Clinical trial NCT03836261: Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL
Official title: A Randomized, Multicenter, Open-Label, Phase 3 Study to Compare the Efficacy and Safety of Acalabrutinib (ACP-196) in Combination With Venetoclax With and Without Obinutuzumab Compared to Investigator's Choice of Chemoimmunotherapy in Subjects With Previously Untreated Chronic Lymphocytic Leukemia Without Del(17p) or TP53 Mutation (AMPLIFY)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
Chronic Leukemia Lymphocytic
Leukemia
Lead sponsor: Acerta Pharma BV
Sponsor class: INDUSTRY
Collaborators: name: AstraZeneca
First posted: 2019-02-11
Enrollment: 984
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the efficacy and safety of acalabrutinib in combination with venetoclax and acalabrutinib in combination with venetoclax with and without obinutuzumab compared to chemoimmunotherapy in subjects with previously untreated CLL

Detailed description: This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy and safety of AV and AVG versus chemoimmunotherapy (FCR or BR) in subjects with previously untreated CLL without del(17p) or TP53. Subjects will be randomized in a 1:1:1 ratio into 3 arms through a block stratified randomization procedure.

The study includes screening (35 days), treatment (from randomization until study drug discontinuation) and follow-up phase.

Eligibility criteria: Inclusion Criteria:

* Men and women ≥18 years of age.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
* Diagnosis of CLL that meets published diagnostic criteria (Hallek et al. 2018)
* Active disease per IWCLL 2018 criteria that requires treatment.
* Participants must use highly effective birth control throughout the study.

Exclusion Criteria:

* Any prior CLL-specific therapies.
* Detected del(17p) or TP53 mutation.
* Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (e.g., Richter's transformation, prolymphocytic leukemia \[PLL\], or diffuse large B cell lymphoma \[DLBCL\]), or central nervous system (CNS) involvement by leukemia.
* History of confirmed progressive multifocal leukoencephalopathy (PML).
* Received any investigational drug within 30 days before first dose of study drug.
* Major surgical procedure within 30 days before the first dose of study drug.
* Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 or 4 cardiac disease. Note: Subjects with controlled, asymptomatic atrial fibrillation are allowed to enroll on study.
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach, or extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
* Received a live virus vaccination within 28 days of first dose of study drug.
* Known history of infection with human immunodeficiency virus (HIV).
* Serologic status reflecting active hepatitis B or C infection.
* History of known hypersensitivity or anaphylactic reactions to study drugs or excipients.
* History of stroke or intracranial hemorrhage within 6 months before first dose of study drug.
* Known bleeding disorders.
* Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
* Female participants must not be breastfeeding or pregnant.
* Concurrent participation in another therapeutic clinical trial.

Primary outcomes:
measure: To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared to chemoimmunotherapy fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR] (Arm C): PFS
timeFrame: 6 years
Secondary outcomes:
measure: To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS
timeFrame: 6 years
measure: To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared with FCR or BR (Arm C): PFS defined the same as above per investigator assessment.
timeFrame: 6 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Redondo Beach
country: United States
facility: Research Site
state: California
city: Fort Wayne
country: United States
facility: Research Site
state: Indiana
city: Wichita
country: United States
facility: Research Site
state: Kansas
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: New Orleans
country: United States
facility: Research Site
state: Louisiana
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Canton
country: United States
facility: Research Site
state: Ohio
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Fort Sam Houston
country: United States
facility: Research Site
state: Texas
city: Spokane
country: United States
facility: Research Site
state: Washington
city: Tacoma
country: United States
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state: Washington
city: Buenos Aires
country: Argentina
facility: Research Site
city: Buenos Aires
country: Argentina
facility: Research Site
city: Capital Federal
country: Argentina
facility: Research Site
city: Córdoba
country: Argentina
facility: Research Site
city: Adelaide
country: Australia
facility: Research Site
city: Darlinghurst
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Kogarah
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: Nedlands
country: Australia
facility: Research Site
city: Waratah
country: Australia
facility: Research Site
city: Woolloongabba
country: Australia
facility: Research Site
city: Krems
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: Vienna
country: Austria
facility: Research Site
city: Goiania
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio de Janeiro
country: Brazil
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city: Rio de Janeiro
country: Brazil
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city: Sao Paulo
country: Brazil
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city: Sao Paulo
country: Brazil
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city: São Paulo
country: Brazil
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Vratsa
country: Bulgaria
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Beijing
country: China
facility: Research Site
city: Changchun
country: China
facility: Research Site
city: Changsha
country: China
facility: Research Site
city: Chengdu
country: China
facility: Research Site
city: Chongqing
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Guangzhou
country: China
facility: Research Site
city: Hangzhou
country: China
facility: Research Site
city: Nanchang
country: China
facility: Research Site
city: Nanjing
country: China
facility: Research Site
city: Shenyang
country: China
facility: Research Site
city: Shenyang
country: China
facility: Research Site
city: Tianjin
country: China
facility: Research Site
city: Urumchi
country: China
facility: Research Site
city: Wenzhou
country: China
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city: Wuhan
country: China
facility: Research Site
city: Wuhan
country: China
facility: Research Site
city: Xian
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Zhengzhou
country: China
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava - Poruba
country: Czechia
facility: Research Site
city: Plzen - Lochotin
country: Czechia
facility: Research Site
city: Praha
country: Czechia
facility: Research Site
city: Aarhus
country: Denmark
facility: Research Site
city: Copenhagen
country: Denmark
facility: Research Site
city: Roskilde
country: Denmark
facility: Research Site
city: Montpellier Cedex 5
country: France
facility: Research Site
city: Paris Cedex 10
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Rennes Cedex 9
country: France
facility: Research Site
city: Rouen Cedex 1
country: France
facility: Research Site
city: Toulouse Cedex 9
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Paderborn
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Kaposvár
country: Hungary
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Petah Tiqva
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Tel Hashomer
country: Israel
facility: Research Site
city: Meldola
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Novara
country: Italy
facility: Research Site
city: Ravenna
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Incheon
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Research Site
city: Almere
country: Netherlands
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Arnhem
country: Netherlands
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Den Bosch
country: Netherlands
facility: Research Site
city: Brzozów
country: Poland
facility: Research Site
city: Bydgoszcz
country: Poland
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city: Gdynia
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Lublin
country: Poland
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city: Wroclaw
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint-Petersburg
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Sochi
country: Russian Federation
facility: Research Site
city: St Petersburg
country: Russian Federation
facility: Research Site
city: Tula
country: Russian Federation
facility: Research Site
city: Volgograd
country: Russian Federation
facility: Research Site
city: Dammam
country: Saudi Arabia
facility: Research Site
city: Jeddah
country: Saudi Arabia
facility: Research Site
city: Riyadh
country: Saudi Arabia
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Bloemfontein
country: South Africa
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Randburg
country: South Africa
facility: Research Site
city: Soweto
country: South Africa
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Majadahonda
country: Spain
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: Santander
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Goteborg
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
city: Örebro
country: Sweden
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Tainan City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan City
country: Taiwan
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Kurupelit
country: Turkey
facility: Research Site
city: Talas
country: Turkey
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Canterbury
country: United Kingdom
facility: Research Site
city: Wolverhampton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Dana Farber Mass General Brigham Cancer Care Inc
name: Jennifer Brown
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitätsklinikum Köln
name: Barbara Eichhorst
role: PRINCIPAL_INVESTIGATOR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Arnon Kater
role: PRINCIPAL_INVESTIGATOR
affiliation: OSPEDALE S. RAFFAELE - MILANO
name: Paolo Ghia
role: PRINCIPAL_INVESTIGATOR
affiliation: Peter MacCallum Cancer Ctr
name: John Seymour
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. doi: 10.1016/S1470-2045(21)00455-1. Epub 2021 Sep 14.
citation: Gordon MJ, Danilov AV. The evolving role of Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia. Ther Adv Hematol. 2021 Jan 30;12:2040620721989588. doi: 10.1177/2040620721989588. eCollection 2021.