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Patients will undergo a single \[11c\]acetate PET scan OR Patients will undergo an \[11c\]acetate PET scan, initiate treatment with rapamycin or rapalogs and receive a second \[11c\]acetate PET scan 3 or 4 months after starting the treatment.

[11C]acetate

Carmen Priolo

Carmen P Priolo, MD PhD

This study aims to assess \[11C\]acetate positron emission tomography (PET)/computed tomography (CT) as a biomarker for renal angiomyolipomas and pulmonary lymphangioleiomyomatosis (LAM) and an early biomarker of response to rapamycin in LAM patients.

\[11C\]Acetate is a radioactive form of acetate, a nutrient commonly processed in our body's cells to generate fat and energy. Preclinical studies support the hypothesis that TSC tumors enhance lipid synthesis compared to normal tissues, suggesting that quantification of \[11C\]acetate in these tumors by PET/CT may provide a metabolic biomarker of disease.

Participants in the study will undergo 1 or 2 PET/CT scans over 3 to 6 months at the Massachusetts General Hospital (Boston, MA). \[11C\]acetate is administered through an intravenous catheter. This small amount of radioactivity is short-lived and eliminated from the body within a few hours.

Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease of women, consisting of a diffuse proliferation of smooth muscle actin-positive cells (LAM cells), which harbor inactivating mutations in either the TSC1 or TSC2 tumor suppressor gene. These inactivating mutations result in constitutive activation of mammalian/mechanistic TOR (target of rapamycin) complex 1 (mTORC1), which integrates growth factor and nutrient signaling to stimulate cell growth and metabolism. Pulmonary LAM is characterized by associated progressive cystic destruction of the lung parenchyma, recurrent pneumothorax, and chylous pleural effusions. Extrapulmonary proliferative lesions of LAM include renal angiomyolipomas and lymphangiomyomas. LAM can occur as a sporadic disorder where LAM cells harbor somatic inactivating mutations of the TSC1 or TSC2 gene, or in women with Tuberous Sclerosis Complex (TSC).

Rapamycin is an FKBP12-dependent allosteric inhibitor of mTORC1 approved by the FDA for the treatment of LAM and TSC-associated renal angiomyolipomas. Clinical trials of TSC and LAM have shown that 12 month-treatment with rapamycin induces response of renal angiomyolipomas and stabilization of pulmonary function. However, lung function decline and tumor growth resume when treatment is interrupted.

Sensitive and specific biomarkers of response to therapy and/or disease progression, including biomarkers of tumor metabolic activity, would facilitate clinical trials of novel therapeutic agents for LAM and enable optimization of current rapamycin-based regimens.

Our preclinical studies showed that lipogenic pathways can be detected in preclinical animal models of TSC and LAM using PET-based metabolic imaging.

The proposed study aims to quantitatively and non-invasively assess metabolic activity and response to rapamycin in LAM patients using \[11C\]acetate positron emission tomography (PET) imaging.

Feasibility of [11C]Acetate-PET in LAM and TSC

Feasibility Study of [11C]Acetate Positron Emission Tomography (PET) as an Indicator of Early Response to Rapamycin in Lymphangioleiomyomatosis (LAM) Patients

Standardized uptake value (SUV) will be used to quantify uptake

Massachusetts General Hospital

Brigham and Women's Hospital

Assistant Professor of Medicine

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Deoxyglucose

Antimetabolites

Antiviral Agents

All participants will receive multi-tracer PET scans at up to 3 time points: baseline, at the conclusion of standard of care chemoradiation, and at the time of documented recurrence within two years.

Brain scan with metabolic imaging tracer that aids in assessment, diagnosis, and staging of patients with cancer.

[18F]fluoro-2-deoxy-D-glucose (FDG)

Brain scan with a radiolabeled imaging agent for investigating cellular proliferation of tumors

3'-deoxy-3'-[18F]fluorothymidine (FLT)

Brain scan with imaging agent to determine tumor blood flow

[15O]-H2O

Brain scan with imaging agent to determine growth activity of tumor

[11C]Acetate

John M Hoffman, MD

Daniel Kadrmas, PhD

Randy Jensen, MD,PhD

Howard Colman, MD,PhD

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.

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 glucose (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, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (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.

Multi-Tracer PET Assessment of Primary Brain Tumors

University of Utah

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Recurrence

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

intravenous injection of an average of 40 mCi of \[11C\]Acetate

Wendell Yap, MD

When evaluating prostate cancer patients for recurrent disease, computed tomography (CT), and magnetic resonance imaging (MRI) are both highly sensitive methods for detecting lymph nodes, but are not specific as to whether the lymph nodes are malignant or benign.

While positron emission tomography (PET) utilizing radioactive glucose (FDG) has revolutionized staging, restaging, and monitoring response to therapy in many prevalent cancers such as breast, colorectal, esophageal, head and neck, lung, lymphoma, and melanoma, findings with prostate cancer have proven less sensitive because prostate cancer has a lower avidity for glucose. A newer PET isotope, utilizing acetate that is incorporated into the cell membrane of rapidly proliferating cells, has shown greater sensitivity than FDG in detecting prostate cancer.

This study will assess the clinical effectiveness of utilizing \[11C\]Acetate PET scans in identifying recurrent prostate cancer.

FDG-PET imaging uses a form of radioactive glucose (18-fluoro-deoxyglucose or FDG), which allows the measurement of glucose metabolic rate of any tissue in the body. The most prevalent tumors have a glucose avidity that is typically greater than 2.5 times the avidity of benign tissue. Therefore, FDG-PET is able to discriminate between benign lymph nodes and those containing metastases, and similarly between scar tissue and recurrence of tumor.

Unfortunately, prostate cancer is only minimally glucose avid, and therefore, FDG-PET is much less effective in staging prostate cancer. The current FDA-approved imaging agent for prostate cancer is a monoclonal antibody specific for prostate cancer cells, capromab pendetide, labeled with a long-lived radionuclide \[111\]Indium that is used to image the patient over a six day period. However, recent data show that another PET radiopharmaceutical, \[11C\]Acetate (which has been FDA approved for years for cardiac imaging), is avidly taken up by prostate metastasis and is more sensitive than either \[111\]Indium capromab pendetide or FDG-PET.

This study will assess the clinical effectiveness of utilizing \[11C\]Acetate PET scans in identifying recurrent prostate cancer and aim to find at what PSA levels it is most effective.

Clinical Management Decisions for Recurrent Prostate Cancer Patients Based on [11C]Acetate PET Scan

Clinical Management Decisions Based on [11C]Acetate Positron Emission Tomography Performed on Prostate Cancer Patients With Biochemical Recurrence

University of Kansas Medical Center

Assistant Professor, Department of Radiology

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Feasibility of [11C]Acetate-PET in LAM and TSC	NCT05467397	Lymphangioleiom... Tuberous Sclero...	[11C]acetate	18 Years -	Brigham and Women's Hospital
Multi-Tracer PET Assessment of Primary Brain Tumors	NCT00813566	Brain Tumors Cancer	[18F]fluoro-2-d... 3'-deoxy-3'-[18... [15O]-H2O [11C]Acetate	18 Years -	University of Utah
Clinical Management Decisions for Recurrent Prostate Cancer Patients Based on [11C]Acetate PET Scan	NCT01777061	Prostate Cancer	[11C]Acetate	45 Years - 80 Years	University of Kansas Medical Center

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