Back to resultsA Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)
Primary Purpose
Myelodysplastic Syndromes (MDS)
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
venetoclax
azacitidine
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes (MDS) focused on measuring Relapsed/refractory, Venetoclax, Azacitidine
Eligibility Criteria
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:
- 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
- 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.
Sites / Locations
- University of Arizona Cancer Center - North Campus /ID# 157503
- University of Colorado Hospital /ID# 155365
- Yale University /ID# 162544
- Duplicate_University of Chicago /ID# 155364
- Pediatric Endocrine Associates /ID# 171227
- Dana-Farber Cancer Institute /ID# 155361
- University of Massachusetts - Worcester /ID# 155366
- Columbia Univ Medical Center /ID# 156388
- Oregon Health and Science University /ID# 155360
- University of Texas MD Anderson Cancer Center /ID# 155362
- St George Hospital /ID# 156037
- Liverpool Hospital /ID# 155952
- St Vincent's Hospital Melbourne /ID# 155950
- The Royal Melbourne Hospital /ID# 155949
- Royal Perth Hospital /ID# 155951
- Universitatsklinikum Mannheim /ID# 156038
- Marien Hospital Duesseldorf /ID# 155518
- Universitaetsklinikum Duesseldorf /ID# 154899
- Universitaetsklinikum Koeln /ID# 155519
- Universitaetsklinikum Leipzig /ID# 154897
- Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898
- Universitaetsklinikum Halle (Saale) /ID# 158643
- Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Venetoclax monotherapy (Cohort 1)
Venetoclax + azacitidine (Cohort 2)
Safety Expansion (Cohort 3)
Arm Description
Outcomes
Primary Outcome Measures
AUCt for azacitidine
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine
Clearance (CL) for azacitidine
Cmax for azacitidine
Maximum plasma concentration (Cmax) of azacitidine
Tmax for venetoclax
Time to Cmax (peak time, Tmax) for venetoclax
Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine
AUC[0 to infinity] for azacitidine
Area under the plasma concentration-time curve from Time 0 to infinite time.
Tmax for azacitidine
Time to Cmax (peak time, Tmax) for azacitidine
AUC [0-24] for venetoclax
AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax
AUCt for venetoclax
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax
Cmax of venetoclax
Maximum plasma concentration (Cmax) of venetoclax
Half-life (t[1/2]) for azacitidine
Terminal elimination half-life (t[1/2]) for azacitidine
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.
Secondary Outcome Measures
Event-Free Survival (EFS)
Overall Survival (OS)
Rate of Modified Overall Response (mORR)
Proportion of participants with a mORR using best outcome will be calculated.
Time to next treatment (TTNT)
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..
Rate of platelet (PLT) transfusion independence
Proportion of participants who become platelet transfusion-independent
Time to Transformation acute myeloid leukemia (AML)
Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.
Progression-Free Survival (PFS)
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.
Complete Remission (CR) Rate
Proportion of subjects who achieved a complete remission.
Rate of red blood cell (RBC) transfusion independence
Proportion of red blood cell (RBC) transfusion independence.
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.
Rate of Hematologic Improvement (HI)
Proportion of participants with HI (erythroid/platelet/neutrophil responses)
Rate of marrow complete remission (mCR)
Proportion of participants with marrow complete remission with or without hematological improvement.
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.
Full Information
NCT ID
NCT02966782
First Posted
November 15, 2016
Last Updated
May 8, 2023
Sponsor
AbbVie
Collaborators
Celgene; Genentech, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02966782
Brief Title
A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
March 7, 2017 (Actual)
Primary Completion Date
April 5, 2023 (Actual)
Study Completion Date
April 5, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AbbVie
Collaborators
Celgene; Genentech, Inc.
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
Brief Summary
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes (MDS)
Keywords
Relapsed/refractory, Venetoclax, Azacitidine
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
70 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Venetoclax monotherapy (Cohort 1)
Arm Type
Experimental
Arm Title
Venetoclax + azacitidine (Cohort 2)
Arm Type
Experimental
Arm Title
Safety Expansion (Cohort 3)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
venetoclax
Other Intervention Name(s)
ABT-199, GDC-0199
Intervention Description
Tablet
Intervention Type
Drug
Intervention Name(s)
azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
Powder for injection, subcutaneously or intravenous
Primary Outcome Measure Information:
Title
AUCt for azacitidine
Description
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine
Time Frame
Up to 32 days
Title
Clearance (CL) for azacitidine
Time Frame
Up to 32 days
Title
Cmax for azacitidine
Description
Maximum plasma concentration (Cmax) of azacitidine
Time Frame
Up to 32 days
Title
Tmax for venetoclax
Description
Time to Cmax (peak time, Tmax) for venetoclax
Time Frame
Up to 32 days
Title
Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine
Time Frame
Measured from Day 1 until day 28 per dose level.
Title
AUC[0 to infinity] for azacitidine
Description
Area under the plasma concentration-time curve from Time 0 to infinite time.
Time Frame
Up to 32 days
Title
Tmax for azacitidine
Description
Time to Cmax (peak time, Tmax) for azacitidine
Time Frame
Up to 32 days
Title
AUC [0-24] for venetoclax
Description
AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax
Time Frame
Up to 32 days
Title
AUCt for venetoclax
Description
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax
Time Frame
Up to 32 days
Title
Cmax of venetoclax
Description
Maximum plasma concentration (Cmax) of venetoclax
Time Frame
Up to 32 days
Title
Half-life (t[1/2]) for azacitidine
Description
Terminal elimination half-life (t[1/2]) for azacitidine
Time Frame
Up to 32 days
Title
Number of Participants With Adverse Events (AEs)
Description
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.
Time Frame
Up to Maximum of 24 months
Secondary Outcome Measure Information:
Title
Event-Free Survival (EFS)
Time Frame
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.
Title
Overall Survival (OS)
Time Frame
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.
Title
Rate of Modified Overall Response (mORR)
Description
Proportion of participants with a mORR using best outcome will be calculated.
Time Frame
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.
Title
Time to next treatment (TTNT)
Time Frame
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.
Title
Duration of mORR
Description
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..
Time Frame
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.
Title
Rate of platelet (PLT) transfusion independence
Description
Proportion of participants who become platelet transfusion-independent
Time Frame
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.
Title
Time to Transformation acute myeloid leukemia (AML)
Description
Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.
Time Frame
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.
Title
Progression-Free Survival (PFS)
Time Frame
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.
Title
Overall Response Rate (ORR)
Description
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.
Time Frame
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.
Title
Complete Remission (CR) Rate
Description
Proportion of subjects who achieved a complete remission.
Time Frame
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.
Title
Rate of red blood cell (RBC) transfusion independence
Description
Proportion of red blood cell (RBC) transfusion independence.
Time Frame
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.
Title
Duration of Complete Response (CR)
Description
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.
Time Frame
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.
Title
Rate of Hematologic Improvement (HI)
Description
Proportion of participants with HI (erythroid/platelet/neutrophil responses)
Time Frame
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.
Title
Rate of marrow complete remission (mCR)
Description
Proportion of participants with marrow complete remission with or without hematological improvement.
Time Frame
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.
Title
Duration of ORR
Description
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.
Time Frame
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
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
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
ABBVIE INC.
Organizational Affiliation
AbbVie
Official's Role
Study Director
Facility Information:
Facility Name
University of Arizona Cancer Center - North Campus /ID# 157503
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85719-1478
Country
United States
Facility Name
University of Colorado Hospital /ID# 155365
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Yale University /ID# 162544
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Facility Name
Duplicate_University of Chicago /ID# 155364
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Pediatric Endocrine Associates /ID# 171227
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber Cancer Institute /ID# 155361
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
University of Massachusetts - Worcester /ID# 155366
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
Columbia Univ Medical Center /ID# 156388
City
New York
State/Province
New York
ZIP/Postal Code
10032-3725
Country
United States
Facility Name
Oregon Health and Science University /ID# 155360
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
University of Texas MD Anderson Cancer Center /ID# 155362
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
St George Hospital /ID# 156037
City
Kogarah
State/Province
New South Wales
ZIP/Postal Code
2217
Country
Australia
Facility Name
Liverpool Hospital /ID# 155952
City
Liverpool
State/Province
New South Wales
ZIP/Postal Code
2170
Country
Australia
Facility Name
St Vincent's Hospital Melbourne /ID# 155950
City
Fitzroy Melbourne
State/Province
Victoria
ZIP/Postal Code
3065
Country
Australia
Facility Name
The Royal Melbourne Hospital /ID# 155949
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Royal Perth Hospital /ID# 155951
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
Facility Name
Universitatsklinikum Mannheim /ID# 156038
City
Mannheim
State/Province
Baden-Wuerttemberg
ZIP/Postal Code
68167
Country
Germany
Facility Name
Marien Hospital Duesseldorf /ID# 155518
City
Duesseldorf
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
40479
Country
Germany
Facility Name
Universitaetsklinikum Duesseldorf /ID# 154899
City
Düsseldorf
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
40225
Country
Germany
Facility Name
Universitaetsklinikum Koeln /ID# 155519
City
Köln
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
50937
Country
Germany
Facility Name
Universitaetsklinikum Leipzig /ID# 154897
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
Universitaetsklinikum Halle (Saale) /ID# 158643
City
Halle (Saale)
ZIP/Postal Code
06120
Country
Germany
Facility Name
Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896
City
Munich
ZIP/Postal Code
81675
Country
Germany
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33191169
Citation
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.
Results Reference
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A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)
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