Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Active 21 and under at diagnosis NCI NANT-2001-03 NCT00084422

Objectives

Primary

1. Determine the maximum tolerated dose of CEP-701 in pediatric patients with recurrent or refractory high-risk neuroblastoma.
2. Determine the dose-limiting toxicity of this drug in these patients.
3. Determine the pharmacokinetic behavior of this drug in these patients.

Secondary

1. Determine the degree of TrkB tyrosine kinase inhibition activity present in the serum of patients treated with this drug.
2. Correlate the degree of TrkB tyrosine kinase inhibition activity in these patients with dose level, pharmacokinetics, and antitumor activity data of this drug.
3. Determine the antitumor activity of this drug in these patients.

Entry 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/10⁶ 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

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
  • 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

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/mm³
• Platelet count ≥ 50,000/mm³ (transfusion independent)
• Hemoglobin ≥ 8.0 g/dL (red blood cell transfusions allowed)

Hepatic

• ALT and AST normal
• Bilirubin normal

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

Expected Enrollment

A total of 60 patients will be accrued for this study.

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.

Maris J, Minturn J, Evans A, et al.: Phase I trial of the orally bioavailable TRK tyrosine kinase inhibitor CEP-701 in refractory neuroblastoma: a New Approaches to Neuroblastoma Therapy (NANT) study. [Abstract] Pediatr Blood Cancer 45 (4 Suppl 1): A-0.129, 416, 2005.

Trial Contact Information

Trial Lead Organizations

New Approaches to Neuroblastoma Therapy Consortium

John Maris, MD, Protocol chair		Ph: 215-590-2821 Email: maris@chop.edu
Garrett Brodeur, MD, Protocol co-chair		Ph: 215-590-2817 Email: brodeur@email.chop.edu

U.S.A.
California
	Los Angeles
	Childrens Hospital Los Angeles
		Judith Villablanca, MD	Ph:  323-361-5654
			Email: jvillablanca@chla.usc.edu
	Palo Alto
	Lucile Packard Children's Hospital at Stanford University Medical Center
		Clare Twist, MD	Ph:  650-723-5535
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Katherine Matthay, MD	Ph:  415-476-3831
			Email: matthayk@peds.ucsf.edu
Georgia
	Atlanta
	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
		Howard Katzenstein, MD	Ph:  404-785-0853
Illinois
	Chicago
	University of Chicago Comer Children's Hospital
		Susan Cohn, MD	Ph:  773-703-2571 800-289-6333
			Email: scohn@peds.bsd.uchicago.edu
Massachusetts
	Boston
	Children's Hospital Boston
		Suzanne Shusterman, MD	Ph:  617-632-4901
			Email: suzanne_shusterman@dfci.harvard.edu
Michigan
	Ann Arbor
	University of Michigan Comprehensive Cancer Center
		Gregory Yanik, MD	Ph:  734-936-8785
			Email: gyanik@umich.edu
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		John Perentesis, MD	Ph:  513-636-6090
			Email: john.perentesis@chmcc.org
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		John Maris, MD	Ph:  215-590-2821
			Email: maris@chop.edu
Texas
	Houston
	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
		Heidi Russell, MD	Ph:  832-822-4277
			Email: hmrussel@txccc.org
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie Park, MD	Ph:  206-987-2106
Wisconsin
	Madison
	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
		Paul Sondel, MD, PhD	Ph:  608-263-9069
			Email: pmsondel@humonc.wisc.edu

Registry Information
Official Title		A Phase I Study Of CEP-701 In Patients With Refractory Neuroblastoma (IND # 67,722)
Trial Start Date		2003-08-11
Registered in ClinicalTrials.gov		NCT00084422
Date Submitted to PDQ		2004-03-23
Information Last Verified		2008-03-30
NCI Grant/Contract Number		CA81403