Vincristine Sulfate, Topotecan Hydrochloride, and Cyclophosphamide With or Without Bevacizumab in Treating Young Patients With Refractory or First Recurrent Extracranial Ewing Sarcoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00516295
First received: August 14, 2007
Last updated: October 30, 2013
Last verified: October 2013
  Purpose

This 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.


Condition Intervention Phase
Ewing Sarcoma of Bone
Extraosseous Ewing Sarcoma
Peripheral Primitive Neuroectodermal Tumor
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Drug: topotecan hydrochloride
Drug: vincristine sulfate
Drug: cyclophosphamide
Biological: bevacizumab
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Bevacizumab (NSC 704865, BB-IND #7921) Combined With Vincristine, Topotecan and Cyclophosphamide in Patients With First Recurrent Ewing Sarcoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Feasibility of administering bevacizumab with chemotherapy [ Time Frame: First 2 courses (42 days) ] [ Designated as safety issue: Yes ]
    Any Grade IV hematological toxicities lasting longer than 7 days, myelosuppression causing delays > 14 days in delivery of therapy, > Grade 3 thromboembolic events, > Grade 3 bleeding events, > Grade 2 hypertension, > Grade 2 proteinuria.

  • Time to disease progression in patients receiving VTC with or without bevacizumab [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]
    Time from enrollment to disease progression, death, second malignant neoplasm, or last patient follow-up whichever occurs first. Patients who experience disease progression, death or second malignant neoplasm will be considered to have experienced an event; otherwise the patient will be considered censored at last follow-up.


Enrollment: 78
Study Start Date: February 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (Feasibility assessment of VTCB)
Patients receive bevacizumab IV over 30-90 minutes on day 1, vincristine sulfate 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.
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Experimental: Arm II (VTCB)
Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Active Comparator: Arm III (CTC)
Patients receive vincristine, topotecan hydrochloride, and cyclophosphamide as in arm I.
Drug: topotecan hydrochloride
Given IV
Other Names:
  • hycamptamine
  • Hycamtin
  • SKF S-104864-A
  • TOPO
Drug: vincristine sulfate
Given IV
Other Names:
  • leurocristine sulfate
  • VCR
  • Vincasar PFS
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the feasibility of administering bevacizumab in combination with vincristine (vincristine sulfate), topotecan hydrochloride, and cyclophosphamide (VTC) to younger patients with refractory or first recurrent Ewing sarcoma.

II. To compare the progression-free survival of patients treated with VTC with bevacizumab vs VTC without bevacizumab.

SECONDARY OBJECTIVES:

I. To estimate the response rate to 2 cycles of VTC compared to 2 cycles of VTC/bevacizumab.

II. 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.

OUTLINE: This is a single therapy feasibility study followed by a randomized controlled portion. Patients are stratified according to time to disease recurrence (< 2 years vs >= 2 years).

ARM I (Feasibility assessment of VTCB): Patients receive bevacizumab intravenously (IV) over 30-90 minutes on day 1, vincristine sulfate 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 (VTCB): Patients receive bevacizumab, vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in Arm I.

ARM III (VTC): Patients receive vincristine sulfate, topotecan hydrochloride, and cyclophosphamide as in arm I.

After completion of study therapy, patients are followed periodically.

  Eligibility

Ages Eligible for Study:   1 Year to 29 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00516295

Locations
United States, California
Children's Oncology Group
Arcadia, California, United States, 91006-3776
Sponsors and Collaborators
Investigators
Principal Investigator: Patrick Leavey Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00516295     History of Changes
Other Study ID Numbers: NCI-2009-00369, NCI-2009-00369, AEWS0521, AEWS0521, U10CA098543
Study First Received: August 14, 2007
Last Updated: October 30, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Sarcoma, Ewing
Neuroectodermal Tumors, Primitive, Peripheral
Sarcoma
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Antibodies
Antibodies, Monoclonal
Cyclophosphamide
Bevacizumab
Vincristine
Topotecan
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014