MRI and PET Scan Using 18F-Fluoromisonidazole In Assessing Tumor Hypoxia in Patients With Newly Diagnosed Glioblastoma Multiforme

• Association of baseline FMISO PET uptake (HV and T/Bmax) and MRI parameters (Ktrans and CBV) with TTP and PFS-6 as assessed using multi-variate Cox model and multi-variate Logistic regression model [ Time Frame: Up to 5 years after completion of study ] [ Designated as safety issue: No ]

  Cox-regression model will be used to study the relationship between TTP and baseline FMISO PET uptake and MRI parameters. Logistic regression model will be used to study the relationship between PFS-6 and baseline FMISO PET uptake and MRI parameters. Uni-variate analysis will be carried out for each parameter individually. Any parameter that has achieved statistical significance (P ≤ 0.05) will be included.

  Disease progression defined by Macdonald criteria: ≥ 25% increase of enhancing tumor area; Neurological status worsened; Stable or increased dose of steroids

• 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) ] [ Designated as safety issue: No ]

  The reproducibility of the baseline FMISO PET will be quantified through intra-class correlation coefficient (ICC) which is defined as the ratio of σb^2 and (σb^2+ σc^2) where σb^2 is the variance of measurements between participants and σc^2 is the variance of measurements within participants.

  For a subset of 15 participants who enroll in the test-retest substudy only. Patients must be scanned using the same ACRIN-approved PET scanner used for trial qualification, using the same protocol-specific parameters consistently at each time point.

• Correlation between T/Cmax and T/Bmax [ Time Frame: At baseline, week 4, and week 10 ] [ Designated as safety issue: No ]
  Pearson correlation coefficient and Spearman's rank correlation coefficient will be used to quantify the correlation between T/Cmax and T/Bmax.
• Correlation between other MRI parameters (T1Gd, VCI, small vessel CBV, ADC, NAA-Cho ratio, changes in BOLD signal, and T2 lesion volume) and OS, TTP, and PFS-6 [ Time Frame: Baseline and every 3 months for up to 5 years after completion of study ] [ Designated as safety issue: No ]

  Other MRI parameters include: initial size of the lesion measured on T1 post Gd images [T1Gd], vessel caliber index [VCI], small vessel CBV, apparent diffusion coefficient [ADC], values measured from MR spectroscopy such as NAA-Cho ratio, changes in BOLD signal with transient exposure to hyperoxia, and T2 lesion volume.

  Cox-regression model will be used to study the relationship between OS and other MRI parameters. Logistic regression model will be used to study the relationship between PFS-6 and other MRI parameters. Uni-variate analysis will be carried out for each parameter individually.

• Levels of hypoxic marker expression (HIF1-alpha, GLUT1, CAIX, CD31, and alpha-SMA) as assessed by immunohistochemical staining and MGMT methylation-specific polymerase chain reaction (MSP) [ Time Frame: Tumor tissue obtained at time of diagnosis for marker expression analysis; Patients evaluated for FMISO uptake, PFS-6, and OS every 3 months for up to 5 years after completion of study ] [ Designated as safety issue: No ]
  HIF1-alpha, GLUT1, and CAIX will be used to evaluate degree of hypoxia. CD31 and alpha-SMA will be used to look at tumor blood vessels and pericyte coverage. HIF1-alpha will be scored for percentage of tumor cells positive for cytoplasmic (non-activated) and nuclear (activated) staining; GLUT1 and CAIX will be scored for percentage of tumor cells demonstrating positive membrane staining; CD31 and alpha-SMA staining will be scored by standard microvascular density techniques in the areas of highest vessel density. Each biopsy will be assigned a composite score for each marker.

• Relationship between time to progression (TTP) and baseline FMISO PET uptake and MRI parameters [ Designated as safety issue: No ]
• Relationship between of 6-month progression free survival (PFS-6) with FMISO PET uptake and MRI parameters [ Designated as safety issue: No ]
• Relationship between OS, TTP, and PFS-6 with changes from baseline to week 4 in FMISO PET uptake and MRI parameters [ Designated as safety issue: No ]
• Relationship between OS, TTP, and PFS-6 with changes from baseline to week 10 in FMISO PET uptake and MRI parameters [ Designated as safety issue: No ]
• Reproducibility of the baseline FMISO PET uptake parameters by implemented baseline test and retest"PET scans performed within 1 to 7 days of each other [ Designated as safety issue: No ]
• Correlation between T/Cmax (tumor:cerebellum) and T/Bmax (tumor:blood) at baseline, week 4, and week 10 [ Designated as safety issue: No ]
• Relationship between other MRI parameters and OS, and PFS [ Designated as safety issue: No ]

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 (T1Gd, VCI, CBV-S, ADC, NAA-Cho, 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 PCR assays.

After completion of study therapy, patients are followed up every 3 months for up to 5 years.

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma

• Drug: 18F-fluoromisonidazole
  Undergo FMISO PET scans
  Other Name: 18F-FMISO
• Procedure: positron emission tomography
  Undergo FMISO PET scan
  Other Names:

  • FDG-PET
  • PET
  • PET scan
  • tomography, emission computed
• Procedure: magnetic resonance imaging
  Undergo MRI
  Other Names:

  • MRI
  • NMR imaging
  • NMRI
  • nuclear magnetic resonance imaging

Inclusion Criteria:

• Pathologically confirmed glioblastoma multiforme

  • Newly diagnosed disease
  • Grade IV according to WHO criteria

• Residual tumor required after surgery, including T2/FLAIR hyperintensity

  • Amount of residual tumor will not impact patient eligibility

• Scheduled to receive standard fractionated radiation therapy and temozolomide

  • May also receive an anti-VEGF or PARP-inhibiting therapy
• Karnofsky performance status 60-100%
• Not pregnant or nursing
• Negative pregnancy test

• Able to undergo MRI and use gadolinium-contrast agent, meeting the following criteria:

  • No claustrophobia
  • No metallic objects or implanted medical devices in the 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)
  • No sickle cell disease
  • No renal failure
  • No reduced renal function, as determined by glomerular filtration rate < 30 mL/min based on a serum creatinine level obtained within 28 days prior to study entry
• No other concurrent condition that, in the judgment of the investigator, might increase patient's risk

• No concurrent serious systemic illness, including any of the following:

  • Uncontrolled intercurrent infection
  • Uncontrolled malignancy
  • Significant renal disease
  • Psychiatric or social situations that might impact the survival endpoint of the study or limit compliance with study requirements
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to FMISO
• Able to undergo PET or MRI (i.e., weight ≤ 350 lbs)
• Able to tolerate 100% oxygen < 10 minutes (e.g., no history of chronic obstructive pulmonary disease)
• No prior implanted radiotherapy or chemotherapy sources (i.e., wafers of polifeprosan 20 with carmustine)

• Not scheduled to receive chemotherapy, immunotherapy, or biologic agent other than temozolomide, including any anti-tumor investigational agent

  • Concurrent anti-VEGF agent allowed