| Eligibility |
Inclusion Criteria:
- Patients at least 18 years of age will be considered for inclusion without bias
against gender identity, race, or ethnicity
- Ability to comprehend the investigational nature of the study and provide written
informed consent
- Patients with previously untreated, morphologically documented AML based on World
Health Organization (WHO) 2008 definitions who are ineligible for standard of care
(SOC) intensive chemotherapy induction and also meet the following criteria:
- Documented intermediate- or adverse-risk AML based on European Leukemia Network
(ELN) 2022 criteria
- Note: Cases of AML/myelodysplastic syndrome (MDS) overlap with 10-19% bone marrow
(BM) or peripheral blood (PB) blasts will be considered
- Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1 fusions
will be excluded
- Eastern Cooperative Oncology Group (ECOG) performance = 2 (Patients aged = 75 years,
at the time of consent)
- Total bilirubin = 1.5 x upper limit of normal (ULN) (Patients aged = 75 years, at the
time of consent)
- High total bilirubin values may require indirect and direct bilirubin testing.
Individuals with known Gilbert's syndrome may be considered for enrollment
despite high indirect (and total) bilirubin
- Creatinine clearance (CrCl) of = 60 mL/min (estimated using the Cockcroft Gault
formula or measured by 24 hours urine collection) (Patients aged = 75 years, at the
time of consent)
- Patients aged = 18 to 74 years (ECOG performance status [PS] = 3 is accepted) at
consent must meet = 1 of the following criteria defining a co morbidity:
- ECOG PS of 2 or 3 (Note: Patients = 18 to 74 years of age with PS of 0-1 must
meet criteria of one of the following comorbidities.)
- Cardiac history of congestive heart failure (CHF) requiring treatment or ejection
fraction = 50% or chronic stable angina
- Diffusing capacity of the lung for carbon monoxide (DLCO) = 65% or forced
expiratory volume in 1 second (FEV1) = 65%
- CrCl = 30 mL/min to < 45 ml/min
- Moderate hepatic impairment with total bilirubin > 1.5 to = 3.0 × ULN;
- High total bilirubin values may require indirect and direct bilirubin
testing. Individuals with known Gilbert's syndrome may be considered for
enrollment despite high indirect (and total) bilirubin
- Other comorbidities that the physician judges to be incompatible with intensive
chemotherapy (IC). In these cases, the comorbidity must be reviewed and approved
by the principal investigator (PI) before study enrollment
- Ability to swallow oral medications
- No ongoing anticoagulation or antiplatelet therapy within 14 days of start of
treatment with IADA (i.e., cycle 0 day 1 [C0D1])
- No history of severe bleeding disorder such as hemophilia A, hemophilia B, von
Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or
other medical intervention
- No history of stroke or intracranial hemorrhage within 180 days of start of IADA
- No major bleeding event, as defined by the International Society of Thrombosis and
Hemostasis (ISTH), within 12 weeks of start of IADA
- Uncorrected international normalized ratio (INR) or activated partial thromboplastin
time (aPTT) of < 1.5 x ULN.
- If INR or aPTT > 1.5 x ULN has been corrected (prior to enrollment), then history
of disseminated intravascular coagulation (DIC) must be absent
- White blood cell (WBC) < 20 x 10^9/L prior to study start. Cytoreduction prior to
study treatment is allowed with
- Hydroxyurea for up to 14 days and until 24 hours prior to start of IADA; or
- Leukapheresis for up to 14 days prior to start of IADA
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) or
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) = 2.0 x
institutional ULN
- Lower hepatic function may be considered if liver enzyme abnormalities are
determined by the treating MD and principal investigator (PI) to be due to
leukemic infiltration
- Willing and able to
- Adhere to study schedule of activities and life style restrictions while on
treatment;
- Provide bone marrow (BM) aspirate and core biopsy samples; and
- Accept supportive and prophylactic care for hematologic toxicities, infection,
and immediate sequelae, including transfusions
- Negative pregnancy test within 72 hours of start of IADA for persons of childbearing
potential (PCBP)
- Willingness to comply with study requirements for contraception, as follows: PCBP and
sperm-producing participants who are sexually active with a PCBP must use study
approved contraception from start of investigational product (first dose of IADA)
until 6 months after the last dose of IADA. Pregnancy is exclusionary because the
agents used in this study have the potential for teratogenic or abortifacient effects
Exclusion Criteria:
- Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or any
excipients in the formulations
- Body weight < 50 kg
- Investigational therapy within 5 half-lives or, if unknown, within 28 days prior to
start of IADA
- Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patients
with proliferative disease must meet the criteria listed in inclusion criteria
- Radiotherapy less than 14 days prior to start of IADA
- Recent and significant medical interventions, such as major surgery within 28 days
prior to the start of IADA, or stem cell transplant within 100 days prior to the start
of IADA. Patients with active treatment for graft-versus-host disease (GVHD) are
excluded
- Another active malignancy within 5 years prior to the start of IADA, or at the
investigator's discretion
- Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to the
start of IADA
- Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions that
limit the ingestion or gastrointestinal absorption of drugs administered orally
- Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment is
not finalized at least 3 weeks prior to the start of IADA
- Active central nervous system involvement with AML
- Uncontrolled infection. Participants with controlled infection must be afebrile and
hemodynamically stable for at least 72 hours prior to start of IADA and must be
amenable to alternate treatment if current treatment will interact with
investigational regimen
- Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV,
respectively) status, except in cases of undetectable HBV/HCV viral load for at least
3 months prior to the start of IADA. (Hepatitis B or C testing is not required for
eligibility assessment.)
- Individuals serology positive for human immunodeficiency virus (HIV) and under active
treatment with highly active antiretroviral therapy (HAART) (or another therapy that
may interfere with metabolism of study agents). Otherwise, enrollment may be
considered in cases of HIV that is controlled with another treatment type or in cases
that that acceptable modification of the patient's HIV treatment exists
- Use a P-gp inhibitor within 23 days prior to treatment with venetoclax
- Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives
whichever is longer, prior to start of treatment with venetoclax
- Unwillingness to stop breastfeeding. Because there is a potential risk for adverse
events in nursing infants secondary to treatment of the mother with the chemotherapy
agents, breastfeeding should also be avoided throughout the study and until at least
60 days after last dose of IADA
- Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood
pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertension before
C1D1 is allowed
- Patients with poorly controlled diabetes. Poorly controlled diabetes mellitus defined
as glycosylated hemoglobin (HbA1c) = 8%; patients with a history of transient glucose
intolerance due to corticosteroid administration may be enrolled in this study if all
other inclusion/exclusion criteria are met
- Patients with mean of triplicate corrected QT interval (Fridericia's correction
formula [QTcF]) > 450 ms at Screening based on central reading
- Uncontrolled intercurrent illness including, but not limited to ongoing or active
uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency
(e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia), or psychiatric illness or social situation that could limit compliance
with study requirements, at the discretion of the investigator
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