Gilteritinib-Azacitidine-Venetoclax Combination Therapy in Patients With Relapsed/Refractory Leukemia

Prior treatment

• Currently considered as eligible for intensive chemotherapy treatment in the opinion of the Investigator
• Localized breast or prostate cancer receiving androgen deprivation therapy
• A previously treated malignancy that is considered cured with minimal risk of recurrence
• Extramedullary disease without concomitant marrow based disease (blasts ≤5%)
• Any comorbidity that the investigator believes would be incompatible with safe receipt or therapy
• Unable or unwilling to use Health Canada-approved highly effective methods of contraception (i.e., hormonal contraceptives, vasectomy, tubal ligation, or double-barrier method), or abstinence while on the trial and for at least 6 months following the last dose of trial drugs.
  • Waivers to the exclusion criteria will NOT be allowed.

Other illness

• Renal function: estimated glomerular filtration rate of \< 30 mL/min as calculated by the Modification of Diet in Renal Disease equation.
• Active solid organ malignancy requiring treatment in the last 24 months, with the exception of:
• Treated nonmelanoma skin cancer
• Uncontrolled, active infection or untreated hepatitis B, C, or HIV
• Known allergy or intolerance to azacitidine, venetoclax, or gilteritinib

Lab values

• Liver function: Serum aspartate aminotransferase and alanine aminotransferase ≥ 2.5 x upper limit of normal (ULN) and total bilirubin ≥ 1.5 x ULN
• Cardiac function: New York Heart Association (NYHA) class 3 or 4 heart failure or known history of left ventricular ejection fraction ≤ 40% or known history of prolonged QTc syndrome
• Corrected QTc of \> 450ms that is not corrected on repeat electrocardiogram (ECG) testing

Other

• Participants are excluded from the trial if any of the following criteria apply:
• Diagnosis of acute promyelocytic leukemia (APL), BCR-ABL positivity, or favorable risk AML
• Inadequate organ function, defined as:
• Active and untreated CNS leukemia
• Completely treated breast carcinoma that is considered cured
• Completely treated cervical carcinoma that is considered cured
• Inability to comply with requirements of the trial protocol
• Pregnancy or breastfeeding

• Participants must meet all the following inclusion criteria to be eligible for participation in this trial.
• Age ≥ 18 years old at the time of informed consent.
• Pathologically confirmed diagnosis of AML previously treated with azacitidine and venetoclax that are azacitidine and venetoclax-refractory, defined as:
• Primary refractory: Defined as no complete remission (CR) or CR with incomplete recovery (CRi) following at least 2 cycles of azacitidine and venetoclax with AML blasts ≥5% in the bone marrow, or
• Relapsed: Defined as recurrence of AML blasts ≥5% in the bone marrow after a previous CR or CRi to azacitidine and venetoclax
• Confirmed to be negative for FLT3- internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations on repeat clinical testing following their last line of therapy
• Adequate functional status (ECOG ≤ 2)
• Participant is willing to provide informed consent and comply with trial procedures
• Participants of either biological sex must be able and willing to use Health-Canada approved effective contraception methods starting 2-weeks prior to trial treatment, throughout the trial, and for 6 months following the last dose of trial drugs
• For participants of child-bearing potential (menstruation within \<2 years): negative serum pregnancy test within 14-days prior to enrollment.
• Not currently breastfeeding and will not breastfeed while on the trial and for at least 2 months following the last trial dose.
  • Waivers to the inclusion criteria will NOT be allowed.