A Phase 2 interventional study of docetaxel and tariquidar in Lung Neoplasms, Ovarian Neoplasms and Cervix Neoplasms, sponsored by National Cancer Institute (NCI). Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2012-10-12.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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.
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This study's enrollment of 48 is close to the median of 50 across 7,253 interventional studies indexed under Neoplasms.
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Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.
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Exclusion Criteria:
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 dose.
Drug: docetaxel · Drug: tariquidar · Other: 99mTc-sestamibi imaging
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.
Drug: docetaxel · Drug: tariquidar · Other: 99mTc-sestamibi imaging
Patients receive docetaxel intravenous (IV) over 1 hour on days 1 and 8.
Also known as: Taxotere
Patients receive tariquidar intravenous (IV) over 30 minutes on days 8 and 22.
Also known as: XR9576
Bolus injection of 29 mCi of 99mTc-sestamibi intravenously for each imaging study.
Also known as: Cardiolite
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
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
Geometric Mean of Area Under Curve (AUC0)-24
Time frame: 24 hours
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
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
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
| Milestone | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 |
|---|---|---|
| Started | 23 | 25 |
| Completed | 23 | 25 |
| Not completed | 0 | 0 |
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.
| Cmax (ng/mL) | Docetaxel Alone | With Tariquidar |
|---|---|---|
| C1D1 | 1315 (1081 to 1598) | 1093 (791.2 to 1510) |
| C1D8 | 1060 (773.5 to 1452) | 1026 (807.3 to 1303) |
| Both Groups (C1D1 + C1D8) | 1190 (999.9 to 1416) | 1063 (869.2 to 1301) |
Here are the total number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
| participants | Patients on Docetaxel on Days 1, 8 & Tariquidar on Day 8, 22 | Patients on Docetaxel on Days 1, 8 & Tariquidar on Days 1, 22 |
|---|---|---|
| The Number of Participants With Adverse Events. | 23 | 25 |
| h*ng/mL | Docetaxel Alone | With Tariquidar |
|---|---|---|
| C1D1 | 1367 (1126 to 1658) | 1409 (1172 to 1694) |
| C1D8 | 1308 (989.8 to 1730) | 1327 (1084 to 1623) |
| Both Groups (C1D1 + C1D8) | 1339 (1144 to 1568) | 1373 (1206 to 1563) |
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.
| Percentage of participants | All Patients Who Received Docetaxel and Tariquidar |
|---|---|
| Clinical Response Rate | 8 |
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 AUC | All Patients Who Received Docetaxel and Tariquidar |
|---|---|
| Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar | 82.2 (5.8 to 252) |
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.
| Percent | All Patients Who Received Docetaxel and Tariquidar |
|---|---|
| Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue | 12.4 (7.2 to 24.1) |
Collected over 4 years and 11 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Patients on Docetaxel on Days 1, 8 & Tariquidar on Day 8, 22 | — | 6/23 (26.1%) | 23/23 (100%) |
| Patients on Docetaxel on Days 1, 8 & Tariquidar on Days 1, 22 | — | 8/25 (32%) | 25/25 (100%) |
| Event | Patients on Docetaxel on Days 1, 8 & Tariquidar on Day 8, 22 | Patients on Docetaxel on Days 1, 8 & Tariquidar on Days 1, 22 |
|---|---|---|
| PULMONARY:: Dyspnea (shortness of breath)Respiratory, thoracic and mediastinal disorders | 2/23 | 3/25 |
| CONSTITUTIONAL SYMPTOMS::General disorders | 1/23 | 2/25 |
| CARDIOVASCULAR (GENERAL):: Thrombosis/embolismCardiac disorders | 0/23 | 2/25 |
| BLOOD/BONE MARROW:: Leukocytes (total WBC)Investigations | 1/23 | 1/25 |
| CONSTITUTIONAL SYMPTOMS:: Fatigue (lethargy, malaise, asthenia)General disorders | 1/23 | 0/25 |
| CONSTITUTIONAL SYMPTOMS:: Rigors, chillsGeneral disorders | 1/23 | 0/25 |
| DERMATOLOGY/SKIN:: AlopeciaSkin and subcutaneous tissue disorders | 1/23 | 0/25 |
| MUSCULOSKELETAL:: Musculoskeletal-Other (Specify,musculoskeletal-lethargic)Musculoskeletal and connective tissue disorders | 1/23 | 0/25 |
| NEUROLOGY:: Dizziness/lightheadednessNervous system disorders | 1/23 | 0/25 |
| PULMONARY:: Pulmonary-Other (Specify,clinical deterioration)Respiratory, thoracic and mediastinal disorders | 1/23 | 0/25 |
| Event | Patients on Docetaxel on Days 1, 8 & Tariquidar on Day 8, 22 | Patients on Docetaxel on Days 1, 8 & Tariquidar on Days 1, 22 |
|---|---|---|
| BLOOD/BONE MARROW:: HemoglobinBlood and lymphatic system disorders | 18/23 | 21/25 |
| BLOOD/BONE MARROW:: Leukocytes (total WBC)Blood and lymphatic system disorders | 18/23 | 21/25 |
| CONSTITUTIONAL SYMPTOMS:: Fatigue (lethargy, malaise, asthenia)General disorders | 18/23 | 21/25 |
| BLOOD/BONE MARROW:: Neutrophils/granulocytes (ANC/AGC)Blood and lymphatic system disorders | 19/23 | 16/25 |
| BLOOD/BONE MARROW:: HemoglobinInvestigations | 0/23 | 20/25 |
| GASTROINTESTINAL:: Diarrhea patients without colostomyGastrointestinal disorders | 17/23 | 17/25 |
| HEPATIC:: HypoalbuminemiaMetabolism and nutrition disorders | 16/23 | 12/25 |
| METABOLIC/LABORATORY:: HyponatremiaMetabolism and nutrition disorders | 14/23 | 15/25 |
| GASTROINTESTINAL:: NauseaGastrointestinal disorders | 13/23 | 12/25 |
| GASTROINTESTINAL:: AnorexiaGastrointestinal disorders | 12/23 | 13/25 |
| Age, Categorical(Participants) | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 19 | 20 | 39 |
| >=65 years | 4 | 5 | 9 |
| Age Continuous(years) | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 | Total |
|---|---|---|---|
| Mean | 50.76 ± 9.54 | 55.77 ± 9.57 | 53.37 ± 9.79 |
| Sex: Female, Male(Participants) | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 | Total |
|---|---|---|---|
| Female | 18 | 20 | 38 |
| Male | 5 | 5 | 10 |
| Region of Enrollment(participants) | Pts Who Received Docetaxel on Day 1, 8, & Tariquidar Day 8,22 | Pts Who Received Docetaxel on Days 1, 8, & Tariquidar Day 1,22 | Total |
|---|---|---|---|
| United States | 23 | 25 | 48 |
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