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

Sponsor

Goethe University (Other)

Overall Status

Recruiting

CT.gov ID

NCT06061094

Collaborator

Deutsche Leukämie- & Lymphom-Hilfe (Other), German Federal Ministry of Education and Research (Other)

220

Enrollment

Location

Arms

71.6

Anticipated Duration (Months)

3.1

Patients Per Site Per Month

Study Details

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

Anticipated 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 :

Jul 14, 2023

Anticipated Primary Completion Date :

Jul 1, 2029

Anticipated Study Completion Date :

Jul 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

OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care) [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

Rate of molecular complete remission at week 11 after consolidation [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

Probability of remission duration [at 2 years, 3 years, 4 yrs]
Probability of remission duration
Cumulative incidence of relapse [at 2 years, 3 years, 4 yrs]
Cumulative incidence of relapse
Mortality in CR [at 2 years, 3 years, 4 yrs]
Mortality in CR
Probability of relapse-free survival [at 2 years, 3 years, 4 yrs]
Probability relapse-free survival
Hematologic/Molecular response [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 [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 [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) [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 [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 [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 [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 [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 [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 [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Department of Medicine, Hematology and Oncology, Goethe University Hospital Frankfurt	Frankfurt		Germany	60580

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