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Philadelphia, Pennsylvania 19104


RATIONALE: CEP-701 may stop the growth of tumor cells by blocking the enzymes necessary for their growth. PURPOSE: This phase I trial is studying the side effects and best dose of CEP-701 in treating young patients with recurrent or refractory high-risk neuroblastoma.

Study summary:

OBJECTIVES: Primary - Determine the maximum tolerated dose of CEP-701 in pediatric patients with recurrent or refractory high-risk neuroblastoma. - Determine the dose-limiting toxicity of this drug in these patients. - Determine the pharmacokinetic behavior of this drug in these patients. Secondary - Determine the degree of TrkB tyrosine kinase inhibition activity present in the serum of patients treated with this drug. - Correlate the degree of TrkB tyrosine kinase inhibition activity in these patients with dose level, pharmacokinetics, and antitumor activity data of this drug. - Determine the antitumor activity of this drug in these patients. OUTLINE: This is an open-label, dose-escalation, multicenter study. Patients receive oral CEP-701 twice daily* on days 1-5, 8-12, 15-19, and 22-26. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: *On day 1 of course 1 only, patients receive oral CEP-701 once instead of twice. Cohorts of 3-6 patients receive escalating doses of CEP-701 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, the dose level is expanded up to 9 patients. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.


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



Primary Contact:

Principal Investigator
John M. Maris, MD
Children's Hospital of Philadelphia

Backup Contact:


Location Contact:

Philadelphia, Pennsylvania 19104
United States

There is no listed contact information for this specific location.

Site Status: N/A

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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