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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


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Thank you

Trial Information

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


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.


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 ≤ 150 mm Hg or 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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

6-month PFS as assessed using MacDonald criteria and Response Evaluation Criteria in Solid Tumors (RECIST)

Outcome Description:

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.

Outcome Time Frame:

From registration to 6 months

Safety Issue:

No

Principal Investigator

Tracy Batchelor

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radiation Therapy Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02012

NCT ID:

NCT01062425

Start Date:

February 2010

Completion Date:

Related Keywords:

  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Glioblastoma
  • Gliosarcoma

Name

Location

Akron City HospitalAkron, Ohio  44304
Washington University School of MedicineSaint Louis, Missouri  63110
Abington Memorial HospitalAbington, Pennsylvania  19001
Medical University of South CarolinaCharleston, South Carolina  29425-0721
University of Washington Medical CenterSeattle, Washington  98195-6043
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
United HospitalSt. Paul, Minnesota  55102
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Rapid City Regional HospitalRapid City, South Dakota  57709
Henry Ford HospitalDetroit, Michigan  48202
Akron General Medical CenterAkron, Ohio  44302
Reading Hospital and Medical CenterReading, Pennsylvania  19612-6052
University of Texas Medical BranchGalveston, Texas  77555-1329
LDS HospitalSalt Lake City, Utah  84143
Rush University Medical CenterChicago, Illinois  60612-3824
University of Kansas Medical CenterKansas City, Kansas  66160-7353
Bay Medical CenterPanama City, Florida  32401
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Central Baptist HospitalLexington, Kentucky  40503
McKay-Dee Hospital CenterOgden, Utah  84403
Brigham and Women's HospitalBoston, Massachusetts  02115
Methodist Estabrook Cancer CenterOmaha, Nebraska  68114-4199
Paoli Memorial HospitalPaoli, Pennsylvania  19301-1792
Bryn Mawr HospitalBryn Mawr, Pennsylvania  19010
Mercy HospitalCoon Rapids, Minnesota  55433
Poudre Valley Radiation OncologyFort Collins, Colorado  80528
Saint Joseph Mercy HospitalAnn Arbor, Michigan  48106
Regions HospitalSaint Paul, Minnesota  55101
Cancer Treatment CenterWooster, Ohio  44691
Allegheny Cancer Center at Allegheny General HospitalPittsburgh, Pennsylvania  15212
Spartanburg Regional Medical CenterSpartanburg, South Carolina  29303
Genesys Regional Medical CenterGrand Blanc, Michigan  48439-8066
Arizona Oncology Services FoundationPhoenix, Arizona  85013
City of HopeDuarte, California  91010
Queen's Medical CenterHonolulu, Hawaii  96813
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Northwestern UniversityChicago, Illinois  60611
Northwest Cancer SpecialistsVancouver, Washington  98664
Cancer Care Center, IncorporatedSalem, Ohio  44460
University of RochesterRochester, New York  14642
Saint Alphonsus Regional Medical CenterBoise, Idaho  83706
Yale UniversityNew Haven, Connecticut  06520
Emory UniversityAtlanta, Georgia  30322
Ohio State University Medical CenterColumbus, Ohio  43210
University of Arizona Health Sciences CenterTucson, Arizona  85724
Radiation Therapy Oncology GroupPhiladelphia, Pennsylvania  19107
Providence Portland Medical CenterPortland, Oregon  97213-3635
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
Virginia Mason CCOPSeattle, Washington  98101
Thomas Jefferson University HospitalPhiladelphia, Pennsylvania  19131
Lankenau HospitalWynnewood, Pennsylvania  19096
Florida HospitalOrlando, Florida  32803
University of CincinnatiCincinnati, Ohio  45267-0502
Hawaii Medical Center EastHonolulu, Hawaii  96817
Penn State Milton S Hershey Medical CenterHershey, Pennsylvania  17033
Clackamas Radiation Oncology CenterClackamas, Oregon  97015
Froedtert and the Medical College of WisconsinMilwaukee, Wisconsin  53226
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
OSF Saint Francis Medical CenterPeoria, Illinois  61637
Saint Joseph HospitalOrange, California  92868
Saint Francis Hospital and Medical CenterHartford, Connecticut  06105
The Hospital of Central ConnecticutNew Britain, Connecticut  06050
University of HawaiiHonolulu, Hawaii  96813
Carle Foundation dba Carle Cancer CenterUrbana, Illinois  61801
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Sparrow HospitalLansing, Michigan  48912
Saint Joseph Mercy OaklandPontiac, Michigan  48341-2985
Saint Joseph Mercy Port HuronPort Huron, Michigan  48060
Saint Mary's of MichiganSaginaw, Michigan  48601
Saint John Macomb-Oakland HospitalWarren, Michigan  48093
Minnesota Oncology Hematology PA-MaplewoodMaplewood, Minnesota  55109
Sparta Cancer Treatment CenterSparta, New Jersey  07871
Summa Barberton HospitalBarberton, Ohio  44203
Natalie W Bryant Cancer CenterTulsa, Oklahoma  74136
Legacy Good Samaritan Hospital and Medical CenterPortland, Oregon  97210
Providence Saint Vincent Medical CenterPortland, Oregon  97225
Saint Luke's HospitalBethlehem, Pennsylvania  18015
Swedish Medical Center-First HillSeattle, Washington  98122-4307
Wheeling HospitalWheeling, West Virginia  26003
Aspirus Regional Cancer CenterWausau, Wisconsin  54401
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
Northeast Radiation Oncology CenterDunmore, Pennsylvania  18512
Henry Ford Macomb HospitalClinton Township, Michigan  48038
Christiana Healthcare Services - Christian HospitalNewark, Delaware  19718
Maine Medical Center- Scarborough CampusScarborough, Maine  04074
Intermountain Medical CenterMurray, Utah  84157
Utah Valley Regional Medical CenterProvo, Utah  84603
Dixie Medical Center Regional Cancer CenterSaint George, Utah  84770
Utah Cancer Specialists-Salt Lake CitySalt Lake City, Utah  84106
Crawford-Long Hospital of Emory UniversityAtlanta, Georgia  30308
Kansas City CCOPPrairie Village, Kansas  66208
Forsyth Memorial HospitalWinston-Salem, North Carolina  27103
Robinson Radiation OncologyRavenna, Ohio  44266
Dana-Farber Harvard Cancer CenterBoston, Massachusetts  02115
The Kirklin Clinic at Acton RoadBirmingham, Alabama  35243
Radiation Oncology Associates PCFort Wayne, Indiana  46804
Parkview Memorial HospitalFort Wayne, Indiana  46805
Clarian Health - Methodist HospitalIndianapolis, Indiana  46202
University PointeWest Chester, Ohio  45069