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Ewing's Sarcoma

AEWS0521: A Randomized Phase II Study of Bevacizumab Combined with Vincristine, Topotecan and Cyclophosphamide in Patients with First Recurrent Ewing Sarcoma

Type

Status

Age Range (yrs.)

Sponsor

Protocol ID

Treatment

Active

1-29

COG

AEWS0521

Outline

This is a multicenter study. Patients are stratified according to time to disease recurrence (< 2 years vs ≥ 2 years).

  • Arm I (VTCB): Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine IV on days 1, 8, and 15, and topotecan hydrochloride IV over 30 minutes and cyclophosphamide IV over 60 minutes on days 1-5. Treatment repeats every 21 days (except during weeks 14, 15 [course 5], 17, 18 [course 6], 26, 27 [course 9], 29, and 30 [course 10] when no chemotherapy is given) for up to 12 courses in the absence of disease progression or unacceptable toxicity.
  • Arm II (VTC): Patients receive vincristine, topotecan hydrochloride, and cyclophosphamide as in arm I.

After completion of study therapy, patients are followed periodically.

Objectives

Primary

  1. To determine the feasibility of administering bevacizumab in combination with vincristine, topotecan hydrochloride, and cyclophosphamide (VTC) to younger patients with refractory or first recurrent Ewing sarcoma.
  2. To compare the progression-free survival of patients treated with VTC with bevacizumab vs VTC without bevacizumab.

Secondary

  1. To estimate the response rate to 2 cycles of VTC compared to 2 cycles of VTC/bevacizumab.
  2. To evaluate biological markers as related to prognosis and specifically related to angiogenesis by encouraging concurrent enrollment on the Ewing sarcoma banking studies (COG-AEWS02B1 and/or COG-AEWS07B1 ) and ancillary correlative endothelial cell, surrogate marker, and angiogenic gene studies.

Projected Accrual

A total of 78 patients will be accrued for this study.

Mechanism of Action

Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine. Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels.

Entry Criteria

Disease Characteristics:

  • Diagnosis of extracranial Ewing sarcoma or primitive neuroectodermal tumor of bone or soft tissue meeting 1 of the following criteria:
  • A first recurrence of localized disease
  • A first recurrence of initially metastatic disease
  • Disease refractory to initial conventional therapy
  • Patients must have histological verification of the malignancy at original diagnosis
  • Histological confirmation of relapse is highly recommended but not mandatory
  • 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
  • No radiological or clinical evidence for parenchymal brain metastases or neuroaxis involvement

Patient Characteristics

Age

  • Patients must be > 1 year and < 30 years of age at the time of study enrollment.

Performance status

  • Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age )

Life expectancy

  • Life expectancy ≥ 8 weeks

Hematopoietic

  • Absolute neutrophil count ≥ 1,000/μL
  • Platelet count ≥ 75,000/μL* (transfusion independent)
  • Hemoglobin ≥ 8.0 g/dL* (may receive RBC transfusions)

[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.]

Hepatic

  • Direct bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
  • ALT ≤ 5 times ULN for age

Renal

  • Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine normal for age
  • Urine protein:creatinine ratio ≤ 0.5 OR 24-hour urine protein < 1,000 mg

Cardiovascular

  • Shortening fraction > 28% OR ejection fraction > 50%
  • Hypertension must be well controlled on stable doses of medication for ≥ 2 weeks prior to enrollment
  • No history of myocardial infarction, severe or unstable angina, or peripheral vascular disease

Pulmonary

  • Not specified

Other

  • Negative pregnancy test
  • Female patients who are lactating must agree to stop breast-feeding
  • Sexually active patients of childbearing potential must agree to use effective contraception
  • No documented, chronic non-healing wound, ulcer, or significant traumatic injury (those with bone fractures, including pathological fractures, or requiring surgical intervention) within the past 28 days
  • No other bone complications
  • No deep venous thrombosis (including pulmonary embolism) within the past 3 months
  • No recent (i.e., within 6 months) arterial thromboembolic events, including transient ischemic attack or cerebrovascular accident

Prior Concurrent Therapy:

Biologic therapy

  • At least 3 months since prior autologous stem cell transplantation (SCT)
  • No prior allogeneic SCT
  • At least 1 week since prior therapy with a biologic agent or growth factor

Chemotherapy

  • No other concurrent cancer chemotherapy
  • At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)
  • No prior bevacizumab
  • 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

Endocrine therapy

  • No immunomodulating agents
  • Steroid use is allowed

Radiotherapy

  • At least 6 months since prior craniospinal radiotherapy or radiotherapy to ≥ 50% of the pelvis
  • At least 6 weeks since other prior substantial bone marrow radiation
  • At least 2 weeks since prior local palliative radiotherapy (e.g., small port)
  • No 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

Surgery

  • Recovered from any prior surgical procedure
  • At least 28 days since prior major surgical procedures (e.g., resection of tumor, laparotomy, thoracotomy, or open biopsy)
  • 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

Other

  • Fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
  • Patients on full-dose anticoagulants (e.g., warfarin) with PT INR > 1.5 are eligible if both of these criteria are met:
  • 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
  • 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)

For more information, contact:

Rebecca Turner, MS, CCRP
Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org