A Study of Avastin (Bevacizumab) in Combination With Standard Chemotherapy in Children and Adolescents With Sarcoma.

Study Overview
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Brief Summary
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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.

Official Title
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An Open-label, Multi-center, Randomized Study of the Safety and Effect on Event-free Survival of Bevacizumab in Combination With Standard Chemotherapy in Childhood and Adolescent Patients With Metastatic Rhabdomyosarcoma and Non-rhabdomyosarcoma Soft Tissue Sarcoma

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: Standard chemotherapy
* Drug: bevacizumab [Avastin]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: childhood and adolescent patients aged >/=6 months to 18 years of age metastatic rhabdomyosarcoma or non-rhabdomyosarcoma soft tissue sarcoma adequate bone marrow function adequate renal and liver function adequate blood clotting Exclusion Criteria: previous malignant tumors tumor invading major blood vessels prior systemic anti-tumor treatment

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + Chemotherapy<br>Participants received continuous IV infusion of bevacizumab (7.5 mg/kg every 3 weeks) on Day 1 of 3-week cycles followed by induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy) as per institutional practice for a total of 9 cycles during induction treatment phase. As per the investigator decision, local therapy (radiotherapy and /or surgery) was expected to start after 4 weeks of the last bevacizumab administration in the induction phase and resumed to bevacizumab in the maintenance phase at least 4 weeks after the last dose of local therapy. During maintenance treatment phase, participants received IV infusion of bevacizumab (5 mg/kg every 2 weeks) followed by vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Days 1 and 15 of 4-week cycles for a total of 12 cycles. | Drug: Standard chemotherapy<br>* As prescribed<br>Drug: bevacizumab [Avastin]<br>* 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<br>|
| Active Comparator: Chemotherapy<br>Participants received 9 cycles of induction chemotherapy (4 cycles of IVADo-containing chemotherapy followed by 5 cycles of IVA-containing chemotherapy administered every 3 weeks as per institutional practice. As per the investigator evaluation, participants had option to undergo local therapy (radiotherapy and /or surgery) during last 3 cycles of IVA (i.e. from Cycle 6 to Cycle 9). During maintenance treatment phase, participants received vinorelbine- and cyclophosphamide-containing chemotherapy (as per institutional practice) on Day 1 and 15 of 4-week cycles for a total of 12 cycles. | Drug: Standard chemotherapy<br>* As prescribed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Screening up to approximately 6.75 years | 
| Percentage of Participants Who Died |  | 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. | 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). | 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. | 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. | 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). | 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) |