Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Conditions
Keywords
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia, Tyrosinekinase Inhibitors, Blinatumomab
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).
Interventions
DRUGImatinib
Imatinib 600mg QD plus Chemotherapy
DRUGPonatinib
Ponatinib 45 mg QD plus chemotherapy
DRUGBlinatumomab
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
OTHERIndication 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.
Sponsors
Deutsche Leukämie- & Lymphom-Hilfe
German Federal Ministry of Education and Research
Goethe University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Incidence of TKI changes | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | — |
| 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 |
| 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 |
| Incidence of TKI treatment interruptions | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | — |
| Incidence of TKI dose reductions | for each cycle - approximately 28 days each - number of cycles depends on treatment arm | — |
| Probability of remission duration | at 2 years, 3 years, 4 yrs | Probability of remission duration |
Countries
Germany
Contacts
Primary ContactNicola Goekbuget, MD
Backup ContactFabian Lang, MD
Outcome results
None listed