Study of Acalabrutinib Versus Chlorambucil Plus Rituximab in Adult Subjects With Previously Untreated Chronic Lymphocytic Leukemia

A Randomized, Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Acalabrutinib Versus Chlorambucil Plus Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia

This is a randomized, multicenter, open-label, Phase 3 study to evaluate the efficacy and safety of Acalabrutinib versus Chlorambucil plus Rituximab in subjects with Previously Untreated Chronic Lymphocytic Leukemia.

Study Overview

• Status: Active, not recruiting
• Conditions: Untreated Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Acalabrutinib; Drug: Rituximab; Drug: Chlorambucil

Detailed Description

Patients be randomized in a 1:1 ratio into 2 arms to receive either acalabrutinib monotherapy (Arm A) or rituximab in combination with chlorambucil (Arm B). The primary objective of this study is to compare the efficacy of acalabrutinib relative to chlorambucil plus rituximab in subjects with previously untreated chronic lymphocytic leukemia without del(17p) or TP53 mutation.

• Study Type: Interventional
• Enrollment (Actual): 155
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100191
    • Research Site
  • Changchun, China, 130021
    • Research Site
  • Changsha, China, 410013
    • Research Site
  • Changzhou, China, 272100
    • Research Site
  • Guangzhou, China, 510100
    • Research Site
  • Guangzhou, China, 510515
    • Research Site
  • Guiyang, China, 550004
    • Research Site
  • Hangzhou, China, 310003
    • Research Site
  • Hefei, China, 230031
    • Research Site
  • Hefei, China, 230001
    • Research Site
  • Nanchang, China, 330006
    • Research Site
  • Nanjing, China, 210029
    • Research Site
  • Qingdao, China, 110016
    • Research Site
  • Shanghai, China, 200025
    • Research Site
  • Shanghai, China, 200040
    • Research Site
  • Shanghai, China, 200050
    • Research Site
  • Shenyang, China, 110001
    • Research Site
  • Shijiazhuang, China, 050020
    • Research Site
  • Suzhou, China, 215006
    • Research Site
  • Taiyuan, China, 030001
    • Research Site
  • Tianjin, China, 300020
    • Research Site
  • Xuzhou, China, 221000
    • Research Site
  • Zhengzhou, China, 450008
    • Research Site
  • Zhengzhou, China, 450052
    • Research Site
• Philippines
  • Baguio City, Philippines, 2600
    • Research Site
  • Cebu, Philippines, 6000
    • Research Site
  • Davao City, Philippines, 8000
    • Research Site
  • Makati, Philippines, 1229
    • Research Site
  • Manila, Philippines, 1000
    • Research Site
  • Quezon City, Philippines, 1112
    • Research Site
• Taiwan
  • Chiayi City, Taiwan, 613
    • Research Site
  • Hualien City, Taiwan, 97002
    • Research Site
  • Kaohsiung City, Taiwan, 833
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 404
    • Research Site
  • Tainan, Taiwan, 704
    • Research Site
  • Taipei, Taiwan, 10002
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
• Thailand
  • Bangkok, Thailand, 10330
    • Research Site
  • Bangkok, Thailand, 10400
    • Research Site
  • Bangkok, Thailand, 10700
    • Research Site
  • Chiang Mai, Thailand, 50200
    • Research Site
  • Hat Yai, Thailand, 90110
    • Research Site
  • Khon Kaen, Thailand, 40002
    • Research Site
• Vietnam
  • Hanoi, Vietnam, 100000
    • Research Site
  • Ho Chi Minh City, Vietnam, 700000
    • 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: (a) ≥65 years of age OR (b) >18 and <65 years of age, provided that they meet at least one of the following criteria: (i) Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation (iwCLL guidelines) (ii) A score higher than 6 on the Cumulative Illness Rating Score-Geriatric (CIRS G)
• ECOG performance status of 0, 1, or 2
• Diagnosis of CLL that meets published diagnostic criteria (Hallek 2018)
• Active disease per IWCLL 2018 criteria that requires treatment
• Adequate bone marrow function
• Adequate renal and hepatic function

Exclusion Criteria:

• Known detected del(17p) or TP53 mutation
• Transformation of CLL to aggressive non-Hodgkin lymphoma (NHL) (eg, Richter's transformation, PLL, or diffuse large B cell lymphoma [DLBCL]), or central nervous system (CNS) involvement by leukemia
• History of prior malignancy except for the following: (a) Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study (b) Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy from which subject is disease-free for ≥3 years without further treatment
• Significant cardiovascular disease
• Known history of infection with human immunodeficiency virus (HIV)
• Serologic status reflecting active hepatitis B or C infection
• Any active systemic infection (eg, bacterial, viral, or fungal infection) requiring systemic treatment
• History of stroke or intracranial hemorrhage within 6 months before first dose of study drug
• Major surgical procedure within 30 days of first dose of study drug
• Any prior CLL-specific therapies
• Corticosteroid use >20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions
• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
• For women only: breastfeeding or pregnant

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acalabrutinib; Acalabrutinib will be orally administered until disease progression or unacceptable toxicity	Drug: Acalabrutinib; acalabrutinib 100 mg twice daily orally
Active Comparator: Rituximab and Chlorambucil; Chlorambucil orally administered and Rituximab via IV infusion for 6 cycles	Drug: Rituximab; Rituximab: 375 mg/m2 IV infusion on Day 1 of Cycle 1. 500 mg/m2 IV infusion on Day 1 for each of subsequent cycles (Cycles 2-6); Drug: Chlorambucil; Chlorambucil: 0.5 mg/kg body weight orally on Day 1 and Day 15 of Cycles 1-6

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Assessed by BICR	PFS was defined as the time from randomization to PD (assessed by BICR according to International Workshop on Chronic Lymphocytic Leukaemia [iwCLL] 2018 guideline criteria) or death due to any cause. PD was defined as meeting at least 1 of the below criteria of groups(g) A or B. gA: increase of ≥50% from baseline (BL) or from response in lymph nodes or liver and/or spleen size; any constitutional symptoms; increase of ≥50% over nadir with absolute count ≥ 5×10^9/liter (L) in circulating lymphocyte count (CLC); gB: decrease of ≥50% from BL secondary to CLL in platelet count; decrease of ≥2 gram per deciliter (g/dL) from BL secondary to CLL in hemoglobin (Hb); increase of CLL cells by ≥50% on successive biopsies in bone marrow (BM). Median PFS was calculated using Kaplan-Meier method and its confidence interval (CI) using Brookmeyer-Crowley method.	Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Assessed by BICR and Investigator	ORR:percentage of participants with complete response(CR),CR with incomplete BM recovery(CRi), partial response(PR)/nodular PR(nPR) assessed by BICR;investigator per IWCLL 2018 criteria at/before initiation of subsequent anti-cancer therapy.CR:No lymph nodes(target lesions)≥1.5 centimeter(cm), spleen<13cm,normal liver;CLC,no constitutional symptoms,platelets≥100,000/microliter(μL),Hb≥11.0 g/dL,BM:normocellular,no CLL cells&B-lymphoid nodules.PR:atleast 2 gA parameters;1 gB parameter need to improve if previously abnormal.If only 1 parameter of both gA,B was abnormal prior to therapy,only 1 needs to improve.gA:Decrease≥50% from BL in lymph nodes,liver & or spleen size,CLC;any constitutional symptoms, gB:platelet≥100,000/μL or increase 50% over BL;Hb≥11g/dL or increase≥50% over BL;BM:presence of CLL cells/B-lymphoid nodules/not done.CRi:all CR criteria+persistent anemia,thrombocytopenia or neutropenia unrelated to CLL,related to drug toxicity.nPR:CR+presence of B-lymphoid nodules in BM.	Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)
Duration of Response (DOR) Assessed by BICR and Investigator	DOR was defined as the time from response (date of first documented response) to PD or death (absence of PD) as judged by BICR and investigator. PD was defined as meeting at least 1 of the below criteria of group A or group B. Group A: Increase of ≥ 50% from BL or from response in lymph nodes or liver and/or spleen size; any constitutional symptoms; increase of ≥50% over nadir with absolute count ≥ 5×10^9/L in CLC; group B: decrease of ≥50% from BL secondary to CLL in platelet count; decrease of ≥2 g/dL from BL secondary to CLL in hemoglobin; increase of CLL cells by ≥50% on successive biopsies in marrow. Median DOR was calculated using Kaplan-Meier method and its CI using Brookmeyer-Crowley method.	Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD or death, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)
Time to Next Treatment (TTNT)	TTNT was defined as the time from the date of randomization to the date of initiation of non-protocol-specified anti-CLL therapy (either medication or radiotherapy for CLL) or death from any cause, whichever occurred first. Median TTNT was calculated using Kaplan-Meier method and its CI was calculated using Brookmeyer-Crowley method.	Response evaluations performed every 12 weeks from Cycle 4 Day 1 to Cycle 25, then every 24 weeks until PD, and survival follow-ups performed every 12 weeks thereafter, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)
Overall Survival (OS)	OS was defined as the time from the date of randomization until death due to any cause. The median OS was calculated using Kaplan-Meier method and its CI was calculated using Brookmeyer-Crowley method.	From date of randomization until death due to any cause, up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)
Minimal Residual Disease (MRD) Negativity Rate	The MRD negative rate was defined as the percentage of participants with MRD-negativity (defined as <1 CLL cell per 10,000 leukocytes) measured in the peripheral blood by flow cytometry.	At Cycle 9 (cycle duration: 28 days)
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862	Blood samples were collected to determine the concentration of acalabrutinib and its metabolite ACP-5862 in plasma.	Pre-dose, and at 1, 2, 4 hours post-dose on Day 1 of Cycle 2 (cycle duration: 28 days)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any untoward medical occurrence (other than progression of the malignancy under evaluation) in participant or clinical study participant administered medicinal product and which does not necessarily had a causal relationship with treatment. A serious adverse event (SAE) was an AE occurring during any study phase, that fulfilled 1 or more of following criteria: resulted in death, was life-threatening, required in-participant hospitalization/prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was congenital abnormality or birth defect, and was an important medical event that jeopardized participant or required medical treatment to prevent 1 of outcomes listed above. TEAE was any AE that occurred or worsened in severity on or after date of the first dose of study drug up to 30 days after last dose of study drug or prior to initiation of a new anti-CLL therapy, whichever occurred first.	From first dose of study drug (Day 1) up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Lugui Qiu, MD, Chinese Academy of Medical Science Affiliated Hospital of Hematology

Publications and helpful links

Helpful Links

• CSR synopsis
• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2020
• Primary Completion (Actual): January 3, 2024
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: August 19, 2019
• First Submitted That Met QC Criteria: August 29, 2019
• First Posted (Actual): August 30, 2019

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Chronic Lymphocytic Leukemia; Acalabrutinib; Progression-free Survival
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Leukemia, Lymphocytic, Chronic, B-Cell; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Antibodies, Monoclonal, Murine-Derived; Rituximab; Chlorambucil; acalabrutinib
• Other Study ID Numbers: D822BC00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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