Clinical trial NCT02942290: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Myelodysplastic Syndromes (MDS)
Keywords: Higher-Risk (HR) Myelodysplastic Syndromes (MDS)
Pharmacokinetic
Venetoclax
Azacitidine
Acute Myelogenous Leukemia
Myelodysplastic Syndromes (MDS)
Treatment-Naïve Higher-Risk
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Genentech, Inc.
First posted: 2016-10-24
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: AUCt for Azacitidine
timeFrame: Up to 32 days
measure: Cmax of venetoclax
timeFrame: Up to 32 days
measure: AUCt for venetoclax
timeFrame: Up to 32 days
measure: Tmax of venetoclax
timeFrame: Up to 32 days
measure: AUC[0 to infinity] for azacitidine
timeFrame: Up to 32 days
measure: Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine
timeFrame: Measured from Day 1 until Day 28 per dose level.
measure: Half-life (t[1/2]) for azacitidine
timeFrame: Up to 32 days
measure: Cmax for azacitidine
timeFrame: Up to 32 days
measure: AUC[0-24] for venetoclax
timeFrame: Up to 32 days
measure: Clearance (CL) for azacitidine
timeFrame: Up to 32 days
measure: Tmax for azacitidine
timeFrame: Up to 32 days
measure: Complete Remission (CR) Rate
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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.
Secondary outcomes:
measure: Rate of red blood cell (RBC) transfusion independence
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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: Progression-Free Survival (PFS)
timeFrame: 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.
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 participant is enrolled.
measure: Hematologic Improvement (HI) rate
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 platelet (PLT) transfusion independence
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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: Event-Free Survival (EFS)
timeFrame: 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 participant is enrolled
measure: Time to transformation to acute myeloid leukemia (AML)
timeFrame: 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.
measure: Overall Response Rate (OR)
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 the first dose of study drug to start of new non-protocol specified MDS therapy, and for up to 5 years after the last participant is enrolled.
measure: Marrow Complete Remission (mCR) Rate
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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: Modified Overall Response Rate (mOR)
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 CR
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 mOR
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 OR
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 AML transformation
timeFrame: 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.
measure: Time to First Response (CR)
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 First Response (mOR)
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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 First Response (OR)
timeFrame: Measured from Cycle 1 Day 1 as long as the participant 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center - North Campus /ID# 154155
state: Arizona
city: Chicago
country: United States
facility: The University of Chicago Medical Center /ID# 153673
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center /ID# 153669
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center /ID# 153672
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 152735
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University-School of Medicine /ID# 153671
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center /ID# 153661
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College /ID# 155524
state: New York
city: Portland
country: United States
facility: Oregon Medical Research Center /ID# 152734
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh MC /ID# 153662
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology-Nashville Centennial /ID# 222769
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center /ID# 152738
state: Tennessee
city: Houston
country: United States
facility: UT MD Anderson Cancer Center /ID# 153809
state: Texas
city: Concord
country: Australia
facility: Concord Repatriation General Hospital /ID# 154958
state: New South Wales
city: Darlinghurst
country: Australia
facility: Duplicate_St. Vincent's Hospital, Darlinghurst /ID# 222846
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital /ID# 154954
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital /ID# 222410
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle /ID# 154957
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital /ID# 154990
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Health /ID# 154955
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital /ID# 154956
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital /ID# 222847
state: Western Australia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre /ID# 152947
state: Ontario
city: Nantes
country: France
facility: CHU de Nantes, Hotel Dieu -HME /ID# 153828
state: Pays-de-la-Loire
city: Paris
country: France
facility: AP-HP - Hopital Saint-Louis /ID# 153827
city: Mannheim
country: Germany
facility: Universitatsklinikum Mannheim /ID# 153140
state: Baden-Wuerttemberg
city: Köln
country: Germany
facility: Universitaetsklinikum Koeln /ID# 153141
state: Nordrhein-Westfalen
city: Dresden
country: Germany
facility: Duplicate_Universitaetsklinikum Carl Gus /ID# 153958
state: Sachsen
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig /ID# 153142
state: Sachsen
city: Halle (Saale)
country: Germany
facility: Universitaetsklinikum Halle (Saale) /ID# 153760
city: Munich
country: Germany
facility: Klinikum rechts der Isar /ID# 153139
city: Rome
country: Italy
facility: Duplicate_Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 153764
state: Roma
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 153763
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals NHS Foundation Trust /ID# 156492
state: Norfolk
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust /ID# 222567
state: Oxfordshire
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust /ID# 158810
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust /ID# 156489
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References: