Clinical Trials /

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

NCT02966782

Description:

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).

Related Conditions:
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Subjects With Higher-Risk Myelodysplastic Syndromes (MDS) After Hypomethylating Agent-Failure
  • 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 Higher-Risk Myelodysplastic Syndromes After Hypomethylating Agent-Failure

Clinical Trial IDs

  • ORG STUDY ID: M15-522
  • SECONDARY ID: 2016-001904-46
  • NCT ID: NCT02966782

Conditions

  • Myelodysplastic Syndromes (MDS)

Interventions

DrugSynonymsArms
venetoclaxABT-199, GDC-0199Cohort 1 venetoclax monotherapy
azacitidineVidazaCohort 2 venetoclax + azacitidine

Purpose

This is a Phase 1b, dose-ranging, 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 higher-risk Myelodysplastic Syndromes (MDS) after Hypomethylating Agent (HMA)-Failure.

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 venetoclax monotherapyExperimentalCohort 1 has two portions. 1 cycle = 28 days Arm A: venetoclax 400 mg once daily (qd), n=12 Arm B: venetoclax 800mg once daily (qd), n=12 Both arms will be followed with a safety review.
  • venetoclax
Cohort 2 venetoclax + azacitidineExperimentalCohort 2 is dose escalation. 1 cycle = 28 days 3 dose level cohorts: Dose level 1: Venetoclax 100 mg (Days 1-14) + azacitidine 75 mg/m2 (Days 1-7). n=3 Dose Level 2: Venetoclax 200 mg (Days 1-14) + azacitidine 75 mg/m2 (Days 1 -7). n=3 Dose Level 3: Venetoclax 400 mg (Days 1-14) + azacitidine 75 mg/m2 (Days 1-7). n=3
  • venetoclax
  • azacitidine
Cohort 3 (Safety Expansion)ExperimentalAfter completion of Cohorts 1 and 2, an aggregate safety and efficacy review of Cohorts 1 and 2 will be conducted to determine the treatment regimen (venetoclax monotherapy or venetoclax in combination with azacitidine) and preliminary RPTD for the chosen treatment regimen to be evaluated in the safety expansion cohort (Cohort 3).
  • venetoclax
  • azacitidine

Eligibility Criteria

        Inclusion Criteria: - Subject must have failure of prior therapy with HMA for HR MDS as
        first-line MDS treatment with HMA-failure being defined as i) Relapse after initial
        complete or partial response or hematological improvement after at least 6 cycles of
        azacitidine or at least 4 cycles of decitabine within the last 2 years or ii) Failure to
        achieve complete or partial response or hematological improvement after at least 6 cycles
        of azacitidine or at least 4 cycles of decitabine within the last 2 years.

        Note: High-Risk MDS is defined as comprising International Prognostic Scoring System (IPSS)
        risk categories Int-2 or High (IPSS overall score ≥ 1.5)

          -  Subjects must have presence of ≥ 5% and < 20% bone marrow blasts per bone marrow
             biopsy/aspirate at screening.

          -  Subject must have an Eastern Cooperative Oncology Group (ECOG) performance score of
             ≤2.

          -  Participant must have adequate hematologic, renal, and hepatic function.

        Exclusion Criteria: - Subject has received more than 1 prior therapy for MDS. Note: Prior
        supportive care in form in of transfusions or growth factors, etc., is not considered prior
        therapy.

        Supportive care should be discontinued ≥ 14 days prior to the first dose of study drug.

        Subjects may continue oral corticosteroids for management of conditions other than MDS
        (e.g., asthma, rheumatoid arthritis) at a stable daily dose equivalent to ≤ 10 mg
        prednisone during screening and study participation.

          -  Subject had received prior HMA therapy with HMAs for lower-risk MDS with IPSS risk
             categories Low or Int-1 (overall IPSS score < 1.5).

          -  Subject has received therapy other than azacitidine or decitabine for the treatment of
             MDS.

          -  Subject has received prior therapy with a BH3 mimetic.

          -  Subject has therapy-related MDS (t-MDS).

          -  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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description:Maximum plasma concentration (Cmax) of venetoclax

Secondary Outcome Measures

Measure: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.
Safety Issue:
Description:ORR (equals the sum of rates of complete remission [CR] + partial remission [PR]) of venetoclax as a single-agent and in combination with azacitidine.
Measure: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.
Safety Issue:
Description:CR 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)
Measure: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.
Safety Issue:
Description:Percentages of participants with HI (erythroid/platelet/neutrophil responses)
Measure: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.
Safety Issue:
Description:Percentages of red blood cell (RBC) transfusion independence.
Measure: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.
Safety Issue:
Description:Percentages of participants who become platelet transfusion-independent
Measure:Rate of 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.
Safety Issue:
Description:Percentages of participants with cytogenetic response
Measure:Rate of bone marrow blast 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.
Safety Issue:
Description:Percentages of participants with a bone marrow blast response
Measure: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, defined as a bone marrow blast count greater than or equal to 20%, and for an anticipated maximum duration of 24 months.
Safety Issue:
Description:
Measure:Duration of Response (DOR)
Time Frame:Measured from the date of first response (CR or PR) to the earliest documentation of progressive disease (PD), and for an anticipated maximum duration of 24 months.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AbbVie

Trial Keywords

  • Azacitidine
  • Venetoclax
  • Higher-Risk (HR) Myelodysplastic Syndromes (MDS)
  • International Prognostic Scoring System (IPSS)
  • Hypomethylating Agent-Failure (HMA)

Last Updated

October 9, 2017