A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 1b Study Evaluating the Safety and Pharmacokinetics of Venetoclax as a Single-Agent and in Combination With Azacitidine in Subjects With Relapsed/Refractory Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes (MDS)

Intervention / Treatment
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* Drug: venetoclax
* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax monotherapy (Cohort 1)<br> | Drug: venetoclax<br>* Tablet<br>* Other names: GDC-0199;|
| Experimental: Venetoclax + azacitidine (Cohort 2)<br> | Drug: venetoclax<br>* Tablet<br>* Other names: GDC-0199;Drug: azacitidine<br>* Powder for injection, subcutaneously or intravenous<br>* Other names: Vidaza;|
| Experimental: Safety Expansion (Cohort 3)<br> | Drug: venetoclax<br>* Tablet<br>* Other names: GDC-0199;Drug: azacitidine<br>* Powder for injection, subcutaneously or intravenous<br>* Other names: Vidaza;|

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 | 
| Clearance (CL) for azacitidine |  | Up to 32 days | 
| Cmax for azacitidine | Maximum plasma concentration (Cmax) of azacitidine | Up to 32 days | 
| Tmax for venetoclax | Time to Cmax (peak time, Tmax) for venetoclax | Up to 32 days | 
| 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. | 
| AUC[0 to infinity] for azacitidine | Area under the plasma concentration-time curve from Time 0 to infinite time. | Up to 32 days | 
| Tmax for azacitidine | Time to Cmax (peak time, Tmax) for 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 | 
| 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 | 
| Cmax of venetoclax | Maximum plasma concentration (Cmax) of venetoclax | Up to 32 days | 
| Half-life (t[1/2]) for azacitidine | Terminal elimination half-life (t[1/2]) for azacitidine | Up to 32 days | 
| Number of Participants With Adverse Events (AEs) | 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. | Up to Maximum of 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Proportion of participants with a mORR using best outcome will be calculated. | 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. | 
| 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 | 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.. | 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. | 
| Rate of platelet (PLT) transfusion independence | Proportion of participants who become platelet transfusion-independent | 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. | 
| Time to Transformation acute myeloid leukemia (AML) | Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow. | 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. | 
| 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) | 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. | 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. | 
| Complete Remission (CR) Rate | Proportion of subjects who achieved a complete remission. | 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. | 
| Rate of red blood cell (RBC) transfusion independence | Proportion 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. | 
| Duration of Complete Response (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 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. | 
| Rate of Hematologic Improvement (HI) | Proportion of participants with HI (erythroid/platelet/neutrophil responses) | 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. | 
| Rate of marrow complete remission (mCR) | Proportion of participants with marrow complete remission with or without hematological improvement. | 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. | 
| 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 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/refractory, Venetoclax, Azacitidine