Clinical trial NCT01114555: Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma
Official title: Combination of Bevacizumab, Irinotecan and Temozolomide for Relapsed or Refractory Neuroblastoma: A Phase II Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neuroblastoma
Keywords: Bevacizumab
Irinotecan
Temozolomide
10-015
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2010-05-03
Enrollment: 34
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to find how good and how safe the combination of irinotecan, temozolomide and bevacizumab is for patients with resistant or recurrent neuroblastoma. These drugs have each been given separately to patients, but they have never been given all together. Irinotecan and temozolomide are two drugs that have been used together to treat neuroblastoma in many people. These drugs are considered chemotherapy. Bevacizumab is another drug used to treat cancer. It is made by a company called Genentech. Bevacizumab is an antibody. Antibodies are proteins that are found in the blood and can attach themselves to bacteria and viruses. Bevacizumab attaches itself to a special protein in the bloodstream. This protein helps tumors grow new blood vessels. Blood vessels carry nutrients to feed the tumor. Bevacizumab is thought to block this growth of new blood vessels and starve tumors. It has been used for the treatment of many cancers in adults. It is approved by the FDA for the treatment of adults with colon cancer and other cancers but not for people with neuroblastoma. There is only a small amount of information known on using this drug in children. It has been used with irinotecan before to treat cancer but not in children with neuroblastoma.


Eligibility criteria: 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 program.

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 anticoagulation)
* 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.

Primary outcomes:
measure: Overall Responses
timeFrame: 15-35 days after cycle 2
Secondary outcomes:
measure: Number of Participants With Treatment Related Toxicity
timeFrame: Patients will be evaluated at least once weekly for toxicity. Observation for toxicities for up to 42 days
measure: To Evaluate Changes in Angiogenic Markers After Treatment With the Combination of Irinotecan, Temozolomide and Bevacizumab.
timeFrame: days 1,4, 15 and once between days 22-35 during cycle 1 and cycle 2
measure: To Measure Time to Progression in Patients With Resistant NB Treated With the Combination of Irinotecan, Temozolomide and Bevacizumab.
timeFrame: 3 years
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Shakeel Modak, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Modak S, Kushner BH, Basu E, Roberts SS, Cheung NK. Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study. Pediatr Blood Cancer. 2017 Aug;64(8):10.1002/pbc.26448. doi: 10.1002/pbc.26448. Epub 2017 Jan 23.