A Phase 2 interventional study of FMISO and MRI in Adult Giant Cell Glioblastoma, Adult Glioblastoma and Adult Gliosarcoma, sponsored by National Cancer Institute (NCI). Completed at 14 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-04-08.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Diagnostic
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.
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.
1,951 studies on the registry are indexed under Glioblastoma; 457 are open to participants now.
This study's enrollment of 50 is above the median of 36 across 1,645 interventional studies indexed under Glioblastoma.
Browse Glioblastoma studies →National Cancer Institute (NCI) is the lead sponsor of 3,554 studies on the registry; 334 are open to participants now.
Of its 407 completed or terminated interventional studies of FDA-regulated products, 370 (91%) have results posted.
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Residual tumor after surgery (amount of residual tumor will not impact patient eligibility and visible residual disease can include T2/FLAIR hyperintensity)
Exclusion Criteria:
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 · Other: MRI · Other: PET · Other: MRS
FMISO PET scans
Also known as: 18F-fluoromisonidazole, 18F-MISO, 18F-Misonidazole
Undergo MRI
Also known as: 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)
Undergo FMISO PET scan
Also known as: Medical Imaging, Positron Emission Tomography, PET Scan, Positron Emission Tomography, Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging
Also known as: Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging Spectroscopy (MRIS), Magnetic Resonance Spectroscopy Imaging (MRSI)
Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model
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
Time frame: "assessed from baseline up to 5 years, survival status at 1-year reported
Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP)
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
Time frame: assessed from baseline up to 5 years, progression status at months 6 and 9 reported
Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans
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.
Time frame: Baseline and retest within 1 to 7 days after (but prior to the start of therapy)
Correlation Between T/Cmax and T/Bmax
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.
Time frame: At baseline
Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia
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
Time frame: baseline
Overall and Progression Free Survival
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.
Time frame: Baseline, every 3 months through study completion (up to 5 years for progression and survivorship)
SUVpeak and T/Bmax as Measures of Tumor Hypoxia
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.
Time frame: baseline
Hypoxic Volume as a Measure of Tumor Hypoxia
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)
Time frame: baseline
DWI Apparent Diffusion Coefficient (ADC)
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
Time frame: baseline
Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF)
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
Time frame: baseline
Summary of Mean and Median Ktrans Across Participants.
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))
Time frame: baseline
Fifty patients with newly diagnosed GBM were enrolled from 11 academic centers in the United States.
| Milestone | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Started | 50 |
| Fmiso/pet | 38 |
| Dce mri | 31 |
| Dse mri | 37 |
| Dwi mri | 39 |
| Completed | 42 |
| Not completed | 8 |
| Withdrew: Withdrawal by subject | 6 |
| Withdrew: Fmiso production failure | 2 |
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
| Participants | Evaluable | FMISO-PET | DSC MRI | DCE MRI | DWI-MRI |
|---|---|---|---|---|---|
| OS-1 Alive | 25 | 22 | 24 | 20 | 24 |
| OS-1 Death | 17 | 16 | 13 | 11 | 15 |
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
| Participants | Evaluable | FMISO-PET | DSC MRI | DCE MRI | DWI-MRI |
|---|---|---|---|---|---|
| 6 month Progression Status — Progression Free | 29 | 26 | 27 | 20 | 28 |
| 6 month Progression Status — Progressed | 13 | 12 | 10 | 11 | 11 |
| 9 Month Progression Status — Progression Free | 19 | 17 | 18 | 12 | 18 |
| 9 Month Progression Status — Progressed | 23 | 21 | 19 | 19 | 21 |
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.
| Within Subj. Coefficient of Variation % | FMISO Reproducibility |
|---|---|
| SUVmax : Average across all lesions by participant | 7.03 (-17.18 to 20.74) |
| SUVmax : Maximum across all lesions by participant | 9.60 (-22.43 to 28.92) |
| SUVmax : Target Lesion | 8.18 (-19.59 to 24.36) |
| SUVpeak: Average across all lesions by participant | 7.08 (-17.27 to 20.88) |
| SUVpeak: Maximum across all lesions by participant | 9.20 (-21.65 to 27.63) |
| SUVpeak: Target Lesion | 8.24 (-19.71 to 24.55) |
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.
| correlation coefficient | DSC MRI |
|---|---|
| Correlation Between T/Cmax and T/Bmax | 0.98 |
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
| correlation coefficient | nrCBV | nCBF | Median K-trans | SUV Max |
|---|---|---|---|---|
| NAA/Cho Tumor | -0.38 | -0.41 | -0.08 | -.33 |
| NAA/Cho Periphery | -0.33 | -0.34 | 0.14 | -0.41 |
| Cho/Cr Tumor | 0.24 | 0.28 | -0.2 | 0.03 |
| Cho/Cr Periphery | 0.17 | 0.20 | -0.27 | 0.11 |
| Lac/Cr Tumor | -0.27 | -0.25 | -0.06 | -0.29 |
| Lac/Cr Periphery | -0.09 | -0.11 | 0.10 | -0.15 |
| Lac/NAA Tumor | -0.02 | -0.01 | 0.23 | -0.18 |
| Lac/NAA Periphery | -0.01 | -0.01 | 0.33 | -0.04 |
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.
| days | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Median OS time | 408 (316 to 642) |
| Median PFS | 258 (190 to 335) |
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.
| ratio | FMISO-PET |
|---|---|
| SUVpeak | 2.49 ± 0.89 |
| T/Bmax | 2.13 ± 0.77 |
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)
| milliliters | FMISO-PET |
|---|---|
| Hypoxic Volume as a Measure of Tumor Hypoxia | 14.21 ± 11.61 |
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
| mm^2/s | DWI-MRI |
|---|---|
| Low | 0.99 ± 0.15 |
| High | 1.48 ± 0.39 |
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
| ratio | DSC MRI |
|---|---|
| nRCBV | 3.13 ± 1.86 |
| nCBF | 3.36 ± 2.02 |
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))
| 1/min | DCE MRI |
|---|---|
| Mean kTrans | 0.04 ± 0.03 |
| Median kTrans | 0.03 ± 0.07 |
Collected over until 24hrs after FMISO administration, evaluated up to 72hours post FMISO injection.. Non-serious events are listed at a 3% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Evaluable Cases | 0/42 (0%) | 0/42 (0%) | 0/42 (0%) |
| Diagnostic PET (Using FMISO) | 0/38 (0%) | 0/38 (0%) | 0/38 (0%) |
| Diagnostic MRI (DCE MRI) | 0/37 (0%) | 0/37 (0%) | 0/37 (0%) |
| Diagnostic MRI (DSE MRI) | 0/31 (0%) | 0/31 (0%) | 0/31 (0%) |
| Diagnostic MRI (DWI MRI) | 0/39 (0%) | 0/39 (0%) | 0/39 (0%) |
Patients with newly diagnosed GBM who received both FMISO-PRT imaging two weeks before initiation of chemoradiotherapy with temozolomide
| Age, Continuous(years) | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Mean | 57 ± 9.07 |
| Sex: Female, Male(Participants) | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Female | 15 |
| Male | 27 |
| Ethnicity (NIH/OMB)(Participants) | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Hispanic or Latino | 5 |
| Not Hispanic or Latino | 36 |
| Unknown or Not Reported | 1 |
| Race (NIH/OMB)(Participants) | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| American Indian or Alaska Native | 1 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 2 |
| White | 38 |
| More than one race | 0 |
| Unknown or Not Reported | 0 |
| Median Tumor Volume(mm^3) | Newly Diagnosed Glioblastoma Multiforme Patients |
|---|---|
| Median | 14.94 (.84 to 59.5) |
Documents are hosted by the registry — open the source record to download them.
Ran from Aug 2009 to primary completion in Jan 2018, 101 months.
Results were first posted in Apr 2019, 1 year 2 months after primary completion.
Of 186 non-industry phase 2 interventional studies under Glioblastoma, half reached primary completion within 60 months of starting (the median), counting those still running; a quarter within 42 and three quarters within 88. This study's 101 months is above that.
Counting every sponsor, half of 237 studies reached it within 56 months; a quarter within 41 and three quarters within 87.
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Studies of the drug tested here: Fluoromisonidazole
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