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)

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).

2023-07-14

2029-07-01

2029-07-01

Recruiting

Early phase I

220

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

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE2'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 220, 'type': 'ESTIMATED'}}

2024-05-06