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Irinotecan and Vincristine With 131I-MIBG Therapy for Resistant/Relapsed High-Risk Neuroblastoma, A Phase I Study

Phase 1
1 Year
30 Years
Open (Enrolling)

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Trial Information

Irinotecan and Vincristine With 131I-MIBG Therapy for Resistant/Relapsed High-Risk Neuroblastoma, A Phase I Study



- To determine the maximum tolerated dose (MTD) of iodine I 131 metaiodobenzylguanidine
when given in combination with fixed-dose irinotecan hydrochloride and vincristine in
young patients with refractory or relapsed high-risk neuroblastoma.

- To determine the dose-limiting toxicities of iodine I 131 metaiodobenzylguanidine when
combined with fixed-dose irinotecan hydrochloride and vincristine.


- To determine if there is a therapeutic response to this regimen.

OUTLINE: This is a multicenter, dose-escalation study of iodine I 131
metaiodobenzylguanidine (^131I-MIBG).

Patients receive ^131I-MIBG IV over 1½-2 hours on day 1, vincristine IV on days 0 and 7, and
irinotecan hydrochloride IV over 1 hour on days 0-4 and 7-11. Treatment repeats every 56
days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 1 year and
then every 6 months thereafter.

Inclusion Criteria


Inclusion criteria:

- Must have a diagnosis of neuroblastoma by histologic verification and/or
demonstration of tumor cells in the bone marrow with increased urinary catecholamines

- Must have high-risk neuroblastoma AND meets at least one of the following criteria:

- Recurrent or progressive disease at any time

- Biopsy not required, even if there is partial response to intervening

- Refractory disease (i.e., less than a partial response to frontline therapy,
including a minimum of 4 courses of chemotherapy)

- Biopsy not required

- If the patient has not had previous myeloablative therapy, preference will
be given to NANT-2001-02 (iodine I 131 metaiodobenzylguanidine [^131I-MIBG]
+ CEM)

- Persistent disease after at least a partial response to frontline therapy (i.e.,
patient still has residual disease by MIBG scan, CT/MRI scan, or bone marrow)

- Biopsy required (bone marrow biopsy included) of at least one residual site
demonstrating viable neuroblastoma

- If the patient has not had previous myeloablative therapy, preference will
be given to NANT-2001-02 (^131I-MIBG + CEM)

- Must have evidence of MIBG uptake into tumor at ≥ 1 site within 4 weeks prior to
study entry and subsequent to any intervening therapy

- Must have autologous hematopoietic stem cell product available and it must be free of
tumor cell contamination (0 tumor cells /1,000,000 nucleated cells), cryopreserved,
and available for re-infusion after ^131I-MIBG treatment, if immunocytology has been
performed on the stem cell product

- If immunocytology has not been performed on the stem cell product, then
bilateral bone marrow aspirates and biopsies must have been negative by
morphology within 4 weeks before or after the stem cell collection

- If the patient had no bone marrow disease documented at diagnosis or at any time
prior to peripheral blood stem cell (PBSC) harvest then the criteria for
bilateral bone marrow aspirates/biopsies is waived

- The minimum dose is as follows:

- Purged PBSC 2.0 x 10^6 viable CD34+ cells/kg

- Immuno-magnetically purged cells are permitted

- Unpurged PBSC 2 x 10^6 CD34+ cells/kg (minimum is same for PBSC from
identical twin)

- Cells from identical twins are permitted

- Other allogeneic cells are not allowed

- CD34+ selected cells are not permitted


Inclusion criteria:

- Lansky or Karnofsky performance status ≥ 50%

- Life expectancy ≥ 6 weeks

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- ANC ≥ 750/μL (no hematopoietic growth factors within 7 days of starting irinotecan

- Platelet count ≥ 50,000/μL (transfusion independent, defined as no platelet
transfusion for 2 weeks)

- Glomerular filtration rate (GFR) or creatinine clearance ≥ 60 mL/min OR age-adjusted
serum creatinine ≤ 1.5 x normal, according to the following:

- 0.8 mg/dL (≤ 5 years of age)

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

- 1.2 mg/dL (11 to 15 years of age)

- 1.5 mg/dL (≥ 16 years of age)

- Total bilirubin ≤ 1.5 x normal for age

- ALT and AST < 3 x normal for age

- All post-menarchal females must have a negative beta-HCG

- Males and females of reproductive age and childbearing potential must use effective
contraception for the duration of study participation

- Ejection fraction ≥ 55% by echocardiogram or radionuclide MUGA OR fractional
shortening ≥ 27% by echocardiogram

- Normal lung function

- Patients with other ongoing serious medical issues must be approved by the study
chair prior to study registration

Exclusion criteria:

- Pregnancy or breast feeding

- Dyspnea at rest, exercise intolerance, pleural effusion, or oxygen requirement

- Disease of any major organ system that would compromise the patient's ability to
withstand therapy

- Documented allergy to third generation cephalosporins

- Active diarrhea (defined as ≥ grade 2 per CTCAE v3)

- Active or uncontrolled infection, including C. difficile

- Patients on prolonged antifungal therapy are eligible if suspected radiographic
lesions are culture and biopsy negative and patient meets other organ function

- Patients and/or families who are physically and psychologically unable to cooperate
with the radiation safety isolation

- Patient weight that would require exceeding a maximum total allowable dose of
^131I-MIBG (per institutional guidelines)

- Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study


Inclusion criteria:

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy before study entry

- At least 3 weeks since prior myelosuppressive or biologic therapy

- At least 2 weeks since prior radiation therapy

- Radiation therapy should not be given to the only site of measurable or
evaluable disease

- At least 3 months since prior large field radiation therapy (i.e., craniospinal
radiation therapy, total lung radiation therapy, or radiation therapy to > 50% of
marrow space)

- At least 3 months since prior autologous stem cell transplantation

- Must meet adequate bone marrow function postmyeloablative therapy

- At least 7 days since prior cytokines or hematopoietic growth factors

- Prior irinotecan hydrochloride and vincristine therapy allowed provided the patient
recovered to adequate bone marrow function as specified in the protocol

Exclusion criteria:

- Prior ^131I-MIBG

- Prior external beam radiation therapy to the liver or kidneys

- Prior allogeneic stem cell transplantation

- Prior whole abdominal radiation therapy, total-body irradiation, or local radiation
therapy that includes any of the following:

- 1,200 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)

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

- Other concurrent cancer chemotherapy or immunomodulating agents (including steroids)

- Steroids may be used in the prevention and treatment of transfusion/infusion
reactions and for the treatment of edema associated with CNS lesions

- Concurrent palliative radiotherapy to localized painful lesions

- Concurrent aprepitant (Emend)

- Concurrent ketoconazole or St. John's wort

- Medications that interfere with MIBG uptake during the week prior to or after MIBG

- Concurrent enzyme-inducing anticonvulsants (e.g., phenobarbital, phenytoin, or

- Nonenzyme-inducing anticonvulsants (e.g., Keppra) may be allowed

- Concurrent hemodialysis

- Any other concurrent anticancer agents or radiation therapy

Type of Study:


Study Design:

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

Outcome Measure:

To determine the maximum tolerated dose (MTD) of 131I-MIBG given in combination with fixed-dose irinotecan/vincristine to children with high-risk refractory/relapsed neuroblastoma.

Outcome Time Frame:

Tolerability will be assessed throughout the study.

Safety Issue:


Principal Investigator

Steven DuBois, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UCSF Medical Center at Parnassus


United States: Food and Drug Administration

Study ID:




Start Date:

January 2007

Completion Date:

December 2013

Related Keywords:

  • Neuroblastoma
  • recurrent neuroblastoma
  • Neuroblastoma



Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center Madison, Wisconsin  53792-6164
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Cook Children's Medical Center - Fort Worth Fort Worth, Texas  76104
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Childrens Hospital Los Angeles Los Angeles, California  90027
Lucile Packard Children's Hospital at Stanford University Medical Center Palo Alto, California  95798
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California  94115
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Atlanta, Georgia  30322
C.S. Mott Children's Hospital at University of Michigan Medical Center Ann Arbor, Michigan  48109-0286
University of Chicago Comer Children's Hospital Chicago, Illinois  60637
Children's Hospital Boston Boston, Massachusetts  02115