Rosen BR, Sorensen AG, Jain RK. Vessel caliber--a potential MRI biomarker of tumour response in clinical trials. Nat Rev Clin Oncol. 2014 Oct;11(10):566-84. doi: 10.1038/nrclinonc.2014.126. Epub 2014 Aug 12.

Reference Type: DERIVED

PMID: 25113840 (View on PubMed)

Pinho MC, Polaskova P, Kalpathy-Cramer J, Jennings D, Emblem KE, Jain RK, Rosen BR, Wen PY, Sorensen AG, Batchelor TT, Gerstner ER. Low incidence of pseudoprogression by imaging in newly diagnosed glioblastoma patients treated with cediranib in combination with chemoradiation. Oncologist. 2014 Jan;19(1):75-81. doi: 10.1634/theoncologist.2013-0101. Epub 2013 Dec 5.

Reference Type: DERIVED

PMID: 24309981 (View on PubMed)

Other Identifiers

NCI-2009-00267

Identifier Type: REGISTRY

Identifier Source: secondary_id

MGH-07-344

Identifier Type: -

Identifier Source: secondary_id

PHS 398/2590

Identifier Type: -

Identifier Source: secondary_id

CDR0000593717

Identifier Type: -

Identifier Source: secondary_id

PHS 398/2590

Identifier Type: OTHER

Identifier Source: secondary_id

8030

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA006516

Identifier Type: NIH

Identifier Source: secondary_id

View Link

R01CA129371

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2009-00267

Identifier Type: -

Identifier Source: org_study_id