Clinical trial NCT03643276: Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017
Official title: International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Lymphoblastic Leukemia, Pediatric
Keywords: Acute Lymphoblastic Leukemia
Childhood
Pediatric
Immunotherapy
Blinatumomab
Proteasome Inhibitor
Bispecific antibody
Bortezomib
Chemotherapy
Randomized trial
Lead sponsor: University Hospital Schleswig-Holstein
Sponsor class: OTHER
Collaborators: name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2018-08-22
Enrollment: 5000
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: pB-ALL/MR: 2 parallel groups (R-MR) or 2x2 factorial design (R-eHR, R-MR) depending on early risk group assignment.

pB-ALL/HR: 2 parallel groups (R-HR) or 2x2 factorial design (R-eHR, R-HR) depending on early risk group assignment.

T-ALL/early non-SR: 2 parallel groups (R-T).

pB-ALL/SR: Single group.

T-ALL/early SR: Single group.
Primary purpose: TREATMENT

Brief summary: The understanding of acute lymphoblastic leukemia (ALL) in childhood and adolescence has largely changed due to extensive genetic research in recent years: ALL is now considered to be a very heterogeneous disease group. The leukemia cells present themselves with quite differently activated regulatory mechanisms of the malignant phenotype. The introduction of more accurate methods of assessing therapy response ("minimal residual disease \[MRD\] tests") has provided new insights into very different mechanisms of action, including factors influenced by host factors; this has had practical clinical consequences for the use of more individualized therapy. Multimodal therapies have enabled a cure level of over 80% for ALL in this age group. However, the own and international study data show that the therapy toxicity of the contemporary chemotherapy concepts has become unacceptably high, in particular with respect to those intensified therapies used for the treatment of patients at high risk of ALL relapse.

The AIEOP-BFM ALL 2017 study therefore aims for an innovative integrated approach that will not only adapt the risk stratification to new prognostic markers using more comprehensive diagnostics, but above all, qualitatively reorient the therapy. The most important consequence will be that this study is testing immunotherapy with the bispecific antibody blinatumomab as an alternative to particularly intensive and toxic chemotherapy elements in precursor B-cell ALL (pB-ALL) patients with detectable chemotherapy resistance and at high risk of relapse. With the aim to complement the effects of the conventional chemotherapy, Blinatumomab is in addition tested in the large group of pB-ALL patients at intermediate relapse risk with seemingly unremarkable leukemia, but who account for a large proportion of all relapses. Targeted therapy is also used in the form of the proteasome inhibitor bortezomib for patients with pB-ALL and slow response to the drugs of the induction chemotherapy with the aim to overcome intrinsic chemotherapy resistance of the ALL cells. In patients with T-lineage ALL, who have particularly poor chances for cure after relapse, the established consolidation chemotherapy has proved to be particularly effective. This chemotherapy phase is therefore tested in a longer and more intensive form in such T-ALL patients with intermediate or slow early treatment response with the aim to reduce the relapses rate in this subgroup.

Detailed description: Patients are stratified into 4 early risk groups for therapy during the consolidation phase (T/early SR, T/early non-SR, pB/early non-HR, pB/early HR) and 5 risk groups for post-consolidation therapy (T/non-HR, T/HR, pB/SR, pB/MR, pB/HR). Risk stratification is based on immunophenotypic lineage, genetics of leukemic cells and treatment response on the basis of cytomorphology and methods for detection minimal residual disease.

The trial includes four randomized study questions testing experimental treatments on top of the risk-stratified standard chemotherapy backbone:

Primary study questions:

Randomization R-eHR: Early High-risk (early HR) pB-ALL defined by genetics and/or inadequate treatment response over the course of induction: Can the probability of event-free survival (pEFS) from time of randomization be improved by additional therapy with the proteasome inhibitor bortezomib during an extended consolidation treatment phase compared with standard extended consolidation?

Randomization R-HR: High-risk (HR) pB-ALL defined by genetics and/or inadequate treatment response by the end of consolidation: Can the pEFS from time of randomization be improved by a treatment concept including two cycles of post-consolidation immunotherapy with blinatumomab (15 µg/m²/d for 28 days per cycle) plus 4 doses intrathecal Methotrexate replacing two conventional highly intensive chemotherapy courses?

Randomization R-MR: Intermediate risk (MR) pB-ALL defined by genetics and intermediate MRD response: Can the probability of disease-free survival (pDFS) from time of randomization be improved by additional therapy with one cycle of post-reintensification immunotherapy with blinatumomab (15 µg/m²/d for 28 days)?

Randomization R-T: Early non-standard risk (early non-SR) T-ALL patients defined by treatment response over the course of induction: Can the pEFS from time of randomization be improved by the extension of the standard of care consolidation phase by 14 days with an increase of the consolidation cumulative doses of Cyclophosphamide, Cytarabine and 6-Mercaptopurine by 50%?

Secondary study questions:

All randomizations: Can the overall survival be improved by the treatment in the experimental arm?

All randomizations: What is the incidence of treatment-related toxicities and mortality in the experimental arm compared to the standard arm?

Randomization R-eHR: Can the MRD load after consolidation treatment be reduced by the additional treatment with bortezomib?

Randomization R-HR: Can treatment-related life-threatening complications and mortality during the intensified consolidation phase of high-risk treatment be reduced when replacing two intensive chemotherapy courses by two cycles of immunotherapy with blinatumomab?

Randomization R-HR: What is the proportion of patients with insufficient MRD response to blinatumomab as defined in the protocol as compared to the MRD response after the HR-2' block in the control arm?

Randomization R-HR: Can the MRD load after the first treatment cycle (HR 2'/blinatumomab) and the second cycle (HR-3'/blinatumomab) be reduced in the experimental arm when compared with conventional intensive chemotherapy? Randomization R-MR: What is the proportion of patients with positive MRD after reintensification Protocol II who become MRD-negative over the blinatumomab cycle compared to 4 weeks of standard maintenance therapy?

Randomization R-T: Can the MRD load after consolidation treatment be reduced by extension of the consolidation phase?

Standard-risk patients: Is the clinical outcome comparable to that obtained for standard-risk patients in study AIEOP-BFM ALL 2009?

A small subgroup of patients at very high relapse risk is eligible for allogeneic hematopoietic stem cell transplantation after the intensified consolidation therapy phase.

Patients with T-ALL and hyperleukocytosis (\>=100,000/µL) and patients with CNS involvement at diagnosis (CNS3 status) are eligible for cranial irradiation with 12 Gy if age at time of irradiation is at least 4 years.

Eligibility criteria: Inclusion Criteria:

* newly diagnosed acute lymphoblastic leukemia or
* newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
* biphenotypic with a dominant T or B lineage assignment
* bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
* newly diagnosed acute undifferentiated leukemia
* age \< 18 years (up to 17 years and 365 days) at the day of diagnosis
* patient enrolled in a participating center
* written informed consent to trial participation and transfer and processing of data A subsequent removal from the study is only allowed if the inclusion criteria turn out not to be fulfilled or in the case of pregnancy of the patient.

Exclusion Criteria:

* Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
* bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset
* pre-treatment with cytostatic drugs
* glucocorticoid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis
* treatment started according to another protocol
* underlying disease that does not allow treatment according to the protocol (e.g. severe congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangiectasia...)
* ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
* evidence of pregnancy or lactation period
* Sexually active adolescents not willing to use highly effective contraceptive method (pearl index \<1) until 12 months after end of anti-leukemic therapy
* participation in another clinical trial except for add-on trials within the scope of supportive care approved by the sponsor
* live vaccine immunization within 2 weeks before start of protocol treatment

Primary outcomes:
measure: Event-free survival
timeFrame: Assessed up to 120 months from start of study
measure: Disease-free survival
timeFrame: Assessed up to 120 months from start of study
Secondary outcomes:
measure: Survival
timeFrame: Assessed up to 120 months from start of study
measure: Treatment-related mortality
timeFrame: Assessed up to 120 months from start of study
measure: Adverse Events of interest/Serious Adverse Events
timeFrame: Assessed up to 120 months from start of study
measure: MRD response
timeFrame: Measurements of MRD response at end of randomized treatments (intended time frame 13 weeks in R-eHR/R-T, 26 weeks in R-HR, 34 weeks in R-MR).
measure: Proportion of patients with Blina Poor-Response
timeFrame: Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: Sydney Children's Hospital
city: Westmead
country: Australia
facility: The Children's Hospital at Westmead
city: Graz
country: Austria
facility: Univ.Klinik für Kinder- und Jugendheilkunde Graz
city: Innsbruck
country: Austria
facility: Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck
city: Linz
country: Austria
facility: Kepler Universitätsklinikum
city: Salzburg
country: Austria
facility: LKH Salzburg
city: Vienna
country: Austria
facility: St. Anna Kinderspital
city: Brno
country: Czechia
facility: University Hospital Brno
city: Hradec Králové
country: Czechia
facility: University Hospital Hradec Králové
city: Olomouc
country: Czechia
facility: University Hospital Olomouc
city: Ostrava-Poruba
country: Czechia
facility: University Hospital Ostrava-Poruba
city: Plzeň
country: Czechia
facility: University Hospital Plzeň
city: Praha
country: Czechia
facility: University Hospital Motol
city: Ústí nad Labem
country: Czechia
facility: Masaryk´s Hospital Ústí nad Labem
city: České Budějovice
country: Czechia
facility: Regional Hospital České Budějovice
city: Aachen
country: Germany
facility: Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie
city: Augsburg
country: Germany
facility: I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie
city: Berlin
country: Germany
facility: Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie
city: Berlin
country: Germany
facility: Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie
city: Braunschweig
country: Germany
facility: Städtisches Krankenhaus, Kinderklinik
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie
city: Datteln
country: Germany
facility: Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke
city: Dortmund
country: Germany
facility: Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Düsseldorf
country: Germany
facility: Universitätsklinik
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde
city: Erlangen
country: Germany
facility: Universitaets - Kinderklinik
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetskinderklinik - Universitaetsklinikum Freiburg
city: Gießen
country: Germany
facility: Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie
city: Greifswald
country: Germany
facility: Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie
city: Göttingen
country: Germany
facility: Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin
city: Heidelberg
country: Germany
facility: Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie
city: Heilbronn
country: Germany
facility: Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus Herdecke, Kinderabteilung
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Jena
country: Germany
facility: Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel
city: Köln
country: Germany
facility: Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl
city: Köln
country: Germany
facility: Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station
city: Leipzig
country: Germany
facility: Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie
city: Lübeck
country: Germany
facility: Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie
city: Mannheim
country: Germany
facility: Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie
city: Mannheim
country: Germany
facility: Universitätsklinikum
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU
city: München
country: Germany
facility: Ludwig-Maximilian-Universität, Dr. von Haunersches Kinderspital
city: Münster
country: Germany
facility: Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie
city: Nürnberg
country: Germany
facility: Cnopf'sche Kinderklinik, Onkologie
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)
city: Regensburg
country: Germany
facility: Universitätsklinikum
city: Rostock
country: Germany
facility: Universitäts-Kinderklinik
city: Sankt Augustin
country: Germany
facility: Asklepios-Klinik, Sankt Augustin GmbH
city: Schwerin
country: Germany
facility: HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin
city: Stuttgart
country: Germany
facility: Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie
city: Trier
country: Germany
facility: Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Ulm
country: Germany
facility: Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm
city: Wolfsburg
country: Germany
facility: Stadtkrankenhaus, Kinderklinik
city: Wuerzburg
country: Germany
facility: Universitaets - Kinderklinik Wuerzburg
city: Beer Sheva
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah Medical center
city: Petach-Tikva
country: Israel
facility: Schneider Children Medical Center of Israel
city: Ramat Gan
country: Israel
facility: Sheba Medical Center Tel-Hashomer
city: Tel-Aviv
country: Israel
facility: Dana children hospital
city: Ancona
country: Italy
facility: Azienda ospedali riuniti
city: Bari
country: Italy
facility: AOUC Policlinico Bari
city: Bergamo
country: Italy
facility: A.O. Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Università di Bologna
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Cagliari
country: Italy
facility: Ospedale Businco
city: Catania
country: Italy
facility: Azienda ospedaliero universitaria
city: Catanzaro
country: Italy
facility: AO Pugliese Ciaccio
city: Cosenza
country: Italy
facility: S.O. Annunziata - A. O. Cosenza
city: Firenze
country: Italy
facility: Ospedale Meyer
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Modena
country: Italy
facility: Policlinico di Modena Azienda Ospedaliero-Universitaria
city: Monza
country: Italy
facility: Clinica pediatrica Fondazione MBBM
city: Napoli
country: Italy
facility: A.O.U. Vanvitelli
city: Napoli
country: Italy
facility: AORN Santobono Pausilipon
city: Padova
country: Italy
facility: Azienda ospedaliera di Padova
city: Palermo
country: Italy
facility: Ospedale Civico ARNAS Civico e Di Cristina
city: Parma
country: Italy
facility: Azienda ospedaliero-universitaria di Parma
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Perugia
country: Italy
facility: Ospedale S. Maria della misericordia
city: Pescara
country: Italy
facility: Ospedale Civile di Pescara
city: Pisa
country: Italy
facility: Ospedale Santa Chiara Pisa
city: Reggio Calabria
country: Italy
facility: Grande ospedale metropolitano B-M-M
city: Rimini
country: Italy
facility: Ospedale infermi
city: Roma
country: Italy
facility: Fondazione Policlinico Gemelli
city: Roma
country: Italy
facility: Ospedale Bambino Gesù
city: Roma
country: Italy
facility: Policlinico Umberto I Università Sapienza di Roma
city: San Giovanni Rotondo
country: Italy
facility: Ospedale "Casa sollievo della sofferenza"
city: Torino
country: Italy
facility: A.O.U. Città della salute e della scienza di Torino
city: Trieste
country: Italy
facility: IRCCS Burlo Garofolo
city: Verona
country: Italy
facility: AOU Verona
city: Banská Bystrica
country: Slovakia
facility: Klinika pediatrickej hematológie a onkológie SZU a DFNsP
city: Bratislava
country: Slovakia
facility: Comenius University Children's Hospital
city: Košice
country: Slovakia
facility: Detská fakultná nemocnica Košice
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Basel
country: Switzerland
facility: Universitäts-Kinderspital beider Basel
city: Bellinzona
country: Switzerland
facility: Ospedale San Giovanni Bellinzona
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Genève
country: Switzerland
facility: HUG Hôpitaux Universitaires de Gèneve
city: Lausanne
country: Switzerland
facility: CHUV Centre Hospitalier Universitaire Vaudois
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital-Kinderspital Luzern
city: St. Gallen
country: Switzerland
facility: Ostschweizer Kinderspital
city: Zürich
country: Switzerland
facility: Universitäts-Kinderspital Zürich
Study officials:
affiliation: Department of Pediatrics, University Hospital of Schleswig-Holstein, Campus Kiel
name: Martin Schrappe, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tufekci O, Evim MS, Gunes AM, Celkan T, Karapinar DY, Kaya Z, Baysal B, Baytan B, Kocak U, Yilmaz S, Cinar S, Oren H. Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey. J Pediatr Hematol Oncol. 2022 Mar 1;44(2):e396-e402. doi: 10.1097/MPH.0000000000002419.