NCT00902577

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

Completed Phase 2 Results posted Last updated 8 April 2019

What this trial tests

Phase 2 trial testing FMISO in Adult Giant Cell Glioblastoma in 50 participants. Completed in 31 January 2018.

Timeline

24 August 2009

Primary endpoint
31 January 2018

31 January 2018

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	single group
Masking	none
Primary purpose	diagnostic
Enrollment	50
Start date	24 August 2009
Primary completion	31 January 2018
Estimated completion	31 January 2018
Sites	14 locations across United States

Drugs / interventions tested

• FMISO — full drug profile →
• MRI — full drug profile →
• PET — full drug profile →
• MRS

Conditions studied

• Adult Giant Cell Glioblastoma — all drugs for Adult Giant Cell Glioblastoma →
• Adult Glioblastoma — all drugs for Adult Glioblastoma →
• Adult Gliosarcoma — all drugs for Adult Gliosarcoma →

Sponsor

National Cancer Institute (NCI)

Who can join

18 and older, any sex, with Adult Giant Cell Glioblastoma or Adult Glioblastoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model Primary · "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) D

OS-1 Alive

Group	Value	95% CI
Evaluable	25
FMISO-PET	22
DSC MRI	24
DCE MRI	20
DWI-MRI	24

OS-1 Death

Group	Value	95% CI
Evaluable	17
FMISO-PET	16
DSC MRI	13
DCE MRI	11
DWI-MRI	15

Association of Baseline FMISO PET and MRI Features With Time-to-Progression (TTP) Secondary · 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

6 month Progression Status

Group	Value	95% CI
Evaluable	29
FMISO-PET	26
DSC MRI	27
DCE MRI	20
DWI-MRI	28
Evaluable	13
FMISO-PET	12
DSC MRI	10
DCE MRI	11
DWI-MRI	11

9 Month Progression Status

Group	Value	95% CI
Evaluable	19
FMISO-PET	17
DSC MRI	18
DCE MRI	12
DWI-MRI	18
Evaluable	23
FMISO-PET	21
DSC MRI	19
DCE MRI	19
DWI-MRI	21

Reproducibility of the Baseline FMISO PET Uptake Parameters as Assessed by Baseline "Test" and "Retest" PET Scans Secondary · 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

SUVmax : Average across all lesions by participant

Group	Value	95% CI
FMISO Reproducibility	7.03	-17.18 – 20.74

SUVmax : Maximum across all lesions by participant

Group	Value	95% CI
FMISO Reproducibility	9.60	-22.43 – 28.92

SUVmax : Target Lesion

Group	Value	95% CI
FMISO Reproducibility	8.18	-19.59 – 24.36

SUVpeak: Average across all lesions by participant

Group	Value	95% CI
FMISO Reproducibility	7.08	-17.27 – 20.88

SUVpeak: Maximum across all lesions by participant

Group	Value	95% CI
FMISO Reproducibility	9.20	-21.65 – 27.63

SUVpeak: Target Lesion

Group	Value	95% CI
FMISO Reproducibility	8.24	-19.71 – 24.55

Correlation Between T/Cmax and T/Bmax Secondary · 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.

Group	Value	95% CI
DSC MRI	0.98

Correlation Between MRS Markers and MR Imaging Markers of Vascularity as Well as Between MRS Markers and PET Markers of Tumor Hypoxia Secondary · 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

NAA/Cho Tumor

Group	Value	95% CI
nrCBV	-0.38
nCBF	-0.41
Median K-trans	-0.08
SUV Max	-.33

NAA/Cho Periphery

Group	Value	95% CI
nrCBV	-0.33
nCBF	-0.34
Median K-trans	0.14
SUV Max	-0.41

Cho/Cr Tumor

Group	Value	95% CI
nrCBV	0.24
nCBF	0.28
Median K-trans	-0.2
SUV Max	0.03

Cho/Cr Periphery

Group	Value	95% CI
nrCBV	0.17
nCBF	0.20
Median K-trans	-0.27
SUV Max	0.11

Lac/Cr Tumor

Group	Value	95% CI
nrCBV	-0.27
nCBF	-0.25
Median K-trans	-0.06
SUV Max	-0.29

Lac/Cr Periphery

Group	Value	95% CI
nrCBV	-0.09
nCBF	-0.11
Median K-trans	0.10
SUV Max	-0.15

Lac/NAA Tumor

Group	Value	95% CI
nrCBV	-0.02
nCBF	-0.01
Median K-trans	0.23
SUV Max	-0.18

Lac/NAA Periphery

Group	Value	95% CI
nrCBV	-0.01
nCBF	-0.01
Median K-trans	0.33
SUV Max	-0.04

Overall and Progression Free Survival Secondary · 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.

Median OS time

Group	Value	95% CI
Newly Diagnosed Glioblastoma Multiforme Patients	408	316 – 642

Median PFS

Group	Value	95% CI
Newly Diagnosed Glioblastoma Multiforme Patients	258	190 – 335

SUVpeak and T/Bmax as Measures of Tumor Hypoxia Secondary · 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.

SUVpeak

Group	Value	95% CI
FMISO-PET	2.49	± 0.89

T/Bmax

Group	Value	95% CI
FMISO-PET	2.13	± 0.77

Hypoxic Volume as a Measure of Tumor Hypoxia Secondary · 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)

Group	Value	95% CI
FMISO-PET	14.21	± 11.61

DWI Apparent Diffusion Coefficient (ADC) Secondary · 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

Low

Group	Value	95% CI
DWI-MRI	0.99	± 0.15

High

Group	Value	95% CI
DWI-MRI	1.48	± 0.39

Normalized Relative Cerebral Blood Volume (nRCBV) and Normalized Cerebral Blood Flow (nCBF) Secondary · 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

nRCBV

Group	Value	95% CI
DSC MRI	3.13	± 1.86

nCBF

Group	Value	95% CI
DSC MRI	3.36	± 2.02

Summary of Mean and Median Ktrans Across Participants. Secondary · 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))

Mean kTrans

Group	Value	95% CI
DCE MRI	0.04	± 0.03

Median kTrans

Group	Value	95% CI
DCE MRI	0.03	± 0.07

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions.
   Chen Z, Han F, Du Y, Shi H, et al · · 2023 · cited 913× · PMID 36797231 · DOI 10.1038/s41392-023-01332-8
2. Glioma stem cells and their roles within the hypoxic tumor microenvironment.
   Boyd NH, Tran AN, Bernstock JD, Etminan T, et al · · 2021 · cited 174× · PMID 33391498 · DOI 10.7150/thno.41692
3. ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI.
   Gerstner ER, Zhang Z, Fink JR, Muzi M, et al · · 2016 · cited 89× · PMID 27185374 · DOI 10.1158/1078-0432.ccr-15-2529
4. ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy.
   Ratai EM, Zhang Z, Fink J, Muzi M, et al · · 2018 · cited 18× · PMID 29902200 · DOI 10.1371/journal.pone.0198548
5. Teaching NeuroImages: sacral spine chloroma.
   Chamberlain MC, Tredway TL, Born D, Fink J. · · 2013 · cited 9× · PMID 24019392 · DOI 10.1212/wnl.0b013e3182a43aed
6. Emerging PET Imaging Agents and Targeted Radioligand Therapy: A Review of Clinical Applications and Trials.
   Palihati M, Das JP, Yeh R, Capaccione K. · · 2025 · cited 5× · PMID 40863874 · DOI 10.3390/tomography11080083
7. Heterogeneity, Measurement, and Clinical Implications of Oxygenation, Cell Signaling, and Redox Biology in Glioblastoma and Adult Diffuse Gliomas, with Context from Other Brain Tumors.
   Das A, Bailes JE, Barlow A, Aksenov DP. · · 2026 · PMID 42072147 · DOI 10.3390/antiox15040505
8. Metabolic Heterogeneity in High-Grade Glioma Assessed by Multi-Tracer PET and Ex Vivo Metabolomics: A Systematic Review and Meta-Analysis.
   Todeschi J, Cebula H, Bund C, Namer IJ. · · 2025 · PMID 41590625 · DOI 10.3390/metabo16010017