International Study for Treatment of High Risk Childhood Relapsed ALL 2010

Phase 2RecruitingNCT03590171

Charite University, Berlin, Germany250 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

250

Conditions

Acute Lymphoblastic Leukemia (ALL)

Interventions

BortezomibDRUG

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.

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

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

Locations (15)

Australian & New Zealand Childhood Hematology & Oncology Group

Clayton, Victoria, Australia

RECRUITING

St. Anna Kinderkrebsforschung, CCRI

Vienna, Austria

Outcomes

Primary Outcomes

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).

Time frame: Week 4

Secondary Outcomes

Event-free Survival

Improvement of three years event-free survival (EFS)

Time frame: Year 3

Overall Survival

Improvement of three years overall survival (OS)

Time frame: Year 3

Minimal Residual Disease Reduction (MRD)

Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib

Time frame: Week 4

Minimal Residual Disease Load

Improvement of MRD load prior to stem cell transplantation (SCT).

Time frame: 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.

Time frame: Week 15

Complete Remission/Minimal Residual Disease Rates During Consolidation

Improvement of CR2 and/or MRD rates during consolidation

Time frame: Week 5, 8, 11, 15

Central Contacts

Arend von Stackelberg, MD

CONTACT

+49(0)30-450666 arend.stackelberg@charite.de

Data from ClinicalTrials.gov

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