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

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ClinicalTrials.gov Identifier: NCT02966782
Recruitment Status : Recruiting
First Posted : November 17, 2016
Last Update Posted : June 3, 2019
Sponsor:
Collaborators:
Celgene
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes (MDS) Drug: venetoclax Drug: azacitidine Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Relapsed/Refractory Myelodysplastic Syndromes
Actual Study Start Date : March 7, 2017
Estimated Primary Completion Date : August 4, 2020
Estimated Study Completion Date : August 4, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Venetoclax monotherapy (Cohort 1) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Experimental: Venetoclax + azacitidine (Cohort 2) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Drug: azacitidine
Powder for injection, subcutaneously or intravenous
Other Name: Vidaza

Experimental: Safety Expansion (Cohort 3) Drug: venetoclax
Tablet
Other Names:
  • ABT-199
  • GDC-0199

Drug: azacitidine
Powder for injection, subcutaneously or intravenous
Other Name: Vidaza




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. 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


Secondary Outcome Measures :
  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 bone marrow blast response [ 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 bone marrow blast response

  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 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.

  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. Rate of complete cytogenetic response [ 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 complete cytogenetic response

  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.



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:

  • 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:

    1. 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
    2. 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.

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): NCT02966782


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

Locations
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United States, Arizona
University of Arizona Cancer Center - North Campus /ID# 157503 Recruiting
Tucson, Arizona, United States, 85719-1478
United States, Colorado
University of Colorado /ID# 155365 Recruiting
Aurora, Colorado, United States, 80045
United States, Connecticut
Yale University /ID# 162544 Recruiting
New Haven, Connecticut, United States, 06510
United States, Illinois
University of Chicago /ID# 155364 Recruiting
Chicago, Illinois, United States, 60637
United States, Massachusetts
Mass General Hospital /ID# 171227 Recruiting
Boston, Massachusetts, United States, 02114-4724
Dana-Farber Cancer Institute /ID# 155361 Recruiting
Boston, Massachusetts, United States, 02215
University of Massachusetts Wo /ID# 155366 Recruiting
Worcester, Massachusetts, United States, 01655
United States, New York
Columbia Univ Medical Center /ID# 156388 Recruiting
New York, New York, United States, 10032-3725
United States, Oregon
Oregon Health and Science University /ID# 155360 Recruiting
Portland, Oregon, United States, 97239-3098
United States, Texas
Univ TX, MD Anderson /ID# 155362 Recruiting
Houston, Texas, United States, 77030
Australia, New South Wales
St George Hospital /ID# 156037 Recruiting
Kogarah, New South Wales, Australia, 2217
Liverpool Hospital /ID# 155952 Recruiting
Liverpool, New South Wales, Australia, 2170
Australia, Victoria
St. Vincents Hosp Melbourne /ID# 155950 Recruiting
Fitzroy, Victoria, Australia, 3065
Australia, Western Australia
Royal Perth Hospital /ID# 155951 Recruiting
Shenton Park, Western Australia, Australia, 6008
Australia
Royal Melbourne Hospital /ID# 155949 Recruiting
Melbourne, Australia, 3050
Germany
Universitatsklinikum Mannheim /ID# 156038 Recruiting
Mannheim, Baden-Wuerttemberg, Germany, 68167
Univ Klinikum Duesseldorf /ID# 154899 Recruiting
Dusseldorf, Nordrhein-Westfalen, Germany, 40225
Marien Hospital Dusseldorf /ID# 155518 Recruiting
Dusseldorf, Nordrhein-Westfalen, Germany, 40479
Uniklinik Koln /ID# 155519 Recruiting
Köln, Nordrhein-Westfalen, Germany, 50937
Universitaetsklinikum Carl Gus /ID# 154898 Recruiting
Dresden, Sachsen, Germany, 01307
Universitaetsklinikum Leipzig /ID# 154897 Recruiting
Leipzig, Sachsen, Germany, 04103
Universitatsklinikum Halle /ID# 158643 Recruiting
Halle, Germany, 6120
Klinikum Rechts der Isar /ID# 154896 Recruiting
Munich, Germany, 81675
Sponsors and Collaborators
AbbVie
Celgene
Genentech, Inc.
Investigators
Layout table for investigator information
Study Director: AbbVie Inc. AbbVie

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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT02966782     History of Changes
Other Study ID Numbers: M15-522
2016-001904-46 ( EudraCT Number )
First Posted: November 17, 2016    Key Record Dates
Last Update Posted: June 3, 2019
Last Verified: May 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:
Relapsed/refractory
Venetoclax
Azacitidine
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