Background:

-Ixabepilone is a member of a new class of anticancer drugs called epothilones, which interfere with the ability of cancer cells to divide. Ixabepilone kills cancer cells in the test tube and in animals.

-Epothilones are similar to a class of drugs called taxanes, which include Taxol® (Registered Trademark) (paclitaxel) and Taxotere® (Registered Trademark) (docetaxel). Epothilones can kill cancer cells that are resistant to Taxol® (Registered Trademark) in the laboratory.

-Ixabepilone has been tested in a small number of adults and children with cancers resistant to standard treatment.

Objectives:

-To measure the response of solid tumors to treatment with ixabepilone.

-To determine for how long ixabepilone can stop tumors from growing.

-To evaluate a new method of measuring tumors in the chest with a method that measures tumor volume.

-To further define the side effects of ixabepilone.

Eligibility:

-Patients with osteosarcoma, Ewing's sarcoma/peripheral neuroectodermal tumor, rhabdomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, neuroblastoma, or Wilms tumor.

-Patients must be 12 months or older when entering the study.

-Patients with sarcoma must have been no more than 35 years old at the time of diagnosis.

-Patients with Wilms tumor or neuroblastoma must have been no more than 21 years old at the time of diagnosis.

Design:

-Up to 20 patients with each type of tumor may be enrolled.

-Patients are given ixabepilone as a 1-hour infusion through a vein on days 1-5 of every 21-day cycle.

-Patients have a physical exam and urine test before each cycle, blood tests weekly, pregnancy test (for women who can bear children) every other cycle, and tests to evaluate the tumor (radiological, imaging, or others, depending on the tumor type) after the first cycle and then after every other cycle.

-Patients may continue treatment as long as their tumor responds to therapy and the side effects are not unacceptable.

Condition	Intervention	Phase
Refractory Solid Tumors	Drug: Ixabepilone	Phase II

Further study details as provided by National Institutes of Health Clinical Center (CC):

Expected Total Enrollment:  120

Background: Ixabepilone (BMS-247550) is a semi-synthetic analog of the natural product epothilone B. The epothilones are a novel class of non-taxane microtubule-stabilizing agents obtained from the fermentation of the cellulose degrading myxobacteria, Sorangium cellulosum. Ixabepilone is active against preclinical cancer models that are naturally insensitive to paclitaxel or have developed resistance to paclitaxel, both in-vitro and in-vivo. The National Cancer Institute (NCI) Pediatric Oncology Branch is conducting a phase I trial of Ixabepilone on a daily x 5 consecutive day schedule. The drug has been well tolerated in children at doses of up to 8 mg/m(2)/d.

Objectives: This Phase II trial is designed to establish the objective response rate (CR+PR) using RECIST criteria of Ixabepilone in solid tumors occurring in pediatric and young adult patients. Time to disease progression is a secondary trial endpoint. In addition, for patients with measurable chest disease, comparison of automated volumetric tumor measurement with standard RECIST and WHO methods is a secondary endpoint on this trial.

Eligibility: Patients will be accrued in one of six disease strata: osteosarcoma, Ewing's sarcoma/Peripheral neuroectodermal tumor (PNETs), rhabdomyosarcoma, synovial sarcoma and malignant peripheral nerve sheath tumor (MPNSTs), neuroblastoma, or Wilms tumor. Patients are eligible if they have measurable disease and have not previously received taxanes. Patients must be greater than or equal to 12 months old at trial entry. Patients with sarcoma must have been less than or equal to 35 years old at original diagnosis; patients with Wilms tumor or neuroblastoma must have been less than or equal to 21 years old at original diagnosis.

Design: Ixabepilone will be administered as a one-hour infusion on Days 1 to 5 every 21 days at a dose of 8 mg/m(2)/dose. The trial will use a two-stage design targeting a response rate of 30%. Up to 20 patients will be accrued to each tumor stratum.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:

Important note: The eligibility criteria listed below are interpreted literally and cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data required for determining eligibility of a patient enrolled on this trial must be available in the patient's medical/research record which will serve as the source document for verification at the time of audit.

Age

-Patients must be greater than or equal to 12 months old at trial entry.

-Patients with neuroblastoma or Wilms tumor must have been less than 22 years of age when originally diagnosed with the malignancy to be treated on this protocol.

-All other patients must have been less than 36 years of age when originally diagnosed with the malignancy to be treated on this protocol.

Histologic Diagnosis

The target tumors are:

-Embryonal or alveolar rhabdomyosarcoma

-Osteosarcoma

-Ewing's sarcoma/Peripheral neuroectodermal tumor (PNET)

-Synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST)

-Wilms tumor

-Neuroblastoma

Patients must have had histologic verification of the malignancy at original diagnosis or at recurrence.

All patients must have refractory or recurrent tumors with no known curative treatment options.

For patients with sarcoma and Wilms tumor:

Patients must have measurable disease. Measurable disease is defined as lesions that can be measured in at least one dimension by medical imaging techniques (CT or MRI scan). Ascites, pleural effusions, bone marrow disease, and lesions detectable only by bone scan will not be considered measurable disease.

For patients with neuroblastoma:

Patients with either clinically or radiographically measurable disease or evaluable disease by 123I-MIBG or bone scan are eligible.

-For evaluable tumor, (123)I-MIBG or bone scan must be positive at a minimum of one site. If the lesion was previously radiated, a biopsy must be done at least 6 weeks after radiation is complete and demonstrate viable neuroblastoma.

Performance Level

Patients must have an ECOG performance status of 0, 1 or 2, or Karnofsky greater than or equal to 50% (patients greater than 16 years of age) or Lansky greater than or equal to 50% (patients less than or equal to 16 years).

Life Expectancy

Patients must have a life expectancy of greater than or equal to 8 weeks.

Prior Therapy

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

-Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea).

-Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent.

-XRT: greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 6 months must have elapsed if prior craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation.

-Stem Cell Transplant (SCT): No evidence of active graft vs. host disease. For allogeneic SCT, greater than or equal to 4 months must have elapsed; for autologous SCT greater than or equal to 2 months must have elapsed.

-Study specific limitations on prior therapy: Patients may not have received prior taxane (paclitaxel, docetaxel) therapy.

Concomitant Medications Restrictions

No other cancer chemotherapy or immunomodulating agents (including steroids) will be used. However, steroids may be used for the treatment and prevention of hypersensitivity reactions, if necessary.

Growth factor(s): Must not have received within 1 week of entry onto this study, with the exception of erythropoietin.

Study Specific: Patients may not be currently receiving strong inhibitors of CYP3A4, and may not have received these medications within 1 week of entry. These include:

-Antibiotics: clarithromycin, erythromycin, troleandomycin

-Antifungals: itraconazole, ketoconazole, fluconazole (doses greater than 3 mg/kg/day), voriconazole

-Antidepressants: nefazodone, fluovoxamine

-Calcium channel blockers: verapamil, diltiazem

-Antiemetics: Do not use aprepitant (Emend® (Registered Trademark)) as it is CYP3A4 substrate, moderate inhibitor and inducer.

-Miscellaneous: amiodarone,

-In addition, grapefruit juice should be avoided, as it inhibits CYP3A4.

-Patients must also avoid St. John's Wort, an inducer of CYP3A4.

-Patients may not be taking enzyme -inducing anticonvulsants, and may not have received these medications within 1 week of entry, as these patients may experience different drug disposition. These medications include:

-Carbamazepine (Tegretol)

-Felbamate (Felbtol)

-Phenobarbital

-Phenytoin (Dilantin)

-Primidone (Mysoline)

-Oxcarbazepine (Trileptal)

Organ Function Requirements

All patients must have:

Adequate Bone Marrow Function Defined As

-Peripheral absolute neutrophil count (ANC) greater than or equal to 1500/uL (off growth factors)

-Platelet count greater than or equal to 75,000/uL (transfusion independent)

-Hemoglobin greater than or equal to 10.0 gm/dL (may receive RBC transfusions)

Adequate Renal Function Defined As

Creatinine clearance or radioisotope GFR greater than or equal to 60mL/min/1.73m(2)

OR

A serum/plasma creatinine calculation of GFR 60mL/min/1.73m(2) using the Schwartz formula

(Schwartz et al. J. Peds, 106:522, 1985)

Estimated Creatinine Clearance (in mL/min/1.73 m(2))

(k)(L)/Pcr

Where L &eq; child's length in cm

Pcr &eq; plasma (or serum) creatinine (in mg/dL)

K Values &eq;

0.33 low birth weight infant

0.45 term infant

0.55 child

0.55 adolescent female

0.70 adolescent male

**The conversion formula for serum/plasma creatinine when reported in

uMol/L units:

(k " ht)/(sCr in uMol/L " 88.4)

Adequate Liver Function Defined As

-Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) for age, and

-SGPT (ALT) less than or equal to 2.5 x upper limit of normal (ULN) for age.

Nervous System Function Defined As

-Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. Enzyme inducing anticonvulsant drugs are not allowed on this trial.

-CNS toxicity less than or equal to Grade 2.

-Existing sensory or motor neuropathy must be grade less than or equal to1.

EXCLUSION CRITERIA:

-Clinically significant unrelated systemic illness, such as serious infections, hepatic, renal or other organ dysfunction, which would, in the judgment of the treating physician, compromise the patient's ability to tolerate the investigational agent or is likely to interfere with the study procedures or results.

-Pregnant or breast-feeding females, because Ixabepilone may be harmful to the developing fetus or nursing child. Patients of child-bearing potential must use appropriate birth control measures.

-Patients with known severe prior hypersensitivity reaction to agents containing Cremophor EL.

-Patients with active brain metastases.

For patients with sarcoma and Wilms tumor:

Ascites, pleural effusions, bone marrow disease, and lesions detectable only by bone scan will not be considered measurable disease. Patients who have disease in these locations without radiographically measurable (CT, MRI) disease are excluded.

For patients with neuroblastoma:

Patients with elevated urinary catecholamines and/or bone marrow evidence of tumor, without measurable or evaluable disease clinically or by imaging modalities (CT, MRI, MIBG, or Bone Scan) are excluded.

Please refer to this study by ClinicalTrials.gov identifier  NCT00318526

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  060146; 06-C-0146
Last Updated:  June 3, 2006
Record first received:  April 25, 2006
ClinicalTrials.gov Identifier:  NCT00318526
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2006-07-03