Trial Outcomes & Findings for An Open-Label, Phase 1b Study of Acalabrutinib With and Without Dexamethasone in Subjects With Multiple Myeloma (NCT NCT02211014)

Last Updated: 2020-07-31

Results Overview

AEs and SAEs were coded by system organ class (SOC) and preferred term (PT) based on the Medical Dictionary for Regulatory Activities (MedDRA) reporting system. All AEs summarized were treatment-emergent. Summaries were also presented by the severity of the AE (per Common Toxicity Criteria for Adverse Events \[CTCAE\]) and by relationship to study drug as assessed by the investigator. Events of clinical interest (ECIs) selected for dedicated analysis were evaluated using Standardized MedDRA Queries, where available, by SOC, or by Sponsor-defined baskets of MedDRA Adverse Event Grouped Terms (AEGTs). The following ECIs were summarized: Cardiac events (including a subset of atrial fibrillation), cytopenias (anemia, leukopenia, neutropenia, and thrombocytopenia), hemorrhage (including a subset of major hemorrhage), hepatic events, hypertension, infection, interstitial lung disease/pneumonitis, second primary malignancies (second primary malignancies excluding skin), tumor lysis syndrome.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

27 participants

Primary outcome timeframe

From first dose of study drug up to Cycle 12 (48 weeks). Subjects who showed benefit from study drugs were allowed to continue until disease progression.

Results posted on

2020-07-31

Participant Flow

Multicenter, open-label, randomized, parallel-group study to evaluate the safety, pharmacokinetics, pharmacodynamics and activity of acalabrutinib with/without dexamethasone in subjects with relapsed/refractory multiple myeloma in US and United Kingdom. 27 subjects enrolled into 2 cohorts. Enrollment was discontinued because of lack of efficacy.

Participant milestones

Participant milestones
Measure	Cohort 1 Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Overall Study STARTED	13	14
Overall Study COMPLETED	11	8
Overall Study NOT COMPLETED	2	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1 Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Overall Study Adverse Event	0	2
Overall Study Physician Decision	1	2
Overall Study Started another cancer therapy	1	0
Overall Study Withdrawal by Subject	0	1
Overall Study In agreement with patient, no benefit	0	1

Baseline Characteristics

An Open-Label, Phase 1b Study of Acalabrutinib With and Without Dexamethasone in Subjects With Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 n=13 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=14 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Total n=27 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Age, Categorical >=65 years	4 Participants n=5 Participants	10 Participants n=7 Participants	14 Participants n=5 Participants
Age, Continuous	60.0 years n=5 Participants	68.5 years n=7 Participants	65.0 years n=5 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	10 Participants n=7 Participants	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=5 Participants	14 Participants n=7 Participants	25 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	11 Participants n=5 Participants	9 Participants n=7 Participants	20 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants	7 participants n=7 Participants	13 participants n=5 Participants
Region of Enrollment United Kingdom	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug up to Cycle 12 (48 weeks). Subjects who showed benefit from study drugs were allowed to continue until disease progression.

Outcome measures

Outcome measures
Measure	Cohort 1 n=13 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=14 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 22 Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 22 Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Post Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Post Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 28 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 28 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 56 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 56 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Safety Profile of Acalabrutinib With and Without Dexamethasone Treatment-emergent adverse events (TEAE)	13 Participants	14 Participants	—	—	—	—	—	—	—	—	—	—
Safety Profile of Acalabrutinib With and Without Dexamethasone SAE	5 Participants	9 Participants	—	—	—	—	—	—	—	—	—	—
Safety Profile of Acalabrutinib With and Without Dexamethasone Treatment-related TEAE	7 Participants	7 Participants	—	—	—	—	—	—	—	—	—	—
Safety Profile of Acalabrutinib With and Without Dexamethasone Treatment-related SAE	1 Participants	2 Participants	—	—	—	—	—	—	—	—	—	—
Safety Profile of Acalabrutinib With and Without Dexamethasone TEAE leading to actions taken on study drug	1 Participants	8 Participants	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: On Days 1 and 22: pre-dose, and at 0.5, 0.75, 1, 2, 4, and 6 hours after the morning dose. On Days 8, 15, and 28: pre-dose and 1 hour after the morning dose.

Population: Day 1: 24 (of 27 subjects enrolled) were equally randomized (1:1 ratio) into two cohorts to receive Acalabrutinib (12 in Cohort 1), or with dexamethasone (12 in Cohort 2). Day 22: 17 (of 24) subjects with PK data were remaining: 9 in Cohort 1 and 8 in Cohort 2. Seven subjects discontinued the study prior to Day 22.

The plasma PK of study drug was characterized using noncompartmental analysis. PK parameters were calculated whenever possible, from plasma concentrations of acalabrutinib. Missing dates or times could have been imputed for PK and pharmacodynamic (PD) samples if the missing values could be established with an acceptable level of accuracy based on other information obtained during the visit in question. If PK and PD sampling for a 33 Final Clinical Study Report Drug Substance Acalabrutinib Study Code ACE-MY-001 Edition Number 2 Date 31 October 2018 given subject was not performed according to protocol, the subject could have been excluded from the PK and PD analyses. The PK parameters were tabulated and summarized using descriptive statistics. For each PD variable, the concentration at each assessment was described. The change from baseline to each assessment was summarized. As appropriate the on treatment values were compared with the pretreatment baseline values using paired t-tests.

Outcome measures

Outcome measures
Measure	Cohort 1 n=12 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=12 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 22 n=9 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 22 n=8 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Post Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Post Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 28 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 28 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 56 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 56 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Pharmacokinetic (PK) Parameters Calculated for Acalabrutinib: AUC0-4, AUClast, AUCINF, Cmax, Tmax, λz, t1/2, CL/F, and Vz/F. PK Parameters Calculated for Dexamethasone: Tmax, Cmax, AUC0-4 and AUClast. Cmax (ng/mL) - the maximum concentration observed	524 percentage of CV Standard Deviation 112	437 percentage of CV Standard Deviation 91.5	271 percentage of CV Standard Deviation 103	607 percentage of CV Standard Deviation 90.8	—	—	—	—	—	—	—	—
Pharmacokinetic (PK) Parameters Calculated for Acalabrutinib: AUC0-4, AUClast, AUCINF, Cmax, Tmax, λz, t1/2, CL/F, and Vz/F. PK Parameters Calculated for Dexamethasone: Tmax, Cmax, AUC0-4 and AUClast. AUC (area under the curve)_0-4 (hr*ng/mL)	604 percentage of CV Standard Deviation 72.9	621 percentage of CV Standard Deviation 64	390 percentage of CV Standard Deviation 105	766 percentage of CV Standard Deviation 60.5	—	—	—	—	—	—	—	—
Pharmacokinetic (PK) Parameters Calculated for Acalabrutinib: AUC0-4, AUClast, AUCINF, Cmax, Tmax, λz, t1/2, CL/F, and Vz/F. PK Parameters Calculated for Dexamethasone: Tmax, Cmax, AUC0-4 and AUClast. AUC_last (hr*ng/mL)	638 percentage of CV Standard Deviation 69.5	675 percentage of CV Standard Deviation 56.9	423 percentage of CV Standard Deviation 102	812 percentage of CV Standard Deviation 58.3	—	—	—	—	—	—	—	—
Pharmacokinetic (PK) Parameters Calculated for Acalabrutinib: AUC0-4, AUClast, AUCINF, Cmax, Tmax, λz, t1/2, CL/F, and Vz/F. PK Parameters Calculated for Dexamethasone: Tmax, Cmax, AUC0-4 and AUClast. AUC_INF (infinity) (hr*ng/mL)	754 percentage of CV Standard Deviation 67.8	732 percentage of CV Standard Deviation 63.1	411 percentage of CV Standard Deviation 111	826 percentage of CV Standard Deviation 62.6	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: On Days 1 and 8: pre-dose and at 4 hours after the morning dose. On Days 28 and 56: morning pre-dose only.

Population: 17 (of 27) subjects with evaluable data. For 10 subjects the data was excluded due to: no Day 1 sample received, low cells events or parent populations, or other deviation. Day 1 post and additional time points, further decrease of evaluable data due to: subject discontinuation, low cells events or parent populations, or other deviation.

The percent occupied BTK was calculated in each subject's peripheral blood mononuclear cells (PBMC) sample for each assessment timepoint using an ELISA-based method. Samples from 17 subjects met the criteria for data inclusion, having a dynamic range (signal to noise) of ≥5 for the Day 1 pre-dose timepoint. Acalabrutinib administered at 100 mg bid resulted in a median steady-state (Day 8) BTK target occupancy level of 95% and 98% for Cohort 1 and Cohort 2, respectively. The Days 28 and 56 assessments, both taken at pre-dose, were \>97% occupancy for each cohort. Intersubject variability was low, with 6 of 7 (86%) subjects in Cohort 1 and 4 of 5 (80%) subjects in Cohort 2 having \>90% BTK occupancy at steady-state trough (12h post-dose). The single subject in Cohort 2 with \<90% occupancy at Day 8 pre-dose did not take their Day 7 doses.

Outcome measures

Outcome measures
Measure	Cohort 1 n=9 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=8 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 22 n=8 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 22 n=8 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Pre n=7 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Pre n=5 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Post n=7 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Post n=6 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 28 Pre n=7 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 28 Pre n=6 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 56 Pre n=5 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 56 Pre n=4 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Bruton Tyrosine Kinase (BTK) Occupancy	0 percentage of occupied BTK Standard Deviation 0	0 percentage of occupied BTK Standard Deviation 0	98.5 percentage of occupied BTK Standard Deviation 0.9	98.5 percentage of occupied BTK Standard Deviation 1.3	93.2 percentage of occupied BTK Standard Deviation 6.6	94.3 percentage of occupied BTK Standard Deviation 8.8	98.6 percentage of occupied BTK Standard Deviation 1.1	96.8 percentage of occupied BTK Standard Deviation 4.8	97.6 percentage of occupied BTK Standard Deviation 1.8	95.8 percentage of occupied BTK Standard Deviation 5.5	95.7 percentage of occupied BTK Standard Deviation 6.2	97.6 percentage of occupied BTK Standard Deviation 1.3

SECONDARY outcome

Timeframe: From first dose of study drug up to Cycle 12 (48 weeks). Subjects who showed benefit from study drugs were allowed to continue until disease progression

Per EBMT: CR, negative immunofixation of serum and urine, disappearance of plasmacytomas and \< 5% plasma cells; Stringent complete response (SCR), CR + normal flow cytometry and absence of clonal plasma cells; Very good partial response (VGPR), Serum and urine M-protein detectable on immunofixation but not on electrophoresis or \> 90% reduction is serum and urine M protein; Partial response (PR), \> 50% reduction in serum M-protein and \> 90% reduction in 24 hour urine M-protein, \> 50% reduction in baseline soft tissue plasmacytoma; Minimal response (MR), 25-49% reduction of serum M-protein and 50-59% reduction in 24 hour urine M-protein, 25-49% reduction in plasmacytomas and no increase in lytic bone lesions; Stable disease (SD), not meeting criteria for CR, VGPR, MR, PR or progressive disease (PD); PD, increase of 25% or more from nadir in serum M-protein, urine M-protein, new or increased bone lesions or plasmacytomas, or hypercalcemia solely attributed to multiple myeloma.

Outcome measures

Outcome measures
Measure	Cohort 1 n=13 Participants Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=14 Participants Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 22 Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 22 Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 8 Post Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 8 Post Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 28 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 28 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly	Cohort 1 - Day 56 Pre Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 - Day 56 Pre Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant sCR	0 Participants	0 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant CR	0 Participants	0 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant VGPR	0 Participants	0 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant PR	0 Participants	0 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant MR	1 Participants	2 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant SD	5 Participants	6 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant PD	4 Participants	1 Participants	—	—	—	—	—	—	—	—	—	—
Response Assessed According to Guidelines Proposed by the International Myeloma Workshop Consensus Panel and European Group for Blood and Marrow Transplant NE (not evaluable)	3 Participants	5 Participants	—	—	—	—	—	—	—	—	—	—

Adverse Events

Cohort 1

Serious events: 5 serious events

Other events: 13 other events

Deaths: 2 deaths

Cohort 2

Serious events: 9 serious events

Other events: 14 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Acerta Clinical Trials

Acerta Pharma B.V.

Phone: 1-888-292-9613

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Site and PI can publish/publicly present the results of the study only with prior written consent of Sponsor or otherwise after expiry of 12 months following completion of the study. Site and PI agree to provide 30 days written notice to Sponsor prior to submission for publication or presentation."
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1 n=13 participants at risk Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=14 participants at risk Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Metabolism and nutrition disorders Hypercalcaemia	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Renal and urinary disorders Acute kidney injury	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Cardiac disorders Angina pectoris	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Bacteraemia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Cellulitis	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Fatigue	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Nervous system disorders Headache	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Blood and lymphatic system disorders Hyperviscosity syndrome	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Muscular weakness	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Investigations Norovirus test positive	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Pain	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Pneumonia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Pneumonia influenzal	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Renal and urinary disorders Renail impairment	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Sepsis	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Skin and subcutaneous tissue disorders Skin mass	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Nervous system disorders Syncope	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Urinary tract infection	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.

Measure	Cohort 1 n=13 participants at risk Acalabrutinib 100 mg twice daily (bid) continuously	Cohort 2 n=14 participants at risk Acalabrutinib 100 mg bid continuously and 40 mg dexamethasone once weekly
Blood and lymphatic system disorders Anaemia	53.8% 7/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	42.9% 6/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Diarrhoea	46.2% 6/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	42.9% 6/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Nervous system disorders Headache	46.2% 6/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	28.6% 4/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Respiratory, thoracic and mediastinal disorders Dyspnoea	38.5% 5/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	28.6% 4/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Fatigue	30.8% 4/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Nausea	23.1% 3/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	21.4% 3/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Back pain	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	28.6% 4/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Psychiatric disorders Confusional state	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Constipation	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Psychiatric disorders Contusion	23.1% 3/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Respiratory, thoracic and mediastinal disorders Cough	30.8% 4/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Respiratory, thoracic and mediastinal disorders Epistaxis	23.1% 3/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Psychiatric disorders Insomnia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Metabolism and nutrition disorders Decreased appetite	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Metabolism and nutrition disorders Hypercalcaemia	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Pain in extremity	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Pyrexia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Rhinitis	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Blood and lymphatic system disorders Thrombocytopenia	23.1% 3/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Upper respiratory tract infection	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Vomiting	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Abdominal distension	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Renal and urinary disorders Acute kidney injury	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Investigations Cardiac murmur	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Nervous system disorders Dizziness	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Gastrointestinal disorders Dyspepsia	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Ear and labyrinth disorders Ear pain	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Respiratory, thoracic and mediastinal disorders Haemoptysis	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Nervous system disorders Lethargy	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Lower respiratory tract infection	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Muscular weakness	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Respiratory, thoracic and mediastinal disorders Nasal congestion	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Oedema peripheral	0.00% 0/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	14.3% 2/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
General disorders Pain	15.4% 2/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	0.00% 0/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Investigations Platelet count decreased	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Infections and infestations Sepsis	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.
Investigations White blood cell count decreased	7.7% 1/13 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.	7.1% 1/14 • Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 1210.