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A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk 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: NCT02942290
Recruitment Status : Active, not recruiting
First Posted : October 24, 2016
Last Update Posted : January 26, 2023
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Study Description
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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.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes (MDS) Drug: Azacitidine Drug: Venetoclax Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 129 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : January 12, 2017
Estimated Primary Completion Date : June 28, 2024
Estimated Study Completion Date : June 28, 2024

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Venetoclax + Azacitidine Drug: Azacitidine
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.

Drug: Venetoclax
Oral; Tablet
Other Names:
  • ABT-199
  • GDC-0199
  • VENCLEXTA


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

  3. 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.

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

  5. 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.

  6. Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine [ Time Frame: 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].

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

  8. Cmax for azacitidine [ Time Frame: Up to 32 days ]
    Maximum plasma concentration (Cmax) of azacitidine.

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

  10. Clearance (CL) for azacitidine [ Time Frame: Up to 32 days ]
    Clearance is defined as the volume of plasma cleared of the drug per unit time.

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

  12. Complete Remission (CR) Rate [ 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. ]
    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 Outcome Measures :
  1. Rate of red blood cell (RBC) transfusion independence [ 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. ]
    Percentages of participants who become RBC transfusion-independent.

  2. Progression-Free Survival (PFS) [ 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. ]
    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.

  3. 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 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.

  4. Hematologic Improvement (HI) rate [ 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. ]
    Percentages of participants with HI (erythroid/platelet/neutrophil responses).

  5. Rate of platelet (PLT) transfusion independence [ 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. ]
    Percentages of participants who become platelet transfusion-independent.

  6. Event-Free Survival (EFS) [ 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 ]
    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.

  7. Time to transformation to acute myeloid leukemia (AML) [ 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. ]
    Defined as the number of days from the date of the first dose of study drug to the date of documented AML transformation.

  8. Overall Response Rate (ORR) [ 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. ]
    ORR (equals the rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine.

  9. Time to next treatment (TTNT) [ 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. ]
    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.

  10. Marrow Complete Remission (mCR) Rate [ 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. ]
    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.

  11. Modified Overall Response Rate (mORR) [ 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. ]
    mORR (equals CR + PR + mCR) of venetoclax in combination with azacitidine.

  12. Duration 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. ]
    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. Duration of mORR [ 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 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.

  14. Duration of ORR [ 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 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.

  15. Rate of 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. ]
    The AML transformation rate is defined as the proportion of participants transformed to Acute Myelogenous Leukemia.

  16. Time to First Response (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 (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.

  17. Time to First Response (mORR) [ 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 (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).

  18. Time to First Response (ORR) [ 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 (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).


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

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.
Contacts and Locations
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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): NCT02942290


Locations
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Sponsors and Collaborators
AbbVie
Genentech, Inc.
Investigators
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Study Director: ABBVIE INC. AbbVie
More Information
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Additional Information:

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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02942290    
Other Study ID Numbers: M15-531
2016-001657-41 ( EudraCT Number )
First Posted: October 24, 2016    Key Record Dates
Last Update Posted: January 26, 2023
Last Verified: January 2023
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:
Higher-Risk (HR) Myelodysplastic Syndromes (MDS)
Pharmacokinetic
Venetoclax
Azacitidine
 Acute Myelogenous Leukemia
Myelodysplastic Syndromes (MDS)
Treatment-Naïve Higher-Risk
Additional relevant MeSH terms:
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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