Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Clinical Trial
— GMALL-EVOLVEOfficial 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)
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).
| Status | Recruiting |
| Enrollment | 220 |
| Est. completion date | July 1, 2029 |
| Est. primary completion date | July 1, 2029 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years to 65 Years |
| Eligibility | 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 |
| Country | Name | City | State |
|---|---|---|---|
| Germany | Department of Medicine, Hematology and Oncology, Goethe University Hospital Frankfurt | Frankfurt |
| Lead Sponsor | Collaborator |
|---|---|
| Goethe University | Deutsche Leukämie- & Lymphom-Hilfe, German Federal Ministry of Education and Research |
Germany,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | Probability of remission duration | Probability of remission duration | at 2 years, 3 years, 4 yrs | |
| Other | Cumulative incidence of relapse | Cumulative incidence of relapse | at 2 years, 3 years, 4 yrs | |
| Other | Mortality in CR | Mortality in CR | at 2 years, 3 years, 4 yrs | |
| Other | Probability of relapse-free survival | Probability relapse-free survival | at 2 years, 3 years, 4 yrs | |
| Other | Hematologic/Molecular response | Proportion of patients who achieve hematological and molecular remission or experience molecular failure | after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) | |
| Other | Overall incidence and severity of AEs | Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving ponatinib versus imatinib during induction therapy | during induction therapy (approximately 6 weeks) | |
| Other | Probability of continuous molecular remission | Probability of continuous molecular remission at different time-points of Ponatinib versus Imatinib-based therapy | at 2, 3 and 4 yrs | |
| Other | Measuring log-reduction (kinetic on MRD response) | Measuring log-reduction (kinetic on MRD response) in patients with a Ponatinib versus Imatinib-based therapy | after induction I (3 wks), after induction II (6 wks) and after consolidation I (11 wks) | |
| Other | Probability of MRD response including the induction of complete molecular remission and measurement the log-reduction of MRD | 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 | after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) | |
| Other | Probability of continuous MRD response and molecular remission and duration of molecular remission | 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 | After consolidation 1 approximately every three months | |
| Other | Overall incidence and severity of AEs in patients | Overall incidence and severity of AEs in patients (CTC-AE 4.0) receiving Ponatinib or Imatinib in combination with Blinatumomab and chemotherapy | during each treatment cycle | |
| Other | Probability of continuous MRD response | 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 | at 2, 3 and 4 years | |
| Other | Time to molecular remission | Time to molecular remission measured by time-point of first achievement | after induction I (3 weeks), after induction II (6 weeks) and after consolidation I (11 weeks) | |
| Other | Incidence of TKI dose reductions | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | ||
| Other | Incidence of TKI changes | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | ||
| Other | Incidence of TKI treatment interruptions | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | ||
| Primary | 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 | 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 |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
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