Venetoclax + Azacitidine vs. Induction Chemotherapy in AML


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Trial ID: NCT04801797


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)

Official Title

A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Induction Chemotherapy for Newly Diagnosed Fit Adults With Acute Myeloid Leukemia

Stanford Investigator(s)

Gabriel Mannis
Gabriel Mannis

Associate Professor of Medicine (Hematology)


Inclusion Criteria:

   - Age ≥ 18 years

   - Participants must have pathologically confirmed, newly diagnosed acute myeloid
   leukemia (AML), and characterized by 20% or more blasts in the peripheral blood or
   bone marrow. 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 renal function as defined by calculated creatinine clearance ≥ 30 mL/min
   (Cockcroft-Gault formula or measured by 24 hours urine collection).

   - Adequate hepatic function per local laboratory reference ranges as follows:

      - Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0X ULN (unless
      secondary to leukemia, in which case patient may be eligible after consideration
      and approval by the Overall PI)

      - 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
   childbearing 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.

Exclusion Criteria:

   - 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) - see notes below.

      - Institutional FLT3 mutational assays can be used to assess for detection of the

      - A patient with a FLT3 mutation detected at a level of 5% VAF or less, below that
      typically detectable on the companion diagnostics approved for use by the FDA
      (, would be deemed eligible to enroll.

      - A negative FLT3 mutation result using an outside laboratory assay that is
      equivalent or similar to that approved as a companion diagnostic by the FDA
      ( is sufficient to rule out FLT3 mutated

   - Patients with a known diagnosis of CML or known presence of BCR-Abl alteration

   - 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 a history of
   other malignancies within 3 years and without any evidence of disease progression may
   be considered, but only after consideration and approval by the Overall PI.
   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 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 known history of an 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"
   induction chemotherapy.

   - WBC > 25 x 109/L. Note: hydroxyurea is permitted to meet this criterion. If WBC cannot
   be controlled to <25 x 109/L at the time of enrollment, the WBC management plan must
   be discussed and approved by the Overall PI.

   - Patients who might refuse to receive blood products and/or have a hypersensitivity to
   blood products

   - 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 β-human
   chorionic gonadotropin (β-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
   the investigator.


drug: Cytarabine

drug: Idarubicin

drug: Daunorubicin

drug: Liposomal daunorubicin and cytarabine

drug: Venetoclax

drug: Azacitidine


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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Kyle Cobarrubias

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