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Tariquidar and Docetaxel to Treat Patients With Lung, Ovarian, Renal and Cervical Cancer

Primary Purpose

Lung Neoplasms, Ovarian Neoplasms, Cervix Neoplasms

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
docetaxel
tariquidar
99mTc-sestamibi imaging
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lung Neoplasms focused on measuring Pharmacokinetics, Pharmacodynamics, Multidrug Resistance Reversal, Molecular Target, P-Glycoprotein Inhibition, Lung Cancer, Ovarian Cancer, Cervical Cancer, Renal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • National Institutes of Health

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Pts who received docetaxel on day 1, 8, & tariquidar day 8,22

Pts who received docetaxel on days 1, 8, & tariquidar day 1,22

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.
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.
Geometric Mean of Area Under Curve (AUC0)-24
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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
September 15, 2003
Last Updated
September 12, 2012
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00069160
Brief Title
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

2. Study Status

Record Verification Date
September 2012
Overall Recruitment Status
Completed
Study Start Date
September 2003 (undefined)
Primary Completion Date
December 2009 (Actual)
Study Completion Date
December 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pts who received docetaxel on day 1, 8, & tariquidar day 8,22
Arm Type
Experimental
Arm Description
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.
Arm Title
Pts who received docetaxel on days 1, 8, & tariquidar day 1,22
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
docetaxel
Other Intervention Name(s)
Taxotere
Intervention Description
Patients receive docetaxel intravenous (IV) over 1 hour on days 1 and 8.
Intervention Type
Drug
Intervention Name(s)
tariquidar
Other Intervention Name(s)
XR9576
Intervention Description
Patients receive tariquidar intravenous (IV) over 30 minutes on days 8 and 22.
Intervention Type
Other
Intervention Name(s)
99mTc-sestamibi imaging
Other Intervention Name(s)
Cardiolite
Intervention Description
Bolus injection of 29 mCi of 99mTc-sestamibi intravenously for each imaging study.
Primary Outcome Measure Information:
Title
Geometric Mean of Maximum Concentration of the Drug (Cmax)
Description
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
Title
The Number of Participants With Adverse Events.
Description
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
Title
Geometric Mean of Area Under Curve (AUC0)-24
Time Frame
24 hours
Title
Clinical Response Rate
Description
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
Secondary Outcome Measure Information:
Title
Percent Increase in Sestamibi Area Under Curve (AUC) in Liver After Tariquidar
Description
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
Title
Percent Increase in Sestamibi Area Under Curve (AUC) in Tumor Tissue
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susan E Bates, M.D.
Organizational Affiliation
NCI, NIH
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
4855907
Citation
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. doi: 10.1002/jcp.1040830114. No abstract available.
Results Reference
background
PubMed Identifier
3856953
Citation
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. doi: 10.1007/BF01534700.
Results Reference
background
PubMed Identifier
6579344
Citation
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.
Results Reference
background
PubMed Identifier
21081657
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.
Results Reference
result
Links:
URL
http://www.nlm.nih.gov/medlineplus/
Description
Medline Plus
URL
http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp
Description
Drug Information
URL
http://www.clinicaltrials.gov/ct2/info/fdalinks
Description
U.S. FDA Resources

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Tariquidar and Docetaxel to Treat Patients With Lung, Ovarian, Renal and Cervical Cancer

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