Leukemia, Myeloid, Acute
Conditions
Keywords
Acute myeloid leukemia, FLT3 mutation, midostaurin, venetoclax
Brief summary
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.
Detailed description
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.
Interventions
DRUGVenetoclax in association with 3+7 and midostaurin
(1) induction with daunorubicin 60 mg/m²/day for 3 days, cytarabine 200 mg/m²/day for 7 days and MIDO 50 mg x 2/day from D8 to D21, (2) consolidation with 3 courses of intermediate dose cytarabine 1-1.5 gr/m² x 2/day at D1, D2 and D3 and MIDO 50 mg x 2/day from D8 to D21 in 35-day cycles, and (3) a maintenance with MIDO 50 mg x 2/day from D1 to D28 in 28-day cycles for 12 cycles. VEN is a highly potent BCL-2 inhibitor, synergistic with cytarabine, anthracyclines, and tyrosine kinase inhibitors. In the current study we aim at harnessing this synergistic effect with standard chemotherapy (cytarabine, anthracyclines) and tyrosine kinase inhibitor (MIDO) during induction, consolidation and maintenance. Our strategy aims at determining the best schedule of combination during induction chemotherapy whereas we do not foresee specific safety issues during consolidation and maintenance strategy
Sponsors
University Hospital, Bordeaux
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Main inclusion criteria: 1. Age ≥18 years and ≤70 years 2. Newly diagnosed AML according to World Health Organization (WHO) 2022 classification 3. 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%. 4. Patient must be eligible for intensive chemotherapy. Main
Exclusion criteria
1. Prior treatment for AML or myelodysplastic (MDS) phase. 2. Prior exposure to VEN or other BCL2 inhibitors 3. AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML. 4. Acute promyelocytic leukemia, CBF-AML, Phi+ AML 5. Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia's formula (QTcF) ≥ 450 msec. 6. Cardiac ejection fraction \<45%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum tolerated schedule (MTS) of VEN in combination with 3+7+MIDO to define the recommended phase 2 schedule (RP2S). | 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) | From day 1 of induction chemotherapy up to 8 weeks | Measured by multiparameter flow cytometry (MFC) according to European Leukemia Net (ELN) 2022 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Number of participants with Dose Limiting Toxicities (DLTs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to treatment discontinuation, defined according to the NCI CTCAE v5 |
| 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: 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 1-2: 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 | Number of participants experiencing at least one treatment-related adverse event, or at least one serious treatment-related adverse event, , defined according to the NCI CTCAE v5 |
| 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 | Number of participants experiencing at least one adverse event that led to discontinuation of treatment, defined according to the NCI CTCAE v5 |
| 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 | Measured by MFC according to ELN2022 and with a sensitivity at 10-4 or limit of detection (LOD) |
| 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 | Measured by MFC according to ELN2022 and with a sensitivity at 10-4 or LOD |
| 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 | Measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup |
| 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 | Measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup |
| 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 | Measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup |
| Overall survival (OS) | From day 1 of inclusion until the date of end of study or to the date of death from any cause | Time from start of treatment to death due to 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 | From day 1 of inclusion to the date of treatment failure, hematologic relapse from CR/CRh/CRi or death from any cause, whichever occurs first (ELN 2022 criteria). MRD relapse is also considered as an event for EFSMRD |
| 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 | Defined only for patients achieving CR, CRh, or CRi; measured from the date of achievement of remission until the date of hematologic relapse or death from any cause (ELN 2022 criteria). MRD relapse is also considered as an event for RFSMRD |
| 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 | Defined for all patients achieving CR, CRh, CRi; measured from the date of achievement of a remission until the date of hematologic relapse (ELN 2022 criteria). MRD relapse is also considered as an event for CIRMRD |
| 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 | During induction, plasma samples will be collected at the following time points for VEN treatment: Pre-dose, 1, 2, 4, and a last one between 6- and 8-hours post-dose at D14 for schedule A, at D10 for schedule B, at D17 forschedule C and D13 for schedule D At each consolidation, only pre-dose at D14 of each consolidation cycle During maintenance, only pre-dose at D14 of 2nd, 3rd and 4th maintenance cycles |
| 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 | During induction, plasma samples will be collected at the following time points for MIDO treatment: Pre-dose, 1, 2, 4, and a last one between 6- and 8-hours post-dose at D21 of induction At each consolidation, only pre-dose at D14 or D15 or D16 of each consolidation cycle, During maintenance, only pre-dose at D1 of 2nd, 3rd and 4th maintenance cycles |
Countries
France
Contacts
CONTACTPierre-Yves DUMAS, PU-PH
CONTACTSarah BERTOLI
Outcome results
None listed