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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Bordeaux

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-05-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministère de la Santé [Ministry of Health] (PHRC-I, 2023)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

- To identify the maximum tolerated schedule (MTS) of VEN in combination with 3+7+MIDO during induction and to define the recommended phase 2 schedule (RP2S)

- To estimate the proportion of participants with CR/CRi without MRD, after induction chemotherapy with the RP2S, measured by multiparameter flow cytometry (MFC) according to European Leukemia Net (ELN) 2022

Secondary objectives 20

1. To describe the incidence of Dose Limiting Toxicities (DLTs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to treatment discontinuation, in induction, consolidation and maintenance
2. To describe pharmacokinetics (PK) of VEN, MIDO and MIDO metabolites CPG52421 and CPG62221 at various schedules during induction and during consolidation and maintenance
3. To estimate safety and tolerance of the combination of 3+7+MIDO+VEN in induction, combination of IDAC+MIDO+VEN in consolidation and MIDO+VEN in maintenance
4. To estimate the 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)
5. To estimate the proportion of participants with CR, CRi, CRh, MLFS, PR, no response, non-evaluable for response after induction chemotherapy with the RP2S, according to ELN2022
6. To estimate the 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
7. To estimate the 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
8. To estimate the 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
9. To estimate the 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
10. To estimate the 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
11. To estimate the 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
12. To estimate the 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
13. To estimate the overall survival
14. To estimate the event-free survival (EFS) and EFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (EFSMRD)
15. To estimate the relapse-free survival (RFS), and RFS including MRD relapse (RT-qPCR on NPM1 and/or NGS FLT3-ITD and/or MFC) as event (RFSMRD)
16. To estimate the 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)
17. To estimate the proportion of participants with HSCT performed in CR/CRi in eligible patients
18. To estimate the proportion of participants with HSCT performed in CR/CRi/CRh in eligible patients
19. To estimate the proportion of participants with HSCT performed in CR/CRi/CRh/MLFS in eligible patients
20. To describe PK of VEN, MIDO and MIDO metabolites CPG52421 and CPG62221 at the RP2S

Conditions and MedDRA coding

FLT3-mutated Acute Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

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) 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%.
4. Patient must be affiliated to the French social security (health insurance)
5. Patient must have signed written informed consent for the study
6. Patient must be eligible for intensive chemotherapy
7. ECOG performance status 0-2
8. 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)
9. Adequate renal function as defined by eGFR>50 ml/min as assessed by eCCr
10. 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
11. Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration
12. 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
13. 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
14. Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration

Exclusion criteria 24

1. 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
2. Prior treatment for AML or myelodysplastic (MDS) phase
3. Central nervous system (CNS) leukemia
4. Prior exposure to VEN or other BCL2 inhibitors
5. Prior anthracycline exposure for previous cancer
6. AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML
7. Acute promyelocytic leukemia, CBF-AML, Phi+ AML
8. Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia’s formula (QTcF) ≥ 450 msec
9. Subject with a history of Long QT Syndrome
10. Any serious medical condition which the investigator feels may lead to an unacceptably high risk of treatment-related death from 7+3 induction
11. Concurrent malignancy likely to affect treatment safety or study procedures
12. Subject with positive HIV test due to potential drug-drug interactions
13. Uncontrolled viral hepatitis type B or C
14. Cardiac ejection fraction <45%
15. 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)
16. Subject has received CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin within 5 days prior to the initiation of study treatment
17. 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
18. 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
19. 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
20. 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
21. Severe medical or mental condition precluding the administration of protocol treatments
22. 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
23. 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
24. Known hypersensitivity to the study medication

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Proportion of participants with DLTs during the induction phase of VEN in combination with 3+7+MIDO
2. 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)

Secondary endpoints 22

1. Proportion of participants with, and mean number of, DLT, SAE and AE leading to treatment discontinuation
2. 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
3. Proportion of participants with AEs and SAEs during induction
4. Proportion of participants with AEs and SAEs during consolidation
5. Proportion of participants with AEs and SAEs during maintenance
6. 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)
7. Proportion of participants with CR, CRi, CRh, MLFS, PR, no response, non-evaluable for response after induction chemotherapy with the RP2S, according to ELN2022
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. Proportion of participants with HSCT performed in CR/CRi in eligible patients
20. Proportion of participants with HSCT performed in CR/CRi/CRh in eligible patients
21. Proportion of participants with HSCT performed in CR/CRi/CRh/MLFS in eligible patients
22. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Bordeaux

Sponsor organisation

Centre Hospitalier Universitaire De Bordeaux

Address

12 Rue Dubernat

City

Talence

Postcode

33400

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Coordinating Investigator

Public contact point

Organisation

Centre Hospitalier Universitaire De Bordeaux

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications