Cervix Neoplasms, Lung Neoplasms, Ovarian Neoplasms, Renal Neoplasms
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics, Multidrug Resistance Reversal, Molecular Target, P-Glycoprotein Inhibition, Lung Cancer, Ovarian Cancer, Cervical Cancer, Renal Cancer
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.
Interventions
DRUGdocetaxel
Patients receive docetaxel intravenous (IV) over 1 hour on days 1 and 8.
DRUGtariquidar
Patients receive tariquidar intravenous (IV) over 30 minutes on days 8 and 22.
OTHER99mTc-sestamibi imaging
Bolus injection of 29 mCi of 99mTc-sestamibi intravenously for each imaging study.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean of Maximum Concentration of the Drug (Cmax) | 24 hours | In the first cycle patients were to receive docetaxel on days 1 and 8 and to be randomized to receive tariquidar on either day 1 or 8. Thus pharmacokinetic data with and without tariquidar can be compared. |
| The Number of Participants With Adverse Events. | 4 yrs 8-11 months | Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module. |
| Geometric Mean of Area Under Curve (AUC0)-24 | 24 hours | — |
| Clinical Response Rate | 4 years, 8-11 months | Response is determined by RECIST criteria defined as changes in only the largest diameter (unidimensional measurement) of the tumor lesion. Lesions are either measurable or non-measurable. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>/- 20 mm with conventional techniques (CT, MRI, xray) or as \>/- 10 mm with a spiral CT scan. Non-measurable lesions are defined as all other lesions (or sites of disease) including small lesions (longest diameter \<20 mm with conventional techniques or \<10 mm using spiral CT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar | 3 - 24 hours | A significant change in the area under the curve(AUC) in liver tissue (normal tissue as a surrogate) is defined as P\<0.001. A secondary objective of this study was to establish whether tariquidar (150 mg) modulates Pgp in liver. Sestamibi is a Pgp substrate that may be a surrogate for measuring drug efflux from tumors. A baseline Tc-sestamibi scan was obtained before the administration of tariquidar. A minimum of 48 hours later, on or about day 22 a single dose of tariquidar was administered, followed by a second Tc-sestamibi scan. |
| Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue | 3-24 hours | 99mTc-sestamibi is a radionuclide imaging agent used to study cardiac function that has also been shown to be a substrate for P-glycoprotein- mediated drug efflux. Because of the high expression of Pgp in liver tissue, sestamibi uptake in liver tissue is often monitored as a marker of Pgp inhibition. A significant change in the area under the curve(AUC) in liver tissue (normal tissue as a surrogate) is defined as P\<0.001. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 Patients receive 40 mg/m\^2 docetaxel intravenous (IV) over 1 hour on days 1 and 8 and 150 mg tariquidar intravenous (IV) over 30 minutes on days 8 and 22. From cycle 2 and onward 75 mg/m\^2 docetaxel was administered every 21 days in combination with a single 150 mg tariquidar dose. | 23 |
| Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 Patients receive docetaxel intravenous (IV) over 1 hour on days 1 and 8 and tariquidar intravenous (IV) over 30 minutes on days 1 and 22.From cycle 2 and onward 75 mg/m\^2 docetaxel was administered every 21 days in combination with a single 150 mg tariquidar dose. | 25 |
| Total | 48 |
Baseline characteristics
| Characteristic | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 19 Participants | 39 Participants |
| Age Continuous | 55.77 years STANDARD_DEVIATION 9.57 | 50.76 years STANDARD_DEVIATION 9.54 | 53.37 years STANDARD_DEVIATION 9.79 |
| Region of Enrollment United States | 25 participants | 23 participants | 48 participants |
| Sex: Female, Male Female | 20 Participants | 18 Participants | 38 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 23 | 25 / 25 |
| serious Total, serious adverse events | 6 / 23 | 8 / 25 |
Outcome results
Primary
Clinical Response Rate
Response is determined by RECIST criteria defined as changes in only the largest diameter (unidimensional measurement) of the tumor lesion. Lesions are either measurable or non-measurable. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>/- 20 mm with conventional techniques (CT, MRI, xray) or as \>/- 10 mm with a spiral CT scan. Non-measurable lesions are defined as all other lesions (or sites of disease) including small lesions (longest diameter \<20 mm with conventional techniques or \<10 mm using spiral CT.
Time frame: 4 years, 8-11 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel Alone | Clinical Response Rate | 8 Percentage of participants |
Primary
Geometric Mean of Area Under Curve (AUC0)-24
Time frame: 24 hours
Population: Docetaxel alone (C1D1 = 21 patients; C1D8 = 18 patients) Docetaxel with Tariquidar (C1D1 = 21 patients; C1D8 = 16 patients) Pharmacokinetic data were evaluable in 39 patients. Paired data from 31 participants were evaluable.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Docetaxel Alone | Geometric Mean of Area Under Curve (AUC0)-24 | Both Groups (C1D1 + C1D8) | 1339 h*ng/mL |
| Docetaxel Alone | Geometric Mean of Area Under Curve (AUC0)-24 | C1D1 | 1367 h*ng/mL |
| Docetaxel Alone | Geometric Mean of Area Under Curve (AUC0)-24 | C1D8 | 1308 h*ng/mL |
| With Tariquidar | Geometric Mean of Area Under Curve (AUC0)-24 | Both Groups (C1D1 + C1D8) | 1373 h*ng/mL |
| With Tariquidar | Geometric Mean of Area Under Curve (AUC0)-24 | C1D1 | 1409 h*ng/mL |
| With Tariquidar | Geometric Mean of Area Under Curve (AUC0)-24 | C1D8 | 1327 h*ng/mL |
p-value: >0.05t-test, 2 sided
Primary
Geometric Mean of Maximum Concentration of the Drug (Cmax)
In the first cycle patients were to receive docetaxel on days 1 and 8 and to be randomized to receive tariquidar on either day 1 or 8. Thus pharmacokinetic data with and without tariquidar can be compared.
Time frame: 24 hours
Population: Docetaxel alone (C1D1 = 21 patients; C1D8 = 18 patients) Docetaxel with Tariquidar (C1D1 = 21 patients; C1D8 = 16 patients) Data were evaluable in 39 patients. Paired data from 31 participants were evaluable.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Docetaxel Alone | Geometric Mean of Maximum Concentration of the Drug (Cmax) | C1D1 | 1315 Cmax (ng/mL) |
| Docetaxel Alone | Geometric Mean of Maximum Concentration of the Drug (Cmax) | C1D8 | 1060 Cmax (ng/mL) |
| Docetaxel Alone | Geometric Mean of Maximum Concentration of the Drug (Cmax) | Both Groups (C1D1 + C1D8) | 1190 Cmax (ng/mL) |
| With Tariquidar | Geometric Mean of Maximum Concentration of the Drug (Cmax) | C1D1 | 1093 Cmax (ng/mL) |
| With Tariquidar | Geometric Mean of Maximum Concentration of the Drug (Cmax) | C1D8 | 1026 Cmax (ng/mL) |
| With Tariquidar | Geometric Mean of Maximum Concentration of the Drug (Cmax) | Both Groups (C1D1 + C1D8) | 1063 Cmax (ng/mL) |
Primary
The Number of Participants With Adverse Events.
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time frame: 4 yrs 8-11 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Docetaxel Alone | The Number of Participants With Adverse Events. | 23 participants |
| With Tariquidar | The Number of Participants With Adverse Events. | 25 participants |
Secondary
Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar
A significant change in the area under the curve(AUC) in liver tissue (normal tissue as a surrogate) is defined as P\<0.001. A secondary objective of this study was to establish whether tariquidar (150 mg) modulates Pgp in liver. Sestamibi is a Pgp substrate that may be a surrogate for measuring drug efflux from tumors. A baseline Tc-sestamibi scan was obtained before the administration of tariquidar. A minimum of 48 hours later, on or about day 22 a single dose of tariquidar was administered, followed by a second Tc-sestamibi scan.
Time frame: 3 - 24 hours
Population: Percent increase in sestamibi AUC in liver after tariquidar.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Alone | Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar | 82.2 percent increase in sestamibi AUC |
Secondary
Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue
99mTc-sestamibi is a radionuclide imaging agent used to study cardiac function that has also been shown to be a substrate for P-glycoprotein- mediated drug efflux. Because of the high expression of Pgp in liver tissue, sestamibi uptake in liver tissue is often monitored as a marker of Pgp inhibition. A significant change in the area under the curve(AUC) in liver tissue (normal tissue as a surrogate) is defined as P\<0.001.
Time frame: 3-24 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Docetaxel Alone | Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue | 12.4 Percent |