Brain Neoplasms
Conditions
Keywords
Brain neoplasms, Children, Positron-Emission Tomography, 18F-FLT
Brief summary
Brain tumors are the leading cause of death from solid tumors in children. Tumor imaging is important in the management of these tumors, but current imaging methods have limitations in providing the necessary information for optimal treatment of these patients. The goal of this study is to evaluate the potential utility of positron emission tomography (PET) with 3'-deoxy-3'-\[F-18\] fluorothymidine (18F-FLT) in the medical management of brain tumors in children. Funding source - FDA Office of Orphan Product Development (OOPD)
Detailed description
Although pediatric central nervous system tumors are rare, they are a significant contributor to morbidity and mortality in children. Tumor staging, detecting recurrent tumor, and assessing the response to therapy are critical in the treatment of brain tumors, but current imaging methods have major limitations in providing such information. The objective of this study is to validate 3'-deoxy-3'-\[F-18\] fluorothymidine (18F-FLT) as a measure of tumor proliferation and to demonstrate the utility of 18F-FLT as a PET imaging agent in children with central nervous system tumors. The proposed studies will evaluate 18F-FLT PET in three groups: 1. Children with a new diagnosis of central nervous system tumor. 2. Children in whom conventional imaging has raised concern for possible recurrence of a central nervous system tumor. 3. Children receiving post-operative chemotherapy for a central nervous system tumor. In these three groups, correlation of 18F-FLT uptake with tumor histopathology and patient outcome will be used to assess the utility of 18F-FLT for grading tumors at diagnosis, for accurate identification of tumor recurrence, and for early assessment of the response to chemotherapy.
Interventions
DRUG[18F] FLT
\[18F\] FLT, intravenous, at a dose of 0.15 mCi/kg once before a PET scan
Sponsors
Dana-Farber Cancer Institute
Frederick Daniel Grant
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* age 21 years or less * capable of achieving imaging without need for sedation or anesthesia (typically age 8 years or greater, but there is no lower limit for age for eligibility) * Karnofsky Performance Status of 50 or greater in subjects age 12 years or greater, for age less than 12 years a Lansky play scale of 50% or greater * Patients receiving steroids and/or anti-seizure medications are eligible
Exclusion criteria
* clinically active infection * pregnancy or breast-feeding * serious intercurrent medical illness * require emergency surgical intervention that would be inappropriately delayed by FLT-PET imaging
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [18F] Fluorothymidine ([18F]-FLT) Uptake as a Marker of Cellular Proliferation | on average 1 week | \[18F\] FLT uptake, as determined by pre-operative positron emission tomography (PET) imaging, will be compared to histological markers of cellular proliferation in the resected brain tumor. This will be performed in three groups of subjects (3 arms): (1)children with newly diagnosed central nervous system tumors, (2) children in whom there is concern for recurrence of central nervous system tumor,(3) children with central nervous system tumors that are treated with post-operative chemotherapy. |
| MIB Positive (Percent) | 30 days | On pathological specimens, tumor proliferation was assessed as the fraction of cells with positive MIB immunostaining |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biodistribution of [18F]FLT | 6 hours | The distribution, localization, and kinetics of localization of \[18F\] FLT will be assessed by FLT-PET in 12 subjects. |
| Preliminary Evaluation of Clinical Utility of [18F] FLT PET | 3 months | In individuals with a diagnosed primary brain tumor in whom therapy will include chemotherapy,.\[18F\] FLT uptake, as determined by positron emission tomography (PET) imaging, will assessed before and after two cycles of chemotherapy. Response will be determined by comparing the FL uptake before and after therapy. |
Countries
United States
Participant flow
Recruitment details
Potential participants were identified by clinicians participating in their care.
Pre-assignment details
Participants were assigned to one of three arms, depending on clinical presentation: 1) Clinical concern for new brain tumor, 2) Clinical concern for recurrent brain tumor, or 3) Planned initiation of new chemotherapy for a known brain tumor
Participants by arm
| Arm | Count |
|---|---|
| New Diagnosis of Brain Tumor In children with a new diagnosis of central nervous system tumor, a PET scan will be performed using \[18F\] FLT.
\[18F\] FLT: \[18F\] FLT, intravenous, at a dose of 0.15 milliCurie (mCi)/kg once before a PET scan | 16 |
| Possible Recurrent Brain Tumor In children in whom there is concern for recurrent central nervous system tumor, a PET scan will be performed using \[18F\] PET.
\[18F\] FLT: \[18F\] FLT, intravenous, at a dose of 0.15 mCi/kg once before a PET scan | 28 |
| Brain Tumor Response to Chemotherapy In children with a newly diagnosed central nervous system tumor who will be treated with post-operative chemotherapy, a PET scan will be performed using \[18F\] FLT before the start and after two cycles of chemotherapy.
Despite much effort and working with referring physicians at multiple hospitals, enrollment in this arm remained low, and it seemed unlikely that meaningful enrollment would be accomplished. A revised study plan was submitted to the granting agency and FDA, and this arm was closed to further enrollment.
\[18F\] FLT: \[18F\] FLT, intravenous, at a dose of 0.15 mCi/kg once before a PET scan | 6 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | MIB immunopathology results not available | 3 | 2 | 0 |
| Overall Study | PET data failure | 0 | 1 | 0 |
| Overall Study | Physician Decision | 2 | 18 | 5 |
| Overall Study | Radiopharmaceutical FLT (18F-fluorothymidine) unavailable to perform PET scan before surgery | 1 | 1 | 0 |
| Overall Study | Surgical pathology did not confirm evaluable brain tumor | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | New Diagnosis of Brain Tumor | Possible Recurrent Brain Tumor | Brain Tumor Response to Chemotherapy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 27 Participants | 6 Participants | 49 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Brain Tumor classification Embryonal Tumors (including former PNET) | 1 Participants | 7 Participants | 1 Participants | 9 Participants |
| Brain Tumor classification Germ Cell Tumors (Teratoma) | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Brain Tumor classification Gliomas, Glioneuronal, and Neuronal Tumors | 11 Participants | 18 Participants | 5 Participants | 34 Participants |
| Brain Tumor classification Hematolymphoid Tumors (Lymphoma) | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Brain Tumor classification Non-neoplastic Process/No Diagnosis | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Brain Tumor classification Pineal Tumors | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 1 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 19 Participants | 4 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 9 Participants | 16 Participants | 3 Participants | 28 Participants |
| Region of Enrollment United States | 16 participants | 28 participants | 6 participants | 50 participants |
| Sex/Gender, Customized Female | 1 Participants | 15 Participants | 1 Participants | 17 Participants |
| Sex/Gender, Customized Male | 13 Participants | 11 Participants | 4 Participants | 28 Participants |
| Sex/Gender, Customized Other/ Not recorded | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 28 | 0 / 6 |
| other Total, other adverse events | 1 / 16 | 3 / 28 | 0 / 6 |
| serious Total, serious adverse events | 0 / 16 | 2 / 28 | 0 / 6 |
Outcome results
Primary
[18F] Fluorothymidine ([18F]-FLT) Uptake as a Marker of Cellular Proliferation
\[18F\] FLT uptake, as determined by pre-operative positron emission tomography (PET) imaging, will be compared to histological markers of cellular proliferation in the resected brain tumor. This will be performed in three groups of subjects (3 arms): (1)children with newly diagnosed central nervous system tumors, (2) children in whom there is concern for recurrence of central nervous system tumor,(3) children with central nervous system tumors that are treated with post-operative chemotherapy.
Time frame: on average 1 week
Population: Participants were evaluable if brain tumor surgery was performed within 30 days of the FLT-PET scan, if surgical pathology confirmed the diagnosis of brain tumor, and the results of tissue immunohistology were available. On the brain PET scan, tumor uptake of FLT was assessed by SUVmax, the standard clinical measure of tracer uptake, and tumor proliferation was assessed as the fraction of cells with positive MIB immunostaining
| Arm | Measure | Value (MEAN) |
|---|---|---|
| New Diagnosis of Brain Tumor | [18F] Fluorothymidine ([18F]-FLT) Uptake as a Marker of Cellular Proliferation | 1.57 SUV max |
| Possible Recurrent Brain Tumor | [18F] Fluorothymidine ([18F]-FLT) Uptake as a Marker of Cellular Proliferation | 3.00 SUV max |
Comparison: This is a diagnostic test of FLT uptake (SUV max) as a predictor of cellular proliferation (MIB) and is performed as an analysis of correlation using each evaluable participant enrolled in either Arm 1 (New Diagnosis) or Arm 2 (Possible recurrent tumor). The groups (Arm 1 and Arm 2) provide pathways for enrollment. Correlation between the two measures of outcome (SUV max and MIB) is evaluated.p-value: <0.001Regression, Linear
Primary
MIB Positive (Percent)
On pathological specimens, tumor proliferation was assessed as the fraction of cells with positive MIB immunostaining
Time frame: 30 days
Population: Participants in Arm 3 (Brain tumor response to chemotherapy) were not expected to undergo surgery during their chemotherapy. Therefore, they did have FLT-PET, but no assessment for tumor proliferation (percent MIB positive) was performed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| New Diagnosis of Brain Tumor | MIB Positive (Percent) | 17.3 percent positive cells |
| Possible Recurrent Brain Tumor | MIB Positive (Percent) | 32.8 percent positive cells |
Secondary
Biodistribution of [18F]FLT
The distribution, localization, and kinetics of localization of \[18F\] FLT will be assessed by FLT-PET in 12 subjects.
Time frame: 6 hours
Population: Saved PET scan data has not been retrievable or usable due to 1) storage/format incompatibility among PET cameras from different vendors, 2) lack of interoperablity among different generations of cameras from the same vendor, and 3) backup data in institutional radiology archiving systems is not universally available for retrieval for quantitative image analysis. To date, working with camera vendors and software developers has been unsuccessful in overcoming this problem.
Secondary
Preliminary Evaluation of Clinical Utility of [18F] FLT PET
In individuals with a diagnosed primary brain tumor in whom therapy will include chemotherapy,.\[18F\] FLT uptake, as determined by positron emission tomography (PET) imaging, will assessed before and after two cycles of chemotherapy. Response will be determined by comparing the FL uptake before and after therapy.
Time frame: 3 months
Population: Despite much effort and working with referring physicians at multiple hospitals, enrollment in this arm remained low and participant completion of the entire protocol was low. As it seemed unlikely that meaningful enrollment would be accomplished, a revised study plan was submitted to the granting agency and FDA, and this arm was closed to further enrollment. Due to the small number of participants completing the protocol, FLT uptake was assessed, but clinical outcome was not evaluated.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| New Diagnosis of Brain Tumor | Preliminary Evaluation of Clinical Utility of [18F] FLT PET | FLT uptake pre-therapy | 0.85 SUV max |
| New Diagnosis of Brain Tumor | Preliminary Evaluation of Clinical Utility of [18F] FLT PET | FLT uptake post-therapy | 0.47 SUV max |
p-value: 0.04t-test, 2 sided