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Combination of Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma: A Phase II Study

Phase 2
Open (Enrolling)

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Trial Information

Combination of Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma: A Phase II Study

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.

- Patients of all ages are eligible.

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

- Minimum life expectancy of eight weeks.

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

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 4.0 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 > 35,000/ul and hemoglobin should be > 8gm/dl. Patients should not have
received filgrastim, platelet or red blood cell transfusions for 2 days prior to
achieving the above ANC, platelet and hemoglobin 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 (in the absence of therapeutic

- 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.

- Known CNS metastases, except for treated brain metastasis. Treated brain metastases
are defined as having no evidence of progression or hemorrhage after treatment and no
ongoing requirement except for dexamethasone, as ascertained by clinical examination
and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable
dose) are allowed. Treatment for brain metastases may include radiotherapy,
chemotherapy or immunotherapy Patients with CNS metastases treated by neurosurgical
resection or biopsy performed within 3 months of treatment will be excluded.

- Proteinuria: Urine protein: creatinine ratio ≥ 1.0.

- Uncontrolled (lasting >24 hrs on antihypertensive medication) hypertension as defined
by age-appropriate criteria. Hypertension is defined as average systolic blood
pressure and/or diastolic blood pressure that is 95th percentile for gender, age, and
height on 3 occasions93. 95th percentiles for gender, age and height are provided in
Appendix A. For patients ≥18 years of age, hypertension is defined as systolic blood
pressure >150mmHg and/or diastolic blood pressure >100mmHg.

- Prior history of hypertensive crisis or hypertensive encephalopathy

- History of hypersensitivity to any component of bevacizumab

- History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month
prior to Day 1.

- 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 protocol requirements.

Type of Study:


Study Design:

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

Outcome Measure:

To evaluate tumor responses to combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB.

Outcome Time Frame:

15-35 days after cycle 2

Safety Issue:


Principal Investigator

Shakeel Modak, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

April 2010

Completion Date:

April 2016

Related Keywords:

  • Neuroblastoma
  • Bevacizumab
  • Irinotecan
  • Temozolomide
  • 10-015
  • Neuroblastoma



Memorial Sloan Kettering Cancer CenterNew York, New York  10021