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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Imatinib
* Drug: Ponatinib
* Drug: Blinatumomab
* Other: Indication for stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A: Imatinib + low dose chemotherapy<br>Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I) | Drug: Imatinib<br>* Imatinib 600mg QD plus Chemotherapy<br>|
| Experimental: B: Ponatinib + low dose chemotherapy<br>Ponatinib 45mg QD (reduction to 30mg QD after Induction) + low dose chemotherapy induction and consolidation I (Experimental Arm of Randomization I) | Drug: Ponatinib<br>* Ponatinib 45 mg QD plus chemotherapy<br>|
| Active Comparator: C: Molecular CR: End of therapy with indication for SCT<br>Molecular CR: End of therapy with indication for SCT (Standard Arm of Randomization II) | Other: Indication for stem cell transplantation<br>* 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.<br>|
| Experimental: D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab<br>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<br>* Imatinib 600mg QD plus Chemotherapy<br>Drug: Ponatinib<br>* Ponatinib 45 mg QD plus chemotherapy<br>Drug: Blinatumomab<br>* 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<br>|
| Experimental: E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina<br>Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm) | Drug: Imatinib<br>* Imatinib 600mg QD plus Chemotherapy<br>Drug: Ponatinib<br>* Ponatinib 45 mg QD plus chemotherapy<br>Drug: Blinatumomab<br>* 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<br>Other: Indication for stem cell transplantation<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia, Tyrosinekinase Inhibitors, Blinatumomab