Induction Therapy Including 131 I-MIBG and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant, Radiation Therapy, and Maintenance Therapy With Isotretinoin

Study ID
ANBL09P1

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Children’s Medical Center (Dallas, Plano, Southlake)

Contact
Sarmistha Sen
214-456-0437
sarmistha.sen@childrens.com

Principal Investigator
Tanya Watt

Official Title

A COG Pilot Study of Intensive Induction Chemotherapy and 131I-MIBG Followed by Myeloablative Busulfan/Melphalan (Bu/Mel) for Newly Diagnosed High-Risk Neuroblastoma

Brief Overview


This clinical trial is studying induction therapy followed by meta-iodobenzylguanidine
(MIBG) labeled with iodine-131 and chemotherapy in treating patients with newly diagnosed
high-risk neuroblastoma undergoing stem cell transplant, radiation therapy, and maintenance
therapy with isotretinoin. Radioisotope therapy, such as MIBG labeled with iodine-131,
releases radiation that kills tumor cells. Drugs used in chemotherapy, such as cisplatin,
etoposide, busulfan, and melphalan, work in different ways to stop the growth of tumor
cells, either by killing the cells or by stopping them from dividing. A peripheral stem cell
transplant can replace blood-forming cells that are damaged by MIBG labeled with iodine-131
and chemotherapy.

Summary


PRIMARY OBJECTIVE:

I. To assess the feasibility of treating high-risk neuroblastoma patients, age 365 days - 30
years, with a) an induction block of meta-iodobenzylguanidine labeled with iodine-131
(131I-MIBG [iobenguane I 131]) delivered after multi-agent chemotherapy, and b)
post-induction busulfan/melphalan (Bu/Mel) consolidation therapy.

SECONDARY OBJECTIVES:

I. To assess the tolerability of treating high-risk neuroblastoma patients, age 365 days -
30 years, with a) an induction block of 131I-MIBG therapy delivered after multi-agent
chemotherapy, and b) the tolerability of receiving post-induction Bu/Mel consolidation
therapy with autologous stem-cell rescue (ASCR), and local radiation therapy.

TERTIARY OBJECTIVES:

I. To assess the response rate after a regimen of induction chemotherapy and 131I-MIBG and
after a consolidation regimen of Bu/Mel with ASCR and local radiation therapy.

II. To describe the relationship of tumor norepinephrine transporter (hNET) expression with
radioiodinated MIBG uptake, at diagnosis as well as with tumor response.

III. To assess the relative reliability of 123 I-MIBG and fludeoxyglucose F-18
(18FDG)-positron emission tomography (PET) imaging in assessment of tumor activity at
diagnosis, and prior to surgical resection.

IV. To compare detectable tumor burden on the pre-surgical resection radioiodinated-MIBG
diagnostic scan and the immediate post-MIBG therapy 131I-MIBG scan.

V. To test for the relationship of occurrence of sinusoidal obstruction syndrome (SOS) to
Bu/Mel or to whole-body radiation dose or delayed radiation clearance due to 131I-MIBG.

VI. To analyze busulfan pharmacokinetics as measured by area under the curve (AUC) and
relate exposure to SOS incidence.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive 5 courses of induction therapy.

Courses 1-2: Patients receive cyclophosphamide intravenously (IV) over 15-30 minutes and
topotecan hydrochloride IV over 30 minutes on days 1-5. Patients undergo peripheral blood
stem cell (PBSC) collection after course 2.

Course 3 and 5: Patients receive cisplatin IV over 1 hour on days 1-4 and etoposide
phosphate IV over 1-2 hours on days 1-3. Patients undergo surgery to remove remaining tumor
following course 5.

Course 4: Patients receive cyclophosphamide IV over 1-6 hours on days 1-2 and vincristine
sulfate IV over 1 minute and doxorubicin hydrochloride IV over 24 hours on days 1-3.

Treatment repeats every 21 days for a total of 5 courses in the absence of disease
progression or unacceptable toxicity. Patients without progressive disease proceed to
iobenguane I 131 induction therapy beginning 3-6 weeks after course 5. Patients receive
iobenguane I 131 IV over 90-120 minutes on day 1.

SURGERY: Patients undergo surgery after course 4 or before consolidation therapy.

CONSOLIDATION THERAPY: Within 10-12 weeks from the date of iobenguane I 131 infusion,
patients receive busulfan IV over 2 hours every 6 hours on days -6 to -3 and melphalan IV on
day -1.

AUTOLOGOUS STEM CELL RESCUE: Patients undergo infusion of PBSC on day 0.

RADIOTHERAPY: Beginning no sooner than 42 days after peripheral blood stem cell infusion,
patients undergo 12 fractions of external-beam radiotherapy (2 dimensional [D],
3D-conformal, or intensity-modulated) to all areas of residual disease, primary tumor site,
and involved nodal disease.

MAINTENANCE THERAPY: Beginning 66 days after transplantation, patients receive isotretinoin
orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 28 days for 6 courses.

After completion of study therapy, patients are followed up every 3 months for 1 year, every
6 months for 4 years, and then annually for 5 years.

Participant Eligibility


Inclusion Criteria:

- Patients have a diagnosis of neuroblastoma (International Classification of Diseases
for Oncology [ICD-O] morphology 9500/3) or ganglioneuroblastoma verified by histology
or demonstration of clumps of tumor cells in bone marrow with elevated urinary
catecholamine metabolites; patients with the following disease stages at diagnosis
are eligible, if they meet the other specified criteria:

- Patients with newly diagnosed neuroblastoma with International Neuroblastoma
Staging System (INSS) stage 4 are eligible with the following:

- v-MYC myelocytomatosis viral related oncogene, neuroblastoma derived
(avian) (MYCN) amplification (> 4-fold increase in MYCN signals as compared
to reference signals) and age >= 365 days regardless of additional biologic
features

- Age > 18 months (> 547 days) regardless of biologic features

- Age 12-18 months (365-547 days) with any of the following 3 unfavorable
biologic features (MYCN amplification, unfavorable pathology and/or
deoxyribonucleic acid [DNA] index = 1) or any biologic feature that is
indeterminant/unsatisfactory/unknown

- Patients with newly diagnosed neuroblastoma with INSS stage 3 are eligible with
the following:

- MYCN amplification (> 4-fold increase in MYCN signals as compared to
reference signals), and age >= 365 days, regardless of additional biologic
features

- Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN
status

- Patients with newly diagnosed INSS stage 2a/2b with MYCN amplification (> 4-fold
increase in MYCN signals as compared to reference signals) and age >= 365 days,
regardless of additional biologic features

- Patients >= 365 days initially diagnosed with: INSS stage 1, 2, 4S who
progressed to a stage 4 without interval chemotherapy; these patients must have
been enrolled on ANBL00B1; it is to be noted that study enrollment must occur
within 4 weeks of progression to stage 4 for INSS stage 1, 2, 4S

- Patients must have had no prior systemic therapy except for localized emergency
radiation to sites of life-threatening or function-threatening disease and/or no more
than 1 cycle of chemotherapy per low- or intermediate-risk neuroblastoma therapy
(P9641, A3961, ANBL0531) prior to determination of MYCN amplification and histology

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 OR serum creatinine based on age and/or gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

- 1.7 mg/dL (male) or 1.4 mg/dL (female) ( >= 16 years of age)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN for age

- Shortening fraction >= 27% by echocardiogram or

- Ejection fraction >= 50% by radionuclide evaluation

- No known contraindication to peripheral blood stem cell (PBSC) collection; examples
of contraindications might be a weight or size less than the collecting institution
finds feasible, or a physical condition that would limit the ability of the child to
undergo apheresis catheter placement (if necessary) and/or the apheresis procedure

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met

Exclusion Criteria:

- Females of childbearing potential must have a negative pregnancy test; patients of
childbearing potential must agree to use an effective birth control method

- Female patients who are lactating must agree to stop breast-feeding

- Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic
features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1) are not
eligible

- Patients are not eligible if they have received local radiation which includes any of
the following: 1200 centigray (cGy) to more than 33% of both kidneys (patient must
have at least 1 kidney that has not exceeded the dose/volume of radiation listed) or
1800 cGy to more than 30% of liver and/or 900 cGy to more than 50% of liver;
emergency local irradiation is allowed prior to study entry, provided the patient
still meets eligibility criteria