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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier:
NCT00084422
First received: June 10, 2004
Last updated: August 28, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Neuroblastoma
Drug: lestaurtinib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study Of CEP-701 In Patients With Refractory Neuroblastoma (IND # 67,722)

Resource links provided by NLM:


Further study details as provided by New Approaches to Neuroblastoma Therapy Consortium:

Primary Outcome Measures:
  • 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. ] [ Designated as safety issue: Yes ]
  • To determine dose limiting toxicities (DLTs) of CEP-701 given on this schedule [ Time Frame: Within first 28 days of therapy. ] [ Designated as safety issue: Yes ]
  • To characterize the pharmacokinetic (PK) behavior of CEP-701 in children with residual or refractory high-risk neuroblastoma. [ Time Frame: Days 1,5 and 26 of first course only. ] [ Designated as safety issue: Yes ]
    Participation in PK studies is voluntary and not a requirement for study entry.


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]

Enrollment: 47
Study Start Date: August 2003
Study Completion Date: February 2011
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: lestaurtinib
    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.
    Other Name: CEP-701
Detailed Description:

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

Ages Eligible for Study:   up to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00084422

Locations
United States, California
Childrens Hospital Los Angeles
Los Angeles, California, United States, 90027-0700
Lucille Salter Packer Children's Hospital, Stanford University
Palo Alto, California, United States, 94305
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94143
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Comer Children's Hospital
Chicago, Illinois, United States, 60637
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Michigan
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, New York
Morgan Stanley Children's Hospital of New York-Presbyterian
New York, New York, United States, 10032
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
United States, Washington
Children's Hospital and Regional Medical Center - Seattle
Seattle, Washington, United States, 98105
Canada, Ontario
Hospital for Sick Children
Toronto, Ontario, Canada, M5G 1X8
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
Investigators
Principal Investigator: John M. Maris, MD Children's Hospital of Philadelphia
Study Chair: Garrett M. Brodeur, MD Children's Hospital of Philadelphia
  More Information

Additional Information:
Publications:
Minturn JE, Villablanca J, Yanik GA, et al.: Phase I trial of lestaurtinib for children with refractory neuroblastoma (NB): A New Approach to Neuroblastoma Therapy (NANT) Consortium study. [Abstract] J Clin Oncol 28 (Suppl 15): A-9532, 2010.
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.

Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT00084422     History of Changes
Other Study ID Numbers: CDR0000363630, P01CA081403, NANT-2001-03
Study First Received: June 10, 2004
Last Updated: August 28, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by New Approaches to Neuroblastoma Therapy Consortium:
recurrent neuroblastoma

Additional relevant MeSH terms:
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue

ClinicalTrials.gov processed this record on September 14, 2014