(11C)dLop as a Marker of P-Glycoprotein Function in Patients With Gliomas

BACKGROUND:

A potential impedance to successful glioma chemotherapy is sanctuary for tumor behind the
blood brain barrier. P-glycoprotein (Pgp) is an efflux transporter encoded by MDR1 that
contributes to the functional regulation of substrates across the cerebrovasular endothelium.
Pgp activity in patients with gliomas may influence response to therapy and neurotoxicity.
(11C) N-desmethyl-loperamide (11C)dLop) is a radioligand substrate for Pgp, and PET imaging
with this molecular marker may provide a non-invasive, in vivo method of examining Pgp
function in brain tumor patients.

OBJECTIVES:

Primary:

-To measure the uptake of (11C)N-desmethyl-loperamide ((11C)dLop) using PET imaging as a
marker of Pglycoprotein function in patients with intracranial gliomas

Secondary:

- Correlate (11C)dLop PET uptake with perfusion MRI parameters and FDG PET uptake for
volumes of interest (VOI) determined by the baseline MRI

- Develop exploratory data for the correlation of (11C)dLop PET imaging with patient
outcomes such as response to therapy, survival, and neurotoxicity

- Develop exploratory data for the correlation of (11C)dLop PET imaging with
immunohistochemical and molecular genomic assays of MDR1 and Pgp

ELIGIBILITY:

Patients with predominantly non-enhancing intracranial gliomas will be eligible.

DESIGN:

This is a pilot study of (11C)dLop PET imaging in 10 patients with intracranial glioma.
Standard uptake values (SUVs) corrected for cerebral blood flow determined by (15O)H20 PET
scans will be correlated to DCE-MRI (obtained within prior 2 weeks) and FDG-PET (obtained
within prior 4 weeks) to characterize locoregional differences in Pgp function. When
available, correlative studies performed on archived tumor tissue acquired immediately
subsequent to (11C)dLop scanning will include immunohistochemical assays of Pgp expression,
as well as characterization of MDR1 polymorphisms. Patient case histories will be followed
longitudinally to make observations about how (11C)dLop imaging may correlate with patient
outcomes such as response to therapy, survival, and neurotoxicity.

- INCLUSION CRITERIA:

- Patients with histologically proven intracranial glioma will be eligible for this
protocol. Eligible histologies include glioblastoma multiforme (GBM), gliosarcoma
(GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed
oligoastrocytoma (AMO), malignant astrocytoma NOS (not otherwise specified), low grade
astrocytoma (LGA), low grade oligoastocytoma (LOA), and low grade oligodendroglioma
(LGO). Patients with radiographically diagnosed or suspected low grade glioma will
also be eligible.

- Patients having undergone recent resection will be eligible as long as all of the
following conditions apply:

- They have recovered from the effects of surgery, not to have been performed
within 2 weeks of the study scan.

- Residual enhancing or non-enhancing disease following resection of recurrent
tumor is mandated for eligibility into the study. To best assess the extent of
residual disease post-operatively, a CT/ MRI should be done:

- no later than 96 hours in the immediate post-operative period, or

- at least 4 weeks post-operatively, and

- within 14 days of registration, and

- on a steroid dosage that has been stable for at least 5 days.

- Normal organ and marrow function defined as: total leukocyte count greater than or
equal to 3000 cells/ul, ANC greater than or equal to 1500 cells/ul, platelet count
greater than or equal to 100,000 cells/ul, serum creatinine less than or equal to 2.0
X upper limit of normal, and bilirubin less than or equal to 1.5X upper limit of
normal, hemoglobin greater than or equal to 9.0 g/dL , serum calcium less than12.0
mg/dL, AST/ALT less than or equal to1.5 times the upper limit of normal, PT less than
or equal to1.5 ULN.

- All patients or their previously designated DPA (if the patient is deemed by the
treating physician to be impaired or questionably impaired in such a way that the
ability of the patient to give informed consent is questionable) must sign an informed
consent indicating that they are aware of the investigational nature of this study.

- Patients must be greater than or equal to 18 years old.

- Patients must have a Karnofsky performance status of greater than or equal to 60.

- Patients must not have any significant medical illnesses that in the investigator s
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patients ability to tolerate this study.

- This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender. No exclusion to this study will be based on race. Minorities
will actively be recruited to participate.

EXCLUSION CRITERIA:

- Patients who, in the view of the treating physician, have significant active cardiac,
hepatic, renal, or psychiatric diseases are ineligible.

- Patients who have an active infection.

- Pregnant (positive pregnancy test) or nursing women.

- Patients cannot take loperamide within three days of (11C)dLop imaging.

- Concurrent use of a Pgp inducer as listed in Appendix A within 2 weeks of a study
scan. Use of these medications is allowed over the course of participation in the
study, but must not be administered within 2 weeks of the study imaging.

- Prior participation in other research protocols or clinical care in the last year such
that radiation exposure, including that from this protocol, would exceed the
guidelines set by the Radiation Safety Committee (RSC).

- Patients who have any contraindication to gadolinium enhanced MRI.