n2001-03: cep-701 in treating young patients with recurrent or refractory high-risk neuroblastoma

Conditions: Neuroblastoma

Summary: 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.

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.

Eligibility 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

Keywords: recurrent neuroblastoma