Clinical Trials /

International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010

NCT01802814

Description:

The main goal of this study is to improve the outcome of children and adolescents with standard risk first relapsed acute lymphoblastic leukemia. Furthermore, goal is to set up a large international study group platform allowing for optimization of standard treatment strategies and integration of new agents.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010
  • Official Title: International Study for Treatment of Standard Risk Childhood Relapsed ALL 2010 A Randomized Phase III Study Conducted by the Resistant Disease Committee of the International BFM Study Group

Clinical Trial IDs

  • ORG STUDY ID: IntReALL SR 2010
  • NCT ID: NCT01802814

Conditions

  • Acute Lymphoblastic Leukemia (ALL)

Interventions

DrugSynonymsArms
SR-A + EpratuzumabEpratuzumabSR-A + Epratuzumab
SR-B + EpratuzumabEpratuzumabSR-B + Epratuzumab

Purpose

The main goal of this study is to improve the outcome of children and adolescents with standard risk first relapsed acute lymphoblastic leukemia. Furthermore, goal is to set up a large international study group platform allowing for optimization of standard treatment strategies and integration of new agents.

Detailed Description

      ALL is the most frequent malignancy in childhood and has favourable event-free and overall
      survival rates. About 15% of patients suffer relapse. At relapse prognosis is much inferior
      (about 50% survival) leukemic clones exhibit much more resistance to conventional
      chemotherapy. Patients with relapse require treatment intensification and different
      therapeutic strategies. At relapse, new targeted agents can provide the chance for better
      cure rates and need to be investigated in prospective controlled trials before they may be
      even eligible for frontline treatment strategies.

      The IntReALL SR 2010 trial is designed to achieve 2 major aims: Establishment of the best
      available standard chemotherapy treatment. This is addressed with the randomization of the 2
      best developed strategies for treatment of childhood relapsed ALL, the German ALL-REZ BFM
      2002 Protocol with the Protocol II IDA arm, and the British ALL-R3 protocol with the
      mitoxantrone arm. This randomization allows confirming the feasibility of both protocols in a
      large variety of different countries and study groups with different frontline therapy
      strategies. As result from this trial a common standard chemotherapy for childhood relapsed
      ALL will be developed which can serve as backbone for investigation of the most attractive
      targeted new agents.

      The 2nd aim is the investigation of the efficacy and tolerability of the humanized CD22
      directed monoclonal antibody Epratuzumab, manufactured and provided by the company
      Immunomedics, US. The drug will be randomly added to the respective consolidation
      chemotherapy, using EFS as primary endpoint. Epratuzumab has been developed in adult
      rheumatology indications and in B-cell malignancies. A phase I and early phase II combination
      trial in childhood relapse ALL has been conducted and published by the Children's Oncology
      Group (COG), and results of an extended phase II trial have been recently presented at the
      ASH meeting (12/2011). The drug showed a very favourable safety profile as single drug and in
      combination with multidrug chemotherapy. Activity was moderate, the recent trial showed a
      significantly better elimination of minimal residual disease (MRD) in patients achieving a
      2nd complete remission. This finding supports the strategy to use Epratuzumab in combination
      with consolidation chemotherapy after induction in patients having reduced the leukemia
      burden in the bone marrow to at least below 25%, most of them will be in 2nd complete
      remission. Epratuzumab will be given weekly at the established dose. Pharmacokinetics will be
      investigated in a reduced number of patients. The further treatment will be conventional
      intensive chemotherapy and maintenance therapy in patients with good MRD response after
      induction, or with allogeneic stem-cell transplantation (SCT) in those with insufficient MRD
      response. SCT will be considered as standard treatment element and will not lead to censoring
      of the patients of considered as endpoint. Epratuzumab is not licensed so far and the trial
      may add to the approval process in case.

      Scientific advice for the trial has been requested at the FDA and the EMA. Both institutions
      have responded supportively. Concerns and recommendations of FDA and EMA have been addressed
      in the protocol and the corresponding statistical analysis plan.

      The IntReALL SR 2010 trial will be financed within the FP7 project IntReALL 2010 supported by
      the European Commission. Within the project next to the SR trial a strategy for HR patients
      will be addressed, the establishment of harmonized diagnostic procedures, an international
      tumour bank and a comprehensive biologic/scientific programme will be set up, a web-based GCP
      conform database will be established, a comprehensive statistical strategy for both trials
      are established, and drug development in this indication will be promoted and organized from
      side of the disease experts in cooperation with the established academic structures ITCC
      (Innovative Therapies for Children with Cancer), the ENCCA project (European Network for
      Cancer in Children and Adolescents) and SIOPe (International Society for Pediatric Oncology
      Europe), the central authorities (EMA, FDA) and Industry. Parent organisation and former
      patients are integrated into and accompany the process.

      Main aims of the IntReALL FP7 project are to establish a therapeutic platform for children
      with relapsed ALL in Europe and beyond and to give them access to the most promising new
      agents under academic control and free from commercial interests.

      Randomized evidence for efficacy and tolerability of new drugs are demanded by competent
      authorities. These trials are conducted beyond the mostly palliative patient group eligible
      for phase I/II trials in curative indications. Treatment protocols for with curative
      indications need to be conducted in the best interests of the patients, ideally with an
      academic sponsor. The design should be driven by medical and scientific evidence and not by
      commercial interests as is the case in industry sponsored trials. This concept was
      acknowledged by the European Commission selecting the project for funding from many other
      powerful applications.
    

Trial Arms

NameTypeDescriptionInterventions
SR-ANo InterventionPatients randomized to the SR-A Arm receive induction, consolidation and maintenance therapy according to a modified protocol ALL-REZ BFM 2002 with Protocol II-IDA as 1st consolidation element. In this arm patients are randomized not to receive epratuzumab.
    SR-A + EpratuzumabActive ComparatorPatients randomized to the SR-A Arm receive induction, consolidation and maintenance therapy according to a modified protocol ALL-REZ BFM 2002 with Protocol II-IDA as 1st consolidation element. In this arm patients are randomized to receive epratuzumab.
    • SR-A + Epratuzumab
    SR-BNo InterventionPatients randomized to the SR-B Arm receive induction, post-induction and maintenance therapy according to the protocol ALL-R3. In this arm patients are randomized not to receive epratuzumab.
      SR-B + EpratuzumabActive ComparatorPatients randomized to the SR-B Arm receive induction, post-induction and maintenance therapy according to the protocol ALL-R3. In this arm patients are randomized to receive epratuzumab.
      • SR-B + Epratuzumab

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or T-cell ALL
      
                -  Children less than 18 years of age at inclusion
      
                -  Meeting SR criteria: late isolated or late/early combined BCP BM relapse, any
                   late/early isolated extramedullary relapse
      
                -  Patient enrolled in a participating centre
      
                -  Written informed consent
      
                -  Start of treatment falling into the study period
      
                -  No participation in other clinical trials 30 days prior to study enrolment that
                   interfere with this protocol, except trials for primary ALL Inclusion criteria
                   specific for the epratuzumab randomization
      
                -  Precursor B-cell immunophenotype. A specific CD22 expression level is not required
      
                -  M1 or M2 status of the bone marrow after induction
      
              Exclusion Criteria:
      
                -  BCR-ABL / t(9;22) positive ALL
      
                -  Pregnancy or positive pregnancy test (urine sample positive for β-HCG > 10 U/l)
      
                -  Sexually active adolescents not willing to use highly effective contraceptive method
                   (pearl index <1) until 2 years after end of antileukemic therapy
      
                -  Breast feeding
      
                -  Relapse post allogeneic stem-cell transplantation
      
                -  The whole protocol or essential parts are declined either by patient himself/herself
                   or the respective legal guardian
      
                -  No consent is given for saving and propagation of pseudonymized medical data for study
                   reasons
      
                -  Severe concomitant disease that does not allow treatment according to the protocol at
                   the investigator's discretion (e.g. malformation syndromes, cardiac malformations,
                   metabolic disorders)
      
                -  Karnovsky / Lansky score < 50%
      
                -  Subjects unwilling or unable to comply with the study procedures
      
                -  Subjects who are legally detained in an official institute
            
      Maximum Eligible Age:17 Years
      Minimum Eligible Age:N/A
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:SR induction/consolidation ALL-REZ BFM 2002 versus UK-ALL-R3 (randomisation 1)
      Time Frame:Up to 9 years
      Safety Issue:
      Description:SR induction/consolidation ALL-REZ BFM 2002 versus UK-ALL-R3 (randomisation 1): 10% pEFS superiority of arm B above a 65% pEFS at 4 years of arm A

      Secondary Outcome Measures

      Measure:SR induction/consolidation
      Time Frame:Up to 9 years
      Safety Issue:
      Description:SR induction/consolidation: comparison of OS, toxicity, rate of CR2, and rate of MRD between treatment groups
      Measure:SR consolidation +/- epratuzumab
      Time Frame:Up to 9 years
      Safety Issue:
      Description:SR consolidation +/- epratuzumab: comparison of OS, toxicity, MRD levels, rate of MRD and evaluation of pharmacokinetic parameters of Epratuzumab

      Details

      Phase:Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Charite University, Berlin, Germany

      Trial Keywords

      • ALL

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