Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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 25, 2021
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE October 18, 2016
First Posted Date  ICMJE October 24, 2016
Last Update Posted Date January 25, 2021
Actual Study Start Date  ICMJE January 12, 2017
Estimated Primary Completion Date July 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 22, 2020)
  • 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.
  • Cmax of venetoclax [ Time Frame: Up to 32 days ]
    Maximum plasma concentration (Cmax) of venetoclax.
  • 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.
  • Tmax of venetoclax [ Time Frame: Up to 32 days ]
    Time to Cmax (peak time, Tmax) of venetoclax.
  • 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.
  • 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].
  • Half-life (t[1/2]) for azacitidine [ Time Frame: Up to 32 days ]
    Terminal elimination half-life (t[1/2]) for azacitidine.
  • Cmax for azacitidine [ Time Frame: Up to 32 days ]
    Maximum plasma concentration (Cmax) of azacitidine.
  • AUC[0-24] for venetoclax [ Time Frame: Up to 32 days ]
    AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax.
  • 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.
  • Tmax for azacitidine [ Time Frame: Up to 32 days ]
    Time to Cmax (peak time, Tmax) of azacitidine.
Original Primary Outcome Measures  ICMJE
 (submitted: October 20, 2016)
  • Maximum plasma concentration (Cmax) of venetoclax [ Time Frame: Pharmacokinetic (PK) samples for venetoclax will be collected on Cycle 1 Days 1, 2-4, Cycle 2 Day 4 and on Day 5 of Cycles 3, 4, 6, and 8; 28-day cycles. ]
  • Time to Cmax (peak time, Tmax) for venetoclax [ Time Frame: PK samples for venetoclax will be collected on Cycle 1 Days 1, 2-4, Cycle 2 Day 4 and on Day 5 of Cycles 3, 4, 6, and 8; 28-day cycles. ]
  • Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax [ Time Frame: PK samples for venetoclax will be collected on Cycle 1 Days 1, 2-4, Cycle 2 Day 4 and on Day 5 of Cycles 3, 4, 6, and 8; 28-day cycles. ]
  • AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax [ Time Frame: PK samples for venetoclax will be collected on Cycle 1 Days 1, 2-4, Cycle 2 Day 4 and on Day 5 of Cycles 3, 4, 6, and 8; 28-day cycles. ]
  • Cmax for azacitidine [ Time Frame: PK samples for IV and subcutaneous (SC) azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • Tmax for azacitidine [ Time Frame: PK samples for IV and SC azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • Half-life (t[1/2]) for for azacitidine [ Time Frame: PK samples for IV and SC azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • AUCt for azacitidine [ Time Frame: PK samples for IV and SC azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • AUC from 0 to infinity (AUC∞) for azacitidine [ Time Frame: PK samples for IV and SC azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • Clearance (CL) for azacitidine [ Time Frame: PK samples for IV and SC azacitidine collected on Day 5 of Cycles 1, 3, 4, 6, and 8 as well as Day 4 of Cycle 2; 28-day cycles. ]
  • Overall Response Rate (ORR) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years.. ]
    ORR (equals the sum of rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine (venetoclax 400 mg + azacitidine and venetoclax 800 mg + azacitidine) and of azacitidine monotherapy.
  • Determine recommended dose (RD) and dosing schedule of venetoclax in combination with azacitidine [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years.. ]
  • Percentage of participants with adverse events [ Time Frame: From participants first visit until 30 days after the participant's last dose of study drug to 5 years. ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 22, 2020)
  • 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 or death from any cause.
  • 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.
  • 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.
  • 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. ]
    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.
  • 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).
  • 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.
  • 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 ]
    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.
  • 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.
  • 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).
  • 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 rates of complete remission [CR] + marrow complete remission [mCR] + partial remission [PR]) of venetoclax in combination with azacitidine.
  • 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. ]
    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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 20, 2016)
  • Complete Response (CR) rate [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Complete response rate will be defined as the proportion of subjects who achieved a complete response per the International Working Group (IWG) criteria for Myelodysplastic Syndromes (MDS).
  • Hematologic Improvement (HI) rate [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Percentages of participants with HI (erythroid/platelet/neutrophil responses)
  • Percentage of red blood cell (RBC) transfusion independence [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Percentages of participants who become RBC transfusion-independent
  • Percentage of platelet transfusion independence [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years . ]
    Percentages of participants who become platelet transfusion-independent
  • Percentage of cytogenetic response [ Time Frame: Measured from Screening until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Percentages of participants with cytogenetic response
  • Percentage of bone marrow blast response [ Time Frame: Measured from Screening until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Percentages of participants with a bone marrow blast response
  • Time to transformation to acute myelogenous leukemia (AML) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    Time to AML transformation will be defined as the number of days from the date of randomization to the date of documented AML transformation, defined as a bone marrow blast count greater than or equal to 30% independent of baseline bone marrow count.
  • Duration of Response (DOR) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years . ]
    DOR is defined as the number of days from the date of first response (CR or PR) to the earliest documentation of progressive disease.
  • Overall Survival (OS) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    OS defined as the number of days from the date of randomization to the date of death.
  • Progression-Free Survival (PFS) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    PFS defined as the number of days from the date of randomization to the date of earliest disease progression or death. If the subject does not experience disease progression or death, then the data will be censored at the date of the last disease assessment.
  • Time to next anti-MDS treatment (TTNT) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
    TTNT defined as the time from randomization to start of new non-protocol specified MDS therapy.
  • Event-Free Survival (EFS) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years . ]
    EFS defined as the number of days from the date of randomization to the date of earliest disease progression, death, or initiation of new non-protocol-specified anti-MDS therapy without documented progression.
  • Patient-Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue Short Form (SF) 7a [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
  • PROMIS Physical Function SF 10a [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years. ]
  • Global Health Status/Quality of Life (GHS/QoL) [ Time Frame: Measured from Day 1 until evidence of MDS progression, the occurrence of unacceptable toxicity, death, exercise of investigator discretion, withdrawal of consent or, if clinically indicated up to 5 years . ]
    Global health status/quality of life will be assessed using the GHS/QoL scale from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core [EORTC QLQ-C30]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)
Official Title  ICMJE 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)
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Myelodysplastic Syndromes (MDS)
Intervention  ICMJE
  • 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
Study Arms  ICMJE Experimental: Venetoclax + Azacitidine
Interventions:
  • Drug: Azacitidine
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 22, 2021)
137
Original Estimated Enrollment  ICMJE
 (submitted: October 20, 2016)
90
Estimated Study Completion Date  ICMJE July 15, 2022
Estimated Primary Completion Date July 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   France,   Germany,   Italy,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02942290
Other Study ID Numbers  ICMJE M15-531
2016-001657-41 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP