Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk CLL

• Sponsor: Acerta Pharma BV (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02477696
• Collaborator: (none)
• Enrollment: 533
• Locations: 131
• Arms: 2
• Anticipated Duration (Months): 145.1
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is designed to evaluate PFS endpoint for acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: ACP-196; Drug: ibrutinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 533 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Multicenter, Open-Label, Non-Inferiority, Phase III Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Subjects With High Risk Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jul 28, 2015
• Actual Primary Completion Date: Sep 15, 2020
• Anticipated Study Completion Date: Aug 31, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACP-196 acalabrutinib 100 mg BID (Arm A; N=250)	Drug: ACP-196; acalabrutinib 100 mg BID (Arm A; N=250)
Active Comparator: ibrutinib ibrutinib 420 mg QD (Arm B; N=250)	Drug: ibrutinib; ibrutinib 420 mg QD (Arm B; N=250)

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) by Independent Review Committee (IRC) Assessment [Randomization to Disease Progression, Death, or Censoring. Assessed for up to 5 years at the time of analysis.]

   The time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause. Progression by IRC is defined per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria as lymphocyte count >/= 50% from baseline; >/= 50% increase in lymph nodes, liver or spleen; >/= 50% decrease in platelets from baseline or decrease in hemoglobin > 2 g/dL from baseline and related to CLL.

Secondary Outcome Measures

1. Number of Patients With Atrial Fibrillation [Date of first dose until 30 days after the last dose of study drug or the start of new anticancer therapy (whichever comes first). Median follow-up was 41 months.]

   Includes MedDRA preferred terms 'atrial fibrillation' and 'atrial flutter'.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Men and women ≥ 18 years of age.

• ECOG performance status of 0 to 2.

• Diagnosis of CLL.

• Must have ≥ 1 of the following high-risk prognostic factors:

• Presence of 17p del by central laboratory.

• Presence of 11q del by central laboratory.

• Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment

• Must have received ≥ 1 prior therapies for CLL.

• Meet the following laboratory parameters:

• ANC ≥ 750 cells/μL or ≥ 500 cells/μL in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment.

• Platelet count ≥ 30,000 cells/μL without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded.

• Serum AST/SGOT and ALT/SGPT ≤ 3.0 x ULN.

• Total bilirubin ≤ 1.5 x ULN.

• Estimated creatinine clearance ≥ 30 mL/min.

Exclusion Criteria:

• Known CNS lymphoma or leukemia.

• Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome.

• Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

• Prior exposure to ibrutinib or to a BCR inhibitor or a BCL-2 inhibitor.

• Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.

• Prior radio- or toxin-conjugated antibody therapy.

• Prior allogeneic stem cell or autologous transplant.

• Major surgery within 4 weeks before first dose of study drug.

• Prior malignancy, except for adequately treated lentigo maligna melanoma, non-melanomatous skin cancer, in situ cervical carcinoma or other malignancy treated with no evidence of active disease > 3 years before Screening and at low risk for recurrence.

• Significant cardiovascular disease within 6 months of screening.

• Known history of infection with HIV.

• History of stroke or intracranial hemorrhage within 6 months before randomization.

• History of bleeding diathesis.

• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug.

• Requires treatment with a strong CYP3A inhibitor/inducer.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Phoenix	Arizona	United States	85054
2	Research Site	Anaheim	California	United States	92801
3	Research Site	Berkeley	California	United States	94704
4	Research Site	Duarte	California	United States	91010
5	Research Site	La Jolla	California	United States	92093
6	Research Site	Los Angeles	California	United States	90095
7	Research Site	Palo Alto	California	United States	94304
8	Research Site	Santa Rosa	California	United States	95403
9	Research Site	Jacksonville	Florida	United States	32224
10	Research Site	Tampa	Florida	United States	33612
11	Research Site	Athens	Georgia	United States	30607
12	Research Site	Harvey	Illinois	United States	60426
13	Research Site	Peoria	Illinois	United States	61615
14	Research Site	Wichita	Kansas	United States	67214
15	Research Site	Minneapolis	Minnesota	United States	55426
16	Research Site	Rochester	Minnesota	United States	55905
17	Research Site	Billings	Montana	United States	59102
18	Research Site	Hackensack	New Jersey	United States	?07601
19	Research Site	Lake Success	New York	United States	11042
20	Research Site	New Hyde Park	New York	United States	11042
21	Research Site	New York	New York	United States	10021
22	Research Site	New York	New York	United States	10029
23	Research Site	New York	New York	United States	10065
24	Research Site	Durham	North Carolina	United States	27710
25	Research Site	Columbus	Ohio	United States	43210
26	Research Site	Philadelphia	Pennsylvania	United States	19104
27	Research Site	Houston	Texas	United States	77030
28	Research Site	Round Rock	Texas	United States	78665
29	Research Site	Charlottesville	Virginia	United States	22908
30	Research Site	Tacoma	Washington	United States	98405
31	Research Site	Northwest WA	Wisconsin	United States	20007
32	Research Site	Darlinghurst		Australia	2010
33	Research Site	Frankston		Australia	3199
34	Research Site	Melbourne		Australia	3000
35	Research Site	St Leonards		Australia	2065
36	Research Site	Waratah NSW		Australia	2298
37	Research Site	Wollongong		Australia	2500
38	Research Site	Brugge		Belgium	8000
39	Research Site	Bruxelles		Belgium	1200
40	Research Site	Ghent		Belgium	9000
41	Research Site	Leuven		Belgium	3000
42	Research Site	Yvoir		Belgium	5530
43	Research Site	Aalborg		Denmark	9100
44	Research Site	Indgang 27B		Denmark	DK-4000
45	Research Site	Bobigny		France	93000
46	Research Site	Creteil		France	94010
47	Research Site	Pierre-Benite		France	69310
48	Research Site	Rennes Cedex		France	35000
49	Research Site	Rouen		France	76038
50	Research Site	Toulouse Cedex		France	31059
51	Research Site	München		Germany	81241
52	Research Site	Ulm		Germany	89081
53	Research Site	Budapest		Hungary	1083
54	Research Site	Budapest		Hungary	1122
55	Research Site	Debrecen		Hungary	4032
56	Research Site	Kaposvár		Hungary	7400
57	Research Site	Haifa		Israel	31000
58	Research Site	Haifa		Israel	31096
59	Research Site	Haifa		Israel	34362
60	Research Site	Jerusalem		Israel	9103102
61	Research Site	Nahariya		Israel	22100
62	Research Site	Petah Tikvah		Israel	49102
63	Research Site	Tel Hashomer		Israel	52621
64	Research Site	Tiberias		Israel	15208
65	Research Site	Bologna		Italy	40138
66	Research Site	Cagliari		Italy	9121
67	Research Site	Cona		Italy	44124
68	Research Site	Firenze		Italy	50134
69	Research Site	Meldola		Italy	47014
70	Research Site	Milano		Italy	20132
71	Research Site	Milan		Italy	20162
72	Research Site	Modena		Italy	41100
73	Research Site	Ravenna		Italy	48121
74	Research Site	Rome		Italy	168
75	Research Site	Almere		Netherlands	1315 RA
76	Research Site	Amsterdam		Netherlands	1105 AZ
77	Research Site	Blaricum		Netherlands	1261
78	Research Site	Breda		Netherlands	4818 CK
79	Research Site	Delft		Netherlands	2600 GA
80	Research Site	Dordrecht		Netherlands	3317
81	Research Site	Geleen		Netherlands	6162 BG
82	Research Site	Groningen		Netherlands	9700
83	Research Site	Haarlem		Netherlands	2035 RC
84	Research Site	Leiden		Netherlands	2333
85	Research Site	Rotterdam		Netherlands	3062 PA
86	Research Site	Rotterdam		Netherlands	3083 AN
87	Research Site	Utrecht		Netherlands	3584
88	Research Site	Zutphens		Netherlands	7207 AE
89	Research Site	Addington		New Zealand	8011
90	Research Site	Auckland		New Zealand	?0620
91	Research Site	Tauranga		New Zealand	3112
92	Research Site	Bydgoszcz		Poland	85-168
93	Research Site	Gdansk		Poland	80-129
94	Research Site	Gdynia		Poland	81-519
95	Research Site	Krakow		Poland	30-510
96	Research Site	Lodz		Poland	93-510
97	Research Site	Olsztyn		Poland	10-228
98	Research Site	Opole		Poland	46-020
99	Research Site	Slupsk		Poland	76-200
100	Research Site	Wroclaw		Poland	50-001
101	Research Site	Barcelona		Spain	8907
102	Research Site	Barcelona		Spain	?08041
103	Research Site	Madrid		Spain	28006
104	Research Site	Madrid		Spain	28009
105	Research Site	Madrid		Spain	28031
106	Research Site	Madrid		Spain	28041
107	Research Site	Majadahonda		Spain	28222
108	Research Site	Murcia		Spain	30008
109	Research Site	Santander		Spain	39008
110	Research Site	Ankara		Turkey	6230
111	Research Site	Ankara		Turkey	6560
112	Research Site	Instabul		Turkey	34365
113	Research Site	Istanbul		Turkey	34452
114	Research Site	Izmir		Turkey	35040
115	Research Site	Izmir		Turkey	35340
116	Research Site	Kayseri		Turkey	38030
117	Research Site	Birmingham		United Kingdom	B9 5SS
118	Research Site	Bournemouth		United Kingdom	BH7 7DW
119	Research Site	Cambridge		United Kingdom	CB2 0QQ
120	Research Site	Cardiff		United Kingdom	CF14 4XW
121	Research Site	Greater London		United Kingdom	E1 2AD
122	Research Site	Hull		United Kingdom	HU32JZ
123	Research Site	Leeds		United Kingdom	LS9 7TF
124	Research Site	Leicester		United Kingdom	LE1 7RH
125	Research Site	Liverpool		United Kingdom	L7 8XP
126	Research Site	London		United Kingdom	SE5 9RS
127	Research Site	Manchester		United Kingdom	M20 4BX
128	Research Site	Nottingham		United Kingdom	NG5 1PB
129	Research Site	Plymouth		United Kingdom	PL6 8DH
130	Research Site	Southampton		United Kingdom	SO16 6YD
131	Research Site	Surrey		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Acerta Pharma BV

Investigators

• Study Director: Acerta Clinical Trials, 1-888-292-9613

Study Documents (Full-Text)

• Study Protocol - Oct 21, 2020
• Statistical Analysis Plan - Oct 23, 2020

More Information

Additional Information:

• Redacted CSR Synopsis
• Redacted CSP
• Redacted SAP

Publications

None provided.

• Responsible Party: Acerta Pharma BV
• ClinicalTrials.gov Identifier: NCT02477696
• Other Study ID Numbers: ACE-CL-006
• First Posted: Jun 23, 2015
• Last Update Posted: Jun 16, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Acalabrutinib

Study Results

Participant Flow

Recruitment Details

Identify viable recruitment capabilities of potential sites Select qualified investigators who can meet recruitment goal Ensure qualified subjects are recruited at a rate that allows each site to reach randomization goal within planned timeline Track screening and enrolment metrics Provide solutions, strategic and contingency plans to enhance recruitment Assess study-specific constraints to recruitment Select resources for successful, timely recruitment Outline periodic progress assessments

Pre-assignment Detail

Acalabrutinib = Arm A Ibrutinib = Arm B. No wash-out, run-in, escalations or other pre-assignments are required for this clinical trial.

Arm/Group Title	Acalabrutinib - Arm A	Ibrutinib - Arm B
Arm/Group Description	Participants in this arm receive the Investigational Product (IP), ACP196, also known as Acalabrutinib. Patients take 100mg two times daily indefinitely, or until disease progression.	Participants in this arm receive the comparator drug and current standard of treatment, Ibrutinib, also known as brand name 'Imbruvica'. Patients take 420mg once daily indefinitely, or until disease progression.
Period Title: Overall Study
STARTED	268	265
COMPLETED	127	110
NOT COMPLETED	141	155

Baseline Characteristics

Arm/Group Title	Acalabrutinib - Arm A	Ibrutinib - Arm B	Total
Arm/Group Description	Participants in this arm receive the Investigational Product (IP), ACP196, also known as Acalabrutinib. Patients take 100mg two times daily indefinitely, or until disease progression.	Participants in this arm receive the comparator drug and current standard of treatment, Ibrutinib, also known as brand name 'Imbruvica'. Patients take 420mg once daily indefinitely, or until disease progression.	Total of all reporting groups
Overall Participants	268	265	533
Age (Years) [Mean (Standard Deviation) ]
Age (years)	65.5 (9.3)	65.3 (9.6)	65.4 (9.4)
Sex: Female, Male (Count of Participants)
Female	83 31%	71 26.8%	154 28.9%
Male	185 69%	194 73.2%	379 71.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 3%	5 1.9%	13 2.4%
Not Hispanic or Latino	235 87.7%	237 89.4%	472 88.6%
Unknown or Not Reported	25 9.3%	23 8.7%	48 9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.4%	2 0.8%	3 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 1.9%	8 3%	13 2.4%
White	257 95.9%	245 92.5%	502 94.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	5 1.9%	10 3.8%	15 2.8%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) by Independent Review Committee (IRC) Assessment
Description	The time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause. Progression by IRC is defined per International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria as lymphocyte count >/= 50% from baseline; >/= 50% increase in lymph nodes, liver or spleen; >/= 50% decrease in platelets from baseline or decrease in hemoglobin > 2 g/dL from baseline and related to CLL.
Time Frame	Randomization to Disease Progression, Death, or Censoring. Assessed for up to 5 years at the time of analysis.

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (All Randomized Patients)

Arm/Group Title	Acalabrutinib	Ibrutinib
Arm/Group Description	Participants in this arm receive the Investigational Product (IP), ACP196, also known as Acalabrutinib. Patients take 100mg two times daily indefinitely, or until disease progression.	Participants in this arm receive the comparator drug and current standard of treatment, Ibrutinib, also known as brand name 'Imbruvica'. Patients take 420mg once daily indefinitely, or until disease progression.
Measure Participants	268	265
Median (95% Confidence Interval) [Months]	38.4	38.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib, Ibrutinib
	Comments	The hypothesis to be evaluated in the analysis of the primary efficacy endpoint is that acalabrutinib is not inferior to ibrutinib where noninferiority is defined by a pre-specified margin.
	Type of Statistical Test	Non-Inferiority
	Comments	If the upper bound of the 2-sided 95% CI for the HR is below 1.429, acalabrutinib will be concluded to be non-inferior to ibrutinib.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Acalabrutinib/Ibrutinib

2. Secondary Outcome

Title	Number of Patients With Atrial Fibrillation
Description	Includes MedDRA preferred terms 'atrial fibrillation' and 'atrial flutter'.
Time Frame	Date of first dose until 30 days after the last dose of study drug or the start of new anticancer therapy (whichever comes first). Median follow-up was 41 months.

Outcome Measure Data

Analysis Population Description

Safety Population (All Treated Patients)

Arm/Group Title	Acalabrutinib	Ibrutinib
Arm/Group Description	Participants in this arm receive the Investigational Product (IP), ACP196, also known as Acalabrutinib. Patients take 100mg two times daily indefinitely, or until disease progression.	Participants in this arm receive the comparator drug and current standard of treatment, Ibrutinib, also known as brand name 'Imbruvica'. Patients take 420mg once daily indefinitely, or until disease progression.
Measure Participants	266	263
Count of Participants [Participants]	25 9.3%	42 15.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acalabrutinib, Ibrutinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0228
	Comments	If the primary endpoint was met, the superiority of each secondary endpoint was tested at a 2-sided 0.05 significance level in a pre-specified order (afib, gr ≥3 infections, Richter's transformation, OS) following the gate-keeping strategy.
	Method	Cochran-Mantel-Haenszel
	Comments	2-sided Cochran-Mantel-Haenszel test adjusted for 17p deletion status (yes vs. no) and number of prior therapies (1-3 vs. >=4).

Adverse Events

Time Frame	Date of first dose until 30 days after the last dose of study drug or the start of new anticancer therapy (whichever comes first). Median follow-up was 41 months.
Adverse Event Reporting Description	After the signing of the ICF and prior to the first dose of study drug, all SAEs must be reported. After the first dose of study drug, all AEs/SAEs, irrespective of attribution of causality, must be reported. All AEs will be reported until 30 days after the last dose of study drug or the start of new anticancer therapy (whichever comes first). After this period, investigators should report SAEs or other AEs of concern that are believed to be related to prior treatment with study drug.
Arm/Group Title	Acalabrutinib - Arm A		Ibrutinib - Arm B
Arm/Group Description	Participants in this arm receive the Investigational Product (IP), ACP196, also known as Acalabrutinib. Patients take 100mg two times daily indefinitely, or until disease progression.		Participants in this arm receive the comparator drug and current standard of treatment, Ibrutinib, also known as brand name 'Imbruvica'. Patients take 420mg once daily indefinitely, or until disease progression.
All Cause Mortality
	Acalabrutinib - Arm A		Ibrutinib - Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	62/266 (23.3%)		73/263 (27.8%)
Serious Adverse Events
	Acalabrutinib - Arm A		Ibrutinib - Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	143/266 (53.8%)		154/263 (58.6%)
Blood and lymphatic system disorders
Anaemia	14/266 (5.3%)		13/263 (4.9%)
Thrombocytopenia	5/266 (1.9%)		2/263 (0.8%)
Febrile neutropenia	4/266 (1.5%)		5/263 (1.9%)
Neutropenia	3/266 (1.1%)		1/263 (0.4%)
Autoimmune haemolytic anaemia	1/266 (0.4%)		0/263 (0%)
Lymphadenopathy	1/266 (0.4%)		0/263 (0%)
Pancytopenia	1/266 (0.4%)		1/263 (0.4%)
Thrombocytopenic purpura	1/266 (0.4%)		0/263 (0%)
Coagulopathy	0/266 (0%)		1/263 (0.4%)
Haemolytic anaemia	0/266 (0%)		1/263 (0.4%)
Lymphadenitis	0/266 (0%)		1/263 (0.4%)
Cardiac disorders
Atrial Fibrilation	6/266 (2.3%)		14/263 (5.3%)
Angina Pectoris	3/266 (1.1%)		0/263 (0%)
Cardiac Failure	3/266 (1.1%)		5/263 (1.9%)
Pericardial effusion	2/266 (0.8%)		1/263 (0.4%)
Atrial flutter	1/266 (0.4%)		0/263 (0%)
Atrioventricular block second degree	1/266 (0.4%)		1/263 (0.4%)
Bradyarrhythmia	1/266 (0.4%)		0/263 (0%)
Cardiac tamponade	1/266 (0.4%)		0/263 (0%)
Cardio-respiratory arrest	1/266 (0.4%)		0/263 (0%)
Myocardial infarction	1/266 (0.4%)		0/263 (0%)
Palpitations	1/266 (0.4%)		0/263 (0%)
Atrioventricular block	0/266 (0%)		1/263 (0.4%)
Cardiac arrest	0/266 (0%)		2/263 (0.8%)
Mitral valve incompetence	0/266 (0%)		2/263 (0.8%)
Myocardial ischaemia	0/266 (0%)		1/263 (0.4%)
Pericarditis	0/266 (0%)		1/263 (0.4%)
Supraventricular tachycardia	0/266 (0%)		1/263 (0.4%)
Ventricular fibrillation	0/266 (0%)		1/263 (0.4%)
Ear and labyrinth disorders
Sudden hearing loss	0/266 (0%)		1/263 (0.4%)
Endocrine disorders
Hypercalcaemia of malignancy	1/266 (0.4%)		0/263 (0%)
Eye disorders
Cataract	1/266 (0.4%)		0/263 (0%)
Dacryoadenitis acquired	1/266 (0.4%)		0/263 (0%)
Retinal detachment	1/266 (0.4%)		0/263 (0%)
Vitreous haemorrhage	1/266 (0.4%)		0/263 (0%)
Gastrointestinal disorders
Diarrhoea	2/266 (0.8%)		3/263 (1.1%)
Abdominal pain	1/266 (0.4%)		5/263 (1.9%)
Abdominal wall haematoma	1/266 (0.4%)		0/263 (0%)
Colitis	1/266 (0.4%)		0/263 (0%)
Colitis ischaemic	1/266 (0.4%)		0/263 (0%)
Colitis ulcerative	1/266 (0.4%)		0/263 (0%)
Gastrointestinal haemorrhage	1/266 (0.4%)		0/263 (0%)
Incarcerated inguinal hernia	1/266 (0.4%)		0/263 (0%)
Intestinal obstruction	1/266 (0.4%)		0/263 (0%)
Pharyngo-oesophageal diverticulum	1/266 (0.4%)		0/263 (0%)
Pneumatosis intestinalis	1/266 (0.4%)		0/263 (0%)
Abdominal hernia	0/266 (0%)		1/263 (0.4%)
Abdominal pain upper	0/266 (0%)		1/263 (0.4%)
Ascites	0/266 (0%)		1/263 (0.4%)
Constipation	0/266 (0%)		2/263 (0.8%)
Duodenal ulcer perforation	0/266 (0%)		1/263 (0.4%)
Erosive oesophagitis	0/266 (0%)		1/263 (0.4%)
Gastric ulcer	0/266 (0%)		1/263 (0.4%)
Gastrointestinal ulcer	0/266 (0%)		1/263 (0.4%)
Ileus	0/266 (0%)		1/263 (0.4%)
Inguinal hernia	0/266 (0%)		1/263 (0.4%)
Intestinal perforation	0/266 (0%)		2/263 (0.8%)
Mallory-Weiss syndrome	0/266 (0%)		1/263 (0.4%)
Pancreatitis acute	0/266 (0%)		1/263 (0.4%)
Splenic artery aneurysm	0/266 (0%)		1/263 (0.4%)
Upper gastrointestinal haemorrhage	0/266 (0%)		1/263 (0.4%)
Volvulus	0/266 (0%)		1/263 (0.4%)
Vomiting	0/266 (0%)		2/263 (0.8%)
Rectal haemorrhage	0/266 (0%)		1/263 (0.4%)
General disorders
Pyrexia	10/266 (3.8%)		5/263 (1.9%)
Fatigue	2/266 (0.8%)		1/263 (0.4%)
Chest pain	1/266 (0.4%)		1/263 (0.4%)
Mass	1/266 (0.4%)		0/263 (0%)
Soft tissue inflammation	1/266 (0.4%)		0/263 (0%)
Chest discomfort	0/266 (0%)		1/263 (0.4%)
General physical health deterioration	0/266 (0%)		2/263 (0.8%)
Malaise	0/266 (0%)		1/263 (0.4%)
Multiple organ dysfunction syndrome	0/266 (0%)		1/263 (0.4%)
Tissue infiltration	0/266 (0%)		1/263 (0.4%)
Hepatobiliary disorders
Cholecystitis acute	2/266 (0.8%)		0/263 (0%)
Cholelithiasis	1/266 (0.4%)		1/263 (0.4%)
Hyperbilirubinaemia	1/266 (0.4%)		0/263 (0%)
Immune system disorders
Amyloidosis	0/266 (0%)		1/263 (0.4%)
Food allergy	0/266 (0%)		1/263 (0.4%)
Haemophagocytic lymphohistiocytosis	0/266 (0%)		1/263 (0.4%)
Infections and infestations
Pneumonia	27/266 (10.2%)		26/263 (9.9%)
Pneumocystis jirovecii pneumonia	5/266 (1.9%)		0/263 (0%)
Pneumonia pseudomonal	5/266 (1.9%)		0/263 (0%)
Bronchitis	4/266 (1.5%)		2/263 (0.8%)
Cellulitis	3/266 (1.1%)		3/263 (1.1%)
Influenza	3/266 (1.1%)		3/263 (1.1%)
Sepsis	3/266 (1.1%)		7/263 (2.7%)
Upper respiratory tract infection	3/266 (1.1%)		1/263 (0.4%)
Brain Abscess	2/266 (0.8%)		0/263 (0%)
Bronchopulmonary aspergillosis	2/266 (0.8%)		1/263 (0.4%)
COVID-19 pneumonia	2/266 (0.8%)		1/263 (0.4%)
Clostridium difficile colitis	2/266 (0.8%)		0/263 (0%)
Escherichia sepsis	2/266 (0.8%)		0/263 (0%)
Escherichia urinary tract infection	2/266 (0.8%)		2/263 (0.8%)
Neutropenic sepsis	2/266 (0.8%)		0/263 (0%)
Septic shock	2/266 (0.8%)		2/263 (0.8%)
Urinary tract infection	2/266 (0.8%)		4/263 (1.5%)
Aspergillus infection	1/266 (0.4%)		0/263 (0%)
Blister infected	1/266 (0.4%)		0/263 (0%)
COVID-19	1/266 (0.4%)		2/263 (0.8%)
Cerebral aspergillosis	1/266 (0.4%)		1/263 (0.4%)
Chronic sinusitis	1/266 (0.4%)		1/263 (0.4%)
Clostridium difficile infection	1/266 (0.4%)		1/263 (0.4%)
Cryptococcosis	1/266 (0.4%)		0/263 (0%)
Dermatitis infected	1/266 (0.4%)		0/263 (0%)
Diarrhoea infectious	1/266 (0.4%)		0/263 (0%)
Gastroenteritis	1/266 (0.4%)		2/263 (0.8%)
Gastrointestinal infection	1/266 (0.4%)		0/263 (0%)
Groin abscess	1/266 (0.4%)		0/263 (0%)
Haemophilus infection	1/266 (0.4%)		1/263 (0.4%)
Herpes zoster meningoencephalitis	1/266 (0.4%)		0/263 (0%)
Lower respiratory tract infection	1/266 (0.4%)		4/263 (1.5%)
Meningococcal infection	1/266 (0.4%)		0/263 (0%)
Necrotising ulcerative gingivostomatitis	1/266 (0.4%)		0/263 (0%)
Oral candidiasis	1/266 (0.4%)		0/263 (0%)
Oral fungal infection	1/266 (0.4%)		0/263 (0%)
Otitis media	1/266 (0.4%)		0/263 (0%)
Picornavirus infection	1/266 (0.4%)		0/263 (0%)
Pneumococcal infection	1/266 (0.4%)		0/263 (0%)
Pneumococcal sepsis	1/266 (0.4%)		0/263 (0%)
Pneumonia acinetobacter	1/266 (0.4%)		0/263 (0%)
Pneumonia bacterial	1/266 (0.4%)		1/263 (0.4%)
Pneumonia haemophilus	1/266 (0.4%)		1/263 (0.4%)
Pneumonia klebsiella	1/266 (0.4%)		0/263 (0%)
Pneumonia mycoplasmal	1/266 (0.4%)		0/263 (0%)
Pneumonia staphylococcal	1/266 (0.4%)		0/263 (0%)
Pneumonia streptococcal	1/266 (0.4%)		0/263 (0%)
Pneumonia viral	1/266 (0.4%)		0/263 (0%)
Postoperative wound infection	1/266 (0.4%)		1/263 (0.4%)
Respiratory tract infection	1/266 (0.4%)		1/263 (0.4%)
Staphylococcal infection	1/266 (0.4%)		2/263 (0.8%)
Stenotrophomonas infection	1/266 (0.4%)		0/263 (0%)
Urosepsis	1/266 (0.4%)		0/263 (0%)
Wound infection staphylococcal	1/266 (0.4%)		0/263 (0%)
Abscess limb	0/266 (0%)		1/263 (0.4%)
Arthritis bacterial	0/266 (0%)		1/263 (0.4%)
Bacteraemia	0/266 (0%)		1/263 (0.4%)
Bacterial infection	0/266 (0%)		1/263 (0.4%)
Bacterial sepsis	0/266 (0%)		1/263 (0.4%)
Biliary sepsis	0/266 (0%)		1/263 (0.4%)
Bone abscess	0/266 (0%)		1/263 (0.4%)
Campylobacter infection	0/266 (0%)		1/263 (0.4%)
Candida infection	0/266 (0%)		1/263 (0.4%)
Cellulitis staphylococcal	0/266 (0%)		1/263 (0.4%)
Coccidioidomycosis	0/266 (0%)		1/263 (0.4%)
Cystitis	0/266 (0%)		1/263 (0.4%)
Epstein-Barr virus infection reactivation	0/266 (0%)		1/263 (0.4%)
Escherichia pyelonephritis	0/266 (0%)		1/263 (0.4%)
Gastroenteritis norovirus	0/266 (0%)		1/263 (0.4%)
Haematoma infection	0/266 (0%)		1/263 (0.4%)
Hepatitis E	0/266 (0%)		1/263 (0.4%)
Herpes zoster	0/266 (0%)		2/263 (0.8%)
Hydrocele male infected	0/266 (0%)		1/263 (0.4%)
Infected bite	0/266 (0%)		1/263 (0.4%)
Infected skin ulcer	0/266 (0%)		1/263 (0.4%)
Infection	0/266 (0%)		2/263 (0.8%)
Infective exacerbation of bronchiectasis	0/266 (0%)		1/263 (0.4%)
Meningitis	0/266 (0%)		1/263 (0.4%)
Metapneumovirus infection	0/266 (0%)		1/263 (0.4%)
Nocardiosis	0/266 (0%)		2/263 (0.8%)
Orchitis	0/266 (0%)		1/263 (0.4%)
Parainfluenzae virus infection	0/266 (0%)		2/263 (0.8%)
Peritonsillar abscess	0/266 (0%)		1/263 (0.4%)
Pneumonia influenzal	0/266 (0%)		1/263 (0.4%)
Pneumonia pneumococcal	0/266 (0%)		1/263 (0.4%)
Post procedural cellulitis	0/266 (0%)		1/263 (0.4%)
Pseudomonal sepsis	0/266 (0%)		1/263 (0.4%)
Rhinovirus infection	0/266 (0%)		1/263 (0.4%)
Salmonella sepsis	0/266 (0%)		1/263 (0.4%)
Soft tissue infection	0/266 (0%)		1/263 (0.4%)
Tonsillitis	0/266 (0%)		1/263 (0.4%)
Urinary tract infection bacterial	0/266 (0%)		1/263 (0.4%)
Urinary tract infection enterococcal	0/266 (0%)		1/263 (0.4%)
Urinary tract infection pseudomonal	0/266 (0%)		1/263 (0.4%)
Varicella zoster virus infection	0/266 (0%)		1/263 (0.4%)
Appendicitis	2/266 (0.8%)		2/263 (0.8%)
Injury, poisoning and procedural complications
Fall	2/266 (0.8%)		1/263 (0.4%)
Clavicle fracture	1/266 (0.4%)		0/263 (0%)
Fibula fracture	1/266 (0.4%)		0/263 (0%)
Hand fracture	1/266 (0.4%)		0/263 (0%)
Humerus fracture	1/266 (0.4%)		0/263 (0%)
Lower limb fracture	1/266 (0.4%)		0/263 (0%)
Pelvic fracture	1/266 (0.4%)		0/263 (0%)
Subdural haematoma	1/266 (0.4%)		0/263 (0%)
Upper limb fracture	1/266 (0.4%)		0/263 (0%)
Ankle fracture	0/266 (0%)		1/263 (0.4%)
Contusion	0/266 (0%)		1/263 (0.4%)
Femur fracture	0/266 (0%)		1/263 (0.4%)
Hip fracture	0/266 (0%)		1/263 (0.4%)
Limb injury	0/266 (0%)		1/263 (0.4%)
Meniscus injury	0/266 (0%)		1/263 (0.4%)
Splenic rupture	0/266 (0%)		2/263 (0.8%)
Tibia fracture	0/266 (0%)		1/263 (0.4%)
Investigations
Blood lactate dehydrogenase increased	1/266 (0.4%)		0/263 (0%)
Clostridium test positive	1/266 (0.4%)		0/263 (0%)
Weight decreased	1/266 (0.4%)		0/263 (0%)
Hepatic enzyme increased	0/266 (0%)		1/263 (0.4%)
Metabolism and nutrition disorders
Hypercalcaemia	2/266 (0.8%)		2/263 (0.8%)
Hyponatraemia	2/266 (0.8%)		2/263 (0.8%)
Dehydration	1/266 (0.4%)		1/263 (0.4%)
Hyperglycaemia	1/266 (0.4%)		0/263 (0%)
Hypernatraemia	1/266 (0.4%)		0/263 (0%)
Hypokalaemia	1/266 (0.4%)		1/263 (0.4%)
Hypophagia	1/266 (0.4%)		0/263 (0%)
Tumour lysis syndrome	1/266 (0.4%)		1/263 (0.4%)
Cachexia	0/266 (0%)		1/263 (0.4%)
Hyperuricaemia	0/266 (0%)		1/263 (0.4%)
Hypocalcaemia	0/266 (0%)		1/263 (0.4%)
Hypoglycaemia	0/266 (0%)		1/263 (0.4%)
Hypomagnesaemia	0/266 (0%)		1/263 (0.4%)
Hypophosphataemia	0/266 (0%)		1/263 (0.4%)
Malnutrition	0/266 (0%)		1/263 (0.4%)
Musculoskeletal and connective tissue disorders
Myalgia	2/266 (0.8%)		1/263 (0.4%)
Joint instability	1/266 (0.4%)		0/263 (0%)
Osteoarthritis	1/266 (0.4%)		0/263 (0%)
Arthralgia	0/266 (0%)		1/263 (0.4%)
Back pain	0/266 (0%)		1/263 (0.4%)
Flank pain	0/266 (0%)		2/263 (0.8%)
Groin pain	0/266 (0%)		1/263 (0.4%)
Muscle spasms	0/266 (0%)		1/263 (0.4%)
Musculoskeletal chest pain	0/266 (0%)		1/263 (0.4%)
Osteonecrosis	0/266 (0%)		1/263 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	2/266 (0.8%)		2/263 (0.8%)
Acute myeloid leukaemia	1/266 (0.4%)		0/263 (0%)
Burkitt's lymphoma	1/266 (0.4%)		0/263 (0%)
Leukaemic infiltration pulmonary	1/266 (0.4%)		0/263 (0%)
Lung neoplasm malignant	1/266 (0.4%)		0/263 (0%)
Non-small cell lung cancer	1/266 (0.4%)		0/263 (0%)
Ovarian cancer metastatic	1/266 (0.4%)		0/263 (0%)
Prostate cancer	1/266 (0.4%)		5/263 (1.9%)
Renal cancer	1/266 (0.4%)		0/263 (0%)
Renal cell carcinoma	1/266 (0.4%)		0/263 (0%)
Squamous cell carcinoma of skin	1/266 (0.4%)		2/263 (0.8%)
Squamous cell carcinoma of the vulva	1/266 (0.4%)		0/263 (0%)
Thymoma	1/266 (0.4%)		0/263 (0%)
Adenocarcinoma of colon	0/266 (0%)		1/263 (0.4%)
Basal cell carcinoma	0/266 (0%)		2/263 (0.8%)
Benign mesenteric neoplasm	0/266 (0%)		1/263 (0.4%)
Bladder transitional cell carcinoma	0/266 (0%)		1/263 (0.4%)
Endometrial adenoma	0/266 (0%)		1/263 (0.4%)
Malignant melanoma	0/266 (0%)		2/263 (0.8%)
Malignant melanoma in situ	0/266 (0%)		1/263 (0.4%)
Polycythaemia vera	0/266 (0%)		2/263 (0.8%)
Squamous cell carcinoma of lung	0/266 (0%)		1/263 (0.4%)
Squamous cell carcinoma of the parotid gland	0/266 (0%)		1/263 (0.4%)
Tumour associated fever	0/266 (0%)		1/263 (0.4%)
Tumour pain	0/266 (0%)		1/263 (0.4%)
Nervous system disorders
Cerebrovascular accident	3/266 (1.1%)		1/263 (0.4%)
Syncope	3/266 (1.1%)		3/263 (1.1%)
Haemorrhage intracranial	2/266 (0.8%)		0/263 (0%)
Headache	2/266 (0.8%)		2/263 (0.8%)
Guillain-Barre syndrome	1/266 (0.4%)		0/263 (0%)
Muscle spasticity	1/266 (0.4%)		0/263 (0%)
Paraesthesia	1/266 (0.4%)		0/263 (0%)
Post herpetic neuralgia	1/266 (0.4%)		0/263 (0%)
Cerebral ischaemia	0/266 (0%)		1/263 (0.4%)
Cerebrovascular disorder	0/266 (0%)		1/263 (0.4%)
Demyelinating polyneuropathy	0/266 (0%)		1/263 (0.4%)
Ischaemic stroke	0/266 (0%)		1/263 (0.4%)
Memory impairment	0/266 (0%)		1/263 (0.4%)
Multifocal motor neuropathy	0/266 (0%)		1/263 (0.4%)
Seizure	0/266 (0%)		1/263 (0.4%)
Somnolence	0/266 (0%)		1/263 (0.4%)
Transient ischaemic attack	0/266 (0%)		2/263 (0.8%)
Psychiatric disorders
Psychotic disorder	0/266 (0%)		1/263 (0.4%)
Renal and urinary disorders
Acute kidney injury	2/266 (0.8%)		6/263 (2.3%)
Nephrolithiasis	1/266 (0.4%)		1/263 (0.4%)
Renal colic	1/266 (0.4%)		0/263 (0%)
Renal failure	1/266 (0.4%)		2/263 (0.8%)
Renal impairment	1/266 (0.4%)		0/263 (0%)
Haematuria	0/266 (0%)		1/263 (0.4%)
Reproductive system and breast disorders
Cervical dysplasia	1/266 (0.4%)		0/263 (0%)
Oedema genital	1/266 (0.4%)		0/263 (0%)
Prostatitis	0/266 (0%)		1/263 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/266 (1.1%)		2/263 (0.8%)
Bronchospasm	1/266 (0.4%)		0/263 (0%)
Epistaxis	1/266 (0.4%)		1/263 (0.4%)
Lung disorder	1/266 (0.4%)		1/263 (0.4%)
Mediastinal haematoma	1/266 (0.4%)		0/263 (0%)
Pneumonitis	1/266 (0.4%)		1/263 (0.4%)
Pulmonary embolism	1/266 (0.4%)		0/263 (0%)
Pulmonary granuloma	1/266 (0.4%)		0/263 (0%)
Pulmonary mass	1/266 (0.4%)		1/263 (0.4%)
Tonsillar disorder	1/266 (0.4%)		0/263 (0%)
Tonsillar hypertrophy	1/266 (0.4%)		0/263 (0%)
Bronchiectasis	0/266 (0%)		1/263 (0.4%)
Chronic obstructive pulmonary disease	0/266 (0%)		1/263 (0.4%)
Cough	0/266 (0%)		1/263 (0.4%)
Hypoxia	0/266 (0%)		1/263 (0.4%)
Interstitial lung disease	0/266 (0%)		1/263 (0.4%)
Lung infiltration	0/266 (0%)		2/263 (0.8%)
Pleural effusion	0/266 (0%)		5/263 (1.9%)
Pneumothorax	0/266 (0%)		2/263 (0.8%)
Pulmonary haematoma	0/266 (0%)		1/263 (0.4%)
Pulmonary hypertension	0/266 (0%)		1/263 (0.4%)
Respiratory failure	0/266 (0%)		2/263 (0.8%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/266 (0.4%)		0/263 (0%)
Skin haemorrhage	0/266 (0%)		1/263 (0.4%)
Skin ulcer	0/266 (0%)		1/263 (0.4%)
Vascular disorders
Hypotension	1/266 (0.4%)		0/263 (0%)
Orthostatic hypotension	1/266 (0.4%)		1/263 (0.4%)
Thrombophlebitis superficial	1/266 (0.4%)		0/263 (0%)
Vasculitis	1/266 (0.4%)		0/263 (0%)
Aortic dissection	0/266 (0%)		1/263 (0.4%)
Circulatory collapse	0/266 (0%)		1/263 (0.4%)
Embolism	0/266 (0%)		1/263 (0.4%)
Thrombophlebitis	0/266 (0%)		1/263 (0.4%)
Other (Not Including Serious) Adverse Events
	Acalabrutinib - Arm A		Ibrutinib - Arm B
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	256/266 (96.2%)		255/263 (97%)
Blood and lymphatic system disorders
Neutropenia	55/266 (20.7%)		64/263 (24.3%)
Anaemia	51/266 (19.2%)		44/263 (16.7%)
Thrombocytopenia	37/266 (13.9%)		34/263 (12.9%)
Cardiac disorders
Atrial fibrillation	20/266 (7.5%)		35/263 (13.3%)
Eye disorders
Cataract	10/266 (3.8%)		15/263 (5.7%)
Gastrointestinal disorders
Diarrhoea	92/266 (34.6%)		120/263 (45.6%)
Nausea	47/266 (17.7%)		49/263 (18.6%)
Constipation	31/266 (11.7%)		35/263 (13.3%)
Vomiting	28/266 (10.5%)		35/263 (13.3%)
Abdominal pain	18/266 (6.8%)		19/263 (7.2%)
Abdominal pain upper	17/266 (6.4%)		18/263 (6.8%)
Dyspepsia	10/266 (3.8%)		32/263 (12.2%)
Stomatitis	8/266 (3%)		23/263 (8.7%)
General disorders
Pyrexia	57/266 (21.4%)		46/263 (17.5%)
Fatigue	53/266 (19.9%)		44/263 (16.7%)
Oedema peripheral	26/266 (9.8%)		38/263 (14.4%)
Asthenia	23/266 (8.6%)		26/263 (9.9%)
Influenza like illness	14/266 (5.3%)		14/263 (5.3%)
Chills	8/266 (3%)		17/263 (6.5%)
Infections and infestations
Upper respiratory tract infection	69/266 (25.9%)		64/263 (24.3%)
Bronchitis	33/266 (12.4%)		22/263 (8.4%)
Pneumonia	31/266 (11.7%)		24/263 (9.1%)
Nasopharyngitis	29/266 (10.9%)		27/263 (10.3%)
Herpes zoster	23/266 (8.6%)		13/263 (4.9%)
Urinary tract infection	21/266 (7.9%)		34/263 (12.9%)
Oral herpes	16/266 (6%)		16/263 (6.1%)
Respiratory tract infection	12/266 (4.5%)		14/263 (5.3%)
Influenza	10/266 (3.8%)		14/263 (5.3%)
Lower respiratory tract infection	8/266 (3%)		18/263 (6.8%)
Sinusitis	25/266 (9.4%)		22/263 (8.4%)
Injury, poisoning and procedural complications
Contusion	31/266 (11.7%)		47/263 (17.9%)
Investigations
Weight decreased	25/266 (9.4%)		19/263 (7.2%)
Metabolism and nutrition disorders
Decreased appetite	18/266 (6.8%)		25/263 (9.5%)
Hyperuricaemia	13/266 (4.9%)		18/263 (6.8%)
Hypokalaemia	10/266 (3.8%)		24/263 (9.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	42/266 (15.8%)		59/263 (22.4%)
Myalgia	23/266 (8.6%)		26/263 (9.9%)
Back pain	20/266 (7.5%)		34/263 (12.9%)
Pain in extremity	20/266 (7.5%)		26/263 (9.9%)
Musculoskeletal pain	19/266 (7.1%)		10/263 (3.8%)
Muscle spasms	16/266 (6%)		35/263 (13.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	14/266 (5.3%)		9/263 (3.4%)
Squamous cell carcinoma of skin	14/266 (5.3%)		9/263 (3.4%)
Nervous system disorders
Headache	91/266 (34.2%)		53/263 (20.2%)
Dizziness	28/266 (10.5%)		26/263 (9.9%)
Psychiatric disorders
Insomnia	26/266 (9.8%)		12/263 (4.6%)
Respiratory, thoracic and mediastinal disorders
Cough	77/266 (28.9%)		55/263 (20.9%)
Dyspnoea	34/266 (12.8%)		23/263 (8.7%)
Oropharyngeal pain	21/266 (7.9%)		19/263 (7.2%)
Epistaxis	19/266 (7.1%)		28/263 (10.6%)
Nasal congestion	18/266 (6.8%)		14/263 (5.3%)
Productive cough	18/266 (6.8%)		12/263 (4.6%)
Skin and subcutaneous tissue disorders
Rash	26/266 (9.8%)		33/263 (12.5%)
Pruritus	17/266 (6.4%)		11/263 (4.2%)
Petechiae	12/266 (4.5%)		24/263 (9.1%)
Rash maculo-papular	11/266 (4.1%)		16/263 (6.1%)
Onychoclasis	2/266 (0.8%)		17/263 (6.5%)
Vascular disorders
Haematoma	24/266 (9%)		19/263 (7.2%)
Hypertension	23/266 (8.6%)		60/263 (22.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.