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

Primary Purpose

Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

FMISO

MRI

PET

MRS

About this trial

This is an interventional diagnostic trial for Adult Giant Cell Glioblastoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of Alabama at Birmingham Cancer Center
USC / Norris Comprehensive Cancer Center
Moffitt Cancer Center
Johns Hopkins University/Sidney Kimmel Cancer Center
Massachusetts General Hospital Cancer Center
Dana-Farber Cancer Institute
Washington University School of Medicine
Mount Sinai Hospital
Duke University Medical Center
Wake Forest University Health Sciences
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
American College of Radiology Imaging Network
University of Pennsylvania/Abramson Cancer Center
University of Washington Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Diagnostic (MRI and PET using FMISO)

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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.

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.

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

Full Information

NCT ID

NCT00902577

First Posted

May 14, 2009

Last Updated

March 14, 2019

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00902577

Brief Title

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

Official Title

Multicenter, Phase II Assessment of Tumor Hypoxia in Glioblastoma Using 18F-Fluoromisonidazole (FMISO) With PET and MRI

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Completed

Study Start Date

August 24, 2009 (Actual)

Primary Completion Date

January 31, 2018 (Actual)

Study Completion Date

January 31, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Diagnostic (MRI and PET using FMISO)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

FMISO

Other Intervention Name(s)

18F-fluoromisonidazole, 18F-MISO, 18F-Misonidazole

Intervention Description

FMISO PET scans

Intervention Type

Other

Intervention Name(s)

MRI

Other Intervention Name(s)

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)

Intervention Description

Undergo MRI

Intervention Type

Other

Intervention Name(s)

PET

Other Intervention Name(s)

Medical Imaging, Positron Emission Tomography, PET Scan, Positron Emission Tomography, Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging

Intervention Description

Undergo FMISO PET scan

Intervention Type

Other

Intervention Name(s)

MRS

Other Intervention Name(s)

Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging Spectroscopy (MRIS), Magnetic Resonance Spectroscopy Imaging (MRSI)

Primary Outcome Measure Information:

Title

Association of Baseline FMISO PET and MRI Features With OS as Assessed Using Cox-regression Model

Description

Time Frame

"assessed from baseline up to 5 years, survival status at 1-year reported

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

assessed from baseline up to 5 years, progression status at months 6 and 9 reported

Title

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

Description

Time Frame

Baseline and retest within 1 to 7 days after (but prior to the start of therapy)

Title

Correlation Between T/Cmax and T/Bmax

Description

Time Frame

At baseline

Title

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

Description

Time Frame

baseline

Other Pre-specified Outcome Measures:

Title

Overall and Progression Free Survival

Description

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)

Title

SUVpeak and T/Bmax as Measures of Tumor Hypoxia

Description

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

Title

Hypoxic Volume as a Measure of Tumor Hypoxia

Description

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

Title

DWI Apparent Diffusion Coefficient (ADC)

Description

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

Title

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

Description

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

Title

Summary of Mean and Median Ktrans Across Participants.

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Elizabeth Gerstner

Organizational Affiliation

American College of Radiology Imaging Network

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Alabama at Birmingham Cancer Center

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35233

Country

United States

Facility Name

USC / Norris Comprehensive Cancer Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90033

Country

United States

Facility Name

Moffitt Cancer Center

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

Johns Hopkins University/Sidney Kimmel Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Massachusetts General Hospital Cancer Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Dana-Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Washington University School of Medicine

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Mount Sinai Hospital

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

Facility Name

Wake Forest University Health Sciences

City

Winston-Salem

State/Province

North Carolina

ZIP/Postal Code

27157

Country

United States

Facility Name

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

American College of Radiology Imaging Network

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19103

Country

United States

Facility Name

University of Pennsylvania/Abramson Cancer Center

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

University of Washington Medical Center

City

Seattle

State/Province

Washington

ZIP/Postal Code

98195

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

29902200

Citation

Ratai EM, Zhang Z, Fink J, Muzi M, Hanna L, Greco E, Richards T, Kim D, Andronesi OC, Mintz A, Kostakoglu L, Prah M, Ellingson B, Schmainda K, Sorensen G, Barboriak D, Mankoff D, Gerstner ER; ACRIN 6684 trial group. ACRIN 6684: Multicenter, phase II assessment of tumor hypoxia in newly diagnosed glioblastoma using magnetic resonance spectroscopy. PLoS One. 2018 Jun 14;13(6):e0198548. doi: 10.1371/journal.pone.0198548. eCollection 2018.

Results Reference

result

PubMed Identifier

27185374

Citation

Gerstner ER, Zhang Z, Fink JR, Muzi M, Hanna L, Greco E, Prah M, Schmainda KM, Mintz A, Kostakoglu L, Eikman EA, Ellingson BM, Ratai EM, Sorensen AG, Barboriak DP, Mankoff DA; ACRIN 6684 Trial Group. ACRIN 6684: Assessment of Tumor Hypoxia in Newly Diagnosed Glioblastoma Using 18F-FMISO PET and MRI. Clin Cancer Res. 2016 Oct 15;22(20):5079-5086. doi: 10.1158/1078-0432.CCR-15-2529. Epub 2016 May 16.

Results Reference

result

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

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