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

NCT02966782 | Completed Phase 1 FDA Drug

• 2 other identifiers: M15-5222016-001904-46
• Study Type: interventional
• Target: 70
• Locations: 3 countries
• Sites: 23

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).

Conditions

Myelodysplastic Syndromes (MDS)

Keywords

Relapsed/refractory; Venetoclax; Azacitidine

Outcome Measures

Primary Outcomes (12)

• AUCt for azacitidine

  Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine

  Up to 32 days

• Clearance (CL) for azacitidine

  Up to 32 days

• Cmax for azacitidine

  Maximum plasma concentration (Cmax) of azacitidine

  Up to 32 days

• Tmax for venetoclax

  Time to Cmax (peak time, Tmax) for venetoclax

  Up to 32 days

• Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine

  Measured from Day 1 until day 28 per dose level.

• AUC[0 to infinity] for azacitidine

  Area under the plasma concentration-time curve from Time 0 to infinite time.

  Up to 32 days

• Tmax for azacitidine

  Time to Cmax (peak time, Tmax) for azacitidine

  Up to 32 days

• AUC [0-24] for venetoclax

  AUC over a 24-hour dose interval (AUC\[0-24\]) for venetoclax

  Up to 32 days

• AUCt for venetoclax

  Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax

  Up to 32 days

• Cmax of venetoclax

  Maximum plasma concentration (Cmax) of venetoclax

  Up to 32 days

• Half-life (t[1/2]) for azacitidine

  Terminal elimination half-life (t\[1/2\]) for azacitidine

  Up to 32 days

• Number of Participants With Adverse Events (AEs)

  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.

  Up to Maximum of 24 months

Secondary Outcomes (15)

• Event-Free Survival (EFS)

  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.

• Overall Survival (OS)

  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.

• Rate of Modified Overall Response (mORR)

  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.

• Time to next treatment (TTNT)

  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.

• Duration of mORR

  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.

Study Arms (3)

Venetoclax monotherapy (Cohort 1)

EXPERIMENTAL

Drug: venetoclax

Venetoclax + azacitidine (Cohort 2)

EXPERIMENTAL

Drug: venetoclax; Drug: azacitidine

Safety Expansion (Cohort 3)

EXPERIMENTAL

Drug: venetoclax; Drug: azacitidine

Interventions

venetoclax DRUG

Tablet

Also known as: ABT-199, GDC-0199

Safety Expansion (Cohort 3); Venetoclax + azacitidine (Cohort 2); Venetoclax monotherapy (Cohort 1)

azacitidine DRUG

Powder for injection, subcutaneously or intravenous

Also known as: Vidaza

Safety Expansion (Cohort 3); Venetoclax + azacitidine (Cohort 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AbbVie: lead
• Celgene; Genentech, Inc.: collaborator

Study Sites (23)

University of Arizona Cancer Center - North Campus /ID# 157503

Tucson, Arizona, 85719-1478, United States

Location

University of Colorado Hospital /ID# 155365

Aurora, Colorado, 80045, United States

Location

Yale University /ID# 162544

New Haven, Connecticut, 06510, United States

Location

Duplicate_University of Chicago /ID# 155364

Chicago, Illinois, 60637, United States

Location

Pediatric Endocrine Associates /ID# 171227

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute /ID# 155361

Boston, Massachusetts, 02215, United States

Location

University of Massachusetts - Worcester /ID# 155366

Worcester, Massachusetts, 01655, United States

Location

Columbia Univ Medical Center /ID# 156388

New York, New York, 10032-3725, United States

Location

Oregon Health and Science University /ID# 155360

Portland, Oregon, 97239, United States

Location

University of Texas MD Anderson Cancer Center /ID# 155362

Houston, Texas, 77030, United States

Location

St George Hospital /ID# 156037

Kogarah, New South Wales, 2217, Australia

Location

Liverpool Hospital /ID# 155952

Liverpool, New South Wales, 2170, Australia

Location

St Vincent's Hospital Melbourne /ID# 155950

Fitzroy Melbourne, Victoria, 3065, Australia

Location

The Royal Melbourne Hospital /ID# 155949

Parkville, Victoria, 3050, Australia

Location

Royal Perth Hospital /ID# 155951

Perth, Western Australia, 6000, Australia

Location

Universitatsklinikum Mannheim /ID# 156038

Mannheim, Baden-Wurttemberg, 68167, Germany

Location

Universitaetsklinikum Koeln /ID# 155519

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Universitaetsklinikum Duesseldorf /ID# 154899

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Marien Hospital Duesseldorf /ID# 155518

Düsseldorf, North Rhine-Westphalia, 40479, Germany

Location

Universitaetsklinikum Leipzig /ID# 154897

Leipzig, Saxony, 04103, Germany

Location

Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898

Dresden, 01307, Germany

Location

Universitaetsklinikum Halle (Saale) /ID# 158643

Halle, 06120, Germany

Location

Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896

Munich, 81675, Germany

Location

Related Publications (2)

• Zeidan AM, Borate U, Pollyea DA, Brunner AM, Roncolato F, Garcia JS, Filshie R, Odenike O, Watson AM, Krishnadasan R, Bajel A, Naqvi K, Zha J, Cheng WH, Zhou Y, Hoffman D, Harb JG, Potluri J, Garcia-Manero G. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. 2023 Feb;98(2):272-281. doi: 10.1002/ajh.26771. Epub 2022 Nov 10.

  PMID: 36309981 DERIVED

• Franke GN, Luckemeier P, Platzbecker U. Allogeneic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes and Prevention of Relapse. Clin Lymphoma Myeloma Leuk. 2021 Jan;21(1):1-7. doi: 10.1016/j.clml.2020.10.008. Epub 2020 Oct 16.

  PMID: 33191169 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes; Recurrence

Interventions

venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2016
• First Posted: November 17, 2016
• Study Start: March 7, 2017
• Primary Completion: April 5, 2023
• Study Completion: April 5, 2023
• Last Updated: May 9, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); AU (5); DE (8)