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

Phase 1
30 Years
Open (Enrolling)

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Trial Information

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



- 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.


- 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.

Inclusion Criteria


- 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

- 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



- 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


- 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)


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

- Total bilirubin ≤ 1.5 times ULN


- Creatinine ≤ 1.5 times normal OR

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


- Ejection fraction ≥ 50% by echocardiogram or MUGA OR

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


- Lung function normal

- No dyspnea at rest

- No exercise intolerance

- No supplemental oxygen requirement


- Not pregnant

- Negative pregnancy test

- Fertile patients must use effective contraception

- No uncontrolled infection

- No other concurrent illness that would preclude study treatment


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


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

- 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


- 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)


- Not specified


- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

Within 28 days of treatment at each dose level.

Safety Issue:


Principal Investigator

John M. Maris, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Hospital of Philadelphia


United States: Food and Drug Administration

Study ID:




Start Date:

August 2003

Completion Date:

December 2013

Related Keywords:

  • Neuroblastoma
  • recurrent neuroblastoma
  • Neuroblastoma



University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan  48109-0752
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Childrens Hospital Los Angeles Los Angeles, California  90027
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Atlanta, Georgia  30322
University of Chicago Comer Children's Hospital Chicago, Illinois  60637
Children's Hospital Boston Boston, Massachusetts  02115
Lucille Salter Packer Children's Hospital, Stanford University Palo Alto, California  94305
Morgan Stanley Children's Hospital of New York-Presbyterian New York, New York  10032