This research is being done to assess the therapeutic activity of a promising combination
(azacitidine and venetoclax) versus conventional cytotoxic chemotherapy in induction-eligible
patients with acute myeloid leukemia.
This study involves the following:
- Venetoclax and azacitidine (investigational combination)
- Cytarabine and idarubicin or daunorubicin (per standard of care) or Liposomal
daunorubicin and cytarabine (per standard of care)
This is an open-label, multicenter, phase II randomized clinical trial to compare the
therapeutic activity of conventional induction chemotherapy (7+3 regimen or liposomal
daunorubicin and cytarabine) to the combination of venetoclax and azacitidine among fit,
traditionally induction-eligible adults with newly diagnosed acute myeloid leukemia (AML).
The U.S. Food and Drug Administration (FDA) has approved the combinations of liposomal
daunorubicin and cytarabine as well as cytarabine and idarubicin or daunorubicin as treatment
options for acute myeloid leukemia (AML)
The FDA has approved the combination of venetoclax and azacitidine for people with acute
myeloid leukemia (AML) that are over the age of 75 or who have comorbidities that preclude
intensive induction chemotherapy.
Venetoclax may interact with BCL-2 (a protein that initiates tumor growth, disease
progression, and drug resistance) and inhibit BLC-2 which can lead to cancer cell death.
Azacitidine may cause cell death in rapidly dividing cells, which may lead to cancer cell
death since cancer cells do not grow at a normal rate. Induction Chemotherapy which includes
the drugs idarubicin or daunorubicin, cytarabine, and liposomal daunorubicin and cytarabine
is the standard of care chemotherapy treatment for someone with acute myeloid leukemia (AML).
The research study procedures include screening for eligibility and study treatment,
including evaluations and follow up visits.
Participants will receive study treatment for as long as they and their doctor believe they
are benefitting from the study drugs. Participants will then be followed for 3 years or until
they withdraw their consent to be contacted.
It is expected that about 172 people will take part in this research study.
AbbVie, a biopharmaceutical company, is supporting this research study by providing funding
for the study, including one of the study drugs.
- Age ≥ 18 years
- Participants must have pathologically confirmed, newly diagnosed acute myeloid
leukemia (AML). The AML may be either:
- De Novo: AML in patients with no clinical history of prior myelodysplastic
syndrome (MDS), myeloproliferative disorder, or exposure to potentially
leukemogenic therapies or agents
- Secondary AML (sAML): refers to an acute leukemic process (1) evolving from known
prior myelodysplasia, myeloproliferative disorder, or aplastic anemia with or
without treatment or; (2) as a product of previous exposure to a proven
leukemogenic chemotherapeutic agent
- Eligible for intensive induction chemotherapy, according to their treating physician
- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
- Left ventricular ejection fraction > 50% as measured by echocardiogram or MUGA scan
- Must not have received systemic prior antineoplastic therapy for treatment for the
newly diagnosed AML, including radiation therapy, except hydroxyurea for the purposes
of cytoreduction. Patients may also have received all-trans retinoic acid (ATRA) if
there is an early suspicion of acute promyelocytic leukemia (APL, M3-AML), although if
confirmed to have APL these patients will be excluded from the study.
- Adequate hepatic function per local laboratory reference ranges as follows:
- Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0X ULN
- Total bilirubin ≤ 2.0 x ULN (unless bilirubin rise is known to be due to
Gilbert's syndrome or of non-hepatic origin)
- The effects of venetoclax on the developing human fetus are unknown. For this reason
and because other chemotherapeutic agents are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately. Women should use contraceptives for at least 30 days
following the last dose of venetoclax. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of therapy.
- Ability to understand and the willingness to sign a written informed consent document.
- Diagnosis of Acute promyelocytic leukemia (APL) or AML with favorable cytogenetics
[t(8;21), inv(16), t(16;16)]
- Patients < 60 years old with NPM1-mutated AML:
- Patients with FLT3-mutated AML (TKD or ITD).
- Patients with acute leukemia with ambiguous lineage or mixed phenotype
- Patients that have received strong and/or moderate CYP3A inducers within 7 days prior
to the initiation of study treatment.
- 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.
- Patients who have had prior systemic cytotoxic chemotherapy or radiotherapy for AML
(excluding patients with therapy-related AML), except for hydroxyurea or 6-MP as
noted. Empiric intrathecal chemotherapy during a diagnostic lumbar puncture is
allowed, as long as CNS disease is not suspected.
- Patients treated with prior hypomethylating therapy (such as azacitidine or
- Patients who will exceed a lifetime anthracycline exposure of >550 mg/m2 daunorubicin
or equivalent (or >400 mg/m2 daunorubicin or equivalent in the event of prior
mediastinal radiation) if they receive the maximum potential exposure to
anthracyclines per protocol (including both induction and consolidation cycles.
- Individuals with a history of a different malignancy are ineligible except for the
following circumstances. Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 3 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer
in situ, breast DCIS, and basal cell or squamous cell carcinoma of the skin.
- Current clinical central nervous system (CNS) symptoms deemed by the investigator to
be related to leukemic CNS involvement (no lumbar puncture required, clinical
assessment per investigator's judgment is sufficient).
- Prior bone marrow transplantation for a myeloid malignancy
- Participants who are receiving any other investigational agents within the prior 14
- Currently clinically active hepatitis C or hepatitis B infection, as suggested by
serology or viral load.
- Human immunodeficiency virus (HIV)-infected participants. Patients with no detectable
viral load on a stable anti-viral regimen may be eligible, after discussion with the
study overall PI.
- Current or history of congestive heart failure New York Heart Association (NYHA) class
3 or 4, or any history of documented diastolic or systolic dysfunction (LVEF <50%, as
measured by MUGA scan or echocardiogram). Prior to study entry, any ECG abnormality at
screening has to be documented by the investigator as not medically relevant.
- Known hypersensitivity to the trial drugs or other contraindication to standard "7+3"
- WBC > 25 x 109/L. Note: hydroxyurea is permitted to meet this criterion
- Patients who might refuse to receive blood products and/or have a hypersensitivity to
- Patients with clinically significant persistent electrolyte abnormalities such as
hypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, and
hypermagnesemia of Grade > 1 per NCI CTCAE, v5.0. Treatment for correction of above
electrolyte imbalances is permitted during screening to meet eligibility.
- Uncontrolled intercurrent illness including, but not limited to, clinically ongoing or
active infection requiring intravenous antibiotics (IV antibiotics are allowed if
infection is deemed to be controlled), symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements.
- Known GI disease or GI procedures that could interfere with the oral absorption or
tolerance of the study drugs. Examples include, but are not limited to partial
gastrectomy, history of small intestine surgery, and celiac disease.
- Pregnant women are excluded from this study because venetoclax and azacitidine, along
with standard induction chemotherapy, carries the potential for teratogenic or
abortifacient effects. Because there is potential risk for adverse events in nursing
infants secondary to treatment of the mother with venetoclax as well as azacitidine,
cytarabine, daunorubicin and idarubicin, breastfeeding should be avoided. Confirmation
that the subject is not pregnant must be established by a negative serum ß-human
chorionic gonadotropin (ß-hCG) pregnancy test result obtained during screening.
Pregnancy testing is not required for post-menopausal or surgically sterilized women.
- Patients with psychological, familial, social, or geographic factors that otherwise
preclude them from giving informed consent, following the protocol, or potentially
hamper compliance with study treatment and follow-up.
- Patients who are otherwise felt unable to comply with the protocol, in the opinion of