A Study of Avastin (Bevacizumab) in Combination With Standard Chemotherapy in Children and Adolescents With Sarcoma.
- Conditions
- Sarcoma
- Interventions
- Drug: Standard chemotherapyDrug: bevacizumab [Avastin]
- Registration Number
- NCT00643565
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 154
- 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
- previous malignant tumors
- tumor invading major blood vessels
- prior systemic anti-tumor treatment
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Chemotherapy Standard chemotherapy 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. Bevacizumab + Chemotherapy bevacizumab [Avastin] 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. Bevacizumab + Chemotherapy Standard chemotherapy 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Experienced Event-Free Survival (EFS) Events as Per Independent Review Committee (IRC) Assessment 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 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.
EFS Duration as Per IRC Assessment 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 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.
- Secondary Outcome Measures
Name Time Method Clearance of Bevacizumab 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) 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).
Half-Life of Bevacizumab 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 is the time measured for the plasma concentration to decrease by one half.
Area Under the Curve at Steady State (AUCss) of Bevacizumab 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 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).
Percentage of Participants With Objective Response Prior to First Local Therapy Assessed by RECIST v1.0 Criteria Screening up to approximately 6.75 years 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.
Volume of Distribution of Bevacizumab 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) 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.
Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response Screening up to approximately 6.75 years EFS events was described in Outcome Measure 1 and Outcome Measure 3.
Duration of Response Screening up to approximately 6.75 years 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.
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 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 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.
Trial Locations
- Locations (61)
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
Hôpital Enfants Reine Fabiola
🇧🇪Bruxelles, Belgium
UZ Gent
🇧🇪Gent, Belgium
Instituto de Oncologia Pediatrica
🇧🇷Sao Paulo, SP, Brazil
ITACI - Instituto de Tratamento do Cancer Infantil
🇧🇷Sao Paulo, SP, Brazil
Institut Gustave Roussy; Service Pediatrique
🇫🇷Villejuif, France
Hopital Des Enfants; Service d Hemato-Oncologie
🇫🇷Toulouse, France
University Hospital Essen; Department of Pediatric Oncology
🇩🇪Essen, Germany
Hospital Santa Marcelina
🇧🇷Sao Paulo, SP, Brazil
Clinica de Oncologia de Porto Alegre - CliniOnco
🇧🇷Porto Alegre, RS, Brazil
Hospital Luis Calvo Mackenna; Oncologia
🇨🇱Santiago, Chile
Universitaetsklinikum Freiburg - PS; Partnersite - Onkologie
🇩🇪Freiburg, Germany
Rambam Health Care Campus; Pediatric Hematology Oncology Department
🇮🇱Haifa, Israel
Uniwersytet Medyczny W Lublinie; Klinika Hematologii i Onkologii Dzieciecej
🇵🇱Lublin, Poland
Universitatsklinikum Munster; Padiatrische Hamatologie und Onkologie
🇩🇪Münster, Germany
Soroka Medical Center
🇮🇱Beer Sheva, Israel
Ospedale Pediatrico Bambino Gesu
🇮🇹Roma, Lazio, Italy
Dipartimento di Scienze Pediatriche Adolescenza; Osp. Infantile Regina Margherita
🇮🇹Torino, Piemonte, Italy
Saint-Petersburg SHI City Clinical Hospital #31
🇷🇺St. Petersburg, Russian Federation
Prinses Maxima Centrum
🇳🇱Utrecht, Netherlands
Alder Hey Children s Hospital; Department of Pediatrics
🇬🇧Liverpool, United Kingdom
Hospital Regional Universitario Carlos Haya;Servicio Oncologia Pediatrica
🇪🇸Malaga, Spain
Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii
🇵🇱Warsaw, Poland
Center for Children's Hematology, Oncology and Immunology
🇷🇺Moscow, Russian Federation
Hospital Universitario Virgen del Rocio; Servicio de Onco-Hematologia Pediatrica
🇪🇸Sevilla, Spain
Hospital de Cruces
🇪🇸Barakaldo, Vizcaya, Spain
Royal Marsden Hospital; Pediatric Unit
🇬🇧Surrey, United Kingdom
Hospital Universitario La Fe
🇪🇸Valencia, Spain
Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology
🇳🇱Rotterdam, Netherlands
Hospital Infantil Universitario Nino Jesus
🇪🇸Madrid, Spain
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
🇬🇧Newcastle Upon Tyne, United Kingdom
Centre Leon Berard; Pediatrie
🇫🇷Lyon, France
U.O.A University Onco-Ematologia Pedicatria; Azienda Ospedaliera A.Meyer
🇮🇹Firenze, Toscana, Italy
Emma Kinderziekenhuis; Dept of Pediatric Oncology
🇳🇱Amsterdam, Netherlands
Birmingham Childrens Hospital; Oncology Dept
🇬🇧Birmingham, United Kingdom
Azienda Ospedaliera di Padova; Clinica di Onco-ematologia pediatrica
🇮🇹Padova, Veneto, Italy
Royal Hospital For Children
🇬🇧Glasgow, United Kingdom
Bristol Royal Hospital For Children
🇬🇧Bristol, United Kingdom
Hospital Universitari Vall d'Hebron; Servicio de Nefrologia
🇪🇸Barcelona, Spain
Royal Hospital for Sick Children
🇬🇧Edinburgh, United Kingdom
St. James's University Hospital; Leeds Regional Paediatric Oncology Unit
🇬🇧Leeds, United Kingdom
Great Ormond Street Hospital; Dept. Of Pediatric Oncology
🇬🇧London, United Kingdom
Instituto Nacional do Cancer - INCA
🇧🇷Rio de Janeiro, RJ, Brazil
Hospital de Cancer de Barretos
🇧🇷Barretos, SP, Brazil
Hospital For Sick Children
🇨🇦Toronto, Ontario, Canada
Pavillion Chul-Chuq
🇨🇦Sainte-foy, Quebec, Canada
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
CHU Bordeaux; Unite Onco-Hematologie Pediatrique
🇫🇷Bordeaux, France
Fakultni nemocnice v Motole
🇨🇿Praha 5, Czechia
Centre Oscar Lambret; Service de Pediatrie
🇫🇷Lille, France
Hopital Timone Enfants; Onco Pediatrie
🇫🇷Marseille, France
Chr De Nantes; Service D'oncologie Pediatrique
🇫🇷Nantes, France
Institut Curie; Oncologie Medicale
🇫🇷Paris, France
CHU Hopital Sud; Service d'Hematologie Pediatrique
🇫🇷Rennes, France
CHU Hopital d Enfants; Centre hospitalier Universitaire Nancy
🇫🇷Vandoeuvre Les Nancy, France
Schneider Children's Medical Center
🇮🇱Petach-Tikva, Israel
Tel Aviv Sourasky MC, Dana Children's Hospital; Pediatric Hemato-Oncology Clinic
🇮🇱Tel Aviv, Israel
Istituto Gaslini Ospedale Pediatrico; Dipartimento di Oncoematologia pediatrica
🇮🇹Genova, Liguria, Italy
Istituto Nazionale Tumori di Milano; S.C. Oncologia Pediatrica
🇮🇹Milano, Lombardia, Italy
University Hospital Queens Medical Centre; Department of Paediatric Oncology
🇬🇧Nottingham, United Kingdom