Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00902577
Recruitment Status : Completed
First Posted : May 15, 2009
Results First Posted : April 8, 2019
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Drug: FMISO Other: MRI Other: PET Other: MRS Phase 2

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Multicenter, Phase II Assessment of Tumor Hypoxia in Glioblastoma Using 18F-Fluoromisonidazole (FMISO) With PET and MRI
Actual Study Start Date : August 24, 2009
Actual Primary Completion Date : January 31, 2018
Actual Study Completion Date : January 31, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Diagnostic (MRI and PET using 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.
Drug: FMISO
FMISO PET scans
Other Names:
  • 18F-fluoromisonidazole
  • 18F-MISO
  • 18F-Misonidazole

Other: MRI
Undergo MRI
Other Names:
  • Magnetic Resonance Imaging (MRI)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance
  • MRI Scan
  • NMR Imaging
  • Nuclear Magnetic Resonance Imaging (NMRI)
  • Nuclear Magnetic Resonance Imaging
  • Medical Imaging, Nuclear Magnetic Resonance
  • Magnetic Resonance (MR)

Other: PET
Undergo FMISO PET scan
Other Names:
  • Medical Imaging, Positron Emission Tomography
  • PET Scan
  • Positron Emission Tomography
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging

Other: MRS
Other Names:
  • Magnetic Resonance Spectroscopy (MRS)
  • Magnetic Resonance Imaging Spectroscopy (MRIS)
  • Magnetic Resonance Spectroscopy Imaging (MRSI)




Primary Outcome Measures :
  1. Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model [ Time Frame: "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 :
  1. Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) [ Time Frame: 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


  2. Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans [ Time Frame: 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.


  3. Correlation Between T/Cmax and T/Bmax [ Time Frame: 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.

  4. Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia [ Time Frame: 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



Other Outcome Measures:
  1. Overall and Progression Free Survival [ Time Frame: Baseline, every 3 months through study completion (up to 5 years for progression and survivorship) ]
    Disease progression was defined by Macdonald criteria. Survival and Progression were evaluated every 3months and at the end of study (up to 5 years) and time to event evaluated.

  2. SUVpeak and T/Bmax as Measures of Tumor Hypoxia [ Time Frame: baseline ]

    The FMISO image data were normalized by the average blood activity to produce pixel level tissue-to-blood ratio (T/B) values for all image slices. And the severity of the hypoxia was determined by the pixel with the maximum T/B value (TBmax).

    FMISO SUVpeak was determined as the average SUV from a 1 cm circular ROI centered over the hottest pixel. Since FMISO selectively binds to hypoxic tissues, SUVpeak within a region provides a measure of tumor hypoxia.


  3. Hypoxic Volume as a Measure of Tumor Hypoxia [ Time Frame: baseline ]

    The hypoxic volume (HV) was determined as the volume of pixels in the tumor on in the FMISO\PET with a tumor to blood activity ratio ≥ 1.2.

    HV is a measure of the spatial extent of tumor hypoxia (in milliliters)


  4. DWI Apparent Diffusion Coefficient (ADC) [ Time Frame: baseline ]

    Apparent Diffusion Coefficient (ADC) measures water diffusion through tissue (mm^2/s). Cerebral infarction leads to diffusion restriction resulting in a low ADC signal in the infarcted area.

    A double Gaussian mixed model was fit to the ADC histogram and the mean of the lower and the mean of the higher ADC curves were evaluated


  5. Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF) [ Time Frame: baseline ]
    Relative cerebral blood volume (RCBV) maps, computed from the integral of ∆R2*(t), were corrected for leakage effects and normalized to normal appearing white matter (nRCBV); nRCBV provides a measure of tumor vasculature Cerebral blood flow (CBF) maps were was normalized to the mean of the region of interest (ROI) in normal appearing white matter (nCBF); nCBF provides a measure of vascular permeability and perfusion

  6. Summary of Mean and Median Ktrans Across Participants. [ Time Frame: baseline ]

    ktrans is a measure of vascular permeability and reflects the rate of gadolinium moves from plasma to extravascular extracellular space (predominantly though blood flow and capillary leakage), which can be represented by the mean or median rate.

    Mean & Median ktrans within subject were computed using a matrix-based linearization method to fit tissue ∆R1(t) to the extended Tofts model.

    The mean across subjects is presented below (Mean (Mean-ktrans) and Mean(Median-Ktrans))




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00902577


Locations
Layout table for location information
United States, Alabama
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States, 35233
United States, California
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Mount Sinai Hospital
New York, New York, United States, 10029
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
American College of Radiology Imaging Network
Philadelphia, Pennsylvania, United States, 19103
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
United States, Washington
University of Washington Medical Center
Seattle, Washington, United States, 98195
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Elizabeth Gerstner American College of Radiology Imaging Network
  Study Documents (Full-Text)

Documents provided by National Cancer Institute (NCI):

Publications of Results:
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00902577     History of Changes
Other Study ID Numbers: NCI-2011-01912
NCI-2011-01912 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000640413 ( Registry Identifier: ClinicalTrials.gov )
ACRIN 6684 ( Other Identifier: American College of Radiology Imaging Network )
ACRIN-6684 ( Other Identifier: CTEP )
U01CA080098 ( U.S. NIH Grant/Contract )
First Posted: May 15, 2009    Key Record Dates
Results First Posted: April 8, 2019
Last Update Posted: April 8, 2019
Last Verified: March 2019
Additional relevant MeSH terms:
Layout table for MeSH terms
Glioblastoma
Gliosarcoma
Hypoxia
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Signs and Symptoms, Respiratory
Signs and Symptoms
Misonidazole
Antineoplastic Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents