Phase I Trial of Tariquidar (XR9576) in Combination With Doxorubicin, Vinorelbine, or Docetaxel in Pediatric Patients With Solid Tumors
Condition: Wilms' Tumor; Sarcoma; Adenaocortical Carcinoma; Refractory Cancer; Coldrhood Cancer
MeSH terms: Wilms Tumor
Study type: Interventional
Phase: Phase 1

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.
    

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 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).

      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, 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.
    

Intervention name(s): Tariquidar
Intervention type(s): Drug
Intervention description(s): 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).
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Drug Resistance; PEDIATRIC SOLID TUMORS; Chemotherapy; p-glycoprotien; Brain Tumors; Childhood Cancer; Brain Tumor