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: May 6, 2024
• Sponsor: Goethe University
• Collaborators: Deutsche Leukämie- & Lymphom-Hilfe; German Federal Ministry of Education and Research
• Information provided by (Responsible Party): Nicola Goekbuget, Goethe University

Tracking Information

• First Submitted Date: August 20, 2023
• First Posted Date: September 29, 2023
• Last Update Posted Date: May 6, 2024
• Actual Study Start Date: July 14, 2023
• Estimated Primary Completion Date: July 1, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 24, 2023)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 24, 2023)

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

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: September 24, 2023)

• Probability of remission duration [ Time Frame: at 2 years, 3 years, 4 yrs ]
  Probability of remission duration
• Cumulative incidence of relapse [ Time Frame: at 2 years, 3 years, 4 yrs ]
  Cumulative incidence of relapse
• Mortality in CR [ Time Frame: at 2 years, 3 years, 4 yrs ]
  Mortality in CR
• Probability of relapse-free survival [ Time Frame: at 2 years, 3 years, 4 yrs ]
  Probability relapse-free survival
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Incidence of TKI dose reductions [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]
• Incidence of TKI changes [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]
• Incidence of TKI treatment interruptions [ Time Frame: for each cycle - approximately 28 days each - number of cycles depends on treatment arm ]

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: 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)

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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Intervention

• 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.

Study Arms

• Active Comparator: A: Imatinib + low dose chemotherapy
  Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I)
  Intervention: Drug: Imatinib
• 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)
  Intervention: Drug: Ponatinib
• 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)
  Intervention: Other: Indication for stem cell transplantation
• 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)
  Interventions:

  • Drug: Imatinib
  • Drug: Ponatinib
  • Drug: Blinatumomab
• 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)
  Interventions:

  • Drug: Imatinib
  • Drug: Ponatinib
  • Drug: Blinatumomab
  • Other: Indication for stem cell transplantation

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 24, 2023): 220
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 1, 2029
• Estimated Primary Completion Date: July 1, 2029 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

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

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT06061094
• Other Study ID Numbers: GMALL-EVOLVE; 2022-000760-21 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nicola Goekbuget, Goethe University
• Original Responsible Party: Same as current
• Current Study Sponsor: Goethe University
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: Goethe University
• Verification Date: May 2024