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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 220
- 试验地点
- 85
- 主要终点
- OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
A: Imatinib + low dose chemotherapy
Imatinib 600mg QD + low dose chemotherapy induction and consolidation I (Standard Arm of Randomization I)
干预措施: Imatinib (Drug)
B: Ponatinib + low dose chemotherapy
Ponatinib 45mg QD (reduction to 30mg QD after Induction) + low dose chemotherapy induction and consolidation I (Experimental Arm of Randomization I)
干预措施: Ponatinib (Drug)
C: Molecular CR: End of therapy with indication for SCT
Molecular CR: End of therapy with indication for SCT (Standard Arm of Randomization II)
干预措施: Indication for stem cell transplantation (Other)
D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab
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)
干预措施: Imatinib (Drug)
D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab
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)
干预措施: Ponatinib (Drug)
D: Molecular CR: continuation with Imatinib/Ponatinib (per Rando I), chemotherapy and Blinatumomab
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)
干预措施: Blinatumomab (Drug)
E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina
Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)
干预措施: Imatinib (Drug)
E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina
Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)
干预措施: Ponatinib (Drug)
E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina
Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)
干预措施: Blinatumomab (Drug)
E: Mol Fail / Mol NE: Continuation with Imatinib/Ponatinib (per Rando I) and addition of Blina
Molecular Failure / Molecular Not Evaluable: Continuation with Imatinib/Ponatinib (per Randomization I) and addition of Blinatumomab (Experimental Arm)
干预措施: Indication for stem cell transplantation (Other)
结局指标
主要结局
OS in MolCR patients treated with TKI-Chemo-Blina versus (vs) EOT with indication for SCT (Standard of Care)
时间窗: 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
次要结局
- Rate of molecular complete remission at week 11 after consolidation(week 11 after consolidation)
研究者
Nicola Goekbuget
Dr. Nicola Gökbuget
Goethe University