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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Drug: lestaurtinib

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90027-0700
      • Childrens Hospital Los Angeles
    • Palo Alto, California, United States, 94305
      • Lucille Salter Packer Children's Hospital, Stanford University
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comer Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • New York
    • New York, New York, United States, 10032
      • Morgan Stanley Children's Hospital of New York-Presbyterian
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Group	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 Names: CEP-701

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.		Within 28 days of treatment at each dose level.
To determine dose limiting toxicities (DLTs) of CEP-701 given on this schedule		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.	Days 1,5 and 26 of first course only.

Secondary Outcome Measures

Outcome Measure	Time Frame
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.	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.	Evaluation at end of courses 1, 2, 4 and then every 4 courses until patient goes off therapy.

Collaborators and Investigators

• Sponsor: New Approaches to Neuroblastoma Therapy Consortium
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Garrett M. Brodeur, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2003
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Actual): April 10, 2023
• Last Update Submitted That Met QC Criteria: April 6, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: recurrent neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma
• Other Study ID Numbers: CDR0000363630; P01CA081403 (U.S. NIH Grant/Contract); NANT-2001-03