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
- 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)
-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.
Primary Purpose: Treatment
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.
Brigitte C Widemann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Childrens Hospital, Philadelphia||Philadelphia, Pennsylvania 19104|