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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01222715
• Collaborator: (none)
• Enrollment: 87
• Locations: 184
• Arms: 2
• Duration (Months): 56
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
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	Biological: Bevacizumab; Drug: Cyclophosphamide; Other: Laboratory Biomarker Analysis; Drug: Temsirolimus; Drug: Vinorelbine Tartrate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

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

2. 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:

1. 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.

2. 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 Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

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.	Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin 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: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vinorelbine Tartrate; Given IV; Other Names: Biovelbin Eunades KW-2307 Navelbine Navelbine Ditartrate NVB 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.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Temsirolimus; Given IV; Other Names: CCI-779 CCI-779 Rapamycin Analog Cell Cycle Inhibitor 779 Rapamycin Analog Rapamycin Analog CCI-779 Torisel ; Drug: Vinorelbine Tartrate; Given IV; Other Names: Biovelbin Eunades KW-2307 Navelbine Navelbine Ditartrate NVB Vinorelbine Ditartrate

Outcome Measures

Primary Outcome Measures

1. Event Free Survival Probability [1 year]

   Probability of no relapse, secondary malignancy, or death after 1 year in the study.

2. Rate of Dose-Limiting Toxicities [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.]

   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).

Secondary Outcome Measures

1. Response Rate (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.]

   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.

Other Outcome Measures

1. Biomarker Levels [Up to 36 weeks]

   Biomarker data will be summarized for each response category, at each time point using either means and standard deviations or medians and ranges.

2. Changes in Angiogenesis-associated Plasma Markers Between Patients by Treatment [Baseline up to day 42]

   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.

3. Clinical Predictors, Including Histologic and Molecular Subtype, Age, Stage, and Site [Up to 5 years]

   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.

4. Clinical Response [Up to 5 years]

   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.

5. Levels of Biomarkers Related to the Effect of Temsirolimus on the Unfolded Protein Response [Up to 36 weeks]

6. Progression-free Survival [Up to 5 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 29 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	Phoenix Childrens Hospital	Phoenix	Arizona	United States	85016
4	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202-3591
5	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
6	Southern California Permanente Medical Group	Downey	California	United States	90242
7	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
8	Loma Linda University Medical Center	Loma Linda	California	United States	92354
9	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
10	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
11	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
12	Children's Hospital Central California	Madera	California	United States	93636-8762
13	Children's Hospital and Research Center at Oakland	Oakland	California	United States	94609-1809
14	Children's Hospital of Orange County	Orange	California	United States	92868
15	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
16	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
17	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
18	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
19	Children's Hospital Colorado	Aurora	Colorado	United States	80045
20	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado	United States	80218
21	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
22	Yale University	New Haven	Connecticut	United States	06520
23	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
24	Children's National Medical Center	Washington	District of Columbia	United States	20010
25	Lee Memorial Health System	Fort Myers	Florida	United States	33901
26	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida	United States	33021
27	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
28	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
29	Florida Hospital Orlando	Orlando	Florida	United States	32803
30	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
31	UF Cancer Center at Orlando Health	Orlando	Florida	United States	32806
32	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
33	All Children's Hospital	Saint Petersburg	Florida	United States	33701
34	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
35	Saint Mary's Hospital	West Palm Beach	Florida	United States	33407
36	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
37	Memorial University Medical Center	Savannah	Georgia	United States	31404
38	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
39	Saint Luke's Mountain States Tumor Institute	Boise	Idaho	United States	83712
40	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
41	University of Illinois	Chicago	Illinois	United States	60612
42	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
43	Loyola University Medical Center	Maywood	Illinois	United States	60153
44	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
45	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
46	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
47	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
48	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
49	Blank Children's Hospital	Des Moines	Iowa	United States	50309
50	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
51	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
52	Kosair Children's Hospital	Louisville	Kentucky	United States	40202
53	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
54	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
55	Ochsner Medical Center Jefferson	New Orleans	Louisiana	United States	70121
56	Eastern Maine Medical Center	Bangor	Maine	United States	04401
57	Maine Children's Cancer Program	Scarborough	Maine	United States	04074
58	Sinai Hospital of Baltimore	Baltimore	Maryland	United States	21215
59	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
60	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
61	Floating Hospital for Children at Tufts Medical Center	Boston	Massachusetts	United States	02111
62	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
63	Dana-Farber/Harvard Cancer Center	Boston	Massachusetts	United States	02115
64	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
65	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
66	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
67	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
68	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
69	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
70	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan	United States	49008
71	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
72	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
73	Mayo Clinic	Rochester	Minnesota	United States	55905
74	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
75	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
76	The Childrens Mercy Hospital	Kansas City	Missouri	United States	64108
77	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
78	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
79	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
80	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
81	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
82	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
83	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
84	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
85	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
86	Morristown Medical Center	Morristown	New Jersey	United States	07960
87	Saint Peter's University Hospital	New Brunswick	New Jersey	United States	08901
88	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
89	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
90	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
91	Overlook Hospital	Summit	New Jersey	United States	07902
92	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
93	Albany Medical Center	Albany	New York	United States	12208
94	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467-2490
95	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
96	Winthrop University Hospital	Mineola	New York	United States	11501
97	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
98	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
99	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
100	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
101	University of Rochester	Rochester	New York	United States	14642
102	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
103	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
104	New York Medical College	Valhalla	New York	United States	10595
105	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
106	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
107	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
108	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
109	Duke University Medical Center	Durham	North Carolina	United States	27710
110	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
111	Sanford Medical Center-Fargo	Fargo	North Dakota	United States	58122
112	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
113	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
114	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
115	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
116	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
117	Dayton Children's Hospital	Dayton	Ohio	United States	45404
118	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
119	Mercy Children's Hospital	Toledo	Ohio	United States	43608
120	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
121	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
122	Legacy Emanuel Children's Hospital	Portland	Oregon	United States	97227
123	Legacy Emanuel Hospital and Health Center	Portland	Oregon	United States	97227
124	Oregon Health and Science University	Portland	Oregon	United States	97239
125	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
126	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
127	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
128	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
129	Rhode Island Hospital	Providence	Rhode Island	United States	02903
130	Medical University of South Carolina	Charleston	South Carolina	United States	29425
131	Palmetto Health Richland	Columbia	South Carolina	United States	29203
132	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
133	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
134	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
135	T C Thompson Children's Hospital	Chattanooga	Tennessee	United States	37403
136	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
137	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
138	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
139	Texas Tech University Health Science Center-Amarillo	Amarillo	Texas	United States	79106
140	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
141	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
142	Medical City Dallas Hospital	Dallas	Texas	United States	75230
143	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
144	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
145	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
146	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
147	M D Anderson Cancer Center	Houston	Texas	United States	77030
148	Covenant Children's Hospital	Lubbock	Texas	United States	79410
149	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
150	Scott and White Memorial Hospital	Temple	Texas	United States	76508
151	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
152	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
153	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
154	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
155	Childrens Hospital-King's Daughters	Norfolk	Virginia	United States	23507
156	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
157	Seattle Children's Hospital	Seattle	Washington	United States	98105
158	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
159	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
160	West Virginia University Charleston	Charleston	West Virginia	United States	25304
161	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
162	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
163	Midwest Children's Cancer Center	Milwaukee	Wisconsin	United States	53226
164	Sydney Children's Hospital	Randwick	New South Wales	Australia	2031
165	The Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
166	Princess Margaret Hospital for Children	Perth	Western Australia	Australia	6008
167	Alberta Children's Hospital	Calgary	Alberta	Canada	T3B 6A8
168	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2B7
169	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
170	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
171	Janeway Child Health Centre	Saint John's	Newfoundland and Labrador	Canada	A1B 3V6
172	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
173	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8N 3Z5
174	Chedoke Hospital at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8S 4L8
175	Cancer Centre of Southeastern Ontario at Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
176	Children's Hospital	London	Ontario	Canada	N6A 5W9
177	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
178	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
179	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
180	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
181	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
182	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2
183	Starship Children's Hospital	Grafton	Auckland	New Zealand	1145
184	Christchurch Hospital	Christchurch		New Zealand	8011

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leo Mascarenhas, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01222715
• Other Study ID Numbers: NCI-2011-02607; NCI-2011-02607; COG-ARST0921; CDR0000687113; ARST0921; ARST0921; ARST0921; U10CA098543
• First Posted: Oct 18, 2010
• Last Update Posted: May 5, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Sarcoma; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma, Alveolar; Recurrence; Sirolimus; Cyclophosphamide; Bevacizumab; Vinorelbine; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Endothelial Growth Factors

Study Results

Participant Flow

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Bevacizumab was administered at 15 mg/kg every 3 weeks.	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Temsirolimus was administered at 15 mg/m2/week intravenously.
Period Title: Overall Study
STARTED	44	43
COMPLETED	8	16
NOT COMPLETED	36	27

Baseline Characteristics

Arm/Group Title	Regimen A	Regimen B	Total
Arm/Group Description	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Bevacizumab was administered at 15 mg/kg every 3 weeks.	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Temsirolimus was administered at 15 mg/m2/week intravenously.	Total of all reporting groups
Overall Participants	44	43	87
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	116.35 (72.82)	140.65 (75.93)	128.36 (74.94)
Sex: Female, Male (Count of Participants)
Female	22 50%	20 46.5%	42 48.3%
Male	22 50%	23 53.5%	45 51.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 20.5%	10 23.3%	19 21.8%
Not Hispanic or Latino	35 79.5%	31 72.1%	66 75.9%
Unknown or Not Reported	0 0%	2 4.7%	2 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.3%	1 2.3%	2 2.3%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	1 2.3%	1 2.3%	2 2.3%
Black or African American	7 15.9%	7 16.3%	14 16.1%
White	30 68.2%	27 62.8%	57 65.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	5 11.4%	7 16.3%	12 13.8%

Outcome Measures

1. Primary Outcome

Title	Event Free Survival Probability
Description	Probability of no relapse, secondary malignancy, or death after 1 year in the study.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Only eligible participants were analyzed.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Bevacizumab was administered at 15 mg/kg every 3 weeks.	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Temsirolimus was administered at 15 mg/m2/week intravenously.
Measure Participants	44	42
Number (95% Confidence Interval) [Probability]	0.23	0.43

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A, Regimen B
	Comments	The event free survival distributions of patients in Regimen A and Regimen B were compared using the log-rank test.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0124
	Comments
	Method	Log Rank
	Comments

2. Primary Outcome

Title	Rate of Dose-Limiting Toxicities
Description	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).
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Only eligible participants were analyzed.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Bevacizumab was administered at 15 mg/kg every 3 weeks.	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Temsirolimus was administered at 15 mg/m2/week intravenously.
Measure Participants	44	42
Number (95% Confidence Interval) [Percentage of participants]	2 4.5%	21 48.8%

3. Secondary Outcome

Title	Response Rate (CR + PR)
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

Only eligible participants with overall response evaluated were analyzed.

Arm/Group Title	Regimen A	Regimen B
Arm/Group Description	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Bevacizumab was administered at 15 mg/kg every 3 weeks.	The cyclophosphamide plus vinorelbine combination was administered at 1.2 g/m2 every 3 weeks and 25 mg/m2/dose (administered weekly on the first 2 out of every 3 weeks), respectively. Temsirolimus was administered at 15 mg/m2/week intravenously.
Measure Participants	40	38
Number (95% Confidence Interval) [Proportion of participants]	0.3250 0.7%	0.4737 1.1%

4. Other Pre-specified Outcome

Title	Biomarker Levels
Description	Biomarker data will be summarized for each response category, at each time point using either means and standard deviations or medians and ranges.
Time Frame	Up to 36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Changes in Angiogenesis-associated Plasma Markers Between Patients by Treatment
Description	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.
Time Frame	Baseline up to day 42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Clinical Predictors, Including Histologic and Molecular Subtype, Age, Stage, and Site
Description	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.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Clinical Response
Description	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.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Levels of Biomarkers Related to the Effect of Temsirolimus on the Unfolded Protein Response
Time Frame	Up to 36 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Progression-free Survival
Description	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.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Regimen A		Regimen B
Arm/Group Description	Vinorelbine/cyclophosphamide (VC) + bevacizumab		Vinorelbine/cyclophosphamide (VC) + temsirolimus
All Cause Mortality
	Regimen A		Regimen B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Regimen A		Regimen B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/44 (79.5%)		32/42 (76.2%)
Blood and lymphatic system disorders
Anemia	1/44 (2.3%)	1	1/42 (2.4%)	1
Febrile neutropenia	4/44 (9.1%)	7	9/42 (21.4%)	15
Gastrointestinal disorders
Abdominal pain	1/44 (2.3%)	1	0/42 (0%)	0
Dental caries	1/44 (2.3%)	1	0/42 (0%)	0
Diarrhea	1/44 (2.3%)	1	1/42 (2.4%)	2
Esophagitis	0/44 (0%)	0	1/42 (2.4%)	2
Mucositis oral	1/44 (2.3%)	1	6/42 (14.3%)	6
Nausea	1/44 (2.3%)	1	1/42 (2.4%)	1
Oral pain	0/44 (0%)	0	1/42 (2.4%)	1
Small intestinal obstruction	0/44 (0%)	0	1/42 (2.4%)	1
Typhlitis	0/44 (0%)	0	1/42 (2.4%)	1
Vomiting	1/44 (2.3%)	1	1/42 (2.4%)	1
General disorders
Death NOS	27/44 (61.4%)	27	15/42 (35.7%)	15
General disorders and administration site conditions - Other, specify	1/44 (2.3%)	1	0/42 (0%)	0
Pain	1/44 (2.3%)	1	0/42 (0%)	0
Infections and infestations
Catheter related infection	0/44 (0%)	0	1/42 (2.4%)	1
Esophageal infection	0/44 (0%)	0	1/42 (2.4%)	1
Sepsis	3/44 (6.8%)	3	0/42 (0%)	0
Wound infection	0/44 (0%)	0	1/42 (2.4%)	1
Investigations
Aspartate aminotransferase increased	0/44 (0%)	0	1/42 (2.4%)	1
CPK increased	0/44 (0%)	0	1/42 (2.4%)	1
Ejection fraction decreased	1/44 (2.3%)	1	0/42 (0%)	0
Lymphocyte count decreased	1/44 (2.3%)	1	0/42 (0%)	0
Neutrophil count decreased	0/44 (0%)	0	2/42 (4.8%)	2
Platelet count decreased	0/44 (0%)	0	1/42 (2.4%)	1
Weight loss	0/44 (0%)	0	1/42 (2.4%)	1
Metabolism and nutrition disorders
Dehydration	1/44 (2.3%)	1	3/42 (7.1%)	4
Hypertriglyceridemia	0/44 (0%)	0	4/42 (9.5%)	6
Hypokalemia	0/44 (0%)	0	2/42 (4.8%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukemia secondary to oncology chemotherapy	0/44 (0%)	0	1/42 (2.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	3/44 (6.8%)	3	7/42 (16.7%)	7
Treatment related secondary malignancy	1/44 (2.3%)	2	1/42 (2.4%)	1
Renal and urinary disorders
Acute kidney injury	0/44 (0%)	0	1/42 (2.4%)	1
Urinary tract obstruction	1/44 (2.3%)	1	0/42 (0%)	0
Reproductive system and breast disorders
Reproductive system and breast disorders - Other, specify	1/44 (2.3%)	2	0/42 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/44 (0%)	0	1/42 (2.4%)	1
Epistaxis	2/44 (4.5%)	2	0/42 (0%)	0
Hypoxia	0/44 (0%)	0	1/42 (2.4%)	1
Pleural effusion	0/44 (0%)	0	2/42 (4.8%)	2
Pneumonitis	0/44 (0%)	0	1/42 (2.4%)	1
Respiratory failure	1/44 (2.3%)	1	1/42 (2.4%)	1
Stridor	1/44 (2.3%)	1	0/42 (0%)	0
Skin and subcutaneous tissue disorders
Skin and subcutaneous tissue disorders - Other, specify	1/44 (2.3%)	4	0/42 (0%)	0
Vascular disorders
Hypotension	0/44 (0%)	0	2/42 (4.8%)	2
Other (Not Including Serious) Adverse Events
	Regimen A		Regimen B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/44 (63.6%)		30/42 (71.4%)
Blood and lymphatic system disorders
Anemia	7/44 (15.9%)	8	8/42 (19%)	8
Febrile neutropenia	7/44 (15.9%)	12	7/42 (16.7%)	20
Cardiac disorders
Pericardial effusion	0/44 (0%)	0	1/42 (2.4%)	1
Endocrine disorders
Adrenal insufficiency	1/44 (2.3%)	1	0/42 (0%)	0
Hypothyroidism	1/44 (2.3%)	1	0/42 (0%)	0
Eye disorders
Conjunctivitis	2/44 (4.5%)	2	0/42 (0%)	0
Eye disorders - Other, specify	1/44 (2.3%)	1	0/42 (0%)	0
Eye pain	1/44 (2.3%)	1	0/42 (0%)	0
Eyelid function disorder	0/44 (0%)	0	1/42 (2.4%)	1
Keratitis	1/44 (2.3%)	1	0/42 (0%)	0
Photophobia	1/44 (2.3%)	1	0/42 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/44 (0%)	0	4/42 (9.5%)	4
Ascites	0/44 (0%)	0	1/42 (2.4%)	1
Constipation	1/44 (2.3%)	1	1/42 (2.4%)	1
Dental caries	1/44 (2.3%)	1	0/42 (0%)	0
Diarrhea	1/44 (2.3%)	1	1/42 (2.4%)	1
Esophagitis	0/44 (0%)	0	1/42 (2.4%)	1
Ileus	1/44 (2.3%)	1	1/42 (2.4%)	2
Mucositis oral	1/44 (2.3%)	1	2/42 (4.8%)	3
Nausea	0/44 (0%)	0	1/42 (2.4%)	1
Oral pain	1/44 (2.3%)	1	0/42 (0%)	0
Vomiting	1/44 (2.3%)	1	0/42 (0%)	0
General disorders
Edema face	0/44 (0%)	0	1/42 (2.4%)	1
Facial pain	1/44 (2.3%)	1	0/42 (0%)	0
Fatigue	1/44 (2.3%)	1	1/42 (2.4%)	1
Fever	0/44 (0%)	0	1/42 (2.4%)	1
Non-cardiac chest pain	0/44 (0%)	0	1/42 (2.4%)	1
Pain	6/44 (13.6%)	6	2/42 (4.8%)	2
Infections and infestations
Infections and infestations - Other, specify	1/44 (2.3%)	2	0/42 (0%)	0
Mucosal infection	0/44 (0%)	0	1/42 (2.4%)	1
Pelvic infection	0/44 (0%)	0	1/42 (2.4%)	1
Skin infection	0/44 (0%)	0	1/42 (2.4%)	1
Upper respiratory infection	1/44 (2.3%)	1	0/42 (0%)	0
Urinary tract infection	0/44 (0%)	0	1/42 (2.4%)	1
Wound infection	1/44 (2.3%)	1	0/42 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	2/44 (4.5%)	2	0/42 (0%)	0
Alanine aminotransferase increased	1/44 (2.3%)	1	5/42 (11.9%)	8
Alkaline phosphatase increased	0/44 (0%)	0	1/42 (2.4%)	1
Aspartate aminotransferase increased	0/44 (0%)	0	3/42 (7.1%)	4
Blood bilirubin increased	1/44 (2.3%)	1	0/42 (0%)	0
Cholesterol high	1/44 (2.3%)	1	1/42 (2.4%)	1
Creatinine increased	0/44 (0%)	0	1/42 (2.4%)	1
Ejection fraction decreased	0/44 (0%)	0	1/42 (2.4%)	1
INR increased	1/44 (2.3%)	1	0/42 (0%)	0
Investigations - Other, specify	1/44 (2.3%)	1	0/42 (0%)	0
Lymphocyte count decreased	6/44 (13.6%)	11	6/42 (14.3%)	9
Neutrophil count decreased	3/44 (6.8%)	12	4/42 (9.5%)	6
Platelet count decreased	6/44 (13.6%)	9	4/42 (9.5%)	8
White blood cell decreased	5/44 (11.4%)	10	5/42 (11.9%)	6
Metabolism and nutrition disorders
Anorexia	2/44 (4.5%)	3	2/42 (4.8%)	2
Hyperglycemia	5/44 (11.4%)	5	4/42 (9.5%)	6
Hyperkalemia	1/44 (2.3%)	1	0/42 (0%)	0
Hypertriglyceridemia	1/44 (2.3%)	1	5/42 (11.9%)	5
Hypoalbuminemia	7/44 (15.9%)	7	1/42 (2.4%)	1
Hypocalcemia	1/44 (2.3%)	1	1/42 (2.4%)	1
Hypokalemia	1/44 (2.3%)	2	5/42 (11.9%)	10
Hyponatremia	3/44 (6.8%)	3	1/42 (2.4%)	1
Hypophosphatemia	1/44 (2.3%)	1	2/42 (4.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	5/44 (11.4%)	5	3/42 (7.1%)	3
Generalized muscle weakness	1/44 (2.3%)	1	0/42 (0%)	0
Muscle weakness lower limb	0/44 (0%)	0	1/42 (2.4%)	1
Musculoskeletal and connective tissue disorder - Other, specify	0/44 (0%)	0	1/42 (2.4%)	2
Pain in extremity	0/44 (0%)	0	1/42 (2.4%)	1
Trismus	0/44 (0%)	0	1/42 (2.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/44 (2.3%)	1	0/42 (0%)	0
Tumor pain	1/44 (2.3%)	1	3/42 (7.1%)	3
Nervous system disorders
Ataxia	0/44 (0%)	0	1/42 (2.4%)	1
Facial muscle weakness	1/44 (2.3%)	1	0/42 (0%)	0
Facial nerve disorder	1/44 (2.3%)	1	0/42 (0%)	0
Headache	1/44 (2.3%)	1	0/42 (0%)	0
Neuralgia	0/44 (0%)	0	1/42 (2.4%)	1
Oculomotor nerve disorder	0/44 (0%)	0	1/42 (2.4%)	1
Peripheral motor neuropathy	1/44 (2.3%)	1	2/42 (4.8%)	2
Peripheral sensory neuropathy	0/44 (0%)	0	3/42 (7.1%)	3
Psychiatric disorders
Anxiety	2/44 (4.5%)	2	3/42 (7.1%)	3
Depression	2/44 (4.5%)	2	2/42 (4.8%)	2
Renal and urinary disorders
Hematuria	0/44 (0%)	0	1/42 (2.4%)	1
Proteinuria	1/44 (2.3%)	1	0/42 (0%)	0
Renal calculi	0/44 (0%)	0	1/42 (2.4%)	1
Urinary retention	0/44 (0%)	0	1/42 (2.4%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/44 (2.3%)	1	0/42 (0%)	0
Epistaxis	1/44 (2.3%)	2	0/42 (0%)	0
Hypoxia	0/44 (0%)	0	2/42 (4.8%)	2
Nasal congestion	1/44 (2.3%)	1	0/42 (0%)	0
Pleural effusion	0/44 (0%)	0	3/42 (7.1%)	3
Pleuritic pain	0/44 (0%)	0	1/42 (2.4%)	1
Stridor	1/44 (2.3%)	1	0/42 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/44 (0%)	0	1/42 (2.4%)	1
Dry skin	0/44 (0%)	0	2/42 (4.8%)	2
Rash acneiform	1/44 (2.3%)	1	0/42 (0%)	0
Rash maculo-papular	1/44 (2.3%)	1	0/42 (0%)	0
Vascular disorders
Hypertension	1/44 (2.3%)	1	1/42 (2.4%)	1
Hypotension	0/44 (0%)	0	1/42 (2.4%)	1
Lymphedema	0/44 (0%)	0	1/42 (2.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.