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Combination of Targeted I -3F8-Mediated Radioimmunotherapy and Bevacizumab in Patients With Relapsed or Refractory Neuroblastoma: A Phase I Study

Phase 1
1 Year
Open (Enrolling)

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Trial Information

Combination of Targeted I -3F8-Mediated Radioimmunotherapy and Bevacizumab in Patients With Relapsed or Refractory Neuroblastoma: A Phase I Study



- Determine the toxicity of iodine I 131 monoclonal antibody 3F8 (^131I-3F8) and
bevacizumab in patients with relapsed or refractory neuroblastoma.

- Determine the hematopoietic recovery after autologous stem cell rescue in patients
treated with this regimen.


- Determine the clinical response rates in patients treated with this regimen.

- Assess whole body dosimetry for ^131I-3F8.

- Assess tumor targeting of ^131I-3F8 before and after bevacizumab.

OUTLINE: This is a dose-escalation study of iodine I 131 monoclonal antibody 3F8

Patients receive ^131I-3F8 IV over 20-30 minutes on day 0 and bevacizumab IV over 30-90
minutes on days 1 and 15. Treatment repeats every 28 days for up to 4 courses. Patients
whose blood counts do not recover and whose human antimouse antibody (HAMA) titer < 1,000
U/mL after course 1 receive one dose of ^131I-3F8 alone followed by autologous stem cell
rescue (ASCR) and filgrastim (G-CSF). Patients whose blood counts do not recover and whose
HAMA titer ≥ 1,000 U/mL after course 1 undergo ASCR followed by G-CSF. Patients whose blood
counts recover and whose HAMA titer < 1,000 U/mL after course 1 receive 3 more courses of
^131I-3F8 and bevacizumab in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of ^131I-3F8 and bevacizumab 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.

After completion of study treatment, patients are followed at 3-4 weeks and then every 3-6
months thereafter.


Inclusion Criteria:

- Patients must have the diagnosis of NB in accordance with the International Criteria,
i.e., either histopathology (confirmed by the MSKCC Department of Pathology) or BM
involvement plus elevated urinary catecholamines.

- Must have a history of tumor progression or recurrence or failure to achieve complete
response with standard therapy.

- Patients must have evaluable (microscopic marrow metastasis, MIBG or PET scans) or
measurable (CT, MRI) disease.

- Prior Therapy: At least 2 weeks should have elapsed since any biologic therapy. Three
weeks should have elapsed since last dose of chemotherapy or radioimmunotherapy.

- Age >1 year and able to cooperate with radiation safety restrictions during therapy

- Stem cells: Patients must have an autologous hematopoietic stem cell product
cryopreserved and available for re-infusion after MIBG treatment. The minimum dose
for hematopoietic stem cells is 2 X106 CD34+ cells/kg.

- Minimum life expectancy of four weeks.

- Signed informed consent indicating awareness of the investigational nature of this

Subject Exclusion Criteria:

- Severe major organ toxicity. Renal, cardiac, hepatic, pulmonary, gastrointestinal and
neurologic toxicity should all be grade 2 or less (per NCI CTC version 3 criteria).
Specifically, serum creatinine should be ≤3 x upper limit of normal (ULN), serum AST
and ALT ≤5 x ULN, serum bilirubin ≤ 3 x ULN, LV shortening fraction should be ≥15%.

- Patients with myelosuppression are not excluded if ANC ≥ 500/uL. Platelet count
should be > 50,000/ul and hemoglobin should be > 8gm/dl. Patients may receive
platelet or red blood cell transfusions to maintain hemoglobin and platelets at
clinical appropriate levels.

- Patients with documented chronic non-healing wound, ulcer or bone fracture

- Surgical procedures.

- Patients who have undergone major surgery <28 days prior to beginning therapy with
bevacizumab are excluded.

- Patients must be least 24 hours from having after surgical procedures such as
placement of central catheter.

- Patients <7days from minor surgeries (e.g. fine needle or core biopsies) and/or the
unhealed wounds from these procedures are excluded.

- Patients will be excluded if major surgery (e.g. abdominal or thoracic surgery for
resection of tumor) is anticipated during the course of the study.

Known bleeding diathesis or coagulopathy. Patients on anti-coagulants (except for heparin
flushes for centra venous catheter maintenance) are excluded.

- Thrombosis: patients must not have had a deep venous or arterial thrombosis
(non-central venous catheter related) within the last three months prior to study
entry. Patients with cerebrovascular accident or transient ischemic attack within 6
months of therapy are excluded. Patients with history of peripheral vascular disease,
myocardial infarction or unstable angina are excluded.

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study entry.

- Pulmonary or CNS metastases: pre-therapy CT or MRI of head and chest must be carried

- Proteinuria: Urine protein: creatinine ratio ≥ 1.0

- Uncontrolled hypertension.

- HAMA >1000 ELISA units/ml.

- History of allergy to mouse proteins, Chinese hamster ovary cells products or other
recombinant human antibodies

- Active serious infections not controlled by antibiotics.

- Pregnant women are excluded for fear of danger to the fetus. Therefore negative
pregnancy test is required for all women of child-bearing age, and appropriate
contraception is used during the study period.

- Inability or unwillingness to comply with radiation safety procedures or protocol

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD)

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Shakeel Modak, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2006

Completion Date:

August 2014

Related Keywords:

  • Neuroblastoma
  • recurrent neuroblastoma
  • Neuroblastoma



Memorial Sloan-Kettering Cancer Center New York, New York  10021