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

Myelodysplastic Syndromes (MDS) Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02966782
• Other study ID #: M15-522
• Secondary ID: 2016-001904-46
• Status: Completed
• Phase: Phase 1
• Start date: March 7, 2017
• Est. completion date: April 5, 2023

Study information

• Verified date: May 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: April 5, 2023
• Est. primary completion date: April 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• venetoclax
Tablet
• azacitidine
Powder for injection, subcutaneously or intravenous

Locations

Country	Name	City	State
Australia	St Vincent's Hospital Melbourne /ID# 155950	Fitzroy Melbourne	Victoria
Australia	St George Hospital /ID# 156037	Kogarah	New South Wales
Australia	Liverpool Hospital /ID# 155952	Liverpool	New South Wales
Australia	The Royal Melbourne Hospital /ID# 155949	Parkville	Victoria
Australia	Royal Perth Hospital /ID# 155951	Perth	Western Australia
Germany	Universitaetsklinikum Carl Gustav Carus an der TU Dresden /ID# 154898	Dresden
Germany	Marien Hospital Duesseldorf /ID# 155518	Duesseldorf	Nordrhein-Westfalen
Germany	Universitaetsklinikum Duesseldorf /ID# 154899	Düsseldorf	Nordrhein-Westfalen
Germany	Universitaetsklinikum Halle (Saale) /ID# 158643	Halle (Saale)
Germany	Universitaetsklinikum Koeln /ID# 155519	Köln	Nordrhein-Westfalen
Germany	Universitaetsklinikum Leipzig /ID# 154897	Leipzig	Sachsen
Germany	Universitatsklinikum Mannheim /ID# 156038	Mannheim	Baden-Wuerttemberg
Germany	Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 154896	Munich
United States	University of Colorado Hospital /ID# 155365	Aurora	Colorado
United States	Dana-Farber Cancer Institute /ID# 155361	Boston	Massachusetts
United States	Pediatric Endocrine Associates /ID# 171227	Boston	Massachusetts
United States	Duplicate_University of Chicago /ID# 155364	Chicago	Illinois
United States	University of Texas MD Anderson Cancer Center /ID# 155362	Houston	Texas
United States	Yale University /ID# 162544	New Haven	Connecticut
United States	Columbia Univ Medical Center /ID# 156388	New York	New York
United States	Oregon Health and Science University /ID# 155360	Portland	Oregon
United States	University of Arizona Cancer Center - North Campus /ID# 157503	Tucson	Arizona
United States	University of Massachusetts - Worcester /ID# 155366	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Celgene; Genentech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Germany, 

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	Clearance (CL) for azacitidine		Up to 32 days
Primary	Cmax for azacitidine	Maximum plasma concentration (Cmax) of azacitidine	Up to 32 days
Primary	Tmax for venetoclax	Time to Cmax (peak time, Tmax) for venetoclax	Up to 32 days
Primary	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.
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	Tmax for azacitidine	Time to Cmax (peak time, Tmax) for 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	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	Cmax of venetoclax	Maximum plasma concentration (Cmax) of venetoclax	Up to 32 days
Primary	Half-life (t[1/2]) for azacitidine	Terminal elimination half-life (t[1/2]) for azacitidine	Up to 32 days
Primary	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	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.
Secondary	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.
Secondary	Rate of Modified Overall Response (mORR)	Proportion of participants with a mORR using best outcome will be calculated.	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.
Secondary	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.
Secondary	Duration of mORR	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 of any cause, whichever occurs earlier..	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	Rate of platelet (PLT) transfusion independence	Proportion of participants who become platelet transfusion-independent	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	Time to Transformation acute myeloid leukemia (AML)	Defined as blast count greater than or equal to 20% in either peripheral blood or bone marrow.	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.
Secondary	Progression-Free Survival (PFS)		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.
Secondary	Overall Response Rate (ORR)	ORR (equals the sum of rates of complete remission [CR] + marrow complete remission (mCR) + partial remission [PR]) of venetoclax as a single-agent and in combination with azacitidine.	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	Complete Remission (CR) Rate	Proportion of subjects who achieved a complete remission.	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	Rate of red blood cell (RBC) transfusion independence	Proportion of red blood cell (RBC) transfusion independence.	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	Duration of Complete Response (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 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.
Secondary	Rate of Hematologic Improvement (HI)	Proportion of participants with HI (erythroid/platelet/neutrophil responses)	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	Rate of marrow complete remission (mCR)	Proportion of participants with marrow complete remission with or without hematological improvement.	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.
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 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.