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

Prior treatment

• 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
• Concurrent malignancy likely to affect treatment safety or study procedures
• 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)
• Subject has received CYP3A inhibitors such as fluconazole, ketoconazole, and clarithromycin within 5 days prior to the initiation of study treatment
• 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
• 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
• Prior treatment for AML or myelodysplastic (MDS) phase
• 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
• Prior exposure to VEN or other BCL2 inhibitors
• AML secondary to prior hematological disorders, including myelodysplastic syndrome, myeloproliferative disorders and/or therapy-related AML

Other illness

• Any serious medical condition which the investigator feels may lead to an unacceptably high risk of treatment-related death from 7+3 induction
• Subject with positive HIV test due to potential drug-drug interactions
• Uncontrolled viral hepatitis type B or C
• Severe medical or mental condition precluding the administration of protocol treatments
• 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
• Known hypersensitivity to the study medication
• Prior anthracycline exposure for previous cancer

Lab values

• Cardiac ejection fraction <45%
• 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
• Significant active cardiac disease within 6 months prior to the start of study treatment or QTc interval using Fridericia’s formula (QTcF) ≥ 450 msec
• Subject with a history of Long QT Syndrome

Age

• 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

Other

• Central nervous system (CNS) leukemia
• Acute promyelocytic leukemia, CBF-AML, Phi+ AML

• Age ≥18 years and ≤70 years
• 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
• Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration
• 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
• 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
• Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration
• Newly diagnosed AML according to World Health Organization (WHO) 2022 classification
• 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%.
• Patient must be affiliated to the French social security (health insurance)
• Patient must have signed written informed consent for the study
• Patient must be eligible for intensive chemotherapy
• ECOG performance status 0-2
• 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)
• Adequate renal function as defined by eGFR>50 ml/min as assessed by eCCr