This open-label two-arm study will assess the safety and efficacy of a combination of bevacizumab + standard chemotherapy with standard chemotherapy alone as active comparator in childhood and adolescent patients with metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma. Patients will be randomized to receive bevacizumab + standard chemotherapy or standard chemotherapy alone. Treatment will consist of 9 x 3-week cycles of induction treatment (standard chemotherapy with or without bevacizumab 7.5 mg/kg iv on day 1 of each cycle) followed by 12 x 4-week cycles of maintenance treatment (standard chemotherapy with or without bevacizumab 5 mg/kg iv on days 1 and 15 of each cycle). The anticipated time on study treatment is 1-2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
154
As prescribed
7.5 mg/kg iv on day 1 of 9 x 3-week cycles, followed by 5 mg/kg iv on days 1 and 15 of each 4-week cycle
Hôpital Enfants Reine Fabiola
Brussels, Belgium
Cliniques Universitaires St-Luc
Brussels, Belgium
UZ Gent
Ghent, Belgium
Instituto Nacional do Cancer - INCA
Rio de Janeiro, Rio de Janeiro, Brazil
Clinica de Oncologia de Porto Alegre - CliniOnco
Porto Alegre, Rio Grande do Sul, Brazil
Hospital de Cancer de Barretos
Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment
EFS events included tumor progression (IRC assessed), no evidence of response after 3 cycles of induction (derived from IRC assessment), second primary cancer, or death due to any cause. Data for participants who had not experienced an event by the time of clinical cut-off were censored at the date of the last disease assessment prior to the clinical cut-off date. Data for participants who did not have any post-baseline disease assessments were censored at the time of randomization. Tumor progression was defined using Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0) as at least a 20% increase in the disease measurement, taking as reference the smallest disease measurement recorded since the start of treatment, or the appearance of one or more new lesions, or evidence of clinical progression and unequivocal progression of existing non-target lesions.
Time frame: Screening up to approximately 6.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
EFS Duration as Per IRC Assessment
EFS was defined as the time between randomization and occurrence of EFS event. EFS events are described in Outcome Measure 1. Median EFS was estimated using Kaplan-Meier estimates and 95% confidence intervals (CI) for median was computed using the method of Brookmeyer and Crowley.
Time frame: Screening up to approximately 6.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
Percentage of Participants With Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria
Objective response prior to first local therapy (surgery and/or radiotherapy) was defined as complete response (CR) or partial response (PR) determined on two consecutive occasions \>/=4 weeks apart. Tumor response was assessed as per IRC using RECIST v1.0. CR was defined as disappearance of all target and non-target lesions. If immunocytology was available, no disease was to be detected by that methodology. PR was defined as at least a 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry.
Time frame: Screening up to approximately 6.75 years
Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response
EFS events was described in Outcome Measure 1 and Outcome Measure 3.
Time frame: Screening up to approximately 6.75 years
Duration of Response
Duration of Response was defined as time between first objective response and the occurrence of an EFS event (described in Outcome Measure 1). Objective response was defined in Outcome Measure 3. Median duration of response was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Screening up to approximately 6.75 years
Percentage of Participants Who Died
Time frame: Screening up to approximately 10.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years.
Overall Survival Duration
Overall survival was defined as the time between randomization and death due to any cause. Participants without an event were censored at the last time they were known to be alive. Median overall survival was estimated using Kaplan-Meier estimates and 95% CI for median was computed using the method of Brookmeyer and Crowley.
Time frame: Screening up to approximately 10.75 years (assessed at screening, Cycles 4, 7 of induction phase, Cycles 1, 4, 7, 10 of maintenance, then every 3 months for 1.5 years and thereafter every 6 months for 2.5 years)
Area Under the Curve at Steady State (AUCss) of Bevacizumab
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUCss is expressed in milligrams times days per milliliter (mg\*day/mL).
Time frame: Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase
Volume of Distribution of Bevacizumab
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
Time frame: Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
Half-Life of Bevacizumab
Half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
Clearance of Bevacizumab
CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL is expressed in milliliters per day (mL/day).
Time frame: Pre- and within 3 hours post-dose on Days 1, 8, and 15 of Cycle 1, Day 1 of Cycle 2-4 of induction phase (1 cycle = 3 weeks)
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Barretos, São Paulo, Brazil
Instituto de Oncologia Pediatrica
São Paulo, São Paulo, Brazil
ITACI - Instituto de Tratamento do Cancer Infantil
São Paulo, São Paulo, Brazil
Hospital Santa Marcelina
São Paulo, São Paulo, Brazil
Hospital For Sick Children
Toronto, Ontario, Canada
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