Vinorelbine Tartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma
|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|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
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|
- Event Free Survival Probability [ Time Frame: 1 year ]Probability of no relapse, secondary malignancy, or death after 1 year in the study.
- Rate of Dose-Limiting Toxicities [ 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. ]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).
- Response Rate (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. ]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.
- Biomarker Levels [ Time Frame: 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.
- Changes in Angiogenesis-associated Plasma Markers Between Patients by Treatment [ Time Frame: 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.
- Clinical Predictors, Including Histologic and Molecular Subtype, Age, Stage, and Site [ Time Frame: 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.
- Clinical Response [ Time Frame: 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.
- Levels of Biomarkers Related to the Effect of Temsirolimus on the Unfolded Protein Response [ Time Frame: Up to 36 weeks ]
- Progression-free Survival [ Time Frame: 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.
|Study Start Date:||October 2010|
|Study Completion Date:||June 2015|
|Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
Experimental: Arm I (vinorelbine tartrate, cyclophosphamide, bevacizumab)
Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8 and cyclophosphamide IV over 30-60 minutes on day 1. Patients also receive bevacizumab IV over 30-90 minutes on day 1.
Other Names:Drug: Cyclophosphamide
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Vinorelbine Tartrate
Experimental: Arm II (vinorelbine tartrate, cyclophosphamide, temsirolimus)
Patients receive vinorelbine tartrate and cyclophosphamide as in arm I. Patients also receive temsirolimus IV over 30-60 minutes on days 1, 8, and 15.
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Temsirolimus
Other Names:Drug: Vinorelbine Tartrate
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01222715
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|Principal Investigator:||Leo Mascarenhas||Children's Oncology Group|