Gilteritinib in Combination With Azacitidine and Venetoclax Compared to Induction Chemotherapy "7+3" in Combination With a FLT3-inhibitor in Fit, Newly Diagnosed, FLT3-ITD Mutated Adult AML Patients: a Randomized Trial of the EORTC Leukemia Group and GIMEMA.
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 230
- 主要终点
- Phase II: Achievement of CR/CRi documented within 6 months from randomization, occurring prior to allografting and before initiation of any post-protocol treatments.
研究概览
简要总结
This international, multicenter, randomized (1:1), open-label phase II/III trial will evaluate the efficacy and safety of gilteritinib combined with azacitidine and venetoclax (experimental arm) versus standard "7+3" induction plus a FLT3inhibitor (quizartinib or midostaurin) (control arm) in newly diagnosed FLT3-ITD mutated AML patients eligible for intensive chemotherapy.
详细描述
Newly diagnosed AML patients deemed fit by the investigator to receive intensive chemotherapy will be screened for FLT3-ITD mutation. Eligible patients will be randomized in a 1:1 ratio between experimental and control arms, stratified by age and WBC at diagnosis:
- Participants assigned to the experimental arm will receive a triplet regimen consisting of VEN, AZA, and gilteritinib, administered for up to 12 cycles. This will be followed by up to 12 additional cycles of AZA in combination with gilteritinib, and subsequently up to 12 cycles of gilteritinib monotherapy
- Participants in the control arm will be treated following the local standard of care, consisting of induction with '7+3', consolidation with high-dose cytarabine, and maintenance with a FLT3 inhibitor (midostaurin, quizartinib, or sorafenib) as per local practice.
Participants in the experimental arm with an available donor should proceed to HSCT based on the local investigator's judgement, but this should not occur prior to the end of cycle 2. For participants in the control group, HSCT is as per the local investigator's judgement, but recommended in first CR/CRi.
For patients with no available donor and not proceeding to HSCT, treatment in the experimental arm is recommended to continue for a minimum of 6 cycles before transitioning to maintenance treatment with AZA and gilteritinib.
Following HSCT, patients in the experimental arm will receive gilteritinib maintenance for up to 36 cycles and in the control arm, FLT3-inhibitor as per local standard of care (i.e., midostaurin, quizartinib or sorafenib).
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed AML cytopathologically confirmed according to the 5th WHO classification
- •Age between 18 and 75 years
- •FLT3-ITD mutation as per local IVDR-compliant testing. Positivity is defined as a FLT3-ITD / FLT3-wild type (WT) ratio of ≥ 0.05 (5%))
- •Eligibility for standard induction chemotherapy
- •ECOG PS ≤ 2
- •WBC ≤25 x 10^9/L (hydroxyurea, leukapheresis or cytarabine in specific clinical circumstances, are allowed to meet this criterion. Please refer to Section 4.1.1 - Inclusion Criteria).
- •Adequate hepatic function (as indicated by total serum bilirubin level ≤2.5 x the institutional upper limit of normal range (UNL), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the investigator; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3 x UNL)
- •Adequate renal function as defined by an eGFR ≥ 30 mL/min according to the 2021 CKD-EPI equation
排除标准
- •Acute promyelocytic leukemia (APL)
- •BCR-ABL positive leukemia or Ph1-positive chronic myeloid leukemia
- •History of myeloproliferative neoplasm (MPN), including myelofibrosis, essential thrombocythemia, polycythemia vera
- •Active central nervous system involvement by AML
- •Active, uncontrolled infection (viral, bacterial or fungal): an infection controlled with an approved or closely monitored antibiotic/antifungal treatment is allowed.
- •HIV, HBV or HCV active infection
- •Grade >3 CTCAE (v. 6) clinically relevant (as per local investigator) adverse events at the time of enrolment
- •Prior treatment for myelodysplastic syndrome (MDS) with Venetoclax or hypomethylating agents (decitabine, azacitidine).
- •Any prior AML therapies (except for emergency treatment with hydroxyurea or cytarabine for hyperleukocytosis) Note: Subjects who undergo diagnostic workup for APL and treatment with all-trans retinoic acid, but who are found not to have APL, are eligible (treatment with all-trans retinoic acid must be discontinued before starting induction chemotherapy).
- •Any prior treatment with a FLT3 inhibitor
- •Serious organ dysfunction as left ventricular ejection fraction <40%, FEV1, FVC, DLCO (diffusion capacity) <40% of predicted
- •Cardiovascular disability status of New York Heart Association class ≥ 2
- •Congenital long QT syndrome or QT Interval Corrected Using Fridericia's Formula (QTcF) >450 msec Note: repeat electrocardiograms after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria. In cases where QTcF >450 msec is considered to be falsely increased due to inaccurate automated reading and not clinically significant (e.g. due to bundle branch block), patients are still eligible if cardiologist reviews and documents that QTcF is ≤ 450 msec when manually measured.
- •Participant with a prior or concurrent malignancy or autoimmune disease requiring immunosuppressive therapy.
- •Note: diseases whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the 2467 medical monitor and the study coordinator.
- •Consumed strong or moderate inducers of Cytochrome P450, family 3, subfamily A (CYP3A) or p-glycoprotein within 14 days of study enrolment or requiring treatment with such a medication during the trial.
- •Inability to swallow and/or any gastrointestinal disorders, malabsorption or other abnormalities that would interfere with absorption of the oral study drug.
- •Other life-threatening concurrent disease.
研究组 & 干预措施
Triplet combination of venetoclax, azacitidine and gilteritinib
Triplet regimen consisting of venetoclax, azacitidine and gilteritinib, administered for up to 12 cycles (28-day cycles). This will be followed by up to 12 additional cycles of azacitidine in combination with gilteritinib (28-day cycles).
干预措施: Gilteritinib (Drug)
Triplet combination of venetoclax, azacitidine and gilteritinib
Triplet regimen consisting of venetoclax, azacitidine and gilteritinib, administered for up to 12 cycles (28-day cycles). This will be followed by up to 12 additional cycles of azacitidine in combination with gilteritinib (28-day cycles).
干预措施: Venetoclax (Drug)
Triplet combination of venetoclax, azacitidine and gilteritinib
Triplet regimen consisting of venetoclax, azacitidine and gilteritinib, administered for up to 12 cycles (28-day cycles). This will be followed by up to 12 additional cycles of azacitidine in combination with gilteritinib (28-day cycles).
干预措施: Azacitidine (AZA) (Drug)
Local standard of care
Local standard of care, consisting of induction with '7+3', consolidation with high-dose cytarabine, and maintenance with a FLT3 inhibitor (midostaurin, quizartinib, or sorafenib) as per local practice.
干预措施: Local standard of care (SOC) (Drug)
结局指标
主要结局
Phase II: Achievement of CR/CRi documented within 6 months from randomization, occurring prior to allografting and before initiation of any post-protocol treatments.
时间窗: Within 6 months from randomization
The European LeukemiaNet (ELN) 2022 criteria will be used to evaluate CR/CRi.
Phase III: Overall survival
时间窗: From baseline through study completion, an average of 7 years
次要结局
- Overall survival (for the phase II component of the trial only)(From baseline through study completion, an average of 7 years)
- High burden of treatment ("Quite a bit" / "Very much") measured by item Q168 from IL471(Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization)
- High burden of illness ("Quite a bit" / "Very much") measured by item Q46 from IL471(Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization)
- Incidence of adverse events(From baseline through study completion, an average of 7 years)
- Deterioration from baseline by ≥10 points in global health status measured by EORTC QLQ-C30(Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization)
- Achievement of CR/CRi documented within 6 months from randomization, occurring prior to allografting and before initiation of any post-protocol treatments (for the phase III component of the trial only)(Within 6 months from randomization)
- Event-free survival(From baseline through study completion, an average of 7 years)
- Deterioration from baseline by ≥10 points in physical functioning measured by EORTC QLQ-C30(Weeks 1, 2, 3, 4, 10 and month 6, 12 and 30 from randomization)
- Deterioration from baseline by ≥10 points in role functioning measured by EORTC QLQ-C30(Weeks 1, 2, 3, 4, 10 and month 6, 12 and 30 from randomization)
- Deterioration from baseline by ≥10 points in fatigue measured by EORTC QLQ-C30(Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization)
- Deterioration from baseline by ≥10 points in pain measured by EORTC QLQ-C30(Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization)