Clinical trial NCT00069160: Tariquidar and Docetaxel to Treat Patients With Lung, Ovarian, Renal and Cervical Cancer
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lung Neoplasms
Ovarian Neoplasms
Cervix Neoplasms
Renal Neoplasms
Keywords: Pharmacokinetics
Pharmacodynamics
Multidrug Resistance Reversal
Molecular Target
P-Glycoprotein Inhibition
Lung Cancer
Ovarian Cancer
Cervical Cancer
Renal Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2003-09-16
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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, electrocardiogram (EKG); and possibly echocardiogram.

Participants will undergo the following tests and procedures:

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 and tariquidar is administered on either day 1 or day 8. The order of tariquidar administration is randomized to generate optimal pharmacokinetic data. 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.

Detailed description: Intrinsic and acquired drug resistance remain major obstacles in the treatment of cancer. Accumulating evidence indicates that in some malignancies P-glycoprotein (Pgp) can confer resistance, and that its reversal can improve therapeutic outcome. Clinical trials investigating Pgp antagonists have been hampered by the occurrence of unpredictable pharmacokinetic interactions, which have required dose reductions of the chemotherapeutic agents to avert excessive toxicity. Tariquidar (XR9576) is a new Pgp antagonist that is more potent and has prolonged activity. Phase I trials with paclitaxel, vinorelbine, and docetaxel have demonstrated that tariquidar (XR9576) has minimal pharmacokinetic interactions while surrogate studies have confirmed in vivo inhibition of Pgp-mediated drug transport.This study seeks to determine the pharmacokinetic interaction, if any between docetaxel and tariquidar and to evaluate the potential for activity in lung, ovarian, primary peritoneal, fallopian tube and cervical cancers. Renal cell cancer has been added in a 3/1/06 amendment. The secondary goal is to evaluate the impact of tariquidar on uptake of (99m)Tc-sestamibi in recurrent or metastatic tumors of patients with lung, ovarian, renal or cervical cancer.

Eligibility criteria: Inclusion Criteria:

* Patients must fulfill all of the following criteria to be eligible for study admission:
* Age greater than or equal to 18 years.
* 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.
* Histologic or cytologic confirmation of renal cell carcinoma (clear cell, type 1 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 Interleukin-2 (IL- 2) and deemed to be ineligible; or (c) have been evaluated for therapy with IL2 and refused treatment.
* Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2
* Life expectancy of 3 months or greater.
* 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 greater than or equal to 1,500/mL, serum creatine 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) and serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5 x normal limit (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).
* Patients must be greater than or equal to 4 weeks 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 UCN01 treatment.
* No serious intercurrent medical illness.
* Measurable disease by radiographic means or physical examination. For ovarian cancer, assessable disease by cancer antigen 125 (CA125) measurement is allowed.
* Willingness to sign a written consent form, and to comply with the protocol.

Exclusion Criteria:

* The following patient populations are not eligible for this study.
* 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.
* The presence of a second malignancy that has not received primary treatment or would complicate the primary objective of this study.
* Patients who are poor medical risk because of active, uncontrolled infection or other nonmalignant systemic disease.
* Human immunodeficiency virus (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.
* Patients receiving agents which have major interactions with the cytochrome P450 3A4 (CYP3A4)drug metabolizing system and which cannot be discontinued may not be included in the trial.
* 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.

Primary outcomes:
measure: Geometric Mean of Maximum Concentration of the Drug (Cmax)
timeFrame: 24 hours
measure: The Number of Participants With Adverse Events.
timeFrame: 4 yrs 8-11 months
measure: Geometric Mean of Area Under Curve (AUC0)-24
timeFrame: 24 hours
measure: Clinical Response Rate
timeFrame: 4 years, 8-11 months
Secondary outcomes:
measure: Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar
timeFrame: 3 - 24 hours
measure: Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue
timeFrame: 3-24 hours
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health
state: Maryland
Study officials:
affiliation: NCI, NIH
name: Susan E Bates, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Kelly RJ, Draper D, Chen CC, Robey RW, Figg WD, Piekarz RL, Chen X, Gardner ER, Balis FM, Venkatesan AM, Steinberg SM, Fojo T, Bates SE. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res. 2011 Feb 1;17(3):569-80. doi: 10.1158/1078-0432.CCR-10-1725. Epub 2010 Nov 16.