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

Recurrent Adult Soft Tissue Sarcoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01222715
• Other study ID #: NCI-2011-02607
• Secondary ID: NCI-2011-02607CO
• Status: Completed
• Phase: Phase 2
• First received: October 15, 2010
• Last updated: June 8, 2016
• Start date: October 2010
• Est. completion date: June 2015

Study information

• Verified date: June 2016
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 85
• Est. completion date: June 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 29 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Adult Rhabdomyosarcoma
• Childhood Alveolar Rhabdomyosarcoma
• Childhood Pleomorphic Rhabdomyosarcoma
• Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features
• Previously Treated Childhood Rhabdomyosarcoma
• Recurrent Adult Soft Tissue Sarcoma
• Recurrent Childhood Rhabdomyosarcoma
• Rhabdomyosarcoma
• Sarcoma

Intervention

Biological:
• Bevacizumab
Given IV

Drug:
• Cyclophosphamide
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Temsirolimus
Given IV
• Vinorelbine Tartrate
Given IV

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Chedoke Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario
Canada	Children's Hospital	London	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Starship Children's Hospital	Grafton	Auckland
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Dana-Farber/Harvard Cancer Center	Boston	Massachusetts
United States	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Vermont College of Medicine	Burlington	Vermont
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston	Charleston	West Virginia
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	T C Thompson Children's Hospital	Chattanooga	Tennessee
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	University of Missouri - Ellis Fischel	Columbia	Missouri
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sanford Medical Center-Fargo	Fargo	North Dakota
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	Children's Hospital Central California	Madera	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	Morristown Medical Center	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Saint Peter's University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University/Herbert Irving Cancer Center	New York	New York
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Florida Hospital Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	UF Cancer Center at Orlando Health	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Memorial University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Scott and White Memorial Hospital	Temple	Texas
United States	Mercy Children's Hospital	Toledo	Ohio
United States	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	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	No
Other	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	No
Other	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	No
Other	Levels of biomarkers related to the effect of temsirolimus on the unfolded protein response		Up to 36 weeks	No
Other	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	No
Primary	Event-free survival	Estimated using Kaplan-Meier curves. EFS experience for the 2 regimens will be compared using the log-rank test.	From enrollment to the first occurrence of disease recurrence or death from any cause, up to 5 years	No
Primary	Feasibility, assessed by rate of grade 3+ non-hematologic toxicity, graded using Common Terminology Criteria for Adverse Events version 4.0		42 days	Yes
Secondary	Response rate (CR + PR)		Up to day 42	No