A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)
- Conditions
- Myelodysplastic Syndromes (MDS)
- Interventions
- Registration Number
- NCT02942290
- Lead Sponsor
- AbbVie
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 129
-
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.
-
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Venetoclax + Azacitidine Venetoclax - Venetoclax + Azacitidine Azacitidine -
- Primary Outcome Measures
Name Time Method Cmax for azacitidine Up to 32 days Maximum plasma concentration (Cmax) of azacitidine.
Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine Measured from Day 1 until Day 28 per dose level. 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 \[upon completion of the dose escalation phase\].
AUCt for Azacitidine Up to 32 days Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine.
Cmax of venetoclax Up to 32 days Maximum plasma concentration (Cmax) of venetoclax.
Half-life (t[1/2]) for azacitidine Up to 32 days Terminal elimination half-life (t\[1/2\]) for azacitidine.
AUC[0 to infinity] for azacitidine Up to 32 days Area under the plasma concentration-time curve from Time 0 to infinite time.
AUCt for venetoclax Up to 32 days Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax.
Tmax of venetoclax Up to 32 days Time to Cmax (peak time, Tmax) of venetoclax.
AUC[0-24] for venetoclax Up to 32 days AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax.
Clearance (CL) for azacitidine Up to 32 days Clearance is defined as the volume of plasma cleared of the drug per unit time.
Tmax for azacitidine Up to 32 days Time to Cmax (peak time, Tmax) of azacitidine.
Complete Remission (CR) Rate 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. 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).
- Secondary Outcome Measures
Name Time Method Overall Response Rate (OR) 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. OR (equals the rates of complete remission \[CR\] + partial remission \[PR\]) of venetoclax in combination with azacitidine.
Marrow Complete Remission (mCR) Rate 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. 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.
Rate of 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. The AML transformation rate is defined as the proportion of participants transformed to Acute Myelogenous Leukemia.
Rate of platelet (PLT) transfusion independence 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. Percentages of participants who become platelet transfusion-independent.
Modified Overall Response Rate (mOR) 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. mOR (equals CR + PR + mCR) of venetoclax in combination with azacitidine.
Duration 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. 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.
Hematologic Improvement (HI) rate 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. Percentages of participants with HI (erythroid/platelet/neutrophil responses).
Rate of red blood cell (RBC) transfusion independence 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. Percentages of participants who become RBC transfusion-independent.
Progression-Free Survival (PFS) 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. 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.
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 participant is enrolled. 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.
Event-Free Survival (EFS) 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 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.
Time to next treatment (TTNT) 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. 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.
Time to transformation to acute myeloid leukemia (AML) 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. Defined as the number of days from the date of the first dose of study drug to the date of documented AML transformation.
Duration of mOR 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 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.
Duration of OR 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 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.
Time to First Response (mOR) 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) 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).
Time to First Response (OR) 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) 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).
Time to First Response (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. 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.
Trial Locations
- Locations (37)
Tufts Medical Center /ID# 153672
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute /ID# 152735
🇺🇸Boston, Massachusetts, United States
University of Arizona Cancer Center - North Campus /ID# 154155
🇺🇸Tucson, Arizona, United States
Concord Repatriation General Hospital /ID# 154958
🇦🇺Concord, New South Wales, Australia
Duplicate_St. Vincent's Hospital, Darlinghurst /ID# 222846
🇦🇺Darlinghurst, New South Wales, Australia
St George Hospital /ID# 154954
🇦🇺Kogarah, New South Wales, Australia
Liverpool Hospital /ID# 222410
🇦🇺Liverpool, New South Wales, Australia
Calvary Mater Newcastle /ID# 154957
🇦🇺Waratah, New South Wales, Australia
Universitatsklinikum Mannheim /ID# 153140
🇩🇪Mannheim, Baden-Wuerttemberg, Germany
University Hospitals Birmingham NHS Foundation Trust /ID# 158810
🇬🇧Birmingham, United Kingdom
Norfolk and Norwich University Hospitals NHS Foundation Trust /ID# 156492
🇬🇧Norwich, Norfolk, United Kingdom
Oxford University Hospitals NHS Foundation Trust /ID# 222567
🇬🇧Oxford, Oxfordshire, United Kingdom
King's College Hospital NHS Foundation Trust /ID# 156489
🇬🇧London, United Kingdom
Fiona Stanley Hospital /ID# 222847
🇦🇺Murdoch, Western Australia, Australia
Duplicate_Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 153764
🇮🇹Rome, Roma, Italy
Princess Alexandra Hospital /ID# 154990
🇦🇺Woolloongabba, Queensland, Australia
IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 153763
🇮🇹Bologna, Italy
The Alfred Hospital /ID# 154956
🇦🇺Melbourne, Victoria, Australia
Universitaetsklinikum Koeln /ID# 153141
🇩🇪Köln, Nordrhein-Westfalen, Germany
Duplicate_Universitaetsklinikum Carl Gus /ID# 153958
🇩🇪Dresden, Sachsen, Germany
Universitaetsklinikum Leipzig /ID# 153142
🇩🇪Leipzig, Sachsen, Germany
Universitaetsklinikum Halle (Saale) /ID# 153760
🇩🇪Halle (Saale), Germany
Klinikum rechts der Isar /ID# 153139
🇩🇪Munich, Germany
Austin Health /ID# 154955
🇦🇺Heidelberg, Victoria, Australia
University of Maryland Medical Center /ID# 153669
🇺🇸Baltimore, Maryland, United States
Juravinski Cancer Centre /ID# 152947
🇨🇦Hamilton, Ontario, Canada
The University of Chicago Medical Center /ID# 153673
🇺🇸Chicago, Illinois, United States
Columbia University Medical Center /ID# 153661
🇺🇸New York, New York, United States
Washington University-School of Medicine /ID# 153671
🇺🇸Saint Louis, Missouri, United States
Weill Cornell Medical College /ID# 155524
🇺🇸New York, New York, United States
University of Pittsburgh MC /ID# 153662
🇺🇸Pittsburgh, Pennsylvania, United States
Oregon Medical Research Center /ID# 152734
🇺🇸Portland, Oregon, United States
Tennessee Oncology-Nashville Centennial /ID# 222769
🇺🇸Nashville, Tennessee, United States
Vanderbilt University Medical Center /ID# 152738
🇺🇸Nashville, Tennessee, United States
UT MD Anderson Cancer Center /ID# 153809
🇺🇸Houston, Texas, United States
CHU de Nantes, Hotel Dieu -HME /ID# 153828
🇫🇷Nantes, Pays-de-la-Loire, France
AP-HP - Hopital Saint-Louis /ID# 153827
🇫🇷Paris, France