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

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ClinicalTrials.gov Identifier: NCT02942290
Recruitment Status : Recruiting
First Posted : October 24, 2016
Last Update Posted : August 7, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Brief Summary:
This is a Phase 1b, open-label, non-randomized, multicenter, dose-finding study evaluating venetoclax in combination with azacitidine in subjects 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
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 : March 1, 2020
Estimated Study Completion Date : June 30, 2021


Arm Intervention/treatment
Experimental: Venetoclax + Azacitidine Drug: Azacitidine
Powder for injection; taken subcutaneously 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
Tablet
Other Names:
  • ABT-199
  • GDC-0199




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


Secondary Outcome Measures :
  1. Duration of Response (DOR) [ 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.

  2. 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. ]
    Percentages of participants who become RBC transfusion-independent

  3. 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. ]
  4. 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. ]
  5. Hematologic Improvement (HI) 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. ]
    Percentages of participants with HI (erythroid/platelet/neutrophil responses)

  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. ]
    Percentages of participants who become platelet transfusion-independent

  7. 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 subject is enrolled ]
  8. 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.

  9. 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. ]
    Complete remission rate will be defined as the proportion of subjects who achieved a complete response per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes (MDS).

  10. 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 in combination with azacitidine.

  11. Rate of complete cytogenetic response [ Time Frame: Measured from Screening 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. ]
    Percentages of participants with complete cytogenetic response

  12. 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 subject is enrolled. ]
  13. Marrow Complete Remission (mCR) 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. ]
    Defined as the proportion of subjects who achieved a marrow complete response with or without hematological improvement per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes.



Information from the National Library of Medicine

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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 de novo MDS with:

    • International Prognostic Scoring System (IPSS) risk categories Int-2 or High (minimum IPSS overall score of 1.5) and
    • Presence of less than 20% bone marrow blasts per bone marrow
  • Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2.
  • Participant is not a candidate to undergo intensive chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT).

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 BH3 mimetic.
  • Participant has a diagnosis other than previously untreated de novo MDS with IPSS risk categories Int-2 or High, 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 HSCT or solid organ transplantation.
  • Participant has received a live attenuated vaccine within 4 weeks prior to the first dose of study drug.

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


Contacts
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Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com

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Sponsors and Collaborators
AbbVie
Genentech, Inc.
Investigators
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Study Director: AbbVie Inc. AbbVie

Additional Information:
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02942290     History of Changes
Other Study ID Numbers: M15-531
2016-001657-41 ( EudraCT Number )
First Posted: October 24, 2016    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
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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Venetoclax
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors