Study of Acalabrutinib (ACP-196) in Combination With Venetoclax (ABT-199), With and Without Obinutuzumab (GA101) Versus Chemoimmunotherapy for Previously Untreated CLL (AMPLIFY)

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)

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

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Acalabrutinib; Drug: Venetoclax; Drug: Obinutuzumab; Drug: Chemoimmunotherapy

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.

• Study Type: Interventional
• Enrollment (Actual): 984
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1426ANZ
    • Research Site
  • Buenos Aires, Argentina, 1114
    • Research Site
  • Capital Federal, Argentina, 1118
    • Research Site
  • Córdoba, Argentina, 5000
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• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Darlinghurst, Australia, 2010
    • Research Site
  • Heidelberg, Australia, 3084
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  • Kogarah, Australia, 2217
    • Research Site
  • Melbourne, Australia, 3000
    • Research Site
  • Nedlands, Australia, 6009
    • Research Site
  • Waratah, Australia, 2298
    • Research Site
  • Woolloongabba, Australia, 4102
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• Austria
  • Krems, Austria, 3500
    • Research Site
  • Salzburg, Austria, 5020
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  • Vienna, Austria, 1140
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• Brazil
  • Goiania, Brazil, 74605-020
    • Research Site
  • Porto Alegre, Brazil, 90035-003
    • Research Site
  • Porto Alegre, Brazil, 90020-090
    • Research Site
  • Porto Alegre, Brazil, 90110-270
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  • Rio de Janeiro, Brazil, 22793-080
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  • Rio de Janeiro, Brazil, 20230-130
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  • Sao Paulo, Brazil, 01236-030
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  • Sao Paulo, Brazil, 05403-010
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  • São Paulo, Brazil, 01308-050
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• Bulgaria
  • Plovdiv, Bulgaria
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  • Sofia, Bulgaria, 1606
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  • Vratsa, Bulgaria, 3000
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• Canada
  • Quebec, Canada, G1J 1Z4
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  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Research Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • Research Site
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
    • Toronto, Ontario, Canada, M4N 3M5
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  • Quebec
    • Montreal, Quebec, Canada, H4J 1C5
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• China
  • Beijing, China, 100034
    • Research Site
  • Beijing, China, 100044
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  • Beijing, China, 100191
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  • Changchun, China, 130021
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  • Changsha, China, 410008
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  • Chengdu, China, 610041
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  • Chongqing, China, 400037
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  • Guangzhou, China, 510100
    • Research Site
  • Guangzhou, China, 510515
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  • Hangzhou, China, 310003
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  • Nanchang, China, 330006
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  • Nanjing, China, 210029
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  • Shengyang, China, 110004
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  • Shenyang, China, 110001
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  • Shenyang, China, 110004
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  • Tianjin, China, 300020
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  • Urumchi, China, 830054
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  • Wenzhou, China, 325000
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  • Wuhan, China, 430022
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  • Wuhan, China, 430030
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  • Xian, China, 710061
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  • Zhengzhou, China, 450008
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  • Zhengzhou, China, 450052
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• Czechia
  • Brno, Czechia, 625 00
    • Research Site
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Olomouc, Czechia, 779 00
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  • Ostrava, Czechia, 708 52
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  • Plzen, Czechia, 304 60
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  • Praha, Czechia
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• Denmark
  • Aarhus, Denmark, 8200
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  • Copenhagen, Denmark, 2100
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  • Roskilde, Denmark, 4000
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• France
  • Montpellier Cedex 5, France, 34090
    • Research Site
  • Paris, France, 75015
    • Research Site
  • Paris, France, 75013
    • Research Site
  • Paris Cedex 10, France, 75475
    • Research Site
  • Rennes Cedex 9, France, 35033
    • Research Site
  • Rouen Cedex 1, France, 76038
    • Research Site
  • Toulouse Cedex 9, France, 31059
    • Research Site
  • Villejuif, France, 94800
    • Research Site
• Germany
  • Paderborn, Germany, 33098
    • Research Site
  • Würzburg, Germany, 97080
    • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
  • Budapest, Hungary, 1125
    • Research Site
  • Debrecen, Hungary, 4032
    • Research Site
  • Kaposvár, Hungary, 7400
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• Israel
  • Haifa, Israel, 31999
    • Research Site
  • Jerusalem, Israel
    • Research Site
  • Jerusalem, Israel, 91120
    • Research Site
  • Petah Tiqva, Israel, 49100
    • Research Site
  • Tel Aviv, Israel, 64239
    • Research Site
  • Tel Hashomer, Israel, 52620
    • Research Site
• Italy
  • Meldola, Italy, 47014
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Milano, Italy, 20162
    • Research Site
  • Novara, Italy, 28100
    • Research Site
  • Ravenna, Italy, 48121
    • Research Site
  • Torino, Italy, 10126
    • Research Site
• Korea, Republic of
  • Incheon, Korea, Republic of, 21565
    • Research Site
  • Seoul, Korea, Republic of, 03722
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
• Netherlands
  • Almere, Netherlands, 1315 RA
    • Research Site
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Arnhem, Netherlands, 6815 AD
    • Research Site
  • Breda, Netherlands, 4818 CK
    • Research Site
  • Den Bosch, Netherlands, 5223 GZ
    • Research Site
• Poland
  • Brzozów, Poland, 36-200
    • Research Site
  • Bydgoszcz, Poland, 85-168
    • Research Site
  • Gdynia, Poland, 81-519
    • Research Site
  • Krakow, Poland, 30-727
    • Research Site
  • Lublin, Poland, 20-081
    • Research Site
  • Wrocław, Poland, 50-556
    • Research Site
  • Wrocław, Poland, 50-367
    • Research Site
  • Łódź, Poland, 93-510
    • Research Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Research Site
  • Moscow, Russian Federation, 125284
    • Research Site
  • Saint Petersburg, Russian Federation, 197347
    • Research Site
  • Saint-Petersburg, Russian Federation
    • Research Site
  • Samara, Russian Federation, 443095
    • Research Site
  • Sochi, Russian Federation, 354057
    • Research Site
  • St Petersburg, Russian Federation, 197341
    • Research Site
  • Tula, Russian Federation, 300053
    • Research Site
  • Volgograd, Russian Federation, 400138
    • Research Site
• Saudi Arabia
  • Dammam, Saudi Arabia, 31444
    • Research Site
  • Jeddah, Saudi Arabia, 21423
    • Research Site
  • Riyadh, Saudi Arabia, 12713
    • Research Site
• Slovakia
  • Bratislava, Slovakia, 83310
    • Research Site
• South Africa
  • Bloemfontein, South Africa, 9301
    • Research Site
  • Cape Town, South Africa, 7925
    • Research Site
  • Johannesburg, South Africa, 2013
    • Research Site
  • Pretoria, South Africa, 0044
    • Research Site
  • Randburg, South Africa, 2125
    • Research Site
• Spain
  • Badalona(Barcelona), Spain, 08916
    • Research Site
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08041
    • Research Site
  • Madrid, Spain, 28031
    • Research Site
  • Madrid, Spain, 28007
    • Research Site
  • Majadahonda, Spain, 28222
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
  • Santander, Spain, 39008
    • Research Site
  • Valencia, Spain, 46009
    • Research Site
• Sweden
  • Göteborg, Sweden, 41345
    • Research Site
  • Uppsala, Sweden, 75185
    • Research Site
  • Örebro, Sweden, 70185
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan, 833
    • Research Site
  • Taichung, Taiwan, 404
    • Research Site
  • Tainan City, Taiwan, 70403
    • Research Site
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
  • Taoyuan City, Taiwan, 333
    • Research Site
• Turkey
  • Ankara, Turkey
    • Research Site
  • Ankara, Turkey, 06100
    • Research Site
  • Izmir, Turkey, 35340
    • Research Site
  • Kurupelit, Turkey, 55139
    • Research Site
  • Talas, Turkey, 38280
    • Research Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Research Site
  • Canterbury, United Kingdom, CT1 3NG
    • Research Site
  • Wolverhampton, United Kingdom, WV10 OQP
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Research Site
    • Redondo Beach, California, United States, 90277
      • Research Site
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Research Site
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Research Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70056
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • New York
    • New York, New York, United States, 10021
      • Research Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Research Site
  • Ohio
    • Canton, Ohio, United States, 44718
      • Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15224
      • Research Site
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Research Site
  • Washington
    • Spokane, Washington, United States, 99208
      • Research Site
    • Tacoma, Washington, United States, 98405
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acalabrutinib, Venetoclax; Acalabrutinib in combination with Venetoclax	Drug: Acalabrutinib; Acalabrutinib,; Other Names: Calquence (acalabrutinib); Drug: Venetoclax; Venetoclax; Other Names: Venclyxto, Venclexta
Experimental: Acalabrutinib, Venetoclax, Obinutuzumab; Acalabrutinib in combination with Venetoclax with Obinutuzumab	Drug: Acalabrutinib; Acalabrutinib,; Other Names: Calquence (acalabrutinib); Drug: Venetoclax; Venetoclax; Other Names: Venclyxto, Venclexta; Drug: Obinutuzumab; Obinutuzumab; Other Names: Gazyva, Gazyvaro
Active Comparator: Chemoimmunotherapy; Chemoimmunotherapy FCR: Fludarabine, Cyclophosphamide and Rituximab BR: Bendamustine and Rituximab	Drug: Chemoimmunotherapy; fludarabine/cyclophosphamide/rituximab (FCR), bendamustine/rituximab (BR)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the efficacy of acalabrutinib with venetoclax (Arm A) compared to chemoimmunotherapy fludarabine/cyclophosphamide/rituximab [FCR] or bendamustine/rituximab [BR] (Arm C): PFS	Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2018 criteria	6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the efficacy of acalabrutinib with venetoclax in combination with obinutuzumab (Arm B) compared with FCR or BR (Arm C): PFS	PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment	6 years
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.	PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the IRC assessment and investigator assessment	6 years

Collaborators and Investigators

• Sponsor: Acerta Pharma BV
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Jennifer Brown, Dana Farber Mass General Brigham Cancer Care Inc; Principal Investigator: Barbara Eichhorst, Universitätsklinikum Köln; Principal Investigator: Arnon Kater, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Principal Investigator: Paolo Ghia, OSPEDALE S. RAFFAELE - MILANO; Principal Investigator: John Seymour, Peter MacCallum Cancer Ctr

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2019
• Primary Completion (Estimated): January 6, 2027
• Study Completion (Estimated): January 6, 2027

Study Registration Dates

• First Submitted: February 6, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Leukemia; CLL; Chronic Leukemia Lymphocytic
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Hematologic Diseases; Leukemia, B-Cell; Chronic Disease; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Venetoclax; Obinutuzumab; Acalabrutinib
• Other Study ID Numbers: ACE-CL-311; D8221C00001 (Other Identifier: AstraZeneca); 2018-002443-28 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No