Cyclophosphamide, Topotecan, and Bevacizumab (CTB) in Patients With Relapsed/Refractory Ewing's Sarcoma and Neuroblastoma

Inclusion Criteria

• Patients must have histologically confirmed relapsed/refractory Ewing's sarcoma or neuroblastoma.
• Patients must have measurable disease. Patients with a diagnosis of neuroblastoma with MIBG avid disease only are permitted to enroll on this study.
• Patients must be ≤ 21 years of age at time of diagnosis
• Life expectancy ≥ 3 months
• Lansky or Karnofsky performance ≥ 70%
• Written informed consent
• Organ and marrow function defined as follows:

Hematologic function, as follows

• Absolute neutrophil count ≥ 1000/μL
• Platelets ≥ 100 x 109/L (without transfusion 3 years prior to enrollment.
• Known infection with human immunodeficiency virus (HIV).
• Uncontrolled hypertension (sBP >150 mmHg and/or diastolic BP > 100 mmHg, found on two consecutive measurements separated by a one week period of time despite adequate medical support).
• Prior history of hypertensive crisis or hypertensive encephalopathy.
• New York Heart Association (NYHA) Grade II or greater congestive heart failure
• History of myocardial infarction or unstable angina within 6 months prior to Day - 3.
• History of stroke or transient ischemic attack within 6 months prior to Day -3.
• Known CNS disease, except for treated brain metastases.
• Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement 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 whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day -3 will be excluded.
• Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day -3.
• History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day -3.
• Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day -3 or anticipation of need for major surgical procedure during the course of the study. (A major procedure constitutes an invasive procedure which requires general anesthetic support, hospitalization, and supportive care such as laparotomy, laminectomy, etc.)
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1. (Minor surgical procedures include minimally invasive procedures such as fine needle aspiration, core biopsy, etc requiring little if any supportive care excluding lumbar puncture and bone marrow aspiration/biopsy.)
• History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day -3.
• Serious, non-healing wound, active ulcer, or untreated bone fracture.
• Thrombolytics or treatment doses of warfarin within 28 days of initiating treatment. Patients who require low dose warfarin for central venous catheter patency are allowed to enter if their dose is 325 mg per day or non-steroidal anti-inflammatory medications known to inhibit platelet function. Patients taking cyclooxygenase-2 inhibitors (COX-2) inhibitors are allowed to enroll.
• History or clinical evidence of deep venous thrombosis including pulmonary embolus within 6 months of treatment.
• Patients with proteinuria > 1+ on urine dipstick or UPC ratio ≥ 1.0 at screening. If >1+ proteinuria is detected on surveillance, a 24-hour collection must be performed if eligibility is desired. Patients with a 24-hour urine protein content of ≤ 500 mg are eligible.
• Known hypersensitivity to any component of bevacizumab.
• Pregnancy (positive pregnancy test) or lactation.