Azacitidine and Venetoclax as Induction Therapy With Venetoclax Maintenance in the Elderly With AML

Azacitidine and Venetoclax (ABT-199) as Induction Therapy With Venetoclax Maintenance in Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML)

This study is being done to determine if treatment with azacitidine and venetoclax is effective treatment for elderly patients with acute myeloid leukemia (AML) who have not received previous treatment. Azacitidine and venetoclax will be given as induction treatment followed by venetoclax maintenance treatment for patients who respond to the induction treatment.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacitidine and Venetoclax

Detailed Description

This is a phase 2 study for elderly patients who have not received previous treatment for acute myeloid leukemia (AML). Up to 42 patients will be enrolled. All patients will be treated with azacitidine and venetoclax until a minimal residual disease (MRD) negative response is achieved. Once patients achieve a MRD negative composite response, azacitidine will be discontinued and venetoclax dose will be decreased to "maintenance" dose.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject must have confirmation of non-APL AML by WHO criteria and be ineligible or unwilling to undergo treatment with a standard cytarabine and anthracycline induction regimen due to co-morbidities or other factors
2. Subject must have received no prior treatment for AML; hydroxyurea is not considered a treatment and is allowed
3. Subject must be ≥ 60 years of age
4. Subject must have a projected life expectancy of at least 12 weeks
5. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status of ≤2
6. Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula

7. Subject must have adequate liver function as demonstrated by:

   • aspartate aminotransferase (AST) ≤ 3.0 × ULN*
   • alanine aminotransferase (ALT) ≤ 3.0 × ULN*

   • bilirubin ≤ 3.0 × ULN, unless due to Gilbert's syndrome*

     • Unless considered due to leukemic organ involvement
8. Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.

9. Female subjects must be either:

   • Postmenopausal; defined as Age > 55 years with no menses for 12 or more months without an alternative medical cause; OR
   • Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
10. Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

1. Subject has received treatment with a hypomethylating agent and/or other chemotherapeutic agent either conventional or experimental for myelodysplastic syndrome (MDS) or AML
2. Subject has acute promyelocytic leukemia
3. Subject has known active CNS involvement from AML
4. Subject is known to be positive for HIV. HIV testing is not required
5. Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag, anti-HBs+ and anti-HBc-) may participate
6. Subject has received anticancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents within 5 half-lives prior to first dose of study drug
7. Subject has received biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent within 30 days prior to first dose of study drug

8. Subject has received the following within 7 days prior to the first dose of the study drug:

   • Steroid therapy for anti-neoplastic intent;
   • Strong and Moderate CYP3A inhibitors (see Appendix A for examples)
   • Strong and Moderate CYP3A inducers (see Appendix A for examples)
9. Subject has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit within 3 days prior to the initiation of study treatment

10. Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:

    • New York Heart Association heart failure > class 2
    • Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia
11. Subject has a malabsorption syndrome or other condition that precludes enteral route of administration
12. Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal)

13. Subject has a history of other malignancies prior to study entry, with the exception of:

    • Adequately treated in situ carcinoma of the breast or cervix uteri
    • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
    • Prostate cancer with no plans for therapy of any kind
    • Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
14. Subject has a white blood cell count > 25 × 109/L. Note: hydroxyurea is permitted to meet this criteria
15. Any subject who is a candidate for intensive induction therapy and agrees to receive this therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Azacitidine and Venetoclax; On day 1 of cycle 1, Azacitidine 75 mg/m2 will be given by injection or infusion, and will continue for 7 days. Azacitidine doses will be given in subsequent cycles for patients who do not achieve response. Venetoclax will be administered orally once daily on days 2 through 28 in cycle 1. Beginning with cycle 2, and each subsequent cycle, venetoclax will be administered Days 1 through 28.

Drug: Azacitidine and Venetoclax; Azacitidine will be given at dose of 75mg/m2 in Cycle 1 days 1-7; repeat in cycle 2 and 3 if no response. Starting on day 2 of cycle 1, venetoclax will be administered orally with doses increased to a target dose of 600 mg (administer 100 mg on day 2, 200 mg on day 3, 400 mg on day 4 and 600 mg on day 5), then 600 mg daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Remission Response to Azacitidine and Venetoclax Treatment + Maintenance Therapy	To determine the remission duration experienced by elderly previously untreated AML patients with azacitidine plus venetoclax followed by venetoclax alone as a maintenance therapy for patients who achieve a minimal residual disease (MRD) negative remission	From the first day a response is documented to the first day of disease progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate, With Responses Defined as Complete Remission (CR), Complete Remission With Incomplete Blood Count Recovery (CRi) and Morphologic Leukemia Free State (MLFS).	To determine the rate of MRD negative composite responses (includes complete remission [CR], complete remission with incomplete count recovery [CRi], and morphologic leukemia free state [MLFS]) with azacitidine plus venetoclax.	From Day 28, the first day a response is documented to end of cycle bone marrow biopsies, through 5 years
MRD-Negativity Incidence	MRD assessments by flow cytometry were employed for patients who achieved CR/CRI/MLFS. MRD-negative by this modality was defined as no evidence of aberrant myeloid antigen expression or abnormal myeloblasts at a level of detection <0.1% in an adequate sample.	From Day 28, the first day a response is documented to end of cycle bone marrow biopsies, through 5 years
To Determine the Median Time to Achieve a MRD Negative Composite Response	The median time to achieve MRD negative composite response	From first dose of treatment to first day response is documented by bone marrow biopsy, on average 30 days

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Investigators: Principal Investigator: Dan Pollyea, University of Colorado, Denver

Publications and helpful links

General Publications

• Shallis RM, Podoltsev NA. Maintenance therapy for acute myeloid leukemia: sustaining the pursuit for sustained remission. Curr Opin Hematol. 2021 Mar 1;28(2):110-121. doi: 10.1097/MOH.0000000000000637.

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2018
• Primary Completion (Actual): January 29, 2025
• Study Completion (Actual): December 4, 2025

Study Registration Dates

• First Submitted: March 2, 2018
• First Submitted That Met QC Criteria: March 8, 2018
• First Posted (Actual): March 15, 2018

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: AML; Venetoclax; Azacitidine
• 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; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax
• Other Study ID Numbers: 17-7821.cc

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No