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

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

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.

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