MRI and PET/FMISO In Assessing Tumor Hypoxia in Patients With Newly Diagnosed Glioblastoma Multiforme

Phase 2

Completed

Conditions: Adult Gliosarcoma
Adult Glioblastoma
Adult Giant Cell Glioblastoma

Interventions: Drug: FMISO
Other: MRI
Other: PET
Other: MRS

Registration Number: NCT00902577

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well positron emission tomography (PET) scan using 18F-fluoromisonidazole works when given together with magnetic resonance imaging (MRI) ) in assessing tumor hypoxia in patients with newly diagnosed glioblastoma multiforme (GBM). Diagnostic procedures, such as MRI and PET scan using 18F-fluoromisonidazole (FMISO), may help predict the response of the tumor to the treatment and allow doctors to plan better treatment.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the association of baseline FMISO PET uptake (hypoxic volume \[HV\]), highest tumor:blood ratio \[T/Bmax\]) and MRI parameters (Ktrans, CBV) with overall survival (OS) in participants with newly diagnosed GBM.

SECONDARY OBJECTIVES:

I. To determine the association of baseline FMISO PET uptake (HV, T/Bmax) and MRI parameters (Ktrans, CBV) with time to progression (TTP) and 6-month progression free survival (PFS-6) in participants with newly diagnosed GBM.

II. To assess the reproducibility of the baseline FMISO PET uptake parameters by implementing baseline "test" and "retest" PET scans (performed within 1 to 7 days of each other).

III. To assess the correlation between highest tissue:cerebellum ratio \[T/Cmax\] and T/Bmax at baseline.

IV. To assess the correlation between other MRI parameters (for example Gadolinium-enhanced T1-weighted (T1Gd), vessel caliber index (VCI), , CBV-S, apparent diffusion coefficient (ADC) , N-acetylaspartate (NAA) to choline (Cho) ratio, blood oxygenation level-dependent (BOLD), T2) and OS, TTP, and PFS-6.

OUTLINE: This is a multicenter study.

Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy. Blood samples are collected at baseline and periodically during study to compare image measures of tissue uptake of FMISO to blood concentrations. Tumor samples are collected from diagnostic biopsy or surgery for analysis of tumor hypoxic markers and methylguanine methyl transferase by immunohistochemical and Polymerase chain reaction (PCR) assays.

After completion of study therapy, patients are followed up every 3 months for up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

Inclusion Criteria

Must be able to provide a written informed consent
Newly diagnosed glioblastoma multiforme (GBM), World Health Organization (WHO) grade IV based on pathology confirmation
Residual tumor after surgery (amount of residual tumor will not impact patient eligibility and visible residual disease can include T2/FLAIR hyperintensity)
- Note: If patient had a biopsy only, postoperative MRI is not needed to assess residual tumor prior to enrollment
Scheduled to receive standard fractionated radiation therapy
Scheduled to receive Temozolomide (TMZ) in addition to radiation therapy
Karnofsky Performance Score > 60

Exclusion Criteria

Pregnant or breastfeeding (if a female is of child-bearing potential, and unsure of pregnancy status, a standard urine pregnancy test should be done)
Scheduled to receive chemotherapy, immunotherapy, or investigational agents in trials unwilling to share data with ACRIN (i.e., additional therapy added to radiation and TMZ is allowed if ACRIN is able to obtain treatment information)
Not suitable to undergo MRI or use the contrast agent Gd because of:
Claustrophobia
Presence of metallic objects or implanted medical devices in body (i.e., cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants)
Sickle cell disease
Renal failure
Reduced renal function, as determined by Glomerular Filtration Rate (GFR) < 30 mL/min/1.73 m^2 based on a serum creatinine level obtained within 28 days prior to registration
Presence of any other co-existing condition which, in the judgment of the investigator, might increase the risk to the subject
Presence of serious systemic illness, including: uncontrolled intercurrent infection, uncontrolled malignancy, significant renal disease, or psychiatric/social situations which might impact the survival endpoint of the study or limit compliance with study requirements
History of allergic reactions attributed to compounds of similar chemical or biologic composition to FMISO; an allergic reaction to nitroimidazoles is highly unlikely
Not suitable to undergo PET or MRI, including weight greater than 350 lbs (the weight limit for the MRI and PET table)
Prior treatment with implanted radiotherapy or chemotherapy sources such as wafers of polifeprosan 20 with carmustine

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Diagnostic (MRI and PET using FMISO)	MRI	Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.
Diagnostic (MRI and PET using FMISO)	PET	Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.
Diagnostic (MRI and PET using FMISO)	MRS	Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.
Diagnostic (MRI and PET using FMISO)	FMISO	Two weeks before initiation of chemoradiotherapy with temozolomide, patients undergo MRI (DSC, DCE,DWI and MRS) and PET scan using FMISO. A subset of 15 patients undergo FMISO PET scans approximately 1 week before chemoradiotherapy.

Primary Outcome Measures

Name	Time	Method
Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model	"assessed from baseline up to 5 years, survival status at 1-year reported	Overall Survival (OS) was evaluated every 3 months through end of the study (up to 5 years). A variety of continuous quantitative (functional) imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated at baseline for their association with Survival time. Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions

Secondary Outcome Measures

Name	Time	Method
Correlation Between T/Cmax and T/Bmax	At baseline	Pearson correlation coefficient will be used to quantify the correlation between T/Bmax, the maximum tissue-to-blood ratio activity value, and T/Cmax, the tissue-to-cerebellum activite value Since T/Cmax does not requiring blood sampling and is image derived, a high correlation would indicate that T/Cmax could be an advantageous surrogate for T/Bmax.
Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans	Baseline and retest within 1 to 7 days after (but prior to the start of therapy)	Reproducibility, defined as the variation of repeated measurements in an experiment performed under the same conditions, will be measured as the within subject coefficient of variation with upper an lower repeatability coefficients (LRC, URC) computed as percents from log-transformed data, per Velaquez, et al (J Nucl Med. 2009 Oct;50(10):1646-54. doi: 10.2967/jnumed.109.063347. Epub 2009 Sep 16. PMID: 19759105 ). Where Within Subject Coefficient of Variation (wCV) is a percentage defined as wCV(%)=100\* (exp( SD\[ld\]/√2) - 1) and LRC and URC are calculated as: RC=100 (exp(±1.96 SD\[ld\]) -1). here SD\[ld\] is the standard deviation of the difference of the log-transformed PET measurements. These bounds provide an estimate of the lower and upper bounds of percent change observed between scans for each measurement.
Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia	baseline	Correlation between MRS markers and MR imaging markers and PET markers of tumor hypoxia MRS markers include: NAA/Cho, Cho/Cr, Lac/Cr, and Lac/NAA measured within tumor and at the periphery. MR imaging markers of vascularity include: CBV, CBF, and ktrans PET tumor hypoxia marker: SUVmax
Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP)	assessed from baseline up to 5 years, progression status at months 6 and 9 reported	Disease progression was defined by Macdonald criteria. PFS was evaluated every 3months through the end of study (up to 5yrs), features were measured at baseline. Quantitative imaging features measuring abnormal tumor vasculature (MRI) and hypoxia (FMISO) were evaluated for their association with TTP (cox model) and to discriminate between responders and non-responders at 6 and 9 mos (PFS6 and PFS9) (logistic) Features include PET Hypoxia measures: Peak standardized uptake values (SUVpeak); maximum tumor:blood ratio (T/Bmax); and Hypoxia Volume (HV) DCE MRI perfusion measures: Mean/median volume transfer constant for gadolinium between blood plasma and the tissue extravascular extracellular space (ktrans) DSC MRI tumor vasculature: Normalized Relative cerebral blood volume (nRCBV); and Cerebral blood flow (CBF) DWI MRI magnitude of diffusion of water through tissue (cell density): Apparent diffusion coefficient (ADC) using low and high Gaussian distributions

Trial Locations

Locations (14): Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
University of Alabama at Birmingham Cancer Center
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Birmingham, Alabama, United States
USC / Norris Comprehensive Cancer Center
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Los Angeles, California, United States
Moffitt Cancer Center
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Tampa, Florida, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
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Baltimore, Maryland, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States
Massachusetts General Hospital Cancer Center
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Boston, Massachusetts, United States
Washington University School of Medicine
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Saint Louis, Missouri, United States
University of Pennsylvania/Abramson Cancer Center
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Philadelphia, Pennsylvania, United States
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
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Cleveland, Ohio, United States
University of Washington Medical Center
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Seattle, Washington, United States
Duke University Medical Center
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Durham, North Carolina, United States
American College of Radiology Imaging Network
🇺🇸
Philadelphia, Pennsylvania, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States