Vincristine Sulfate, Topotecan Hydrochloride, and Cyclophosphamide With or Without Bevacizumab in Treating Young Patients With Refractory or First Recurrent Extracranial Ewing Sarcoma
Condition: Ewing Sarcoma of Bone; Extraosseous Ewing Sarcoma; Peripheral Primitive Neuroectodermal Tumor; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
MeSH terms: Sarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Recurrence
Intervention: topotecan hydrochloride; vincristine sulfate; cyclophosphamide; bevacizumab
Intervention description: Given IV; Given IV; Given IV; Given IV
Intervention MeSH terms: Cyclophosphamide; Bevacizumab; Vincristine; Topotecan; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 1 Year
Maximum age: 29 Years
Healthy volunteers: No

Summary:

      This phase II trial study has a 6-patient feasibility portion studying the tolerability of
      chemotherapy with vincristine sulfate together with topotecan hydrochloride,
      cyclophosphamide, and bevacizumab in treating young patients with refractory or first
      recurrent extracranial Ewing's sarcoma. If the therapy is considered tolerable, this
      feasibility run-in will be followed by a randomized phase II portion studying giving
      vincristine sulfate together with topotecan hydrochloride, and cyclophosphamide to see how
      well it works compared with giving vincristine sulfate together with topotecan hydrochloride,
      cyclophosphamide, and bevacizumab in treating young patients with refractory or first
      recurrent extracranial Ewing's sarcoma. Drugs used in chemotherapy, such as vincristine
      sulfate, topotecan hydrochloride, and cyclophosphamide, work in different ways to stop the
      growth of tumor cells, either by killing the cells or by stopping them from dividing.
      Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some
      block the ability of tumor cells to grow and spread. Others find tumor cells and help kill
      them or carry tumor-killing substances to them. Bevacizumab may also stop tumor growth by
      blocking blood flow to the tumor. Giving combination chemotherapy together with bevacizumab
      may kill more tumor cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ALT =< 5 times ULN for age

          -  Urine protein: creatinine ratio =< 0.5 OR 24-hour urine protein < 1,000 mg

          -  At least 6 weeks since other prior substantial bone marrow radiation

          -  At least 28 days since prior major surgical procedures (e.g., resection of tumor,
             laparotomy, thoracotomy, or open biopsy)

          -  At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)

          -  At least 2 weeks since prior local palliative radiotherapy (e.g., small port)

          -  Diagnosis of extracranial Ewing sarcoma or primitive neuroectodermal tumor of bone or
             soft tissue meeting 1 of the following criteria: I) a first recurrence of localized
             disease; II) a first recurrence of initially metastatic disease; III) disease
             refractory to initial conventional therapy

          -  Patients must have RECIST-measurable disease documented by clinical, radiographic, or
             histological criteria

          -  Patients who do not have measurable disease (e.g., bone scan-determined metastatic
             disease only) remain eligible for the study and will be evaluable for disease-free
             progression

          -  Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (=<
             16 years of age )

          -  Life expectancy >= 8 weeks

          -  Absolute neutrophil count >= 1,000/μL

          -  NOTE: Patients with tumor metastatic to bone marrow are permitted to receive
             transfusions to maintain hemoglobin and platelet counts. These patients will not be
             evaluable for hematologic toxicity. Patients who are refractory to platelet infusions
             (i.e., unable to maintain platelet counts > 75,000/μL) and have marrow involvement and
             platelet counts < 75,000/μL are not eligible

          -  Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy,
             or radiotherapy

          -  At least 1 week since prior therapy with a biologic agent or growth factor

          -  Patients must have histological verification of the malignancy at original diagnosis

          -  Histological confirmation of relapse is highly recommended but not mandatory

          -  Prior initial therapy with topotecan hydrochloride is allowed as long as > 2 years
             have elapsed since the initial diagnosis of Ewing sarcoma

          -  Prior therapy with cyclophosphamide or vincristine is allowed

          -  Minor surgical procedures (e.g., biopsies) for limited purposes of tissue retrieval
             allowed

          -  Minor procedures include indwelling IV catheter placement and needle biopsy for
             diagnostic purposes

          -  For minor surgeries, patients should not receive the first planned dose of bevacizumab
             until the wound is healed and 7 days have elapsed

          -  At least 6 months since prior craniospinal radiotherapy or radiotherapy to >= 50% of
             the pelvis

          -  At least 3 months since prior autologous stem cell transplantation (SCT)

          -  Platelet count >= 75,000/μL (transfusion independent)

          -  Hemoglobin >= 8.0 g/dL (may receive RBC transfusions)

          -  Direct bilirubin =< 1.5 times upper limit of normal (ULN) for age

          -  Creatinine clearance or radioisotope GFR >= 70 mL/min OR serum creatinine normal for
             age

          -  Hypertension must be well controlled on stable doses of medication for >= 2 weeks
             prior to enrollment

          -  Negative pregnancy test

          -  Female patients who are lactating must agree to stop breast-feeding

          -  II) The patient has no active bleeding or pathological condition that carries a high
             risk of bleeding (e.g., tumor involving major vessels or known varices)

          -  Shortening fraction > 28% OR ejection fraction > 50%

          -  Recovered from any prior surgical procedure

          -  Sexually active patients of childbearing potential must agree to use effective
             contraception

          -  Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible
             if both of these criteria are met:

          -  I) The patient has an in-range INR (usually between 2 and 3) on a stable dose of oral
             anticoagulant or on a stable dose of low molecular weight heparin

        Exclusion Criteria:

          -  Radiological or clinical evidence for parenchymal brain metastases or neuro axis
             involvement

          -  Documented, chronic nonhealing wound, ulcer, or significant traumatic injury (those
             with bone fractures, including pathological fractures, or requiring surgical
             intervention) within the past 28 days

          -  Other bone complications

          -  Deep venous thrombosis (including pulmonary embolism) within the past 3 months

          -  Recent (i.e., within 6 months) arterial thromboembolic events, including transient
             ischemic attack or cerebrovascular accident

          -  History of myocardial infarction, severe or unstable angina, or peripheral vascular
             disease Prior bevacizumab

          -  Radiotherapy or surgery for local control of recurrent disease concurrently with
             bevacizumab (bevacizumab must be held if radiotherapy or surgery is required)

          -  Radiotherapy to localized painful lesions is allowed, provided >= 1 measurable lesion
             is not irradiated

          -  Radiotherapy for local metastatic tumor control allowed after the first 2 courses of
             therapy

          -  Other cancer chemotherapy or immunomodulating agents

          -  Steroid use is allowed

          -  Prior allogeneic SCT