Acute Lymphoblastic Leukemia (ALL)
Conditions
Keywords
ALL
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.
Interventions
DRUGBortezomib
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.
Sponsors
Charite University, Berlin, Germany
Australian & 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
Rigshospitalet, 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, Zurich
Central Manchester University Hospitals NHS Foundation Trust (co-sponsor, UK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Complete Remission | 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
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | Year 3 | Improvement of three years event-free survival (EFS) |
| Overall Survival | Year 3 | Improvement of three years overall survival (OS) |
| Minimal Residual Disease Reduction (MRD) | Week 4 | Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib |
| Minimal Residual Disease Load | Week 15 | Improvement of MRD load prior to stem cell transplantation (SCT). |
| Minimal Residual Disease (MRD) | 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. |
| Complete Remission/Minimal Residual Disease Rates During Consolidation | Week 5, 8, 11, 15 | Improvement of CR2 and/or MRD rates during consolidation |
| Toxicity of induction classified with the COMMON TOXICITY CRITERIA (CTC) | 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). |
Countries
Australia, Austria, Belgium, Czechia, Denmark, Finland, France, Israel, Italy, Netherlands, Norway, Poland, Portugal, Sweden, United Kingdom
Contacts
CONTACTArend von Stackelberg, MD
PRINCIPAL_INVESTIGATORArend von Stackelberg, MD
Charite University, Berlin, Germany
Outcome results
None listed