Myelodysplastic Syndromes (MDS)
Conditions
Keywords
Higher-Risk (HR) Myelodysplastic Syndromes (MDS), Pharmacokinetic, Venetoclax, Azacitidine, Acute Myelogenous Leukemia, Myelodysplastic Syndromes (MDS), Treatment-Naïve Higher-Risk
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.
Interventions
DRUGAzacitidine
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.
DRUGVenetoclax
Oral; Tablet
Sponsors
AbbVie
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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 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 \[upon completion of the dose escalation phase\]. |
| Half-life (t[1/2]) for azacitidine | Up to 32 days | Terminal elimination half-life (t\[1/2\]) for azacitidine. |
| Cmax for azacitidine | Up to 32 days | Maximum plasma concentration (Cmax) of azacitidine. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 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. |
| 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 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
Countries
Australia, Canada, France, Germany, Italy, United Kingdom, United States
Contacts
STUDY_DIRECTORABBVIE INC.
AbbVie
Outcome results
None listed