A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1b Dose Escalation Study Evaluating the Safety and Pharmacokinetics of Venetoclax in Combination With Azacitidine in Subjects With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

Conditions
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Myelodysplastic Syndromes (MDS)

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + Azacitidine<br> | Drug: Azacitidine<br>* 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.<br>Drug: Venetoclax<br>* Oral; Tablet<br>* Other names: VENCLEXTA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCt for Azacitidine | Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine. | Up to 32 days | 
| Cmax of venetoclax | Maximum plasma concentration (Cmax) of venetoclax. | 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. | Up to 32 days | 
| Tmax of venetoclax | Time to Cmax (peak time, Tmax) of venetoclax. | Up to 32 days | 
| AUC[0 to infinity] for azacitidine | Area under the plasma concentration-time curve from Time 0 to infinite time. | 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]. | 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. | Up to 32 days | 
| Cmax for azacitidine | Maximum plasma concentration (Cmax) of azacitidine. | Up to 32 days | 
| AUC[0-24] for venetoclax | AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax. | Up to 32 days | 
| Clearance (CL) for azacitidine | Clearance is defined as the volume of plasma cleared of the drug per unit time. | Up to 32 days | 
| Tmax for azacitidine | Time to Cmax (peak time, Tmax) of azacitidine. | 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). | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of red blood cell (RBC) transfusion independence | Percentages of participants who become RBC transfusion-independent. | 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. | 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. | 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). | 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. | 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. | 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. | 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 (ORR) | ORR (equals the rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine. | 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. | 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. | 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 (mORR) | mORR (equals CR + PR + mCR) of venetoclax in combination with azacitidine. | 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. | 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 mORR | Duration of response (mORR) 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. | 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 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. | 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. | 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. | 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 (mORR) | Time to first response (mORR) 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). | 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 (ORR) | Time to first response (ORR) 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). | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Higher-Risk (HR) Myelodysplastic Syndromes (MDS), Pharmacokinetic, Venetoclax, Azacitidine, Acute Myelogenous Leukemia, Myelodysplastic Syndromes (MDS), Treatment-Naïve Higher-Risk