Venetoclax + Azacitidine vs. Induction Chemotherapy in AML

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

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)

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Venetoclax; Drug: Cytarabine; Drug: Idarubicin; Drug: Daunorubicin; Drug: Liposomal daunorubicin and cytarabine; Drug: Azacitidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Palo Alto, California, United States, 94304
      • Stanford Cancer Center
    • Sacramento, California, United States, 95817
      • University of California - Davis
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Atrium Health Levine Cancer Institute
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 mutation.
  • 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 (http://www.fda.gov/CompanionDiagnostics), 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 (http://www.fda.gov/CompanionDiagnostics) is sufficient to rule out FLT3 mutated disease.
• 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 decitabine).
• 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 days.
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard of Care (Conventional Induction); Randomized participants will receive cytarabine and idarubicin [or daunorubicin) per standard of care as follows: Induction: cytarabine on days 1-7 and idarubicin (or daunorubicin) on days 1-3 of induction. Second Induction (if needed): Cytarabine on days 1-5 and idarubicin (or daunorubicin) on days 1-2 of re-induction. Consolidation (if needed): If < 60 years, cytarabine days 1,3,5 of consolidation cycles, and if ≥60 years, cytarabine days 1-5 of consolidation cycles Those with secondary or therapy-related AML can receive liposomal daunorubicin and cytarabine (Vyxeos) per standard of care as follows: Induction: Liposomal daunorubicin and cytarabine (Vyxeos) on Days 1,3, 5 of induction. Second Induction (if needed): Liposomal daunorubicin and cytarabine (Vyxeos) on days 1,3 of re-induction Consolidation (if needed): liposomal daunorubicin and cytarabine (Vyxeos) on days 1,3 of consolidation cycles	Drug: Cytarabine; Intravenous infusion; Other Names: Ara-C; Arabinosylcytosine; Drug: Idarubicin; Intravenous infusion; Drug: Daunorubicin; Intravenous infusion; Drug: Liposomal daunorubicin and cytarabine; Intravenous infusion; Other Names: Vyxeos
Experimental: Investigational (Venetoclax and Azacitidine); Participants will receive azacitidine on days 1-7 and venetoclax daily for up to (3) three 28-day study cycles and evaluated for response or benefit. If benefit/response is achieved, azacitidine on days 1-7 and venetoclax on days 1-28 (or less if deemed necessary per protocol) will be given in repeating 28-day cycles until benefit/response is no longer achieved or until patient proceeds to transplantation.	Drug: Venetoclax; Orally by mouth; Other Names: Venclexta; Drug: Azacitidine; Intravenous infusion; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event free survival	Primary endpoint is event-free-survival of patients treated with venetoclax and azacitidine compared to patients treated with standard induction with either 7+3 regimen or liposomal daunorubicin and cytarabine Events are described in the protocol and will include; Progressive Disease as defined above; Any change in therapy due to leukemic persistence.; Transition to hospice; Relapse following CR, CRi, or CRh; Any death Assessments of differences in EFS between the randomized arms will be made with the log-rank test; modeling will employ the Cox proportional hazards model. We also plan to assess the difference in estimated EFS at one year, using Kaplan-Meier estimates with standard deviation calculated by Greenwood's formula. EFS will be assessed using the Kaplan-Meier method. EFS will be assessed with the log-rank test, and cox proportional hazards model when appropriate.	From the time from randomization to time for up to 3 years, per protocol.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of response	Evaluated overall and separately for patients with primary and secondary AML, comparisons will be based on the Fisher exact test. CR and CRi will be assessed. Study also includes CRh as a possible response, CRh aims to describe marrow blast clearance and evidence of partial hematologic recovery not captured by current CR or CRi, criteria.	From the time from randomization to time for up to 6 months.
Treatment-related toxicity	Assessed using CTCAE 5	Enrollment to end of treatment duration for up to 12 months.
Rate of Minimal Residual Disease (MRD) negativity	Assessed by flow cytometry and next-generation sequencing	From time of enrollment until up to the first 6 months.
30-day mortality	Analyzed using the Kaplan Meier method.	From the time of start of therapy until through the first 30 days.
60-day mortality	Analyzed using the Kaplan Meier method.	From the time of start of therapy until through the first 60 days.
Overall survival (OS)	Survival will be summarized using the method of Kaplan Meier, and assessed using the log rank test and Cox proportional hazards when appropriate.	Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive, or for up to 3 years.
Rate of stem cell transplantation (SCT) following induction	The proportion of patients that receive a hematopoietic stem cell transplant following induction therapy or consolidation/continuation therapy.	From time of enrollment until up to 3 years following start of treatment.
Patient reported quality of life (QOL)	To compare quality of life between the two groups using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leuk). the FACT-Leukemia ranges from 0-176 with higher scores indicating better quality of life	up to one year
Patient-reported depression symptoms	To compare depression symptoms between the two groups using the Hospital Anxiety and Depression Scale (HADS-Depression). the HADS-depression ranges from 0 (no distress) to 21 (maximum distress) with higher scores indicating worse depression symptoms	up to one year
Patient-reported anxiety symptoms	To compare anxiety symptoms between the two groups using the Hospital Anxieyt and Depression Scale (HADS-Anxiety). the HADS-Anxiety ranges from 0 (no distress) to 21 (maximum distress) with higher scores indicating worse anxiety symptoms	up to one year
Patient-reported symptom burden	To compare symptom burden between the two groups using the Edmonton Symptom Assessment Scale (ESAS-revised). ESAS ranges from 0-100 with higher scores indicating worse symptom burden	up to one year
Patient-reported post-traumatic stress symptoms	To compare post-traumatic stress (PTSD) symptoms between the two groups using the PTSD-Checklist-Civilian Version. The PTSD-Checklist ranges from 17-85 with higher scores indicating worse PTSD symptoms	up to one year
Health care utilization - hospitalizations	To compare number of hospitalizations between the two groups using linear regression (and adjusting for any potential imbalances between the groups	up to 1 year
Health care utilization - days alive and out of the hospital	To compare days alive and out of the hospital between the two groups using linear regression (and adjusting for any potential imbalances between the groups)	up to 1 year
Health care utilization - Intensive care unit admissions	To compare intensive care unit admissions (yes vs. no) between the two groups using logistic regression (and adjusting for any potential imbalances between the groups)	up to 1 year
Cost of care	To compare cost of care between the two groups using parametric and non-parametric tests based on distribution of the data	up to 1 year
Incidence of neutropenic infections	Number of patients that experience neutropenic fever during induction cycles (up to 2 cycles).	Up to 8 weeks
100-Day post-transplant mortality	Assessed using the Kaplan Meier method	From date of transplantation through 100 days following transplantation.
Incidence of grade 3 or greater acute graft versus host disease (GVHD)	Assessed among patients that receive HSCT following induction.	Patients that receive a SCT will be followed post-SCT through up to 100 days.

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: AbbVie
• Investigators: Principal Investigator: Amir T Fathi, MD, Massachusetts General Hospital

Publications and helpful links

General Publications

• Waclawiczek A, Leppa AM, Renders S, Stumpf K, Reyneri C, Betz B, Janssen M, Shahswar R, Donato E, Karpova D, Thiel V, Unglaub JM, Grabowski S, Gryzik S, Vierbaum L, Schlenk RF, Rollig C, Hundemer M, Pabst C, Heuser M, Raffel S, Muller-Tidow C, Sauer T, Trumpp A. Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax. Cancer Discov. 2023 Jun 2;13(6):1408-1427. doi: 10.1158/2159-8290.CD-22-0939.

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2021
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: March 8, 2021
• First Submitted That Met QC Criteria: March 12, 2021
• First Posted (Actual): March 17, 2021

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Cytarabine; Azacitidine; Daunorubicin; Idarubicin; venetoclax
• Other Study ID Numbers: 21-113

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No