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

Официальное название

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)

Обзор

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).

Вмешательства

• Препарат Imatinib
  Imatinib 600mg QD plus Chemotherapy
• Препарат Ponatinib
  Ponatinib 45 mg QD plus chemotherapy
• Препарат Blinatumomab
  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
• Другое Indication 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.

Первичные конечные точки

• OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care) [Срок оценки: up to 4 years from randomization I]

Вторичные конечные точки (1)

• Rate of molecular complete remission at week 11 after consolidation [Срок оценки: week 11 after consolidation]

Критерии участия

Критерии включения

• 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)

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Германия · 85 центров

• Uniklinik RWTH Aachen — Aachen
• Klinikum Aschaffenburg — Aschaffenburg
• Klinikum Augsburg — Augsburg
• Helios Klinikum Bad Saarow — Bad Saarow
• Klinikum Bayreuth — Bayreuth
• Vivantes Klinikum am Urban — Berlin
• Charité Universitätsmedizin Berlin — Berlin
• Vivantes Klinikum Neukölln — Berlin
• … и ещё 77 центров

Публикации

• Davis KL, Yao CC, Zimmerman JAO, Rau RE. Immunotherapy in B-Cell Acute Lymphoblastic Leukemia. J Natl Compr Canc Netw. 2025 Dec;23(12):e257067. doi: 10.6004/jnccn.2025.7067. PMID 41671463

Идентификаторы

NCT: NCT06061094 · GMALL-EVOLVE · 2022-000760-21

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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