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A Randomized Phase II Trial of Bevacizumab (IND# 7921, Avastin) and Temsirolimus (IND# 61010, Torisel) in Combination With Intravenous Vinorelbine and Cyclophosphamide in Patients With Recurrent/Refractory Rhabdomyosarcoma

Phase 2
29 Years
Open (Enrolling)
Adult Rhabdomyosarcoma, Alveolar Childhood Rhabdomyosarcoma, Mixed Childhood Rhabdomyosarcoma, Pleomorphic Childhood Rhabdomyosarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Childhood Rhabdomyosarcoma

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Trial Information

A Randomized Phase II Trial of Bevacizumab (IND# 7921, Avastin) and Temsirolimus (IND# 61010, Torisel) in Combination With Intravenous Vinorelbine and Cyclophosphamide in Patients With Recurrent/Refractory Rhabdomyosarcoma


l. To determine the feasibility of administering bevacizumab in combination with intravenous
vinorelbine 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.


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

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: This is a multicenter study. Patients are stratified according to histologic sub
type at initial diagnosis. 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. Blood and tissue samples may be collected for
correlative studies.

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

Inclusion Criteria:

- Patients must have had a previous histological verification of rhabdomyosarcoma at
original 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)

- Patients without measurable or evaluable disease are eligible

- 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

- No myelosuppressive chemotherapy within 3 weeks prior to entry onto this study (4
weeks if prior nitrosourea)

- 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

- 3 half-lives (or 6 weeks) must have elapsed since previous monoclonal antibody
therapy prior to enrollment on this study

- No myeloid growth factor within 1 week prior to entry onto this study

- At least 4 weeks must have elapsed between radiotherapy and study entry

- Previously radiated lesions cannot be used to assess response unless those sites
are the sites of disease progression

- For autologous stem cell transplantation (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

- 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

- 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:

- For patients aged =< 17 years, UPC ratio must be =< 1 for patient to be eligible

- For 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

- All patients and/or their parents or legal guardians must sign a written informed

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 VEGF/VEGFR- or 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

- 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, 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

- Pregnant or nursing

- 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

- 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

- 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

- Clinically significant peripheral vascular disease

- Patients diagnosed with rhabdomyosarcoma as a second malignant neoplasm are not

- Patients with history of any second malignant neoplasm who have received chemotherapy
or radiation for the treatment of that malignancy are not eligible

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival

Outcome Description:

Estimated using Kaplan-Meier curves. EFS experience for the 2 regimens will be compared using the log-rank test.

Outcome Time Frame:

From enrollment to the first occurrence of disease recurrence or death from any cause, up to 5 years

Safety Issue:


Principal Investigator

Leo Mascarenhas

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

October 2010

Completion Date:

Related Keywords:

  • Adult Rhabdomyosarcoma
  • Alveolar Childhood Rhabdomyosarcoma
  • Mixed Childhood Rhabdomyosarcoma
  • Pleomorphic Childhood Rhabdomyosarcoma
  • Previously Treated Childhood Rhabdomyosarcoma
  • Recurrent Adult Soft Tissue Sarcoma
  • Recurrent Childhood Rhabdomyosarcoma
  • Rhabdomyosarcoma
  • Rhabdomyosarcoma, Embryonal
  • Sarcoma



Baylor College of Medicine Houston, Texas  77030
Johns Hopkins University Baltimore, Maryland  21205
Memorial Sloan Kettering Cancer Center New York, New York  10021
Cleveland Clinic Foundation Cleveland, Ohio  44195
Roswell Park Cancer Institute Buffalo, New York  14263
Mayo Clinic Rochester, Minnesota  55905
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Iowa Hospitals and Clinics Iowa City, Iowa  52242
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Washington University School of Medicine Saint Louis, Missouri  63110
Medical University of South Carolina Charleston, South Carolina  29425-0721
Rhode Island Hospital Providence, Rhode Island  02903
Medical City Dallas Hospital Dallas, Texas  75230
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
Sinai Hospital of Baltimore Baltimore, Maryland  21225
Bronson Methodist Hospital Kalamazoo, Michigan  49007
Geisinger Medical Center Danville, Pennsylvania  17822-0001
Loyola University Medical Center Maywood, Illinois  60153
Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Morristown Memorial Hospital Morristown, New Jersey  07962-1956
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Newark Beth Israel Medical Center Newark, New Jersey  07112
New York Medical College Valhalla, New York  10595
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Cedars-Sinai Medical Center Los Angeles, California  90048
University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Brooke Army Medical Center Fort Sam Houston, Texas  78234-6200
Eastern Maine Medical Center Bangor, Maine  04401
University of Nebraska Medical Center Omaha, Nebraska  68198-3330
Hackensack University Medical Center Hackensack, New Jersey  07601
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's National Medical Center Washington, District of Columbia  20010-2970
All Children's Hospital St. Petersburg, Florida  33701
Saint Jude Midwest Affiliate Peoria, Illinois  61637
Ochsner Clinic Foundation New Orleans, Louisiana  70121
Maine Children's Cancer Program Scarborough, Maine  04074-9308
Carolinas Medical Center Charlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health Center Portland, Oregon  97227
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Driscoll Children's Hospital Corpus Christi, Texas  78466
Scott and White Memorial Hospital Temple, Texas  76508
Inova Fairfax Hospital Falls Church, Virginia  22042-3300
Southern California Permanente Medical Group Downey, California  90242
Children's Hospital Central California Madera, California  93638-8762
Kosair Children's Hospital Louisville, Kentucky  40202-3830
Children's Hospital Medical Center of Akron Akron, Ohio  44308
Covenant Children's Hospital Lubbock, Texas  79410
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001
Overlook Hospital Summit, New Jersey  07902-0220
Winthrop University Hospital Mineola, New York  11501
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Primary Children's Medical Center Salt Lake City, Utah  84113-1100
Montefiore Medical Center Bronx, New York  10467-2490
Saint Peter's University Hospital New Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San Diego San Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - Minneapolis Minneapolis, Minnesota  55404
University of New Mexico Cancer Center Albuquerque, New Mexico  87131-5636
Nationwide Children's Hospital Columbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMC Pittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central Texas Austin, Texas  78723
Children's Hospital and Research Center at Oakland Oakland, California  94609-1809
Mary Bridge Children's Hospital and Health Center Tacoma, Washington  98415-0299
Presbyterian Hospital Charlotte, North Carolina  28233-3549
City of Hope Duarte, California  91010
Lee Memorial Health System Fort Myers, Florida  33902
University of Virginia Charlottesville, Virginia  22908
University of Alabama at Birmingham Birmingham, Alabama  35294-3300
Children's Hospital of Alabama Birmingham, Alabama  35233
Connecticut Children's Medical Center Hartford, Connecticut  06106
Vanderbilt University Nashville, Tennessee  37232-6305
University of North Carolina Chapel Hill, North Carolina  27599
Duke University Medical Center Durham, North Carolina  27710
University of Rochester Rochester, New York  14642
Nemours Children's Clinic - Pensacola Pensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum Health Grand Rapids, Michigan  49503
Yale University New Haven, Connecticut  06520
Wayne State University Detroit, Michigan  48202
Mercy Children's Hospital Toledo, Ohio  43608
Legacy Emanuel Children's Hospital Portland, Oregon  97227
BI-LO Charities Children's Cancer Center Greenville, South Carolina  29605
Dartmouth Hitchcock Medical Center Lebanon, New Hampshire  03756
University Of Vermont Burlington,, Vermont  05403
Albany Medical Center Albany, New York  12208
University of Texas Southwestern Medical Center Dallas, Texas  
University of Kentucky Lexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer Center Sacramento, California  95817
Oregon Health and Science University Portland, Oregon  97201
Tulane University Health Sciences Center New Orleans, Louisiana  70112
Virginia Commonwealth University Richmond, Virginia  
Florida Hospital Orlando, Florida  32803
Memorial Health University Medical Center Savannah, Georgia  31404
University of Chicago Comprehensive Cancer Center Chicago, Illinois  60637-1470
M D Anderson Cancer Center Houston, Texas  77030
Seattle Children's Hospital Seattle, Washington  98105
Wake Forest University Health Sciences Winston-Salem, North Carolina  27157
Childrens Memorial Hospital Chicago, Illinois  60614
M D Anderson Cancer Center- Orlando Orlando, Florida  32806
University of Hawaii Honolulu, Hawaii  96813
Saint Luke's Mountain States Tumor Institute Boise, Idaho  83712
Saint Vincent Hospital and Health Services Indianapolis, Indiana  46260
Saint John Hospital and Medical Center Detroit, Michigan  48236
Michigan State University - Breslin Cancer Center East Lansing, Michigan  48824-1313
Kalamazoo Center for Medical Studies Kalamazoo, Michigan  49008
Saint John's Mercy Medical Center Saint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOP Las Vegas, Nevada  89106
New York University Langone Medical Center New York, New York  10016
Columbia University Medical Center New York, New York  10032
State University of New York Upstate Medical University Syracuse, New York  13210
Mission Hospitals Inc Asheville, North Carolina  28801
Natalie W Bryant Cancer Center Tulsa, Oklahoma  74136
Saint Vincent Hospital Green Bay, Wisconsin  54301
University of Illinois Chicago, Illinois  60612
Stony Brook University Medical Center Stony Brook, New York  11794
Cook Children's Medical Center Fort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's Hospital Hollywood, Florida  33021
West Virginia University Charleston Charleston, West Virginia  25304
The Children's Medical Center of Dayton Dayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer Center Miami, Florida  33136
University of Minnesota Medical Center-Fairview Minneapolis, Minnesota  55455
C S Mott Children's Hospital Ann Arbor, Michigan  48109
Southern Illinois University Springfield, Illinois  62702
University Of Missouri-Columbia Columbia, Missouri  65212
Walter Reed National Military Medical Center Bethesda, Maryland  20889
Riley Hospital for Children Indianapolis, Indiana  46202
Cardinal Glennon Children's Medical Center St. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University Hospital New Brunswick, New Jersey  08903
Miller Children's Hospital Long Beach, California  90806
Childrens Hospital of Orange County Orange, California  92868-3874
Alfred I duPont Hospital for Children Wilmington, Delaware  19803
Nemours Children's Clinic - Jacksonville Jacksonville, Florida  32207-8426
Nemours Childrens Clinic - Orlando Orlando, Florida  32806
Saint Joseph Children's Hospital of Tampa Tampa, Florida  33607
Children's Healthcare of Atlanta - Egleston Atlanta, Georgia  30322
The Childrens Mercy Hospital Kansas City, Missouri  64108
Rainbow Babies and Childrens Hospital Cleveland, Ohio  44106
Penn State Hershey Children's Hospital Hershey, Pennsylvania  17033
Palmetto Health Richland Columbia, South Carolina  29203
East Tennessee Childrens Hospital Knoxville, Tennessee  37916
Saint Mary's Hospital West Palm Beach, Florida  33407
Children's Hospital and Medical Center of Omaha Omaha, Nebraska  68114
Saint Joseph's Regional Medical Center Paterson, New Jersey  07503
Texas Tech University Health Science Center-Amarillo Amarillo, Texas  79106
Childrens Hospital-King's Daughters Norfolk, Virginia  23507
Sanford Medical Center-Fargo Fargo, North Dakota  58122
Children's Hospital Colorado Aurora, Colorado  80045
Floating Hospital for Children at Tufts Medical Center Boston, Massachusetts  02111
Lucile Packard Children's Hospital Stanford University Palo Alto, California  94304
University of California San Francisco Medical Center-Parnassus San Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center Denver, Colorado  80218
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Children's Hospital-Main Campus New Orleans, Louisiana  70118
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Greenville Cancer Treatment Center Greenville, South Carolina  29605
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