A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)
- Conditions
- Myelodysplastic Syndromes (MDS)
- Interventions
- Registration Number
- NCT02966782
- Lead Sponsor
- AbbVie
- 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).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 70
-
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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Safety Expansion (Cohort 3) venetoclax - Venetoclax monotherapy (Cohort 1) venetoclax - Venetoclax + azacitidine (Cohort 2) venetoclax - Venetoclax + azacitidine (Cohort 2) azacitidine - Safety Expansion (Cohort 3) azacitidine -
- Primary Outcome Measures
Name Time Method AUC [0-24] for venetoclax Up to 32 days AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax
Half-life (t[1/2]) for azacitidine Up to 32 days Terminal elimination half-life (t\[1/2\]) for azacitidine
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
Cmax of venetoclax Up to 32 days Maximum plasma concentration (Cmax) of venetoclax
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
Clearance (CL) for azacitidine Up to 32 days Cmax for azacitidine Up to 32 days Maximum plasma concentration (Cmax) of azacitidine
Tmax for venetoclax Up to 32 days Time to Cmax (peak time, Tmax) for venetoclax
AUC[0 to infinity] for azacitidine Up to 32 days Area under the plasma concentration-time curve from Time 0 to infinite time.
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. Tmax for azacitidine Up to 32 days Time to Cmax (peak time, Tmax) for azacitidine
Number of Participants With Adverse Events (AEs) Up to Maximum of 24 months 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
Name Time Method 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) 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. Proportion of participants with a mORR using best outcome will be calculated.
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 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. 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 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. Proportion of participants who become platelet transfusion-independent
Time to Transformation acute myeloid leukemia (AML) 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. Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.
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) 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. 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 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. Proportion of subjects who achieved a complete remission.
Rate 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. Proportion of red blood cell (RBC) transfusion independence.
Duration of Complete Response (CR) 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. 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) 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. Proportion of participants with HI (erythroid/platelet/neutrophil responses)
Rate of marrow complete remission (mCR) 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. Proportion of participants with marrow complete remission with or without hematological improvement.
Duration of ORR 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. 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.
Trial Locations
- Locations (23)
Duplicate_University of Chicago /ID# 155364
🇺🇸Chicago, Illinois, United States
University of Massachusetts - Worcester /ID# 155366
🇺🇸Worcester, Massachusetts, United States
Royal Perth Hospital /ID# 155951
🇦🇺Perth, Western Australia, Australia
Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898
🇩🇪Dresden, Germany
Universitaetsklinikum Halle (Saale) /ID# 158643
🇩🇪Halle (Saale), Germany
Columbia Univ Medical Center /ID# 156388
🇺🇸New York, New York, United States
Liverpool Hospital /ID# 155952
🇦🇺Liverpool, New South Wales, Australia
Universitatsklinikum Mannheim /ID# 156038
🇩🇪Mannheim, Baden-Wuerttemberg, Germany
St Vincent's Hospital Melbourne /ID# 155950
🇦🇺Fitzroy Melbourne, Victoria, Australia
The Royal Melbourne Hospital /ID# 155949
🇦🇺Parkville, Victoria, Australia
Marien Hospital Duesseldorf /ID# 155518
🇩🇪Duesseldorf, Nordrhein-Westfalen, Germany
Universitaetsklinikum Koeln /ID# 155519
🇩🇪Köln, Nordrhein-Westfalen, Germany
Universitaetsklinikum Duesseldorf /ID# 154899
🇩🇪Düsseldorf, Nordrhein-Westfalen, Germany
Universitaetsklinikum Leipzig /ID# 154897
🇩🇪Leipzig, Sachsen, Germany
University of Colorado Hospital /ID# 155365
🇺🇸Aurora, Colorado, United States
Dana-Farber Cancer Institute /ID# 155361
🇺🇸Boston, Massachusetts, United States
Oregon Health and Science University /ID# 155360
🇺🇸Portland, Oregon, United States
University of Texas MD Anderson Cancer Center /ID# 155362
🇺🇸Houston, Texas, United States
Pediatric Endocrine Associates /ID# 171227
🇺🇸Boston, Massachusetts, United States
St George Hospital /ID# 156037
🇦🇺Kogarah, New South Wales, Australia
Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896
🇩🇪Munich, Germany
University of Arizona Cancer Center - North Campus /ID# 157503
🇺🇸Tucson, Arizona, United States
Yale University /ID# 162544
🇺🇸New Haven, Connecticut, United States