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

• ClinicalTrials.gov Identifier: NCT06061094
• Recruitment Status: Recruiting
• First Posted: September 29, 2023
• Last Update Posted: September 29, 2023
• Sponsor: Goethe University
• Collaborators: Deutsche Leukämie- & Lymphom-Hilfe; German Federal Ministry of Education and Research
• Information provided by (Responsible Party): Nicola Goekbuget, Goethe University

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia	Drug: Imatinib; Drug: Ponatinib; Drug: Blinatumomab; Other: Indication for stem cell transplantation	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: July 14, 2023
• Estimated Primary Completion Date: July 1, 2029
• Estimated Study Completion Date: July 1, 2029

Arms and Interventions

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; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care) [ Time Frame: up to 4 years from randomization I ]
   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

Secondary Outcome Measures :

1. Rate of molecular complete remission at week 11 after consolidation [ Time Frame: week 11 after consolidation ]
   Rate of molecular complete remission at week 11 after consolidation with chemotherapy in combination with Ponatinb versus Imatinib

Other Outcome Measures:

1. Probability of remission duration [ Time Frame: at 2 years, 3 years, 4 yrs ]
   Probability of remission duration
2. Cumulative incidence of relapse [ Time Frame: at 2 years, 3 years, 4 yrs ]
   Cumulative incidence of relapse
3. Mortality in CR [ Time Frame: at 2 years, 3 years, 4 yrs ]
   Mortality in CR
4. Probability of relapse-free survival [ Time Frame: at 2 years, 3 years, 4 yrs ]
   Probability relapse-free survival
5. Hematologic/Molecular response [ Time Frame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) ]
   Proportion of patients who achieve hematological and molecular remission or experience molecular failure
6. Overall incidence and severity of AEs [ Time Frame: during induction therapy (approximately 6 weeks) ]
   Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving ponatinib versus imatinib during induction therapy
7. Probability of continuous molecular remission [ Time Frame: at 2, 3 and 4 yrs ]
   Probability of continuous molecular remission at different time-points of Ponatinib versus Imatinib-based therapy
8. Measuring log-reduction (kinetic on MRD response) [ Time Frame: after induction I (3 wks), after induction II (6 wks) and after consolidation I (11 wks) ]
   Measuring log-reduction (kinetic on MRD response) in patients with a Ponatinib versus Imatinib-based therapy
9. Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD [ Time Frame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) ]
   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
10. Probability of continuous MRD response and molecular remission and duration of molecular remission [ Time Frame: After consolidation 1 approximately every three months ]
    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
11. Overall incidence and severity of AEs in patients [ Time Frame: during each treatment cycle ]
    Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving Ponatinib or Imatinib in combination with Blinatumomab and chemotherapy
12. Probability of continuous MRD response [ Time Frame: at 2, 3 and 4 years ]
    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
13. Time to molecular remission [ Time Frame: after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) ]
    Time to molecular remission measured by time-point of first achievement
14. Incidence of TKI dose reductions [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]
15. Incidence of TKI changes [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]
16. Incidence of TKI treatment interruptions [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Nicola Goekbuget, MD; 0049-6963016365; goekbuget@em.uni-frankfurt.de

Contact: Fabian Lang, MD; 0049-69630183044; fabian.lang@kgu.de

Locations

Germany

Department of Medicine, Hematology and Oncology, Goethe University Hospital Frankfurt; Recruiting

Frankfurt, Germany, 60580

Contact: Nicola Goekbuget, MD 0049-6963016365 goekbuget@em.uni-frankfurt.de

Contact: Fabian Lang, MD 0049-69630183044 fabian.lang@kgu.de

Sponsors and Collaborators

Goethe University

Deutsche Leukämie- & Lymphom-Hilfe

German Federal Ministry of Education and Research

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

More Information

• Responsible Party: Nicola Goekbuget, Dr. Nicola Gökbuget, Goethe University
• ClinicalTrials.gov Identifier: NCT06061094
• Other Study ID Numbers: GMALL-EVOLVE; 2022-000760-21 ( EudraCT Number )
• First Posted: September 29, 2023
• Last Update Posted: September 29, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Nicola Goekbuget, Goethe University:

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia; Tyrosinekinase Inhibitors; Blinatumomab

Additional relevant MeSH terms:

Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Philadelphia Chromosome; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Translocation, Genetic; Chromosome Aberrations; Pathologic Processes; Imatinib Mesylate; Blinatumomab; Ponatinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents