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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02966782
Recruitment Status : Active, not recruiting
First Posted : November 17, 2016
Last Update Posted : August 9, 2022
Sponsor:
Collaborator:
Celgene; Genentech, Inc.
Information provided by (Responsible Party):
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).

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes (MDS) Drug: venetoclax Drug: azacitidine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 7, 2017
Estimated Primary Completion Date : January 31, 2023
Estimated Study Completion Date : January 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Venetoclax monotherapy (Cohort 1) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Experimental: Venetoclax + azacitidine (Cohort 2) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Drug: azacitidine
Powder for injection, subcutaneously or intravenous
Other Name: Vidaza

Experimental: Safety Expansion (Cohort 3) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Drug: azacitidine
Powder for injection, subcutaneously or intravenous
Other Name: Vidaza




Primary Outcome Measures :
  1. AUCt for azacitidine [ Time Frame: 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

  2. Clearance (CL) for azacitidine [ Time Frame: Up to 32 days ]
  3. Cmax for azacitidine [ Time Frame: Up to 32 days ]
    Maximum plasma concentration (Cmax) of azacitidine

  4. Tmax for venetoclax [ Time Frame: Up to 32 days ]
    Time to Cmax (peak time, Tmax) for venetoclax

  5. Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine [ Time Frame: Measured from Day 1 until day 28 per dose level. ]
  6. AUC[0 to infinity] for azacitidine [ Time Frame: Up to 32 days ]
    Area under the plasma concentration-time curve from Time 0 to infinite time.

  7. Tmax for azacitidine [ Time Frame: Up to 32 days ]
    Time to Cmax (peak time, Tmax) for azacitidine

  8. AUC [0-24] for venetoclax [ Time Frame: Up to 32 days ]
    AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax

  9. AUCt for venetoclax [ Time Frame: 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

  10. Cmax of venetoclax [ Time Frame: Up to 32 days ]
    Maximum plasma concentration (Cmax) of venetoclax

  11. Half-life (t[1/2]) for azacitidine [ Time Frame: Up to 32 days ]
    Terminal elimination half-life (t[1/2]) for azacitidine

  12. Number of Participants With Adverse Events (AEs) [ Time Frame: 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 :
  1. Event-Free Survival (EFS) [ Time Frame: 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. ]
  2. Overall Survival (OS) [ 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 subject is enrolled. ]
  3. Rate of Modified Overall Response (mORR) [ Time Frame: 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.

  4. Time to next treatment (TTNT) [ Time Frame: 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. ]
  5. Duration of mORR [ Time Frame: 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..

  6. Rate of platelet (PLT) transfusion independence [ Time Frame: 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

  7. Time to Transformation acute myeloid leukemia (AML) [ Time Frame: 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.

  8. Progression-Free Survival (PFS) [ Time Frame: 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. ]
  9. Overall Response Rate (ORR) [ Time Frame: 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.

  10. Complete Remission (CR) Rate [ Time Frame: 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.

  11. Rate of red blood cell (RBC) transfusion independence [ Time Frame: 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.

  12. Duration of Complete Response (CR) [ Time Frame: 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.

  13. Rate of Hematologic Improvement (HI) [ Time Frame: 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)

  14. Rate of marrow complete remission (mCR) [ Time Frame: 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.

  15. Duration of ORR [ Time Frame: 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.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. 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
    2. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02966782


Locations
Show Show 23 study locations
Sponsors and Collaborators
AbbVie
Celgene; Genentech, Inc.
Investigators
Layout table for investigator information
Study Director: ABBVIE INC. AbbVie
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02966782    
Other Study ID Numbers: M15-522
2016-001904-46 ( EudraCT Number )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: August 9, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AbbVie:
Relapsed/refractory
Venetoclax
Azacitidine
Additional relevant MeSH terms:
Layout table for MeSH terms
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors