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 \< 14 days before enrollment) Hemoglobin ≥ 9 gm/dl

Renal function, as follows:

* Serum creatinine ≤ ULN for age. Refer to Appendix H for normal values for serum creatinine in children.
* If serum creatinine above these values, the calculated creatinine clearance or radioisotope GFR must be ≥ 60 ml/min/1.73 m2
* Urinary protein \< 2+ (unless total quantitative protein is \< 500 mg protein/day as determined by 24 H urine collection) for pediatric patients please refer to the CTCAE V4.0 for values.

Hepatic function, as follows:

* Total bilirubin ≤ 1.5x ULN
* AST and ALT ≤ 2.5x ULN for institution or ≤ 5x ULN for institution if clearly attributable to liver metastases
* Albumin ≥ 2.5 g/dl. Coagulation: INR ≤ 1.5x ULN.
* Prior Treatment: Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiation therapy prior to entry on study. Patients must have had at least one prior treatment regimen. Patients may have received treatment previously with cyclophosphamide or topotecan but no prior bevacizumab.
* Myelosuppressive chemotherapy: Two weeks must have elapsed since administration of previous chemotherapy.
* Biologic agents: At least 2 weeks must have elapsed since the completion of therapy with a monoclonal antibody. Seven days must have elapsed since the last dose of retinoids
* Radiation therapy: For all patients, ≥ 4 weeks must have elapsed for local XRT; ≥ 6 months must have elapsed if prior radiation to ≥ 50% of the pelvis or if substantial bone marrow irradiation. Patients with a history of prior radiation with field including the heart (e.g. mantle) will be excluded.
* Stem cell transplant: Patients who have undergone prior stem cell transplantation will not be excluded from study entry. At least 3 months must have elapsed since autologous or allogeneic stem cell transplantation. Patients must have no evidence of active graft versus host disease.

Exclusion Criteria:

* Patients with centrally-located pulmonary or mediastinal primary tumors or metastases adjacent to or invading large blood vessels.
* Prior left chest wall irradiation or a cumulative anthracycline dose of greater or equal to 300 mg/m2, unless the ejection fraction or fraction shortening is within normal institutional limits, in which case the patient can be enrolled.
* Inability to comply with study and/or follow-up procedures
* Life expectancy of less than 3 months
* Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
* Active second malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years
* History of other malignancies, except for other solid tumors curatively treated with no evidence of disease for \> 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 \< 2 mg per day total AND their International Normalized Ratio (INR) is ≤ 1.5.
* Patients requiring treatment doses of heparin for any reason. The use of heparin flushes for maintenance of central venous catheters is permitted
* Patients requiring aspirin \> 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. (An effective means of contraception (men and women) in subjects of child-bearing potential must be used.)