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A Pharmacodynamic Study of the P-glycoprotein (Pgp) Antagonist, CBT-1(Registered Trademark), Evaluating Pgp Inhibition in Tumors and Normal Tissues

18 Years
80 Years
Not Enrolling
Cervical, Ovarian, Lung, Breast, Renal

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Trial Information

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.

Inclusion Criteria


Patients must fulfill all of the following criteria to be eligible for study admission:

1. Age greater than 18 years.

2. Histologic or cytologic confirmation at National Cancer Institute (NCI) Laboratory of
Pathology, of recurrent or refractory, or advanced metastatic cancer of the
gastrointestinal tract, breast, Taxol (Trademark) naive breast cancer, small cell
lung, ovarian, prostate, head and neck, multiple myeloma, non-small cell lung cancer,
Taxol (Trademark) naive non-small cell lung cancer.

3. Performance status of Eastern Cooperative Oncology Group (ECOG) 0-2.

4. Life expectancy of 3 months or greater.

5. Patient must have adequate hematologic, renal, hepatic, and metabolic functions as
defined: platelet count greater than 100,000 /mL, absolute granulocyte count (AGC)
greater than 1500/mL, serum creatinine less than 2.0 mg/dl (or if greater than 2.0, a
measured 24 hour creatinine clearance greater than 50 mL/min), serum glutamic
oxaloacetic transaminase (SGOT) 4 times institutional upper limit of normal,
bilirubin 2.0 mg/dl, prothrombin time (PT) less than 1.5 times institutional upper
limit of normal, partial thromboplastin time (PTT) less than 1.5 times institutional
upper limit of normal, calcium less than 5.3mEq/L, albumin greater than 2.0 g/dl.

6. Electrocardiogram (EKG) showing, at most, minor abnormalities that in the judgment of
the protocol chairman would not compromise the patient's ability to tolerate therapy.

7. Patients must be greater than 4 weeks from prior radiation or chemotherapy; greater
than 2 weeks from hormonal or immunotherapy; greater than 4 weeks from prior
experimental therapy; greater than 6 weeks from mitomycin; and greater than 8 weeks
from prior UCN01 treatment. Patients receiving dexamethasone as a pretreatment for
anaphylactic reactions to Taxol (Trademark) or the cremophor vehicle will not be
excluded from this study.

8. No serious intercurrent medical illness or serious infection that requires parenteral

9. Measurable disease by radiographic means or physical examination.

10. Willingness to sign a written informed consent.

11. Patients must agree to an effective method of contraception for the study
(abstinence, hormonal or barrier method of birth control, or condom) for the study
and 30 days after completion of protocol.


The following patient populations are not eligible for study:

1. Women of childbearing potential and potentially fertile men will be excluded unless
using an effective contraception (ie. a barrier intrauterine device (IUD), birth
control pill, or condom), during the treatment. Women who are pregnant or nursing
will also be excluded.

2. Patients with significant intercurrent disease.

3. Human Immunodeficiencey virus (HIV) seropositive patients. Note: There may be an
impact of CBT-1 on the pharmacokinetics of the drugs used in the therapy of HIV.

4. Ongoing serious infections that require parenteral antibiotics.

5. Patients with significant central nervous system (CNS) disease, including a history
of seizures within the last 3 months or psychiatric history which would impair the
ability to give informed consent or prevent compliance with protocol requirements.

6. Patients must not be eligible for surgery, or radiotherapy that is of known benefit
to them, in terms of extension of survival. Patients with tumors sensitive to
potentially curative chemotherapy must have failed such chemotherapy. Patients who
have received radiation therapy may participate in this study one week after the
conclusion of radiation therapy provided that the lesion being irradiated is not one
that is being used to assess the efficacy of CBT-1 plus Taxol.

7. History of significant coronary artery disease, cardiac arrhythmias requiring
treatment, or history of other cardiac disease that in the judgment of the
investigators, would compromise the patient's ability to tolerate the therapy.

8. Patients with active bleeding due to peptic ulcer disease.

9. History of anaphylactic reactions to paclitaxel or cremophor despite adequate

10. Clinically significant bleeding disorders.

11. Patients with solid organ allografts.

12. Patients on daily gastric acid secretion inhibitors.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percent Increase in Sestamibi Retention in the Liver as a Measure of P-glycoprotein Inhibition

Outcome Description:

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.

Outcome Time Frame:

sestamibi scanning was performed on day 0 and day 6, allowing scans to be performed pre and post CBT-1 administration

Safety Issue:


Principal Investigator

Susan S Bates, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

December 2007

Completion Date:

June 2009

Related Keywords:

  • Cervical
  • Ovarian
  • Lung
  • Breast
  • Renal
  • Pgp
  • Solid Tumors
  • Drug Resistance
  • Sestamibi
  • Cancer
  • Solid Tumor



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892