International Study for Treatment of High Risk Childhood Relapsed ALL 2010

Acute Lymphoblastic Leukemia (ALL) Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03590171
• Other study ID #: IntReALL HR 2010
• Status: Recruiting
• Phase: Phase 2
• Start date: September 1, 2017
• Est. completion date: December 31, 2027

Study information

• Verified date: February 2024
• Source: Charite University, Berlin, Germany
• Contact: Arend von Stackelberg, MD
• Phone: +49(0)30-450666
• Email: arend.stackelberg[@]charite.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

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 ß-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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia (ALL)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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.

Locations

Country	Name	City	State
Australia	Australian & New Zealand Childhood Hematology & Oncology Group	Clayton	Victoria
Austria	St. Anna Kinderkrebsforschung, CCRI	Vienna
Belgium	Hòpital Universitaire des Enfants Reine Fabiola	Bruxelles
Czechia	University Hospital Motol	Prague
Denmark	Copenhagen University Hospital (Rigshospitalet)	Copenhagen
Finland	Turku University Central Hospital	Turku
France	CHU Nice	Nice
Israel	Tel Aviv Sourasky Medical Centre	Tel Aviv
Italy	Ospedale Pediatrico Bambino Gesù	Roma
Netherlands	Prinses Máxima Centrum, Lundlaan	Utrecht
Norway	Oslo University Hospital	Oslo
Poland	Dpt. SCT and Hematology/Oncology University Wroclaw	Wroclaw
Portugal	Instituto Português de Oncologia de Lisboa	Lisboa
Sweden	University Hospital Stockholm	Stockholm
United Kingdom	Royal Manchester Children's Hospital	Manchester

Sponsors (19)

Lead Sponsor

Collaborator

Charite University, Berlin, Germany

Australian & New Zealand Children's Haematology/Oncology Group, Central Manchester University Hospitals NHS Foundation Trust (co-sponsor, UK), Centre Hospitalier Universitaire de Nice, Copenhagen University Hospital, Rigshospitalet (co-sponsor, Denmark), European Organisation for Research and Treatment of Cancer - EORTC, Instituto Português de Oncologia de Lisboa (co-sponsor, Portugal), Karolinska University Hospital Stockholm (co-sponsor, Sweden), Medical University of Wroclaw (Co-Sponsor Poland), Oslo University Hospital (co-sponsor, Norway), Ospedale Pediatrico Bambino (co-sponsor, Italy), Our Lady's Chilrden's Hospital (Co-Sponsor Ireland), Prinses Máxima Centrum (Co-Sponsor Netherlands), Spanish Society of Pediatric Hematology and Oncology (SEHOP) (Co-Sponsor Spain), St. Anna Kinderkrebsforschung, CCRI (co-sponsor, Austria), Tel Aviv Sourasky Medical Centre (Co-Sponsor Israel), Turku University Central Hospital (co-sponsor, Finland), University Children's Hospital, Zurich, University Hospital Motol (Co-Sponsor Czech Republic)

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Czechia,  Denmark,  Finland,  France,  Israel,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Minimal Residual Disease in Isolated Extramedullary Relapse	The rate and extent of sub-microscopic bone marrow (BM) involvement in extramedullary leukemia will be investigated prospectively.	Day 0; Week 5, 8, 11, 15
Other	Extended Genetic Characterization	Extension of genetic characterization and correlation with clinical data	Day 0
Other	In-vitro drug response profile	Generation of primografts from patient samples for bio-banking and drug testing by using immunodeficient mice. The outcome measure is the in-vitro drug response profile using the primograft of primary patient sample. The in-vitro drug response profile will be compared to the in-vivo drug response of a patient. In order to get an "in-vitro drug response profile" apoptosis/viability of the primary patient sample or patient-derived xenograft sample is measured using different concentrations of novel drugs normally after 48 hours of treatment. These drugs could be potentially given to a patient, when there will be no response to conventional protocol treatment. Apoptosis/viability is measured by live cell imaging microscopy or/and by flow cytometry. The report will include half maximal inhibitory concentration (IC50), the concentration of a drug which kills half of the cell after a defined time (normally 48h) for a variety of potential drugs.	Day 0
Primary	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	Event-free Survival	Improvement of three years event-free survival (EFS)	Year 3
Secondary	Overall Survival	Improvement of three years overall survival (OS)	Year 3
Secondary	Minimal Residual Disease Reduction (MRD)	Improvement of Minimal Residual Disease (MRD) reduction after induction with versus without bortezomib	Week 4
Secondary	Minimal Residual Disease Load	Improvement of MRD load prior to stem cell transplantation (SCT).	Week 15
Secondary	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
Secondary	Complete Remission/Minimal Residual Disease Rates During Consolidation	Improvement of CR2 and/or MRD rates during consolidation	Week 5, 8, 11, 15
Secondary	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