A Pharmacodynamic Study of the P-glycoprotein (Pgp) Antagonist, CBT-1(Registered Trademark), Evaluating Pgp Inhibition in Tumors and Normal Tissues
This is a pharmacodynamic study aimed at evaluating the efficacy of CBT-1(Registered
Trademark) as a modulator of Pgp-mediated drug efflux in patient tumors and normal tissues.
The study will build on over a decade of experience with 99mTc-sestamibi imaging and
rhodamine accumulation and efflux in normal circulating CD56 plus cells as surrogates for
Pgp function. CBA Research, Inc., has carried out Phase I and II testing of CBT-1(Registered
Trademark) as a drug resistance reversal agent, but has not yet confirmed that the inhibitor
is able to block drug efflux.
Evaluate the impact of CBT-1(Registered Trademark) on the hepatic accumulation and retention
of 99mTc-sestamibi in patients with relapsed or refractory solid tumor malignancies.
Evaluate the impact of CBT-1(Registered Trademark) on P-glycoprotein-mediated efflux from
CD56 plus peripheral mononuclear cells.
Patients over 18 years of age who have histologic confirmation of relapsed/refractory
cancer, following at least once standard treatment regimen, for whom there is no known
standard therapy option capable of extending life expectancy. Patients must have an Eastern
Cooperative Oncology Group (ECOG) performance status of 2 or better, and have hematologic,
renal, hepatic, and metabolic parameters suggestive of adequate organ function.
Patients will be treated according to CBA Research Phase II trial of CBT-1 and Taxol.
Patients will begin protocol treatment with orally administered CBT-1(Registered Trademark)
in two or three divided doses daily for 7 days. On day 6, 135 mg/m^2 paclitaxel will be
administered by intravenous infusion over 3 hours. Prior to the initiation of
CBT-1(Registered Trademark), and on Day 6, patients will undergo blood sampling for the
rhodamine assay in CD56 plus circulating mononuclear cells. In addition, patients will
undergo imaging of tumors and normal tissue with the 99mTc-sestamibi radionuclide scan.
These two assays have shown convincing inhibition of Pgp-mediated drug efflux in past
studies with Pgp inhibitors such as tariquidar and valspodar. Twelve patients are planned
for enrollment to this study, which is powered to determine a difference between the control
scan and the post-treatment scan but not to compare CBT-1(Registered Trademark) with
previous inhibitors tested in the intramural program.
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Percent Increase in Sestamibi Retention in the Liver as a Measure of P-glycoprotein Inhibition
An area under the concentration curve (AUC) was calculated for 99mTc counts over the liver, lungs, and heart. An equation was applied to determine the increase in sestamibi in the liver: [(AUCpost - AUC baseline)/(AUC baseline)] x 100.
sestamibi scanning was performed on day 0 and day 6, allowing scans to be performed pre and post CBT-1 administration
Susan S Bates, M.D.
National Cancer Institute, National Institutes of Health
United States: Federal Government
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