For Part 1 and Part 2 (All Subjects): 1. Pregnant or breast feeding 2. Are not committed to aggressive management. For example, the subject’s family or primary physician are unwilling to place the subject on mechanical ventilation or an advanced directive to withhold life support, with the exception of cardiopulmonary resuscitation, is present. 3. Suspected, uncontrolled active bacterial, fungal, viral, or other infection (besides COVID 19) 4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab) 5. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 6 weeks, congestive heart failure (New York Heart Association [NYHA] Grade 3 or 4), or require home oxygen for a chronic lung disorder. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. 6. Use of active systemic or inhaled corticosteroids. Subjects who stop active systemic or inhaled corticosteroids before the first dose of acalabrutinib will not be excluded. 7. Concomitant use of JAK, PI3K, or Btk (other than acalabrutinib) inhibitors with acalabrutinib. Subjects who stop JAK or PI3K inhibitors before the first dose of acalabrutinib will not be excluded. Use of other Btk inhibitors must be stopped 30 days before the first dose of acalabrutinib. For Part 1: 1. In ICU or on invasive mechanical ventilation or ECMO machine before randomization. 2. Known medical resuscitation within 14 days of randomization For Part 2: 1. Randomization to Part 1

For Part 1 and Part 2 (All Subjects): 1. Pregnant or breast feeding 2. Are not committed to aggressive management. For example, the subject’s family or primary physician are unwilling to place the subject on mechanical ventilation or an advanced directive to withhold life support, with the exception of cardiopulmonary resuscitation, is present. 3. Suspected, uncontrolled active bacterial, fungal, viral, or other infection (besides COVID 19) 4. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab) 5. Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 6 weeks, congestive heart failure (New York Heart Association [NYHA] Grade 3 or 4), or require home oxygen for a chronic lung disorder. Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study. 6. Use of active systemic or inhaled corticosteroids. Subjects who stop active systemic or inhaled corticosteroids before the first dose of acalabrutinib will not be excluded. 7. Concomitant use of JAK, PI3K, or Btk (other than acalabrutinib) inhibitors with acalabrutinib. Subjects who stop JAK or PI3K inhibitors before the first dose of acalabrutinib will not be excluded. Use of other Btk inhibitors must be stopped 30 days before the first dose of acalabrutinib. For Part 1: 1. In ICU or on invasive mechanical ventilation or ECMO machine before randomization. 2. Known medical resuscitation within 14 days of randomization For Part 2: 1. Randomization to Part 1