Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

Acute Lymphoblastic Leukemia, Pediatric Clinical Trial

Official title:

International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia - AIEOP-BFM ALL 2017

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03643276
• Other study ID #: AIEOP-BFM ALL 2017
• Status: Recruiting
• Phase: Phase 3
• Start date: July 15, 2018
• Est. completion date: July 14, 2028

Study information

• Verified date: November 2023
• Source: University Hospital Schleswig-Holstein
• Contact: Anja Möricke, MD
• Phone: +4943150020150
• Email: a.moericke[@]pediatrics.uni-kiel.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5000
• Est. completion date: July 14, 2028
• Est. primary completion date: July 14, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia, Pediatric
• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Blinatumomab
Experimental therapy in randomizations R-HR and R-MR
• Bortezomib
Experimental therapy in randomization R-eHR
• Cyclophosphamide
Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
• Cytarabine
Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T and in the intensification block Myocet-FLA for patients with very high relapse risk
• Daunorubicin
Part of standard chemotherapy
• Myocet
Part of intensification block Myocet-FLA for patients with very high relapse risk
• Dexamethasone
Part of standard chemotherapy
• Doxorubicin
Part of standard chemotherapy
• Etoposide
Part of standard chemotherapy
• Fludarabine Phosphate
Part of intensification block Myocet-FLA for patients with very high relapse risk
• Ifosfamide
Part of standard chemotherapy
• 6-Mercaptopurine
Part of standard chemotherapy and included in experimental treatment phase Protocol IB long in randomization R-T
• Methotrexate
Part of standard chemotherapy
• Pegaspargase
Part of standard chemotherapy
• Prednisolone
Part of standard chemotherapy
• Tioguanin
Part of standard chemotherapy
• Vincristine
Part of standard chemotherapy
• Vindesine
Part of standard chemotherapy
• Erwinase
Part of standard chemotherapy as substitute for PEG-L-Asparaginase in case of allergic reaction

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital	Sydney
Australia	The Children's Hospital at Westmead	Westmead
Austria	Univ.Klinik für Kinder- und Jugendheilkunde Graz	Graz
Austria	Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck	Innsbruck
Austria	Kepler Universitätsklinikum	Linz
Austria	LKH Salzburg	Salzburg
Austria	St. Anna Kinderspital	Vienna
Czechia	University Hospital Brno	Brno
Czechia	Regional Hospital Ceské Budejovice	Ceské Budejovice
Czechia	University Hospital Hradec Králové	Hradec Králové
Czechia	University Hospital Olomouc	Olomouc
Czechia	University Hospital Ostrava-Poruba	Ostrava-Poruba
Czechia	University Hospital Plzen	Plzen
Czechia	University Hospital Motol	Praha
Czechia	Masaryk´s Hospital Ústí nad Labem	Ústí nad Labem
Germany	Kinderklinik der med. Fakultät der RWTH, Bereich Hämatologie/Onkologie	Aachen
Germany	I. Klinik für Kinder u. Jugendliche, Klinikum Augsburg, Hämatologie/ Onkologie	Augsburg
Germany	Kinderklinik der Charité, Campus Virchow Klinikum (CVK), Abt.: Kinderhämatologie	Berlin
Germany	Klinikum Berlin-Buch II. Kinderklinik, Bereich Onkologie/Allg. Pädiatrie	Berlin
Germany	Städtisches Krankenhaus, Kinderklinik	Braunschweig
Germany	Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie / Onkologie	Chemnitz
Germany	Carl-Thiem-Klinikum, Kinderklinik, Abt. Hämatologie/Onkologie	Cottbus
Germany	Vestische Kinder- u. Jugendklinik, Universitätsklinik Witten/Herdecke	Datteln
Germany	Klinikum Dortmund, Klinik f. Kinder- und Jugendmedizin	Dortmund
Germany	Universitatsklinikum Carl Gustav Carus	Dresden
Germany	Universitätsklinik	Düsseldorf
Germany	Helios Klinikum Erfurt GmbH, Klinik für Kinderheilkunde	Erfurt
Germany	Universitaets - Kinderklinik	Erlangen
Germany	Universitaetsklinikum Essen	Essen
Germany	Klinikum der J.W. Goethe Universitaet	Frankfurt
Germany	Universitaetskinderklinik - Universitaetsklinikum Freiburg	Freiburg
Germany	Klinikum der Justus-Liebig-Universität, Zentrum für Kinderheilkunde, Abt. Hämatologie/Onkologie	Gießen
Germany	Universitäts-Kinderklinik Päd. I, Hämatologie/Onkologie	Göttingen
Germany	Klinik und Poliklinik für Kinder und Jugendmedizin, Allgemeine Pädiatrie mit Poliklinik/Pädiatrische Onkologie und Hämatologie	Greifswald
Germany	Medizinische Hochschule Hannover, Zentrum Kinderheilkunde u. Jugendmedizin	Hannover
Germany	Universitäts-Kinderklinik, Päd. Onkologie, Hämatologie, und Immunologie	Heidelberg
Germany	Klinikum Heilbronn GmbH, Klinik für Kinderheilkunde und Jugendmedizin/Perinatalzentrum	Heilbronn
Germany	Gemeinschaftskrankenhaus Herdecke, Kinderabteilung	Herdecke
Germany	Universitaetsklinikum des Saarlandes	Homburg
Germany	Klinikum, der Friedrich-Schiller-Universität, Klinik für Kinder- und Jugendmedizin	Jena
Germany	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Klinikum Kassel	Kassel
Germany	Klinik für Allgemeine Paediatrie, Univ.-Klinikum Schleswig-Holstein, Campus Kiel	Kiel
Germany	Kliniken der Stadt Köln GmbH, Kinderkrankenhaus Riehl	Köln
Germany	Med. Einrichtungen der Universität zu Köln, Klinik für Allg. Kinderheilkunde, Onkologisch-hämatologische Station	Köln
Germany	Department für Frauen- und Kindermedizin, Abteilung für Pädiatrische Onkologie, Hämatologie und Hämostaseologie	Leipzig
Germany	Universität zu Lübeck, Klinik für Kinder- u. Jugendmedizin, Abt. Hämatologie/ Onkologie/Immunologie	Lübeck
Germany	Universitätsklinikum Magdeburg, Klinik für Päd. Hämatologie/Onkologie	Magdeburg
Germany	Klinikum Mannheim gGmbH, Kinderklinik, Abt. Hämatologie/Onkologie	Mannheim
Germany	Universitätsklinikum	Mannheim
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Ludwig-Maximilian-Universität, Dr. von Haunersches Kinderspital	München
Germany	Städt. Krankenhaus München GmbH, Krankenhaus München-Schwabingen, Kinderklinik d. TU	München
Germany	Universitäts-Kinderklinik, Päd. Hämatologie und Onkologie	Münster
Germany	Cnopf'sche Kinderklinik, Onkologie	Nürnberg
Germany	Klinikum Oldenburg gGmbH, Zentrum für Kinder- u. Jugendmedizin, (Elisabeth Kinderkrankenhaus)	Oldenburg
Germany	Universitätsklinikum	Regensburg
Germany	Universitäts-Kinderklinik	Rostock
Germany	Asklepios-Klinik, Sankt Augustin GmbH	Sankt Augustin
Germany	HELIOS Kliniken Schwerin, Klinik f. Kinder-u. Jugendmedizin	Schwerin
Germany	Olga-Hospital, Kinderklinik, Pädiatrisches Zentrum, Abt. Hämatologie/Onkologie	Stuttgart
Germany	Krankenanstalt Trier, Mutterhaus der Borromaeerinnen, Pädiatrische Abteilung	Trier
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm
Germany	Stadtkrankenhaus, Kinderklinik	Wolfsburg
Germany	Universitaets - Kinderklinik Wuerzburg	Wuerzburg
Israel	Soroka University Medical Center	Beer Sheva
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah Medical center	Jerusalem
Israel	Schneider Children Medical Center of Israel	Petach-Tikva
Israel	Sheba Medical Center Tel-Hashomer	Ramat Gan
Israel	Dana children hospital	Tel-Aviv
Italy	Azienda ospedali riuniti	Ancona
Italy	AOUC Policlinico Bari	Bari
Italy	A.O. Papa Giovanni XXIII	Bergamo
Italy	Università di Bologna	Bologna
Italy	ASST Spedali Civili di Brescia	Brescia
Italy	Ospedale Businco	Cagliari
Italy	Azienda ospedaliero universitaria	Catania
Italy	AO Pugliese Ciaccio	Catanzaro
Italy	S.O. Annunziata - A. O. Cosenza	Cosenza
Italy	Ospedale Meyer	Firenze
Italy	Istituto Giannina Gaslini	Genova
Italy	Policlinico di Modena Azienda Ospedaliero-Universitaria	Modena
Italy	Clinica pediatrica Fondazione MBBM	Monza
Italy	A.O.U. Vanvitelli	Napoli
Italy	AORN Santobono Pausilipon	Napoli
Italy	Azienda ospedaliera di Padova	Padova
Italy	Ospedale Civico ARNAS Civico e Di Cristina	Palermo
Italy	Azienda ospedaliero-universitaria di Parma	Parma
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Ospedale S. Maria della misericordia	Perugia
Italy	Ospedale Civile di Pescara	Pescara
Italy	Ospedale Santa Chiara Pisa	Pisa
Italy	Grande ospedale metropolitano B-M-M	Reggio Calabria
Italy	Ospedale infermi	Rimini
Italy	Fondazione Policlinico Gemelli	Roma
Italy	Ospedale Bambino Gesù	Roma
Italy	Policlinico Umberto I Università Sapienza di Roma	Roma
Italy	Ospedale "Casa sollievo della sofferenza"	San Giovanni Rotondo
Italy	A.O.U. Città della salute e della scienza di Torino	Torino
Italy	IRCCS Burlo Garofolo	Trieste
Italy	AOU Verona	Verona
Slovakia	Klinika pediatrickej hematológie a onkológie SZU a DFNsP	Banská Bystrica
Slovakia	Comenius University Children's Hospital	Bratislava
Slovakia	Detská fakultná nemocnica Košice	Košice
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitäts-Kinderspital beider Basel	Basel
Switzerland	Ospedale San Giovanni Bellinzona	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	HUG Hôpitaux Universitaires de Gèneve	Genève
Switzerland	CHUV Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Luzerner Kantonsspital-Kinderspital Luzern	Luzern
Switzerland	Ostschweizer Kinderspital	St. Gallen
Switzerland	Universitäts-Kinderspital Zürich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Martin Schrappe	Deutsche Krebshilfe e.V., Bonn (Germany)

Countries where clinical trial is conducted

Australia,  Austria,  Czechia,  Germany,  Israel,  Italy,  Slovakia,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free survival	Randomization R-eHR, R-HR and R-T: Time from randomization until the first event defined as follow: cytomorphological or molecular non-response (resistance to protocol treatment, considered as event at day zero), relapse, second malignancy or death from any cause. This will be called EFS time.	Assessed up to 120 months from start of study
Primary	Disease-free survival	Randomization R-MR: Time from randomization until the first event defined as follow: Relapse, second malignancy or death from any cause. This will be called DFS time.	Assessed up to 120 months from start of study
Secondary	Survival	All patients/randomizations: Time until death from any cause, starting at the same time point as the EFS/DFS.	Assessed up to 120 months from start of study
Secondary	Treatment-related mortality	Frequency and incidence of treatment-related mortality in induction or continuous complete remission	Assessed up to 120 months from start of study
Secondary	Adverse Events of interest/Serious Adverse Events	Frequency and incidence of adverse events of interest and serious adverse events in specific protocol phases, randomized arms and overall during follow-up	Assessed up to 120 months from start of study
Secondary	MRD response	MRD load after the randomized treatment phases (R-eHR, R-HR, R-MR and R-T) as well as after the first/second cycle of Blinatumomab or after the HR 2'/HR 3' block (R-HR)	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).
Secondary	Proportion of patients with Blina Poor-Response	Proportion of patients with poor MRD response to the first Blinatumomab cycle ("Blinatumomab Poor-Response") (R-HR)	Measurements of MRD response intended after 30 weeks from individual start of treatment, assessment of proportion at 120 months from start of study