A Study Evaluating Venetoclax in Combination With Azacitidine in Participants With Treatment-Naïve Higher-Risk Myelodysplastic Syndromes (MDS)

Myelodysplastic Syndromes (MDS) Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02942290
• Other study ID #: M15-531
• Secondary ID: 2016-001657-41
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 12, 2017
• Est. completion date: January 8, 2027

Study information

• Verified date: June 2024
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 129
• Est. completion date: January 8, 2027
• Est. primary completion date: January 8, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Myelodysplastic Syndromes (MDS)
• Preleukemia
• Syndrome

Intervention

Drug:
• 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.
• Venetoclax
Oral; Tablet

Locations

Country	Name	City	State
Australia	Concord Repatriation General Hospital /ID# 154958	Concord	New South Wales
Australia	Duplicate_St. Vincent's Hospital, Darlinghurst /ID# 222846	Darlinghurst	New South Wales
Australia	Austin Health /ID# 154955	Heidelberg	Victoria
Australia	St George Hospital /ID# 154954	Kogarah	New South Wales
Australia	Liverpool Hospital /ID# 222410	Liverpool	New South Wales
Australia	The Alfred Hospital /ID# 154956	Melbourne	Victoria
Australia	Fiona Stanley Hospital /ID# 222847	Murdoch	Western Australia
Australia	Calvary Mater Newcastle /ID# 154957	Waratah	New South Wales
Australia	Princess Alexandra Hospital /ID# 154990	Woolloongabba	Queensland
Canada	Juravinski Cancer Centre /ID# 152947	Hamilton	Ontario
France	CHU de Nantes, Hotel Dieu -HME /ID# 153828	Nantes	Pays-de-la-Loire
France	AP-HP - Hopital Saint-Louis /ID# 153827	Paris
Germany	Duplicate_Universitaetsklinikum Carl Gus /ID# 153958	Dresden	Sachsen
Germany	Universitaetsklinikum Halle (Saale) /ID# 153760	Halle (Saale)
Germany	Universitaetsklinikum Koeln /ID# 153141	Köln	Nordrhein-Westfalen
Germany	Universitaetsklinikum Leipzig /ID# 153142	Leipzig	Sachsen
Germany	Universitatsklinikum Mannheim /ID# 153140	Mannheim	Baden-Wuerttemberg
Germany	Klinikum rechts der Isar /ID# 153139	Munich
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 153763	Bologna
Italy	Duplicate_Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 153764	Rome	Roma
United Kingdom	University Hospitals Birmingham NHS Foundation Trust /ID# 158810	Birmingham
United Kingdom	King's College Hospital NHS Foundation Trust /ID# 156489	London
United Kingdom	Norfolk and Norwich University Hospitals NHS Foundation Trust /ID# 156492	Norwich	Norfolk
United Kingdom	Oxford University Hospitals NHS Foundation Trust /ID# 222567	Oxford	Oxfordshire
United States	University of Maryland Medical Center /ID# 153669	Baltimore	Maryland
United States	Dana-Farber Cancer Institute /ID# 152735	Boston	Massachusetts
United States	Tufts Medical Center /ID# 153672	Boston	Massachusetts
United States	The University of Chicago Medical Center /ID# 153673	Chicago	Illinois
United States	UT MD Anderson Cancer Center /ID# 153809	Houston	Texas
United States	Tennessee Oncology-Nashville Centennial /ID# 222769	Nashville	Tennessee
United States	Vanderbilt University Medical Center /ID# 152738	Nashville	Tennessee
United States	Columbia University Medical Center /ID# 153661	New York	New York
United States	Weill Cornell Medical College /ID# 155524	New York	New York
United States	University of Pittsburgh MC /ID# 153662	Pittsburgh	Pennsylvania
United States	Oregon Medical Research Center /ID# 152734	Portland	Oregon
United States	Washington University-School of Medicine /ID# 153671	Saint Louis	Missouri
United States	University of Arizona Cancer Center - North Campus /ID# 154155	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Cmax of venetoclax	Maximum plasma concentration (Cmax) of venetoclax.	Up to 32 days
Primary	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
Primary	Tmax of venetoclax	Time to Cmax (peak time, Tmax) of venetoclax.	Up to 32 days
Primary	AUC[0 to infinity] for azacitidine	Area under the plasma concentration-time curve from Time 0 to infinite time.	Up to 32 days
Primary	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].	Measured from Day 1 until Day 28 per dose level.
Primary	Half-life (t[1/2]) for azacitidine	Terminal elimination half-life (t[1/2]) for azacitidine.	Up to 32 days
Primary	Cmax for azacitidine	Maximum plasma concentration (Cmax) of azacitidine.	Up to 32 days
Primary	AUC[0-24] for venetoclax	AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax.	Up to 32 days
Primary	Clearance (CL) for azacitidine	Clearance is defined as the volume of plasma cleared of the drug per unit time.	Up to 32 days
Primary	Tmax for azacitidine	Time to Cmax (peak time, Tmax) of azacitidine.	Up to 32 days
Primary	Complete Remission (CR) Rate	Complete remission rate will be defined as the proportion of participants who achieved a complete response per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes (MDS).	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	Rate of red blood cell (RBC) transfusion independence	Percentages of participants who become RBC transfusion-independent.	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	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.	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	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.	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.
Secondary	Hematologic Improvement (HI) rate	Percentages of participants with HI (erythroid/platelet/neutrophil responses).	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	Rate of platelet (PLT) transfusion independence	Percentages of participants who become platelet transfusion-independent.	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	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.	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
Secondary	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.	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	Overall Response Rate (ORR)	ORR (equals the rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine.	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	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.	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.
Secondary	Marrow Complete Remission (mCR) Rate	Defined as the proportion of participants who achieved a marrow complete response with or without hematological improvement per the International Working Group (IWG) 2006 criteria for Myelodysplastic Syndromes.	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	Modified Overall Response Rate (mORR)	mORR (equals CR + PR + mCR) of venetoclax in combination with azacitidine.	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	Duration of CR	Duration of CR will be defined as the number of days from the date of first response CR to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	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	Duration of mORR	Duration of response (mORR) will be defined as the number of days from the date of first response (CR, PR or mCR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	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	Duration of ORR	Duration of response (ORR) will be defined as the number of days from the date of first response (CR or PR) to the earliest documentation of progressive disease or death of any cause, whichever occurs earlier.	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	Rate of AML transformation	The AML transformation rate is defined as the proportion of participants transformed to Acute Myelogenous Leukemia.	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	Time to First Response (CR)	Time to first response (CR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of CR.	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	Time to First Response (mORR)	Time to first response (mORR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of (CR, PR, or mCR).	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	Time to First Response (ORR)	Time to first response (ORR) will be defined as the number of days from the date of first dose of the study drug to the date of the first response of (CR or PR).	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.

External Links

•   This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.