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

Overview

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

• 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

• Rate of Complete Remission [Time frame: Week 4]

Secondary outcome measures (7)

• Event-free Survival [Time frame: Year 3]
• Overall Survival [Time frame: Year 3]
• Minimal Residual Disease Reduction (MRD) [Time frame: Week 4]
• Minimal Residual Disease Load [Time frame: Week 15]
• Minimal Residual Disease (MRD) [Time frame: Week 15]
• Complete Remission/Minimal Residual Disease Rates During Consolidation [Time frame: Week 5, 8, 11, 15]
• Toxicity of induction classified with the COMMON TOXICITY CRITERIA (CTC) [Time frame: At induction up to week 5]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 1 center

• Australian & New Zealand Childhood Hematology & Oncology Group — Clayton

Austria · 1 center

• St. Anna Kinderkrebsforschung, CCRI — Vienna

Belgium · 1 center

• Hòpital Universitaire des Enfants Reine Fabiola — Brussels

Czechia · 1 center

• University Hospital Motol — Prague

Denmark · 1 center

• Copenhagen University Hospital (Rigshospitalet) — Copenhagen

Finland · 1 center

• Turku University Central Hospital — Turku

France · 1 center

• CHU Nice — Nice

Israel · 1 center

• Tel Aviv Sourasky Medical Centre — Tel Aviv

Italy · 1 center

• Ospedale Pediatrico Bambino Gesù — Roma

Netherlands · 1 center

• Prinses Máxima Centrum, Lundlaan — Utrecht

Norway · 1 center

• Oslo University Hospital — Oslo

Poland · 1 center

• Dpt. SCT and Hematology/Oncology University Wroclaw — Wroclaw

Portugal · 1 center

• Instituto Português de Oncologia de Lisboa — Lisbon

Sweden · 1 center

• University Hospital Stockholm — Stockholm

United Kingdom · 1 center

• Royal Manchester Children's Hospital — Manchester

Identifiers

NCT: NCT03590171 · IntReALL HR 2010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗