Feasibility of FMISO in Brain Tumors

PRIMARY OBJECTIVES:

I. Determine the feasibility of obtaining 18F-fluoromisonidazole (FMISO) PET (hypoxic volume and tumor to blood background values \[T/B\]) and dynamic susceptibility contrast enhanced (DSC), diffusion-weighted imaging (DWI), \& segregation \& extravascular localization of ferumoxytol imaging (SELFI) MRI measures in patients with intracranial brain tumors.

II. Determine if MRI contrast-enhancement and hypoxic volume are imaging profiles of glioblastoma immunotherapy-mediated pseudoprogression or true progression in a clinical trial.

III. Determine if SELFI hypoxic fraction are imaging biomarkers of glioblastoma neuroinflammation.

SECONDARY OBJECTIVES:

I. Determine the feasibility of baseline and follow-up ferumoxytol (Fe)-enhanced FMISO PET and MR imaging co-registration.

II. Assess diagnostic performance of imaging metrics to identify failed therapy at earlier imaging timepoints before presumed progression.

III. Determine the reliability of the pre-therapy FMISO PET imaging metrics as assessed by baseline "test" and "retest experiments.

IV. Compare the diagnostic performance of SELFI hypoxic fraction to Modified Response Assessment in Neuro-Oncology (mRANO) criteria.

V. Determine the sensitivity and specificity of SELFI hypoxic fraction for the diagnosis of neuroinflammation and recurrent disease.

VI. Assess progression free survival. VII. Assess overall survival. VIII. Determine change in imaging metrics from post-therapy and disease progression in differentiating neuroinflammation from recurrent disease.

IX. Determine optimal SELFI hypoxic fraction imaging parameters. X. Correlate SELFI hypoxic fraction with innate immune phenotype and hypoxia expression.

TERTIARY OBJECTIVE:

I. Determine the reproducibility of the baseline FMISO PET imaging metrics as assessed by baseline "test" and "retest" experiments.

OUTLINE:

Participants receive FMISO and/or FE IV. Patients also undergo dynamic PET/computed tomography (CT) or PET/MRI over 120 minutes beginning 1 minute prior to FMISO injection, and static PET/CT or PET/MRI over 20-40 minutes approximately 90 minutes after FMISO injection. Participants may then receive FMISO and/or Fe IV and gadolinium IV and undergo PET/MRI scan, followed by an additional PET/MRI scan without FMISO and/or Fe and gadolinium the following day. These scans may repeat every 4 weeks up to 4 times. Supplemental oxygen may be administered to affect MRI signal change.

After conclusion of the diagnostic tests, participants are followed for up to 5 years.

• ¹⁸F-Fluoromisonidazole (Drug), also known as ¹⁸F-MISO, ¹⁸F-Misonidazole, FMISO: Given IV
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computerized Axial Tomography, Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography: Undergo PET/CT
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR Imaging, MRI, MRI Scan, NMR Imaging, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), NMRI, Nuclear Magnetic Resonance Imaging: Undergo PET/MRI or PET/CT
• Positron Emission Tomography (Procedure), also known as Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging: Undergo PET/MRI
• Oxygen Therapy (Procedure), also known as supplemental oxygen therapy: Receive supplemental oxygen
• Ferumoxytol (Drug), also known as Feraheme, Ferumoxytol, ferumoxytol, FERUMOXYTOL NON-STOICHIOMETRIC MAGNETITE, Ferumoxytol Non-Stoichiometric Magnetite: Given IV
• Gadolinium (Drug): Given IV

Primary outcomes

• Successful production of images [Two days of diagnostic imaging]: Assessed as a factor of generating quantitative positron emission tomography (PET)/magnetic resonance imaging (MRI) metrics (intra-tumoral FMISO tumor to blood \[T/B\] level, hypoxic volume, dynamic susceptibility contrast enhanced \[DSC\], diffusion-weighted imaging \[DWI\], and segregation \& extravascular localization of ferumoxytol imaging \[SELFI\] values, and tissue oxygen maps). Images generated during the administration of oxygen will be used to generate tissue oxygen maps of the brain. Following completion of cohort enrollment, the generation of each quantitative PET/MRI metric will be independently scored as a dichotomous variable; successful or non-successful. Proportional assessment will be performed to assess for project feasibility. The estimated proportion of success rate for each metric along with the corresponding 95% binomial confidence interval will be provided.
• SELFI and hypoxic fraction, and T1 ferumoxytol Fe/gadolinium (Gd) log mismatch ratio in patients receiving immunotherapy [Two days of diagnostic imaging at time of suspected progression]: Diagnostic performance of PET/MRI metrics (SELFI and hypoxic fraction) and Gd_MRI to differentiate progression from neuroinflammation (pseudoprogresion) will be evaluated using sensitivity, specificity and area under the receiver operating curve (AUROC). Sensitivity and specificity will be characterized using proportions and exact 95% confidence intervals. Difference in diagnostic performance between PET/MRI metrics (SELFI and hypoxic fraction) and Gd_MRI will be assessed using McNemar's test to compare sensitivity and specificity and using the DeLong test to compare AUROC.
• SELFI and hypoxic fraction, and T1 ferumoxytol Fe/gadolinium (Gd) log mismatch ratio in all patients [Two days of diagnostic imaging at time of suspected progression]: Diagnostic performance of PET/MRI metrics (SELFI and hypoxic fraction) and Gd_MRI to differentiate progression from neuroinflammation (pseudoprogresion) will be evaluated using sensitivity, specificity and AUROC. Sensitivity and specificity will be characterized using proportions and exact 95% confidence intervals. Difference in diagnostic performance between PET/MRI metrics (SELFI and hypoxic fraction) and Gd_MRI will be assessed using McNemar's test to compare sensitivity and specificity and using the DeLong test to compare AUROC.

Secondary outcomes

• Successful co-registration (Yes vs. No) [Baseline to the start of long-term follow-up (up to 5 years)]: The generation of co-registered imaging data sets will be independently scored as a dichotomous variable; successful or non-successful (< 10mm versus \[vs.\] > 10mm alignment error). Proportional assessment will be performed to assess for project feasibility. The estimated proportion along with the corresponding 95% binomial confidence interval will be provided.
• T/B value and hypoxic tumor volume [Time Frame: Baseline to the start of long-term follow-up (up to 5 years)]: Tumor-to-background ratio (TBR) is calculated by dividing the tumor SUV by the mean SUV of the background region, using either voxelwise values or summary measures such as SUVmean. To define hypoxic volume, a threshold-based approach is applied in which all tumor voxels with FMISO uptake above a predetermined TBR cutoff are classified as hypoxic; the hypoxic volume is then calculated as the total volume of these above-threshold voxels. Hypoxic volume is measured in mm3.
• Generation of SELFI Metric [Imaging time points before gadolinium-based contrast agent defined presumed progression, year 1-4]: Will assess generation of whole brain SELFI MRI data set. Generation of SELFI MRI: YES/NO.
• SELFI diagnostic performance of imaging metrics [Imaging time points before gadolinium-based contrast agent defined presumed progression, year 1-4]: SELFI metric will be assessed to identify failed therapy at each imaging timepoint. Assessing Failed Therapy: Area Under the Curve for each metric at each time point to diagnose disease progression
• Generation of Hypoxic Fraction Metric [Imaging time points before gadolinium-based contrast agent defined presumed progression, year 1-4]: Will assess generation of hypoxic fraction data set. Generation of hypoxic fraction: MRI YES/NO.
• Hypoxic Fraction Diagnostic performance of imaging metric [Imaging time points before gadolinium-based contrast agent defined presumed progression, year 1-4]: Hypoxic Fraction metric will be assessed to identify failed therapy at each imaging timepoint. Assessing Failed Therapy: Area Under the Curve for each metric at each time point to diagnose disease progression.
• Hypoxic fraction [Retest will be scheduled within 7 days after the initial PET imaging examination, Baseline, year 1-4]]: Will determine the reproducibility of the pre-therapy FMISO PET imaging metrics as assessed by baseline "test" and "retest experiments. Reproducibility of hypoxic fraction between baseline "test" and "retest experiments will be evaluated by intra-class correlation coefficients (ICC).
• SELFI, hypoxic fraction and Modified Response Assessment in Neuro-Oncology (mRANO) criteria [Year 1-5 at suspected disease progression]: Sensitivity, specificity and AUROC will be used to determine the diagnostic performance of imaging biomarkers (SELFI and hypoxic fraction, change in SELFI and hypoxic fraction between fraction between post-radiation therapy and suspected disease progression) and mRANO to differentiate progression from neuroinflammation (pseudoprogresion). Optimal cutoff points for SELFI and hypoxic fraction will be identified. Sensitivity and specificity will be characterized using proportions and exact 95% confidence intervals. McNemar's test will be used to compare sensitivity and specificity between imaging biomarkers and mRANO. Comparison of diagnostic performance with Gd MRI may also be explored.
• SELFI and hypoxic fraction [Year 1-5 at suspected disease progression]: Will determine the sensitivity and specificity of SELFI hypoxic fraction for the diagnosis of neuroinflammation and recurrent disease. Sensitivity and specificity will be characterized using proportions and exact 95% confidence intervals. McNemar's test will be used to compare sensitivity and specificity between imaging biomarkers and mRANO. Comparison of diagnostic performance with Gd MRI may also be explored.
• Progression free survival (PFS) [Date of diagnosis to date of progression, death or end of study, assessed up to 5 years]: Will be analyzed using the Kaplan-Meier product limit methods for all patients, taking censoring into account. A Cox regression model will be used to explore the association between imaging biomarkers and PFS while adjusting for patient characteristics.
• Overall survival (OS) [Date of diagnosis to date of progression, death or end of study, assessed up to 5 years]: Will be analyzed using the Kaplan-Meier product limit methods for all patients, taking censoring into account. A Cox regression model will be used to explore the association between imaging biomarkers and OS while adjusting for patient characteristics.
• Change in SELFI and hypoxic fraction [From post-therapy to disease progression/pseudoprogression, year 1-5]: Difference of SELFI or hypoxic fraction between post-radiation therapy and suspected disease progression
• SELFI [Baseline at year 1-3]: Will determine optimal SELFI imaging parameters. Outcome Measure: Optimal SELFI imaging echo time (TE) and repetition time (TR). Description: The optimal SELFI imaging parameters will be defined as the echo time (TE) and repetition time (TR) combination that demonstrates the highest correlation coefficient between SELFI and macrophage cellular density measured in tumor tissue samples. Unit of Measure: Milliseconds (ms).
• SELFI and hypoxic fraction [Year 1-4]: Will assess correlation of SELFI hypoxic fraction with innate immune phenotype and hypoxia expression. Since innate immune phenotype is a binary variable (M1, or M2), differences in imaging metrics between M1 and M2 will be evaluated using two sample t-test. If normal assumption is not satisfied, data transformation, or 95% confidence intervals based on bootstrapping method will be used. Hypoxia expression will be measured by an ordinal variable (0,1,2,3,4) based on CA-9 expression, and correlation between SELFI/hypoxic fraction and hypoxia expression will be evaluated by Spearman's rank correlation coefficient.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult patients (18 years of age and older) with a clinically suspected glioma
* Able to provide informed written consent and/or acceptable surrogate capable of providing consent on the patient's behalf
* Legally authorized representative (LAR)-signed informed consent and assent obtained for those subjects identified as decisionally impaired
* Intracranial disease greater than 5 mL as assessed by T2/fluid attenuated inversion recovery (FLAIR) MR imaging
* Karnofsky performance score > 60 or Eastern Cooperative Oncology Group (ECOG) < 3 as assessed by referring clinician.
* Either has previously received therapeutic intervention for an intracranial tumor or is eligible for and agreeable to receiving standard of care stupp protocol radiation and temozolomide after biopsy or maximum safe surgical resection
* Life expectancy of at least 6 months
* Female subject of childbearing potential will be asked for possibility of pregnancy. If unsure of pregnancy status, then a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug (FMISO). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Adequate organ function as demonstrated by a chart review of platelets, renal, hepatic, and coagulation. We will follow the Department of Diagnostic Radiology clinical policy for assessing renal function prior to injecting gadolinium-based contrast. If there is a history of poor kidney function, a point of care serum creatinine test may be performed to ensure adequate kidney function prior to FMISO administration. If there is a history of any other poor organ function, we will not administer Ferumoxytol, but the subject may receive all other study interventions

Exclusion Criteria:

* Pregnant or breastfeeding.
* Contraindication to PET, MRI, FMISO, ferumoxytol, or intravenous gadolinium based contrast agents.
* Claustrophobia is not controlled with medical therapy
* Weight is greater than modality maximum capacity.
* Presence of metallic foreign body or implanted medical devices in body not documented as MRI safe according to the Oregon Health \& Science University (OHSU) Department of Radiology guidelines (including but not limited to cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants).
* Subjects with family history of or known iron overload (genetic hemochromatosis).
* Subject who have received ferumoxytol within 3 weeks of study entry and require another ferumoxytol administration.
* Subjects with three or more drug allergies from separate drug classes.
* History of hypersensitivity allergic reactions attributed to compounds of similar chemical or biologic composition to FMISO. An allergic reaction to nitroimidazoles is highly unlikely.
* Sickle cell disease.
* History of hypersensitivity allergic reactions attributed to compounds of similar chemical or biologic composition to ferumoxytol or gadolinium MRI contrast
* Unsure of pregnancy status as assessed by Department of Radiology and AIRC guidelines.
* Subjects for whom supplemental oxygen could be harmful such as people with potential for hypoventilation (end-stage chronic obstructive pulmonary disease \[COPD\], obstructive sleep apnea \[OSA\] on continuous positive airway pressure \[CPAP\]/biphasic positive airway pressure \[Bi-PAP\], etc).
* Presence of any other co-existing condition that, in the judgment of the principal investigator, might increase the risk to the subject (i.e., plans for hospice or end of life care).
* Poor peripheral intravenous access evaluated by patient history.
* Presence of other serious systemic illnesses, including: uncontrolled infection, other uncontrolled malignancy, uncontrolled diabetes type II, or psychiatric/social situations which might impact the endpoint of the study or limit compliance with study requirements.

• Ramon Barajas, Principal investigator, OHSU Knight Cancer Institute

NIH grants: R37CA288577