Dr. Michael
E.
Phelps
Institute for Molecular Medicine
23-120 CHS
Box 951570
Los Angeles, CA 90095-1570
Phone: 310-825-6539
Fax: 310-825-6267
E-mail: mphelps@mednet.ucla.edu
Number of Human Subjects projects reported: 1
| UCLA-06-DE-FG02-06ER64249 | "Institute for Molecular Medicine Research Program" |
"Institute for Molecular Medicine Research Program"
Principal Investigator: Dr. Michael E. Phelps, University of California, Los Angeles
Project started in: 2006
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 6
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 11/22/05
IRB approval number: 02-08-062
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 2006
Type(s) of Human Subjects Involvement:
Abstract
a. Objectives
The project focuses on determining the effect that use of naproxen (a non-steroidal anti-inflammatory drug, NSAID) 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 are testing 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.
b. Methodology
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 naproxen administration. 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 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 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.
c. Ionizing radiation, radioactive substances, chemical substances. List any chemical or radioactive substances ionizing radiation to which human subjects are exposed.
The amount of whole body radiation dose that subjects receive with each of three FDDNP scans is 250 mrem (for a total of 750 mrem). In the entire study the radiation dose is less than 20 percent of the annual limit for the 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 the radiation workers.
d. Involvement of Human Subjects:
1) 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 a magnetic resonance imaging (MRI) scan for 1 hour.
2) Risks.
Approximately 3 to 9 percent of patients receiving the drug naproxen experience constipation, heartburn, abdominal pain and nausea, headache, drowsiness, and dizziness. Other side effects may include difficulties concentrating, depression, nervousness, irritability, fatigue, insomnia, and sleep disorders. Patients may also experience ringing in the ears, hearing or visual disturbances, and blood conditions. Other 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, and menstrual disturbances.
The PET scan exposes the subject in the entire study 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.
3) 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.
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 11/30/05
IRB approval number: 03-09-042
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 13
Reporting period for number of human subjects:
Fiscal Year 2006
Type(s) of Human Subjects Involvement:
Neoadjuvant therapy prior to surgery is the standard of care in sarcoma patients. There is a need for non-invasively assessing tumor responses to therapy. The goal of this study was to determine whether treatment induced changes in glucose metabolic activity correlate with histological amount of tumor necrosis in patients with sarcomas.
Forty-seven patients were studied with PET/computed tomography(CT) at baseline and then again 11 ± 3.7 weeks later. The time from follow up scan to surgery was 3.8 ± 2.7 weeks. There were 8 bone and 39 soft tissue sarcomas. Tumor glucose metabolic treatment response was estimated by changes in standardized uptake values (SUV). The extent of tumor necrosis was expressed as a fraction of residual viable tumor. All 47 sarcomas had visible FDG uptake with mean SUVs ranging from 1 to 19. Complete data are available in 14 patients. Tumor mean SUV decreased by 45 ± 33 percent from 4.9 ± 3.0 to 2.0 ± 1.1 after therapy (p=0.0007). Relative changes in FDG-uptake as well as residual FDG-uptake after therapy were significantly correlated with the amount of tumor necrosis in the resected specimens (r2=0.66, p=0.007 and r2=0.70, p=0.005, respectively). There was no significant correlation between pre-therapeutic FDG-uptake and percentage of tumor necrosis (r2=0.28, p=0.15).
Patient enrollment continues. A typical PET/CT scan protocol includes the injection of 0.21 mCi/kg of 18F-fluoro-2-deoxyglucose (FDG) followed by a 45- to 60-minute uptake period, after which the patient is positioned in the scanner. A standard spiral CT scan is acquired with and without contrast.
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 11/21/05
IRB approval number: 04-10-091
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 7
Reporting period for number of human subjects:
Fiscal Year 2006
Type(s) of Human Subjects Involvement:
Introduction:
AEE788 is a small molecule inhibitor of the epidermal growth factor receptor (EGFR)-tyrosine kinase and the vascular endothelial cell growth factor receptor (VEGFR) tyrosine kinase pathways. These pathways are associated with tumor cell proliferation and vascular supply to tumors, respectively. It is proposed that by inhibition of EGFR/VEGFR (by AEE788), the modulation of the signal transduction pathways would result in inhibition of tumor growth. In all arms of the trial, in addition to MRI scan, changes in uptake of the PET probe [18F]-fluoro-L-thymidine ([18F]FLT) will be used to assess drug induced changes in tumor cell proliferation. Tumor growth rate is a useful prognostic indicator of tumor aggressiveness and tumor response to therapy. PET imaging can be used to measure tumor cell proliferation using thymidine analogs. 18F-fluoro-L-thymidine ([18F]FLT) is a thymidine analogue labeled with the 18F positron-emitting isotope of fluorine that can be used to measure tumor cell proliferation.
There are two objectives: First, to evaluate the effect of AEE788 treatment on FLT PET changes in patients with recurrent glioblastoma multiforme. Second, to evaluate whether FLT is a good surrogate marker to monitor the treatment effects.
Methods:
FLT PET data from seven patients were analyzed. Of those patients, six patients had analyzable both sets (pre- and post-treatment) of FLT PET studies. One patient had progressive disease and decided not to repeat the second FLT PET. Each FLT PET file was co-registered to the corresponding baseline MRI. PET data were analyzed in several different ways. First, regions of interest (ROIs) were drawn over three consecutive slices. Tumor ROIs were placed on the summed scans by drawing an 80%-of-peak-voxel-intensity isocontour on the slices with maximal tumor uptake to avoid cysts and resection cavities. Activity counts in the ROIs were normalized to injected dose per patient's body weight (SUV). The mean SUV in such an ROI was defined as SUVmax20. For tumors that did not show visible PET uptake, the MRI was used as a reference. Second, tumor to normal tissue ratio (T/N) was generated using the SUVmax20 over the mean SUV of the normal hemispheric brain. Third, a standard ROI was generated using a standard circular ROI over the maximum activity (8-mm diameter). Fourth, tumor volume was determined using a threshold (3 standard deviations over the mean normal brain SUV). The product of the tumor volume and the mean SUV in the volume was defined as "total lesion activity" (TLA). Fifth, each FLT PET file was analyzed by looking at the early vascular phase (0 to 5 min), perfusion phase (5 to 15 min), and cellular uptake phase (30 to 60 min).
Preliminary Results: The mean changes were essentially equivalent using different measuring criteria, such as SUVmax20, T/N, and standard ROI. In non-responding lesions, there was essentially no change in SUVmax20 (-1 percent), 6 percent decrease in T/N ratio, and 2 percent decrease in standard ROI. In responding lesions, there was a 37 percent decrease in SUVmax20, 38 percent decrease in T/N ratio, and 40 percent decrease in standard ROI. TLA seems to be a more robust measuring tool. In non-responding lesions, there was an average of 26 percent increase in tumor volume and 60 percent increase in TLA. In the responding lesion, there was a 14 percent decrease in vascular flow and 9 percent decrease in perfusion which resulted in about 40 percent decrease in intra-cellular FLT uptake. In non-responding lesions, there were no significant changes in vascular flow (2 percent) or perfusion (-3 percent). Though the data were limited, this may indicate that the drug may not have effect by simply changing the vascular flow and perfusion. The bidimensional area on baseline MRI was 14.3 cm2 for one responding tumor and 30.5 cm2 for non-response tumors. The volume on baseline MRI was 33 cm3 for a responding tumor (50300501) and 54 cm3 for non-response tumors. On post-treatment MRI, the average bidimensional area was 27 cm2 for a responding tumor and 35 cm2 for non-response tumors; the average volume was 47 cm3 for a response tumor and 68 cm3 for non-response tumors. There was an increase of 89 percent in bidimensional area in a response tumor and 2 percent in non-response tumors. There was an increase in volume of 42 percent in a response tumor and 11 percent in non-response tumors.
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
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 5
Reporting period for number of human subjects:
Fiscal Year 2006
Type(s) of Human Subjects Involvement:
Since kinase inhibitors have a cytostatic rather than cytotoxic effect, CT measurements of treatment responses are likely to be unreliable. In contrast, measurements of glycolytic activity with PET have been shown to predict treatment responses to cytostatic drugs in some other cancers.
This study aims at monitoring the effects of kinase inhibitor therapy on tumor growth and glucose metabolism. Participants undergo a maximum of three PET/CT scans: the baseline scan before treatment, the scan two weeks after start of treatment, and the scan 12 weeks after start of treatment. Changes in glucose metabolism and tumor size are quantified. Patient outcome (survival, time to recurrence) will serve as the gold standard.
To date, five patients (3 males, 2 females; mean age 70.8±13.2 years) have been enrolled. No adverse events related to PET/CT imaging have been noticed. Patient enrollment continues to allow for a statistical meaningful interpretation of the data.
A typical PET/CT scan protocol includes the injection of 0.21 mCi/kg of 18F-fluoro-2-deoxyglucose (FDG) followed by a 45- to 60-minute uptake period, after which the patient is positioned in the scanner. A standard spiral CT scan is acquired with and without contrast.
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 12/09/05
IRB approval number: 04-10-068
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 7
Reporting period for number of human subjects:
Fiscal Year 2006
Type(s) of Human Subjects Involvement:
Since kinase inhibitors have a cytostatic rather than cytotoxic effect CT measurements of treatment responses are likely to be unreliable. In contrast, measurements of glycolytic activity with PET have been shown to predict treatment responses to cytostatic drugs in some other cancers. This study aims at monitoring the effects of kinase inhibitor therapy on tumor growth and glucose metabolism. Participants undergo a maximum of three PET/CT scans: the baseline scan before treatment, the scan two weeks after start of treatment and the scan 12 weeks after start of treatment. Changes in glucose metabolism and tumor size are quantified. Patient outcome (survival, time to recurrence) will serve as the gold standard.
To date, seven patients (6 males, 1 female; mean age 47.1±15.4 years) have been enrolled. No adverse events related to PET/CT imaging have been noticed. Patient enrollment continues to allow for a statistical meaningful interpretation of the data.
A typical PET/CT scan protocol includes the injection of 0.21 mCi/kg of 18F-fluoro-2-deoxyglucose (FDG) followed by a 45- to 60-minute uptake period, after which the patient is positioned in the scanner. A standard spiral CT scan is acquired with and without contrast.
Institutional Review Board (IRB) Review:
Type of Review:
Full Board
Approving Institution: University of California, Los Angeles
Most recent approval: 02/03/06
IRB approval number: 03-12-094
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 27
Reporting period for number of human subjects:
Year prior to last IRB approval date
Type(s) of Human Subjects Involvement:
Objectives:
Bevacizumab (Avastin), a monoclonal antibody that binds to VEGF-A, is designed to inhibit angiogenesis and has been shown to be clinically effective in various cancers. 18F-fluorothymidine (FLT) and 18F-fluorodopa (FDOPA) are biomarkers that have been used for measuring tumor cell proliferation and amino acid metabolism in brain tumors with PET. The aim of this ongoing study was to prospectively determine in patients with recurrent gliomas whether PET imaging with FLT and FDOPA can be used to predict tumor responses to Avastin in combination with Irinotecan (CPT11).
Methods:
Twenty patients (10 male, 10 female; mean age 53 ± 17 years, range 28 to 78 years), with recurrent gliomas were prospectively studied. The tumor types based on the World Health Organization (WHO) histopathologic classification were as follows: glioblastoma; n=15; anaplastic mixed glioma: n=5. All patients received FLT and FDOPA PET within 3 days prior to therapy. PET was acquired for 60 min after the injection of 3.5 mCi FLT and for 30 min after the injection of 3.5 mCi FDOPA. Frames were summed for 30 to 60 min p. i. for FLT and 10 to 30 min p. i. for FDOPA. Brain T1- and T2-weighted MR images, with and without gadolinium-DTPA, were acquired in all patients within one week prior to therapy. PET studies were repeated after the first and the fourth week of therapy. PET response was defined as >30 percent decline in tumor to normal tissue ratio, and these results were compared with standard response criteria based on MR images at 6 weeks and clinical assessment.
Results:
Nine patients died with mean time to death of 104±64 days. All three failed to meet PET response criteria by both FDOPA and FLT. Eleven patients are alive with mean follow up time of 215±62 days. Seven of the nine non-responders died; two of ten responders died. FDOPA and FLT PET at one week after therapy correctly predicted MR response in 93 percent and 100 percent of patients, respectively. One patient with glioblastoma who had responded by both MR and FLT PET criteria, but not by FDOPA PET, had a large contrast enhancing lesion which resolved completely on MR; nevertheless, non-contrast-enhancing tumor subsequently progressed.
Conclusions:
The response of brain tumors to Avastin/CPT11 therapy as assessed by late MR and clinical criteria was accurately predicted by reduction of FLT or FDOPA activity at one week after initiation of therapy. Imaging results will continue to be correlated with patient outcome data.