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

• ClinicalTrials.gov Identifier: NCT02942290
• Recruitment Status: Active, not recruiting
• First Posted: October 24, 2016
• Last Update Posted: January 25, 2021
• Sponsor: AbbVie
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: October 18, 2016
• First Posted Date: October 24, 2016
• Last Update Posted Date: January 25, 2021
• Actual Study Start Date: January 12, 2017
• Estimated Primary Completion Date: July 15, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (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. ]

Current Secondary Outcome Measures (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 (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: A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)
• 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)
• 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: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelodysplastic Syndromes (MDS)

Intervention

• 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

Experimental: Venetoclax + Azacitidine

Interventions:

• Drug: Azacitidine
• Drug: Venetoclax

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 22, 2021): 137
• Original Estimated Enrollment (submitted: October 20, 2016): 90
• Estimated Study Completion Date: July 15, 2022
• Estimated Primary Completion Date: July 15, 2022 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, France, Germany, Italy, United Kingdom, United States

Administrative Information

• NCT Number: NCT02942290
• Other Study ID Numbers: 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

• Plan to Share IPD: No

• Responsible Party: AbbVie
• Study Sponsor: AbbVie
• Collaborators: Genentech, Inc.

Investigators

• Study Director: AbbVie Inc.; AbbVie

• PRS Account: AbbVie
• Verification Date: January 2021