Protocol Number: 08-C-0035

Title:

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

Number:

08-C-0035

Summary:

Background:

-Some cancer cells have a large amount of a protein called P-glycoprotein, which can pump certain chemotherapy drugs out of their cells. This pump may be part of the reason why it is difficult to shrink some cancers with chemotherapy.

-In laboratory experiments, the drug CBT-1® (Registered Trademark) blocked the P-glycoprotein pump, resulting in accumulation of higher amounts of chemotherapy inside the cancer cells, making the chemotherapy more effective.

-Paclitaxel is a cancer drug that has caused tumors to shrink in many types of cancers, including lung, ovarian, breast, renal, cervical and others.

Objectives:

-To determine whether CBT-1® (Registered Trademark) can block the P-glycoprotein pump on cancer cells and whether it inhibits the action of the pump found in normal blood cells and liver tissue.

-To evaluate the effectiveness of combination therapy using CBT-1® (Registered Trademark) and paclitaxel in treating solid tumors and to determine whether the two drugs together are more effective than paclitaxel alone.

Eligibility:

-Patients over 18 years of age who have a solid tumor that cannot be treated successfully with standard treatments.

Design:

-Patients receive CBT-1® (Registered Trademark) and paclitaxel in 21-day cycles. Treatment continues for two cycles after all the cancer is gone, or until it is decided to surgically remove some or all of the remaining cancer, or until the cancer has grown to the point where it defined as progressive disease.

For each cycle, patients take CBT-1® (Registered Trademark) by mouth in three divided doses daily for 7 days. On day 6, paclitaxel is given through a vein over 3 hours.

Blood tests are done before starting CBT-1® (Registered Trademark) and repeated periodically throughout treatment.

Imaging studies (CT or MRI) are done every two cycles. In addition, for the first cycle only, patients undergo imaging of tumors and normal tissue with a (99m) Tc-sestamibi radionuclide scan before and after administration of CBT-1® (Registered Trademark). This scan helps show how well the P-glycoprotein pump is being blocked by the treatment.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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 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 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), SGOT 4 times institutional upper limit of normal, bilirubin 2.0 mg/dl, PT less than 1.5 times institutional upper limit of normal, 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. 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 antibiotics.

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.

EXCLUSION CRITERIA:

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 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. 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 premedication.

10. Clinically significant bleeding disorders.

11. Patients with solid organ allografts.

12. Patients on daily gastric acid secretion inhibitors.

Special Instructions:

Currently Not Provided

Keywords:

Pgp

Solid Tumors

Drug Resistance

Sestamibi

Recruitment Keyword(s):

Cancer

Solid Tumor

Condition(s):

Cervical

Ovarian

Lung

Breast

Renal

Investigational Drug(s):

CBT-1® (Registered Trademark)

Investigational Device(s):

None

Intervention(s):

Drug: CBT-1® (Registered Trademark)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Ling V, Thompson LH.Reduced permeability in CHO cells as a mechanism of resistance to colchicine.J Cell Physiol. 1974 Feb;83(1):103-16. No abstract available.

Akiyama S, Fojo A, Hanover JA, Pastan I, Gottesman MM. Isolation and genetic characterization of human KB cell lines resistant to multiple drugs.Somat Cell Mol Genet. 1985 Mar;11(2):117-26.

Beck WT, Cirtain MC, Lefko JL.Energy-dependent reduced drug binding as a mechanism of Vinca alkaloid resistance in human leukemic lymphoblasts.Mol Pharmacol. 1983 Nov;24(3):485-92.

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