A Phase I Study Of CEP-701 In Patients With Refractory Neuroblastoma (IND # 67,722)

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Diagnosis of neuroblastoma confirmed by at least 1 of the following:

- Histology

- Demonstrates clumps of tumor cells in the bone marrow with elevated urinary
catecholamine metabolites

- Recurrent or resistant/refractory disease

- Neuroblastoma metastatic to the bone marrow with granulocytopenia, anemia, and/or
thrombocytopenia allowed

- High-risk disease

- Patients in first response after completion of a prior front-line myeloablative
regimen OR who were medically ineligible to receive a front-line myeloablative
regimen must meet at least 1 of the following criteria:

- Viable neuroblastoma determined by biopsy of a persistent lesion as seen on CT
scan, MRI, or metaiodobenzylguanidine (MIBG) scan

- If lesion was irradiated, biopsy must be performed at least 4 weeks after
completion of prior radiotherapy

- Morphologic evidence of tumor in bone marrow

- Second or greater response (without histologic confirmation) allowed

- Meets at least 1 of the following criteria:

- At least 1 unidimensionally measurable lesion on CT scan, MRI, or X-ray

- At least 20 mm by conventional techniques OR at least 10 mm by spiral CT
scan

- MIBG scan with positive uptake at a minimum of 1 site

- Bone marrow with tumor cells on routine morphology (not by NSE staining only) of
bilateral aspirate and/or biopsy AND/OR at least 5 tumor cells/10^6 mononuclear
cells in the bone marrow by immunocytologic analysis of 2 consecutive bone
marrows performed at least 1 day but no more than 4 weeks apart

PATIENT CHARACTERISTICS:

Age

- 21 and under at diagnosis

Performance status

- Karnofsky 50-100% (for patients > 16 years of age)

- Lansky 50-100% (for patients ≤ 16 years of age)

Life expectancy

- More than 2 months

Hematopoietic

- See Disease Characteristics

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 50,000/mm^3 (transfusion independent)

- Hemoglobin ≥ 8.0 g/dL (red blood cell transfusions allowed)

Hepatic

- ALT and AST ≤ 3.0 times upper limit of normal (ULN)

- Total bilirubin ≤ 1.5 times ULN

Renal

- Creatinine ≤ 1.5 times normal OR

- Creatinine clearance or radioisotope glomerular filtration rate ≥ 60 mL/min

Cardiovascular

- Ejection fraction ≥ 50% by echocardiogram or MUGA OR

- Fractional shortening ≥ 28% or above lower limit of normal by echocardiogram

Pulmonary

- Lung function normal

- No dyspnea at rest

- No exercise intolerance

- No supplemental oxygen requirement

Other

- Not pregnant

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infection

- No other concurrent illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

- See Chemotherapy

- At least 2 weeks since prior biologic or non-myelosuppressive therapy and recovered

- More than 7 days since prior growth factors

- No prior allogeneic stem cell transplantation AND no extensive chronic
graft-versus-host disease

- No concurrent growth factors except filgrastim (G-CSF) or sargramostim (GM-CSF)
administered for neutropenia lasting for more than 7 days or for confirmed or
clinical septicemia associated with neutropenia

Chemotherapy

- At least 3 months since prior myeloablative chemotherapy with stem cell
transplantation

- At least 2 weeks since prior chemotherapy and recovered

Endocrine therapy

- No concurrent corticosteroid therapy except replacement therapy for adrenal
insufficiency or treatment for increased intracranial pressure

Radiotherapy

- See Disease Characteristics

- Recovered from prior radiotherapy

- At least 6 weeks since prior therapeutic-dose MIBG

- At least 6 weeks since prior craniospinal or other radiotherapy involving significant
bone marrow (i.e., total pelvis or total abdomen)

- At least 4 weeks since prior radiotherapy to any site biopsied

- At least 2 weeks since prior local palliative radiotherapy (small port)

Surgery

- Not specified

Other

- No prior CEP-701

- No concurrent administration of any of the following CYP3A4 inhibitors:

- Cyclosporine

- Clotrimazole

- Ketoconazole

- Erythromycin

- Clarithromycin

- Troleandomycin

- HIV protease inhibitors

- Nefazodone

- Itraconazole

- Voriconazole