Ignite Creation Date:
2024-05-05 @ 11:23 AM
Last Modification Date:
2024-10-26 @ 9:06 AM
Study NCT ID:
NCT00011414
Status:
COMPLETED
Last Update Posted:
2019-07-16
First Post:
2001-02-17
Brief Title:
Phase I Trial of Tariquidar XR9576 in Combination With Doxorubicin Vinorelbine or Docetaxel in Pediatric Patients With Solid Tumors
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Phase I Trial and Pharmacokinetic Study of Tariquidar XR9576 a P-Glycoprotein Inhibitor in Combination With Doxorubicin Vinorelbine or Docetaxel in Pediatric Patients With Refractory Solid Tumors Including Brain Tumors
Status:
COMPLETED
Status Verified Date:
2016-01-13
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This study will evaluate the tolerance and effects of tariquidar given in combination with one of three anticancer drugs for treating solid tumors Tariquidar works by blocking a pump on a cancer cell The pump on a cell that prevents anticancer drugs from accumulating is called Pgp P-glycoprotein Researchers hope to see whether cancer-fighting drugs can stay in the cells longer
Patients ages 2 to 18 who have solid tumors may be eligible for this study Tariquidar is infused intravenously IV over 30 minutes given every 21 to 28 days with one drug that kills cancer cells Patients are examined by a doctor at least once weekly during treatment and will have routine blood tests twice weekly They will receive one of the following drugs with tariquidar doxorubicin Adriamycin vinorelbine Navelbine or docetaxel Taxotere At the first treatment cycle only there is a baseline Sestamibi scan before treatment and a second one immediately after drug administration If patients receive tariquidar with doxorubicin tariquidar is given alone Then 48 to 72 hours later the second dose is given followed by doxorubicin by IV over 15 minutes Dexrazoxane which decreases damaging effects of doxorubicin on the heart is also given by IV over 15 minutes Granulocyte colony stimulating factor G-CSF is injected daily 48 hours after doxorubicin to alleviate doxorubicin s effect on white blood cells If patients receive tariquidar with vinorelbine tariquidar is given alone Then 48 to 72 hours later the second dose is given immediately followed by vinorelbine by IV over 10 minutes then 1 week later tariquidar is again given immediately followed by vinorelbine by IV for 10 minutes G-CSF is given daily If patients receive tariquidar with docetaxel tariquidar is given alone Then 48 to 72 hours later the second dose is given followed by docetaxel by IV over 60 minutes Drugs to prevent allergic reactions are given before and after each docetaxel dose G-CSF is given daily
Tariquidar may affect blood pressure during infusion and there can be reduction of normal blood cells gastrointestinal problems and allergic reactions The radioactive Sestamibi can cause headache chest pain and nausea Radiation used in this study has been approved as involving a slightly greater than minimal risk for adults and an acceptable risk for children This radiation is considered necessary to obtain information desired One possible effect is a slight increase in the risk of cancer
This study may or may not have a direct benefit for participants However knowledge gained may benefit people with cancer in the future
Patients ages 2 to 18 who have solid tumors may be eligible for this study Tariquidar is infused intravenously IV over 30 minutes given every 21 to 28 days with one drug that kills cancer cells Patients are examined by a doctor at least once weekly during treatment and will have routine blood tests twice weekly They will receive one of the following drugs with tariquidar doxorubicin Adriamycin vinorelbine Navelbine or docetaxel Taxotere At the first treatment cycle only there is a baseline Sestamibi scan before treatment and a second one immediately after drug administration If patients receive tariquidar with doxorubicin tariquidar is given alone Then 48 to 72 hours later the second dose is given followed by doxorubicin by IV over 15 minutes Dexrazoxane which decreases damaging effects of doxorubicin on the heart is also given by IV over 15 minutes Granulocyte colony stimulating factor G-CSF is injected daily 48 hours after doxorubicin to alleviate doxorubicin s effect on white blood cells If patients receive tariquidar with vinorelbine tariquidar is given alone Then 48 to 72 hours later the second dose is given immediately followed by vinorelbine by IV over 10 minutes then 1 week later tariquidar is again given immediately followed by vinorelbine by IV for 10 minutes G-CSF is given daily If patients receive tariquidar with docetaxel tariquidar is given alone Then 48 to 72 hours later the second dose is given followed by docetaxel by IV over 60 minutes Drugs to prevent allergic reactions are given before and after each docetaxel dose G-CSF is given daily
Tariquidar may affect blood pressure during infusion and there can be reduction of normal blood cells gastrointestinal problems and allergic reactions The radioactive Sestamibi can cause headache chest pain and nausea Radiation used in this study has been approved as involving a slightly greater than minimal risk for adults and an acceptable risk for children This radiation is considered necessary to obtain information desired One possible effect is a slight increase in the risk of cancer
This study may or may not have a direct benefit for participants However knowledge gained may benefit people with cancer in the future
Detailed Description:
Background
Pgp is a 170 kDa plasma membrane glycoprotein that functions as a non-specific energy-dependent drug efflux pump Pgp is expressed in a variety of normal human tissues such as renal proximal tubules capillary endothelial cells that comprise the blood-brain barrier epithelial cells lining the bile canaliculi bone marrow stem cells and peripherial blood mononuclear cells
Pgp over-expression in tumor cells results in a multidrug resistance phenotype by preventing the intracellular accumulation of a variety of chemotherapeutic agents including anthracyclines taxanes vinca alkyloids and epipodophyllotoxins Inhibition of Pgp may partially reverse multidrug resistance by increasing intracellular drug accumulation in tumor cells
Tariquidar XR9576 is a specific Pgp inhibitor that blocks Pgp function for up to 24 hours after a single dose without significant toxicity in animals and humans
In adults tariquidar in combination with doxorubicin paxlitaxel or vinorelbine is well tolerated and only minor alterations in the clearance and drug exposure area under the concentration time curve AUC of the anticancer drugs have been observed
Objectives
Study the tolerance and toxicity profile of tariquidar at three dose levels in combination with one of three anticancer drugs doxorubicin docetaxel vinorelbine in pediatric patients with refractory solid tumors including brain tumors
Define the maximum tolerated dose of tariquidar in children if dose-limiting toxicity is observed at doses less than or equal to 2 mgkg
Study the pharmacokinetics of tariquidar alone and in combination with doxorubicin docetaxel or vinorelbine in pediatric patients
Study the pharmacodynamics effect on Pgp function of tariquidar ex vivo in peripheral blood mononuclear cells CD56 with a rhodamine uptake assay and in vivo in tissues and tumor by 99m Tc-sestamibi scan
Study alterations in the acute toxicity and pharmacokinetic profile of doxorubicin vinorelbine or docetaxel when administered in combination with tariquidar
When possible assess Pgp expression in tumor specimens by immunohistochemistry and compare immunohistochemisty results with in vivo Pgp functional studies 99m Tc-sestamibi scan
Eligibility
-Children and adolescents greater than or equal to 2 years and less than or equal to 18 years of age with histologically confirmed relapsed or refractory solid tumors that are measureable or evaluable
Design
Tariquidar will be administered alone and in combination with doxorubicin vinorelbine or doctaxel Tariquidar dose levels will be 1 15 and 2 mgkg Intrapatient dose escalation of tariquidar is permitted
Detailed pharmacokinetic and pharmacodynamic studies are performed in cycle 1
The trial follows a standard phase 1 design with 3 to 6 patients per dose level At the recommedmed dose of tariquidar 6 patients will be enrolled with each cytotoxic agent Up to 36 patients will be entered on this trial
Pgp is a 170 kDa plasma membrane glycoprotein that functions as a non-specific energy-dependent drug efflux pump Pgp is expressed in a variety of normal human tissues such as renal proximal tubules capillary endothelial cells that comprise the blood-brain barrier epithelial cells lining the bile canaliculi bone marrow stem cells and peripherial blood mononuclear cells
Pgp over-expression in tumor cells results in a multidrug resistance phenotype by preventing the intracellular accumulation of a variety of chemotherapeutic agents including anthracyclines taxanes vinca alkyloids and epipodophyllotoxins Inhibition of Pgp may partially reverse multidrug resistance by increasing intracellular drug accumulation in tumor cells
Tariquidar XR9576 is a specific Pgp inhibitor that blocks Pgp function for up to 24 hours after a single dose without significant toxicity in animals and humans
In adults tariquidar in combination with doxorubicin paxlitaxel or vinorelbine is well tolerated and only minor alterations in the clearance and drug exposure area under the concentration time curve AUC of the anticancer drugs have been observed
Objectives
Study the tolerance and toxicity profile of tariquidar at three dose levels in combination with one of three anticancer drugs doxorubicin docetaxel vinorelbine in pediatric patients with refractory solid tumors including brain tumors
Define the maximum tolerated dose of tariquidar in children if dose-limiting toxicity is observed at doses less than or equal to 2 mgkg
Study the pharmacokinetics of tariquidar alone and in combination with doxorubicin docetaxel or vinorelbine in pediatric patients
Study the pharmacodynamics effect on Pgp function of tariquidar ex vivo in peripheral blood mononuclear cells CD56 with a rhodamine uptake assay and in vivo in tissues and tumor by 99m Tc-sestamibi scan
Study alterations in the acute toxicity and pharmacokinetic profile of doxorubicin vinorelbine or docetaxel when administered in combination with tariquidar
When possible assess Pgp expression in tumor specimens by immunohistochemistry and compare immunohistochemisty results with in vivo Pgp functional studies 99m Tc-sestamibi scan
Eligibility
-Children and adolescents greater than or equal to 2 years and less than or equal to 18 years of age with histologically confirmed relapsed or refractory solid tumors that are measureable or evaluable
Design
Tariquidar will be administered alone and in combination with doxorubicin vinorelbine or doctaxel Tariquidar dose levels will be 1 15 and 2 mgkg Intrapatient dose escalation of tariquidar is permitted
Detailed pharmacokinetic and pharmacodynamic studies are performed in cycle 1
The trial follows a standard phase 1 design with 3 to 6 patients per dose level At the recommedmed dose of tariquidar 6 patients will be enrolled with each cytotoxic agent Up to 36 patients will be entered on this trial
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 01-C-0091 | None | None | None |