VENETOCLAX for Acute myeloid leukemia (FLT3-mutated)

Inclusion criteria

• {"criterion_text":"- Age ≥18 years and ≤70 years\n- A male subject with female partner(s) of childbearing potential must agree to use contraception starting at screening and continue throughout the study period, for at least 120 days after the final study drug administration\n- Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration\n- A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented as surgically sterile (at least 1 month prior to Screening) b. WOCBP agrees to follow the contraceptive treatment starting at screening and continue throughout the study period, and for at least 180 days after the final study drug administration\n- Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration\n- Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration\n- Newly diagnosed AML according to World Health Organization (WHO) 2022 classification\n- Documented FLT3 gene mutation (-TKD D835 or I836 or -ITD or both) a. FLT3-ITD is assessed by DNA fragment analysis. Positivity is defined as an ITD/wt ratio of ≥ 0.05 (5%). b.FLT3-TKD D835 or I836 is assessed by NGS. Positivity is defined as a VAF > 5%.\n- Patient must be affiliated to the French social security (health insurance)\n- Patient must have signed written informed consent for the study\n- Patient must be eligible for intensive chemotherapy\n- ECOG performance status 0-2\n- Adequate hepatic function as defined by bilirubin ≤ 1.5 x the upper limit of normal (ULN, excluding Gilbert’s syndrome) and AST & ALT ≤ 2.5 x ULN (unless due to leukemic involvement)\n- Adequate renal function as defined by eGFR>50 ml/min as assessed by eCCr"}

Exclusion criteria

• {"criterion_text":"- Prior anti-leukemia agents, investigational or not, within 14 days of day 1 of study drug; demethylating agents within 14 days of day 1 of study drug. Hydroxyurea is allowed for the control of peripheral leukemic blasts\n- Any serious medical condition which the investigator feels may lead to an unacceptably high risk of treatment-related death from 7+3 induction\n- Concurrent malignancy likely to affect treatment safety or study procedures\n- Subject with positive HIV test due to potential drug-drug interactions\n- Uncontrolled viral hepatitis type B or C\n- Cardiac ejection fraction <45%\n- Subject has received the following within 7 days prior to the initiation of study treatment: a. Potent CYP3A inducers such as rifampicin, carbamazepine, phenytoin, and St. John's wort. b. Warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect)\n- Subject has received CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin within 5 days prior to the initiation of study treatment\n- Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the subject\n- Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Starfruit within 3 days prior to the initiation of study treatment\n- Subject has a history of other malignancies prior to study entry, except for: a. dequately treated in situ carcinoma of the breast or cervix uteri b. Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin c. Prior malignancy treated >2 years ago and no evidence of active disease\n- Prior treatment for AML or myelodysplastic (MDS) phase\n- Any other serious medical condition, laboratory abnormalities or psychiatric illness that would place the participant at an unacceptable risk or prevent them from giving informed consent\n- Severe medical or mental condition precluding the administration of protocol treatments\n- People deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care\n- Other comorbidity that the physician judges to be incompatible with conventional intensive chemotherapy which must be reviewed and approved by the study medical monitor before study enrolment\n- Known hypersensitivity to the study medication\n- Central nervous system (CNS) leukemia\n- Prior exposure to VEN or other BCL2 inhibitors\n- Prior anthracycline exposure for previous cancer\n- AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML\n- Acute promyelocytic leukemia, CBF-AML, Phi+ AML\n- Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia’s formula (QTcF) ≥ 450 msec\n- Subject with a history of Long QT Syndrome"}

Primary endpoints

• {"endpoint_text":"- Proportion of participants with DLTs during the induction phase of VEN in combination with 3+7+MIDO","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with CR/CRi without MRD, after induction chemotherapy with the RP2S, measured by MFC according to ELN2022 (evaluated as soon as possible after hematological recovery or up to D56)","definition_or_measurement_approach":"Measured by multiparameter flow cytometry (MFC) according to European Leukemia Net (ELN) 2022; evaluated as soon as possible after hematological recovery or up to Day 56."}

Secondary endpoints

• {"endpoint_text":"- Proportion of participants with, and mean number of, DLT, SAE and AE leading to treatment discontinuation","definition_or_measurement_approach":""}
• {"endpoint_text":"- Plasma PK profile and corresponding parameters of VEN, MIDO and MIDO metabolites CPG52421 and CPG62221 include area under the concentration-time curve over a 12-hour dosing interval (AUC0–12h), peak concentration (Cmax), time to reach Cmax (Tmax), trough concentration (Cmin), and steady-state accumulation ratios of AUC0-12h and Cmax. If appropriate AUCtau, AUCinf, T1/2, CL/F, Vz/F will be determined","definition_or_measurement_approach":"PK parameters measured from plasma samples: AUC0–12h, Cmax, Tmax, Cmin, accumulation ratios; when appropriate AUCtau, AUCinf, T1/2, CL/F, Vz/F."}
• {"endpoint_text":"- Proportion of participants with AEs and SAEs during induction","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with AEs and SAEs during consolidation","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with AEs and SAEs during maintenance","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with CR/CRi without MRD, after consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by MFC according to ELN2022 and with a sensitivity at 10-4 or limit of detection (LOD)","definition_or_measurement_approach":"Measured by MFC according to ELN2022 with sensitivity at 10^-4 or LOD."}
• {"endpoint_text":"- Proportion of participants with CR, CRi, CRh, MLFS, PR, no response, non-evaluable for response after induction chemotherapy with the RP2S, according to ELN2022","definition_or_measurement_approach":"Response categories defined per ELN2022."}
• {"endpoint_text":"- Proportion of participants with CR/CRi/CRh without MRD, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by MFC according to ELN2022 and with a sensitivity at 10-4 or LOD","definition_or_measurement_approach":"Measured by MFC according to ELN2022 with sensitivity at 10^-4 or LOD."}
• {"endpoint_text":"- Proportion of participants with CR/CRi without MRD, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup","definition_or_measurement_approach":"Measured by RT-qPCR on NPM1 in the FLT3+NPM1 co-mutated subgroup."}
• {"endpoint_text":"- Proportion of participants with CR/CRi/CRh without MRD, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup","definition_or_measurement_approach":"Measured by RT-qPCR on NPM1 in the FLT3+NPM1 co-mutated subgroup."}
• {"endpoint_text":"- Proportion of participants with CR/CRi with MRD low-level (MRDLL), after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup","definition_or_measurement_approach":"Measured by RT-qPCR on NPM1 (MRD low-level) in FLT3+NPM1 co-mutated subgroup."}
• {"endpoint_text":"- Proportion of participants with CR/CRi/CRh with MRDLL, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by RT-qPCR on NPM1 in co-mutated FLT3 and NPM1 subgroup","definition_or_measurement_approach":"Measured by RT-qPCR on NPM1 in FLT3+NPM1 co-mutated subgroup."}
• {"endpoint_text":"- Proportion of participants with CR/CRi without MRD, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by NGS on FLT3 in FLT3-ITD subgroup","definition_or_measurement_approach":"Measured by NGS on FLT3 in FLT3-ITD subgroup."}
• {"endpoint_text":"- Proportion of participants with CR/CRi/CRh without MRD, after induction chemotherapy with the RP2S, consolidation 1, consolidation 2, consolidation 3, HSCT, maintenance 3, maintenance 6, maintenance 9 and maintenance 12, measured by NGS on FLT3 in FLT3-ITD subgroup","definition_or_measurement_approach":"Measured by NGS on FLT3 in FLT3-ITD subgroup."}
• {"endpoint_text":"- OS is defined for all patients in a trial; measured from day 1 of inclusion to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive according to ELN 2022","definition_or_measurement_approach":"Overall survival measured from Day 1 of inclusion to date of death; censoring per ELN 2022."}
• {"endpoint_text":"- Event-free survival (EFS) and EFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (EFSMRD) are defined according to ELN 2022","definition_or_measurement_approach":"EFS defined per ELN 2022; EFSMRD includes MRD relapse detected by RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC as events."}
• {"endpoint_text":"- Relapse-free survival (RFS), and RFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (RFSMRD) are defined according to ELN 2022","definition_or_measurement_approach":"RFS defined per ELN 2022; RFSMRD includes MRD relapse detected by RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC as events."}
• {"endpoint_text":"- 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) are defined according to ELN 2022","definition_or_measurement_approach":"CIR defined per ELN 2022; CIRMRD includes MRD relapse as specified."}
• {"endpoint_text":"- Proportion of participants with HSCT performed in CR/CRi in eligible patients","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with HSCT performed in CR/CRi/CRh in eligible patients","definition_or_measurement_approach":""}
• {"endpoint_text":"- Proportion of participants with HSCT performed in CR/CRi/CRh/MLFS in eligible patients","definition_or_measurement_approach":""}
• {"endpoint_text":"- Plasma PK profile and corresponding parameters of VEN, MIDO and MIDO metabolites CPG52421 and CPG62224 include area under the concentration-time curve over a 12-hour dosing interval (AUC0–12h), peak concentration (Cmax), time to reach Cmax (Tmax), through concentration (Cmin), and steady-state accumulation ratios of AUC0-12h and Cmax. If appropriate AUCtau, AUCinf, T1/2, CL/F, Vz/F will be determined","definition_or_measurement_approach":"PK parameters measured from plasma samples: AUC0–12h, Cmax, Tmax, Cmin, accumulation ratios; where appropriate AUCtau, AUCinf, T1/2, CL/F, Vz/F."}

France

Earliest CTIS Part Ii Submission Date

16-04-2026

Latest Decision Or Authorization Date

13-05-2026

Processing Time Days

27

Number Of Sites

3

Number Of Participants

41

Primary sponsor

Full Name

Centre Hospitalier Universitaire De Bordeaux

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France