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


N/A
1 Year
30 Years
Not Enrolling
Both
Disseminated Neuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4S Neuroblastoma

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Trial Information

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


PRIMARY OBJECTIVE:

I. To assess the feasibility of treating high-risk neuroblastoma patients, age 365 days to
30 years, with an induction block of meta-iodobenzylguanidine labeled with iodine-131
(131I-MIBG)/irinotecan/vincristine delivered after multi-agent chemotherapy, and
post-Induction busulfan/melphalan consolidation therapy.

SECONDARY OBJECTIVES:

I. To assess the tolerability of these regimens in these patients. II. To assess the
response rate of patients treated with these regimens. III. To describe the relationship of
tumor norepinephrine transporter (hNET) expression with radioiodinated MIBG uptake, at
diagnosis as well as with tumor response.

IV. To assess the relative reliability of 123 I-MIBG and 18FDG-PET imaging in assessment of
tumor activity at diagnosis, after 2 courses of induction chemotherapy, before surgical
resection and 131I-MIBG.

V. To compare detectable tumor burden before and immediate after therapy on the 123I-MIBG
diagnostic scan.

VI. 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.

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

VIII. To describe the toxicity of 131I-MIBG combined with vincristine and irinotecan given
on a 5-day schedule.

OUTLINE: This is a pilot, multicenter study.

INDUCTION CHEMOTHERAPY: Patients receive 5 courses of induction therapy.

Courses 1-2: Patients receive cyclophosphamide 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 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 (^131I-MIBG) induction therapy beginning 3-6 weeks after course 5. Patients
receive vincristine IV on day 0, irinotecan IV over 90 minutes on day 0-4, and 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 4-6 weeks after completion of induction therapy, patients
receive busulfan IV over 2 hours every 6 hours on days -6 to -3 and melphalan IV on day -1.
Patients also complete a questionnaire regarding costs for travel and accommodations during
therapy. Blood samples maybe collected after the first dose of busulfan for pharmacokinetic
assays.

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

RADIOTHERAPY: Beginning 28-42 days after peripheral blood stem cell infusion, patients
undergo 12 fractions of external-beam radiotherapy (2D, 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 oral
isotretinoin twice daily 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.


Inclusion Criteria:



- Diagnosis of neuroblastoma (ICD-O morphology 9500/3) or ganglioneuroblastoma by
histology or demonstration of clumps of tumor cells in bone marrow with elevated
urinary catecholamine metabolites meeting 1 of the following staging criteria:

- Newly diagnosed International Neuroblastoma Staging System (INSS) stage 4
disease meeting 1 of the following criteria:

- 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 DNA
index = 1, or any biologic feature that is indeterminant, unsatisfactory,
or unknown

- Newly diagnosed INSS stage 3 disease meeting 1 of the following criteria:

- 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

- 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

- Age ≥ 365 days initially diagnosed with INSS stage 1, 2, or 4S who progressed
(within the past 4 weeks) to a stage 4 without interval chemotherapy

- No patients aged 12-18 months with INSS stage 4 and all 3 favorable biologic
features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1)

- Must be enrolled onto ANBL00B1 biologic study

- Must have ≥ 1 "MIBG-avid target lesion" present on MIBG scan in the past 4 weeks

- Total bilirubin ≤1.5 times upper limit of normal (ULN)

- AST or ALT ≤ 10 times ULN

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min 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)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Shortening fraction ≥ 27% by ECHO OR ejection fraction ≥ 50% by radionuclide
evaluation

- Able to tolerate peripheral blood stem cell (PBSC) collection

- No contraindications to PBSC collection including weight, size, or physical
condition that would preclude apheresis

- No prior systemic therapy

- Localized emergency radiotherapy to sites of life-threatening or
function-threatening disease and ≥ 1 measurable lesion is not irradiated

- No more than 1 course of chemotherapy per low- or intermediate-risk
neuroblastoma therapy before determination of MYCN amplification and histology

- No local radiotherapy that includes any of the following:

- 1,200 cGy to more than 33% of both kidneys

- Patient must have ≥ 1 kidney that has not exceeded the dose/volume of
radiation listed

- 1,800 cGy to more than 30% of liver and/or 900cGy to more than 50% of liver

- No other concurrent cancer chemotherapy or immunomodulating agents (including
steroids)

Type of Study:

Interventional

Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of MIBG avid patients who are able to be treated with 131I-MIBG/irinotecan/vincristine

Outcome Description:

This proportion will be calculated as the number of MIBG avid patients who receive 131I-MIBG/irinotecan/vincristine divided by the number of patients evaluable for the feasibility of MIBG endpoint. The definition of receive 131I-MIBG/irinotecan/vincristine is receiving 131I-MIBG infusion.

Outcome Time Frame:

Up to 6 weeks after course 5 of induction

Safety Issue:

No

Principal Investigator

Brian Weiss

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

ANBL09P1

NCT ID:

NCT01175356

Start Date:

October 2010

Completion Date:

Related Keywords:

  • Disseminated Neuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • Neuroblastoma

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
University of Texas Southwestern Medical CenterDallas, Texas  
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Children's Hospital ColoradoAurora, Colorado  80045
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143