Vinorelbine Tartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma

A Randomized Phase II Trial of Bevacizumab (Avastin) and Temsirolimus (Torisel) in Combination With Intravenous Vinorelbine and Cyclophosphamide in Patients With Recurrent/Refractory Rhabdomyosarcoma

This randomized phase II trial studies how well vinorelbine tartrate and cyclophosphamide work in combination with bevacizumab or temsirolimus in treating patients with recurrent or refractory rhabdomyosarcoma. Drugs used in chemotherapy, such as vinorelbine tartrate 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 the growth of rhabdomyosarcoma by blocking blood flow to the tumor. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective when given together with bevacizumab or temsirolimus in treating rhabdomyosarcoma.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Adult Rhabdomyosarcoma; Childhood Alveolar Rhabdomyosarcoma; Childhood Pleomorphic Rhabdomyosarcoma; Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Biological: Bevacizumab; Drug: Temsirolimus; Drug: Vinorelbine Tartrate

Detailed Description

PRIMARY OBJECTIVES:

l. To determine the feasibility of administering bevacizumab in combination with intravenous vinorelbine (vinorelbine tartrate) and cyclophosphamide (VC) in patients with recurrent rhabdomyosarcoma (RMS).

II. To determine the feasibility of administering temsirolimus in combination with VC in patients with recurrent RMS.

III. To estimate the event-free survival (EFS) of patients with recurrent/refractory RMS treated with bevacizumab and VC and compare with the EFS of those treated with temsirolimus and VC.

SECONDARY OBJECTIVES:

I. To estimate the initial (2 cycle) response rate of patients with recurrent/refractory RMS treated with bevacizumab and VC and compare with the response rate of those treated with temsirolimus and VC, and to also compare the best response rate on each regimen of protocol therapy.

II. To evaluate surrogate biological markers in patients with recurrent RMS and to estimate differences in these markers following treatment with bevacizumab and temsirolimus.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive vinorelbine tartrate intravenously (IV) over 6-10 minutes on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1.

ARM II: Patients receive vinorelbine tartrate and cyclophosphamide as in arm I. Patients also receive temsirolimus IV over 30-60 minutes on days 1, 8, and 15.

In both arms, treatment repeats every 21 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up annually for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Western Australia
    • Perth, Western Australia, Australia, 6008
      • Princess Margaret Hospital for Children
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Newfoundland and Labrador
    • Saint John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Janeway Child Health Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • Hamilton, Ontario, Canada, L8S 4L8
      • Chedoke Hospital at Hamilton Health Sciences
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario At Kingston General Hospital
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • The Montreal Children's Hospital of the MUHC
    • Montreal, Quebec, Canada, H3T 1C5
      • Centre Hospitalier Universitaire Sainte-Justine
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Saskatoon Cancer Centre
• New Zealand
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1145
      • Starship Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham Cancer Center
    • Birmingham, Alabama, United States, 35233
      • Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Childrens Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
    • Little Rock, Arkansas, United States, 72202-3591
      • Arkansas Children's Hospital
  • California
    • Downey, California, United States, 90242
      • Southern California Permanente Medical Group
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Long Beach, California, United States, 90806
      • Miller Children's and Women's Hospital Long Beach
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Madera, California, United States, 93636-8762
      • Children's Hospital Central California
    • Oakland, California, United States, 94609-1809
      • Children's Hospital and Research Center at Oakland
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital - San Diego
    • San Francisco, California, United States, 94143
      • UCSF Medical Center-Parnassus
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I duPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Memorial Health System
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Hospital/Joe DiMaggio Children's Hospital
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic-Jacksonville
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Orlando, Florida, United States, 32803
      • Florida Hospital Orlando
    • Orlando, Florida, United States, 32806
      • Nemours Children's Clinic - Orlando
    • Orlando, Florida, United States, 32806
      • UF Cancer Center at Orlando Health
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33607
      • Saint Joseph's Hospital/Children's Hospital-Tampa
    • West Palm Beach, Florida, United States, 33407
      • Saint Mary's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta - Egleston
    • Savannah, Georgia, United States, 31404
      • Memorial University Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • University of Hawaii Cancer Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Mountain States Tumor Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Chicago, Illinois, United States, 60612
      • University of Illinois
    • Chicago, Illinois, United States, 60611
      • Lurie Children's Hospital-Chicago
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Peoria, Illinois, United States, 61637
      • Saint Jude Midwest Affiliate
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Hospital and Health Care Center
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Children's Hospital
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky/Markey Cancer Center
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
    • New Orleans, Louisiana, United States, 70118
      • Children's Hospital New Orleans
  • Maine
    • Bangor, Maine, United States, 04401
      • Eastern Maine Medical Center
    • Scarborough, Maine, United States, 04074
      • Maine Children's Cancer Program
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University/Sidney Kimmel Cancer Center
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Bethesda, Maryland, United States, 20889-5600
      • Walter Reed National Military Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital For Children at Tufts Medical Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • C S Mott Children's Hospital
    • Detroit, Michigan, United States, 48236
      • Saint John Hospital and Medical Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • East Lansing, Michigan, United States, 48824-7016
      • Michigan State University Clinical Center
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital at Spectrum Health
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49008
      • Kalamazoo Center for Medical Studies
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri - Ellis Fischel
    • Kansas City, Missouri, United States, 64108
      • The Childrens Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68114
      • Children's Hospital and Medical Center of Omaha
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Saint Peter's University Hospital
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
    • Paterson, New Jersey, United States, 07503
      • Saint Joseph's Regional Medical Center
    • Summit, New Jersey, United States, 07902
      • Overlook Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center - Moses Campus
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • The Steven and Alexandra Cohen Children's Medical Center of New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
    • New York, New York, United States, 10032
      • Columbia University/Herbert Irving Cancer Center
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
    • Syracuse, New York, United States, 13210
      • State University of New York Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital-Memorial Campus
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center/Levine Cancer Institute
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • Sanford Medical Center-Fargo
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Childrens Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
    • Toledo, Ohio, United States, 43606
      • The Toledo Hospital/Toledo Children's Hospital
    • Toledo, Ohio, United States, 43608
      • Mercy Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at Saint Francis
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Children's Hospital
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health Richland
    • Greenville, South Carolina, United States, 29605
      • BI-LO Charities Children's Cancer Center
    • Greenville, South Carolina, United States, 29605
      • Greenville Cancer Treatment Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57117-5134
      • Sanford USD Medical Center - Sioux Falls
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T C Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37916
      • East Tennessee Childrens Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University/Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Science Center-Amarillo
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
    • Lubbock, Texas, United States, 79410
      • Covenant Children's Hospital
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • Temple, Texas, United States, 76508
      • Scott and White Memorial Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont College of Medicine
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507
      • Childrens Hospital-King's Daughters
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center and Children's Hospital
    • Tacoma, Washington, United States, 98405
      • Mary Bridge Children's Hospital and Health Center
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • West Virginia University Charleston
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • Saint Vincent Hospital
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 29 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis

  • Patients with first relapse or progression of rhabdomyosarcoma are eligible

  • Patients with primary refractory disease are eligible

    • Primary refractory disease is defined as first progression after receiving at least one course of cyclophosphamide or ifosfamide containing chemotherapy without prior demonstration of a radiographic response to chemotherapy (progression on irinotecan-containing chemotherapy without cyclophosphamide or ifosfamide containing chemotherapy will not be considered a first progression)
  • Note: Patients without measurable or evaluable disease are eligible
• Patients must have had a previous histological verification of rhabdomyosarcoma at original diagnosis
• Patients must have a Karnofsky or Lansky performance status score of >= 50%, corresponding to Eastern Cooperative Oncology Group (ECOG) categories of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age
• Patients must have a life expectancy of >= 8 weeks
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study
• Myelosuppressive chemotherapy: Must not have received within 3 weeks prior to entry onto this study (4 weeks if prior nitrosourea)

• Biologic (anti-neoplastic agent):

  • Patients may have received prior therapy with oral tyrosine kinase inhibitors or other similar agents; at least 7 days must have elapsed since the completion of therapy with a biologic agent and all toxicities must have resolved to < grade 2 prior to enrollment
  • 3 half-lives (or 6 weeks) must have elapsed since previous monoclonal antibody therapy prior to enrollment on this study
• Myeloid growth factor: Must not have received within 1 week prior to entry onto this study
• Radiation therapy (RT): At least 4 weeks must have elapsed between RT and study entry; previously radiated lesions cannot be used to assess response unless those sites are the sites of disease progression
• Stem cell transplant (SCT): For autologous SCT, >= 3 months must have elapsed; for allogeneic SCT, >= 6 months must have elapsed and no evidence of active graft vs. host disease

• Patients must have recovered from any surgical procedure before enrolling on this study

  • Minor surgical procedures (e.g., biopsies involving core or fine-needle aspiration procedures, infusaport or Broviac line placement, paracentesis, or thoracocentesis) need to have fully healed and occurred > 7 days prior to enrollment
  • Patients who have had a major surgical procedure (such as laparotomy, thoracotomy, open biopsy, or resection of tumor) can only be enrolled on study > 28 days from such procedure
• Peripheral absolute neutrophil count (ANC) >= 750/μL
• Platelet count >= 75,000/μL (transfusion independent, defined as without transfusion for >= 1 week prior to enrollment)
• Hemoglobin >= 8.0 g/dL (may receive packed red blood cells [PRBC] transfusions)
• Bone marrow disease involvement of tumor is allowed, however, peripheral blood count criteria must still be met

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows:

  • =< 0.4 mg/dL (for patients aged 1 month to < 6 months)
  • =< 0.5 mg/dL (for patients aged 6 months to < 1 year)
  • =< 0.6 mg/dL (for patients aged 1 to < 2 years)
  • =< 0.8 mg/dL (for patients aged 2 to < 6 years)
  • =< 1 mg/dL (for patients aged 6 to < 10 years)
  • =< 1.2 mg/dL (for patients aged 10 to < 13 years)
  • =< 1.4 mg/dL (for female patients aged >= 13 years)
  • =< 1.5 mg/dL (for male patients aged 13 to < 16 years)
  • =< 1.7 mg/dL (for male patients aged >= 16 years)

• Urine protein level:

  • Patients aged =< 17 years: Urine protein to creatinine (UPC) ratio should be calculated; UPC ratio must be =< 1 for patient to be eligible
  • Patients aged > 17 years: Urine protein should be screened by urine analysis; if protein is 2+ or higher, 24-hour urine protein must be obtained and the level must be < 1,000 mg for patient enrollment
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by radionuclide angiogram

Exclusion Criteria:

• Patients with botryoid histology, any stage or group, are ineligible
• Patients with embryonal histology, stage I or clinical group 1 at initial disease presentation, who present with local or regional recurrence, are ineligible
• Patients who previously received craniospinal irradiation are ineligible
• Patients who previously received vinorelbine, bevacizumab, temsirolimus, or any other direct vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR-) or mammalian target of rapamycin (mTOR-) targeting agents are ineligible

• Patients with known central nervous system (CNS) disease (excluding intracranial/intraspinal extension secondary to local progression of a parameningeal or paraspinal primary), except for those with treated brain metastasis, are ineligible

  • Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]); stable dose of anticonvulsants are allowed; treatment for brain metastases may include whole-brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent), or a combination as deemed appropriate by the treating physician
  • Patients with CNS metastases treated within 3 months prior to enrollment by neurosurgical resection or brain biopsy are ineligible
• Patients who receive radiation or chemotherapy (inclusive of palliative intent) for first disease progression or relapse of rhabdomyosarcoma prior to enrollment are ineligible
• Female patients who are pregnant are ineligible
• Lactating females are not eligible unless they have agreed to discontinue breastfeeding
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation
• Patients with a documented chronic non-healing wound, ulcer, or significant trauma injury (those with bone fractures, including pathological fractures, or requiring surgical intervention) within 28 days prior to beginning therapy are ineligible
• Patients with evidence of intratumoral hemorrhage, gastrointestinal bleeding, or on anticoagulation for thrombosis or history of thrombosis are ineligible

• Patients with uncontrolled hypertension are ineligible; uncontrolled hypertension is defined as follows:

  • Patients aged =< 17 years: greater than 95th percentile systolic and diastolic blood pressure based on age and height that is not controlled by one antihypertensive medication
  • Patients aged > 17 years: systolic blood pressure >= 160 mm Hg and/or diastolic blood pressure >= 90 mm Hg that is not controlled by one antihypertensive medication
• Patients currently taking anticoagulants or antiplatelet agents with the exception of aspirin (=< 81 mg/day) are ineligible
• Patients with history of central venous catheter (CVC)-associated thrombosis requiring systemic anticoagulation are ineligible; Note: Patients with history of sluggish flow from CVC or CVC-associated thrombosis treated with tissue plasminogen activator (TPA) only are not excluded

• Patients with clinically significant cardiovascular disease are excluded:

  • History of cerebrovascular accident (CVA) within the prior 6 months
  • Myocardial infarction or unstable angina within the prior 6 months
  • New York Heart Association grade 2 or greater congestive heart failure
  • Serious and inadequately controlled cardiac arrhythmia
  • Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection)
  • Clinically significant peripheral vascular disease
• Patients diagnosed with rhabdomyosarcoma as a second malignant neoplasm are not eligible
• Patients with history of any second malignant neoplasm who have received chemotherapy or radiation for the treatment of that malignancy are not eligible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm I (vinorelbine tartrate, cyclophosphamide, bevacizumab); Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; Bevacizumab Biosimilar BEVZ92; Bevacizumab Biosimilar BI 695502; Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer; Recombinant Humanized Anti-VEGF Monoclonal Antibody; rhuMab-VEGF; Drug: Vinorelbine Tartrate; Given IV; Other Names: Navelbine; Eunades; NVB; Biovelbin; KW-2307; Navelbine Ditartrate; Vinorelbine Ditartrate
EXPERIMENTAL: Arm II (vinorelbine tartrate, cyclophosphamide, temsirolimus); Patients receive vinorelbine tartrate and cyclophosphamide as in arm I. Patients also receive temsirolimus IV over 30-60 minutes on days 1, 8, and 15.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Temsirolimus; Given IV; Other Names: Torisel; CCI-779; CCI-779 Rapamycin Analog; Cell Cycle Inhibitor 779; Rapamycin Analog; Rapamycin Analog CCI-779; Drug: Vinorelbine Tartrate; Given IV; Other Names: Navelbine; Eunades; NVB; Biovelbin; KW-2307; Navelbine Ditartrate; Vinorelbine Ditartrate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival Probability	Probability of no relapse, secondary malignancy, or death after 1 year in the study.	1 year
Rate of Dose-Limiting Toxicities	The following events will be considered dose-limiting toxicities (DLTs): Toxicity causing delays > 14 days in delivery of a 21-day cycle of therapy; Grade ≥ 3 mucositis > 3 days duration; Grade ≥ 3 thromboembolic events; Grade ≥ 3 bleeding events; Grade ≥ 3 pulmonary events; Grade ≥ 3 hypertension; Grade 3 hyperglycemia (uncontrolled); Grade ≥ 4 hyperglycemia; Grade ≥ 4 hyperlipidemia (including cholesterol and triglycerides) that does not return to ≤ Grade 2 levels with appropriate medical management within 35 days; Grade ≥ 2 perforation including fistula or leak (gastrointestinal or any other organ); Grade ≥ 3 proteinuria; Grade ≥ 3 cardiac toxicity; Grade ≥ 3 intra-abdominal abscess/infection; Grade ≥ 3 wound complication (wound infection or dehiscence); Grade ≥ 1 Reversible Posterior Leukoencephalopathy Syndrome (RPLS); Grade ≥ 1 Microangiopathy, or Hemolytic-uremic syndrome (HUS) or Thrombotic thrombocytopenic Purpura (TTP).	From the date of randomization until a maximum of 12 cycles (21 days per cycle) of treatment in the absence of disease progression or unacceptable toxicities.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate (CR + PR)	Complete or partial anatomical response rate. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.	From the date of randomization until a maximum of 2 cycles (21 days per cycle) of treatment in the absence of disease progression or unacceptable toxicities.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Levels	Biomarker data will be summarized for each response category, at each time point using either means and standard deviations or medians and ranges.	Up to 36 weeks
Changes in Angiogenesis-associated Plasma Markers Between Patients by Treatment	First, the distributions of these markers will be compared at 'end of 2 cycles' between treatments using a 2-independent sample non-parametric test. The mean will also be modeled for each of these markers (or a transformation of the marker to near normality) as a function of time and treatment using GEEs which are designed to take into account the internal correlation of repeated measurements taken on the same subject. Associations between progression-free survival and changes in each of the biomarkers will be investigated using univariate Cox proportional hazards regression analysis.	Baseline up to day 42
Clinical Predictors, Including Histologic and Molecular Subtype, Age, Stage, and Site	These known risk factors will be compared to genomic features like gene and ribonucleic acid (RNA) expression values, as well as combinations of the two and splice variants of known genes, in order to identify those features most related to treatment resistance and poor outcome (overall survival and failure-free survival) using a Cox proportional hazards model of gene expression with cross validation.	Up to 5 years
Clinical Response	The data reported in 2 groups will be summarized using numbers and percentages of patients in each stratum and at each time point (baseline, after course 2, at the time of best response and end of therapy or progressive disease, whichever comes first). A binomial generalized estimating equation (GEE) model will be fitted to the data. The variables in the model will be time, treatment group and a biomarker. The beta coefficient of the biomarker will quantify the strength of the association between clinical response and the biomarker, beyond the association of the outcome to the other variables.	Up to 5 years
Levels of Biomarkers Related to the Effect of Temsirolimus on the Unfolded Protein Response		Up to 36 weeks
Progression-free Survival	Progression-free survival data will be explored using Kaplan Meier analysis. Associations between this outcome and each of the biomarkers will be investigated using univariate Cox proportional hazards regression analysis.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Leo Mascarenhas, Children's Oncology Group

Publications and helpful links

General Publications

• Mascarenhas L, Chi YY, Hingorani P, Anderson JR, Lyden ER, Rodeberg DA, Indelicato DJ, Kao SC, Dasgupta R, Spunt SL, Meyer WH, Hawkins DS. Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2019 Nov 1;37(31):2866-2874. doi: 10.1200/JCO.19.00576. Epub 2019 Sep 12.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2015

Study Registration Dates

• First Submitted: October 15, 2010
• First Submitted That Met QC Criteria: October 15, 2010
• First Posted (ESTIMATE): October 18, 2010

Study Record Updates

• Last Update Posted (ACTUAL): May 5, 2017
• Last Update Submitted That Met QC Criteria: March 24, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Neoplasms, Muscle Tissue; Myosarcoma; Sarcoma; Recurrence; Rhabdomyosarcoma; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cyclophosphamide; Antibodies; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Vinorelbine; Sirolimus; Immunoglobulin G; Endothelial Growth Factors
• Other Study ID Numbers: NCI-2011-02607 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA098543 (U.S. NIH Grant/Contract); COG-ARST0921; CDR0000687113; ARST0921 (OTHER: CTEP)