N2001-03: CEP-701 in Treating Young Patients With Recurrent or Refractory High-Risk Neuroblastoma

New Approaches to Neuroblastoma Therapy Consortium47 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neuroblastoma

Interventions

lestaurtinibDRUG

Given orally twice daily x 5 consecutive days followed by a two day rest. 28 days = 1 treatment course. Courses repeated indefinitely without gap provided patient has recovered course from toxicities and no DLTs. Dose level assigned according to the planned dose escalation schedule.

Eligibility

Sex: ALLMin age: 1 DayMax age: 30 Years

Medical Language ↔ Plain English

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

Locations (12)

Childrens Hospital Los Angeles

Los Angeles, California, United States

Lucille Salter Packer Children's Hospital, Stanford University

Palo Alto, California, United States

Outcomes

Primary Outcomes

To determine the maximum tolerated dose (MTD) of CEP-701 given on a twice daily chronic administration schedule (two days on , two days off) to children with high risk relapsed or residual neuroblastoma.

Time frame: Within 28 days of treatment at each dose level.

To determine dose limiting toxicities (DLTs) of CEP-701 given on this schedule

Time frame: Within first 28 days of therapy.

To characterize the pharmacokinetic (PK) behavior of CEP-701 in children with residual or refractory high-risk neuroblastoma.

Participation in PK studies is voluntary and not a requirement for study entry.

Time frame: Days 1,5 and 26 of first course only.

Secondary Outcomes

To determine the degree of TrkB tyrosine kinase inhibition activity present in the serum of patients treated with CEP-701, and correlate these findings with dose level, pharmacokinetic and anti-tumor activity data.

Time frame: Days 1,5 and 26 of first course only.

To define the antitumor activity of CEP-701, within the confines of a Phase I study.

Time frame: Evaluation at end of courses 1, 2, 4 and then every 4 courses until patient goes off therapy.

Data from ClinicalTrials.gov

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