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

October 10, 2019 updated by: Hoffmann-La Roche

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

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 Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

154

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Belgium
      • Bruxelles, Belgium, 1200
        • Cliniques Universitaires St-Luc
      • Bruxelles, Belgium, 1020
        • Hôpital Enfants Reine Fabiola
      • Gent, Belgium, 9000
        • UZ Gent
  • Brazil
    • RJ
      • Rio de Janeiro, RJ, Brazil, 20560-120
        • Instituto Nacional Do Câncer - Inca
    • RS
      • Porto Alegre, RS, Brazil, 90430-090
        • Clinica de Oncologia de Porto Alegre - CliniOnco
    • SP
      • Barretos, SP, Brazil, 14784-400
        • Hospital de Cancer de Barretos
      • Sao Paulo, SP, Brazil, 08270-070
        • Hospital Santa Marcelina
      • Sao Paulo, SP, Brazil, 04023-062
        • Instituto De Oncologia Pediatrica
      • Sao Paulo, SP, Brazil, 05410-030
        • ITACI - Instituto de Tratamento do Cancer Infantil
  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5G 1X8
        • Hospital for Sick Children
    • Quebec
      • Sainte-foy, Quebec, Canada, G1V 4G2
        • Pavillion Chul-Chuq
  • Chile
      • Santiago, Chile, 7500539
        • Hospital Luis Calvo Mackenna; Oncologia
  • Czechia
      • Brno, Czechia, 613 00
        • Fakultni Nemocnice Brno
      • Praha 5, Czechia, 150 06
        • Fakultni nemocnice v Motole
  • France
      • Bordeaux, France, 33076
        • CHU Bordeaux; Unite Onco-Hematologie Pediatrique
      • Lille, France, 59020
        • Centre Oscar Lambret; Service de Pediatrie
      • Lyon, France, 69373
        • Centre Leon Berard; Pediatrie
      • Marseille, France, 13385
        • Hopital Timone Enfants; Onco Pediatrie
      • Nantes, France, 44093
        • Chr De Nantes; Service D'oncologie Pediatrique
      • Paris, France, 75231
        • Institut Curie; Oncologie Medicale
      • Rennes, France, 35203
        • CHU Hopital Sud; Service d'Hematologie Pediatrique
      • Toulouse, France, 31059
        • Hopital Des Enfants; Service d Hemato-Oncologie
      • Vandoeuvre Les Nancy, France, 54511
        • CHU Hopital d Enfants; Centre hospitalier Universitaire Nancy
      • Villejuif, France, 94805
        • Institut Gustave Roussy; Service Pediatrique
  • Germany
      • Essen, Germany, 45122
        • University Hospital Essen; Department of Pediatric Oncology
      • Freiburg, Germany, 79106
        • Universitaetsklinikum Freiburg - PS; Partnersite - Onkologie
      • Münster, Germany, 48149
        • Universitatsklinikum Munster; Padiatrische Hamatologie und Onkologie
  • Israel
      • Beer Sheva, Israel, 8410101
        • Soroka Medical Center
      • Haifa, Israel, 31096
        • Rambam Health Care Campus; Pediatric Hematology Oncology Department
      • Petach-Tikva, Israel, 49100
        • Schneider Children's Medical Center
      • Tel Aviv, Israel, 64239
        • Tel Aviv Sourasky MC, Dana Children's Hospital; Pediatric Hemato-Oncology Clinic
  • Italy
    • Lazio
      • Roma, Lazio, Italy, 00165
        • Ospedale Pediatrico Bambino Gesù
    • Liguria
      • Genova, Liguria, Italy, 16148
        • Istituto Gaslini Ospedale Pediatrico; Dipartimento di Oncoematologia pediatrica
    • Lombardia
      • Milano, Lombardia, Italy, 20133
        • Istituto Nazionale Tumori di Milano; S.C. Oncologia Pediatrica
    • Piemonte
      • Torino, Piemonte, Italy, 10126
        • Dipartimento di Scienze Pediatriche Adolescenza; Osp. Infantile Regina Margherita
    • Toscana
      • Firenze, Toscana, Italy, 50132
        • U.O.A University Onco-Ematologia Pedicatria; Azienda Ospedaliera A.Meyer
    • Veneto
      • Padova, Veneto, Italy, 35128
        • Azienda Ospedaliera di Padova; Clinica di Onco-ematologia pediatrica
  • Netherlands
      • Amsterdam, Netherlands, 1105 AZ
        • Emma Kinderziekenhuis; Dept of Pediatric Oncology
      • Rotterdam, Netherlands, 3015 GJ
        • Erasmus Mc/Sophia's Childrens Hospital; Dept. of Pediatric Oncology
      • Utrecht, Netherlands, 3584 CS
        • Prinses Maxima Centrum
  • Poland
      • Lublin, Poland, 20-093
        • Uniwersytet Medyczny W Lublinie; Klinika Hematologii i Onkologii Dzieciecej
      • Warsaw, Poland, 04-746
        • Instytut Pomnik-Centrum Zdrowia Dziecka; Klinika Onkologii
  • Russian Federation
      • Moscow, Russian Federation, 117198
        • Center for Children's Hematology, Oncology and Immunology
      • St. Petersburg, Russian Federation, 197110
        • Saint-Petersburg SHI City Clinical Hospital #31
  • Spain
      • Barcelona, Spain, 08035
        • Hospital Universitari Vall d'Hebron; Servicio de Nefrologia
      • Madrid, Spain, 28009
        • Hospital Infantil Universitario Niño Jesús
      • Malaga, Spain, 29011
        • Hospital Regional Universitario Carlos Haya;Servicio Oncologia Pediatrica
      • Sevilla, Spain, 41 41013
        • Hospital Universitario Virgen del Rocio; Servicio de Onco-Hematologia Pediatrica
      • Valencia, Spain, 46014
        • Hospital Universitario La Fe
    • Vizcaya
      • Barakaldo, Vizcaya, Spain, 48903
        • Hospital de Cruces
  • United Kingdom
      • Birmingham, United Kingdom, B4 6NH
        • Birmingham Childrens Hospital; Oncology Dept
      • Bristol, United Kingdom, BS2 8BJ
        • Bristol Royal Hospital for Children
      • Edinburgh, United Kingdom, EH91LF
        • Royal Hospital for Sick Children
      • Glasgow, United Kingdom, G51 4TF
        • Royal Hospital For Children
      • Leeds, United Kingdom, LS9 7TF
        • St. James's University Hospital; Leeds Regional Paediatric Oncology Unit
      • Liverpool, United Kingdom, L12 2AP
        • Alder Hey Children s Hospital; Department of Pediatrics
      • London, United Kingdom, WC1N 3JH
        • Great Ormond Street Hospital; Dept. Of Pediatric Oncology
      • Manchester, United Kingdom, M27 4HA
        • Royal Manchester Children's Hospital
      • Newcastle Upon Tyne, United Kingdom, NE1 4LP
        • The Royal Victoria Infirmary; Paediatric and Adolescent Oncology Unit
      • Nottingham, United Kingdom, NG7 2UH
        • University Hospital Queens Medical Centre; Department of Paediatric Oncology
      • Surrey, United Kingdom, SM2 5PT
        • Royal Marsden Hospital; Pediatric Unit

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months to 18 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Bevacizumab + 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.
Drug: Standard chemotherapy
As prescribed
Drug: bevacizumab [Avastin]
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
ACTIVE_COMPARATOR: 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.
Drug: Standard chemotherapy
As prescribed

What is the study measuring?

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
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 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
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 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
Time Frame: 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.
Screening up to approximately 6.75 years
Percentage of Participants Who Experienced EFS Events Among Participants Who Had Objective Response
Time Frame: Screening up to approximately 6.75 years
EFS events was described in Outcome Measure 1 and Outcome Measure 3.
Screening up to approximately 6.75 years
Duration of Response
Time Frame: 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.
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.
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
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 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
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
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
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)
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
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 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
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)
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hoffmann-La Roche

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 29, 2008

Primary Completion (ACTUAL)

May 31, 2015

Study Completion (ACTUAL)

April 30, 2019

Study Registration Dates

First Submitted

March 20, 2008

First Submitted That Met QC Criteria

March 25, 2008

First Posted (ESTIMATE)

March 26, 2008

Study Record Updates

Last Update Posted (ACTUAL)

October 22, 2019

Last Update Submitted That Met QC Criteria

October 10, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BO20924
  • 2007-005017-19 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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