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 Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
129
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.
Oral; Tablet
AUCt for Azacitidine
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
Cmax of venetoclax
Maximum plasma concentration (Cmax) of venetoclax.
Time frame: 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.
Time frame: Up to 32 days
Tmax of venetoclax
Time to Cmax (peak time, Tmax) of venetoclax.
Time frame: Up to 32 days
AUC[0 to infinity] for azacitidine
Area under the plasma concentration-time curve from Time 0 to infinite time.
Time frame: 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 \[upon completion of the dose escalation phase\].
Time frame: 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.
Time frame: Up to 32 days
Cmax for azacitidine
Maximum plasma concentration (Cmax) of azacitidine.
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Duplicate_University of Arizona Cancer Center - North Campus /ID# 154155
Tucson, Arizona, United States
The University of Chicago Medical Center /ID# 153673
Chicago, Illinois, United States
University of Maryland, Baltimore /ID# 153669
Baltimore, Maryland, United States
Tufts Medical Center /ID# 153672
Boston, Massachusetts, United States
Dana-Farber Cancer Institute /ID# 152735
Boston, Massachusetts, United States
Washington University-School of Medicine /ID# 153671
St Louis, Missouri, United States
Columbia University Medical Center /ID# 153661
New York, New York, United States
Weill Cornell Medical College /ID# 155524
New York, New York, United States
Oregon Medical Research Center /ID# 152734
Portland, Oregon, United States
University of Pittsburgh MC /ID# 153662
Pittsburgh, Pennsylvania, United States
...and 27 more locations
Time frame: Up to 32 days
AUC[0-24] for venetoclax
AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax.
Time frame: Up to 32 days
Clearance (CL) for azacitidine
Clearance is defined as the volume of plasma cleared of the drug per unit time.
Time frame: Up to 32 days
Tmax for azacitidine
Time to Cmax (peak time, Tmax) of azacitidine.
Time frame: 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).
Time frame: 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 red blood cell (RBC) transfusion independence
Percentages of participants who become RBC transfusion-independent.
Time frame: 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.
Time frame: 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.
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 participant is enrolled.
Hematologic Improvement (HI) rate
Percentages of participants with HI (erythroid/platelet/neutrophil responses).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Overall Response Rate (OR)
OR (equals the rates of complete remission \[CR\] + partial remission \[PR\]) of venetoclax in combination with azacitidine.
Time frame: 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 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.