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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02942290




Registration number
NCT02942290
Ethics application status
Date submitted
18/10/2016
Date registered
24/10/2016
Date last updated
25/01/2021

Titles & IDs
Public title
A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)
Scientific 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)
Secondary ID [1] 0 0
2016-001657-41
Secondary ID [2] 0 0
M15-531
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic Syndromes (MDS) 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Azacitidine
Treatment: Drugs - Venetoclax

Experimental: Venetoclax + Azacitidine -


Treatment: Drugs: 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.

Treatment: Drugs: Venetoclax
Oral; Tablet

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
AUCt for azacitidine - Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine.
Timepoint [1] 0 0
Up to 32 days
Primary outcome [2] 0 0
Cmax of venetoclax - Maximum plasma concentration (Cmax) of venetoclax.
Timepoint [2] 0 0
Up to 32 days
Primary outcome [3] 0 0
AUCt for venetoclax - Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax.
Timepoint [3] 0 0
Up to 32 days
Primary outcome [4] 0 0
Tmax of venetoclax - Time to Cmax (peak time, Tmax) of venetoclax.
Timepoint [4] 0 0
Up to 32 days
Primary outcome [5] 0 0
AUC[0 to infinity] for azacitidine - Area under the plasma concentration-time curve from Time 0 to infinite time.
Timepoint [5] 0 0
Up to 32 days
Primary outcome [6] 0 0
Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine - 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].
Timepoint [6] 0 0
Measured from Day 1 until Day 28 per dose level.
Primary outcome [7] 0 0
Half-life (t[1/2]) for azacitidine - Terminal elimination half-life (t[1/2]) for azacitidine.
Timepoint [7] 0 0
Up to 32 days
Primary outcome [8] 0 0
Cmax for azacitidine - Maximum plasma concentration (Cmax) of azacitidine.
Timepoint [8] 0 0
Up to 32 days
Primary outcome [9] 0 0
AUC[0-24] for venetoclax - AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax.
Timepoint [9] 0 0
Up to 32 days
Primary outcome [10] 0 0
Clearance (CL) for azacitidine - Clearance is defined as the volume of plasma cleared of the drug per unit time.
Timepoint [10] 0 0
Up to 32 days
Primary outcome [11] 0 0
Tmax for azacitidine - Time to Cmax (peak time, Tmax) of azacitidine.
Timepoint [11] 0 0
Up to 32 days
Secondary outcome [1] 0 0
Duration of Response (DOR) - 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.
Timepoint [1] 0 0
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.
Secondary outcome [2] 0 0
Rate of red blood cell (RBC) transfusion independence - Percentages of participants who become RBC transfusion-independent.
Timepoint [2] 0 0
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.
Secondary outcome [3] 0 0
Progression-Free Survival (PFS) - 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.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
Overall Survival (OS) - 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.
Timepoint [4] 0 0
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.
Secondary outcome [5] 0 0
Hematologic Improvement (HI) rate - Percentages of participants with HI (erythroid/platelet/neutrophil responses).
Timepoint [5] 0 0
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.
Secondary outcome [6] 0 0
Rate of platelet (PLT) transfusion independence - Percentages of participants who become platelet transfusion-independent.
Timepoint [6] 0 0
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.
Secondary outcome [7] 0 0
Event-Free Survival (EFS) - 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.
Timepoint [7] 0 0
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
Secondary outcome [8] 0 0
Time to transformation to acute myeloid leukemia (AML) - Defined as the number of days from the date of the first dose of study drug to the date of documented AML transformation.
Timepoint [8] 0 0
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.
Secondary outcome [9] 0 0
Complete Remission (CR) rate - 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).
Timepoint [9] 0 0
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.
Secondary outcome [10] 0 0
Overall Response Rate (ORR) - ORR (equals the rates of complete remission [CR] + marrow complete remission [mCR] + partial remission [PR]) of venetoclax in combination with azacitidine.
Timepoint [10] 0 0
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.
Secondary outcome [11] 0 0
Time to next treatment (TTNT) - 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.
Timepoint [11] 0 0
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.
Secondary outcome [12] 0 0
Marrow Complete Remission (mCR) Rate - 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.
Timepoint [12] 0 0
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.

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
Concord Repatriation & Gen Hos /ID# 154958 - Concord
Recruitment hospital [2] 0 0
St. Vincent's Hospital, Darlinghurst /ID# 222846 - Darlinghurst
Recruitment hospital [3] 0 0
St George Hospital /ID# 154954 - Kogarah
Recruitment hospital [4] 0 0
Liverpool Hospital /ID# 222410 - Liverpool
Recruitment hospital [5] 0 0
Calvary Mater Newcastle /ID# 154957 - Waratah
Recruitment hospital [6] 0 0
Princess Alexandra Hospital /ID# 154990 - Woolloongabba
Recruitment hospital [7] 0 0
Austin Hospital /ID# 154955 - Heidelberg
Recruitment hospital [8] 0 0
Alfred Health /ID# 154956 - Melbourne
Recruitment hospital [9] 0 0
Fiona Stanley Hospital /ID# 222847 - Murdoch
Recruitment postcode(s) [1] 0 0
2139 - Concord
Recruitment postcode(s) [2] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [3] 0 0
2217 - Kogarah
Recruitment postcode(s) [4] 0 0
2170 - Liverpool
Recruitment postcode(s) [5] 0 0
2298 - Waratah
Recruitment postcode(s) [6] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 0 0
3084 - Heidelberg
Recruitment postcode(s) [8] 0 0
3004 - Melbourne
Recruitment postcode(s) [9] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
Missouri
Country [6] 0 0
United States of America
State/province [6] 0 0
New York
Country [7] 0 0
United States of America
State/province [7] 0 0
Oregon
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Tennessee
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
Canada
State/province [11] 0 0
Ontario
Country [12] 0 0
France
State/province [12] 0 0
Pays-de-la-Loire
Country [13] 0 0
France
State/province [13] 0 0
Paris
Country [14] 0 0
Germany
State/province [14] 0 0
Baden-Wuerttemberg
Country [15] 0 0
Germany
State/province [15] 0 0
Nordrhein-Westfalen
Country [16] 0 0
Germany
State/province [16] 0 0
Sachsen
Country [17] 0 0
Germany
State/province [17] 0 0
Halle
Country [18] 0 0
Germany
State/province [18] 0 0
Munich
Country [19] 0 0
Italy
State/province [19] 0 0
Emilia-Romagna
Country [20] 0 0
Italy
State/province [20] 0 0
Lazio
Country [21] 0 0
United Kingdom
State/province [21] 0 0
Norfolk
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Birmingham
Country [23] 0 0
United Kingdom
State/province [23] 0 0
London
Country [24] 0 0
United Kingdom
State/province [24] 0 0
Oxford

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
AbbVie
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Genentech, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02942290
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
AbbVie Inc.
Address 0 0
AbbVie
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications