Phase I Trial of Tariquidar (XR9576) in Combination With Doxorubicin, Vinorelbine, or Docetaxel in Pediatric Patients With Solid Tumors

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.