Clinical trial NCT06061094: Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT
Official title: A Multicentre, Randomized Trial in Adults With de Novo Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia to Assess the Efficacy of Ponatinib Versus Imatinib in Combination With Low-intensity Chemotherapy, to Compare End of Therapy With Indication for SCT Versus TKI, Blinatumomab and Chemotherapy in Optimal Responders and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Keywords: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Tyrosinekinase Inhibitors
Blinatumomab
Lead sponsor: Goethe University
Sponsor class: OTHER
Collaborators: name: Deutsche Leukämie- & Lymphom-Hilfe
name: German Federal Ministry of Education and Research
First posted: 2023-09-29
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current Standard of Care (SoC) in younger patients with Ph+ ALL is Imatinib in combination with low-dose chemotherapy, change of TKI in case of persistent MRD above 10-3 after consolidation I and indication for stem cell transplantation.

The EVOLVE trial aims to answer three questions challenging the current SoC:

Use of Ponatinib compared to Imatinib both in combination with low-dose chemotherapy and consolidation I (randomization I).

In MRD good responders: Omit end of therapy in primary care and indication for SCT but continue therapy with TKI, chemotherapy and Blinatumomab as additional antileukemic compound (randomization II).

In MRD poor responders: Omit indication for TKI change but give instead Blinatumomab followed by end of therapy in primary care and indication for SCT (non-randomized).


Eligibility criteria: Inclusion Criteria:

* Male or female patients \>= 18 years, \<=65 years
* Philadelphia chromosome or BCR-ABL1 positive ALL
* Not previously treated except with corticosteroids ≤ 7 days, standard GMALL prephase with dexamethasone and cyclophosphamide including intrathecal therapy, hydroxyurea, a single dose vincristine or other cytostatic drugs and start of standard induction for Ph-positive ALL (1 dose vincristine, 1 dose of Rituximab, 2 doses dexamethasone and up to 5 days Imatinib)
* ECOG performance status ≤2
* Signed written inform consent
* Molecular evaluation for BCR-ABL1 performed
* Negative pregnancy test in women of childbearing potential
* Woman of childbearing potential willing to use 2 highly effective methods of contraception while receiving study treatment and for an additional 3 months after the last dose of study treatment (Pearl-Index \<1%). Male who has a female partner of childbearing potential willing to use 2 highly effective forms of contraception while receiving study treatment and for at least an additional 3 months after the last dose of study treatment (Pearl-Index \<1%).
* Normal serum levels \> LLN (lower limit of normal) of potassium and magnesium, or corrected to within normal limits with supplements, prior to the first dose of study medication
* Serum lipase ≤ 1.5 x ULN. For serum lipase \> ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis
* Normal QTcF interval ≤450 ms for males and ≤470 ms for females
* Signed and dated written informed consent is available
* Participation in the registry of the German Multicenter Study Group for Adult ALL (GMALL)

Exclusion Criteria:

* History of malignancy other than ALL diagnosed within 5 years (yrs) prior to start of protocol-specified therapy with defined exceptions
* Contraindications against the use of Imatinib, Ponatinib, chemotherapy or Blinatumomab
* Patient previously treated with tyrosine kinase inhibitors
* Nursing women
* Known impaired cardiac function, including any of the following: as detailed in protocol
* Symptomatic peripheral vascular disease
* Any history of ischemic stroke or transient ischemic attacks (TIAs)
* Uncontrolled hypertriglyceridaemia
* History or presence of clinically relevant CNS pathology as detailed in protocol
* History or active relevant autoimmune disease
* Known hypersensitivity to immunoglobulins or to any other component of the study drug formulation
* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C
* History of pancreatitis within 6 months previous to start of treatment within the trial
* Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
* Inadequate hepatic functions defined as ASAT or ALAT \> 2,5 times the institutional upper limit of normal or \> 5 times ULN if considered due to leukemia
* Total bilirubin \> 1.5-fold the institutional upper limit unless considered to be due to organ involvement by the leukemia or to M. Gilbert / M. Meulengracht
* Concurrent severe diseases which exclude the administration of therapy e.g. severe, uncontrolled acute or chronic infections
* Inability to understand and/or unwillingness to sign a written informed consent

Primary outcomes:
measure: OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care)
timeFrame: up to 4 years from randomization I
Secondary outcomes:
measure: Rate of molecular complete remission at week 11 after consolidation
timeFrame: week 11 after consolidation
Other outcomes:
measure: Probability of remission duration
timeFrame: at 2 years, 3 years, 4 yrs
measure: Cumulative incidence of relapse
timeFrame: at 2 years, 3 years, 4 yrs
measure: Mortality in CR
timeFrame: at 2 years, 3 years, 4 yrs
measure: Probability of relapse-free survival
timeFrame: at 2 years, 3 years, 4 yrs
measure: Hematologic/Molecular response
timeFrame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
measure: Overall incidence and severity of AEs
timeFrame: during induction therapy (approximately 6 weeks)
measure: Probability of continuous molecular remission
timeFrame: at 2, 3 and 4 yrs
measure: Measuring log-reduction (kinetic on MRD response)
timeFrame: after induction I (3 wks), after induction II (6 wks) and after consolidation I (11 wks)
measure: Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD
timeFrame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
measure: Probability of continuous MRD response and molecular remission and duration of molecular remission
timeFrame: After consolidation 1 approximately every three months
measure: Overall incidence and severity of AEs in patients
timeFrame: during each treatment cycle
measure: Probability of continuous MRD response
timeFrame: at 2, 3 and 4 years
measure: Time to molecular remission
timeFrame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
measure: Incidence of TKI dose reductions
timeFrame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm
measure: Incidence of TKI changes
timeFrame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm
measure: Incidence of TKI treatment interruptions
timeFrame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm
Locations:
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Aschaffenburg
country: Germany
facility: Klinikum Aschaffenburg
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bad Saarow
country: Germany
facility: Helios Klinikum Bad Saarow
city: Bayreuth
country: Germany
facility: Klinikum Bayreuth
city: Berlin
country: Germany
facility: Vivantes Klinikum am Urban
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Berlin
country: Germany
facility: Charite Berlin Virchow Klinikum
city: Bielefeld
country: Germany
facility: Evangelisches Krankenhaus Bielefeld
city: Bochum
country: Germany
facility: UK Knappschaftskrankenhaus Bochum
city: Bonn
country: Germany
facility: Evangelische Kliniken Bonn
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt
city: Dessau-Roßlau
country: Germany
facility: Städtisches Klinikum Dessau
city: Dortmund
country: Germany
facility: Klinikum Dortmund
city: Dortmund
country: Germany
facility: St. Johannes Hospital Dortmund
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Duisburg
country: Germany
facility: Helios Klinikum Duisburg
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Eschweiler
country: Germany
facility: St.-Antonius-Hospital
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Essen
country: Germany
facility: Evangelisches Krankenhaus Essen-Werden
city: Frankfurt
country: Germany
facility: Department of Medicine, Hematology and Oncology, Goethe University Hospital Frankfurt
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Georgsmarienhütte
country: Germany
facility: Niels-Stensen-Kliniken Georgsmarienhütte
city: Goch
country: Germany
facility: Wilhelm-Anton-Hospital
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Gütersloh
country: Germany
facility: Klinikum Gütersloh
city: Hagen
country: Germany
facility: Katholisches Krankenhaus Hagen
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg Hamburg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Herne
country: Germany
facility: Marien Hospital Herne
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
city: Idar-Oberstein
country: Germany
facility: Klinikum Idar-Oberstein
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: Karlsruhe
country: Germany
facility: St. Vincentius-Kliniken Karlsruhe
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: Universitätsklinikum Kiel
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Lüdenscheid
country: Germany
facility: Märkische Kliniken Lüdenscheid
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mainz
country: Germany
facility: UNIVERSITÄTSMEDIZIN der Johannes Gutenberg-Universität Mainz
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim
city: Marburg
country: Germany
facility: Philipps-Universität Marburg
city: Möchengladbach
country: Germany
facility: Kliniken Maria Hilf Möchengladbach
city: München
country: Germany
facility: LMU Klinikum München
city: München
country: Germany
facility: Klinikum Rechts der Isar TU München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Offenburg
country: Germany
facility: Ortenau Klinikum Offenburg
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Passau
country: Germany
facility: Klinikum Passau
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brüder Regensburg
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock
city: Rotenburg/Wümme
country: Germany
facility: Agaplesion Diakonieklinikum Rotenburg
city: Schwäbisch-Hall
country: Germany
facility: Diakonie-Krankenhaus Schwäbisch-Hall
city: Stuttgart
country: Germany
facility: Katharinenhospital Stuttgart
city: Stuttgart
country: Germany
facility: Diakonissenkrankenhaus Stuttgart
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus Stuttgart
city: Traunstein
country: Germany
facility: Klinikum Traunstein
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen Trier
city: Trier
country: Germany
facility: Krankenhaus d. Barmherzigen Brüder
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Klinikum Schwarzwald-Baar
city: Wuppertal
country: Germany
facility: Helios Klinikum Wuppertal
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Zwickau
country: Germany
facility: Heinrich-Braun Klinikum
Study officials:
affiliation: Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany
name: Nicola Goekbuget, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany
name: Fabian Lang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany
name: Heike Pfeifer, MD
role: PRINCIPAL_INVESTIGATOR
References: