Clinical trial NCT00253435: N2001-02: I-MIBG With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma
Official title: I-Metaiodobenzylguanidine (MIBG) With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neuroblastoma
Keywords: recurrent neuroblastoma
Lead sponsor: Children's Hospital Los Angeles
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2005-11-15
Enrollment: 50
Sex: ALL
Minimum age (years): 1
Maximum age (years): 29
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Radioactive drugs, such as iodine I 131 metaiodobenzylguanidine, may carry radiation directly to tumor cells and not harm normal cells. Drugs used in chemotherapy, such as carboplatin, etoposide, and melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. An autologous peripheral stem cell or bone marrow transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Giving iodine I 131 metaiodobenzylguanidine and combination chemotherapy with an autologous peripheral stem cell or bone marrow transplant may allow more chemotherapy to be given so that more tumor cells are killed. Giving radiation therapy after an autologous peripheral stem cell or bone marrow transplant may kill any remaining tumor cells.

PURPOSE: This phase II trial is studying how well giving iodine I 131 metaiodobenzylguanidine together with combination chemotherapy and radiation therapy works in treating patients who are undergoing an autologous peripheral stem cell or bone marrow transplant for relapsed or refractory neuroblastoma.

Detailed description: OBJECTIVES:

Primary

* Determine the response rate in patients with relapsed or refractory neuroblastoma treated with iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy comprising carboplatin, etoposide, and melphalan followed by autologous bone marrow or peripheral blood stem cell transplantation and radiotherapy.

Secondary

* Determine the hematopoietic and nonhematopoietic toxicity of this regimen in these patients.
* Determine the tumor self-absorbed radiation dose (TSARD) in patients with measurable soft tissue lesions treated with this regimen.
* Correlate the TSARD with tumor response in patients with measurable residual soft tissue disease treated with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk (poor-risk group \[mixed or no response to induction therapy or progression during or after induction therapy\] vs good-risk group \[partial response after 4 courses of induction therapy\]) and kidney function at study entry (glomerular filtration rate \[GFR\] ≥ 100 mL/min vs GFR 60-99 mL/min)

* Stem cell harvest: Patients undergo a peripheral blood stem cell harvest or bone marrow harvest provided they have an adequate number of cells available. At least 2 weeks later, patients proceed to iodine I 131 metaiodobenzylguanidine (\^131I-MIBG) and combination chemotherapy.
* 131I-MIBG and combination chemotherapy: Patients receive \^131I-MIBG IV over 2 hours on day -21, carboplatin IV continuously on days -7 to -4, etoposide IV continuously on days -7 to -4, and melphalan IV over 1 hour on days -7 to -5.
* Stem cell infusion and filgrastim (G-CSF): Three days after completion of chemotherapy, patients undergo transplantation of either stem cells or bone marrow on day 0. Patients also receive G-CSF subcutaneously or IV over 1 hour once daily beginning on day 0 and continuing until blood counts return to normal.
* Radiotherapy: Once blood counts return to normal, patients undergo radiotherapy to primary and metastatic sites that have not received previous irradiation over 12 days beginning after day 42.

After completion of study treatment, patients are followed for 2 years and then periodically thereafter.

PROJECTED ACCRUAL: Approximately 50 patients (40 low-risk patients and 8-10 high-risk patients) will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of relapsed or refractory neuroblastoma

  * Histologically confirmed and/or demonstration of tumor cells in bone marrow with elevated urinary catecholamine metabolites
  * High-risk neuroblastoma must meet one of the following:

    * Progressive disease prior to or after completion of induction therapy
    * Mixed response or no response after completion of 4 courses of induction therapy
    * Partial response after 4 courses of induction therapy allowed provided no prior participation in COG-A3973 or other phase III COG trials
* Measurable disease, defined as at least one metaiodobenzylguanidine (MIBG)-avid target lesion determined by diagnostic MIBG scan within 6 weeks of study entry (tumor sites that have received local irradiation within 3 months of study entry are not considered target lesions)

PATIENT CHARACTERISTICS:

Performance status

* Lansky 60-100% OR
* Karnofsky 60-100%

Life expectancy

* At least 2 months

Hematopoietic

* Hemoglobin ≥ 10 g/dL
* Absolute neutrophil count ≥ 750/mm\^3
* Platelet count ≥ 50,000/mm\^3 (if no marrow involvement by morphologic exam/no transfusion allowed) (\> 20,000/mm\^3 if metastatic tumor involvement of marrow by morphologic exam/transfusion allowed)

Hepatic

* Bilirubin \< 1.3 mg/dL
* SGOT and SGPT \< 5 times normal
* Hepatitis B surface antigen negative
* Hepatitis C negative

Renal

* Glomerular filtration rate or creatinine clearance ≥ 60 ml/min
* Creatinine ≤ 1.5 times normal for age as follows:

  * 0.8 mg/dL (for patients ≤ 5 years of age)
  * 1.0 mg/dL (for patients 6 to 10 years of age)
  * 1.2 mg/dL (for patients 11 to 15 years of age)
  * 1.5 mg/dL (for patients \> 15 years of age)

Cardiovascular

* Ejection fraction ≥ 55% by echocardiogram or radionuclide MUGA OR
* Fractional shortening ≥ 27% by echocardiogram

Pulmonary

* Normal lung function defined as no dyspnea at rest and no oxygen requirement OR measured oxygen saturation \> 93% on room air

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No disease of any major organ system that would preclude study compliance
* No concurrent hemodialysis
* No active infection requiring IV antivirals, antibiotics, or antifungals (patients on antifungal therapy are eligible provided they are culture- and biopsy-negative in suspected residual radiographic lesions)
* Patient weight within limits to receive ≤ maximum total allowable dose of \^131I-MIBG

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior myeloablative transplantation

  * Prior submyeloablative transplantation allowed at discretion of principal investigator
* More than 3 weeks since prior biologic therapy

Chemotherapy

* More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for mitomycin C or nitrosoureas)
* No prior melphalan therapy with a total dose of \> 100 mg/m\^2

Radiotherapy

* See Disease Characteristics
* At least 6 weeks since prior radiotherapy (6 months for craniospinal or whole lung radiotherapy)
* No prior total body irradiation
* No prior iodine I 131 MIBG (\^131I-MIBG)
* No prior total abdominal or whole liver radiotherapy
* No prior local radiotherapy, including any of the following:

  * 1200 cGy to more than 33% of both kidneys (patient must have at least one kidney that has not exceeded the dose/volume of radiation listed)
  * 1800 cGy to more than 30% of liver and/or 900 cGy to more than 50% of liver

Other

* Recovered from all prior therapy
* No medications with a potential interference of \^131I-MIBG uptake 1 week before and 2 weeks after completion of \^131I-MIBG

Primary outcomes:
measure: Response (Complete Response, Very Good Partial Response, and Partial Response) at 60-days Post Stem Cell Infusion
timeFrame: Response assessed 60 days post stem cell infusion
Secondary outcomes:
measure: Event-free Survival (EFS) at 3 Years
timeFrame: 3 years since start of treatment
measure: Engraftment DLT
timeFrame: From treatment start until 60 days post stem cell infusion
measure: Dose Limiting Veno-occlusive Disease (VOD) / Sinusoidal Obstruction Syndrome SOS
timeFrame: Between start of MIBG treatment and 60 days post stem cell infusion
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford University Medical Center
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: Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C.S. Mott Children's Hospital at University of Michigan Medical 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: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Houston
country: United States
facility: Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
state: Wisconsin
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of Michigan Rogel Cancer Center
name: Gregory Yanik, MD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Katherine K. Matthay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital of Philadelphia
name: John M. Maris, MD
role: PRINCIPAL_INVESTIGATOR
References: