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International Study for Treatment of High Risk Childhood Relapsed ALL 2010

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ClinicalTrials.gov Identifier: NCT03590171
Recruitment Status : Recruiting
First Posted : July 18, 2018
Last Update Posted : July 30, 2019
Sponsor:
Collaborators:
Australian and New Zealand Children's Haematology/Oncology Group
St. Anna Kinderkrebsforschung, CCRI (co-sponsor, Austria)
European Organisation for Research and Treatment of Cancer - EORTC
University Hospital Motol (Co-Sponsor Czech Republic)
Copenhagen University Hospital, Rigshospitalet (co-sponsor, Denmark)
Turku University Central Hospital (co-sponsor, Finland)
Centre Hospitalier Universitaire de Nice
Our Lady's Chilrden's Hospital (Co-Sponsor Ireland)
Tel Aviv Sourasky Medical Centre (Co-Sponsor Israel)
Ospedale Pediatrico Bambino (co-sponsor, Italy)
Prinses Máxima Centrum (Co-Sponsor Netherlands)
Oslo University Hospital (co-sponsor, Norway)
Medical University of Wroclaw (Co-Sponsor Poland)
Instituto Português de Oncologia de Lisboa (co-sponsor, Portugal)
Karolinska University Hospital Stockholm (co-sponsor, Sweden)
Spanish Society of Pediatric Hematology and Oncology (SEHOP) (Co-Sponsor Spain)
University Children's Hospital Zürich (co-sponsor, Switzerland)
Central Manchester University Hospitals NHS Foundation Trust (co-sponsor, UK)
Information provided by (Responsible Party):
PD Dr. Arend von Stackelberg, Charite University, Berlin, Germany

Brief Summary:
The main goal of this study is to improve the outcome of children and adolescents with acute lymphoblastic leukemia with high risk first relapse by optimization of treatment strategies within a large international trial and the integration of new agents.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia (ALL) Drug: Bortezomib Phase 2

Detailed Description:
Though survival of children with acute lymphoblastic leukemia (ALL) has considerably improved over the past few decades, relapsed ALL remains a leading cause of mortality in children with cancer. Risk has been defined by the International (I) Berlin, Frankfurt, Münster (BFM) Study Group (SG) based on duration of first remission, immunophenotype of malignant clone, and site of relapse. Patients classified as high risk (HR) by these criteria have poor response rates to standard induction therapy, high rates of subsequent relapse and require an allogeneic hematopoetic stem cell transplantation (allo-HSCT) for consolidation of 2nd remission. Over the last decade members of the I-BFM-SG have investigated the use of different combinations of conventional cytotoxic agents. Even with allo-HSCT, none of these approaches have improved outcome above 40%. Therefore, for HR patients there is a need to investigate the curative potential of new agents combined with systemic therapy. The proteasome inhibitor bortezomib has shown synergistic activity with acceptable toxicity when combined with corticosteroids, anthracyclines and alkylating agents in adult patients with cancer as well as with dexamethasone, doxorubicin, vincristine and polyethylene glycol (PEG) asparaginase in children with refractory or relapsed ALL. In the I-BFM-SG International Study for Treatment of High Risk Childhood Relapsed ALL (IntReALL) HR 2010 study, the potential of Bortezomib combined with a modified ALL relapse protocol 3 (R3) backbone as induction regimen for HR patients to improve complete 2nd remission (CR2) rates will be investigated in a randomized phase II design. Induction is followed by conventional intensive consolidation. After termination of the trial patients may be subjected to an investigational window, before all of them receive allo-HSCT.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: International Study for Treatment of High Risk Childhood Relapsed ALL 2010 A Randomized Phase II Study Conducted by the Resistant Disease Committee of the International Berlin, Frankfurt, Münster (BFM) Study Group
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Bortezomib

Arm Intervention/treatment
No Intervention: Arm HR-A
Induction: Backbone ALL R3
Experimental: Arm HR-B
Induction: Backbone ALL R3 + Bortezomib
Drug: Bortezomib
Patients randomised to the HR-B arm receive induction, consolidation with the modified ALL R3 protocol. In this arm, patients are randomized to receive Bortezomib together with the ALL R3 protocol during induction. Administration of Bortezomib: 1.3 mg/m2 as intravenous bolus or subcutaneously (SC, at the discretion of the treating physician) on days 1 and 4 of weeks 1 and 3.




Primary Outcome Measures :
  1. Rate of Complete Remission [ Time Frame: Week 4 ]
    Rate of complete second remission (CR2) quantified by cytology after induction with standard chemotherapy + bortezomib (arm B) compared with standard chemotherapy (arm A).


Secondary Outcome Measures :
  1. Event-free Survival [ Time Frame: Year 3 ]
    Improvement of three years event-free survival (EFS)

  2. Overall Survival [ Time Frame: Year 3 ]
    Improvement of three years overall survival (OS)

  3. Minimal Residual Disease Reduction (MRD) [ Time Frame: Week 4 ]
    Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib

  4. Minimal Residual Disease Load [ Time Frame: Week 15 ]
    Improvement of MRD load prior to stem cell transplantation (SCT).

  5. Minimal Residual Disease (MRD) [ Time Frame: Week 15 ]
    Prognostic relevance of MRD pre stem cell transplantation (SCT). MRD will be quantified before stem cell transplantation with polymerase chain reaction (PCR) and will be related to EFS after SCT. Multicolour flow cytometry will be used in parallel with PCR. Flow cytometry is used instead of PCR if PCR based MRD-quantification cannot be performed, because criteria for a reliable and reproducible sensitive quantification are not fulfilled.

  6. Complete Remission/Minimal Residual Disease Rates During Consolidation [ Time Frame: Week 5, 8, 11, 15 ]
    Improvement of CR2 and/or MRD rates during consolidation

  7. Toxicity of induction classified with the COMMON TOXICITY CRITERIA (CTC) [ Time Frame: At induction up to week 5 ]
    Toxicity of induction with versus without bortezomib. Toxicity of the central nervous system and peripheral neuropathy will be classified with the COMMON TOXICITY CRITERIA (CTC).


Other Outcome Measures:
  1. Minimal Residual Disease in Isolated Extramedullary Relapse [ Time Frame: Day 0; Week 5, 8, 11, 15 ]
    The rate and extent of sub-microscopic bone marrow (BM) involvement in extramedullary leukemia will be investigated prospectively.

  2. Extended Genetic Characterization [ Time Frame: Day 0 ]
    Extension of genetic characterization and correlation with clinical data

  3. In-vitro drug response profile [ Time Frame: Day 0 ]
    Generation of primografts from patient samples for bio-banking and drug testing by using immunodeficient mice. The outcome measure is the in-vitro drug response profile using the primograft of primary patient sample. The in-vitro drug response profile will be compared to the in-vivo drug response of a patient. In order to get an "in-vitro drug response profile" apoptosis/viability of the primary patient sample or patient-derived xenograft sample is measured using different concentrations of novel drugs normally after 48 hours of treatment. These drugs could be potentially given to a patient, when there will be no response to conventional protocol treatment. Apoptosis/viability is measured by live cell imaging microscopy or/and by flow cytometry. The report will include half maximal inhibitory concentration (IC50), the concentration of a drug which kills half of the cell after a defined time (normally 48h) for a variety of potential drugs.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Morphologically confirmed diagnosis of 1st relapsed precursor B-cell or T-cell ALL
  • Children less than 18 years of age at date of inclusion into the study
  • Meeting HR criteria any BM relapse, early/very early isolated BM relapse, very early isolated/combined 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 day prior to study enrolment that interfere with this protocol, except trials for primary ALL

Exclusion Criteria:

  • Breakpoint cluster region-Abelson (BCR-ABL)/ t(9;22) positive ALL
  • Pregnancy or positive pregnancy test (urine sample positive for β-humane choriongonadotropin (HCG) > 10 U/l)
  • Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
  • Breast feeding
  • Relapse post allogeneic stem-cell transplantation
  • Neuropathy > II°
  • The whole protocol or essential parts are declined either by patient himself/herself or the respective legal guardian
  • Objection to the study participation by a minor patient, able to object
  • Any patient being dependent on the investigator
  • 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)
  • Subjects unwilling or unable to comply with the study procedures
  • Subjects who are legally detained in an official institute

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03590171


Contacts
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Contact: Arend von Stackelberg, MD +49(0)30-450666 ext 833 arend.stackelberg@charite.de

Locations
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Australia, Victoria
Australian & New Zealand Childhood Hematology & Oncology Group Recruiting
Clayton, Victoria, Australia, 3168
Contact: Tamas Revesz, MD         
Austria
St. Anna Kinderkrebsforschung, CCRI Recruiting
Vienna, Austria, 1090
Contact: Georg Mann, MD         
Contact: Andishe Atterbashi, MD         
Belgium
Hòpital Universitaire des Enfants Reine Fabiola Not yet recruiting
Bruxelles, Belgium, 1020
Contact: Alina Ferster, MD         
Czechia
University Hospital Motol Recruiting
Prague, Czechia
Contact: Lucie Sramkova, MD         
Denmark
Copenhagen University Hospital (Rigshospitalet) Not yet recruiting
Copenhagen, Denmark, 2100
Contact: Thomas Frandsen, MD         
Finland
Turku University Central Hospital Recruiting
Turku, Finland, SF-20520
Contact: Päivi Lähteenmäki, MD         
France
CHU Nice Recruiting
Nice, France
Contact: Pierre Rohrlich, MD         
Israel
Tel Aviv Sourasky Medical Centre Not yet recruiting
Tel Aviv, Israel, 64239
Contact: Ronit Elhasid, MD         
Italy
Ospedale Pediatrico Bambino Gesù Recruiting
Roma, Italy, 00165
Contact: Franco Locatelli, MD         
Netherlands
Prinses Máxima Centrum, Lundlaan Not yet recruiting
Utrecht, Netherlands
Contact: Peter Hoogerbrugge, MD         
Norway
Oslo University Hospital Not yet recruiting
Oslo, Norway, 0027
Contact: Marit Hellebostad, MD         
Poland
Dpt. SCT and Hematology/Oncology University Wroclaw Recruiting
Wroclaw, Poland, 50354
Contact: Ewa Goczynska, MD         
Portugal
Instituto Português de Oncologia de Lisboa Not yet recruiting
Lisboa, Portugal
Contact: Joaquin Duarte, MD         
Sweden
University Hospital Stockholm Not yet recruiting
Stockholm, Sweden, 17176
Contact: Stefan Soderhall, MD         
United Kingdom
Royal Manchester Children's Hospital Not yet recruiting
Manchester, United Kingdom, M13 9WL
Contact: Denise Bonney, MD         
Sponsors and Collaborators
Charite University, Berlin, Germany
Australian and New Zealand Children's Haematology/Oncology Group
St. Anna Kinderkrebsforschung, CCRI (co-sponsor, Austria)
European Organisation for Research and Treatment of Cancer - EORTC
University Hospital Motol (Co-Sponsor Czech Republic)
Copenhagen University Hospital, Rigshospitalet (co-sponsor, Denmark)
Turku University Central Hospital (co-sponsor, Finland)
Centre Hospitalier Universitaire de Nice
Our Lady's Chilrden's Hospital (Co-Sponsor Ireland)
Tel Aviv Sourasky Medical Centre (Co-Sponsor Israel)
Ospedale Pediatrico Bambino (co-sponsor, Italy)
Prinses Máxima Centrum (Co-Sponsor Netherlands)
Oslo University Hospital (co-sponsor, Norway)
Medical University of Wroclaw (Co-Sponsor Poland)
Instituto Português de Oncologia de Lisboa (co-sponsor, Portugal)
Karolinska University Hospital Stockholm (co-sponsor, Sweden)
Spanish Society of Pediatric Hematology and Oncology (SEHOP) (Co-Sponsor Spain)
University Children's Hospital Zürich (co-sponsor, Switzerland)
Central Manchester University Hospitals NHS Foundation Trust (co-sponsor, UK)
Investigators
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Principal Investigator: Arend von Stackelberg, MD Charite University, Berlin, Germany

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Responsible Party: PD Dr. Arend von Stackelberg, Prinicipal Investigator, Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT03590171     History of Changes
Other Study ID Numbers: IntReALL HR 2010
First Posted: July 18, 2018    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PD Dr. Arend von Stackelberg, Charite University, Berlin, Germany:
ALL

Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bortezomib
Antineoplastic Agents