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

Goethe University

Status and phase: Enrolling; Phase 2

Conditions: Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Treatments: Drug: Ponatinib; Drug: Imatinib; Drug: Blinatumomab; Other: Indication for stem cell transplantation

Study type: Interventional

Funder types: Other

Identifiers

NCT06061094

2022-000760-21 (EudraCT Number)

GMALL-EVOLVE

Details and patient eligibility

About

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).

Enrollment: 220 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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220 participants in 5 patient groups

A: Imatinib + low dose chemotherapy

Active Comparator group

Description:

Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I)

Treatment:

Drug: Imatinib

B: Ponatinib + low dose chemotherapy

Experimental group

Description:

Ponatinib 45mg QD (reduction to 30mg QD after Induction) + low dose chemotherapy induction and consolidation I (Experimental Arm of Randomization I)

Treatment:

Drug: Ponatinib

C: Molecular CR: End of therapy with indication for SCT

Active Comparator group

Description:

Molecular CR: End of therapy with indication for SCT (Standard Arm of Randomization II)

Treatment:

Other: Indication for stem cell transplantation

D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab

Experimental group

Description:

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)

Treatment:

Drug: Blinatumomab

Drug: Ponatinib

Drug: Imatinib

E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina

Experimental group

Description:

Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)

Treatment:

Other: Indication for stem cell transplantation

Drug: Blinatumomab

Drug: Ponatinib

Drug: Imatinib