Vinblastine, Celecoxib, and Combination Chemotherapy in Treating Patients With Newly-Diagnosed Metastatic Ewing's Sarcoma Family of Tumors

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00061893
First received: June 5, 2003
Last updated: February 7, 2013
Last verified: January 2013
  Purpose

RATIONALE: Drugs used in chemotherapy, such as vinblastine, work in different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of Ewing's sarcoma by stopping blood flow to the tumor. Combining more than one chemotherapy drug with celecoxib may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining low-dose vinblastine and celecoxib with standard regimens of combination chemotherapy in treating patients who have newly-diagnosed metastatic Ewing's sarcoma family of tumors.


Condition Intervention Phase
Sarcoma
Drug: celecoxib
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Drug: etoposide
Drug: ifosfamide
Drug: vinblastine sulfate
Drug: vincristine sulfate
Procedure: conventional surgery
Radiation: radiation therapy
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Low-Dose Antiangiogenic Chemotherapy in Combination With Standard Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma Family of Tumors

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • Occurrence of Severe Toxicity [ Time Frame: Duration of Protocol Therapy ] [ Designated as safety issue: Yes ]
    An incidence of severe toxicity is defined to be the occurrence of grade 3 or higher infection or grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy. If 12 or more patients experience grade 3 or higher infection or five or more patients experience grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy, the regimen will be flagged as being associated with an excessive rate of severe toxicity.


Secondary Outcome Measures:
  • Event Free Survival [ Time Frame: 24 months after start of protocol therapy ] [ Designated as safety issue: No ]

Enrollment: 38
Study Start Date: April 2004
Study Completion Date: April 2008
Primary Completion Date: April 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Combination chemotherapy
Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Angiogenesis may be a suitable target for cancer therapy because tumor growth is partially dependent upon neovascularization. Vinblastine sulfate has been shown to have antiangiogenic activity and in preclinical studies, celecoxib has demonstrated antiangiogenic activity as well as inducing apoptosis in tumor vessel endothelial cells. The feasibility and safety of adding antiangiogenic agents to conventional chemotherapy will be assessed by imaging studies (DeMRI, PET, Thallium scintigraphy). Local control with conventional surgery, radiation therapy or both will be tailored for each patient to optimally treat all sites of disease.
Drug: celecoxib
Given orally
Drug: cyclophosphamide
Given IV
Drug: doxorubicin hydrochloride
Given IV
Drug: etoposide
Given IV
Drug: ifosfamide
Given IV
Drug: vinblastine sulfate
Given IV
Drug: vincristine sulfate
Given IV
Procedure: conventional surgery
Surgery on week 13
Radiation: radiation therapy
Radiotherapy 5 days a weeks for approximately 6 weeks.

  Hide Detailed Description

Detailed Description:

OBJECTIVES:

  • Determine the feasibility and safety of low-dose vinblastine and celecoxib in combination with standard multiagent chemotherapy in patients with newly diagnosed metastatic Ewing's sarcoma family of tumors.
  • Determine the event-free survival of patients treated with this regimen.
  • Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a pilot, multicenter study.

  • Induction therapy: Patients receive the following alternating regimens:

    • VAC (courses 1 and 3): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on day 1 and doxorubicin IV continuously on days 1 and 2 of weeks 1 and 7.
    • IE (courses 2 and 4): Patients receive ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 4 and 10.

Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning 24-48 hours after the last dose of chemotherapy and continuing until blood counts recover.

Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity.

  • Local control and consolidation therapy: Beginning on week 13, patients are assigned to 1 of 4 regimens based on disease status.

    • Regimen A (surgery only): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients then begin consolidation therapy on week 15 with the following alternating regimens:

      • VAC (courses 5, 7, and 9): Patients receive VAC on weeks 15, 21, and 27.
      • IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.
      • VC (courses 11 and 13): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on weeks 33 and 39.
    • Regimen B (radiotherapy only): Patients with unresectable lesions undergo radiotherapy once daily 5 days a week for up to approximately 6 weeks beginning on week 13. Patients also receive consolidation therapy beginning on week 13, with the following alternating regimens:

      • VAC (courses 5, 9, and 11): Patients receive VAC on weeks 13, 25, and 31.
      • IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 16, 22, 28, 34, and 40.
      • VC (courses 7 and 13): Patients receive VC on weeks 19 and 37.
    • Regimen C (surgery and radiotherapy): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy (as in regimen B) beginning on week 15. Patients also receive consolidation therapy, beginning on week 15, with the following alternating regimens:

      • VAC (courses 5, 9, and 11): Patients receive VAC on weeks 15, 27, and 33.
      • IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.
      • VC (courses 7 and 13): Patients receive VC on weeks 21 and 39.
    • Regimen D (preoperative radiotherapy): Patients with bulky lesions who do not have a good clinical and radiographic response to induction therapy begin consolidation therapy on week 13 with VAC (course 5) and undergo concurrent radiotherapy as in regimen B. Patients then receive IE on weeks 16 and 19 for courses 6 and 7. Patients undergo surgery on week 22. Patients continue consolidation therapy with the following alternating regimens:

      • VAC (courses 8 and 9): Patients receive VAC on weeks 24 and 27.
      • IE (courses 10, 12, and 14): Patients receive IE on weeks 30, 36, and 42.
      • VC (courses 11 and 13): Patients receive VC on weeks 33 and 39. Patients receive G-CSF SC (as in induction therapy) during all consolidation courses.

Consolidation therapy continues for 10 courses in the absence of disease progression or unacceptable toxicity.

  • Vinblastine and celecoxib therapy: Throughout induction, local control, and consolidation therapies, patients also receive vinblastine IV 3 times a week (twice a week during the weeks that vincristine is given) and oral celecoxib twice daily, beginning on day 1 of course 1 and continuing until the completion of course 14.* NOTE: *To assess for safety, the first 6 patients enrolled receive vinblastine only during courses 1 and 2 and celecoxib is then added for all subsequent courses.

Patients are followed every 3 months for 3 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 6-36 patients will be accrued for this study within 1.17 years.

  Eligibility

Ages Eligible for Study:   up to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Newly diagnosed Ewing's sarcoma family of tumors of the bone or soft tissues

    • Paraspinal tumors of extra-dural origin and Askin's tumor of the chest wall are eligible
  • Metastatic disease, defined by the following criteria:

    • Lesions are discontinuous from the primary tumor, are not regional lymph nodes, and do not share a body cavity with the primary tumor
    • A single pulmonary or pleural nodule greater than 1 cm OR multiple nodules greater than 0.5 cm are considered evidence of pulmonary or pleural metastases (unless there is another clear medical explanation for these lesions)
    • Contralateral pleural effusions are considered metastatic disease
  • No CNS involvement

PATIENT CHARACTERISTICS:

Age

  • 50 and under (at diagnosis)

Performance status

  • Lansky 50-100% (under 17 years of age)
  • Karnofsky 50-100% (age 17 and over)

    • Patients whose performance status is affected by a pathological fracture are allowed provided they are able to undergo treatment

Life expectancy

  • Not specified

Hematopoietic

  • Not specified

Hepatic

  • Bilirubin no greater than 1.5 times upper limit of normal (ULN)
  • AST or ALT less than 5 times ULN

Renal

  • Creatinine adjusted according to age as follows*:

    • No greater than 0.4 mg/dL (≤ 5 months)
    • No greater than 0.5 mg/dL (6 months -11 months)
    • No greater than 0.6 mg/dL (1 year-23 months)
    • No greater than 0.8 mg/dL (2 years-5 years)
    • No greater than 1.0 mg/dL (6 years-9 years)
    • No greater than 1.2 mg/dL (10 years-12 years)
    • No greater than 1.4 mg/dL (13 years and over [female])
    • No greater than 1.5 mg/dL (13 years to 15 years [male])
    • No greater than 1.7 mg/dL (16 years and over [male]) OR
  • Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min* NOTE: *Unless these values are related to renal insufficiency secondary to tumor involvement that is expected to improve once the tumor mass is smaller (e.g., pelvic mass causing obstructive hydronephrosis)

Cardiovascular

  • Shortening fraction at least 27% by echocardiogram OR
  • Ejection fraction at least 50% by MUGA

Other

  • Not pregnant or nursing
  • Fertile patients must use effective contraception
  • Body surface area at least 0.4 m^2
  • No allergy to sulfa
  • No aspirin hypersensitivity
  • No asthma triad (asthma with nasal polyps, and urticaria)
  • No other prior cancer, including nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • No prior bone marrow or stem cell transplantation

Chemotherapy

  • No prior chemotherapy

Endocrine therapy

  • Not specified

Radiotherapy

  • No prior radiotherapy

Surgery

  • Not specified

Other

  • No other concurrent nonsteroidal anti-inflammatory medications, including salicylates
  • No concurrent dexrazoxane unless approved by the study investigator
  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: NCT00061893

  Show 101 Study Locations
Sponsors and Collaborators
Children's Oncology Group
Investigators
Study Chair: Judy L. Felgenhauer, MD, PS Sacred Heart Children's Hospital
  More Information

Additional Information:
Publications:
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT00061893     History of Changes
Other Study ID Numbers: AEWS02P1, CDR0000302409
Study First Received: June 5, 2003
Results First Received: January 17, 2013
Last Updated: February 7, 2013
Health Authority: United States: Federal Government

Keywords provided by Children's Oncology Group:
metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor

Additional relevant MeSH terms:
Sarcoma, Ewing
Sarcoma
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Cyclophosphamide
Celecoxib
Ifosfamide
Isophosphamide mustard
Liposomal doxorubicin
Etoposide phosphate
Doxorubicin
Etoposide
Vinblastine
Vincristine
Angiogenesis Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on August 27, 2014