Venetoclax + Azacitidine vs. Induction Chemotherapy in AML

NCT04801797 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 21-113
• Study Type: interventional
• Target: 172
• Locations: 1 country
• Sites: 9

Brief Summary

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)

Conditions

Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• Rate of response

  From the time from randomization to time for up to 6 months.

• Treatment-related toxicity

  Enrollment to end of treatment duration for up to 12 months.

• Rate of Minimal Residual Disease (MRD) negativity

  From time of enrollment until up to the first 6 months.

• 30-day mortality

  From the time of start of therapy until through the first 30 days.

• 60-day mortality

  From the time of start of therapy until through the first 60 days.

Study Arms (2)

Standard of Care (Conventional Induction)

EXPERIMENTAL

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; Drug: Idarubicin; Drug: Daunorubicin; Drug: Liposomal daunorubicin and cytarabine

Investigational (Venetoclax and Azacitidine)

EXPERIMENTAL

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; Drug: Azacitidine

Interventions

Cytarabine DRUG

Intravenous infusion

Also known as: Ara-C, Arabinosylcytosine

Standard of Care (Conventional Induction)

Idarubicin DRUG

Intravenous infusion

Standard of Care (Conventional Induction)

Daunorubicin DRUG

Intravenous infusion

Standard of Care (Conventional Induction)

Liposomal daunorubicin and cytarabine DRUG

Intravenous infusion

Also known as: Vyxeos

Standard of Care (Conventional Induction)

Venetoclax DRUG

Orally by mouth

Also known as: Venclexta

Investigational (Venetoclax and Azacitidine)

Azacitidine DRUG

Intravenous infusion

Also known as: Vidaza

Investigational (Venetoclax and Azacitidine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• AbbVie: collaborator

Study Sites (9)

City of Hope

Duarte, California, 91010, United States

RECRUITING

Stanford Cancer Center

Palo Alto, California, 94304, United States

RECRUITING

University of California - Davis

Sacramento, California, 95817, United States

RECRUITING

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

RECRUITING

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

RECRUITING

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

Atrium Health Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

RECRUITING

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

RECRUITING

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Related Publications (1)

• 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.

  PMID: 36892565 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Cytarabine; Idarubicin; Daunorubicin; venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Aza Compounds; Ribonucleosides

Study Officials

• Amir T Fathi, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amir T Fathi, MD

CONTACT

(617) 724-1124; afathi@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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) (Standard arm) to the combination of venetoclax and azacitidine among fit, traditionally induction-eligible adults with newly diagnosed acute myeloid leukemia (AML).

Study Record Dates

• First Submitted: March 8, 2021
• First Posted: March 17, 2021
• Study Start: May 20, 2021
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: November 14, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation

Locations

US (9)