A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)

A Phase 1b Study Evaluating the Safety and Pharmacokinetics of Venetoclax as a Single-Agent and in Combination With Azacitidine in Subjects With Relapsed/Refractory Myelodysplastic Syndromes

This is a Phase 1b, open-label, multicenter study designed to evaluate the safety and pharmacokinetics of venetoclax as a single-agent and in combination with azacitidine in participants with relapsed/refractory Myelodysplastic Syndromes (MDS).

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes (MDS)
• Intervention / Treatment: Drug: venetoclax; Drug: azacitidine

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital /ID# 156037
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital /ID# 155952
  • Victoria
    • Fitzroy Melbourne, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne /ID# 155950
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital /ID# 155949
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital /ID# 155951
• Germany
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898
  • Halle (Saale), Germany, 06120
    • Universitaetsklinikum Halle (Saale) /ID# 158643
  • Munich, Germany, 81675
    • Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896
  • Baden-Wuerttemberg
    • Mannheim, Baden-Wuerttemberg, Germany, 68167
      • Universitatsklinikum Mannheim /ID# 156038
  • Nordrhein-Westfalen
    • Duesseldorf, Nordrhein-Westfalen, Germany, 40479
      • Marien Hospital Duesseldorf /ID# 155518
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40225
      • Universitaetsklinikum Duesseldorf /ID# 154899
    • Köln, Nordrhein-Westfalen, Germany, 50937
      • Universitaetsklinikum Koeln /ID# 155519
  • Sachsen
    • Leipzig, Sachsen, Germany, 04103
      • Universitaetsklinikum Leipzig /ID# 154897
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719-1478
      • University of Arizona Cancer Center - North Campus /ID# 157503
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital /ID# 155365
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University /ID# 162544
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Duplicate_University of Chicago /ID# 155364
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Pediatric Endocrine Associates /ID# 171227
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute /ID# 155361
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts - Worcester /ID# 155366
  • New York
    • New York, New York, United States, 10032-3725
      • Columbia Univ Medical Center /ID# 156388
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University /ID# 155360
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center /ID# 155362

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects who have relapsed or refractory MDS.

• Subject enrolled in venetoclax monotherapy must have documented failure of prior therapy with a hypomethylating agent (HMA). HMA-failure is defined as:

  1. Relapse after initial complete or partial response or hematological improvement after at least 4 cycles of azacitidine or at least 4 cycles of decitabine within the last 5 years, OR
  2. Failure to achieve complete or partial response or hematological improvement after at least 4 cycles of azacitidine or at least 4 cycles of decitabine within the last 5 years
• Subjects must have presence of < 20% bone marrow blasts per bone marrow biopsy/aspirate at screening.
• Subject is not a candidate to undergo allogenic hematopoietic stem cell transplantation (HSCT).
• Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
• Subject must have adequate hematologic, renal, and hepatic function.

Exclusion Criteria:

• Subject has received prior therapy with a BH3 mimetic.
• Subject has MDS evolving from a pre-existing myeloproliferative neoplasm (MPN).
• Subject has MDS/MPN including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML) and unclassifiable MDS/MPN.
• Subject has received allogeneic HSCT or solid organ transplantation.
• Subject has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug.
• Subject is pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Venetoclax monotherapy (Cohort 1)	Drug: venetoclax; Tablet; Other Names: ABT-199; GDC-0199
Experimental: Venetoclax + azacitidine (Cohort 2)	Drug: venetoclax; Tablet; Other Names: ABT-199; GDC-0199; Drug: azacitidine; Powder for injection, subcutaneously or intravenous; Other Names: Vidaza
Experimental: Safety Expansion (Cohort 3)	Drug: venetoclax; Tablet; Other Names: ABT-199; GDC-0199; Drug: azacitidine; Powder for injection, subcutaneously or intravenous; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Clearance (CL) for azacitidine		Up to 32 days
Cmax for azacitidine	Maximum plasma concentration (Cmax) of azacitidine	Up to 32 days
Tmax for venetoclax	Time to Cmax (peak time, Tmax) for venetoclax	Up to 32 days
Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine		Measured from Day 1 until day 28 per dose level.
AUC[0 to infinity] for azacitidine	Area under the plasma concentration-time curve from Time 0 to infinite time.	Up to 32 days
Tmax for azacitidine	Time to Cmax (peak time, Tmax) for 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
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
Cmax of venetoclax	Maximum plasma concentration (Cmax) of venetoclax	Up to 32 days
Half-life (t[1/2]) for azacitidine	Terminal elimination half-life (t[1/2]) for azacitidine	Up to 32 days
Number of Participants With Adverse Events (AEs)	An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.	Up to Maximum of 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-Free Survival (EFS)		Measured from the date of the first dose of study drug to date of earliest disease progression, death, or initiation of new non-protocol-specified anti-MDS therapy without documented progression, and for up to 5 years after the last subject is enrolled.
Overall Survival (OS)		Measured from the date of first dose of study drug to the date of death, and for up to 5 years after the last subject is enrolled.
Rate of Modified Overall Response (mORR)	Proportion of participants with a mORR using best outcome will be calculated.	Measured from Cycle 1 Day 1 (C1D1) as long as the subject 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 next treatment (TTNT)		Measured from first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last subject is enrolled.
Duration of mORR	Defined as the number of days from the date of first response (CR, mCR or PR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier..	Measured from the date of first response (CR, mCR or PR) to the earliest documentation of progressive disease (PD), and for an anticipated maximum duration of 24 months.
Rate of platelet (PLT) transfusion independence	Proportion of participants who become platelet transfusion-independent	Measured from Cycle 1 Day 1 as long as the subject 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 Transformation acute myeloid leukemia (AML)	Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.	Measured from the date of first dose of study drug to the date of documented AML transformation for an anticipated maximum duration of 24 months.
Progression-Free Survival (PFS)		Measured from the date of the first dose of study drug to the date of earliest disease progression or death, and for an anticipated maximum duration of 24 months.
Overall Response Rate (ORR)	ORR (equals the sum of rates of complete remission [CR] + marrow complete remission (mCR) + partial remission [PR]) of venetoclax as a single-agent and in combination with azacitidine.	Measured from Cycle 1 Day 1 as long as the subject 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.
Complete Remission (CR) Rate	Proportion of subjects who achieved a complete remission.	Measured from Cycle 1 Day 1 as long as the subject 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 red blood cell (RBC) transfusion independence	Proportion of red blood cell (RBC) transfusion independence.	Measured from Cycle 1 Day 1 as long as the subject 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 Complete Response (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 date of first response (CR) to the to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.
Rate of Hematologic Improvement (HI)	Proportion of participants with HI (erythroid/platelet/neutrophil responses)	Measured from Cycle 1 Day 1 as long as the subject 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 marrow complete remission (mCR)	Proportion of participants with marrow complete remission with or without hematological improvement.	Measured from Cycle 1 Day 1 (C1D1) as long as the subject 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 ORR	Duration of response (ORR) 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 the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, and for an anticipated maximum duration of 24 months.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Franke GN, Luckemeier P, Platzbecker U. Allogeneic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes and Prevention of Relapse. Clin Lymphoma Myeloma Leuk. 2021 Jan;21(1):1-7. doi: 10.1016/j.clml.2020.10.008. Epub 2020 Oct 16.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2017
• Primary Completion (Actual): April 5, 2023
• Study Completion (Actual): April 5, 2023

Study Registration Dates

• First Submitted: November 15, 2016
• First Submitted That Met QC Criteria: November 15, 2016
• First Posted (Estimate): November 17, 2016

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Venetoclax; Azacitidine; Relapsed/refractory
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Venetoclax; Azacitidine
• Other Study ID Numbers: M15-522; 2016-001904-46 (EudraCT Number)

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