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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


Phase 1
2 Years
18 Years
Not Enrolling
Both
Brain Tumor, Ewing's Sarcoma, Neuroblastoma, Rhabdomyosarcoma

Thank you

Trial Information

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


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.

Inclusion Criteria


- INCLUSION CRITERIA:

Age: Patients must be greater than or equal to 2 and less than or equal to 18 years of
age.

Diagnosis: Histologically confirmed solid tumors which may include but are not limited to
rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors,
osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, and primary
brain tumors. In patients with brain stem or optic gliomas the requirement for
histological confirmation may be waived.

Measurable/Evaluable Disease: Patients must have measurable or evaluable tumors.

Prior Therapy: The patient's cancer must have relapsed after or failed to respond to
frontline curative therapy and there must not be other potentially curative treatment
options available. Curative therapy may include surgery, radiation therapy, chemotherapy,
or any combination of these modalities.

For patients receiving doxorubicin on this study, the patient must have had their last
dose of radiation therapy at least four weeks prior to study entry; For patients receiving
docetaxel or vinorelbine, the patient must have had their last dose of extensive radiation
(craneospinal or more than 50 percent of pelvis) at least 4 weeks prior to study entry or
last dose of limited field radiation (local) at least 2 weeks prior to study entry.

Patients must have had their last dose of chemotherapy at least 21 days prior to study
entry (28 days for nitrosoureas), and their last dose of any investigational cancer
therapy at least 30 days prior to study entry.

Patients must have recovered from the toxic effects of all prior therapy before entry onto
this trial.

Patients with brain tumors must be on a stable or tapering dose of corticosteriods for 7
days prior to the baseline scan performed for the purpose of assessing response to therapy
on this study.

Patients should be off colony stimulating factors such as G-CSF, GM-CSF, erythropoietin,
and IL-11 for at least 72 hours prior to study entry.

Lifetime cumulative dose of anthracycline: Restrictions on the prior cumulative dose
anthracylines only apply to patients who will receive doxorubicin in combination with
tariquidar.

The lifetime cumulative dose of anthracycline must be less than or equal to 300 mg/m(2) in
patients who will receive doxorubicin in combination with tariquidar, if the anthracycline
was administered as a bolus injection without a cardioprotectant (e.g., dexrazoxane) OR if
the patient had mediastinal radiation.

The lifetime cumulative dose of anthracycline must be less than or equal to 400 mg/m(2),
if the anthracycline was administered by continuous infusion or with a cardioprotectant
and the patient has not had mediastinal radiation.

Performance Status: Patients should have an ECOG performance status of 0,1, or 2.
Patients who unable to walk because of paralysis or weakness, but who are up in a
wheelchair will be considered ambulatory for the purpose of calculating the performance
score.

Hematologic Function: Patients must have adequate bone marrow function, defined as a
peripheral absolute granulocyte count of greater than or equal to 1,500/microL, hemoglobin
greater than or equal to 8 gm/dL, and a platelet count greater than or equal to
100,000/microL.

Hepatic Function: Patients must have adequate liver function, defined as bilirubin within
normal limits, SGPT (ALT) less than 2x the upper limit of normal.

Renal Function: Patients must have an age-adjusted normal serum creatinine OR a
creatinine clearance greater than or equal to 60 mL/min/1.73 m(2).

Cardiac Function: Patients who will receive doxorubicin must have normal cardiac ejection
fraction by echocardiogram. An echocardiogram does not need to be performed in patients
who will receive docetaxel or vinorelbine.

Informed Consent: All patients or their legal guardians (if the patient is less than 18
years old) must sign a document of informed consent indicating their understanding of the
investigational nature and the risks of this study before any protocol related studies are
performed. (This does not include routine laboratory tests or imaging studies required to
establish eligibility).

Durable Power of Attorney (DPA): Patients who have brain tumors and who are greater than
or equal to 18 years of age will be offered the opportunity to assign a DPA so that
another person can make decisions about their medical care if they become incapacitated or
cognitively impaired.

EXCLUSION CRITERIA:

Clinically significant unrelated systemic illness, such as serious infections, hepatic,
renal or other organ dysfunction, which in the judgement of the Principle or Associate
Investigator would compromise the patient's ability to tolerate and of the agents in this
trial or are likely to interfere with the study procedures or results.

Patients with a history of bone marrow transplantation within the previous 4 months or
extensive radiotherapy (craniospinal radiation, total body radiation, or radiation to more
than half of the pelvis) within the previous 4 months.

Pregnant or breast feeding females are excluded because tariquidar in combination with a
cytotoxic drug may be harmful to the developing fetus or nursing child.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

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.

Principal Investigator

Brigitte C Widemann, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

010091

NCT ID:

NCT00011414

Start Date:

February 2001

Completion Date:

November 2007

Related Keywords:

  • Brain Tumor
  • Ewing's Sarcoma
  • Neuroblastoma
  • Rhabdomyosarcoma
  • Multidrug Resistance
  • Childhood Cancer
  • SESTAMIBI
  • Rhodamine
  • Drug Interaction
  • Brain Tumor
  • Drug Resistance
  • Chemotherapy
  • Brain Neoplasms
  • Neuroblastoma
  • Rhabdomyosarcoma
  • Sarcoma, Ewing's
  • Neuroectodermal Tumors, Primitive, Peripheral
  • Sarcoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892
Childrens Hospital, PhiladelphiaPhiladelphia, Pennsylvania  19104