FILOAML-RR-01-OGILAR: Open-label, phase 2 study investigating the efficacy and safety of the addition of oral-azacitidine to salvage treatment by gilteritinib in subjects ≥18 years of age with relapsed/refractory FLT3-mutated acute myeloid leukemia

Prior treatment

• Subjects with any of the following current or previous diagnoses: 1.a. AML secondary to prior myeloproliferative syndrome (MPN) 1.b AML secondary to chronic myelomonocytic leukemia (CMML) 1.c Acute promyelocytic leukemia (APL) and core binding factor (CBF) AML 1.d. DNA fragility or bone marrow (BM) failure syndromes 1.e. Blastic plasmacytoid dendritic cell neoplasm 1.e. Acute lymphoblastic leukemia including ambiguous lineage
• Subjects that have been previously treated by gilteritinib
• Subjects that have been previously treated by oral azacitidine
• Subjects who have received more than 1 prior allogeneic HSCT
• Presence of Grade 2 or above graft-versus-host disease (GVHD), including acute, chronic, or overlap; or escalation of therapy for GVHD within 14 days prior to inclusion
• Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A
• 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
• Patients previously treated by AZA as single agent for AML are not allowed
  • persons deprived of their liberty by judicial or administrative decision, persons subject to a legal protection measure (guardianship, curatorship, legal protection), persons under psychiatric care
• 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

Other illness

• Subject with Positive HIV test (due to potential drug-drug interactions). HIV testing will be performed at screening, if required per local guidelines or institutional standards. Subject known to be positive for hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status with undetectable PCR viral load on antivirals (non-exclusionary medications) are not excluded
• Known hypersensitivity to the study medication
• Severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis or hyperbilirubinemia)
• Subject exhibiting evidence of other clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
• History of another malignancy within the past 3 years except basal cell carcinoma of the skin or cervix in situ carcinoma
• Severe medical or mental condition precluding the administration of protocol treatments

Lab values

• Subject has congestive heart failure classified as New York Heart Association Class III and IV unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
• Subject with mean Fridericia-corrected QT interval (QTcF) > 450 ms at screening
• Subject with a history of Long QT Syndrome at screening
• 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

Other

• Clinically active central nervous system (CNS) leukemia
• Subjects who have relapsed within 100 days after allogeneic HSCT
• Patients ≥ 2nd line of treatment, HSCT being not considered as a line of treatment. Venetoclax-Azacitidine as preemptive treatment for molecular relapse (before morphological relapse) is not considered as 2nd line of treatment.
• Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC).
• Isolated extramedullary leukemia relapse

• Confirmed diagnosis of acute myeloid leukemia (AML) according to world health organization (WHO) 2016 classification
• Patient is suitable for oral administration of study drug.
• A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies: - 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) - 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.
• Patient must be affiliated to the french social security (health insurance)
• Signed written informed consent for the study
• 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
• 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.
• Presence of FLT3-mutation(s) at inclusion: in case of FLT3-ITD, the ITD/wt ratio must be > 0.05 ; in case of FLT3-TKD, the mutation must be at D835 or I836 position with a VAF > 5% by NGS. Pseudonymized results will be uploaded in the eCRF for review by coordinating investigator or sponsor project manager before validation of the patient inclusion.
• Subjects must be primary refractory or relapsed (R/R) to 1st line of treatment for AML. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis. 3a. Primary refractory is defined as no CR or CRi after at least one course of ICT (including “7+3”, gemtuzumab ozogamycin (GO)-based and CPX-351, including or not midostaurine) or two courses (maximum 4) of AZA and venetoclax, or AZA and Ivosidenib as per the investigator’s discretion. 3b. Morphological relapse after 1st line ICT for AML is defined as the first hematologic relapse with bone marrow blasts >5% after one line of treatment for AML that includes at least one course of ICT (one line of treatment for AML can include induction, re-induction, consolidation, allogeneic HSCT and maintenance) 3c. Morphological relapse after 1st line non intensive chemotherapy for AML includes the first hematologic relapse with bone marrow blasts >5% after or during treatment by AZA venetoclax regardless of number of cycles. 3d. Morphological relapse after 1st line non intensive chemotherapy for AML is defined asinclude the first hematologic relapse with bone marrow blasts >5% after or during treatment by AZA ivosidenib regardless of number of cycles
• 1st line treatment may or may not include previous treatment by tyrosine kinase inhibitor (TKI) except gilteritinib.
• Patients who never received previously oral azacitidine
• Age ≥ 18 years
• Adequate baseline organ function defined by the criteria below: - adequate renal function as demonstrated by a creatinine clearance ≥ 50 ml/min; calculated by the Cockcroft gault formula or measured by 24-hours urine collection - aspartate aminotransferase (AST) ≤ 2.5 × ULN - alanine aminotransferase (ALT) ≤ 2.5× ULN - bilirubin ≤ 1.5 × ULN - adequate cardiac function with LVEF ≥45%
• ECOG < 3
• Absence of any psychological, familial, sociological, or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule