Phase I Trial of Tariquidar (XR9576) in Combination With Doxorubicin, Vinorelbine, or Docetaxel in Pediatric Patients With Solid Tumors
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.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Tolerance and toxicity profile [ Time Frame: 1.5 years ] [ Designated as safety issue: Yes ]
- MTD [ Time Frame: 1.5 years ] [ Designated as safety issue: Yes ]
- Pharmacokinetics alone & amp; in combination [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Pharmacodynamics ex vivo [ Time Frame: 3 years ] [ Designated as safety issue: No ]
- Alterations in the acute toxicity profile of doxorubicin, vinorelbine or docetaxel when with tariquidar [ Time Frame: 1.5 years ] [ Designated as safety issue: Yes ]
- Alterations in plasma pharmacokinetics of doxorubicin, vinorelbine, ordocetaxel when with tariquidar [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Assess Pgp expression in tumor specimens [ Time Frame: 3 years ] [ Designated as safety issue: No ]
|Study Start Date:||February 2001|
|Study Completion Date:||January 2016|
|Primary Completion Date:||November 2007 (Final data collection date for primary outcome measure)|
Intervention given with dose escalation of tariquidar
IV alone for 1 dose (Day -1), then in combo for rest of cycle (Day 1, etc). Given in combo with one of the following: Doxorubicin (50 mg/m2 IV over 15 min on day 1), Vinorelbine (20 mg/m2 IV over 10 min on days 1 and 8), or Docetaxel (75 mg/m2 IV over 60 min on day 1).
- 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.
- 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 mg/kg.
- 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).
-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.
- Tariquidar will be administered alone and in combination with doxorubicin, vinorelbine, or doctaxel. Tariquidar dose levels will be 1, 1.5, and 2 mg/kg. 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00011414
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Brigitte C Widemann, M.D.||National Cancer Institute (NCI)|