Neuroblastoma
Conditions
Keywords
Bevacizumab, Irinotecan, Temozolomide, 10-015
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.
Interventions
DRUGBevacizumab, Irinotecan and Temozolomide
Patients will initially receive bevacizumab IV at 15mg/kg/dose (this is defined as Day 1 Three days later (starting day 4), they will receive concurrently, IV irinotecan at 50mg/m2/day x 5 days plus PO temozolomide 150mg/m2/day x 5 days. A second dose of bevacizumab will be administered 14 days after the first one(day 15). The treatment schedule may require minor adjustment as clinically indicated (e.g., due to PDH closure for holidays).
Sponsors
Genentech, Inc.
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Responses | 15-35 days after cycle 2 | To evaluate tumor responses to combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Related Toxicity | Patients will be evaluated at least once weekly for toxicity. Observation for toxicities for up to 42 days | To determine the toxicity of the combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB. |
| To Evaluate Changes in Angiogenic Markers After Treatment With the Combination of Irinotecan, Temozolomide and Bevacizumab. | days 1,4, 15 and once between days 22-35 during cycle 1 and cycle 2 | — |
| To Measure Time to Progression in Patients With Resistant NB Treated With the Combination of Irinotecan, Temozolomide and Bevacizumab. | 3 years | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab, Irinotecan and Temozolomide This is a phase II study of the combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB.
Bevacizumab, Irinotecan and Temozolomide: Patients will initially receive bevacizumab IV at 15mg/kg/dose (this is defined as Day 1 Three days later (starting day 4), they will receive concurrently, IV irinotecan at 50mg/m2/day x 5 days plus PO temozolomide 150mg/m2/day x 5 days. A second dose of bevacizumab will be administered 14 days after the first one(day 15). The treatment schedule may require minor adjustment as clinically indicated (e.g., due to PDH closure for holidays). | 34 |
| Total | 34 |
Baseline characteristics
| Characteristic | Bevacizumab, Irinotecan and Temozolomide |
|---|---|
| Age, Continuous | 6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 34 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 27 / 34 |
| other Total, other adverse events | 33 / 34 |
| serious Total, serious adverse events | 14 / 34 |
Outcome results
Primary
Overall Responses
To evaluate tumor responses to combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB.
Time frame: 15-35 days after cycle 2
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab, Irinotecan and Temozolomide | Overall Responses | Complete Response | 3 Participants |
| Bevacizumab, Irinotecan and Temozolomide | Overall Responses | No Response | 18 Participants |
| Bevacizumab, Irinotecan and Temozolomide | Overall Responses | Progressive Disease | 12 Participants |
| Bevacizumab, Irinotecan and Temozolomide | Overall Responses | Not Treated | 1 Participants |
Secondary
Number of Participants With Treatment Related Toxicity
To determine the toxicity of the combination of irinotecan, temozolomide and bevacizumab in patients with resistant NB.
Time frame: Patients will be evaluated at least once weekly for toxicity. Observation for toxicities for up to 42 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab, Irinotecan and Temozolomide | Number of Participants With Treatment Related Toxicity | 34 Participants |
Secondary
To Evaluate Changes in Angiogenic Markers After Treatment With the Combination of Irinotecan, Temozolomide and Bevacizumab.
Time frame: days 1,4, 15 and once between days 22-35 during cycle 1 and cycle 2
Population: Data were not collected
Secondary
To Measure Time to Progression in Patients With Resistant NB Treated With the Combination of Irinotecan, Temozolomide and Bevacizumab.
Time frame: 3 years
Population: Data were not collected