Clinical trial NCT00084422: N2001-03: CEP-701 in Treating Young Patients With Recurrent or Refractory High-Risk Neuroblastoma
Official title: A Phase I Study Of CEP-701 In Patients With Refractory Neuroblastoma (IND # 67,722)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuroblastoma
Keywords: recurrent neuroblastoma
Lead sponsor: New Approaches to Neuroblastoma Therapy Consortium
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-06-11
Enrollment: 47
Sex: ALL
Minimum age (years): 1
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
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.
timeFrame: Within 28 days of treatment at each dose level.
measure: To determine dose limiting toxicities (DLTs) of CEP-701 given on this schedule
timeFrame: Within first 28 days of therapy.
measure: To characterize the pharmacokinetic (PK) behavior of CEP-701 in children with residual or refractory high-risk neuroblastoma.
timeFrame: Days 1,5 and 26 of first course only.
Secondary outcomes:
measure: 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.
timeFrame: Days 1,5 and 26 of first course only.
measure: To define the antitumor activity of CEP-701, within the confines of a Phase I study.
timeFrame: Evaluation at end of courses 1, 2, 4 and then every 4 courses until patient goes off therapy.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucille Salter Packer Children's Hospital, Stanford University
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Comer Children's Hospital
state: Illinois
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: New York
country: United States
facility: Morgan Stanley Children's Hospital of New York-Presbyterian
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Children's Hospital of Philadelphia
name: John M. Maris, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: Garrett M. Brodeur, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.