Clinical trial NCT03590171: International Study for Treatment of High Risk Childhood Relapsed ALL 2010
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia (ALL)
Keywords: ALL
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: Australian & New Zealand Children's Haematology/Oncology Group
name: St. Anna Kinderkrebsforschung, CCRI (co-sponsor, Austria)
name: European Organisation for Research and Treatment of Cancer - EORTC
name: University Hospital Motol (Co-Sponsor Czech Republic)
name: Copenhagen University Hospital, Rigshospitalet (co-sponsor, Denmark)
name: Turku University Central Hospital (co-sponsor, Finland)
name: Centre Hospitalier Universitaire de Nice
name: Our Lady's Chilrden's Hospital (Co-Sponsor Ireland)
name: Tel Aviv Sourasky Medical Centre (Co-Sponsor Israel)
name: Ospedale Pediatrico Bambino (co-sponsor, Italy)
name: Prinses Máxima Centrum (Co-Sponsor Netherlands)
name: Oslo University Hospital (co-sponsor, Norway)
name: Medical University of Wroclaw (Co-Sponsor Poland)
name: Instituto Português de Oncologia de Lisboa (co-sponsor, Portugal)
name: Karolinska University Hospital Stockholm (co-sponsor, Sweden)
name: Spanish Society of Pediatric Hematology and Oncology (SEHOP) (Co-Sponsor Spain)
name: University Children's Hospital, Zurich
name: Central Manchester University Hospitals NHS Foundation Trust (co-sponsor, UK)
First posted: 2018-07-18
Enrollment: 250
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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 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

Primary outcomes:
measure: Rate of Complete Remission
timeFrame: Week 4
Secondary outcomes:
measure: Event-free Survival
timeFrame: Year 3
measure: Overall Survival
timeFrame: Year 3
measure: Minimal Residual Disease Reduction (MRD)
timeFrame: Week 4
measure: Minimal Residual Disease Load
timeFrame: Week 15
measure: Minimal Residual Disease (MRD)
timeFrame: Week 15
measure: Complete Remission/Minimal Residual Disease Rates During Consolidation
timeFrame: Week 5, 8, 11, 15
measure: Toxicity of induction classified with the COMMON TOXICITY CRITERIA (CTC)
timeFrame: At induction up to week 5
Other outcomes:
measure: Minimal Residual Disease in Isolated Extramedullary Relapse
timeFrame: Day 0; Week 5, 8, 11, 15
measure: Extended Genetic Characterization
timeFrame: Day 0
measure: In-vitro drug response profile
timeFrame: Day 0
Locations:
city: Clayton
country: Australia
facility: Australian & New Zealand Childhood Hematology & Oncology Group
state: Victoria
city: Vienna
country: Austria
facility: St. Anna Kinderkrebsforschung, CCRI
city: Bruxelles
country: Belgium
facility: Hòpital Universitaire des Enfants Reine Fabiola
city: Prague
country: Czechia
facility: University Hospital Motol
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital (Rigshospitalet)
city: Turku
country: Finland
facility: Turku University Central Hospital
city: Nice
country: France
facility: CHU Nice
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Centre
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Utrecht
country: Netherlands
facility: Prinses Máxima Centrum, Lundlaan
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Wroclaw
country: Poland
facility: Dpt. SCT and Hematology/Oncology University Wroclaw
city: Lisboa
country: Portugal
facility: Instituto Português de Oncologia de Lisboa
city: Stockholm
country: Sweden
facility: University Hospital Stockholm
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: Charite University, Berlin, Germany
name: Arend von Stackelberg, MD
role: PRINCIPAL_INVESTIGATOR
References: