A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

A Phase 1b Dose Escalation Study Evaluating the Safety and Pharmacokinetics of Venetoclax in Combination With Azacitidine in Subjects With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

This is a Phase 1b, open-label, non-randomized, multicenter, dose-finding study evaluating venetoclax in combination with azacitidine in participants with treatment-naïve higher-risk MDS comprising a dose-escalation portion and a safety expansion portion.

Study Overview

• Status: Active, not recruiting
• Conditions: Myelodysplastic Syndromes (MDS)
• Intervention / Treatment: Drug: Azacitidine; Drug: Venetoclax

• Study Type: Interventional
• Enrollment (Estimated): 129
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital /ID# 154958
    • Darlinghurst, New South Wales, Australia, 2010
      • Duplicate_St. Vincent's Hospital, Darlinghurst /ID# 222846
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital /ID# 154954
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital /ID# 222410
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle /ID# 154957
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Duplicate_Princess Alexandra Hospital /ID# 154990
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health /ID# 154955
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital /ID# 154956
  • Western Australia
    • Murdoch, Western Australia, Australia, 6150
      • Fiona Stanley Hospital /ID# 222847
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 1C3
      • Juravinski Cancer Centre /ID# 152947
• France
  • Paris, France, 75010
    • Hôpital Saint-Louis /ID# 153827
  • Pays de la Loire Region
    • Nantes, Pays de la Loire Region, France, 44000
      • Centre Hospitalier Universitaire de Nantes, Hotel Dieu -HME /ID# 153828
• Germany
  • Halle, Germany, 06120
    • Universitaetsklinikum Halle (Saale) /ID# 153760
  • Baden-Wurttemberg
    • Mannheim, Baden-Wurttemberg, Germany, 68167
      • Universitatsklinikum Mannheim /ID# 153140
  • Bavaria
    • Munich, Bavaria, Germany, 81675
      • Klinikum rechts der Isar /ID# 153139
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Universitaetsklinikum Koeln /ID# 153141
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Duplicate_Universitaetsklinikum Carl Gus /ID# 153958
    • Leipzig, Saxony, Germany, 04103
      • Universitaetsklinikum Leipzig /ID# 153142
• Italy
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Duplicate_IRCCS AOU di Bologna - Policlinico Sant'Orsola-Malpighi /ID# 153763
  • Roma
    • Rome, Roma, Italy, 00161
      • Duplicate_Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 153764
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • University Hospitals Birmingham NHS Foundation Trust /ID# 158810
  • London, United Kingdom, SE5 9RS
    • King's College Hospital NHS Foundation Trust /ID# 156489
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospitals NHS Foundation Trust /ID# 156492
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • Oxford University Hospitals NHS Foundation Trust /ID# 222567
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719-1478
      • Duplicate_University of Arizona Cancer Center - North Campus /ID# 154155
  • Illinois
    • Chicago, Illinois, United States, 60637-1443
      • The University of Chicago Medical Center /ID# 153673
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Baltimore /ID# 153669
  • Massachusetts
    • Boston, Massachusetts, United States, 02111-1552
      • Tufts Medical Center /ID# 153672
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 152735
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University-School of Medicine /ID# 153671
  • New York
    • New York, New York, United States, 10032-3729
      • Columbia University Medical Center /ID# 153661
    • New York, New York, United States, 10065
      • Weill Cornell Medical College /ID# 155524
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Medical Research Center /ID# 152734
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh MC /ID# 153662
  • Tennessee
    • Nashville, Tennessee, United States, 37203-1632
      • Tennessee Oncology-Nashville Centennial /ID# 222769
    • Nashville, Tennessee, United States, 37232-0011
      • Vanderbilt University Medical Center /ID# 152738
  • Texas
    • Houston, Texas, United States, 77030
      • UT MD Anderson Cancer Center /ID# 153809

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participant must have documented diagnosis of untreated de novo MDS with:

  • International Prognostic Scoring System (IPSS) risk categories Int-2 or High (minimum IPSS overall score of 1.5) OR Revised IPSS (IPSS-R) categories intermediate, high or very high (score of > 3) and
  • Presence of less than 20% bone marrow blasts per bone marrow biopsy/aspirate.
• Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.

Exclusion Criteria:

• Participant has received prior therapy for MDS. (Prior supportive care in form of transfusions or growth factors, etc., is not considered prior therapy).
• Participant has received prior therapy with a BCL-2 Homology 3 (BH3) mimetic.

• Participant has a diagnosis other than previously untreated de novo MDS (as defined in the protocol) including:

  • MDS with IPSS risk categories Low or Int-1 (overall IPSS score < 1.5)
  • Therapy-related MDS (t-MDS).
  • MDS evolving from a pre-existing myeloproliferative neoplasm (MPN).
  • MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
• Participant has received allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or solid organ transplantation.
• Participant has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Venetoclax + Azacitidine	Drug: Azacitidine; Powder for injection; taken subcutaneously (SC) or intravenous (IV); Administered on Days 1-7 of 28 days cycle or Days 1-5 of Week 1 & Days 1-2 of Week 2 of 28 day cycle.; Drug: Venetoclax; Oral; Tablet; Other Names: ABT-199; GDC-0199; VENCLEXTA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC[0 to infinity] for azacitidine	Area under the plasma concentration-time curve from Time 0 to infinite time.	Up to 32 days
AUCt for Azacitidine	Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine.	Up to 32 days
Cmax of venetoclax	Maximum plasma concentration (Cmax) of venetoclax.	Up to 32 days
AUCt for venetoclax	Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax.	Up to 32 days
Tmax of venetoclax	Time to Cmax (peak time, Tmax) of venetoclax.	Up to 32 days
Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine	The RPTD of venetoclax [co-administered venetoclax and azacitidine] will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data [upon completion of the dose escalation phase].	Measured from Day 1 until Day 28 per dose level.
Half-life (t[1/2]) for azacitidine	Terminal elimination half-life (t[1/2]) for azacitidine.	Up to 32 days
Cmax for azacitidine	Maximum plasma concentration (Cmax) of azacitidine.	Up to 32 days
AUC[0-24] for venetoclax	AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax.	Up to 32 days
Clearance (CL) for azacitidine	Clearance is defined as the volume of plasma cleared of the drug per unit time.	Up to 32 days
Tmax for azacitidine	Time to Cmax (peak time, Tmax) of azacitidine.	Up to 32 days
Complete Remission (CR) Rate	Complete remission rate will be defined as the proportion of participants who achieved a complete response per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes (MDS).	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of red blood cell (RBC) transfusion independence	Percentages of participants who become RBC transfusion-independent.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Progression-Free Survival (PFS)	PFS is defined as the number of days from the date of the first dose of study drug to the date of earliest disease progression or death due to disease progression or febrile neutropenia.	Measured from the date of first dose of study drug to the date of earliest disease progression or death due to disease progression or febrile neutropenia, and for an anticipated maximum duration of 24 months.
Overall Survival (OS)	OS is defined as number of days from the date of first dose of the study drug to the date of death of any cause.	Measured from the date of first dose of study drug to the date of death, and for up to 5 years after the last participant is enrolled.
Hematologic Improvement (HI) rate	Percentages of participants with HI (erythroid/platelet/neutrophil responses).	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Rate of platelet (PLT) transfusion independence	Percentages of participants who become platelet transfusion-independent.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Event-Free Survival (EFS)	Event-free survival (EFS) will be defined as the number of days from the date of the first dose of study drug to the date of earliest disease progression or death of any cause.	Measured from the date of the first dose of study drug to the date of earliest disease progression, death of any cause and for up to 5 yrs after the last participant is enrolled
Time to transformation to acute myeloid leukemia (AML)	Defined as the number of days from the date of the first dose of study drug to the date of documented AML transformation.	Measured from the date of first dose of study drug to date of documented AML transformation, defined as the presence of blast count greater than or equal to 20% in either peripheral blood or bone marrow for an anticipated maximum duration of 24 months.
Time to next treatment (TTNT)	Time to next treatment (TTNT) will be defined as the time from the first dose of study drug to start of new non-protocol specified MDS therapy or death from any cause.	Measured from the first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last participant is enrolled.
Marrow Complete Remission (mCR) Rate	Defined as the proportion of participants who achieved a marrow complete response with or without hematological improvement per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Duration of CR	Duration of CR will be defined as the number of days from the date of first response CR to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Rate of AML transformation	The AML transformation rate is defined as the proportion of participants transformed to Acute Myelogenous Leukemia.	Measured from the date of first dose of study drug to date of documented AML transformation, defined as the presence of blast count greater than or equal to 20% in either peripheral blood or bone marrow for an anticipated maximum duration of 24 months.
Time to First Response (CR)	Time to first response (CR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of CR.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent, and for an anticipated maximum duration of 24 months.
Overall Response Rate (OR)	OR (equals the rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.
Modified Overall Response Rate (mOR)	mOR (equals CR + PR + mCR) of venetoclax in combination with azacitidine.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.
Duration of mOR	Duration of response (mOR) will be defined as the number of days from the date of first response (CR, PR or mCR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.
Duration of OR	Duration of response (OR) will be defined as the number of days from the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.
Time to First Response (mOR)	Time to first response (mOR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of (CR, PR, or mCR).	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.
Time to First Response (OR)	Time to first response (OR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of (CR or PR).	Measured from Cycle 1 Day 1 as long as the participant continues to benefit, or until the occurrence of unacceptable toxicity, death, exercise of investigator discretion, or withdrawal of consent and for an anticipated maximum duration of 24 months.

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: Genentech, Inc.
• Investigators: Study Director: ABBVIE INC., AbbVie

Publications and helpful links

General Publications

• Garcia JS, Platzbecker U, Odenike O, Fleming S, Fong CY, Borate U, Jacoby MA, Nowak D, Baer MR, Peterlin P, Chyla B, Wang H, Ku G, Hoffman D, Potluri J, Garcia-Manero G. Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes. Blood. 2025 Mar 13;145(11):1126-1135. doi: 10.1182/blood.2024025464.

Helpful Links

• This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2017
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: October 18, 2016
• First Submitted That Met QC Criteria: October 20, 2016
• First Posted (Estimated): October 24, 2016

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Venetoclax; Azacitidine; Pharmacokinetic; Acute Myelogenous Leukemia; Myelodysplastic Syndromes (MDS); Higher-Risk (HR) Myelodysplastic Syndromes (MDS); Treatment-Naïve Higher-Risk
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; 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: M15-531; 2016-001657-41 (EudraCT Number); 2023-507154-32-00 (Other Identifier: EU CT)

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
• product manufactured in and exported from the U.S.: No