Clinical trial NCT02966782: A Study Evaluating Venetoclax Alone and in Combination With Azacitidine in Participants With Relapsed/Refractory Myelodysplastic Syndromes (MDS)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes (MDS)
Keywords: Relapsed/refractory
Venetoclax
Azacitidine
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Celgene; Genentech, Inc.
First posted: 2016-11-17
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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.

Primary outcomes:
measure: AUCt for azacitidine
timeFrame: Up to 32 days
measure: Clearance (CL) for azacitidine
timeFrame: Up to 32 days
measure: Cmax for azacitidine
timeFrame: Up to 32 days
measure: Tmax for venetoclax
timeFrame: Up to 32 days
measure: Recommended Phase 2 Dose (RPTD) and dosing schedules of venetoclax as monotherapy and in combination with azacitidine
timeFrame: Measured from Day 1 until day 28 per dose level.
measure: AUC[0 to infinity] for azacitidine
timeFrame: Up to 32 days
measure: Tmax for azacitidine
timeFrame: Up to 32 days
measure: AUC [0-24] for venetoclax
timeFrame: Up to 32 days
measure: AUCt for venetoclax
timeFrame: Up to 32 days
measure: Cmax of venetoclax
timeFrame: Up to 32 days
measure: Half-life (t[1/2]) for azacitidine
timeFrame: Up to 32 days
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to Maximum of 24 months
Secondary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: 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.
measure: Overall Survival (OS)
timeFrame: 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.
measure: Rate of Modified Overall Response (mORR)
timeFrame: 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.
measure: Time to next treatment (TTNT)
timeFrame: 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.
measure: Duration of mORR
timeFrame: 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.
measure: Rate of platelet (PLT) transfusion independence
timeFrame: 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.
measure: Time to Transformation acute myeloid leukemia (AML)
timeFrame: 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.
measure: Progression-Free Survival (PFS)
timeFrame: 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.
measure: Overall Response Rate (ORR)
timeFrame: 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.
measure: Complete Remission (CR) Rate
timeFrame: 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.
measure: Rate of red blood cell (RBC) transfusion independence
timeFrame: 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.
measure: Duration of Complete Response (CR)
timeFrame: 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.
measure: Rate of Hematologic Improvement (HI)
timeFrame: 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.
measure: Rate of marrow complete remission (mCR)
timeFrame: 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.
measure: Duration of ORR
timeFrame: 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus /ID# 157503
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Hospital /ID# 155365
state: Colorado
city: New Haven
country: United States
facility: Yale University /ID# 162544
state: Connecticut
city: Chicago
country: United States
facility: Duplicate_University of Chicago /ID# 155364
state: Illinois
city: Boston
country: United States
facility: Pediatric Endocrine Associates /ID# 171227
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 155361
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts - Worcester /ID# 155366
state: Massachusetts
city: New York
country: United States
facility: Columbia Univ Medical Center /ID# 156388
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University /ID# 155360
state: Oregon
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center /ID# 155362
state: Texas
city: Kogarah
country: Australia
facility: St George Hospital /ID# 156037
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital /ID# 155952
state: New South Wales
city: Fitzroy Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne /ID# 155950
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital /ID# 155949
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital /ID# 155951
state: Western Australia
city: Mannheim
country: Germany
facility: Universitatsklinikum Mannheim /ID# 156038
state: Baden-Wuerttemberg
city: Duesseldorf
country: Germany
facility: Marien Hospital Duesseldorf /ID# 155518
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf /ID# 154899
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Universitaetsklinikum Koeln /ID# 155519
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig /ID# 154897
state: Sachsen
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898
city: Halle (Saale)
country: Germany
facility: Universitaetsklinikum Halle (Saale) /ID# 158643
city: Munich
country: Germany
facility: Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: 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.