University of California, Los Angeles

Funding for Human Subjects Research:

DOE: Institute of Molecular Medicine Research Program

$4,000,000.00 (Est.) for: Calendar Year 2005
For performance period 01/01/2005 - 12/31/2005 a total cost of $4,000,000 was received.
Percent of funding associated with the use of human subjects: 0

Information on Use of Human Subjects:

This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2

Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 11/07/05
IRB approval number: 04-10-045-02
Explanation of IRB approval:
Prior to the most recent IRB approval listed above (04-10-045-02) for this project, IRB 04-10-045-01 was approved on 12/21/2004.

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 55
Reporting period for number of human subjects: Fiscal Year 2005

Type(s) of Human Subjects Involvement:

External use of ionizing radiation on human subjects:

• For clinical research
• For diagnostic research

Internal administration of radioactive substances to human subjects:

• For clinical research
• For diagnostic research

Internal use of chemical substances (solid, liquid, or gas) on human subjects:

• For clinical research
• For diagnostic research

Collection of personally identifiable bodily materials (blood or blood products, urine, cells, tissue, teeth, organs, excreta, etc):

• Using existing specimens or samples of bodily materials collected for another purpose.

Use of personally identifiable data from questionnaires, surveys, or epidemiological studies:

• Using existing data that were collected for other purposes or projects.

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

We have extensively studied the role of FDG, FLT, and FDOPA imaging for metabolic phenotyping of patients with glioblastoma. We have also started metabolic phenotyping of patients with lung cancer. Imaging findings are being correlated with histopathology and immunohistochemistry, if available. Initial findings suggest that glioblastoma are best characterized by combining FDOPA and FLT imaging. Patient enrollment continues for all clinical studies.

Objectives: Imaging of tumor metabolism by positron emission tomography (PET) represents an attractive approach for assessing the efficacy of kinase inhibitors in cancer patients. (1) Many signaling pathways altered in malignant tumors play a central role in the regulation of cellular metabolism (e.g., MEK/MAPK, PI3K, and mTOR). (2) Increased metabolic activity is a common feature of most malignant tumors in patients. (3) There are a number of clinically established molecular imaging probes targeting various aspects of tumor metabolism. (4) By using these probes changes in tumor metabolism can be measured clinically with high sensitivity.

Methodology: Fifty-five patients with glioblastoma or non-small cell lung cancer were studied by PET with [18F]fluorodeoxyglucose (FDG), [18F]fluorothymidine (FLT), and/or [18F]DOPA (FDOPA). All studies were conducted in agreement and as approved by the UCLA radiation safety committee. For PET-imaging patients were injected with the positron emitting isotopes and imaged for twenty to sixty minutes on a state-of-the-art PET scanner. For PET studies of the brain, the ECAT Exact HR+ system (CPS Innovations, Knoxville, TN) is used. For the lung cancer studies PET/CT scans are obtained on a high resolution lutetium oxyorthosilicate (LSO) PET/CT Sensation 16 Scanner (CTI, Knoxville, TN). This system consists of an LSO PET system (CTI, Knoxville, TN) and an x-ray computed tomography (CT) system (Siemens Medical Systems, Iselin, NJ). PET data are acquired in the 3D mode. Dynamic images are acquired to permit quantitative metabolic phenotyping.

PET and PET/CT Image Analysis: Abnormal areas of metabolic activity are recorded. Regions of interest will are placed around the primary tumor and/or metastatic lesions on baseline and follow up scans. To quantify metabolic alterations mean and maximum standardized uptake values (SUV) are calculated. Further, FDG, FLT, and FDG net influx constant (Ki), micro parameters (K1,k2,k3), and metabolic rates are determined using non-linear regression as well as linear models (Patlak analysis). For FDOPA the micro parameters K1 and k2 as well as distribution volumes (K1/k2, Logan analysis) are calculated.

The risks of the procedure include a small chance for infection at the site of the intravenous catheter, a small risk of claustrophobia (<5 percent), and the potential risk of application of radioactivity. For the lung cancer studies, patients also undergo injection of intravenous contrast agents. Intravenous contrast administrations can cause allergic or even anaphylactic responses. When this occurs, the patient may experience severe hives and/or difficulty in breathing. This reaction is quite rare but is potentially life-threatening if not treated. Medications that may reverse this adverse reaction include corticosteroids, antihistamines, and epinephrine. If needed, antihistamines can be given to help relieve the symptoms. Toxicity to the kidneys that can result in kidney failure is an extremely rare complication of the intravenous contrast used in CT scans. Patients who already have impaired kidney function are most prone to this reaction. It is estimated that the overall frequency of adverse reactions to IV contrast is 5 to 10 percent. Most of these are very mild and may consist of only a few hives. However, in one of every 1,000 to 2,000 examinations, a moderate or severe reaction can occur. The risk of death from a contrast agent is estimated to be 0.3 to 2.6 per 100,000 uses (comparable in magnitude to the risk of death from receiving a dose of penicillin).The maximum total radiation dose received from all research PET/CT or PET scans is about 93 percent (or 4,650 mrem) of the maximal annual radiation dose that may be legally received by a radiation worker in the USA. The added radiation dose that will be received from this study is well below the levels that are known to result in risks of harmful effects. The risk of radiation exposure associated with PET and PET/CT imaging are specified in the informed consent forms.

Data are collected and stored in accordance with the Health Insurance Portability and Accountability Act (HIPAA), i.e. data are anonymized and kept in a locked file cabinet. Files stored on computers are password protected. Only the principal investigator and investigators immediately involved in the study have access to the data.

Institutional Review Board (IRB) Review:
Type of Review: Expedited
Approving Institution: University of California, Los Angeles
Most recent approval: 11/22/05
IRB approval number: 02-08-062-04A
Explanation of IRB approval:
Prior to the most recent IRB approval listed above (02-08-062-04A) for this project, IRB 02-08-62-03B was approved on 11/01/2004.

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects: Fiscal Year 2005

Type(s) of Human Subjects Involvement:

Internal administration of radioactive substances to human subjects:

• For therapeutic research

Internal use of chemical substances (solid, liquid, or gas) on human subjects:

• For diagnostic research

Collection of personally identifiable bodily materials (blood or blood products, urine, cells, tissue, teeth, organs, excreta, etc):

• Using bodily materials collected specifically for this project.

Use of personally identifiable data from questionnaires, surveys, or epidemiological studies:

• Using data collected from subjects specifically for this project.

Use of human beings to develop/test instruments, materials, devices, objects, and the like or to investigate the "man-machine interface".

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

Objectives:
The proposed project focuses on determining the effect that use of naproxen (a non-steroidal anti-inflammatory drug) has on the binding of 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), a small molecule radiolabeled probe of beta-amyloid, to be used with positron emission tomography (PET) for early detection and treatment monitoring of Alzheimer's disease (AD).

We tested the following hypothesis: Naproxen preferentially binds to the senile plaques (SP) found in the brains of people with mild cognitive impairment or early Alzheimer's disease, displacing the FDDNP probes. This displacement will demonstrate itself as a weaker PET signal for those subjects as compared to the same subjects before oral administration of the anti-inflammatory drug.

Methodology:
We included subjects with mild cognitive impairment or early Alzheimer's disease will be treated with naproxen. Patients will serve as their own controls, before and after the naproxen. We anticipate that approximately 50 percent of the subjects will be male and 50 percent female.

In the control arm of the study, subjects will be asked to abstain from non-steroidal anti-inflammatory drugs (NSAIDs) of any sort for a one-week period prior to the FDDNP scan. Subjects will undergo PET scans at the UCLA PET Center. For the experimental arm, subjects will be asked to take 220 mg sodium naproxen at 9:00 pm the night before the second [18F]FDDNP scan and then another tablet at 12:30 pm the day of the scan. Two weeks after the second scan, the patients will be again asked to refrain from use of NSAIDs and they will have an additional FDDNP scan to demonstrate reversibility of naproxen effects. All scans will take place within two months, with at least two weeks between the second (possibly third) and third (possibly fourth) scans.

Ionizing radiation, radioactive substances, chemical substances:
List any chemical or radioactive substances ionizing radiation to which human subjects are exposed.
The amount of radiation dose that subjects receive with each of three FDDNP scans is 250 mrem (for a total of 750 mrem), and the head computed tomography (CT) scan is 200 mrem. In the entire study the radiation dose is about 19 percent (950 mrem) of the annual limit for these radiation workers. If a fourth FDDNP PET scan is performed, it will add an additional 250 mrem of radiation for a total of 1,200 mrem or 24 percent for these radiation workers. The added radiation dose that will be received from this study is well below the levels that are thought to result in a significant risk of harmful effect.

Involvement of Human Subjects:
Procedures
Subjects will receive a Psychiatric/Neurological Assessment, complete Questionnaires, Routine Laboratory Blood Samples, DNA Blood Samples drawn, and an electrocardiogram (EKG) at first visit. Subsequent visits will involve PET scan lasting 2 hours, neuropsychological evaluation for 3 hours, and an MRI scan for 1 hour.

Risks:
Approximately 3 to 9 percent of patients receiving the drug experience constipation, heartburn, abdominal pain and nausea, headache, drowsiness, or dizziness. Other side effects may include difficulties concentrating, depression, nervousness, irritability, fatigue, insomnia, or sleep disorders. Patients may also experience ringing in the ears, hearing or visual disturbances, or blood conditions. Other potential adverse effects include skin itching, rashes, bruising, sweating, sensitivity to the sun and swelling of the hands, feet, heart failure, increase in heart rate, shortness of breath, increases in blood pressure, thirst, hair loss, muscle pain, muscle weakness and cramps, high temperature, sore throat, pneumonia, bowel inflammation, severe allergic reactions, or menstrual disturbances.

The PET scan exposes the subject in the entire study to less than the annual limit for radiation workers who receive up to 5,000 mrem of radiation dose per year. The added radiation dose that will be received from this study is well below the levels that are thought to result in a significant risk of harmful effect.

If the subject should participate again in the following 12 months in a research study involving radiation at UCLA, the investigator/or associates will ensure through accurate record keeping, that the total amount of radioactivity administered for research purposes will remain small and again is not expected to cause any adverse effects.

Privacy/confidentiality/consent:
No information about the subject will be disclosed to others without the subject's written permission except if necessary to protect their rights or welfare or if required by law. If brain imaging slides are used for educational purposes, any identifying information will be removed before use. Authorized representatives of the Food and Drug Administration (FDA) or funding agencies who review subject data are bound by rules of confidentiality not to reveal their identity. Subject files are stored in locked computer databases and access is only granted to authorized research personnel. An identification number is assigned to each subject, and only these numbers and not the participant names are used in data files.