Trial Outcomes & Findings for Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL) (NCT NCT02477696)

Last Updated: 2025-11-20

Results Overview

The PFS is defined as the time from date of randomization to the date of first IRC-assessed PD or death due to any cause, whichever occurred first. PD (per International Workshop on Chronic Lymphocytic Leukemia \[iwCLL\] 2008 criteria): Lymphocytes \>= 50% increase over baseline, or \>= 50% increase in lymphadenopathy/hepatomegaly/splenomegaly, or \>= 50% platelets or \> 2 g/dL hemoglobin decreases from baseline secondary to chronic lymphocytic leukemia (CLL). The PFS is assessed using the Kaplan-Meier method.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

533 participants

Primary outcome timeframe

Baseline (Days -28 to -1) through 55.2 months (maximum observed duration)

Results posted on

2025-11-20

Participant Flow

A total of 533 participants were randomized in this study of which 529 participants were treated (4 participants were randomized but not treated).

Participant milestones

Participant milestones
Measure	Acalabrutinib Participants received oral acalabrutinib (ACP196) 100 mg twice daily (BID) until disease progression (PD), or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib Participants received oral ibrutinib 420 mg once daily (QD) until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Overall Study STARTED	268	265
Overall Study Treated	265	264
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	268	265

Reasons for withdrawal

Reasons for withdrawal
Measure	Acalabrutinib Participants received oral acalabrutinib (ACP196) 100 mg twice daily (BID) until disease progression (PD), or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib Participants received oral ibrutinib 420 mg once daily (QD) until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Overall Study Death	89	106
Overall Study Lost to Follow-up	7	5
Overall Study Withdrawal by Subject	37	34
Overall Study Physician Decision	7	9
Overall Study Study terminated by sponsor	103	99
Overall Study Other reasons including transition to commercial drug	23	12
Overall Study Missing/Unknown	2	0

Baseline Characteristics

Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Acalabrutinib n=268 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=265 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Total n=533 Participants Total of all reporting groups
Age, Continuous Age (years)	65.5 Years STANDARD_DEVIATION 9.3	65.3 Years STANDARD_DEVIATION 9.6 • n=4 Participants	65.4 Years STANDARD_DEVIATION 9.4 • n=8 Participants
Sex: Female, Male Sex · Female	83 Participants	71 Participants n=4 Participants	154 Participants n=8 Participants
Sex: Female, Male Sex · Male	185 Participants	194 Participants n=4 Participants	379 Participants n=8 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	5 Participants n=4 Participants	13 Participants n=8 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	235 Participants	237 Participants n=4 Participants	472 Participants n=8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	25 Participants	23 Participants n=4 Participants	48 Participants n=8 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Asian	1 Participants	2 Participants n=4 Participants	3 Participants n=8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Black or African American	5 Participants	8 Participants n=4 Participants	13 Participants n=8 Participants
Race (NIH/OMB) White	257 Participants	245 Participants n=4 Participants	502 Participants n=8 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	10 Participants n=4 Participants	15 Participants n=8 Participants

PRIMARY outcome

Timeframe: Baseline (Days -28 to -1) through 55.2 months (maximum observed duration)

Population: ITT population included all participants randomized and were analyzed according to the arm to which they were randomly assigned.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=268 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=265 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Progression-free Survival (PFS) Based on Independent Review Committee (IRC) Assessment	38.4 Months Interval 33.0 to 38.6	38.4 Months Interval 33.0 to 41.6

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Number of participants with treatment-emergent infections Grade \>=3 are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Treatment-emergent Infections Grade >= 3	98 Participants	101 Participants

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Richter's transformation is defined as the occurrence of an aggressive lymphoma in participants with a previous or concomitant diagnosis of CLL. Richter's transformation was assessed by central pathology. Number of participants with treatment-emergent Richter's transformation are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Treatment-emergent Richter's Transformation	13 Participants	14 Participants

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Number of participants with treatment-emergent atrial fibrillation (including atrial flutter) are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Treatment-emergent Atrial Fibrillation	32 Participants	49 Participants

SECONDARY outcome

Timeframe: Baseline (Days -28 to -1) through 83.7 months (maximum observed duration)

Population: ITT population included all participants randomized and were analyzed according to the arm to which they were randomly assigned.

The OS is defined as the time from date of randomization to date of death due to any cause. The OS is assessed using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=268 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=265 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Overall Survival (OS)	NA Months The median was not reached at the time of data cutoff. 95% CI was not calculable because an insufficient number of participants had event.	NA Months Interval 65.0 to The median was not reached at the time of data cutoff. Upper limit of 95% CI was not calculable because an insufficient number of participants had event.

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TEAEs	262 Participants	259 Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) Any TESAEs	161 Participants	177 Participants

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Number of participants with treatment-emergent laboratory abnormalities are reported. Laboratory abnormality is defined as any abnormal finding during analysis of hematology and serum chemistry.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Treatment-emergent Laboratory Abnormalities Bilirubin (increased)	46 Participants	69 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Calcium (decreased)	56 Participants	71 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Calcium (increased)	15 Participants	11 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Creatinine (increased)	164 Participants	168 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Glucose (decreased)	5 Participants	13 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Glucose (increased)	21 Participants	23 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Phosphate (decreased)	93 Participants	74 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Potassium (decreased)	27 Participants	40 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Sodium (increased)	70 Participants	46 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Urate (increased)	70 Participants	96 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Absolute neutrophil count (decreased)	124 Participants	135 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Haemoglobin (decreased)	139 Participants	131 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Leukocytes (increased)	68 Participants	84 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Potassium (increased)	62 Participants	52 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Sodium (decreased)	26 Participants	37 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Aspartate aminotransferase (increased)	42 Participants	58 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Platelets (decreased)	119 Participants	116 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Leukocytes (decreased)	60 Participants	64 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Absolute lymphocyte count (ALC) (decreased)	66 Participants	65 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities ALC (increased)	71 Participants	72 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Alanine aminotransferase (increased)	73 Participants	70 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Albumin (decreased)	31 Participants	44 Participants
Number of Participants With Treatment-emergent Laboratory Abnormalities Alkaline phosphatase (increased)	66 Participants	60 Participants

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Number of participants with abnormal vital signs reported as TEAEs are reported. Abnormal vital signs are defined as any abnormal finding in the vital sign parameters (body temperature, blood pressure, heart rate, and respiratory rate).

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Abnormal Vital Signs Reported as TEAEs Abnormal loss of weight	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Blood pressure fluctuation	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Blood pressure increased	2 Participants	3 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Cardiac murmur	1 Participants	2 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Dyspnoea	40 Participants	27 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Dyspnoea exertional	2 Participants	5 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Heart rate increased	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Weight decreased	29 Participants	23 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Weight increased	13 Participants	10 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs White coat hypertension	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Blood pressure decreased	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Blood pressure systolic increased	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Body temperature decreased	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Body temperature increased	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Bradycardia	3 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Breath sounds abnormal	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Heart rate irregular	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Hypertension	26 Participants	70 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Hypotension	15 Participants	7 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Hyperpyrexia	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Orthostatic hypotension	2 Participants	1 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Palpitations	12 Participants	15 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Pyrexia	66 Participants	55 Participants
Number of Participants With Abnormal Vital Signs Reported as TEAEs Tachycardia	7 Participants	7 Participants

SECONDARY outcome

Timeframe: Day 1 through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Percentage of participants with at least one occurrence of treatment-related lymphocytosis defined as an elevation in ALC of \>= 50% compared with baseline and a postbaseline assessment of \> 5000/μL in the peripheral blood are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Percentage of Participants With Lymphocytosis	72.5 Percentage of participants Interval 66.7 to 77.7	74.3 Percentage of participants Interval 68.6 to 79.5

SECONDARY outcome

Timeframe: Baseline (Days -28 to -1)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated.

Number of participants with ECG abnormality at baseline are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=266 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=263 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline Abnormal, not clinically significant	86 Participants	98 Participants
Number of Participants With Electrocardiogram (ECG) Abnormality at Baseline Abnormal, clinically significant	4 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (Days -28 to -1) through 83.5 months (maximum observed duration)

Population: Safety population included all participants who received at least one dose of study drug and were analyzed as treated. Here, "number of participants analyzed" (N) signified those participants who had a baseline value and at least 1 postbaseline value of ECOG performance status score during the study.

The ECOG performance status assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory (\>50% of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self care, confined to bed/chair \>50% of waking hrs; 4=completely disabled, cannot carry on any self care, totally confined to bed/chair; 5=death. Number of participants with shift from baseline (Days -28 to -1) to worst Grade 3 and 4 in ECOG performance status are reported.

Outcome measures

Outcome measures
Measure	Acalabrutinib n=259 Participants Participants received oral acalabrutinib (ACP196) 100 mg BID until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.	Ibrutinib n=253 Participants Participants received oral ibrutinib 420 mg QD until PD, or unacceptable toxicity, or other reasons for discontinuation, whichever occurred first.
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=0; Postbaseline=3	0 Participants	1 Participants
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=1; Postbaseline=3	3 Participants	5 Participants
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=2; Postbaseline=3	4 Participants	1 Participants
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=0; Postbaseline=4	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=1; Postbaseline=4	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Worst (Grade 3 and 4) Postbaseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Baseline=2; Postbaseline=4	0 Participants	0 Participants

Adverse Events

Acalabrutinib

Serious events: 161 serious events

Other events: 251 other events

Deaths: 89 deaths

Ibrutinib

Serious events: 177 serious events

Other events: 251 other events

Deaths: 106 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Lead

Acerta Pharma BV

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.
Publication restrictions are in place

Restriction type: OTHER