Trial Outcomes & Findings for Study of Acalabrutinib Versus Chlorambucil Plus Rituximab in Adult Subjects With Previously Untreated Chronic Lymphocytic Leukemia (NCT NCT04075292)

Last Updated: 2025-11-21

Results Overview

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.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

155 participants

Primary outcome timeframe

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)

Results posted on

2025-11-21

Participant Flow

This Phase III, multicenter, randomized, open-label study was conducted in participants with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation at 46 sites across 5 countries. Results are presented up to data cut-off (DCO) date of 03 January 2024.

A total of 155 participants were randomized in 1:1 ratio to acalabrutinib treatment arm or chlorambucil plus rituximab treatment arm. All participants should receive the same dose within their respective treatment arms.

Participant milestones

Participant milestones
Measure	Acalabrutinib Participants received acalabrutinib 100 milligram (mg) orally twice daily (BID) in 28-day cycles until progression of disease (PD) or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab Participants received chlorambucil 0.5 milligram per kilogram (mg/kg) body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an intravenous (IV) infusion of rituximab 375 milligram per square meter (mg/m\^2) on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Overall Study STARTED	77	78
Overall Study Safety Analysis Set (SAS)	77	73
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	77	78

Reasons for withdrawal

Reasons for withdrawal
Measure	Acalabrutinib Participants received acalabrutinib 100 milligram (mg) orally twice daily (BID) in 28-day cycles until progression of disease (PD) or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab Participants received chlorambucil 0.5 milligram per kilogram (mg/kg) body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an intravenous (IV) infusion of rituximab 375 milligram per square meter (mg/m\^2) on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Overall Study Withdrawal by Subject	1	9
Overall Study Death	2	5
Overall Study Remained on study at time of DCO	74	64

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.	Total n=155 Participants Total of all reporting groups
Age, Continuous	64.0 years n=68 Participants	67.0 years n=76 Participants	65.0 years n=48 Participants
Sex: Female, Male Female	34 Participants n=68 Participants	31 Participants n=76 Participants	65 Participants n=48 Participants
Sex: Female, Male Male	43 Participants n=68 Participants	47 Participants n=76 Participants	90 Participants n=48 Participants
Race/Ethnicity, Customized Asian	77 Participants n=68 Participants	75 Participants n=76 Participants	152 Participants n=48 Participants
Race/Ethnicity, Customized White	0 Participants n=68 Participants	3 Participants n=76 Participants	3 Participants n=48 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants n=68 Participants	2 Participants n=76 Participants	2 Participants n=48 Participants
Race/Ethnicity, Customized Non-Hispanic or Latino	77 Participants n=68 Participants	76 Participants n=76 Participants	153 Participants n=48 Participants

PRIMARY outcome

Timeframe: 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)

Population: FAS included all randomized participants.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Progression Free Survival (PFS) Assessed by BICR	NA months NA indicated that the median, lower and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	15.54 months Interval 11.53 to 17.54

SECONDARY outcome

Population: FAS included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Overall Response Rate (ORR) Assessed by BICR and Investigator BICR Assessment	76.6 percentage of participants	71.8 percentage of participants
Overall Response Rate (ORR) Assessed by BICR and Investigator Investigator Assessment	81.8 percentage of participants	60.3 percentage of participants

SECONDARY outcome

Population: FAS included all randomized participants. Only participants with response in each specified category were analyzed in this outcome measure.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=63 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=56 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Duration of Response (DOR) Assessed by BICR and Investigator BICR Assessment	NA months NA indicated that the median, lower and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	11.56 months Interval 8.28 to 14.26
Duration of Response (DOR) Assessed by BICR and Investigator Investigator Assessment	NA months Interval 30.55 to NA indicated that the median and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	19.29 months Interval 11.47 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: 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)

Population: FAS included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Time to Next Treatment (TTNT)	NA months NA indicated that the median, lower and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	26.22 months Interval 19.48 to NA indicated that the upper limit of 95% CI was not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: 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)

Population: FAS included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Overall Survival (OS)	NA months NA indicated that the median, lower and upper limit of 95% CI were not estimable due to insufficient number of participants with events.	NA months NA indicated that the median, lower and upper limit of 95% CI were not estimable due to insufficient number of participants with events.

SECONDARY outcome

Timeframe: At Cycle 9 (cycle duration: 28 days)

Population: FAS included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=78 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Minimal Residual Disease (MRD) Negativity Rate	1.3 percentage of participants	11.5 percentage of participants

SECONDARY outcome

Timeframe: Pre-dose, and at 1, 2, 4 hours post-dose on Day 1 of Cycle 2 (cycle duration: 28 days)

Population: Pharmacokinetic (PK) analysis set included all randomized participants who received at least 1 dose of study drug, for whom there was at least 1 reportable post-dose PK concentration available. Only participants with data collected for each specified timepoints are reported.

Blood samples were collected to determine the concentration of acalabrutinib and its metabolite ACP-5862 in plasma.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=71 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 ACP-5862: 1 hour post-dose	183.15 nanogram per milliliter Geometric Coefficient of Variation 176.1	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 ACP-5862: 2 hours post-dose	298.758 nanogram per milliliter Geometric Coefficient of Variation 102.1	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 ACP-5862: 4 hours post-dose	222.881 nanogram per milliliter Geometric Coefficient of Variation 72.0	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 ACP-5862: Pre-dose	52.314 nanogram per milliliter Geometric Coefficient of Variation 60.4	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 Acalabrutinib: 2 hours post-dose	176.728 nanogram per milliliter Geometric Coefficient of Variation 131.9	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 Acalabrutinib: 4 hours post-dose	56.822 nanogram per milliliter Geometric Coefficient of Variation 112.0	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 Acalabrutinib: Pre-dose	4.057 nanogram per milliliter Geometric Coefficient of Variation 123.8	—
Plasma Concentrations of Acalabrutinib and Its Metabolite ACP-5862 Acalabrutinib: 1 hour post-dose	131.941 nanogram per milliliter Geometric Coefficient of Variation 424.5	—

OTHER_PRE_SPECIFIED outcome

Timeframe: From first dose of study drug (Day 1) up to DCO date of 03 January 2024 (a maximum of approximately 47.5 months)

Population: SAS included all participants who received at least 1 dose of study treatment.

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.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=77 Participants Participants received acalabrutinib 100 mg orally BID in 28-day cycles until PD or any other treatment discontinuation criterion was met.	Chlorambucil Plus Rituximab n=73 Participants Participants received chlorambucil 0.5 mg/kg body weight orally on Day 1 and Day 15 of all 28-day treatment cycles (Cycles 1 to 6) along with an IV infusion of rituximab 375 mg/m\^2 on Day 1 of Cycle 1 followed by 500 mg/m\^2 on Day 1 of each subsequent cycles (Cycles 2 to 6). Cycle duration=28 days. Participants received 6 cycles of chlorambucil plus rituximab or until PD or any other treatment discontinuation criterion was met.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) TESAEs	30 Participants	17 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) TEAEs	74 Participants	68 Participants

Adverse Events

Acalabrutinib

Serious events: 30 serious events

Other events: 67 other events

Deaths: 2 deaths

Chlorambucil Plus Rituximab

Serious events: 17 serious events

Other events: 61 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place