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Completed

NCT Number: NCT02966782

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

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).

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Key information

Conditions

Myelodysplastic Syndromes (MDS) Bone Marrow Diseases Disease Attributes Hematologic Diseases Hemic and Lymphatic Diseases Myelodysplastic Syndromes Pathologic Processes Pathological Conditions, Signs and Symptoms Recurrence

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

St George Hospital /ID# 156037, Kogarah, New South Wales, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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:
  • 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
  • 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.

Treatment and study plan

Venetoclax

Drug

Tablet

Other names: ABT-199, GDC-0199

Azacitidine

Drug

Powder for injection, subcutaneously or intravenous

Other names: Vidaza

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

AbbVie

Industry

Collaborators

  • Celgene; Genentech, Inc.

Registry information

Official study 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

Important dates

Study start
2017
Primary completion
2023
Study completion
2023
First posted
Nov 17, 2016
Registry last updated
May 9, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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