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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
N/A
29 Years
Open (Enrolling)
Both
Adult Rhabdomyosarcoma, Alveolar Childhood Rhabdomyosarcoma, Mixed Childhood Rhabdomyosarcoma, Pleomorphic Childhood Rhabdomyosarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Childhood Rhabdomyosarcoma

Thank you

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


PRIMARY OBJECTIVES:

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.

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: 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
enrollment

- 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
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:

- 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
consent

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
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, 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

- 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
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

Type of Study:

Interventional

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:

No

Principal Investigator

Leo Mascarenhas

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02607

NCT ID:

NCT01222715

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

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Rhode Island HospitalProvidence, Rhode Island  02903
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Bronson Methodist HospitalKalamazoo, Michigan  49007
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Loyola University Medical CenterMaywood, Illinois  60153
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Loma Linda University Medical CenterLoma Linda, California  92354
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Cedars-Sinai Medical CenterLos Angeles, California  90048
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
Brooke Army Medical CenterFort Sam Houston, Texas  78234-6200
Eastern Maine Medical CenterBangor, Maine  04401
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
All Children's HospitalSt. Petersburg, Florida  33701
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Ochsner Clinic FoundationNew Orleans, Louisiana  70121
Maine Children's Cancer ProgramScarborough, Maine  04074-9308
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Scott and White Memorial HospitalTemple, Texas  76508
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
Covenant Children's HospitalLubbock, Texas  79410
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Winthrop University HospitalMineola, New York  11501
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Montefiore Medical CenterBronx, New York  10467-2490
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
Mary Bridge Children's Hospital and Health CenterTacoma, Washington  98415-0299
Presbyterian HospitalCharlotte, North Carolina  28233-3549
City of HopeDuarte, California  91010
Lee Memorial Health SystemFort Myers, Florida  33902
University of VirginiaCharlottesville, Virginia  22908
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
Duke University Medical CenterDurham, North Carolina  27710
University of RochesterRochester, New York  14642
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Mercy Children's HospitalToledo, Ohio  43608
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
University Of VermontBurlington,, Vermont  05403
Albany Medical CenterAlbany, New York  12208
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Oregon Health and Science UniversityPortland, Oregon  97201
Tulane University Health Sciences CenterNew Orleans, Louisiana  70112
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
M D Anderson Cancer CenterHouston, Texas  77030
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
University of HawaiiHonolulu, Hawaii  96813
Saint Luke's Mountain States Tumor InstituteBoise, Idaho  83712
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Kalamazoo Center for Medical StudiesKalamazoo, Michigan  49008
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Mission Hospitals IncAsheville, North Carolina  28801
Natalie W Bryant Cancer CenterTulsa, Oklahoma  74136
Saint Vincent HospitalGreen Bay, Wisconsin  54301
University of IllinoisChicago, Illinois  60612
Stony Brook University Medical CenterStony Brook, New York  11794
Cook Children's Medical CenterFort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's HospitalHollywood, Florida  33021
West Virginia University CharlestonCharleston, West Virginia  25304
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Miami Miller School of Medicine-Sylvester Cancer CenterMiami, Florida  33136
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
University Of Missouri-ColumbiaColumbia, Missouri  65212
Walter Reed National Military Medical CenterBethesda, Maryland  20889
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Cardinal Glennon Children's Medical CenterSt. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Miller Children's HospitalLong Beach, California  90806
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Saint Mary's HospitalWest Palm Beach, Florida  33407
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Saint Joseph's Regional Medical CenterPaterson, New Jersey  07503
Texas Tech University Health Science Center-AmarilloAmarillo, Texas  79106
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Sanford Medical Center-FargoFargo, North Dakota  58122
Children's Hospital ColoradoAurora, Colorado  80045
Floating Hospital for Children at Tufts Medical CenterBoston, Massachusetts  02111
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical CenterDenver, Colorado  80218
Raymond Blank Children's HospitalDes Moines, Iowa  50309
Children's Hospital-Main CampusNew Orleans, Louisiana  70118
The Toledo Hospital/Toledo Children's HospitalToledo, Ohio  43606
Greenville Cancer Treatment CenterGreenville, South Carolina  29605
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
T C Thompson Children's HospitalChattanooga, Tennessee  37403
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204
The Steven and Alexandra Cohen Children's Medical Center of New YorkNew Hyde Park, New York  11040