Multi-Tracer PET Assessment of Primary Brain Tumors

Tracking Information
First Submitted Date	December 16, 2008
First Posted Date	December 23, 2008
Last Update Posted Date	January 4, 2018
Study Start Date	December 2008
Estimated Primary Completion Date	July 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures; (submitted: July 23, 2013)	Rapid, single-scan multi-tracer PET imaging can recover PET imaging biomarker information of each tracer that are not significantly different from those obtained from conventional, single-tracer scans of each tracer. [ Time Frame: June 2014 ]; Multi-tracer PET biomarkers, obtained in conjunction, are better able to predict tumor aggressiveness than individual-tracer biomarkers or conventional radiographic imaging. [ Time Frame: June 2014 ]; Multi-tracer PET biomarkers, obtained in conjunction, are better able to detect functional changes in tumor state that occur in response to therapy than individual-tracer biomarkers or conventional radiographic imaging. [ Time Frame: June 2014 ]; Characterization of multiple aspects of tumor function (glucose metabolism, proliferation, membrane growth, and perfusion) provides new insight into tumor status that can guide selection of the most appropriate therapy. [ Time Frame: June 2014 ]
Original Primary Outcome Measures; (submitted: December 19, 2008)	Rapid, single-scan multi-tracer PET imaging can recover PET imaging biomarker information of each tracer that are not significantly different from those obtained from conventional, single-tracer scans of each tracer. [ Time Frame: December 2012 ]; Multi-tracer PET biomarkers, obtained in conjunction, are better able to predict tumor aggressiveness than individual-tracer biomarkers or conventional radiographic imaging. [ Time Frame: December 2012 ]; Multi-tracer PET biomarkers, obtained in conjunction, are better able to detect functional changes in tumor state that occur in response to therapy than individual-tracer biomarkers or conventional radiographic imaging. [ Time Frame: December 2012 ]; Characterization of multiple aspects of tumor function (glucose metabolism, proliferation, membrane growth, and perfusion) provides new insight into tumor status that can guide selection of the most appropriate therapy. [ Time Frame: December 2012 ]
Change History	Complete list of historical versions of study NCT00813566 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures	Not Provided
Original Secondary Outcome Measures	Not Provided
Current Other Outcome Measures	Not Provided
Original Other Outcome Measures	Not Provided
Descriptive Information
Brief Title	Multi-Tracer PET Assessment of Primary Brain Tumors
Official Title	Multi-Tracer PET Assessment of Primary Brain Tumors
Brief Summary	The standard treatment approach for patients with high-grade primary brain tumors includes maximum feasible surgical resection, followed by 6 weeks of concurrent cranial irradiation and daily low-dose temozolomide chemotherapy, followed by 12 cycles of high-dose temozolomide administered for 5 consecutive days every 4 weeks [Stupp 2005]. Contrast-enhanced MRI is the current standard for evaluating the success of therapy and monitoring for tumor recurrence. MRI is typically obtained prior to initial surgery, within 24 hours after surgery, at the conclusions of cranial irradiation, and then every 8 weeks during temozolomide chemotherapy until evidence of recurrence. Despite this careful clinical and radiographic surveillance, and despite decades of research into the histologic and molecular classification of primary brain tumors, our ability to predict tumor behavior remains very limited. Some gliomas will result in overall survival times of only months, whereas other histologically-identical gliomas may yield survivals of years to decades [Carson 2007, Curran 1993, Lamborn 2004]. Current assessment of tumor response to therapy is also poor. Patients with complete radiographic response after cranial irradiation often progress rapidly post-irradiation. In contrast, some patients with enhancing masses at the end of chemoradiotherapy may respond dramatically to further chemotherapy alone, or the masses may even disappear in the absence of further therapy (so called "tumor pseudoprogression") [Chamberlain 2007]. This confounding situation demonstrates a need for better assessment of tumor response.
Detailed Description	Positron emission tomography (PET) is a molecular imaging modality that can probe various aspects of tumor function using a variety of radio-labeled imaging agents ("tracers"). Oncologic PET imaging has seen a dramatic rise in clinical utilization over the past decade for cancer detection, staging, and evaluating residual or recurrent disease following therapy. These clinical scans use the tracer [18F]fluoro-2-deoxy-D-glucose (FDG), which accumulates in cells in proportion to GLUT transporter and hexokinase activity. FDG thus provides a measure of tissue glucose metabolism. Concurrent with this clinical growth, a number of other PET tracers have received significant attention in research for a variety of imaging targets. Of special interest are the tracers 3'-deoxy-3'-[18F]fluorothymidine (FLT), 1-[11C]-acetate (ACE), and [15O]water (H2O). The uptake, retention/washout, and ultimate biodistribution of these tracers are each related to different functional or molecular processes. As such, each can be used to probe a different aspect of tumor function: FLT directly assesses tumor proliferation, ACE provides a measure of tumor growth related to fatty acid and membrane synthesis, and H2O quantifies tumor perfusion. OBJECTIVES: This study has two primary objectives: a translational objective in which a new PET imaging technology will be translated from experimental development (with simulations and in animals) to the first use in human subjects; and an exploratory objective in which the complementary value of multiple PET tracers will be investigated. Each of these objective is described below, where the study design has been carefully setup to fulfill both objectives in the same study population. The translational objective of this study is to implement and evaluate a new imaging technology for rapid, single-scan multi-tracer PET imaging of these tracers. Current PET technology prohibits imaging of more than one tracer in a single scan since the imaging signals from each tracer cannot be distinguished by normal techniques; as such, separate scans with each tracer currently need to be acquired hours or days apart. Our group has developed techniques and algorithms for recovering individual-tracer images from rapidly-acquired multi-tracer PET data using dynamic imaging techniques. These methods have been tested through extensive simulations and verified experimentally in a canine model with spontaneously-occurring tumors. Refinement of the methods with more advanced algorithms is ongoing. The patient imaging studies of this protocol will be implemented in two phases. In Phase A, separate single-tracer imaging of each tracer will be performed. The data from these scans will be co-registered and combined to "emulate" multi-tracer scans, which will then be processed by the multi-tracer signal-separation algorithms. This will permit a direct comparison of imaging biomarkers from multi-tracer vs. single-tracer scans for each tracer. Such comparison techniques have been established by the investigators and have been accepted by peer review for testing multi-tracer signal-separation algorithms. Once statistically-significant evidence is obtained that multi-tracer scans can accurately provide the same imaging biomarkers as separate single-tracer scans, the imaging will transition to Phase B—in which actual multi-tracer scans will be performed. The objectives of this exploratory study is to preliminarily evaluate the complementary value of FDG, FLT, ACE, and H2O PET in patients with primary glial neoplasms. Multi-tracer PET profiles with these four tracers will be obtained in 20 patients with primary glial neoplasms at up to three timepoints: (1) at "baseline" prior to surgery or immediately after surgery providing a complete surgical resection was not possible and confirmed by a post-operative contrast MRI scan where residual tumor greater than 1.0 cm in diameter was present and prior to any tumor-directed therapy; (2) at the conclusions of the initial (~6-8 weeks) chemoradiotherapy; and (3) at the time of MRI-documented recurrence within 2 years. In addition, patients with a known primary brain tumor who have previously undergone treatment and have recurred based on standard clinical and imaging criteria will be eligible for the study. A number of quantitative and pseudo-quantitative imaging biomarkers for each tracer will be computed at each imaging timepoint, and the change in each biomarker between timepoints will also be computed. These data will be compared with clinical endpoints (survival, time to progression), and with tumor biologic information (histology, WHO grade, vascularity, Ki-67, VEGF, EGFR, p53) in cases when tumor tissue becomes available from standard care. These data will provide pilot information into the potential value of concurrent multiple PET biomarkers for predicting tumor behavior prior to the start of therapy, for improved prognostication, for more efficient and effective tumor surveillance, and/or for more appropriate assignment of patients to conventional, aggressive, or investigational therapies early in their clinical courses. The driving hypothesis for the overall line of research is that multiple PET imaging biomarkers obtained in conjunction can provide improved image-guided personalized care of patients with primary glial neoplasms. The term "personalized care" is used here to broadly include the prediction of tumor behavior prior to the start of therapy, tumor surveillance, prognostication, and individualized assignment of patients to conventional, aggressive, or investigational therapies early in their clinical courses. This pilot project will obtain initial data on the value of these PET biomarkers for such image-guided personalized care. Specific hypotheses to be tested include: HYPOTHESIS I a: Rapid, single-scan multi-tracer PET imaging can recover PET imaging biomarker information of each tracer that are not significantly different from those obtained from conventional, single-tracer scans of each tracer.; HYPOTHESIS II b: Multi-tracer PET biomarkers, obtained in conjunction, are better able to predict tumor aggressiveness than individual-tracer biomarkers or conventional radiographic imaging.; HYPOTHESIS III b: Multi-tracer PET biomarkers, obtained in conjunction, are better able to detect functional changes in tumor state that occur in response to therapy than individual-tracer biomarkers or conventional radiographic imaging.; HYPOTHESIS IV b: Characterization of multiple aspects of tumor function (glucose metabolism, proliferation, membrane growth, and perfusion) provides new insight into tumor status that can guide selection of the most appropriate therapy. a Sufficient statistical power is expected to be obtained under this protocol to validate the extensive simulations and experimental evaluations performed previously and concurrently with these patient imaging studies. b Pilot data regarding these three hypotheses will be obtained in this work by studying the correlation of PET imaging biomarkers with clinical outcomes and tumor biologic information. Though high statistical power cannot be expected from the limited number of patients in this pilot study, underlying trends in the data will be identified, permitting the formulation of formal hypotheses to be tested in future rigorous trials.
Study Type	Observational
Study Design	Observational Model: Case-Only; Time Perspective: Prospective
Target Follow-Up Duration	Not Provided
Biospecimen	Not Provided
Sampling Method	Non-Probability Sample
Study Population	Study patients: Adult patients (n = 20) with (Group 1) compelling MRI evidence of a new primary brain tumor who have not yet undergone surgery or any tumor-directed therapy, or (Group 2) newly diagnosed primary malignant brain tumors (WHO Grade II-IV glial-based tumors)who have not had a complete surgical resection and by contrast MRI have residual tumor greater than 1.0 cm in diameter and will be receiving radiotherapy and/or chemotherapy, or (Group 3) patients with recurrent primary barin tumor as determined by standard clinical criteria and MRI imaging. Four to eight patients per year will be enrolled during the first 3 years, for a total of 20 patients. Enrollment will be weighted toward lower-grade tumors during year 1 in order to allow for longer followup times during the life of the project. Dr. Jensen or Dr. Colman will identify and recruit patients for participation and obtain informed consent.
Condition	Brain Tumors; Cancer
Intervention	Radiation: Multi-tracer PET exams of 18F-FDG, 18F-FLT, 11C-ACE, and 15O-H2O; Baseline: prior to surgery or immediately after surgery and prior to any tumor-directed therapy;; After the initial (~6-8 weeks) chemoradiotherapy;; At the time of MRI-documented recurrence within 2 years (patients with a known primary brain tumor who have previously undergone treatment and have recurred will be eligible for study). The PET scanning will be implemented in two phases: Phase A (separate single-tracer scans with each tracer) will be completed with imaging over two consecutive days and Phase B (where two or more tracers will be imaged in a single scan using rapid multi-tracer PET techniques under development) in one or two imaging sessions according to the best method validated from the Phase A results. The exact order and timing of the multi-tracer exams will vary.
Study Groups/Cohorts	Diagnostic; Intervention: Radiation: Multi-tracer PET exams of 18F-FDG, 18F-FLT, 11C-ACE, and 15O-H2O
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status	Recruiting
Estimated Enrollment; (submitted: December 19, 2008)	20
Original Estimated Enrollment	Same as current
Estimated Study Completion Date	July 2018
Estimated Primary Completion Date	July 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria	Inclusion Criteria: Three different adult patient groups will be eligible for inclusion in this study: Group 1: Adult patients with compelling evidence of primary brain tumor based on clinical and MRI imaging characteristics that have not yet received surgery, histological diagnosis, or any tumor-directed therapy. Such evidence will include: MRI or CT scan-documented mass lesion within the brain, accompanied by anatomically appropriate neurological signs and symptoms, in the absence of a probable competing diagnosis such as brain abscess or primary intracranial hematoma.; Group 2: Newly diagnosed primary malignant brain tumors (WHO Grade II - IV glial-based tumors) who have not had a complete surgical resection and by contrast MRI have residual tumor greater than 1.0 cm in diameter and will be receiving radiotherapy and/or chemotherapy.; Group 3: Patients with recurrent primary brain tumor as determined by standard clinical criteria and MRI imaging. Patients must be 18 years or older for inclusion in this study. There is little experience with the safety of [18F]FLT in children, and the risks associated with radiation exposure may be increased for children under 18 years old as well. Karnofsky performance status > 60%. Patients must document their willingness to be followed for at least 24 months after recruitment by signing informed consent documenting their agreement to have clinical endpoints and the results of histopathologic tissue analysis (when tissue becomes available from routine care) entered into a research database. All patients, or their legal guardians, must sign a written informed consent and HIPAA authorization in accordance with institutional guidelines. Determination of pregnancy status: Female patients that are not postmenopausal or surgically sterile will undergo a serum pregnancy test prior to each set of multi-tracer PET scans. A negative test will be necessary for such patients to undergo research PET imaging. Pre-treatment laboratory tests for patients receiving [18F]FLT must be performed within 21 days prior to study entry. These must be less than 2.5 times below or above the upper or lower limit range for the respective laboratory test for entry into the study. In those instances where a baseline laboratory value is outside of this range, then such a patient will be ineligible for enrollment. For the followup scanning sessions after therapy has been instituted, laboratory testing will also be required due to the use of FLT. The patients have brain tumors and will receive various forms of therapy; therefore many routine laboratory tests may not be within the typical normal range. As such, a factor of 4.0 times above or below the upper or lower value for the normal range for any laboratory test will be used to determine the acceptable range for the 2nd and possible 3rd imaging timepoints. The baseline laboratory testing will include liver enzymes (ALT, AST, ALK, LDH), bilirubin (total), serum electrolytes, CBC with platelets and absolute neutrophil counts, prothrombin time, partial thromboplastin time, BUN, creatinine. Previous urinalysis abnormalities will not preclude the patient from being studied. For those patients receiving coumadin or another anticoagulant the upper limit for prothrombin time or partial thromboplastin time must not exceed 6 times the upper limit of the normal range. Exclusion Criteria: Patients with clinically significant signs of uncal herniation, such as acute pupillary enlargement, rapidly developing motor changes (over hours), or rapidly decreasing level of consciousness, are not eligible.; Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals. Patients with significant drug or other allergies or autoimmune diseases may be enrolled at the Investigator's discretion.; Patients who are pregnant or lactating or who suspect they might be pregnant. Serum pregnancy tests will be obtained prior to each set of multi-tracer PET scans in female patients that are not postmenopausal or surgically sterile.; Adult patients who require monitored anesthesia for PET scanning.; HIV positive patients due to the previous toxicity noted with FLT in this patient group.; Patients who have undergone surgery or receive any previous tumor-directed therapy for their brain tumor.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts	Contact: Kelli Rasmussen 801-213-4218 kelli.rasmussen@hci.utah.edu Contact: Britney Beardmore 801-587-5591 britney.beardmore@hci.utah.edu
Listed Location Countries	United States
Removed Location Countries
Administrative Information
NCT Number	NCT00813566
Other Study ID Numbers	HCI31335
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	University of Utah
Study Sponsor	University of Utah
Collaborators	Not Provided
Investigators	Principal Investigator: John M Hoffman, MD Huntsman Cancer Institute Study Chair: Daniel Kadrmas, PhD Huntsman Cancer Institute Study Chair: Randy Jensen, MD,PhD Huntsman Cancer Institute Study Chair: Howard Colman, MD,PhD Huntsman Cancer Institute
PRS Account	University of Utah
Verification Date	January 2018