International Study for Treatment of High Risk Childhood Relapsed ALL 2010

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Lymphoblastic Leukemia (ALL)

Intervention / Treatment
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* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm HR-A<br>Induction: Backbone ALL R3 | |
| Experimental: Arm HR-B<br>Induction: Backbone ALL R3 + Bortezomib | Drug: Bortezomib<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission | Rate of complete second remission (CR2) quantified by cytology after induction with standard chemotherapy + bortezomib (arm B) compared with standard chemotherapy (arm A). | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Improvement of three years event-free survival (EFS) | Year 3 | 
| Overall Survival | Improvement of three years overall survival (OS) | Year 3 | 
| Minimal Residual Disease Reduction (MRD) | Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib | Week 4 | 
| Minimal Residual Disease Load | Improvement of MRD load prior to stem cell transplantation (SCT). | Week 15 | 
| Minimal Residual Disease (MRD) | 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. | Week 15 | 
| Complete Remission/Minimal Residual Disease Rates During Consolidation | Improvement of CR2 and/or MRD rates during consolidation | Week 5, 8, 11, 15 | 
| Toxicity of induction classified with the COMMON TOXICITY CRITERIA (CTC) | 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). | At induction up to week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALL