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

Sponsor

AbbVie (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02942290

Collaborator

Genentech, Inc. (Industry)

129

Enrollment

Locations

Arm

77.8

Anticipated Duration (Months)

3.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes (MDS)	Drug: Azacitidine Drug: Venetoclax	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

129 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jan 12, 2017

Anticipated Primary Completion Date :

Jul 9, 2023

Anticipated Study Completion Date :

Jul 9, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Venetoclax + Azacitidine	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. Drug: Venetoclax Oral; Tablet Other Names: ABT-199 GDC-0199 VENCLEXTA

Arm

Intervention/Treatment

Experimental: Venetoclax + Azacitidine

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.

Drug: Venetoclax

Oral; Tablet

Other Names:

ABT-199

GDC-0199

VENCLEXTA

Outcome Measures

Primary Outcome Measures

AUCt for Azacitidine [Up to 32 days]
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for azacitidine.
Cmax of venetoclax [Up to 32 days]
Maximum plasma concentration (Cmax) of venetoclax.
AUCt for venetoclax [Up to 32 days]
Area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) for venetoclax.
Tmax of venetoclax [Up to 32 days]
Time to Cmax (peak time, Tmax) of venetoclax.
AUC[0 to infinity] for azacitidine [Up to 32 days]
Area under the plasma concentration-time curve from Time 0 to infinite time.
Recommended Phase 2 dose (RPTD) and dosing schedule of venetoclax in combination with azacitidine [Measured from Day 1 until Day 28 per dose level.]
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].
Half-life (t[1/2]) for azacitidine [Up to 32 days]
Terminal elimination half-life (t[1/2]) for azacitidine.
Cmax for azacitidine [Up to 32 days]
Maximum plasma concentration (Cmax) of azacitidine.
AUC[0-24] for venetoclax [Up to 32 days]
AUC over a 24-hour dose interval (AUC[0-24]) for venetoclax.
Clearance (CL) for azacitidine [Up to 32 days]
Clearance is defined as the volume of plasma cleared of the drug per unit time.
Tmax for azacitidine [Up to 32 days]
Time to Cmax (peak time, Tmax) of azacitidine.
Complete Remission (CR) Rate [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.]
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).

Secondary Outcome Measures

Rate of red blood cell (RBC) transfusion independence [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.]
Percentages of participants who become RBC transfusion-independent.
Progression-Free Survival (PFS) [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.]
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.
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 participant is enrolled.]
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.
Hematologic Improvement (HI) rate [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.]
Percentages of participants with HI (erythroid/platelet/neutrophil responses).
Rate of platelet (PLT) transfusion independence [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.]
Percentages of participants who become platelet transfusion-independent.
Event-Free Survival (EFS) [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]
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.
Time to transformation to acute myeloid leukemia (AML) [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.]
Defined as the number of days from the date of the first dose of study drug to the date of documented AML transformation.
Overall Response Rate (ORR) [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.]
ORR (equals the rates of complete remission [CR] + partial remission [PR]) of venetoclax in combination with azacitidine.
Time to next treatment (TTNT) [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.]
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.
Marrow Complete Remission (mCR) Rate [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.]
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.
Modified Overall Response Rate (mORR) [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.]
mORR (equals CR + PR + mCR) of venetoclax in combination with azacitidine.
Duration 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.]
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.
Duration of mORR [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.]
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.
Duration of ORR [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.]
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.
Rate of 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.]
The AML transformation rate is defined as the proportion of participants transformed to Acute Myelogenous Leukemia.
Time to First Response (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.]
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.
Time to First Response (mORR) [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.]
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).
Time to First Response (ORR) [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.]
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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center - North Campus /ID# 154155	Tucson	Arizona	United States	85719-1478
2	The University of Chicago Medical Center /ID# 153673	Chicago	Illinois	United States	60637-1443
3	Univ Maryland School Medicine /ID# 153669	Baltimore	Maryland	United States	21201-1544
4	Tufts Medical Center /ID# 153672	Boston	Massachusetts	United States	02111-1552
5	Dana-Farber Cancer Institute /ID# 152735	Boston	Massachusetts	United States	02215
6	Washington University-School of Medicine /ID# 153671	Saint Louis	Missouri	United States	63110
7	Columbia University Medical Center /ID# 153661	New York	New York	United States	10032-3729
8	Weill Cornell Medical College /ID# 155524	New York	New York	United States	10065
9	Oregon Health and Science University /ID# 152734	Portland	Oregon	United States	97239
10	University of Pittsburgh MC /ID# 153662	Pittsburgh	Pennsylvania	United States	15260
11	Tennessee Oncology-Nashville Centennial /ID# 222769	Nashville	Tennessee	United States	37203-1632
12	Vanderbilt University Medical Center /ID# 152738	Nashville	Tennessee	United States	37232-0011
13	UT MD Anderson Cancer Center /ID# 153809	Houston	Texas	United States	77030
14	Concord Repatriation General Hospital /ID# 154958	Concord	New South Wales	Australia	2139
15	Duplicate_St. Vincent's Hospital, Darlinghurst /ID# 222846	Darlinghurst	New South Wales	Australia	2010
16	St George Hospital /ID# 154954	Kogarah	New South Wales	Australia	2217
17	Liverpool Hospital /ID# 222410	Liverpool	New South Wales	Australia	2170
18	Calvary Mater Newcastle /ID# 154957	Waratah	New South Wales	Australia	2298
19	Princess Alexandra Hospital /ID# 154990	Woolloongabba	Queensland	Australia	4102
20	Austin Health /ID# 154955	Heidelberg	Victoria	Australia	3084
21	Alfred Health /ID# 154956	Melbourne	Victoria	Australia	3004
22	Fiona Stanley Hospital /ID# 222847	Murdoch	Western Australia	Australia	6150
23	Juravinski Cancer Centre /ID# 152947	Hamilton	Ontario	Canada	L8V 1C3
24	CHU de Nantes, Hotel Dieu -HME /ID# 153828	Nantes	Pays-de-la-Loire	France	44000
25	AP-HP - Hopital Saint-Louis /ID# 153827	Paris		France	75010
26	Universitatsklinikum Mannheim /ID# 153140	Mannheim	Baden-Wuerttemberg	Germany	68167
27	Universitaetsklinikum Koeln /ID# 153141	Köln	Nordrhein-Westfalen	Germany	50937
28	Duplicate_Universitaetsklinikum Carl Gus /ID# 153958	Dresden	Sachsen	Germany	01307
29	Universitaetsklinikum Leipzig /ID# 153142	Leipzig	Sachsen	Germany	04103
30	Universitaetsklinikum Halle (Saale) /ID# 153760	Halle (Saale)		Germany	06120
31	Klinikum rechts der Isar - Technische Universitaet Muenchen /ID# 153139	Munich		Germany	81675
32	Azienda Ospedaliero-Universitaria Policlinico Umberto I /ID# 153764	Rome	Lazio	Italy	00161
33	IRCCS Azienda Ospedaliero-Universitaria di Bologna /ID# 153763	Bologna		Italy	40138
34	Norfolk and Norwich University Hospitals NHS Foundation Trust /ID# 156492	Norwich	Norfolk	United Kingdom	NR4 7UY
35	Oxford University Hospitals NHS Foundation Trust /ID# 222567	Oxford	Oxfordshire	United Kingdom	OX3 9DU
36	University Hospitals Birmingham NHS Foundation Trust /ID# 158810	Birmingham		United Kingdom	B15 2TH
37	King's College Hospital NHS Foundation Trust /ID# 156489	London		United Kingdom	SE5 9RS