Randomized Trial in Adult de Novo Ph Positive ALL With Chemotherapy, Imatinib or Ponatinib, Blinatumomab and SCT (GMALL-EVOLVE)

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)

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).

Study Overview

• Status: Recruiting
• Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Imatinib; Drug: Ponatinib; Other: Indication for stem cell transplantation; Drug: Blinatumomab

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nicola Goekbuget, MD; Phone Number: 0049-6963016365; Email: goekbuget@em.uni-frankfurt.de
• Study Contact Backup: Name: Fabian Lang, MD; Phone Number: 0049-69630183044; Email: fabian.lang@kgu.de

Study Locations

• Germany
  • Frankfurt, Germany, 60580
    • Recruiting
    • Department of Medicine, Hematology and Oncology, Goethe University Hospital Frankfurt
    • Contact: Nicola Goekbuget, MD; Phone Number: 0049-6963016365; Email: goekbuget@em.uni-frankfurt.de
    • Contact: Fabian Lang, MD; Phone Number: 0049-69630183044; Email: fabian.lang@kgu.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A: Imatinib + low dose chemotherapy; Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I)	Drug: Imatinib; Imatinib 600mg QD plus Chemotherapy
Experimental: B: Ponatinib + low dose chemotherapy; Ponatinib 45mg QD (reduction to 30mg QD after Induction) + low dose chemotherapy induction and consolidation I (Experimental Arm of Randomization I)	Drug: Ponatinib; Ponatinib 45 mg QD plus chemotherapy
Active Comparator: C: Molecular CR: End of therapy with indication for SCT; Molecular CR: End of therapy with indication for SCT (Standard Arm of Randomization II)	Other: Indication for stem cell transplantation; Patients with molecular CR randomized to the standard arm have an indication for SCT; patients with molecular failure or intermediate response have an indication for SCT. SCT is not part of the trial.
Experimental: D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab; Molecular CR: No end of therapy with indication for SCT but and continuation with Imatinib/Ponatinib (per Randomization I), chemotherapy and Blinatumomab (Experimental Arm of Randomization II)	Drug: Imatinib; Imatinib 600mg QD plus Chemotherapy; Drug: Ponatinib; Ponatinib 45 mg QD plus chemotherapy; Drug: Blinatumomab; Patients with molecular failure or intermediate response receive one cycle Blinatumomab before SCT; Patients with molecular CR randomized to the experimental arm receive 3 cycles Blinatumomab + chemotherapy
Experimental: E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina; Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)	Drug: Imatinib; Imatinib 600mg QD plus Chemotherapy; Drug: Ponatinib; Ponatinib 45 mg QD plus chemotherapy; Other: Indication for stem cell transplantation; Patients with molecular CR randomized to the standard arm have an indication for SCT; patients with molecular failure or intermediate response have an indication for SCT. SCT is not part of the trial.; Drug: Blinatumomab; Patients with molecular failure or intermediate response receive one cycle Blinatumomab before SCT; Patients with molecular CR randomized to the experimental arm receive 3 cycles Blinatumomab + chemotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care)	Probability of overall survival up to 4 years from randomization I in patients with mo-lecular remission after consolidation 1 comparing a combination treatment of TKI, Blina-tumomab and chemotherapy versus EOT with indication for SCT	up to 4 years from randomization I

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of molecular complete remission at week 11 after consolidation	Rate of molecular complete remission at week 11 after consolidation with chemotherapy in combination with Ponatinb versus Imatinib	week 11 after consolidation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Probability of remission duration	Probability of remission duration	at 2 years, 3 years, 4 yrs
Cumulative incidence of relapse	Cumulative incidence of relapse	at 2 years, 3 years, 4 yrs
Mortality in CR	Mortality in CR	at 2 years, 3 years, 4 yrs
Probability of relapse-free survival	Probability relapse-free survival	at 2 years, 3 years, 4 yrs
Hematologic/Molecular response	Proportion of patients who achieve hematological and molecular remission or experience molecular failure	after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
Overall incidence and severity of AEs	Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving ponatinib versus imatinib during induction therapy	during induction therapy (approximately 6 weeks)
Probability of continuous molecular remission	Probability of continuous molecular remission at different time-points of Ponatinib versus Imatinib-based therapy	at 2, 3 and 4 yrs
Measuring log-reduction (kinetic on MRD response)	Measuring log-reduction (kinetic on MRD response) in patients with a Ponatinib versus Imatinib-based therapy	after induction I (3 wks), after induction II (6 wks) and after consolidation I (11 wks)
Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD	Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD in patients with blinatumomab in combination with Ponatinib versus Imatinib in patients with molecular persistence (molecular failure and MRD positivity below quantitative range) after consolidation 1	after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
Probability of continuous MRD response and molecular remission and duration of molecular remission	Probability of continuous MRD response and molecular remission and duration of molecular remission at different time-points in patients with molecular persistence (molecular failure and not quantifiable) receiving Blinatumomab in combination with Ponatinib versus Imatinib after consolidation 1	After consolidation 1 approximately every three months
Overall incidence and severity of AEs in patients	Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving Ponatinib or Imatinib in combination with Blinatumomab and chemotherapy	during each treatment cycle
Probability of continuous MRD response	Probability of continuous MRD response and molecular remission and duration of molecular remission at different time-points in patients with Blinatumomab in combination with Ponatinib and chemotherapy or Imatinib and chemotherapy and rate of molecular relapse	at 2, 3 and 4 years
Time to molecular remission	Time to molecular remission measured by time-point of first achievement	after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks)
Incidence of TKI dose reductions		for each cycle - approximately 28 days each - number of cycles depends on treatment arm
Incidence of TKI changes		for each cycle - approximately 28 days each - number of cycles depends on treatment arm
Incidence of TKI treatment interruptions		for each cycle - approximately 28 days each - number of cycles depends on treatment arm

Collaborators and Investigators

• Sponsor: Goethe University
• Collaborators: German Federal Ministry of Education and Research; Deutsche Leukämie- & Lymphom-Hilfe
• Investigators: Principal Investigator: Nicola Goekbuget, MD, Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany; Principal Investigator: Fabian Lang, MD, Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany; Principal Investigator: Heike Pfeifer, MD, Department of Medicine, Hematology and Oncology, Goethe University Frankfurt, Frankfurt, Germany

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2023
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: August 20, 2023
• First Submitted That Met QC Criteria: September 24, 2023
• First Posted (Actual): September 29, 2023

Study Record Updates

• Last Update Posted (Actual): May 6, 2024
• Last Update Submitted That Met QC Criteria: May 3, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Blinatumomab; Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia; Tyrosinekinase Inhibitors
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Chromosome Aberrations; Translocation, Genetic; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Imatinib Mesylate; Ponatinib; Blinatumomab
• Other Study ID Numbers: GMALL-EVOLVE; 2022-000760-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No