Protocol Number: 03-C-0284

Title:

A Clinical Trial of the P-Glycoprotein Antagonist, Tariquidar (XR9576), in Combination With Docetaxel in Patients With Lung, Ovarian, Renal and Cervical Cancer: Analysis of the Interaction Between Tariquidar and Docetaxel

Number:

03-C-0284

Summary:

The purpose of this study is three-fold: 1) to examine the ability of the experimental drug tariquidar to improve chemotherapy results by blocking a protein (P-glycoprotein) on some cancer cells that acts to pump out cancer drugs; 2) examine how tariquidar interacts with the cancer drug docetaxel; and 3) evaluate the effectiveness of combination treatment with tariquidar and docetaxel in treating patients with lung, ovarian, or cervical cancer.

Patients 18 years of age and older with recurrent or metastatic (spreading) lung, cervical, or ovarian cancer who cannot benefit from any standard treatment may be eligible for this study. Candidates will be screened with a medical history and physical examination; review of pathology slides; blood and urine tests; imaging tests, including computed tomography (CT) or magnetic resonance imaging (MRI) scans; chest x-ray, and possibly a bone scan or other imaging tests needed to evaluate the cancer; electrocardiogram (EKG); and possibly echocardiogram.

Participants will undergo the following tests and procedures:

- Tumor biopsy. Before starting chemotherapy, a small piece of tumor is removed to study the P-glycoprotein pump and to determine the tumor genetics.

- Blood draw. Blood is drawn before treatment begins to establish baseline levels for future blood tests. Blood counts are done twice weekly after chemotherapy begins.

- Central venous catheter placement. A plastic tube is put into a major vein in the chest. It is used to give the study drugs or other medications, including antibiotics and blood transfusions, if needed, and to withdraw blood samples. The line is usually placed under local anesthesia in the radiology department or the operating room. It can stay in the body for months or be removed after each treatment is completed.

- Chemotherapy. Treatment cycles are 21 days. Both drugs are given on day 1 of each cycle. First, tariquidar is given as a 30-minute infusion. One hour after the tariquidar infusion, docetaxel is infused over 1 hour. (For the first cycle only, docetaxel is given in divided doses one week apart. Patients will be hospitalized for several days during this cycle to gather research data.) The tariquidar dose remains the same throughout the study. Docetaxel may be increased or decreased from cycle to cycle, based on side effects. Treatment will continue for two cycles after all the cancer is gone, or until surgery is done to remove some or all of the remaining cancer, or, if surgery is not an option, until the cancer has grown to where it is defined as progressive disease.

- Nuclear scans. Nuclear scans are done during the first treatment cycle before and after administration of tariquidar to see how well the P glycoprotein responds to the drug.

- CT scans. CT scans are done every two treatment cycles to follow disease progress.

- Surgery. Surgery to remove areas of cancer may be considered at any point during the study (including before beginning treatment), if it is deemed beneficial. Treatment with the study drugs will begin or resume after surgery. The length of treatment will depend on the response to treatment before the surgery and on whether there is any cancer remaining after the surgery.

Patients will continue on the study as long as the treatment helps control their disease. When a patient stops the study, he or she will have blood tests, a physical examination, and a CT or MRI scan to determine the response to therapy and guide future 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 or equal to 18 years.

2. Histologic or cytologic confirmation of lung, cervical, or ovarian cancer, following at least one standard treatment regimen, and for which there is no known standard therapy capable of extending life expectancy. Female patients with primary papillary carcinoma of the peritoneum and fallopian tube cancers will be included in the latter group, as the disease entities are closely associated with epithelial ovarian carcinoma, can be difficult to distinguish, have a similar epithelial origin, and are treated in an identical manner.

3. Histologic or cytologic confirmation of renal cell carcinoma

(clear cell, type I and type II papillary chromophobe, collecting duct and medullary). Patients should have received either sunitinib or sorafenib, unless deemed ineligible for treatment with either agent. In addition, patient should either: (a) have received IL-2; (b) have been evaluated for therapy with IL-2 and deemed to be ineligible; or (c) have been evaluated for therapy with IL-2 and refused treatment.

4. Performance status: ECOG 0-2.

5. Life expectancy of 3 months or greater.

6. Suitable candidate for receiving planned therapy as evidenced by screening laboratory assessments hematologic, renal, hepatic, and metabolic functions: platelet count greater than or equal to 90,000/mL absolute granulocyte count (AGC) greater than or equal to 1,500/mL, serum creatinine less than or equal to 1.5 mg/dl (or if greater than 1.5, a measured 24 hour creatinine clearance greater than or equal to 50 mL/min), SGPT and SGOT less than or equal to 2.5 x NL, and bilirubin less than or equal to 1.5 x NL (in patients with clinical evidence of Gilbert's disease, less than or equal to 3 x NL).

7. Patients must be greater than or equal to 4 weeks from prior radiation or chemotherapy; greater than 2 weeks from hormonal therapy; greater than 4 weeks from prior experimental therapy; greater than 6 weeks from mitomycin C; and greater than 8 weeks from prior UCNO1 treatment.

8. No serious intercurrent medical illness.

9. Measurable disease by radiographic means or physical examination. For ovarian cancer, assessable disease by CA125 measurement is allowed.

10. Willingness to sign a written informed consent form, and to comply with the protocol.

EXCLUSION CRITERIA:

The following patient populations are not eligible for study:

1. Pregnant or nursing women are not eligible; women of childbearing age must agree to use an effective method of contraception. Pregnant women are not eligible because of teratogenic effects of chemotherapy.

2. The presence of a second malignancy that has not received primary treatment or would complicate the primary objective of the study.

3. Patients who are poor medical risk because of active, uncontrolled infection or other non-malignant systemic disease.

4. HIV seropositive patients. Patients infected with the HIV virus will be excluded from this trial because the effect of the combination of tariquidar and docetaxel on HIV replication and/or the immune system is unknown and potentially harmful.

5. Patients receiving agents which have major interactions with the CYP3A4 drug metabolizing system and which cannot be discontinued may not be included in the trial.

6. Untreated brain metastases (or local treatment of brain metastases within the last 6 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic toxicities.

Special Instructions:

Currently Not Provided

Keywords:

Pharmacokinetics

Pharmacodynamics

P-glycoprotein Inhibition

Multidrug Resistance Reversal

Molecular Target

Recruitment Keyword(s):

Lung Cancer

Ovarian Cancer

Cervical Cancer

Renal Cancer

Condition(s):

Lung Neoplasms

Ovarian Neoplasms

Cervix Neoplasms

Renal Neoplasms

Investigational Drug(s):

XR9576

Investigational Device(s):

None

Intervention(s):

Drug: XR9576

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, et al, 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.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

Search The Studies | Help | Questions |
Clinical Center Home | NIH Home

National Institutes of Health Clinical Center Bethesda, Maryland 20892. Last update: 09/15/2008