Clinical trial NCT00005978: N99-01: Combination Chemotherapy, Radiation Therapy, and Stem Cell Transplantation in Treating Patients With Neuroblastoma
Official title: Dose Escalation Study of 131 I-Metaiodobenzylguanidine (MIBG) With Intensive Chemotherapy and Autologous Stem Cell Rescue for High-Risk Neuroblastoma - A Phase I Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuroblastoma
Keywords: localized resectable neuroblastoma
regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
recurrent neuroblastoma
localized unresectable neuroblastoma
Lead sponsor: New Approaches to Neuroblastoma Therapy Consortium
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-12-23
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving the drugs in different ways may kill more tumor cells. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell or bone marrow transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy.

PURPOSE: This phase I trial is studying the side effects and best dose of combination chemotherapy when given before stem cell transplant and radiation therapy in treating patients with neuroblastoma that has not responded to previous treatments.

Detailed description: OBJECTIVES:

* Determine the maximum tolerated dose and toxic effects of iodine I 131 metaiodobenzylguanidine (131 I-MIBG) plus ablative doses of carboplatin and etoposide administered with fixed-dose melphalan followed by autologous hematopoietic stem cell transplantation in patients with refractory or residual high-risk neuroblastoma.
* Determine the number of days until blood counts recover in these patients after receiving this treatment regimen.
* Determine the response rate to this treatment regimen in these patients.
* Determine the tumor dosimetry of 131 I-MIBG in patients with measurable soft tissue lesions.

OUTLINE: This is a dose-escalation study of iodine I 131 metaiodobenzylguanidine (131 I-MIBG), carboplatin, and etoposide. Patients are stratified according to glomerular filtration rate (at least 100 mL/min vs 60-99 mL/min).

Patients undergo peripheral blood stem cell harvest or bone marrow harvest at least 2 weeks prior to treatment with 131 I-MIBG.

Patients receive 131 I-MIBG IV over 120 minutes on day -21; melphalan IV on days -7 to -5; carboplatin and etoposide IV continuously over 96 hours on days -7 to -4; autologous hematopoietic stem cell transplantation IV over 15-30 minutes on day 0; and filgrastim (G-CSF) subcutaneously or IV starting on day 0 and continuing until blood counts recover. Radiotherapy is administered to the primary tumor site and metastatic sites twice daily for 7 consecutive days within 6 weeks of transplantation or once blood counts have recovered.

Cohorts of 3-6 patients receive escalating doses of 131 I-MIBG, carboplatin, and etoposide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at day 84, and then 2 months later if there is a complete response and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy. All patients are followed for life for any delayed toxic effects related to study therapy, secondary malignancies, disease status, and survival.

PROJECTED ACCRUAL: A total of 30-60 patients (15-30 per stratum) will be accrued for this study within 2-3 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of neuroblastoma as evidenced by one of the following:

  * Histological confirmation
  * Demonstrates clumps of tumor cells in bone marrow with elevated urinary catecholamine metabolites
* High-risk refractory or residual disease
* Poorly responding disease, meeting 1 of the following criteria:

  * Stable disease or partial response after at least 12 weeks of induction therapy
  * Bone marrow containing greater than 100 tumor cells per 100,000 normal cells after 12 weeks of induction therapy
  * Progressive disease during or after therapy
* At least 1 prior positive iodine I 131 metaiodobenzylguanidine (131 I-MIBG) scan since diagnosis and meets disease status criteria

PATIENT CHARACTERISTICS:

Age:

* 1 to 21 (1 to 20 at diagnosis)

Performance status:

* ECOG 0-2

Life expectancy:

* At least 2 months

Hematopoietic:

* Absolute neutrophil count at least 500/mm\^3
* Platelet count at least 20,000/mm\^3 (transfusion allowed)
* Hemoglobin at least 8 g/dL (transfusion allowed)

Hepatic:

* Bilirubin normal
* AST/ALT no greater than 3 times normal
* No active hepatitis (for HIV-positive patients only)

Renal:

* Glomerular filtration rate or creatinine clearance at least 60 mL/min
* Creatinine less than 1.5 times normal for age

Cardiovascular:

* Ejection fraction at least 55% OR
* Fractional shortening at least 30%

Pulmonary:

* No dyspnea at rest or exercise intolerance
* No requirement for supplemental oxygen
* No active pneumonia (for HIV-positive patients only)

Other:

* No disease of any major organ system that would preclude study participation
* No other active health problems (for HIV-positive patients only)
* No active infections requiring intravenous antivirals, antibiotics, or antifungals
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* At least 3 weeks since prior biologic therapy and recovered

Chemotherapy:

* At least 3 weeks since prior chemotherapy and recovered
* No more than 100 mg/m\^2 total dose of prior melphalan

Endocrine therapy:

* Not specified

Radiotherapy:

* No prior total body, whole abdominal, or whole liver irradiation
* No prior therapy with 131 I-MIBG
* At least 2 weeks since prior radiotherapy (6 months for prior radiotherapy to craniospinal or whole lung fields or greater than 50% of bone marrow space) and recovered

Surgery:

* Prior surgical resection allowed
* Recovered from prior surgery

Other:

* No prior myeloablative therapy

  * Prior submyeloablative therapy with peripheral blood stem cell support allowed
* No concurrent antiretrovirals for HIV-positive patients
* Concurrent prolonged antifungal allowed if culture and biopsy negative in suspected residual radiographic lesions
* No medications that may preclude uptake of 131 I-MIBG for 1 week prior and 2 weeks after administration of study drugs
* No concurrent hemodialysis

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's 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 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: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Bethesda
country: United States
facility: Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
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: University of Michigan Comprehensive Cancer Center
state: Michigan
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: Houston
country: United States
facility: Texas Children's Cancer Center
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 Comprehensive Cancer Center
state: Wisconsin
Study officials:
affiliation: Children's Hospital Los Angeles
name: Katherine K. Matthay, MD
role: STUDY_CHAIR
References:
citation: Matthay KK, Tan JC, Villablanca JG, Yanik GA, Veatch J, Franc B, Twomey E, Horn B, Reynolds CP, Groshen S, Seeger RC, Maris JM. Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol. 2006 Jan 20;24(3):500-6. doi: 10.1200/JCO.2005.03.6400.