Phase 1/2 Evaluating the Addition of Venetoclax to Standard 3+7 and Midostaurin Induction Treatment in Patients With FLT3-mutated Acute Myeloid Leukemia Eligible to Intensive Chemotherapy - MIDOVEN
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 41
- 试验地点
- 3
- 主要终点
- Phase 1: Maximum tolerated schedule (MTS) of VEN in combination with 3+7+MIDO to define the recommended phase 2 schedule (RP2S).
研究概览
简要总结
Acute myeloid leukemia (AML) with FLT3 mutation accounts for 30% of patients and is associated with a poor prognosis. Because of the FLT3 mutation, a tyrosine kinase inhibitor, midostaurin (MIDO), is added to the standard treatment with daunorubicin and cytarabine, from D8 to D21 of induction and of each consolidation cycle, followed by one year of maintenance. Venetoclax (VEN), a BCL2 inhibitor, has revolutionized the management of AML patients ineligible for intensive chemotherapy, in combination with azacitidine or cytarabine. The investigators hypothesize that a four-drug induction regimen (daunorubicin+cytarabine+MIDO+VEN) will increase complete remission (CR) rate without measurable residual disease (MRD) and improve event free survival (EFS), relapse free survival (RFS) and overall survival (OS) of this subgroup of patients with unmet medical need.
详细描述
Screening of 226 clinical trials on ClinTrial.gov showed 26 studies evaluating intensive chemotherapy (daunorubicin+cytarabine) and VEN but none in combination with MIDO even though 30% of patients eligible for intensive chemotherapy do receive such a regimen. Intensive chemotherapy and MIDO showed a significant median overall survival improvement but a moderate increase of patients still alive at 3 years, around an additional 10% 1. Moreover, MIDO does not allow an increase in proportion of patients in first complete remission (CR1) or CR with incomplete hematologic recovery (CRi1) after the 1st induction course. Another study with a second-generation tyrosine kinase inhibitor, quizartinib (QuANTUM-First) showed that among patients with CR1/CRi1, 42% had a measurable residual disease (MRD) <10-4 in quizartinib arm versus 38% in placebo arm, despite, here again, a significant median overall survival improvement 2. These data show that tyrosine kinase inhibitors do not increase the rate of complete remission (CR) without MRD, explaining probably the moderate improvement of definitive cure rate. The investigators hypothesize that adding VEN to this standard treatment will increase complete remission rate without MRD and improve OS of patients with FLT3-mutated AML. Two clinical trials evaluated VEN in AML patients eligible to intensive chemotherapy and showed high levels of complete remission without MRD and a manageable toxicity profile, related to VEN start date and duration of exposure 3,4. In the current study, the investigators propose the following schedule to find the best treatment sequence while preventing the risk of myelosuppression, based on available data from the two clinical trials previously presented: In schedule A, VEN will be used from D8 to D14 to harness the synergy between FLT3 and BCL2 inhibition; in schedule B, VEN will be used from D4 to D10 to harness the synergy between chemotherapy and BCL2 inhibition then between FLT3 and BCL2 inhibition. If previous schedules A and B are safe, the investigators propose to prolong VEN exposure to 10 days allowing longer association between MIDO and VEN with a schedule C with VEN from D8 to D17 and finally a schedule D with VEN from D4 to D13. Follow-up will include up to 3 consolidation courses with intermediate dose cytarabine and VEN according to previous French phase 2 clinical trial COVENIDAC 5 and MIDO in this label from D8 to D21. Finally, patients will receive 12 cycles maintenance by MIDO with VEN D1-D14 in 28-day cycles. Patients will undergo allogeneic stem cell transplantation (HSCT) according to standard indications and procedures.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Main inclusion criteria:
- •Age ≥18 years and ≤70 years
- •Newly diagnosed AML according to World Health Organization (WHO) 2022 classification
- •Documented FLT3 gene mutation (-TKD D835 or I836 or -ITD or both) FLT3-ITD is assessed by DNA fragment analysis. Positivity is defined as an ITD/wt ratio of ≥ 0.05 (5%).
- •FLT3-TKD D835 or I836 is assessed by NGS. Positivity is defined as a VAF > 5%.
- •Patient must be eligible for intensive chemotherapy.
排除标准
- •Prior treatment for AML or myelodysplastic (MDS) phase.
- •Prior exposure to VEN or other BCL2 inhibitors
- •AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML.
- •Acute promyelocytic leukemia, CBF-AML, Phi+ AML
- •Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia's formula (QTcF) ≥ 450 msec.
- •Cardiac ejection fraction <45%
结局指标
主要结局
Phase 1: Maximum tolerated schedule (MTS) of VEN in combination with 3+7+MIDO to define the recommended phase 2 schedule (RP2S).
时间窗: From day 1 of induction chemotherapy up to 8 weeks
Phase 2: Proportion of participants with complete remission (CR)/CR with incomplete hematologic recovery (CRi) without measurable residual disease (MRD)
时间窗: From day 1 of induction chemotherapy up to 8 weeks
Measured by multiparameter flow cytometry (MFC) according to European Leukemia Net (ELN) 2022
次要结局
- Phase 1-2: Peak concentration (Cmax)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Time to reach peak concentration (Tmax)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1:Number of participants with Dose Limiting Toxicities (DLTs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to treatment discontinuation(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Area under the concentration-time curve over a 12-hour dosing interval (- AUC 0-12h)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Through concentration (Cmin)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Steady-state accumulation ratios of AUC 0-12h(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Steady-state accumulation ratios of Cmax(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Area under the plasma concentration-time profile from time zero to time tau (AUCtau)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Area under the concentration-time curve extrapolated to infinity (AUCinf)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1: Half time (T1/2)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Oral clearance (CL/F)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Volume or volume/kg (Vz/F)(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 2: Number of participants experiencing at least one treatment-related adverse event, or at least one serious treatment-related adverse event(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 2: Number of participants experiencing at least one adverse event that led to discontinuation of treatment(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- Phase 1-2: Proportion of participants with complete remission (CR)/CR with incomplete hematologic recovery (CRi) without measurable residual disease (MRD)(Day 1 of Consolidation 2, day 1 of consolidation 3 , day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, day 1 of maintenance cycle 7, day 1 of maintenance cycle 10 and day 28 of maintenance cycle 12)
- Proportion of participants with complete remission (CR), CR with incomplete hematologic recovery (Cri), CR with partial hematological recovery (CRh), morphologic leukemia free state (MLFS), partial response (PR), no response, non-evaluable for response(From day 1 of induction chemotherapy up to 8 weeks)
- Proportion of participants with CR/CRi/CRh without MRD(Day 1 of Consolidation 2, day 1 of consolidation 3, day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, day 1 of maintenance cycle 7, day 1 of maintenance cycle 10 and day 28 of maintenance cycle 12)
- Proportion of participants with CR/CRi without MRD(From day 1 of induction chemotherapy up to 8 weeks, day 1 of Consolidation 2, day 1 of consolidation 3, day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, cycle 7, cycle 10 and day 28 of maintenance cycle 12)
- Proportion of participants with CR/CRi/CRh without MRD(From day 1 of induction chemotherapy up to 8 weeks, day 1 of Consolidation 2, day 1 of consolidation 3, day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, cycle 7, cycle 10 and day 28 of maintenance cycle 12)
- Proportion of participants with CR/CRi with MRD low-level (MRDLL)(From day 1 of induction chemotherapy up to 8 weeks, day 1 of Consolidation 2, day 1 of consolidation 3, day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, cycle 7, cycle 10 and day 28 of maintenance cycle 12)
- Proportion of participants with CR/CRi/CRh with MRDLL(From day 1 of induction chemotherapy up to 8 weeks, day 1 of Consolidation 2, day 1 of consolidation 3, day 28 of consolidation 3, day 1 of maintenance cycle 1, day 1 of maintenance cycle 4, cycle 7, cycle 10 and day 28 of maintenance cycle 12)
- Overall survival (OS)(From day 1 of inclusion until the date of end of study or to the date of death from any cause)
- Event-free survival (EFS) and EFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (EFSMRD)(From date of day 1 of induction chemotherapy until the date of first documented progression, including molecular progression or date of death from any cause, whichever came first, assessed up to 24 months)
- Relapse-free survival (RFS), and RFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (RFSMRD)(From date of CR until the date of first documented progression, including molecular progression or date of death from any cause, whichever came first, assessed up to 24 months)
- Cumulative incidence of relapse (CIR), and CIR including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (CIRMRD)(From date of CR until the date of first documented progression, including molecular progression assessed up to 24 months)
- Proportion of participants with HSCT performed in CR/CRi in eligible patients(From date of CR until the date of first documented progression, including molecular progression assessed up to 24 months)
- Proportion of participants with HSCT performed CR/CRi/CRh in eligible patients(From date of CR until the date of first documented progression, including molecular progression assessed up to 24 months)
- Proportion of participants with HSCT performed in CR/CRi/CRh/MLFS in eligible patients(From date of CR until the date of first documented progression, including molecular progression assessed up to 24 months)
- To describe PK of VEN(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)
- To describe MIDO and MIDO metabolites CPG52421 and CPG62221 at the RP2S(From day 1 of induction chemotherapy up to 8 weeks, then from day 1 of each of 3 consolidation chemotherapy up to 8 weeks and from day 1 of first maintenance cycle up to 12 months)