A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator's Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Subjects With R/R Chronic Lymphocytic Leukemia
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Acerta Pharma BV

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-CL-309 
 
 
Acerta Pharma 
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1 
TITLE PAGE 
 
PROTOCOL 
TITLE: 
A Randomized, Multicenter, Open-Label, Phase 3 Study of 
Acalabrutinib (ACP-196) Versus Investigator’s Choice of 
Either Idelalisib Plus Rituximab or Bendamustine Plus 
Rituximab in Subjects with Relapsed or Refractory Chronic 
Lymphocytic Leukemia 
PROTOCOL NUMBER: 
ACE-CL-309 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
IND NUMBER: 
118717 
EUDRACT NUMBER: 
2015-004454-17 
SPONSOR MEDICAL 
MONITOR: 
 
Phone: 
 
Email: 
  
SPONSOR: 
Acerta Pharma, BV  
Kloosterstraat 9 
5349 AB Oss 
The Netherlands  
ORIGINAL PROTOCOL 
DATE: 
Version 0.0 – 24 March 2016 
AMENDMENT 1 DATE: 
Version 1.0 – 04 August 2016 
AMENDMENT 2.0 DATE:  
Version 2.0 – 03 October 2016  
AMENDMENT 2.1 DATE: 
Version 2.1 – 13 October 2016 
AMENDMENT 3.0 DATE: 
Version 3.0 – 11 May 2017 
AMENDMENT 4.0 DATE: 
Version 4.0 – 29 June 2017 
AMENDMENT 5.0 DATE: 
Version 5.0 – 17 November 2017 
AMENDMENT 6.0 DATE: 
Version 6.0 – 03 June 2020 
AMENDMENT 7.0 DATE: 
Version 7.0 – 17 May 2021 
AMENDMENT 8.0 DATE: 
Version 8.0 – 26 May 2021 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Acerta Pharma BV that 
must not be disclosed to anyone other than the recipient study staff and members of the 
institutional review board (IRB)/independent ethics committee (IEC). This information cannot 
be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Acerta Pharma BV. 
 
 
 
PPD
PPD
PPD

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-CL-309 
 
 
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PROTOCOL APPROVAL PAGE 
Version 8.0 
I have carefully read Protocol ACE-CL-309 entitled “A Randomized, Multicenter, Open-Label, 
Phase 3 Study of Acalabrutinib (ACP-196) Versus Investigator’s Choice of Either Idelalisib Plus 
Rituximab or Bendamustine Plus Rituximab in Subjects with Relapsed or Refractory Chronic 
Lymphocytic Leukemia”.  I agree to conduct this study as outlined herein and in compliance with 
Good Clinical Practice (GCP), all applicable regulatory requirements, and with the ethical 
principles laid down in the Declaration of Helsinki.  Furthermore, I understand that the Sponsor, 
Acerta Pharma, and the IRB/IEC must approve any changes to the protocol in writing before 
implementation. 
I agree not to divulge to anyone, either during or after the termination of the study, any 
confidential information acquired regarding the investigational product and processes or 
methods of Acerta Pharma.  All data pertaining to this study will be provided to Acerta Pharma.  
The policy of Acerta Pharma requires that any presentation or publication of study data by 
clinical Investigators be reviewed by Acerta Pharma, before release, as specified in the protocol. 
 
 
Principal Investigator’s Signature 
Date 
 
 
Print Name 
 
 

Product: Acalabrutinib (ACP-196) 
Protocol: ACE-CL-309 
 
 
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SUMMARY OF AMENDMENT 8.0 
This protocol is being amended to include the following changes: 
x 
No further data will be collected for post-treatment disease follow-up or survival 
follow-up after the final data cutoff.   
Summary of Changes from Amendment 7.0 to Amendment 8.0 
Description of Change 
Sections 
Clarified that no further data will collected after the final data cutoff for 
post-treatment disease follow-up or survival follow-up. 
Section 11.4  
Section 11.5 

Product: Acalabrutinib (ACP-196) 
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2 
SYNOPSIS 
Name of Sponsor/Company: 
Acerta Pharma BV 
Name of Investigational Product: 
Acalabrutinib (ACP-196) 
Name of Active Ingredient: 
Acalabrutinib 
Title of Study:  
A Randomized, Multicenter, Open-Label, Phase 3 Study of Acalabrutinib (ACP-196) Versus 
Investigator’s Choice of Either Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in 
Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia 
Study period: Approximately 4 years, until final data 
cutoff (DCO); approximately >5 years, until last subject 
last visit (LSLV) (total of >9 years) 
Phase of development: 3 
Objectives:  
Primary: 
x 
To evaluate the efficacy of acalabrutinib monotherapy (Arm A) compared with 
idelalisib/rituximab or bendamustine/rituximab (Arm B) based on Independent 
Review Committee (IRC) assessment of progression-free survival (PFS) per 
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria 
(Hallek 2008) with incorporation of the clarification for treatment-related 
lymphocytosis (Cheson 2012) hereafter referred to as IWCLL 2008 criteria in 
subjects with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). 
Secondary: 
To evaluate Arm A compared with Arm B in terms of: 
x 
Investigator (INV)-assessed PFS per IWCLL 2008 criteria. 
x 
INV- and IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria. 
x 
Overall survival (OS). 
x 
Patient-reported outcomes (PROs) by the Functional Assessment of Chronic Illness 
Therapy-Fatigue (FACIT Fatigue) (will no longer be collected as of 
Amendment 6.0). 
x 
INV- and IRC-assessed duration of response (DOR). 
x 
Time to next treatment (TTNT). 
Safety: 
x 
Incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs). 
CCI

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Methodology:  
This randomized, global, multicenter, open-label, Phase 3 study will evaluate the efficacy 
and safety of acalabrutinib monotherapy versus Investigator’s choice of either 
idelalisib/rituximab or bendamustine/rituximab in subjects with R/R CLL. 
Approximately 306 eligible subjects will be randomized in a 1:1 ratio into 2 arms 
(n = 153 each) to receive either: 
Arm A:  Acalabrutinib 100 mg orally (PO) twice per day (BID) administered until an 
unacceptable drug-related toxicity occurs or until disease progression. 
Arm B:  Investigator’s choice of: 
x 
Idelalisib 150 PJ32%,'DGPLQLVWHUHGLQFRPELQDWLRQZLWKGRVHVRILQWUDYHQRXV
(IV) rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 IV every 
2 weeks for 4 infusions, then every 4 weeks for an additional 3 infusions) until 
disease progression or unacceptable toxicity.   
x 
Bendamustine 70 mg/m2 IV (Day 1 and 2 of each cycle) in combination with 
rituximab IV (375 mg/m2/500 mg/m2) on Day 1 of each cycle for up to 6 cycles. 
Subjects will be randomized based on the following stratification factors: 
 
Presence of chromosome deletion 17p13.1 (17p del) 
Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 versus 2) 
1XPEHURISULRUWKHUDSLHVRUYHUVXV 
 
Dose modification provisions for acalabrutinib, idelalisib, and bendamustine are provided in 
the study protocol.  No dose modifications are allowed for rituximab.  Each treatment cycle 
will consist of 28 days (4 weeks).  
Assessment of response and progression will be conducted in accordance with the 
IWCLL 2008 criteria (Hallek 2008), with the modification that treatment-related 
lymphocytosis in the absence of other signs or symptoms of disease progression will not be 
considered progressive disease (Appendix 10).  Disease assessments will be done every 
12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 
Day 1, the second on treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and 
then every 24 weeks (± 14 days) thereafter until confirmation of disease progression or 
death, consent withdrawal, or loss to follow-up.  Subjects from Arm B who have confirmed 
disease progression may be eligible before the final DCO to receive crossover treatment 
single-agent acalabrutinib at 100 mg orally BID at Investigator discretion until disease 
progression or unacceptable toxicity. 
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A treatment termination (TT) visit is required for safety assessments for any subjects who 
permanently discontinue study drug for any reason (except for death, lost to follow up or 
withdrawal of consent), including disease progression, and should be scheduled within 
7 days of his or her last dose of all study drugs, if possible.  In addition to the TT visit, all 
subjects who discontinue study drug(s) will have a safety follow-up (SFU) visit 30 (+ 7) days 
after the last dose of all study drugs, regardless of whether the subject receives a new 
anticancer therapy or demonstrates disease progression within this timeframe.  All subjects 
who discontinue treatment due to an intolerable AE or any reason other than disease 
progression, death, lost to follow-up or consent withdrawn will be followed on study for 
disease progression or death. 
Each subject should be followed until disease progression.  If disease progression has not 
occurred at the time of the 30-day SFU visit, post-treatment disease follow-up visits should 
occur approximately every 3 months (12 weeks) until disease progression, regardless of 
whether the subject receives a new anticancer therapy.  During this period, subjects will be 
followed for disease progression via CT/MRI scans, CBC with differential, physical exams, 
serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).   
Refer to Appendix 1 to Appendix 4 for a comprehensive list of study assessments and their 
timing.  The study schema is provided in Figure 7-1. 
Number of subjects (planned): 306 
Diagnosis and main criteria for inclusion:  
6XEMHFWVZLWK&//ZKRKDYHUHODSVHGDIWHUSULRUWUHDWPHQWregimen. 
Inclusion criteria: 
1. 0HQDQGZRPHQ\HDUVRIDJH 
2. ECOG performance status of 0 to 2. 
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008): 
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are 
clonally co-H[SUHVVLQJ 1 B-cell marker (CD19, CD20, or CD23) and 
CD5.  
b. 3URO\PSKRF\WHVPD\FRPSULVHRIEORRGO\PSKRF\WHV 
c. 3UHVHQFHRI[9 B lymphocytes/L (5000/μL) in the peripheral blood 
(at any point since initial diagnosis). 
4. Must have documented CD20-positive CLL. 
5. $FWLYHGLVHDVHPHHWLQJ 1 of the following IWCLL 2008 criteria for requiring 
treatment: 
a. Evidence of progressive marrow failure as manifested by the development 
of, or worsening of, anemia (hemoglobin < 10 g/dL) and/or 
thrombocytopenia (platelets < ȝ/ 
b. 0DVVLYHLHFPEHORZWKHOHIWFRVWDOPDUJLQSURJUHVVLYHRU
symptomatic splenomegaly. 
c. 0DVVLYHQRGHVLH0 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy. 

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d. Progressive lymphocytosis with an increase of > RYHUD-month 
period or a lymphocyte doubling time (LDT) of < 6 months.  LDT may be 
obtained by linear regression extrapolation of absolute lymphocyte counts 
(ALC) obtained at intervals of 2 weeks over an observation period of 2 to 
3 months.  In subjects with initial blood lymphocyte counts of < 30 x 109/L 
ȝ//'7VKRXOGQRWEHXVHGDVDVLQJOHSDUDPHWHUWRGHILQH
indication for treatment.  In addition, factors contributing to lymphocytosis 
or lymphadenopathy other than CLL (e.g., infections) should be excluded. 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy. 
f. Constitutional symptoms documented in the subject’s chart with 
VXSSRUWLYHREMHFWLYHPHDVXUHVDVDSSURSULDWHGHILQHGDV 1 of the 
following disease-related symptoms or signs: 
i. 8QLQWHQWLRQDOZHLJKWORVV ZLWKLQWKHSUHYLRXVPRQWKV
before screening. 
ii. Significant fatigue (ECOG performance score 2; inability to work or 
perform usual activities). 
iii. )HYHUVKLJKHUWKDQ)RU&IRUZHHNVEHIRUH
screening without evidence of infection. 
iv. Night sweats for > 1 month before screening without evidence of 
infection. 
6. Meet the following laboratory parameters: 
a. $EVROXWHQHXWURSKLOFRXQW$1& 750 FHOOVȝ/[9/L), or 
 500 FHOOVȝ/ x 109/L) in subjects with documented bone marrow 
involvement, and independent of growth factor support 7 days before 
assessment. 
b. 3ODWHOHWFRXQW FHOOVȝ/[9/RU FHOOVȝ/
(30 x 109/L) in subjects with documented bone marrow involvement, and 
without transfusion support 7 days before assessment.  Subjects with 
transfusion-dependent thrombocytopenia are excluded.  If an Investigator 
has chosen bendamustine/rituximab as the Arm B treatment, platelets 
PXVWEHFHOOVȝ/[9/L). 
c. Serum aspartate aminotransferase (AST) and alanine aminotransferase 
$/7 2.0 x upper limit of normal (ULN). 
d. 7RWDOELOLUXELQ 1.5 x ULN. 
e. (VWLPDWHGFUHDWLQLQHFOHDUDQFHRIP/PLQFDOFXODWHGXVLQJWKH
formula of Cockcroft and Gault [(140-Age) • Mass 
(kg)/(72 • creatinine mg/dL); multiply by 0.85 if female]. 
7. 0XVWKDYHUHFHLYHGSULRr systemic therapies for CLL.  Note:  Single-agent 
steroids or localized radiation are not considered a prior line of therapy.  If a 
single-agent anti-CD20 antibody was previously administered, subjects must have 
UHFHLYHG 2 doses. 

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8. Women who are sexually active and can bear children must agree to use highly 
effective forms of contraception while on the study and for 2 days after the last dose 
of acalabrutinib, 90 days after the last dose of idelalisib, 6 months after the last dose 
of bendamustine, or 12 months after the last dose of rituximab, whichever is longer.  
Highly effective forms of contraception are defined in Section 9.2.5.  
9. Men who are sexually active and can beget children must agree to use highly 
effective forms of contraception during the study and for 90 days after the last dose of 
idelalisib, 6 months after the last dose of bendamustine, or 12 months after the last 
dose of rituximab, whichever is longer.  Highly effective forms of contraception are 
defined in Section 9.2.5. 
10. Men must agree to refrain from sperm donation during the study and for 90 days after 
the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months 
after the last dose of rituximab, whichever is longer. 
11. Willing and able to participate in all required evaluations and procedures in this study 
protocol, including swallowing capsules without difficulty. 
12. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (in 
accordance with national and local patient privacy regulations). 
Exclusion criteria: 
1. Known central nervous system (CNS) lymphoma or leukemia. 
2. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s 
syndrome. 
3. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic 
purpura (ITP) defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (> 20 mg daily of prednisone or equivalent). 
4. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a B-cell receptor 
(BCR) inhibitor (e.g., Bruton tyrosine kinase [BTK] inhibitors or phosphoinositide-3 
kinase [PI3K] inhibitors).  Prior bendamustine is allowed if Investigator’s choice for 
treatment in Arm B is idelalisib with rituximab.  Bendamustine retreatment is allowed 
if the prior response to bendamustine lasted > 24 months. 
5. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, 
or investigational drug within 30 days before first dose of study drug. 
6. Corticosteroid use > 20 mg daily prednisone equivalent within 1 week before first 
dose of study drug, except as indicated for other medical conditions such as inhaled 
steroid for asthma, topical steroid use, or as premedication for administration of study 
drug or contrast.  For example, subjects requiring steroids at daily doses > 20 mg 
prednisone equivalent systemic exposure daily, or those who are administered 
steroids for leukemia control or white blood cell count lowering are excluded. 
7. Prior radio- or toxin-conjugated antibody therapy. 
8. Prior allogeneic stem cell transplant or prior autologous transplant within 6 months of 
first dose of study drug(s) or presence of graft-vs-host disease or receiving treatment 
for graft-vs-host disease. 

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9. Major surgical procedure within 30 days of first dose of study drug.  Note:  If a subject 
had major surgery, they must have recovered adequately from any toxicity and/or 
complications from the intervention before the first dose of study drug. 
10. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no evidence of active 
disease present for more than 2 years before screening and felt to be at 
low risk for recurrence by treating physician.   
b. Adequately treated lentigo maligna melanoma without current evidence of 
disease or adequately controlled nonmelanomatous skin cancer. 
c. Adequately treated carcinoma in situ without current evidence of disease. 
11. Significant cardiovascular disease such as uncontrolled or untreated symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or corrected QT interval (QTc) > 480 msec 
(calculated using Fridericia’s formula: QT/RR0.33) at screening.  Exception:  Subjects 
with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll 
on study. 
12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach, or extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
13. Received a live virus vaccination within 28 days of first dose of study drug. 
14. Known history of infection with human immunodeficiency virus (HIV) or any 
uncontrolled active systemic infection (e.g., bacterial, viral, or fungal). For study sites 
in Germany: active infection with human immunodeficiency virus (seropositivity for 
HIV-1 or HIV-2 antibodies, and if positive, reactivity against the HIV-specific p24 
antigen). 
15. Active CMV infection (active viremia as evidenced by positive polymerase chain 
reaction [PCR] result for CMV DNA). 
16. Serologic status reflecting active hepatitis B or C infection.   
a. Subjects who are hepatitis B core antibody (anti-HBc) positive and who 
are surface antigen negative will need to have a negative PCR result 
before randomization.  Those who are hepatitis B surface antigen (HbsAg) 
positive or hepatitis B PCR positive will be excluded. 
b. Subjects who are hepatitis C antibody positive will need to have a 
negative PCR result before randomization.  Those who are hepatitis C 
PCR positive will be excluded. 
17. Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by 
cholelithiasis, cirrhosis of the liver, or portal hypertension. 
18. History of or ongoing drug-induced pneumonitis. 
19. History of serious allergic reactions including anaphylaxis and toxic epidermal 
necrolysis. 

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20. History of stroke or intracranial hemorrhage within 6 months before first dose of study 
drug. 
21. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease). 
22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug. 
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening. 
24. Requires treatment with a strong cytochrome P450 3A (CYP3A) inhibitor/inducer. 
25. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible 
for enrollment to this study. 
26. Breast feeding or pregnant. 
27. Concurrent participation in another therapeutic clinical trial. 
28. Prothrombin time/international normalized ratio (INR) or activated partial 
thromboplastin time (aPTT; in the absence of a Lupus anticoagulant) > 2.0 x ULN.  
Exception:  Subjects receiving warfarin are excluded, however, those receiving other 
anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this 
study after discussion with the medical monitor. 
29. History of confirmed progressive multifocal leukoencephalopathy (PML) 
Investigational product, dosage and mode of administration:  
Acalabrutinib:  
Acalabrutinib is provided as hard gelatin capsules for oral administration.  Acalabrutinib 
100 mg will be administered orally BID.  It is recommended that acalabrutinib be taken as 
close to the scheduled time as possible (preferably within ± 1 hour).  However, if a dose is 
missed, it can be taken up to 3 hours after the scheduled time, with a return to the normal 
schedule with the following dose.   
Duration of treatment:  
For subjects receiving acalabrutinib:  Acalabrutinib will be administered until disease 
progression or unacceptable toxicity.    
For subjects receiving idelalisib/rituximab:  Idelalisib will be administered until disease 
progression or unacceptable toxicity.  Rituximab will be administered for a maximum of 
8 infusions administered in the first 6 cycles. 
For subjects receiving bendamustine/rituximab:  This regimen will be administered for a 
maximum of 6 cycles.  
After the final data cutoff (DCO), the following applies to subjects who are still on treatment 
and deriving clinical benefit: 
x 
In a given country, when acalabrutinib or idelalisib are commercially available and 
reasonably accessible, subjects will be transitioned off study, and treatment will 
continue outside of the study protocol, per local laws and regulations  

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x 
Where idelalisib is not commercially available and reasonably accessible, subjects 
who are receiving idelalisib may be transitioned to receive commercial acalabrutinib 
at the discretion of the investigator.   
x 
Where acalabrutinib is not commercially available and reasonably accessible, 
subjects may be re-consented to continue within this study to receive acalabrutinib in 
line with standards of care.   
Reference therapy, dosage and mode of administration:  
Idelalisib: 
Commercially available idelalisib will be provided as film-coated tablets (150 and 100 mg) for 
oral administration per the instructions in the locally approved labelling (e.g., see United 
States prescribing information) and per institutional standards.   
Idelalisib 150 mg will be administered orally BID. 
Bendamustine: 
Commercially available bendamustine 70 mg/m2 will be administered as an IV infusion on 
Days 1 and 2 of a 28-day cycle according to the instructions in locally approved labelling 
(e.g., see United States prescribing information) and institutional standards.  
Accommodations should be made in the event of doses of bendamustine held or delayed 
due to toxicity to permit a full six cycles to be received, wherever possible.  A maximum of 
6 cycles can be administered.  See further instructions for data entry in such cases in the 
eCRF guidelines. 
Rituximab:  
Commercially available rituximab will be supplied for IV administration according to the 
instructions in the locally approved labelling (e.g., see United States prescribing information) 
and per institutional standards; premedication is required.   
When administered with idelalisib, the rituximab regimen will be 375 mg/m2 IV on Day 1 of 
the first cycle, followed by 500 mg/m2 IV every 2 weeks for 4 doses and then every 4 weeks 
for 3 doses for a total of 8 infusions. 
When administered with bendamustine, the rituximab regimen will be 375 mg/m2 IV on 
Day 1 of the first cycle and 500 mg/m2 IV on Day 1 of Cycles 2 to 6. 
Criteria for Evaluation: 
Primary Endpoint:  
The primary endpoint of the study is PFS (defined as the time from randomization until 
disease progression or death from any cause) as assessed by the IRC per IWCLL 2008 
criteria.   
 
Secondary Endpoints: 
x 
INV-assessed PFS per IWCLL 2008 criteria.   
x 
INV-assessed ORR (defined as the proportion of patients who achieve a best 
response of complete remission [CR], complete remission with incomplete bone 

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marrow recovery [CRi], nodular partial remission [nPR], or partial remission [PR]) per 
IWCLL 2008 criteria. 
x 
IRC-assessed ORR per IWCLL 2008 criteria. 
x 
OS (defined as the time from randomization to the date of death due to any cause). 
x 
PROs as measured by change in scores from baseline to each assessment in the 
FACIT-Fatigue (will no longer be collected as of Amendment 6.0). 
x 
INV- and IRC-assessed DOR (defined as the time from the first documentation of 
objective response to the earlier time of disease progression [assessed by the IRC 
per IWCLL 2008 criteria] or death from any cause). 
x 
TTNT (defined as the time from randomization to institution of nonprotocol-specified 
treatment for CLL.  For crossover patients, TTNT should be defined as time from 
initial treatment of acalabrutinib to institution of nonprotocol-specified treatment for 
CLL). 
Safety Endpoints: 
x 
Frequency, severity, and relatedness of AEs.  
x 
Frequency of AEs requiring discontinuation of study drug or dose reductions. 
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Safety Plan: 
The safety of this study will be monitored by an independent Data Monitoring Committee 
(DMC).  The DMC will meet and review the safety data periodically and the results of the 
interim analysis and provide recommendations according to the DMC charter. 
The first safety data review will be performed by the DMC after 50 subjects have been 
randomized and had the opportunity to receive 8 weeks of study treatment. After the first 
review meeting, the DMC will meet approximately every 6 months and as needed when 
required by the Sponsor or the DMC.  This analysis will focus on deaths, treatment 
discontinuations, SAEs, and Grade 3/4 AEs.   
The medical monitor will review this information on an ongoing basis until the first safety 
data review is conducted by the DMC.   
Concomitant Therapy and Clinical Practice: 
Permitted Concomitant Therapy: 
Standard supportive care medications are permitted; this includes premedication for 
rituximab infusion as per rituximab prescribing information.  Use of hematopoietic growth 
factors is permitted per the American Society of Clinical Oncology (ASCO) guidelines 
(Smith 2015) or per institutional guidelines. 
Subjects with a risk factor for tumor lysis syndrome (TLS) should be considered for hydration 
and uric acid-lowering agent and more frequent monitoring of appropriate laboratory tests.  
Administer appropriate hydration and allopurinol or rasburicase per institutional standards 
before initiating treatment. 
For subjects at risk for pneumonitis:  In selected subjects (e.g., those with a history of 
recurrent pneumonias), anti-infectious prevention should be considered. 
For subjects at risk for infections:  Bacterial/viral/fungal prophylaxis is allowed per 
institutional standards. 
Prohibited Concomitant Therapy: 
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy for 
treating CLL are prohibited.  Short couUVHXVHRIVWHURLGV 2 weeks) > 20 mg/day is 
permitted for premedication use, or to manage infusion-related reactions or to manage other 
inflammatory reactions, such as asthma exacerbations.  Corticosteroids may be 
administered for longer than 2 weeks to treat idelalisib-related adverse events (e.g., 
pneumonitis and colitis).  High-dose corticosteroids used to treat the underlying CLL are not 
allowed on study during or prior to discontinuation of study treatment.  Localized, short 
courses of radiotherapy are allowed for the treatment of lesions unrelated to the disease 
under study, if approved by the medical monitor.  Should a subject develop a second 
primary malignancy while on trial, continuation on trial medication after curative treatment of 
the second primary malignancy may be considered after discussion with the medical 
monitor. Steroids used to premedicate or manage rituximab infusion-related reactions are 
permitted. 
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Required Concomitant Medications: 
Serious and fatal infections have occurred with idelalisib, including opportunistic infections 
such as Pneumocystis jirovecii pneumonia (PJP) and CMV (ZYDELIG SmPC and United 
States prescribing information).  Prophylaxis for PJP in accordance with local guidelines and 
institutional standards should therefore be administered to all patients throughout idelalisib 
treatment, and for a period of 2 to 6 months after discontinuation.  The duration of 
post-treatment prophylaxis should be based on clinical judgment and may take into account 
a patient’s risk factors such as concomitant corticosteroid treatment and prolonged 
neutropenia.  CMV testing will be required for subjects receiving idelalisib or bendamustine 
treatment while on study (see Section 11.1.27). 
Acalabrutinib and Concomitant Therapy: 
The effect of agents that reduce gastric acidity (antacids or proton-pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004).  Results 
from this study indicate that subjects should avoid the use of calcium carbonate-containing 
drugs or supplements for a period of at least 2 hours before and at least 2 hours after taking 
acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole, or any other proton-pump 
inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study 
drug exposure.  The decision to treat with proton-pump inhibitors during the study is at the 
Investigator’s discretion, with an understanding of the potential benefit to the subject’s 
gastrointestinal condition and a potential risk of decreased exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor antagonist 
is required, the H2-receptor antagonist should be taken approximately 2 hours after an 
acalabrutinib dose. 
Concomitant administration of drugs that are strong inhibitors/inducers of CYP3A is not 
recommended (see Section 9.1.3 for more detailed information). 
Statistical Methods: 
All efficacy analyses will be performed using the intent-to-treat (ITT) population, unless 
otherwise specified. 
Primary Efficacy Analysis: 
 
  PFS will be assessed 
between Arm A versus Arm B using a stratified 2-sided log-rank with the strata used for 
randomization (17p del status, ECOG status, and number of prior therapies).  The hazard 
UDWLR+5DQGLWVFRQILGHQFHLQWHUYDO&,ZLOOEHFRPSXWHGIURPDVWUDWLILHG&R[
regression model. 
Secondary Endpoints and Analysis:  
ORR will be assessed for Arms A versus B using a Cochran-Mantel-Haenszel test stratified 
by the randomization strata. 
 
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The following 3 secondary outcomes will be assessed for Arms A vs B in a manner similar to 
the method used for PFS: 
OS 
DOR 
TTNT 
The statistical analysis plan (SAP) will describe the methodology to be used to maintain 
Type I error rate control. 
Safety Analysis: 
Detailed tabulations of safety data (AEs and clinical laboratory tests) will be provided for all 
subjects receiving the study drug.  The number and percent of subjects with 
treatment-emergent adverse events (TEAEs) will be summarized.  Summary of other safety 
parameters by treatment group will be provided where appropriate (refer to Section 12.8). 
Interim Analysis: 
  The stopping rules are based on the primary 
efficacy endpoint of PFS using Lan-DeMets alpha-spending function with the 
O’Brien-Fleming boundary.  
 
 
Sample Size: 
Under the model assumptions, the study is expected to enroll approximately 306 subjects 
with 1:1 randomization ratio.  

A median PFS of 19.4 and 15.2 months has been reported for idelalisib plus rituximab and 
bendamustine plus rituximab, respectively, in patients with R/R CLL (Fischer 2011).  
 
For a full description of statistical analysis methods, please refer to Section 12.  
 
 
 
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3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES
TABLE OF CONTENTS
1
TITLE PAGE................................................................................................... 1
SUMMARY OF AMENDMENT 6.0............................................................................ 3
2
SYNOPSIS ..................................................................................................... 4
3
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ........16
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.......................21
5
INTRODUCTION..........................................................................................25
5.1
Chronic Lymphocytic Leukemia....................................................................25
5.2
BTK Inhibition for the Treatment of CLL .......................................................26
5.3
Acalabrutinib................................................................................................. 26
Mechanism of Action.......................................................................27
Safety Pharmacology......................................................................27
Drug-drug Interaction Potential .......................................................27
5.4
Clinical Experience – Acalabrutinib ..............................................................27
5.5
Idelalisib in Combination with Rituximab ......................................................27
5.6
Bendamustine in Combination with Rituximab .............................................28
5.7
Benefit/Risk ..................................................................................................28
6
TRIAL OBJECTIVES AND PURPOSE.........................................................29
6.1
Primary Objective .........................................................................................29
6.2
Secondary Objectives...................................................................................29
6.3
Safety Objective ...........................................................................................30
6.4
..................................................................................30
7
INVESTIGATIONAL PLAN ...........................................................................30
7.1
Overall Study Design....................................................................................30
7.2
Number of Subjects......................................................................................34
7.3
Estimated Study Duration.............................................................................34
7.4
Treatment Assignment .................................................................................35
7.5
Criteria for Study Termination.......................................................................35
8
SELECTION AND WITHDRAWAL OF SUBJECTS......................................36
8.1
Subject Inclusion Criteria..............................................................................36
8.2
Subject Exclusion Criteria.............................................................................37
8.3
Withdrawal of Subjects from Treatment or Assessment...............................39
Withdrawal of Subjects from Study Treatment................................39
Reasons for Study Exit....................................................................40
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9
TREATMENT OF SUBJECTS......................................................................41
9.1
Concomitant Medications .............................................................................41
Permitted Concomitant Medications................................................41
Prohibited or Restricted Concomitant Medications .........................41
Guideline for Use of CYP Inhibiting/Inducing Drugs........................42
Guidelines for the Use of Drugs that Affect Gastric pH ...................42
Required Concomitant Medications ................................................43
9.2
Risks Associated with Study Treatment .......................................................43
Acalabrutinib ...................................................................................43
Idelalisib..........................................................................................46
Bendamustine.................................................................................47
Rituximab........................................................................................48
Reproductive Toxicity......................................................................49
9.3
Treatment Compliance .................................................................................51
9.4
Enrollment and Randomization Procedures .................................................52
9.5
Restrictions...................................................................................................52
10
STUDY DRUG MATERIALS AND MANAGEMENT .....................................53
10.1
Identification of Investigational Medicinal Product ........................................53
Acalabrutinib ...................................................................................53
Idelalisib..........................................................................................53
Bendamustine.................................................................................54
Rituximab........................................................................................54
10.2
Study Drug Preparation and Administration .................................................54
Acalabrutinib ...................................................................................54
Idelalisib..........................................................................................55
Bendamustine.................................................................................55
Rituximab........................................................................................55
10.3
Dose Delays and Modifications ....................................................................56
Safety Criteria for Adjustment or Stopping Doses...........................56
Dose Delays for Acalabrutinib.........................................................56
Guidelines for Dose Modification and Discontinuation for 
Acalabrutinib ...................................................................................57
Guidelines for Dose Modification and Discontinuation for 
Idelalisib..........................................................................................58
Guidelines for Dose Modification and Discontinuation for 
Bendamustine.................................................................................59
Guidelines for Dose Modification and Discontinuation for 
Rituximab........................................................................................61

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Premedication Requirements (Rituximab).......................................61
10.4
Study Drug Accountability ............................................................................61
11
STUDY ACTIVITIES AND ASSESSMENTS.................................................61
11.1
Description of Procedures ............................................................................62
Informed Consent ...........................................................................62
Medical History ...............................................................................62
Confirmation of Eligibility................................................................. 62
ECOG Performance Status.............................................................63
Physical Examination, Vital Signs, Height & Weight, 
.............................................................63
Electrocardiogram (ECG)................................................................63
Patient Reported Outcomes (PRO).................................................64
Concomitant Medications and Therapy...........................................65
AEs ................................................................................................. 65
Serum/Urine Pregnancy Test..........................................................65
Hepatitis B and C Testing and Monitoring.......................................65
HIV Testing (for Study Sites in Germany) .......................................66
Cytogenetics and FISH Panel.........................................................66
......................................................................67
Hematology.....................................................................................67
Serum Chemistry ............................................................................67
Urinalysis ........................................................................................67
6HUXP,PPXQRJOREXOLQDQGȕ2-microglobulin..................................68
T/B/Natural Killer (NK)/monocyte Cell Count ..................................68
....................................68
.........................................................68
Computed Tomography or Magnetic Resonance Imaging Scans...68
Routine Clinical Assessments.........................................................70
Assessments to Determine Eligibility for Crossover........................70
Overall Response Evaluations........................................................72
Bone Marrow Aspirate and Biopsy..................................................72
Cytomegalovirus Testing................................................................. 74
11.2
TT and SFU Visits ........................................................................................75
11.3
Subsequent Anticancer Therapies................................................................75
11.4
Post-treatment Disease Follow-up................................................................75
11.5
Survival Follow-up ........................................................................................76
11.6
Missed Evaluations.......................................................................................76
11.7
Adverse Events and Serious Adverse Events ..............................................76
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Definition of Adverse Events...........................................................76
Serious Adverse Event....................................................................78
Adverse Events of Special Interest .................................................78
Severity...........................................................................................79
11.8
Documenting and Reporting of AEs and SAEs.............................................79
Adverse Event Reporting Period.....................................................79
Assessment of Adverse Events ......................................................80
Second Primary Malignancies.........................................................80
Hy’s Law .........................................................................................81
Pregnancy.......................................................................................81
Overdose ........................................................................................82
Expedited Reporting Requirements for Serious Adverse Events....82
Type and Duration of Follow-up of Subjects after AEs....................83
12
STATISTICS................................................................................................. 84
12.1
Randomization..............................................................................................84
12.2
Determination of Sample Size ......................................................................85
12.3
Interim Analysis ............................................................................................85
12.4
Final Analysis ...............................................................................................86
12.5
Analysis Populations ....................................................................................86
12.6
Handling of Missing Values/Censoring/Discontinuations..............................86
12.7
Efficacy Analyses .........................................................................................87
Primary Endpoint and Methods.......................................................87
Secondary Endpoints and Methods ................................................87
...............................................88
12.8
Safety Analyses............................................................................................90
13
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ............92
13.1
Direct Access to Source Data/Documents....................................................92
Study Monitoring .............................................................................92
Audits and Inspections....................................................................92
Institutional Review Board and Independent Ethics Committee......92
13.2
Quality Control and Quality Assurance.........................................................93
13.3
Ethics............................................................................................................93
Ethical Conduct of the Study...........................................................93
Written Informed Consent ...............................................................93
13.4
Data Handling and Recordkeeping...............................................................94
Subject Screening Log....................................................................94
CRFs...............................................................................................94
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Inspection of Records .....................................................................94
Retention of Records ......................................................................94
13.5
Protocol Amendments ..................................................................................95
13.6
Publication Policy .........................................................................................95
13.7
Clinical Trial Insurance .................................................................................96
13.8
General Investigator Responsibilities ...........................................................96
14
LIST OF REFERENCES ..............................................................................97
15
APPENDICES ............................................................................................100
LIST OF TABLES
Table 4-1.
Abbreviations and Specialist Terms ................................................................21
Table 10-1.
Drug Modification Actions for Acalabrutinib.....................................................57
Table 10-2.
Dose Modifications for Toxicities Due to Idelalisib...........................................58
LIST OF FIGURES
Figure 7-1.
Study Schema ................................................................................................31
LIST OF APPENDICES
Appendix 1.
Schedule of Assessments – Acalabrutinib Treatment ...................................101
Appendix 2.
Schedule of Assessments – Idelalisib/Rituximab Treatment .........................106
Appendix 3.
Schedule of Assessments – Bendamustine/Rituximab Treatment.................111
Appendix 4.
Schedule of Assessments – Crossover .........................................................116
Appendix 5.
Known Strong in Vivo Inhibitors or Inducers of CYP3A ................................. 121
Appendix 6.
Performance Status Scores ..........................................................................122
Appendix 7.
FACIT-Fatigue ..............................................................................................123
Appendix 8.
.........................................................................................124
Appendix 9.
.....................................................................................................126
Appendix 10.
Response Assessment Criteria (modified from Hallek 2008) – IWCLL 
Criteria (as updated for persistent lymphocytosis in Cheson 2012) ..................................129
Appendix 11.
Adverse Event Assessment of Causality.......................................................131
Appendix 12.
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ....................................................................................................132
Appendix 13.
Management of Study Procedures During Pandemic....................................137
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4-1. 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
11q del 
chromosome deletion 11q22.3 
17p del 
chromosome deletion 17p13.1 
ACP-196 
acalabrutinib 
AE(s) 
adverse event(s) 
AIHA 
autoimmune hemolytic anemia  
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCR 
B-cell receptor 
BID 
twice per day 
BR 
bendamustine with rituximab 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete remission (response) 
CRF 
case report form 
CRi 
CR with incomplete bone marrow recovery  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 

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Abbreviation or Specialist Term 
Explanation 
CYP 
cytochrome P450 
DCO 
data cutoff 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture (system) 
ESMO 
European Society for Medical Oncology 
FACIT-Fatigue 
Functional Assessment of Chronic Illness 
Therapy-Fatigue 
FCR 
fludarabine, cyclophosphamide, and rituximab 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
Gi/L 
giga/liter; x109/liter 
G-CSF 
Granulocyte colony-stimulating factor 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
Ig 
immunoglobulin 
IGHV 
immunoglobulin heavy-chain variable 
IND 
Investigational New Drug 
INV 
Investigator 
INR 
international normalized ratio 
ITP 
idiopathic thrombocytopenic purpura 
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Abbreviation or Specialist Term 
Explanation 
IRB 
institutional review board 
IRC 
independent review committee 
ITT 
intent-to-treat 
IV 
intravenous 
IVIG 
intravenous immunoglobulins 
IWCLL 
International Workshop on Chronic Lymphocytic 
Leukemia 
IXRS 
interactive voice/web response system 
JCV 
John Cunningham virus 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
LDT 
lymphocyte doubling time 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease (defined as the proportion of 
subjects with <1 CLL cell in 104 leukocytes) 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin lymphoma 
NK 
natural killer (cells) 
nPR 
nodular partial remission 
ORR 
overall response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
prescribing information 
PI3K 
phosphoinositide-3 kinase 
PJP  
Pneumocystis jirovecii pneumonia 
3/&Ȗ 
phospholipase C gamma 
PLT 
platelet count 
PO 
per os (by mouth, orally) 
PR 
partial remission (response) 
PML 
Progressive multifocal leukoencephalopathy 
PRL 
partial remission (response) with lymphocytosis 
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Abbreviation or Specialist Term 
Explanation 
PRO(s) 
patient-reported outcome(s) 
PS 
performance status 
Q12W 
every 12 weeks 
Q24W 
every 24 weeks 
QD 
once per day (dosing) 
QM  
every month 
QTc 
corrected QT interval 
R/R 
relapsed/refractory 
RSI 
Reference Safety Information 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SFU 
safety follow-up 
SJS 
Stevens-Johnson syndrome 
SLL 
small lymphocytic leukemia 
SmPC 
summary of product characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE(s) 
treatment-emergent adverse events 
TEN 
toxic epidermal necrolysis 
TLS 
tumor lysis syndrome 
TT 
treatment termination 
TTNT 
time to next treatment 
ULN 
upper limit of normal 
 
 
 
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5 
INTRODUCTION 
5.1 
Chronic Lymphocytic Leukemia 
CLL is a malignancy of B cells that predominantly affects the older population.  The diagnosis of 
CLL is established using peripheral blood and immunophenotyping and requires a minimum of 
5 x 109 monoclonal B cells that co-express CD5 and CD19, CD20 or CD23.  CLL has a variable 
clinical course, where many patients do not require treatment for years and have survival equal 
to age matched controls.  Other patients, however, exhibit aggressive disease and have a poor 
prognosis despite appropriate therapy (Byrd 2004). Staging is predominantly by Rai (Rai 1975) 
or Binet (Binet 1981) both of which distinguish prognostic groups and define patients that should 
be considered for treatment versus those who should be managed with a watch and wait 
approach.  While patients with early disease have not been shown to have a survival advantage 
with early treatment, many patients will eventually require therapy for their disease with the 
onset of symptoms or cytopenias.  International guidelines (IWCLL 2008) that outline indications 
for treatment have been established (Hallek 2008) and are widely used for determining when to 
initiate CLL treatment.  
The treatment of CLL has progressed significantly over the previous decades.  While alkylator 
therapy was used in the past (O'Brien 1995), randomized trials have demonstrated a higher 
response rate and longer PFS with fludarabine and subsequently with fludarabine- and 
cyclophosphamide-based combinations in young, fit patients with CLL (Johnson 1996, 
Rai 2000, Leporrier 2001, Eichhorst 2006, Catovsky 2007, Flinn 2007).  At the same time, the 
chimeric anti-CD20 monoclonal antibody, rituximab was introduced for the treatment of CLL 
(Byrd 2001, O'Brien 2001).  The efficacy of rituximab has been improved by combining it with 
traditional cytotoxic agents such as fludarabine (Byrd 2003, Byrd 2005) or fludarabine plus 
cyclophosphamide (Wierda 2005), which have produced high CR rates and extended PFS 
compared with historical controls.  A large randomized clinical trial, reported by the German CLL 
study group, has shown the benefit of the addition of rituximab to fludarabine and 
cyclophosphamide (FCR) in PFS and OS in patients with previously untreated CLL 
(Hallek 2010).  Bendamustine in combination with rituximab (BR) has also been studied in 
frontline CLL and was found to be less toxic but also less efficacious than FCR 
(Eichhorst 2013). 
Patients who have high risk cytogenetics such as deletions in the long arm of chromosome 11 
[11q del)] or in the short arm of chromosome 17 [17p del], have inferior outcomes and may 

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prove to be refractory to therapy and/or experience short remission durations and rapid 
progression of disease when treated with standard and currently available treatment regimens 
(Hallek 2010, Hillmen 2007).  In addition, elderly patients and those with comorbidities are often 
unable to tolerate combination chemoimmunotherapy regimens, or experience inferior clinical 
outcomes when treated with these regimens.   
Currently, CLL remains an incurable disease with relapse inevitable and most patients requiring 
multiple lines of therapy.  Therapeutic choice after relapse requires the evaluation of the 
intensity of the previous therapies, the duration of response to those therapies, and patient 
comorbidities.  Allogeneic stem cell transplant was the treatment of choice for potentially long 
lasting remissions for those who could tolerate the toxicities.  In the last decade targeted 
therapies against B cell markers/antigens or against components of the B cell receptor such as 
%7.RU3,.įKDYHGHPRQVWUDWHGHIILFDF\ZLWKOHVVWR[LFLW\Wiestner 2015).  However, newer 
therapies with less toxicity and stronger and more durable responses are still needed for the 
treatment of R/R CLL. 
5.2 
BTK Inhibition for the Treatment of CLL 
BTK inhibition is an established therapeutic intervention for the treatment of CLL.  Ibrutinib 
(IMBRUVICA®), a first-generation BTK inhibitor, has demonstrated efficacy in patients with 
R/R CLL based on data from single-arm Phase 2 studies (PCYC 1102/1103) and the 
randomized Phase 3 study (RESONATE) (IMBRUVICA prescribing information).  In the 
RESONATE study, which had a median follow-up of 9.4 months, ibrutinib demonstrated 
improvement over ofatumumab in PFS (HR = 0.22), OS (HR = DQG255YHUVXV
E\LQGHSHQGHQWDVVHVVPHQWDQGYHUVXVE\,QYHVWLJDWRUDVVHVVPHQW 
5.3 
Acalabrutinib 
 
 
 
  For clinical testing, acalabrutinib has been manufactured and formulated according to 
current Good Manufacturing Practices (cGMP). 
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Acalabrutinib is an investigational product.  Acalabrutinib (Calquence) has been approved in the 
United States and other markets for the treatment of adult patients with mantle cell lymphoma 
who have received at least 1 prior therapy, for CLL, and for small lymphocytic lymphoma.  
Mechanism of Action 
  For 
additional details, refer to the Acalabrutinib Investigator Brochure. 
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile; for detailed information on the safety pharmacology of 
acalabrutinib, refer to the Acalabrutinib Investigator Brochure.  
Drug-drug Interaction Potential
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to the 
Acalabrutinib Investigator Brochure.
Please refer to Section 9.1.3 for guidance on drugs that may cause drug-drug interactions.
5.4
Clinical Experience – Acalabrutinib
Acalabrutinib has been studied in a broad range of clinical studies, including subjects with 
hematologic malignancies and solid tumors.  For more detailed and updated information on the 
clinical experience for acalabrutinib, please refer to the Acalabrutinib Investigator Brochure.  
5.5
Idelalisib in Combination with Rituximab
,GHODOLVLELVDQLQKLELWRURI3,.įZKLFKLVK\SHUDFWLYDWHGLQ%-cell malignancies and plays a vital 
role in the B-cell receptor pathway. Idelalisib in combination with rituximab was approved for the 
treatment of R/R CLL based on a multicenter, randomized, double-blind, placebo-controlled, 
Phase 3 study of idelalisib in combination with rituximab (N = 110) versus rituximab plus 
placebo (N = 110) (Furman 2014).  This study enrolled patients were unable to undergo 
chemotherapy due to comorbid conditions (i.e., decreased renal function, previous 
therapy-induced myelosuppression, or major coexisting illnesses).  This study showed 
VLJQLILFDQWO\LPSURYHG3)6+5 S255YVSDQG26DW
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12 PRQWKVYV+5 S 02) in favor of idelalisib in combination with 
rituximab.  The National Comprehensive Cancer Network (NCCN) guidelines (NCCN 2016) 
recommend idelalisib therapy as second-line therapy, ahead of chemoimmunotherapy, in R/R 
CLL.  The European Society for Medical Oncology (ESMO) guidelines (Eichhorst 2015) 
specifically recommend idelalisib/rituximab for patients in the relapsed setting if TP53 
deletion/mutation is present, or if relapsed occurred within 24 to 36 months of 
chemoimmunotherapy, or if the disease did not respond to first-line therapy.   
Therapy with idelalisib is better tolerated than traditional chemoimmunotherapy, but is also 
associated with clinically important safety risks, including hepatotoxicity, severe diarrhea or 
colitis, pneumonitis, severe cutaneous reactions, and intestinal perforation. 
5.6 
Bendamustine in Combination with Rituximab 
Evidence of the efficacy of bendamustine in combination with rituximab in R/R CLL was 
provided by a multicenter Phase 2 trial of this regimen conducted by the German Chronic 
Lymphocytic Group (Fischer 2011).  This single-arm, open-label study enrolled 78 patients, 
including 22 patients with fludarabine-refractory disease and 14 patients with 17p del.  The ORR 
ZDV&,DQGZLWKDPHGLDQIROORZ-up of 24 months the median PFS 
was 14.7 months.  Notable activity was seen in patients with fludarabine-refractory disease but 
not in patients with 17p del.  As mentioned previously, NCCN guidelines recommend 
chemoimmunotherapy, including bendamustine/rituximab as third-line treatment for R/R CLL but 
does not recommend it for patients with 17p del.  ESMO guidelines also do not recommend 
bendamustine/rituximab for patients with 17p del or TP53 mutation.  They do, however, 
recommend repeating first-line chemoimmunotherapy (including bendamustine/rituximab) if 
relapse or progression occurred at least 24 to 36 months after initial chemoimmunotherapy.  
Hematologic toxicity and severe infections are the greatest safety risks associated with this 
regimen; as a result, this regimen is also mostly recommended for younger patients without 
significant comorbidities. 
5.7 
Benefit/Risk 
Clinical studies have shown that acalabrutinib is an orally administered BTK inhibitor with fast 
absorption and rapid clearance that maintains optimal target coverage over 24 hours with a 
dosage of 100 mg BID.  Acalabrutinib has been well tolerated in healthy volunteers and subjects 
with CLL/SLL or Richter’s syndrome.  In the Phase 1/2 study of acalabrutinib in subjects with 

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R/R CLL/SLL (ACE-CL-001), no dose-limiting toxicities (DLTs) were identified at dosages of 
 400 mg once per day (QD) or 100 to 200 mg BID.   Despite poor prognostic characteristics in 
the CLL study population, acalabrutinib has induced sustained decreases in lymphadenopathy 
and provides rapid reduction and/or resolution of lymphocytosis.  In summary, the preliminary 
data suggest that acalabrutinib is well tolerated and has robust activity as a single agent.  Based 
on available data, the risk/benefit for acalabrutinib is likely to be favorable compared with 
idelalisib/rituximab and bendamustine/rituximab for the treatment of patients with R/R CLL.  For 
more detailed and updated information on the benefit/risk profile of acalabrutinib, please refer to 
the Acalabrutinib Investigator Brochure. 
6 
TRIAL OBJECTIVES AND PURPOSE 
6.1 
Primary Objective 
To evaluate the efficacy of acalabrutinib monotherapy (Arm A) compared with 
idelalisib/rituximab or bendamustine/rituximab (Arm B) based on IRC assessment of PFS per 
IWCLL 2008 criteria in subjects with R/R CLL. 
6.2 
Secondary Objectives 
To evaluate Arm A compared with Arm B in terms of: 
x 
INV-assessed PFS per IWCLL 2008 criteria. 
x 
INV- and IRC-assessed overall response rate (ORR) per IWCLL 2008 criteria (defined 
as the proportion of patients who achieve a best response of CR, CRi, nPR, or PR). 
x 
OS. 
x 
PROs by FACIT Fatigue (will no longer be collected as of Amendment 6.0). 
x 
INV- and IRC-assessed DOR (defined as the time from the first documentation of 
objective response to the earlier time of disease progression [assessed by the IRC per 
IWCLL 2008 criteria] or death from any cause). 
x 
Time to next treatment (TTNT) (defined as the time from randomization to institution of 
non-protocol specified treatment for CLL.  For crossover patients, TTNT should be 
defined as time from initial treatment of acalabrutinib to institution of 
nonprotocol-specified treatment for CLL). 
x 
 

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6.3 
Safety Objective 
Incidence and severity of AEs and SAEs. 
6.4 
 
7 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design 
This randomized, global (approximately 150 sites), multicenter, open-label, Phase 3 study will 
evaluate the efficacy and safety of acalabrutinib monotherapy versus idelalisib/rituximab or 
bendamustine/rituximab in subjects with R/R CLL. 
CCI
CCI

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Figure 7-1. 
Study Schema 
Abbreviations:  BID = twice per day; CLL = chronic lymphocytic leukemia; ECOG PS = Eastern 
Cooperative Oncology Group performance status; IV = intravenous; PD = progressive disease; PO = oral. 
Note: Prior to the final data cutoff, subjects who cross over from Arm B to Arm A must meet all eligibility 
requirements for the main study period. 
 
Each treatment cycle will consist of 28 days (4 weeks).  
Approximately 306 eligible subjects will be randomized in a 1:1 ratio into 2 arms (n = 153 each) 
to receive either: 
Arm A:  Acalabrutinib 100 mg PO BID until an unacceptable drug-related toxicity occurs or until 
disease progression. 
Arm B:  Before randomization Investigator’s choice of: 
x 
Idelalisib 150 mg PO BID administered until disease progression or unacceptable toxicity 
LQFRPELQDWLRQZLWK,9LQIXVLRQVRIULWX[LPDE 
x 
Bendamustine 70 mg/m2 IV (Day 1 and 2 of each cycle) in combination with rituximab IV 
(375 mg/m2/500 mg/m2) on Day 1 of each cycle for up to 6 cycles. 
 
Subjects will be randomized based on the following stratification factors: 
x 
Presence of 17p del 

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x 
ECOG performance status (0 or 1 versus 2) 
x 
1XPEHURISULRUWKHUDSLHVRUYHUVXV 
Note:  At Investigator discretion, subjects randomized to Arm B who have confirmed disease 
progression may be eligible to receive crossover treatment with single-agent acalabrutinib at 
100 mg PO BID until disease progression or unacceptable toxicity.  
Crossover: 
Eligible subjects may cross over from Arm B to acalabrutinib monotherapy upon confirmed 
disease progression before the final DCO.  Eligibility for crossover includes meeting all eligibility 
criteria for the main study period.  Screening for eligibility and trial assessments during 
crossover are described in Appendix 4 and should occur within 30 days of disease 
progression.  Subjects may not receive any new systemic therapy between confirmation of 
disease progression and the initiation of crossover therapy with acalabrutinib.   
The following documentation will be reviewed before enrollment to the crossover arm by the 
medical monitor: 
Radiology reports from computed tomography (CT)/magnetic resonance imaging (MRI); CT/MRI 
from disease progression can be used for the new tumor imaging baseline against which to 
assess tumor response on crossover treatment if obtained within 30 days prior to crossover 
dosing Cycle 1 Day 1. 
See also Section 11.1.23 for a more detailed description of crossover-related procedures and 
authorization process. 
Crossover procedures: 
For all treatment arms (Arms A, B, and crossover), radiologic tumor assessment will be done at 
screening, every 12 weeks (± 14 days) with the first on-treatment radiologic assessment 
occurring on Cycle 4 Day 1, the second on-treatment scan on Cycle 7 Day 1, and so on through 
Cycle 25, and then every 24 weeks (± 14 days) thereafter.  For bendamustine-treated subjects, 
the second radiologic tumor assessment will occur at the next 12-week interval (± 14 days) 
regardless of whether the subject is on study drug.  Safety evaluations will consist of 
assessments of AEs, physical exams, and safety laboratory panels.  Assessment of response 
and progression will be conducted in accordance with the IWCLL 2008 criteria for CLL 

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(Hallek 2008), with the modification that treatment-related lymphocytosis in the absence of other 
signs or symptoms of disease progression will not be considered progressive disease 
(Cheson 2012, see Appendix 10).  The Investigator will evaluate sites of disease by radiologic 
imaging (primary); physical examination or other procedures as necessary; review of 
hematology and serum chemistry results; and disease-related symptoms.  The same methods 
of assessment used to assess disease at baseline should be used throughout the study.  A 
central laboratory will perform all hematology testing for the primary endpoint analysis.  
In the setting of suspected CR on the basis of physical exam, laboratory findings (including 
hematologic profile with ALC, ANC, platelet count, and Hgb) and radiologic tumor assessment 
meeting all IWCLL response criteria for CR (Appendix 10), bone marrow analysis (a bone 
marrow aspirate/biopsy and sample of peripheral blood to be obtained between 8-12 weeks 
from the end of treatment or, if study treatment has been discontinued at the time of suspected 
CR, of the radiographic imaging of suspected CR) will be required to confirm CR pathologically 
and to assess minimal residual disease (MRD).    
A treatment termination (TT) visit is required for safety assessments for any subjects who 
permanently discontinue study drug for any reason (except for death, lost to follow up or 
withdrawal of consent), including disease progression, and should be scheduled within 7 days of 
his or her last dose of all study drugs, if possible.  In addition to the TT visit, all subjects who 
discontinue all study drugs will have a safety follow-up visit (SFU) visit 30 days (+ 7 days) after 
the last dose of all study drugs.  If subjects discontinued treatment due to unacceptable toxicity 
or any reason other than disease progression, death, loss to follow-up or consent withdrawal, 
subjects will continue to be followed for disease progression or death.  
Each subject should be followed until disease progression.  If disease progression has not 
occurred at the time of the 30-day SFU visit, post-treatment disease follow-up visits should 
occur approximately every 3 months (12 weeks) until disease progression, regardless of 
whether the subject receives a new anticancer therapy.  During this period, subjects will be 
followed for disease progression via CT/MRI scans, CBC with differential, physical exams, 
serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).  Refer to 
Appendix 1 to Appendix 4 for the full list of assessments required during this period.   
Once the Investigator has confirmed that a subject has progressive disease, subsequent 
anticancer therapy with start date of therapy, IWCLL indication for treatment initiation, additional 

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malignancy occurrence, and subject survival status will be recorded.  Subjects will be followed 
for survival until death, loss to follow-up, consent withdrawal, or study closure, whichever occurs 
first.  Survival status must be assessed, and the date of death must be documented for each 
subject randomized, regardless of whether the subject received treatment. 
The primary efficacy analysis will be based on assessment from an IRC.  As part of the IRC 
review, radiologic evaluations assessed by independent central radiologists and hematology 
results from a central laboratory will be provided.  Detailed procedures will be described in a 
separate charter.  An independent DMC will be formed and constituted according to regulatory 
agency guidelines.  Detailed information regarding the composition of the DMC and DMC 
procedures will be provided in a separate charter.  The DMC will review the safety data 
periodically and provide recommendations according to the charter. 
One interim analysis is planned for the study, when approximately 79 PFS events (two-thirds of 
the primary event goal) have been observed, to assess early efficacy of Arm A versus Arm B 
with respect to the primary efficacy endpoint, PFS (see Section 12.3). 
Refer to Appendix 1, Appendix 2, Appendix 3, and Appendix 4 for a comprehensive list of study 
assessments and their timing.   
7.2 
Number of Subjects 
Approximately 306 eligible subjects will be randomized in a 1:1 ratio into 2 arms (n = 153 each) 
to receive treatment in either Arm A or Arm B. 
7.3 
Estimated Study Duration 
The end of the study is defined as the date of the last visit of the last subject in the study 
(LSLV).  
After the final data cutoff (DCO), the following applies to subjects who are still on treatment and 
deriving clinical benefit: 
x 
In a given country, when acalabrutinib or idelalisib are commercially available and 
reasonably accessible, subjects will be transitioned off study, and treatment will continue 
outside of the study protocol, per local laws and regulations.  

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x 
Where idelalisib is not commercially available and reasonably accessible, subjects who 
are receiving idelalisib may be transitioned to receive commercial acalabrutinib at the 
discretion of the investigator.   
x 
Where acalabrutinib is not commercially available and reasonably accessible, subjects 
may be re-consented to continue within this study to receive acalabrutinib in line with 
standards of care.  
After the DCO, all subjects’ medical procedures and assessments will continue to be 
documented in the subject’s medical records, but only SAEs will be reported using a paper form.  
Of the data collected at the study site after the final DCO, only SAEs will be reported. 
7.4 
Treatment Assignment 
This study will use an interactive voice/web response system (IXRS) for randomization.  
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, 
to increase the likelihood that known and unknown subject attributes (e.g., demographic and 
baseline characteristics) are evenly balanced, and to enhance the validity of statistical 
comparisons across treatment groups.   
Randomization will be performed stratified by the following factors: 
x 
Presence of 17p del 
x 
ECOG performance status (0 or 1 versus 2) 
x 
1XPEHURISULRUWKHUDSLHVRUYHUVXV 
 
7.5 
Criteria for Study Termination 
Acerta Pharma retains the right to terminate the study and remove all study materials from a 
study site at any time.  Specific circumstances that may precipitate such termination are: 
x 
Unsatisfactory subject enrollment with regard to quality or quantity. 
x 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment. 

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8 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1 
Subject Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the following 
criteria:  
1. 0HQDQGZRPHQ\HDUVRIDJH 
2. ECOG performance status of 0 to 2. 
3. Diagnosis of CLL that meets published diagnostic criteria (Hallek 2008): 
a. Monoclonal B-cells (either kappa or lambda light chain restricted) that are 
clonally co-expressinJ 1 B-cell marker (CD19, CD20, or CD23) and CD5.  
b. 3URO\PSKRF\WHVPD\FRPSULVHRIEORRGO\PSKRF\WHV 
c. 3UHVHQFHRI[9 B lymphocytes/L (5000/μL) in the peripheral blood (at 
any point since initial diagnosis). 
4. Must have documented CD20-positive CLL. 
5. $FWLYHGLVHDVHPHHWLQJ 1 of the following IWCLL 2008 criteria for requiring treatment: 
a. Evidence of progressive marrow failure as manifested by the development of, 
or worsening of, anemia (hemoglobin < 10 g/dL) and/or thrombocytopenia 
(platelets < 100ȝ/ 
b. 0DVVLYHLHFPEHORZWKHOHIWFRVWDOPDUJLQSURJUHVVLYHRU
symptomatic splenomegaly. 
c. 0DVVLYHQRGHVLHFP in the longest diameter), progressive, or 
symptomatic lymphadenopathy. 
d. Progressive lymphocytosis with an increase of > RYHUD-month period 
or a LDT of < 6 months.  LDT may be obtained by linear regression 
extrapolation of ALC obtained at intervals of 2 weeks over an observation 
period of 2 to 3 months.  In subjects with initial blood lymphocyte counts of 
< 30 x 109/ȝ//'7VKRXOGQRWEHXVHGDVDVLQJOHSDUDPHWHUWR
define indication for treatment.  In addition, factors contributing to 
lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be 
excluded. 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
standard therapy. 
f. Constitutional symptoms documented in the subject’s chart with supportive 
objective PHDVXUHVDVDSSURSULDWHGHILQHGDV 1 of the following 
disease-related symptoms or signs: 
i. 8QLQWHQWLRQDOZHLJKWORVV ZLWKLQWKHSUHYLRXVPRQWKVEHIRUH
screening. 
ii. Significant fatigue (ECOG performance score 2; inability to work or 
perform usual activities). 
iii. )HYHUVKLJKHUWKDQ)RU&IRUZHHNVEHIRUHVFUHHQLQJ
without evidence of infection. 

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iv. Night sweats for > 1 month before screening without evidence of 
infection. 
6. Meet the following laboratory parameters: 
a. $1& 750 FHOOVȝ/[09/RU 500 FHOOVȝ/ x 109/L) in subjects 
with documented bone marrow involvement, and independent of growth factor 
support 7 days before assessment. 
b. 3ODWHOHWFRXQW FHOOVȝ/[9/RU FHOOVȝ/ x 109/L) 
in subjects with documented bone marrow involvement, and without 
transfusion support 7 days before assessment.  Subjects with 
transfusion-dependent thrombocytopenia are excluded.  If an Investigator has 
chosen bendamustine/rituximab as the Arm B treatment, platelets must be 
 FHOOVȝ/[9/L). 
c. 6HUXP$67DQG$/7 2.0 x ULN. 
d. 7RWDOELOLUXELQ 1.5 x ULN. 
e. (VWLPDWHGFUHDWLQLQHFOHDUDQFHRIP/PLQFDOFXODWHGXVLQJWKHIRUPXOD
of Cockcroft and Gault [(140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply 
by 0.85 if female]. 
7. 0XVWKDYHUHFHLYHGSULRUV\VWHPLFWKHUDSLHVIRU&//1RWH6LQJOH-agent steroids or 
localized radiation are not considered a prior line of therapy.  If a single-agent anti-CD20 
antibody was previously administered, subjects must have UHFHLYHG 2 doses. 
8. Women who are sexually active and can bear children must agree to use highly effective 
forms of contraception while on the study and for 2 days after the last dose of 
acalabrutinib, 90 days after the last dose of idelalisib, 6 months after the last dose of 
bendamustine, or 12 months after the last dose of rituximab, whichever is longer.  Highly 
effective forms of contraception are defined in Section 9.2.5.  
9. Men who are sexually active and can beget children must agree to use highly effective 
forms of contraception during the study and for 90 days after the last dose of idelalisib, 6 
months after the last dose of bendamustine, or 12 months after the last dose of rituximab, 
whichever is longer.  Highly effective forms of contraception are defined in Section 9.2.5. 
10. Men must agree to refrain from sperm donation during the study and for 90 days after the 
last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after 
the last dose of rituximab, whichever is longer. 
11. Willing and able to participate in all required evaluations and procedures in this study 
protocol, including swallowing capsules without difficulty. 
12. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (in accordance 
with national and local patient privacy regulations). 
8.2 
Subject Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Known CNS lymphoma or leukemia. 

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2. Known prolymphocytic leukemia or history of, or currently suspected, Richter’s 
syndrome. 
3. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to 
autoimmune destruction within the screening period or requirement for high doses of 
steroids (> 20 mg daily of prednisone or equivalent). 
4. Prior exposure to a BCL-2 inhibitor (e.g., venetoclax/ABT-199) or a BCR inhibitor (e.g., 
BTK inhibitors or PI3K inhibitors).  Prior bendamustine is allowed if Investigator’s choice 
for treatment in Arm B is idelalisib with rituximab.  Bendamustine retreatment is allowed if 
the prior response to bendamustine lasted > 24 months. 
5. Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or 
investigational drug within 30 days before first dose of study drug. 
6. Corticosteroid use > 20 mg daily prednisone equivalent within 1 week before first dose of 
study drug, except as indicated for other medical conditions such as inhaled steroid for 
asthma, topical steroid use, or as premedication for administration of study drug or 
contrast.  For example, subjects requiring steroids at daily doses > 20 mg prednisone 
equivalent systemic exposure daily, or those who are administered steroids for leukemia 
control or white blood cell count lowering are excluded. 
7. Prior radio- or toxin-conjugated antibody therapy. 
8. Prior allogeneic stem cell transplant or prior autologous transplant within 6 months of first 
dose of study drug(s) or presence of graft-vs-host disease or receiving treatment for 
graft-vs-host disease. 
9. Major surgical procedure within 30 days of first dose of study drug.  Note:  If a subject 
had major surgery, they must have recovered adequately from any toxicity and/or 
complications from the intervention before the first dose of study drug. 
10. History of prior malignancy except for the following: 
a. Malignancy treated with curative intent and with no evidence of active disease 
present for more than 2 years before screening and felt to be at low risk for 
recurrence by treating physician.   
b. Adequately treated lentigo maligna melanoma without current evidence of 
disease or adequately controlled nonmelanomatous skin cancer. 
c. Adequately treated carcinoma in situ without current evidence of disease. 
11. Significant cardiovascular disease such as uncontrolled or untreated symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or QTc > 480 msec (calculated using Fridericia’s 
formula: QT/RR0.33) at screening.  Exception:  Subjects with controlled, asymptomatic 
atrial fibrillation during screening are allowed to enroll on study. 
12. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or 
resection of the stomach, or extensive small bowel resection that is likely to affect 
absorption, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 
13. Received a live virus vaccination within 28 days of first dose of study drug. 
14. Known history of infection with HIV or any uncontrolled active systemic infection (e.g., 
bacterial, viral, or fungal). For study sites in Germany: active infection with human 

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immunodeficiency virus (seropositivity for HIV-1 or HIV-2 antibodies, and if positive, 
reactivity against the HIV-specific p24 antigen).
15. Active CMV infection (active viremia as evidenced by positive polymerase chain reaction 
[PCR] result for CMV DNA).
16. Serologic status reflecting active hepatitis B or C infection.  
a. Subjects who are anti-HBc positive and who are surface antigen negative will 
need to have a negative PCR result before randomization.  Those who are 
HbsAg-positive or hepatitis B PCR positive will be excluded.
b. Subjects who are hepatitis C antibody positive will need to have a negative 
PCR result before randomization.  Those who are hepatitis C PCR positive 
will be excluded.
17. Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, 
primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, 
cirrhosis of the liver, or portal hypertension.
18. History of or ongoing drug-induced pneumonitis.
19. History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
20. History of stroke or intracranial hemorrhage within 6 months before first dose of study 
drug.
21. History of bleeding diathesis (e.g., hemophilia, von Willebrand disease).
22. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 
(e.g., phenprocoumon) within 7 days of first dose of study drug.
23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before 
screening.
24. Requires treatment with a strong CYP3A inhibitor/inducer.
25. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, 
lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving 
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for 
enrollment to this study.
26. Breast feeding or pregnant.
27. Concurrent participation in another therapeutic clinical trial.
28. Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) > 2.0 x ULN.  
Exception:  Subjects receiving warfarin are excluded, however, those receiving other 
anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this 
study after discussion with the medical monitor.
29. History of confirmed progressive multifocal leukoencephalopathy (PML)
8.3
Withdrawal of Subjects from Treatment or Assessment
Withdrawal of Subjects from Study Treatment
Subjects may be withdrawn from study treatment for the following reasons:
x
Progressive disease
x
Completed treatment

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x
Start of alternative anticancer therapy
x
Adverse event
x
Pregnancy
x
Investigator decision
x
Subject’s withdrawal of consent from study
x
Decision by Sponsor to terminate the study
x
Subject lost to follow-up
x
Death
x
Other
Reasons for Study Exit
Reasons for study exit include:
x
Subject’s withdrawal of consent from study
x
Decision by Sponsor to terminate the study
x
Subject lost to follow-up
x
Death
In case a subject is lost to follow-up, every possible effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation.  The measures 
taken to follow up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal must be 
documented in the case report form (CRF) and in the source documents.  Subjects who 
withdraw consent should still be encouraged to complete the SFU assessments before 
withdrawing consent, but these assessments cannot be mandated once consent is withdrawn.
Subjects who are withdrawn or removed from study treatment will not be replaced.

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9
TREATMENT OF SUBJECTS
9.1
Concomitant Medications
Permitted Concomitant Medications
Anti-emetics are permitted if clinically indicated.  Standard supportive care medications are 
permitted.  Use of hematopoietic growth factors is permitted per the ASCO guidelines 
(Smith 2015) or per institutional guidelines.
For subjects considered at risk for tumor lysis syndrome (TLS):  Administer appropriate 
hydration and allopurinol or rasburicase per institutional standards before initiating treatment.
For subjects at risk for pneumonitis:  In selected subjects (e.g., those with a history of recurrent 
pneumonias), anti-infectious prevention should be considered.  
Initiation of antibiotic prophylaxis against pneumocystis infection (e.g., with 
trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning 
before study drug administration may be warranted.  Such support may also offer the benefit of 
reducing the risk for other bacterial infections (Stern 2014).  Prophylaxis with intravenous 
immunoglobulin (IVIG) may be appropriate in subjects with low immunoglobulin levels 
(Raanani 2009).  Local practices or guidelines regarding infection prophylaxis may be followed.
For subjects at risk for infections:  Bacterial/viral/fungal prophylaxis is allowed per institutional 
standards.
Prohibited or Restricted Concomitant Medications
Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy for 
treating CLL are prohibited if being used to treat the disease initially under study.  Short course 
XVHRIVWHURLGV 2 weeks) > 20 mg/day is permitted for premedication use, or to manage 
infusion-related reactions or to manage other inflammatory reactions, such as asthma 
exacerbations.  Corticosteroids may be administered for longer than 2 weeks to treat 
idelalisib-related AEs (e.g., pneumonitis and colitis).  High-dose corticosteroids used to treat the 
underlying CLL are not allowed on study.  Localized, short courses of radiotherapy are allowed 
for the treatment of lesions unrelated to the disease under study, if approved by the medical 
monitor.  Should a subject develop a second primary malignancy while on trial, continuation on 
trial medication after curative treatment of the second primary malignancy may be considered 

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after discussion with the medical monitor.  Steroids used to premedicate or manage rituximab 
infusion-related reactions are permitted.
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited.
Guideline for Use of CYP Inhibiting/Inducing Drugs
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated.  However, concomitant administration of acalabrutinib with a 
strong CYP3A inhibitor increased exposure of acalabrutinib by approximately 5-fold (refer to the 
Investigator Brochure for additional details).  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 5) with acalabrutinib should be avoided when 
possible.  If a subject requires short-term treatment with a strong CYP3A inhibitor while on study 
(such as anti-infectives for up to 7 days), interrupt acalabrutinib treatment.  If a subject requires 
a moderate CYP3A inhibitor while on study, decrease the acalabrutinib dose to 100 mg QD.  
Conversely, concomitant administration of acalabrutinib with a strong CYP3A inducer has the 
potential to decrease acalabrutinib exposure and could reduce efficacy.  If a subject requires 
treatment with a strong CYP3A inducer, increase the acalabrutinib dose to 200 mg BID during 
concomitant administration with the strong CYP3A inducer and return to recommended dose of 
100 mg BID after stopping the strong CYP3A inducer.  For additional information on drugs with 
potential drug-drug interactions, refer to the Acalabrutinib Investigator Brochure.
If subjects receiving idelalisib are taking concomitant strong CYP3A inhibitors, monitor for signs 
of idelalisib toxicity.  Coadministration of strong CYP3A inducers or CYP3A substrates with 
idelalisib should be avoided.  
Based on these considerations, subjects who require therapy with the drugs listed in Appendix 5
should not be enrolled into the study.  If medically justified, subjects may be enrolled if such 
inhibitors or inducers can be discontinued or alternative drugs that do not affect these enzymes 
can be substituted within 7 days before first dose of study drug.  
Guidelines for the Use of Drugs that Affect Gastric pH
The effect of agents that reduce gastric acidity (antacids or proton pump inhibitors) on 
acalabrutinib absorption was evaluated in a healthy volunteer study (ACE HV-004).  Results 
from this study indicate that subjects should avoid the use of calcium carbonate containing 
drugs or supplements for a period of at least 2 hours before and at least 2 hours after taking 

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acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole or any other proton pump 
inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study 
drug exposure.  However, the decision to treat with proton-pump inhibitors during the study is at 
the Investigator’s discretion, with an understanding of balancing the potential benefit to the 
subject’s gastrointestinal condition against a potential risk of decreased exposure to 
acalabrutinib.
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on acalabrutinib 
absorption has not been evaluated, if treatment with an H2-receptor antagonist is required, the 
H2-receptor antagonist should be taken approximately 2 hours after an acalabrutinib dose.
Required Concomitant Medications
Serious and fatal infections have occurred with idelalisib, including opportunistic infections such 
as PJP and CMV (ZYDELIG SmPC and ZYDELIG prescribing information).  Prophylaxis for PJP 
in accordance with local guidelines and institutional standards should therefore be administered 
to all patients throughout idelalisib treatment, and for a period of 2 to 6 months after 
discontinuation.  The duration of post-treatment prophylaxis should be based on clinical 
judgment and may take into account a patient’s risk factors such as concomitant corticosteroid 
treatment and prolonged neutropenia.  
9.2
Risks Associated with Study Treatment
Acalabrutinib
Refer to Section 10.3.3 for specific dose modification and discontinuation guidelines.
Risks Associated with Acalabrutinib
The following summarizes the experience with acalabrutinib in hematological cancer studies. 
For more detailed information on TEAEs, please refer to the Acalabrutinib Investigator 
Brochure.  Full details regarding the clinical safety of acalabrutinib are presented in Sections 5 
and 6 of the Acalabrutinib Investigator’s Brochure.
Hemorrhage
Bleeding events, some fatal, including central nervous system, respiratory, and gastrointestinal 
hemorrhage, have been reported in subjects treated with acalabrutinib. 

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Subjects receiving antiplatelet or anticoagulant therapies may be at increased risk of 
hemorrhage and should be monitored for signs of bleeding.  As a precaution, it is suggested per 
protocol that acalabrutinib be withheld for at least 3 days pre- and post-surgery.  
Subjects with hemorrhage should be managed per institutional guidelines or as clinically 
indicated. 
Infections 
Serious infections, including fatal events, have been reported in subjects treated with 
acalabrutinib.  Consider prophylaxis in subjects who are at increased risk for opportunistic 
infections.  Subjects should be monitored for signs and symptoms of infection and treated as 
medically appropriate.  Refer to the sections below for additional information and monitoring 
guidance for viral hepatitis and additional information and management guidance for signs and 
symptoms of PML. 
Hepatitis B Reactivation 
Cases of hepatitis B virus (HBV) reactivation have been reported in subjects treated with 
acalabrutinib, with one case resulting in liver failure and death.  Please refer to Section 11.1.11 
for monitoring of HBV and management of subjects with HBV reactivation, including subjects 
who are routinely receiving IVIG for CLL management.  
Progressive Multifocal Leukoencephalopathy (PML) 
Cases of PML have been reported in subjects treated with acalabrutinib.  Signs and symptoms 
of PML may include cognitive and behavioral changes, language disturbances, visual 
disturbances, sensory deficits, weakness, and coordination and gait difficulties.  If PML is 
suspected, hold further treatment with acalabrutinib until PML is excluded. A diagnostic 
evaluation may include (but is not limited to): 
x 
Neurologic consultation 
x 
Brain magnetic resonance imaging (MRI) 
x 
Polymerase chain reaction (PCR) analysis for JC virus DNA in cerebrospinal fluid 
 

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If PML is confirmed, permanently discontinue acalabrutinib. 
Cytopenias 
Grade 3 or 4 events of cytopenias, including neutropenia, anemia, and thrombocytopenia have 
occurred in subjects treated with acalabrutinib.  Monitor blood counts as specified in the 
Schedule of Assessments and as medically appropriate.  Please refer to Section 10.3 for study 
drug modification guidance.  Subjects with cytopenias should be managed according to 
institutional guidelines or as clinically indicated. 
Second Primary Malignancies  
Second primary malignancies, including solid tumors and skin cancers, have been reported in 
subjects treated with acalabrutinib.  The most frequent second primary malignancy was skin 
cancer (basal cell carcinoma).  Subjects should be monitored for signs and symptoms of 
malignancy.  Subjects who develop a second primary malignancy should be managed 
according to institutional guidelines with diagnostic evaluations as clinically indicated, and it may 
be necessary for patients to permanently discontinue study treatment.  Continuation of 
acalabrutinib treatment should be discussed with the medical monitor.  Please refer to 
Section 11.8.3 for second primary malignancy reporting guidance.  
Atrial Fibrillation  
Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, syncope, 
chest pain, dyspnea), and obtain an ECG as clinically indicated.  Subjects with atrial fibrillation 
should be managed per institutional guidelines with supportive care and diagnostic evaluations 
as clinically indicated. 
Reference Safety Information 
See the Reference Safety Information (RSI) in the Acalabrutinib Investigator Brochure for 
assessment of expectedness of serious adverse reactions. 

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Idelalisib
For complete information, refer to the United States Prescribing Information or local label, which 
serves as RSI for idelalisib for this global study.  Please refer to Section 10.3.4 for specific dose 
modification and discontinuation guidelines.
Contraindications
History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.
Risks Associated with Idelalisib
x
Monitor hepatic function prior to and during treatment, and in the event of transaminase 
elevation, interrupt, reduce or discontinue idelalisib.
x
Monitor for the development of severe diarrhea or colitis.  Interrupt and then reduce or 
discontinue idelalisib.
x
Monitor for pulmonary symptoms and bilateral interstitial infiltrates associated with 
pneumonitis.  Interrupt or discontinue idelalisib.
x
Monitor for signs and symptoms of infection.  Interrupt idelalisib if infection is suspected.
o
Interrupt idelalisib in subjects with suspected PJP infection of any grade, and 
discontinue idelalisib if PJP infection of any grade is confirmed.
x
Monitor subjects with positive CMV serology at the start of treatment with idelalisib or 
with other evidence of a history of CMV infection.  For subjects with evidence of CMV 
infection of any grade or viremia (PCR above the lower limit of quantitation or positive 
antigen test), hold idelalisib until the infection has resolved.  If treatment with idelalisib is 
resumed, monitor subjects (by PCR or antigen test) for CMV reactivation at least 
monthly and consider administering pre-emptive CMV therapy.
x
Subjects should be monitored for respiratory signs and symptoms throughout treatment.  
Subjects should be advised to report new respiratory symptoms promptly.
x
Discontinue idelalisib if intestinal perforation is suspected.
x
If Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is suspected, 
interrupt idelalisib until the etiology of the reaction has been determined.  If SJS or TEN 
is confirmed, discontinue idelalisib.
x
Monitor subjects for the development of severe cutaneous reactions and discontinue
idelalisib.

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x
Monitor subjects for serious allergic reactions, including anaphylaxis, and discontinue 
idelalisib.
x
Monitor blood counts at least every 2 weeks for the first 6 months of treatment with 
idelalisib, and at least weekly in subjects while ANC is less than 1.0 Gi/L.
x
May cause fetal harm (see Section 9.2.5 for guidelines on contraception).
Drug-drug Interactions
Avoid coadministration of strong CYP3A inducers (Appendix 5) with idelalisib.  Idelalisib is a 
strong CYP3A inhibitor.  If subjects are taking concomitant strong CYP3A inhibitors 
(Appendix 5), monitor for signs of idelalisib toxicity.  Follow dose modifications for adverse 
reactions.  
Bendamustine
For complete information, refer to the United States Prescribing Information/label which, will 
serve as RSI for bendamustine for this global study.  Please refer to Section 10.3.5 for specific 
dose modification and discontinuation guidelines.
Contraindications
History of a hypersensitivity reaction to bendamustine.  Reactions included anaphylaxis and 
anaphylactoid reactions.
Risks Associated with Bendamustine
x
Myelosuppression: Delay or reduce dose.  Restart treatment based on ANC and platelet 
count recovery.  Complications of myelosuppression may lead to death.
x
Infections: Monitor for fever and other signs of infection or reactivation of infections and 
treat promptly. 
x
Subjects should be monitored for respiratory signs and symptoms throughout treatment.  
Subjects should be advised to report new signs of infection, including fever or respiratory 
symptoms promptly. Discontinuation of bendamustine should be considered if there are 
signs of (opportunistic) infections. Anaphylaxis and infusion reactions: Severe and 
anaphylactic reactions have occurred; monitor clinically and discontinue bendamustine.  
Premedicate in subsequent cycles for milder reactions.
x
TLS: Acute renal failure and death; anticipate and use supportive measures. 

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x
Skin reactions: Discontinue for severe skin reactions.  Cases of Stevens-Johnson 
syndrome and toxic epidermal necrolysis, some fatal, have been reported when 
bendamustine was administered concomitantly with allopurinol and other medications 
known to cause these syndromes.
x
Other malignancies: Pre-malignant and malignant diseases have been reported. 
x
Extravasation injury: Assure good venous access and monitor infusion site during and 
after administration.
x
May cause fetal harm (see Section 9.2.5 for guidelines on contraception).
Drug-drug Interactions
Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure of 
bendamustine.
Rituximab
For complete information, refer to the United States label for the RSI for rituximab for this study.  
Also refer to Section 10.3.6 in this protocol for specific dose modification and discontinuation 
guidelines.
Contraindications
None.
Warnings and Precautions
x
)DWDOLQIXVLRQUHDFWLRQVZLWKLQKRXUVRIULWX[LPDELQIXVLRQDSSUR[LPDWHO\RIIDWDO
reactions occurred with first infusion.  Monitor subjects and discontinue rituximab 
infusion for severe reactions
x
Severe, including fatal, mucocutaneous reactions can occur in subjects receiving 
rituximab.  
x
HBV reactivation can occur in patients treated with rituximab, in some cases resulting in 
fulminant hepatitis, hepatic failure, and death.  Monitor subjects for HBV reactivation 
during and after treatment with rituximab.  Discontinue rituximab and concomitant 
medications in the event of HBV reactivation.
x
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in 
subjects receiving rituximab.  

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x
TLS: Administer aggressive intravenous hydration, anti-hyperuricemic agents, monitor 
renal function.
x
Infections: Withhold rituximab and institute appropriate anti-infective therapy.
x
Cardiac arrhythmias and angina: Discontinue infusions in case of serious or 
life-threatening events.
x
Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, 
or related symptoms.
x
Live virus vaccines: Do not administer live virus vaccines prior to or during rituximab.
x
Cytopenias: Monitor blood counts at regular intervals.
Drug-drug Interactions
Renal toxicity may result when rituximab is used in combination with cisplatin.
Reproductive Toxicity
Definition of women of non-reproductive potential: 
Women will be considered of non-reproductive potential if they are either: 
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle-stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy.  In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) Have a congenital or acquired condition that prevents childbearing.

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Women who are sexually active and can bear children must agree to use highly effective forms 
of contraception during the study and 2 days after the last dose of acalabrutinib, 90 days after 
the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the 
last dose of rituximab, whichever is longer.  Men who are sexually active and can beget children 
must agree to use highly effective forms of contraception during the study and for 90 days after 
the last dose of idelalisib, 6 months after the last dose of bendamustine, or 12 months after the 
last dose of rituximab, whichever is longer.  Men must also agree to refrain from donating sperm 
during the study and for 90 days after the last dose of idelalisib, 6 months after the last dose of 
bendamustine, or 12 months after the last dose of rituximab, whichever is longer.  Examples of 
highly effective methods of contraception are defined below. 
Highly effective methods of contraception (to be used during heterosexual activity) are defined 
as meWKRGVWKDWFDQDFKLHYHDIDLOXUHUDWHRISHU\HDUZKHQXVHGFRQVLVWHQWO\DQG
correctly‡.  Such methods include: 
x 
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, which may be oral, intravaginal, or transdermal  
x 
Progestogen-only hormonal contraception associated with inhibition of ovulation, which 
may be oral, injectable, or implantable  
x 
Intrauterine device or intrauterine hormone-releasing system (IUS) 
x 
Bilateral tubal occlusion  
x 
Vasectomy of a female subject’s male partner (with medical assessment and 
confirmation of vasectomy surgical success) 
x 
Sexual abstinence (only if refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments)†  
Hormonal contraception may be susceptible to interaction with study or other drugs, which may 
reduce the efficacy of the contraception method.  
†Abstinence (relative to heterosexual activity) can only be used as the sole method of 
contraception if it is consistently employed during the entire period of risk associated with the 
study treatments as the subject’s preferred and usual lifestyle.  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, and postovulation methods) and withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods 

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of contraception.  Female condom and male condom should not be used together as an 
effective method of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region. 
Developmental and reproductive toxicology studies in rats have not identified 
acalabrutinib-related toxicities for fertility, reproductive success, embryofetal development or 
embryofetal survival.  In rabbits, at dose levels which resulted in maternal toxicities skeletal 
variations were associated with reductions in fetal weights.  Effects on parturition and postnatal 
development are pending.  For additional details, refer to the Acalabrutinib Investigator 
Brochure. 
There are no adequate and well-controlled studies of rituximab in pregnant women.  Based on 
findings in animals, idelalisib may cause fetal harm when administered to a pregnant woman.  
Bendamustine can cause fetal harm when administered to pregnant women. 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
Subjects should promptly notify the Investigator if they, or their partners, become pregnant 
during this period.  If a female subject becomes pregnant during the treatment period, she must 
discontinue study drug(s) immediately.  Pregnancy in a female subject or a male subject’s 
partner must be reported as outlined in Section 11.8.5.   
9.3 
Treatment Compliance 
For treatments that are taken in the clinic, subjects should take the dose from the drug 
dispensed for them for that particular time period.  All other acalabrutinib/idelalisib treatments 
will be taken at home.  Subjects will receive a drug diary to record that each dose was taken 
and to record reasons for any missed doses.   
Subject compliance with acalabrutinib/idelalisib will be assessed at each study visit.  The 
subject will be instructed to bring the diary and any remaining capsules to the clinic at their next 

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visit.  The study staff will review the diary and ask the subject if all of the capsules were 
administered.  Any remaining or returned capsules will be counted and recorded as described in 
Section 10.4.  Returned capsules must not be redispensed to another subject. 
9.4 
Enrollment and Randomization Procedures 
Enrollment of a subject into the study will be performed according to the following procedure:  
x 
After the subject has signed and dated the Informed Consent Form (ICF), all screening 
procedures have been completed, and eligibility has been confirmed, the subject can be 
randomized into the study.  
x 
To confirm eligibility, the study center will fax/email a completed Enrollment Confirmation 
Form to the Sponsor or designee.  The enrollment date will be the date that the Sponsor 
confirms eligibility for randomization. 
x 
The Sponsor, or designee, will aim to fax/email a completed Enrollment Confirmation 
Form to the study center within 48 hours of receipt.   
This study will use an IXRS for randomization.  As subjects qualify for randomization, 
designated study center personnel will contact the IXRS, which will assign a treatment arm to 
each eligible subject.   
Treatment must begin within the screening window (Section 11).  It is recommended to begin 
treatment as soon as possible after randomization.  
9.5 
Restrictions 
Dietary Restrictions 
Acalabrutinib should be taken with water and may be taken with or without food.  Because 
acalabrutinib is metabolized by CYP3A, subjects should be strongly cautioned against using 
herbal remedies or dietary supplements that contain potent CYP3A inhibitors or CYP3A 
inducers (in particular, St John’s wort, which is a potent CYP3A inducer). 
Otherwise, subjects should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea or vomiting. 

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10
STUDY DRUG MATERIALS AND MANAGEMENT
10.1
Identification of Investigational Medicinal Product
The following regimens are being evaluated on this study:
ARM
REGIMEN
A: Acalabrutinib
Acalabrutinib 100 mg PO BID
B: Idelalisib/Rituximab
Idelalisib 150 mg PO BID + rituximab 375 mg/m2 IV on Day 1 
of the first cycle, followed by 500 mg/m2 IV every 2 weeks for 
4 doses, then every 4 weeks for 3 doses for a total of 
8 infusions.
B: Bendamustine/Rituximab
Bendamustine: 70 mg/m2 IV on Days 1 and 2 of a 28-day 
cycle for a maximum of 6 cycles + rituximab 375 mg/m2 IV on 
Day 1 of the first cycle and 500 mg/m2 IV on Day 1 of Cycles 2 
to 6.
Abbreviations:  BID = twice per day; IV = intravenous; PO = orally.
Acalabrutinib 
Acalabrutinib is provided as hard gelatin capsules for oral administration.  The capsules are 
packaged in opaque high-density polyethylene plastic bottles with labels bearing the appropriate 
label text as required by governing regulatory agencies.  The drug product is manufactured for 
Acerta Pharma by a contract manufacturer.  
If a drug shipment arrives damaged, or if there are any other drug complaints, a Product 
Complaint Form should be completed and emailed or faxed to the Sponsor or the Sponsor’s 
representative.  Refer to the Acalabrutinib Investigator Brochure for additional information 
regarding the drug product to be used in this study.
Idelalisib
This study will use commercially available idelalisib.  The Sponsor will either directly supply sites 
with idelalisib or the sites will be reimbursed to prescribe idelalisib; this will be detailed 
separately in each site’s clinical trial agreement.
CCI

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Commercially available idelalisib will be provided as film coated tablets (100 and 150 mg) for 
oral administration per the instructions in the locally approved labelling (e.g., see United States 
prescribing information) and per institutional standards.  
Bendamustine
This study will use commercially available bendamustine.  The Sponsor will either directly 
supply sites with bendamustine or the sites will be reimbursed to prescribe bendamustine; this 
will be detailed separately in each site’s clinical trial agreement.
Commercially available bendamustine will be supplied for IV administration according to the 
instructions in the locally approved labelling (e.g., see United States prescribing information) 
and per institutional standards. 
Rituximab
This study will use commercially available rituximab.  The Sponsor will either directly supply 
sites with rituximab or the sites will be reimbursed to prescribe rituximab; this will be detailed 
separately in each site’s clinical trial agreement.
Commercially available rituximab will be supplied for IV administration according to the 
instructions in the locally approved labelling (e.g., see United States prescribing information) 
and per institutional standards. 
10.2
Study Drug Preparation and Administration
Acalabrutinib
Investigators are prohibited from supplying acalabrutinib to any subjects not properly enrolled in 
this study.  The Investigator must ensure that subjects receive acalabrutinib only from personnel 
who fully understand the procedures for administering the drug.
Acalabrutinib is intended to be administered orally twice daily with 8 ounces (approximately 
240 mL) of water).  Acalabrutinib may be taken with or without food.  The capsules should be 
swallowed intact and subjects should not attempt to open capsules or dissolve them in liquid.
It is recommended that acalabrutinib be taken as close to the scheduled time as possible 
(preferably within ± 1 hour).  However, if a dose is missed, it can be taken up to 3 hours after 
the scheduled time with a return to the normal schedule with the following dose.  If it has been 

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> 3 hours, the dose should not be taken and the subject should take the next dose at the next 
scheduled time.  The missed dose will not be made up and must be returned to the site at the 
next scheduled visit.
Idelalisib
Idelalisib 150 mg will be orally administered BID until disease progression or unacceptable 
toxicity.  Idelalisib may be taken with or without food; tablets should be swallowed whole.  
Idelalisib will be stored and administered according to the instructions in locally approved 
labelling and institutional standards.  The United States Prescribing Information for idelalisib will 
serve as the RSI for this global study, to facilitate determination of expectedness or 
unexpectedness of adverse events possibly associated with idelalisib. 
Bendamustine
Bendamustine 70 mg/m2 will be administered as an IV infusion on Days 1 and 2 of a 28-day 
cycle.  Accommodations should be made in the event of doses of bendamustine held or delayed 
due to toxicity to permit a full six cycles to be received, wherever possible.  See further 
instructions for data entry in such cases in the eCRF guidelines.  A maximum of 6 cycles of 
bendamustine are allowed.  Bendamustine will be reconstituted, administered and stored 
according to the instructions in locally approved labelling and institutional standards.  Consult 
the medical monitor for guidance if the local or institutional standards for bendamustine dosing 
differ from the protocol. In any case, the protocol defined total dose per cycle should be 
administered regardless of local or institutional variation in the dosing schedule.  The United 
States Prescribing Information for bendamustine will serve as the RSI for this global study, to 
facilitate determination of expectedness or unexpectedness of adverse events possibly 
associated with bendamustine. 
Rituximab
When administered with idelalisib, the rituximab regimen will be 375 mg/m2 on Day 1 of the first 
cycle, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses for 
a total of 8 infusions.
When administered with bendamustine, the rituximab regimen will be 375 mg/m2 on Day 1 of 
the first cycle and 500 mg/m2 on Day 1 of Cycles 2 to 6.

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Rituximab will be reconstituted, administered and stored according to the instructions in locally 
approved labelling and institutional standards.  Rituximab should be administered as an IV 
infusion through a dedicated line under the close supervision of an experienced physician.  
Rituximab infusions should not be administered as an IV push or bolus.  Premedication is 
required before each infusion (Section 10.3.7).  The United States Prescribing Information for 
rituximab will serve as RSI for this global study, to facilitate determination of expectedness or 
unexpectedness of adverse events possibly associated with rituximab.
10.3
Dose Delays and Modifications
Safety Criteria for Adjustment or Stopping Doses
The evaluation of potential treatment-induced toxicity in subjects with advanced CLL may be 
quite difficult requiring careful consideration of the manifestations of the underlying disease, as 
well as adverse reactions to the therapy under study.  Dose modification decisions for both 
hematologic and non-hematologic toxicities will be based on the grading scale in the Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03.  
Dose Delays for Acalabrutinib 
Treatment with acalabrutinib should be held for any unmanageable, potentially study 
drug-UHODWHGWR[LFLW\WKDWLV*UDGHLQVHYHULW\$Q\RWKHUFOLQLFDOO\LPSRUWDQWHYHQWVZKHUH
dose delays may be considered appropriate by the Investigator must be discussed with the 
medical monitor.  Study drug may be held for a maximum of 28 consecutive days from expected 
dose due to toxicity.  
Study treatment should be discontinued in the event of a toxicity lasting > 28 days, unless 
reviewed and approved by the medical monitor.
Note:  Temporary withholding of study drug (e.g., for drug-related toxicity, surgery, or 
intercurrent illness) for as little as 7 days can cause a transient worsening of disease and/or of 
constitutional symptoms.  Refer to Section 11.1.25 for more information on assessing disease 
progression under these circumstances.  In such circumstances, and if medically appropriate, 
subjects may resume therapy and relevant clinical, laboratory, and/or radiologic assessments 
should be done to document whether tumor control can be maintained or whether actual 
disease progression has occurred.  

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Surgery
Susceptibility to bleeding has been observed with acalabrutinib use.  As a precaution, it is 
suggested per protocol that acalabrutinib be withheld for 3 days before and 3 days after any 
major surgical procedure (see Section 9.2.1 Hemorrhage).
Guidelines for Dose Modification and Discontinuation for Acalabrutinib 
The actions in Table 10-1 should be followed for the following toxicities (according to CTCAE 
criteria version 4.03) (see Section 11.7.4 for guidelines on the grading of toxicities):
x
Grade 4 ANC (< ȝ/IRU! 7 days (neutrophil growth factors are permitted per ASCO 
guidelines [Smith 2015] and use must be recorded on the CRF).
x
Grade 3 platelet decreases in presence of significant bleeding.
x
Grade 4 platelet decreases. 
x
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal antiemetic 
and/or anti-diarrheal therapy.
x
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity.
Table 10-1.
Drug Modification Actions for Acalabrutinib
Occurrence
Action
1st – 2nd
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level
3rd
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at one dose 
level lower (100 mg PO QD)
4th
Discontinue acalabrutinib
Abbreviation:  PO = orally; QD = once per day.
If acalabrutinib is reduced for apparent treatment-related toxicity, the dose need not be 
re-escalated, even if there is minimal or no toxicity with the reduced dose.  However, if the 
VXEMHFWWROHUDWHVDUHGXFHGGRVHRIDFDODEUXWLQLEIRUZHHNVWKHQWKHGRVHPD\EHLQFUHDVHG
to the next higher dose level, at the discretion of the Investigator.  Such re-escalation may be 
particularly warranted if further evaluation reveals that the AE that led to the dose reduction was 
not treatment-related.  However, the maximum dose of acalabrutinib is 100 mg PO BID for this 
protocol.

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Any changes to the dosing regimen must be recorded in the Dosage Administration CRF.
Guidelines for Dose Modification and Discontinuation for Idelalisib
Idelalisib dose reductions are described below (Table 10-2).  For severe or life-threatening 
toxicities related to idelalisib, withhold drug until toxicity is resolved.  If resuming idelalisib after 
interruption for severe or life-threatening toxicities, reduce the dose to 100 mg PO BID.  
Recurrence of severe or life-threatening idelalisib-related toxicity upon rechallenge should result 
in permanent discontinuation of idelalisib.  If idelalisib is discontinued, subjects can continue to 
receive rituximab up to the maximum number of infusions allowed on this protocol.
Study drug (idelalisib) may be held for a maximum of 28 consecutive days from expected dose 
due to toxicity.  Study treatment (idelalisib) should be discontinued in the event of a toxicity 
lasting > 28 days, unless reviewed and approved by the Medical Monitor.
Table 10-2.
Dose Modifications for Toxicities Due to Idelalisib
Pneumonitis
Any symptomatic pneumonitis
Discontinue idelalisib in subjects with any severity of symptomatic 
pneumonitis
ALT/AST
> 3 to 5 x ULN
> 5 to 20 x ULN
> 20 x ULN
Maintain idelalisib 
dose. Monitor at least 
ZHHNO\XQWLO[
ULN.
Withhold idelalisib. 
Monitor at least 
weekly until ALT/AST 
DUH[8/1WKHQ
may resume idelalisib 
at 100 mg PO BID.
Discontinue idelalisib 
permanently.
Bilirubin
> 1.5 to 3 x ULN
> 3 to 10 x ULN
> 10 x ULN
Maintain idelalisib
dose. Monitor at least 
ZHHNO\XQWLO[
ULN.
Withhold idelalisib. 
Monitor at least 
weekly until bilirubin 
LV[8/1WKHQ
may resume idelalisib 
at 100 mg PO BID.
Discontinue idelalisib 
permanently
Diarrhea*
Moderate diarrhea
Severe diarrhea or 
hospitalization
Life-threatening 
diarrhea
Maintain idelalisib 
dose. Monitor at least 
weekly until resolved.
Withhold idelalisib.  
Monitor at least 
weekly until resolved, 
then may resume 
idelalisib at 100 mg 
PO BID.
Discontinue idelalisib
permanently

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Table 10-2.
Dose Modifications for Toxicities Due to Idelalisib
Neutropenia
ANC 1.0 to < 1.5 Gi/L
ANC 0.5 to < 1.0 
Gi/L
ANC < 0.5 Gi/L
Maintain idelalisib 
dose. 
Maintain idelalisib 
dose.  Monitor ANC 
at least weekly.
Interrupt idelalisib.  
Monitor ANC at least 
weekly until ANC 
 0.5 Gi/L, then may 
resume idelalisib at 
100 mg PO BID.
Thrombocytopenia
Platelets 50 to 
< 75 Gi/L
Platelets 25 to 
< 50 Gi/L
Platelets < 25 Gi/L
Maintain idelalisib 
dose
Maintain idelalisib
dose.  Monitor 
platelet counts at 
least weekly.
Interrupt idelalisib.  
Monitor platelet 
counts at least 
weekly, may resume 
idelalisib at 100 mg 
PO BID when 
SODWHOHWV 25 Gi/L.
Infections
Grade 3 or higher sepsis or pneumonia
Interrupt idelalisib until infection has resolved
Evidence of CMV infection or viremia
Withhold idelalisib in subjects with evidence of CMV infection of any 
grade or viremia (PCR above the lower limit of quantitation or positive 
antigen test).  Idelalisib may be restarted once subject has PCR below 
the lower limit of quantitation; as per Investigator discretion.  If 
idelalisib is resumed, monitor (by PCR or antigen test) for CMV 
reactivation at least monthly.
Evidence of PJP infection
Withhold idelalisib in subjects with suspected PJP infection of any 
grade.  Permanently discontinue idelalisib in subjects with active or 
confirmed PJP infection.
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; BID = twice daily; Gi/L = giga/liter; PO = orally; ULN = upper limit of normal.
*Moderate diarrhea:  Increase of 4 to 6 stools per day over baseline; severe diarrhea:  Increase of 
 stools per day over baseline. 
Guidelines for Dose Modification and Discontinuation for Bendamustine
Bendamustine administration should be delayed in the event of Grade 4 hematologic toxicity or 
FOLQLFDOO\VLJQLILFDQW*UDGHQRQKHPDWRORJLFWR[LFLW\2QFHQRQKHPDWRORJLFWR[LFLW\KDV
UHFRYHUHGWR*UDGHDQGRUWKHEORRGFRXQWVKDYHLPSURYHG$1&[9/L, 
platelets  75 x 109/L), bendamustine can be reinitiated at the discretion of the treating 

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physician.  In addition, dose reduction may be warranted (see the US Prescribing Information 
for bendamustine).  If bendamustine is discontinued, subjects can continue to receive rituximab 
up to the maximum number of infusions allowed on this protocol. 
'RVHPRGLILFDWLRQVIRUKHPDWRORJLFWR[LFLW\IRU*UDGHWR[LFLW\UHGXFHWKHGRVHWR mg/m2 
,9RQ'D\VDQGRIHDFKF\FOHLI*UDGHWR[LFLW\UHFXUVUHGXFHWKH dose to 25 mg/m2 IV 
on Days 1 and 2 of each cycle.  
'RVHPRGLILFDWLRQVIRUQRQKHPDWRORJLFWR[LFLW\IRUFOLQLFDOO\VLJQLILFDQW*UDGHWR[LFLW\
reduce the dose to 50 mg/m2 IV on Days 1 and 2 of each cycle.  
Dose re-escalation in subsequent cycles may be considered at the discretion of the treating 
physician. 
Subjects should be monitored for respiratory signs and symptoms throughout treatment. 
Subjects should be advised to report new signs of infection, including fever or respiratory 
symptoms promptly.  Discontinuation of bendamustine should be considered if there are signs 
of (opportunistic) infections. 
Accommodations should be made in the event of doses of bendamustine held or delayed due to 
toxicity to permit a full six cycles to be received, wherever possible.  See further instructions for 
data entry in such cases in the eCRF guidelines.  Locally and/or regionally approved minor 
schedule variations in administration of bendamustine + rituximab may be accommodated, 
provided the doses of both bendamustine and rituximab remain the same as specified in the 
protocol, and the total doses per cycle remain the same as per protocol, with modifications for 
toxicity as provided above.   
In the event of dosing delays due to toxicity, when possible, dosing of both bendamustine and 
rituximab should be held, and readministered together once toxicity has resolved to grade 1 or 
better (or to study baseline).  In such cases, the cycle schedule will be shifted accordingly (see 
instructions for data entry in the eCRF guidelines).  The protocol schedule of radiographic 
imaging CT/MRI scans will remain fixed, however. 
Study drug (bendamustine) may be held a maximum of 28 consecutive days from expected 
dose due to toxicity.  Study treatment (bendamustine) should be discontinued in the event of a 
toxicity lasting > 28 days, unless reviewed and approved by Medical Monitor. 

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Guidelines for Dose Modification and Discontinuation for Rituximab
No dose modification is allowed for rituximab.  If rituximab is discontinued, subjects can 
continue to receive idelalisib or bendamustine as outlined in this protocol.  If bendamustine or 
idelalisib are discontinued, subjects can continue to receive rituximab up to the maximum 
number of infusions allowed on this protocol.  The initial dose of rituximab may be divided for 
administration, per local or institutional standards.
Premedication Requirements (Rituximab)
Premedicate before each rituximab infusion with acetaminophen and an antihistamine in 
accordance with prescribing information or institutional standards. 
10.4
Study Drug Accountability
Acalabrutinib, rituximab, bendamustine, and idelalisib must be kept in a locked limited access 
cabinet or space, under appropriate storage conditions.  Study drug must not be used outside 
the context of the protocol.  
Study drug accountability records must be maintained and readily available for inspection by 
representatives of Acerta Pharma and are open to inspections by regulatory authorities at any 
time. 
All study supplies and associated documentation will be regularly reviewed and verified by the 
monitor.
11
STUDY ACTIVITIES AND ASSESSMENTS
The Schedule of Assessments are provided in Appendix 1, Appendix 2, Appendix 3, and 
Appendix 4.  See Appendix 13 for management of study procedures during pandemic.  
Descriptions of the scheduled evaluations are outlined below.
Before study entry, throughout the study, and at the follow-up evaluation, various clinical and 
diagnostic laboratory evaluations are outlined.  The purpose of obtaining these detailed 
measurements is to ensure adequate safety and efficacy assessments.  Screening clinical and 
laboratory evaluations may be repeated as medically appropriate and to support eligibility, if 
completed during the 30-day screening window.  Throughout the study clinical evaluations and 
laboratory studies may be repeated more frequently if clinically indicated.  Such unscheduled 

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assessments will be captured in the protocol-specific database as appropriate.  This study will 
primarily use central laboratory testing for laboratory evaluations.  Samples from sites' local 
laboratories will be used if central testing is unavailable. 
11.1
Description of Procedures
Informed Consent
The subject must read, understand and sign the ICF approved by the IRB or IEC, confirming his 
or her willingness to participate in this study before initiating any screening activity that is not 
considered standard of care by institutional standards.  Subjects must also grant permission to 
use protected health information, if required by local regulations.
Medical History
Collect and record the subject’s complete history including concurrent medical signs and 
symptoms, alcohol use and, if a smoker, cigarette use.  Disease history, including the date of 
initial diagnosis, Rai and Binet staging within 30 days of first dose with study drug, 
documentation of refractory disease, prior anticancer treatments with best responses and 
progression-free interval to these treatments, and history of autoimmune CLL complications and 
their treatment will also be recorded based upon available documents and subject history.
Confirmation of Eligibility
Perform all necessary procedures and evaluations to document that the subject meets each 
eligibility criteria (Sections 8.1 and 8.2).  Blood samples for hematology and serum chemistry 
collected at screening will be evaluated by a central laboratory to confirm eligibility.  With the 
exception of fluorescence in situ hybridization (FISH), if central laboratory results submitted 
during the screening period are unable to be analyzed (e.g., specimen clotted or hemolysis) to 
support eligibility, the medical monitor may review local laboratory results and approve the 
subject for randomization based on these lab values on a case-by-case basis provided another 
sample is redrawn and submitted before treatment.  The following de-identified documentation 
is requested before randomization:
x
Copies of a pathology report confirming diagnosis of CLL.
x
Radiology reports from screening CT/MRI.
x
Copies of bone marrow aspirate and biopsy report.
x
Copies of FISH.

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Treatment must begin within the screening window (first dose of study drug should be 
administered within 30 days of signing consent) unless otherwise indicated.  Subjects can be 
re-screened which requires signing the ICF again and repeating screening procedures, with the 
exception of the bone marrow biopsy and aspirate and CT/MRI scan, if still within 30 days of the 
first dose.  Subjects that re-screen must be re-entered in IXRS and will receive a new Subject 
ID.
ECOG Performance Status
The ECOG performance index is provided in Appendix 6.  
Physical Examination, Vital Signs, Height & Weight, 
The screening physical examination will include, at a minimum, the general appearance of the 
subject, height (screening only) and weight, and examination of the skin, eyes, ears, nose, 
throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and 
lymphatic system.
Vital signs (blood pressure, heart rate, and body temperature) will be assessed after the subject 
has rested in the sitting position.  
Electrocardiogram (ECG)
An ECG will be performed at screening.  Subjects should be in supine position and resting for at 
least 10 minutes before any study-related ECGs.  
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Patient Reported Outcomes (PRO)
As of Amendment 6.0, the 
 instruments (i.e., FACIT-Fatigue, 
 will no longer be administered in this study.  Through Amendment 5.0, the subject 
was to complete the questionnaires detailed below before any other study procedures at 
required visits. 
FACIT-Fatigue
The FACIT-Fatigue questionnaire is an instrument for use as a measure of fatigue-related 
quality of life in subjects with cancer and other chronic diseases (http://www.facit.org).  The 
13-item FACIT-Fatigue Scale measures each item on a 5-point Likert scale.  The FACIT-Fatigue 
Scale has been validated in the general population (Cella 2002) as well as in subjects with 
cancer or rheumatoid arthritis.  Refer to Appendix 7 for more information.
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Concomitant Medications and Therapy
Document all concomitant medications and procedures from 30 days before the start of study 
drug administration until 30 days after the last dose of study drug or the start of a new 
anticancer treatment (whichever comes first).
After a subject discontinues study treatment, receipt of all subsequent anticancer therapies will 
be collected.
AEs
The accepted regulatory definition for an AE is provided in Section 11.7.1.  Refer to 
Section 11.8.1 for the AE reporting period.  Important additional requirements for reporting 
SAEs are explained in Section 11.8.7. 
Serum/Urine Pregnancy Test
Serum pregnancy testing, per the Schedule of Assessments (Appendix 1 to Appendix 4), will be 
required only for women of childbearing potential.  More frequent pregnancy testing (either urine 
or serum) than delineated in the Schedule of Assessments may be done if required by local 
regulatory authorities.
Hepatitis B and C Testing and Monitoring
Hepatitis virus serology testing at screening must include HBsAg, hepatitis B surface antibody 
(anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C (HCV) antibody.  Testing will be 
done by local or central laboratory.  Subjects with seropositivity for HBsAg at screening may not 
be enrolled in the study (see Exclusion 16).  Subjects who are HBsAg negative but anti-HBc 
positive at screening may be enrolled provided they have a negative quantitative PCR for HBV 
DNA (undetectable viral load) at screening.  Subjects who are anti-HBc positive should have 
quantitative PCR testing for HBV DNA performed during screening and every month during 
treatment Cycles 2 through 19.  After Cycle 19, monitoring will occur every 3 months. HBV 
monitoring should continue until 12 months after last dose of study drug(s).  Any subject with a 
rising viral load (above lower limit of detection) should discontinue study drug and have antiviral 
therapy instituted and a consultation with a physician with expertise in managing hepatitis B.
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For sites in countries or regions with high endemic levels of HBV infection where prophylactic 
treatment with antiviral agents during treatment with immunosuppressive therapies may be the 
local or regional standard of care, such antiviral prophylaxis may be permitted on study, 
providing the antiviral agent is not a strong inducer or inhibitor of CYP3A. Subjects who receive 
antiviral prophylaxis for HBV on study should still comply with the requirement for serial 
monitoring for HBV reactivation by quantitative PCR for HBV DNA at the frequency prescribed 
above (and in the Schedule of Assessments).   
For subjects with CLL whose disease management includes periodic administration of IVIG, the 
IVIG may cause false positive hepatitis B serologic tests.  Subjects receiving routine IVIG who 
have anti-HBc antibody or surface antigen positivity without evidence of active viremia (e.g., 
negative hepatitis B DNA by quantitative PCR at screening) may still participate in the study, but 
should have monitoring for potential HBV reactivation, as follows.  Monthly PCR testing is not 
required in subjects who are currently receiving or received prophylactic IVIG within 3 months 
before study enrollment and have a documented negative anti-HBc test before the initiation of 
IVIG therapy.  PCR testing in these subjects should be performed when clinically indicated (e.g., 
in the setting of rising transaminase levels).  
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be 
tested by quantitative PCR for HCV RNA during screening.  Such subjects may be enrolled 
provided the quantitative PCR is negative (undetectable viral load).  No further monitoring for 
HCV RNA during treatment is necessary if initial PCR results are negative.
Refer to Section 9.2.1 and Appendix 1 to Appendix 4 regarding monitoring of subjects who are 
anti-HBc positive or hepatitis C antibody positive or who have a known history of HBV or HCV.
HIV Testing (for Study Sites in Germany)
A peripheral blood sample (required) will be drawn and sent at screening to a central vendor to 
be tested for seropositivity for HIV-1 antibody, HIV-2 antibody, and if positive, reactivity for the 
HIV-specific p24 antigen.  Subjects with active infection with HIV-1 or HIV-2 may not enroll in 
the study (Exclusion Criterion #14).
Cytogenetics and FISH Panel
Screening peripheral blood (required) will be sent to a central vendor to be tested for 17p del, 
13q del, trisomy 12, 11q del by FISH and stimulated karyotyping.  A blood sample for FISH 

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evaluation will also be drawn at Cycle 7, and when a subject has disease progression or at the 
TT or SFU visits.
Hematology
Hematology will be evaluated by a central laboratory and will include a complete blood count 
(CBC) with differential including, but not limited to white blood cell count, hemoglobin, 
hematocrit, platelet count, ANC, and ALC.  Any missing central laboratory blood samples should 
be redrawn as soon as possible.  In the event that the missing central laboratory sample is 
unrecoverable, local laboratory results will be collected, if available, and entered in the clinical 
database.
Serum Chemistry
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and uric 
acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, 
magnesium, and potassium) must be done to coincide with the ECG testing.  
Urinalysis
Urinalysis includes pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.  
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Serum ImmunoJOREXOLQDQGȕ2-microglobulin
Sample(s) will be sent to a central laboratory for quantitative immunoglobulin (IgG, IgM, and 
,J$OHYHOVDQGVHUXPȕ2-microglobulin.
T/B/Natural Killer (NK)/monocyte Cell Count
Whole blood samples will be analyzed for absolute T/B/NK cell counts (CD3, CD19, CD4, CD8, 
CD14, CD16/56) using a standard cell marker panel.  
Computed Tomography or Magnetic Resonance Imaging Scans
Radiologic imaging by CT with contrast is required and must include the pelvis, abdomen, chest, 
and neck.  Subjects who are intolerant to IV CT contrast agents will have CT scans performed 
with oral contrast.  When possible, all subjects should have radiologic tumor measurements 
done at the participating study center or at an acceptable alternate imaging facility using an 
identical imaging protocol and similar equipment.  The same imaging equipment should be used 
for all scans whenever possible.  The same radiologist should be assigned to read all the scans 
for a given subject throughout the study as much as possible.  MRI may be used for imaging 
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assessments if a contrast CT scan is contraindicated or unobtainable; in cases where MRI is 
desirable, the MRI must be obtained at baseline and at all subsequent response evaluations.  
Pretreatment radiologic tumor assessment must be obtained within 30 days before the first dose 
and standard of care tumor assessments may be used, provided they comply with the radiologic 
requirements as outlined in the radiology manual.  Radiologic tumor assessment will also be 
performed every 12 weeks (± 14 days) with the first on-treatment radiologic assessment 
occurring on Cycle 4 Day 1, the second on treatment scan on Cycle 7 Day 1, and so on through 
Cycle 25, and then every 24 weeks (± 14 days) thereafter.  For bendamustine-treated subjects, 
the second radiologic tumor assessment will occur at the next 12-week interval (± 14 days) 
regardless of whether the subject is on study drug.  CT or MRI scans can be performed 
 7 days before response evaluation.  CT or MRI scans will be performed until disease 
progression is confirmed, regardless of whether the subject remains on treatment.  In the event 
disease progression is suspected due to physical examination or laboratory test, a CT or MRI 
scan must be performed to confirm disease progression.  If the sole measurable lesion lies 
within the field of prior radiotherapy, there must be evidence of disease progression in that 
lesion that has not been previously irradiated. 
Up to 6 measurable lymph nodes (only target lesions > 1.5 cm in the longest diameter may be 
assessed), clearly measurable in 2 perpendicular dimensions, will be followed as target lesions 
for each subject.  Measurable sites of disease should be chosen such that they are 
representative of the subject’s disease.  In addition, selection of target lesions should be from as 
disparate regions of the body as possible when these areas are significantly involved. Target 
lymph nodes should not be selected from previously irradiated areas.  If at any time (screening 
and postdose) the liver or spleen are abnormal in size, the cranial-caudal measurement of the 
spleen and longest diameter of the liver should be assessed by CT/MRI at response 
evaluations.  The cranial-caudal measurement of the spleen and longest diameter of the liver 
will be assessed at screening and all subsequent response evaluations. 
A central imaging service will be used to provide independent radiologic assessments for the 
purposes of the primary endpoint.  Only confirmation of disease progression by the Sponsor will 
be reported back to the site. 
If the subject’s physical examination findings, laboratory evaluations (with hematology profile 
including absolute lymphocyte count, ANC, platelet count, and Hgb), and radiographic 

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evaluations suggest that CR has been achieved in all response parameters, a bone marrow 
aspirate and biopsy must be obtained to confirm the CR and to evaluate minimal residual 
disease (MRD). The bone marrow aspirate and biopsy must be done within 8-12 weeks of the 
CT/MRI imaging that supported the assessment of CR. In cases where cytopenic progression is 
suspected, a bone marrow aspirate or biopsy must be performed to distinguish autoimmune and 
drug-related cytopenias. In cases where Richter’s transformation is suspected (e.g., rapidly 
progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a low platelet count; 
and elevated serum LDH, caOFLXPDQGȕPLFURJOREXOLQOHYHOVGLDJQRVLVVKRXOGEHFRQILUPHG
by biopsy of lymph nodes, bone marrow, or involved organs. Pathology analyses will be done at 
a central laboratory for confirmation of Richter’s transformation.  Biopsy of the affected site is 
diagnostic and sufficient for confirmation.  If per local standard of care or at Investigator 
discretion an ancillary whole-body PET-CT scan (not required for study) is performed, the 
results of this scan should be captured in the electronic data capture (EDC) system as an 
unscheduled visit.
Routine Clinical Assessments
Routine clinical assessments include physical exams, recording of symptoms, and hematologic 
evaluations to evaluate for both AEs and for disease progression at times when the CT scan is 
not obtained.  The Schedule of Assessments for Arm A (acalabrutinib monotherapy), Arm B 
(separate schedules for idelalisib + rituximab or bendamustine + rituximab), and crossover 
subjects are found in Appendix 1 to Appendix 4, for screening, treatment, post-treatment 
disease follow-up, and long-term survival phases.
Assessments to Determine Eligibility for Crossover
Assessments to determine eligibility for crossover before the final DCO include the following: 
1. Subjects who develop Sponsor-confirmed progressive disease on either of the Arm B 
Investigator choice treatments will be eligible to cross over to acalabrutinib monotherapy 
upon development of Sponsor-confirmed disease progression according to IWCLL 2008 
criteria for CLL; this eligibility for crossover is not time-limited relative to discontinuation 
of active treatment and extends into the post-treatment follow-up period, including 
subjects who may have discontinued study treatment for reasons other than disease 
progression.
2. Arm B subjects who discontinue study treatment (either by completing course of 
treatment, or by premature discontinuation related to toxicity or other reason) remain 
eligible for crossover to acalabrutinib monotherapy.  Such subjects will enter the 
post-treatment follow-up period and continue to be actively monitored according to the 
Schedule of Assessments for their randomized treatment arm with every 3-month study 

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visits, physical exam, labs, collection of adverse events, and radiologic tumor imaging 
scans at the protocol-required frequency; it is important that these scheduled 
assessments not be missed.    
Following the Sponsor communication to study site confirming progressive disease, the 
site may request authorization for crossover of Arm B subjects, contingent on review of 
the following requirements: 
o Eligibility for crossover includes (after Sponsor-assessed disease progression 
has been confirmed) meeting all eligibility criteria for the main study, including 
ECOG performance status and the laboratory parameters as outlined in the 
inclusion criteria.  Screening for eligibility and trial assessments during crossover 
are described in Appendix 4 and should occur within 30 days of disease 
progression.  Subjects who previously tested anti-HBc negative at initial 
screening for the main study period and are approved for Crossover Screening 
will undergo hepatitis serology and HBV DNA PCR testing.  If these patients are 
discovered to be anti-HBc positive but HBV PCR negative (required to meet 
eligibility) at Crossover Screening, they will undergo monthly HBV PCR 
monitoring for reactivation (as required for the main study period). 
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV 
DNA performed during Crossover Screening and every month during treatment 
Cycles 2 through 19.  After Cycle 19, monitoring will occur every 3 months. HBV 
monitoring should continue until 12 months after the last dose of study drug.  Any 
subject with a rising viral load (above lower limit of detection) should discontinue 
study drug and have antiviral therapy instituted and a consultation with a 
physician with expertise in managing hepatitis B.  
o While subjects who have been randomized to any of the study treatment arms 
who discontinue study treatment for reasons other than disease progression 
(e.g., have not yet progressed) may receive alternative (non-protocol specified) 
anticancer treatments without restriction during the post-treatment follow up 
period as clinically indicated per Investigator discretion [such treatments and 
clinical indication for treatment must be entered into the EDC], subjects may not 
receive any new systemic therapy in the interval between Sponsor confirmation 
of disease progression and the initiation of crossover therapy with acalabrutinib. 
x 
The following documentation will be reviewed before enrollment to the crossover arm by 
the medical monitor: 
o Radiology reports from computed tomography (CT)/magnetic resonance imaging 
(MRI); CT/MRI from disease progression can be used for the new tumor imaging 
baseline against which to assess tumor response on crossover treatment if within 
30 days of crossover dosing Cycle 1 Day 1. 
x 
Crossover treatment should be initiated within a window of 30 days after the crossover 
approval is granted. 
x 
Once crossover treatment is initiated, the Schedule of Assessments (Appendix 4) will be 
followed; this is closely similar to that of subjects who were originally randomized to 
Arm A acalabrutinib monotherapy. 
x 
Safety and efficacy data for subjects who cross over to acalabrutinib monotherapy will 
be analyzed as a stand-alone group, independent of Arm B or Arm A.  

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See also Section 7.1, Overall Study Design, for details on crossover procedures.
Overall Response Evaluations
Overall response assessments will be based upon evaluation of physical exams, recording of 
symptoms, radiologic evaluations, and hematologic evaluations per the Schedule of 
Assessments.  (Note:  CBC with differential, including ALC, must be done within 7 days, and 
bone marrow aspirate/biopsy [when applicable] must be done within 8-12 weeks of suspected 
CR, of the contemporaneous radiologic evaluation supporting CR, when all IWCLL response 
criteria for CR/CRi have been met in a subject with no disease-related symptoms, see 
Appendix 10). Subjects who have signs and symptoms of disease progression outside of the 
scheduled study visits and assessments should be evaluated by the Investigator with a physical 
exam and a CBC with differential to determine if disease progression is present.  The blood 
samples for response or disease progression determination should be confirmed by a central 
laboratory (samples from local laboratories can be used if central testing is unavailable).  Any 
suspected case of disease progression should be confirmed with a CT scan if one was not 
obtained and should be reported to the Sponsor or designee.  Subjects may continue study 
treatment until progression is confirmed by a serial exam at least 2 weeks later.  In addition, 
when clinically appropriate, based on Investigator-perceived risk-benefit assessment, a subject 
may continue treatment and remain under close observation until progression is confirmed.  
New anticancer therapy should be withheld if clinically appropriate in the absence of confirmed 
progressive disease. 
Bone Marrow Aspirate and Biopsy
For Eligibility
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before randomization.  The Screening sample must be sent to the central laboratory for 
analysis.  
Subjects who have a bone marrow biopsy done within 3 months of randomization may use 
these results in lieu of the Screening sample required for this study.  If slides (both bone marrow 
and aspirate) are available, these should be sent to the central laboratory for confirmation of 
eligibility, and may be stored for future Acerta CLL-directed research.  

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Bone Marrow Aspirate and Biopsy for Confirmation of CR/CRi and Minimal Residual Disease 
(MRD)/Response Evaluation (additional details are provided in Appendix 10). 
In the setting of suspected CR, when the subject’s physical examination findings, laboratory 
evaluations (including hematology profile with ALC, ANC, platelet count, and Hgb), and 
radiographic findings indicate that all IWCLL response parameters for CR have been achieved 
(Appendix 10), a bone marrow aspirate and biopsy and peripheral blood sample must be 
obtained to confirm the CR/CRi pathologically and to evaluate MRD.  According to IWCLL 
response criteria, CR/CRi requires all of the supporting clinical assessments (see Appendix 10), 
a tabular summary of IWCLL Response Assessment Criteria, per Hallek 2008 and updated for 
persistent lymphocytosis per Cheson 2012) be assessed at least two months following 
completion of therapy (for purposes of this study protocol, within 8-12 weeks of suspected CR).  
The proper timing of bone marrow sampling, therefore, will differ according to the duration of 
treatments in Arm A and Arm B, as outlined in the following sub-section.  A single determination 
of MRD will be made in this study, during the time window noted above for confirmation of CR.  
Per IWCLL guidance, a marrow aspirate sample (as opposed to peripheral blood sample) will be 
used for determination of MRD at this time point. 
In cases where cytopenic progression is suspected, a bone marrow aspirate or biopsy must be 
performed to confirm, and to exclude alternate etiologies such as autoimmune and drug-related 
cytopenias. A bone marrow aspirate and biopsy may also be obtained, if indicated, for 
confirmation of progressive disease by Richter’s transformation.   
Timing of Bone Marrow Aspirate and Biopsy in Setting of Suspected CR, According to 
Treatment Arm. 
Arm A:  Acalabrutinib monotherapy, or Crossover treatment to acalabrutinib 
monotherapy:   
For subjects randomized to Arm A acalabrutinib monotherapy, which is administered 
continuously until the time of disease progression:  if the subject’s physical examination 
findings, laboratory evaluations (including hematology profile with ALC, ANC, platelet count, and 
Hgb), and radiographic evaluations suggest that all IWCLL response assessment criteria for CR 
have been achieved, a bone marrow biopsy/aspirate and peripheral blood sample to confirm 
pathology and evaluate MRD should be obtained between 8-12 weeks from the time of 
supportive clinical assessments, including CT/MRI imaging of suggested CR. 

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Arm B: Idelalisib/Rituximab:
For subjects randomized to Arm B treatment with idelalisib plus rituximab, with idelalisib 
administered continuously until the time of disease progression while the rituximab is 
administered for a maximum of  8 infusions:  if the subject’s physical examination findings, 
laboratory evaluations (including hematology profile with ALC, ANC, platelet count and Hgb), 
and radiographic evaluations suggest that all IWCLL response criteria for CR  have been 
achieved prior to the completion of the 8 cycles of rituximab treatment, a bone marrow 
biopsy/aspirate and peripheral blood sample to confirm pathology and evaluate MRD should be 
obtained between 8-12 weeks after the completion of rituximab treatment.  For subjects who 
continue on idelalisib monotherapy once rituximab treatment has been completed, and have not 
yet developed progressive disease, if the subject’s physical examination findings, laboratory 
evaluations, and radiographic evaluations suggest that CR has been achieved, a confirmatory 
bone marrow biopsy/aspirate and peripheral blood sample should be obtained between 
8-12 weeks from the time of supportive clinical assessments.  
Arm B: Bendamustine/Rituximab:
For subjects on bendamustine plus rituximab, which are both of finite duration and limited to 
6 cycles of treatment:  if the subject’s physical examination findings, laboratory evaluations 
(including hematology profile with ALC, ANC, platelet count and Hgb), and radiographic 
evaluations suggest that a CR has been achieved prior to completion of treatment, a 
confirmatory  bone marrow biopsy/aspirate and peripheral blood sample to confirm pathology 
and to evaluate MRD should be obtained no earlier than between 8-12 weeks after the 
completion of treatment.  For subjects who completed treatment, if the subject’s physical 
examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has 
been achieved, a confirmatory bone marrow biopsy/aspirated and peripheral blood sample to 
confirm pathology and evaluate MRD should be obtained no earlier than between 8-12 weeks 
from the time of supportive clinical assessments.
Cytomegalovirus Testing
CMV testing at screening (and crossover screening) must include serologic testing for CMV 
immunoglobulin G (CMV IgG), CMV IgM, and CMV DNA PCR testing.  Subjects must have a 
result for CMV DNA PCR which is below the lower limit of quantitation at screening.  Subjects 
assigned to Arm B must have monthly CMV DNA PCR testing while on treatment.  Monthly 
monitoring for CMV should continue by CMV DNA PCR testing for previously treated Arm B 

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subjects until 12 months after the last dose of idelalisib or bendamustine, including the 
crossover period.  The screening CMV serologies will be advisory only, to guide Investigators in 
assessing risk of new infection or reactivation of CMV while on study. 
11.2 
TT and SFU Visits 
Until final DCO, a TT visit is required for safety assessments for any subjects who permanently 
discontinue treatment for any reason (except for death, lost to follow up, or withdrawal of 
consent), including disease progression.  The TT visit should be performed within 7 days of the 
last dose of all study drugs, if possible, and is not required for subjects who discontinue from 
study treatment within 10 days of a scheduled study visit or if the TT visit would be performed 
within 14 days of the SFU visit.  If the TT visit and the SFU visit coincide, then these can be 
combined into 1 visit. 
Until final DCO, a SFU visit should be conducted at 30 (+ 7) days after his or her last dose of all 
study drugs to monitor for resolution or progression of AEs and to document the occurrence of 
any new events, regardless of whether the subject receives a new anticancer therapy or 
demonstrates disease progression within this time frame.  Refer to Appendix 1 to Appendix 4 for 
the assessments required for the TT and SFU visits.   
11.3 
Subsequent Anticancer Therapies 
After study drug treatment is complete, the following information on subsequent anticancer 
therapies will be collected approximately every 12 weeks until death, withdrawal by subject, lost 
to follow-up, or study terminated by Sponsor, whichever comes first: 
x 
Receipt of all subsequent anticancer therapies. 
x 
IWCLL indication for initiation of subsequent anticancer therapy. 
x 
Response to all subsequent anticancer therapies. 
After the final DCO, all data collected at the study site, per standard of care, will be recorded in 
the subject’s medical records.  Only SAEs will be reported. 
11.4 
Post-treatment Disease Follow-up 
Each subject should be followed until disease progression.  If disease progression has not 
occurred at the time of the 30-day SFU visit, post-treatment disease follow-up visits should 

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occur approximately every 3 months (12 weeks) until disease progression, regardless of 
whether the subject receives a new anticancer therapy.  During this period, subjects will be 
followed for disease progression via CT/MRI scans, CBC with differential, physical exams, 
serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated). Refer to 
Appendix 1 to Appendix 4 for the full list of assessments required during this period.  
After the final DCO, no further data will be collected for post-treatment disease follow-up.
11.5
Survival Follow-up
After progression, subjects will be contacted to assess survival status approximately every 
12 weeks until death, withdrawal by subject, loss to follow-up, or study termination by the
Sponsor, whichever comes first.  At the time of the interim analysis, final analysis, and at study 
closure, a survival sweep may be conducted.  All subjects who are on study and not known to 
have died before the survival sweep may be contacted at that time.
After the final DCO, no further data will be collected for survival follow-up.
11.6
Missed Evaluations
Missed evaluations should be rescheduled and performed as close to the original scheduled 
date as possible.  An exception is made when rescheduling becomes, in the Investigator’s 
opinion, medically unnecessary or unsafe because it is too close in time to the next scheduled 
evaluation.  In that case, the missed evaluation should be abandoned.
11.7
Adverse Events and Serious Adverse Events
Definition of Adverse Events
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational (medicinal) product, regardless of attribution.  This includes the 
following:
x
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with CLL that were not present 
before the AE reporting period (see Section 11.8.1).
x
Pre-existing medical conditions (other than the condition being studied) judged by the 
Investigator to have worsened in severity or frequency or changed in character during 
the protocol-specified AE reporting period.

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x 
Abnormal laboratory values considered clinically significant by the Investigator should be 
reported as an AE.   
The following are NOT considered an AE: 
x 
Pre-existing condition: A pre-existing condition (documented on the medical history 
CRF) is not considered an AE unless the severity, frequency, or character of the event 
worsens during the study period. 
x 
Preplanned hospitalization: A hospitalization planned before signing the ICF is not 
considered an SAE, but rather a therapeutic intervention.  However, if during the 
preplanned hospitalization an event occurs, which prolongs the hospitalization or meets 
any other SAE criteria, the event will be considered an SAE.  Surgeries or interventions 
that were under consideration, but not performed before signing the ICF, will not be 
considered serious if they are performed after signing the ICF for a condition that has not 
changed from its baseline level.  Elective hospitalizations for social reasons, solely for 
the administration of chemotherapy, or due to long travel distances are also not SAEs.  
x 
Diagnostic testing and procedures: Testing and procedures should not be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported.   If a test 
or procedure is done to rule out a diagnosis, the sign or symptom leading to the 
test/procedure should be the event term, and the event term should only be updated to 
the diagnosis if/when the diagnosis is confirmed.   Testing and procedures performed 
solely as screening measures (e.g., routine screening mammography or colonoscopy) 
should not be reported as AEs or SAEs. 
x 
Abnormal laboratory results that the Investigator considers to not be clinically 
significant:  Abnormal laboratory results are not AEs unless they are clinically 
significant.  For example, a clinically significant laboratory result is one that requires 
treatment (for example a blood transfusion for low hemoglobin) or requires a change in 
study drug (e.g., lowering the dose or withholding study drug while the laboratory finding 
resolves or stabilizes). 
x 
Progression of underlying malignancy:  Progression of underlying malignancy will not 
be reported as an AE if it is clearly consistent with the suspected progression of the 
underlying cancer.  Hospitalization due solely to the progression of underlying 
malignancy should NOT be reported as an SAE.  Clinical symptoms of progression may 
be reported as AEs if the symptoms cannot be determined as exclusively due to the 
progression of the underlying malignancy, or if they do not fit the expected pattern of 
progression for the disease under study. 
Symptomatic deterioration may occur in some subjects.  Symptomatic deterioration is when 
progression is evident in the subject’s clinical symptoms and the Investigator may elect not to 
perform further disease assessments.  

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If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE.
Serious Adverse Event
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to the grade 
of an AE (see below).  “Serious” is a regulatory definition and is based on subject or event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations from the Sponsor to applicable regulatory authorities.
An AE should be classified as an SAE if it meets any 1 of the following criteria:
x
Results in death (i.e., the AE actually causes or leads to death).
x
Is life-threatening (i.e., the AE, in the view of the Investigator, places the subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a more severe 
form, might have caused death).
x
Requires or prolongs inpatient hospitalization.
x
Results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions).
x
Results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the investigational product.
x
Is considered a significant medical event by the Investigator based on medical judgment 
(e.g., may jeopardize the subject or may require medical/surgical intervention to prevent 
1 of the outcomes listed above).
After the final DCO, all data collected at the study site, per standard of care, will be recorded in 
the subject’s medical records.  Only SAEs will be reported.
Adverse Events of Special Interest
The following events are adverse events of special interest and must be reported to the Sponsor 
expeditiously (see Section 11.8.7 for reporting instructions), irrespective of regulatory 
seriousness criteria or causality:
x
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, 
ventricular arrhythmia, ventricular fibrillation)

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Severity
Definitions found in the CTCAE version 4.03 will be used for grading the severity of both 
nonhematologic and hematologic AEs.  The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity:
x
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the subject’s daily activities
x
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the subject, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures
x
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other 
treatment
x
Grade 4 (Life-threatening or disabling AE) – experiences which cause the subject to be 
in imminent danger of death
x
Grade 5 (Death related to AE) – experiences which result in subject death
11.8
Documenting and Reporting of AEs and SAEs
The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study, as outlined in the prior sections, are recorded on the CRF.  All SAEs must be 
reported using the SAE report form or clinical database.
Adverse Event Reporting Period
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.  

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All SAEs that occur during the reporting period should be followed to resolution or until the 
Investigator assesses the subject as stable, or the subject is lost to follow-up or withdraws 
consent.  Resolution/stable means the subject has returned to baseline state of health or the 
Investigator does not expect any further improvement or worsening of the event.
Assessment of Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation timepoints 
during the study.  All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, or other means, will be 
recorded in the subject’s medical record and on the AE CRF. 
Disease progression itself is not considered an AE unless it is considered to be drug-related by 
the Investigator; however, signs and symptoms of disease progression may be recorded as AEs 
or SAEs.
Each recorded AE or SAE will be described by its diagnostic term, duration (e.g., start and end 
dates), severity, regulatory seriousness criteria, if applicable, suspected relationship to the study 
drug (see following guidance), and any actions taken.  The causality of AEs to the study drug 
will be assessed by means of the question: ‘Is there a reasonable possibility that the event may 
have been caused by the study drug?’ per Food and Drug Administration (FDA) guidance on 
safety reporting requirements (Food and Drug Administration Guidance 2012).
See Appendix 11 for more detail on assessing causality.
Second Primary Malignancies
Adverse events for malignant tumors reported during a study should generally be assessed as 
SAEs.  If no other seriousness criteria apply, the “Important Medical Event” criterion should be 
used.  In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
nonserious AE.  For example, if the tumor is included as medical history and progression occurs 
during the study but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur.  Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 

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does not require hospitalization, may be assessed as nonserious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the investigational product (IP) under study and is not the development of new 
or progression of existing metastasis to the tumor under study).  Malignant tumors that—as part 
of normal, if rare, progression—undergo transformation (e.g., Richter's transformation of B cell 
chronic lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a 
new malignant tumor.
Hy’s Law
Cases in which a subject shows elevations in liver biochemistry may require further evaluation, 
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reported as SAEs.  Refer to Appendix 12 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law.
Pregnancy
The Investigator should report all pregnancies and pregnancies in the partners of subjects within 
24 hours using the Pregnancy Report Form.  This form should be faxed or emailed to the Study 
Representative. Any pregnancy-associated SAE must be reported using the SAE report form
according to the usual timelines and directions for SAE reporting (Section 11.8.1).
Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated 
subject during this study will be reported.  All pregnancies and partner pregnancies that are 
identified during or after this study, wherein the estimated date of conception is determined to 
have occurred from the time of consent to 2 days after the last dose of acalabrutinib, 90 days 
after the last dose of idelalisib, 6 months after the last dose of bendamustine or 12 months after 
last dose of rituximab (whichever is longer) will be reported, followed to conclusion, and the 
outcome reported, as long as the subject or partner has consented to participate in follow-up.
A pregnancy itself is not regarded as an AE unless there is suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Likewise, elective abortions without complications are not considered AEs.  Any SAEs 
associated with pregnancy (e.g., congenital abnormalities/birth defects/spontaneous 

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miscarriage or any other serious events) must additionally be reported as such using the SAE 
report form.
Subjects should be instructed to immediately notify the Investigator of any pregnancies.  Any 
female subjects receiving study drug who become pregnant must immediately discontinue study 
drug.  The Investigator should counsel the subject, discussing any risks of continuing the 
pregnancy and any possible effects on the fetus.
Upon completion of the pregnancy, additional information on the mother, pregnancy, and baby 
will be collected and sent to the Study Representative.
Overdose
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study drug is not an AE 
unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on the Study 
Drug Administration eCRF.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated AE fulfills serious criteria, the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event).
For any subject experiencing an acalabrutinib overdose, observation for any symptomatic side 
effects should be instituted, and vital signs and biochemical and hematologic parameters should 
be followed closely (consistent with the protocol or more frequently, as needed).  Appropriate 
supportive management to mitigate adverse effects should be initiated.  If the overdose 
ingestion is recent and substantial, and if there are no medical contraindications, use of gastric 
lavage or induction of emesis may be considered.
Expedited Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest
All SAEs and AESIs must be reported within 24 hours of discovery.  Initial SAE/AESI reports 
and follow-up information will be reported using the protocol-specific EDC system, according to 
the instructions provided in the Investigator site file.   If electronic SAE reporting is not available, 

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paper SAE forms must be emailed or faxed to the Study Representative.  The Study 
representative may request follow-up and other additional information from the Investigator 
(e.g., hospital admission/discharge notes and laboratory results).
After the final DCO, all AEs, SAEs, irrespective of attribution of causality, and periodic 
laboratory results will be collected and recorded in the subject’s medical records.  Only the 
SAEs will be reported to the sponsor using a paper form.
Whenever possible, AEs/SAEs should be reported by diagnosis term, not as a constellation of 
symptoms.  
Death due to disease progression should be recorded on the appropriate form in the EDC 
system.  If the primary cause of death is disease progression, the death due to disease 
progression should not be reported as an SAE.  If the primary cause of death is something other 
than disease progression, then the death should be reported as an SAE with the primary cause 
of death as the event AE term, as death is typically the outcome of the event, not the event 
itself.  The primary cause of death on the autopsy report should be the term reported.  Autopsy 
and postmortem reports must be forwarded to the Study Representative as outlined above.
If study drug is discontinued because of an SAE, this information must be included in the SAE 
report.
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE is 
attributable to the investigational product (or if a causality assessment is not provided for the 
SAE, in which case a default of ‘related’ may be used for expedited reporting purposes) and the 
SAE is not listed in the current Acalabrutinib Investigator Brochure (i.e., an unexpected event).  
In this case, the Study Representative will forward a formal notification describing the suspected 
unexpected serious adverse reaction (SUSAR) to all Investigators.  Each Investigator must then 
notify his or her IRB/IEC of the SUSAR.
Type and Duration of Follow-up of Subjects after AEs
All AEs and SAEs that are encountered during the protocol-specified AE reporting period should 
be followed to resolution, or until the Investigator assesses the subject as stable, or the subject 
is lost to follow-up or withdraws consent.

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12 
STATISTICS 
The statistical and analytical plans presented below summarize the more complete plans to be 
detailed in the SAP.  A change to the data analysis methods described in the protocol will 
require a protocol amendment only if it alters a principal feature of the protocol. 
The SAP will be finalized before database lock.  Any changes to the methods described in the 
final SAP will be described and justified in the clinical study report. 
IRC 
There will be an IRC which will conduct response evaluations in accordance with its charter. 
DMC 
The DMC will review the safety data periodically and the results of the interim analysis and 
provide recommendations according to the DMC charter.   
The first safety data review will be performed by the DMC after approximately 50 subjects have 
been randomized and had the opportunity to be treated for approximately 8 weeks. After the first 
review meeting, the DMC will meet and review data approximately every 6 months and as 
needed when required by the Sponsor or the DMC. This analysis will focus on deaths, treatment 
discontinuations, SAEs, and Grade 3/4 AEs.  The medical monitor will review this information on 
an ongoing basis until the first safety data review is conducted by the DMC.       
12.1 
Randomization 
This study will use an IXRS for randomization.  Approximately 306 eligible subjects will be 
randomized in a 1:1 ratio into 2 arms (n = 153 each) to receive either acalabrutinib 100 mg BID 
(Arm A) or idelalisib/rituximab or bendamustine/rituximab (Arm B). 
Subjects will be randomized based on the following stratification factors: 
x 
Presence of 17p del 
x 
ECOG performance status (0 or 1 versus 2) 
x 
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12.2 
Determination of Sample Size 
The study is expected to enroll approximately 306 subjects with 1:1 randomization ratio.   
EAST6 (Version 6.3.1) was employed to conduct the sample size calculations. 
12.3 
Interim Analysis 
One interim analysis will be conducted to assess early efficacy of Arm A versus Arm B with 
respect to the primary efficacy endpoint, IRC-assessed PFS using Lan and DeMets with 
O’Brien-Fleming boundaries (Lan 1983, O'Brien 1979).  
 
  The 
nominal alpha levels for the interim and final analyses will be determined based the actual 
number of PFS events observed at the time of the analyses.   
If the criterion for early efficacy is met at the time of the interim analysis, the DMC may 
recommend stopping the study in accordance with the terms of the DMC charter. 
CCI
CCI

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If the primary endpoint achieves statistical significance, then selected secondary endpoints will 
be tested in a manner that will preserve the overall Type I error rate at the 2-sided significance 
level of 0.05.  The SAP will describe the methodology for multiplicity adjustment. 
12.4 
Final Analysis 
The final analysis will occur when the primary endpoint is mature, i.e., 
 
  
12.5 
Analysis Populations 
ITT Population 
The ITT population is defined as all randomized subjects.  All efficacy analysis will be performed 
in the ITT population and will be analyzed as randomized unless specified otherwise.  In 
addition, the ITT population will be used to summarize demographics, as well as baseline and 
disease characteristics. 
Safety Population 
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population will be used for the safety analyses.  Subjects will be analyzed as treated.  
Note: safety and efficacy data for subjects who crossover to acalabrutinib monotherapy will be 
analyzed as a stand-alone group, independent of Arm B or Arm A. 
Additional details will be presented in the statistical analysis plan (SAP). 
12.6 
Handling of Missing Values/Censoring/Discontinuations 
Missing or partial start and end dates for AEs and concomitant medications will be imputed 
according to prespecified, conservative imputation rules.  The SAP will describe approaches for 
other missing data. 
CCI
CCI

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12.7
Efficacy Analyses
Primary Endpoint and Methods
The primary efficacy endpoint is PFS, which is defined as the time from the date of 
randomization until disease progression (assessed by the IRC per IWCLL 2008 criteria) or 
death from any cause, whichever occurs first.  Subjects not meeting these criteria and alive by 
the analysis DCO date will be censored and the detailed censoring rules will be specified in the 
SAP.  
A stratified log-rank test will be used for the primary comparison of PFS.  Additionally, a 
stratified Cox regression model will be used to provide the estimated PFS HR and 2-sided 
 CIs for acalabrutinib relative to Investigator’s choice.  Kaplan-Meier (KM) curves will be 
SUHVHQWHGIRUHDFKWUHDWPHQWDUP0HGLDQ3)6DQGLWV CI, as well as landmark PFS and 
DVVRFLDWHG&,DWVHOHFWHGWLPHVZLOOEHSURYLGHG
The SAP will describe the sensitivity analyses to be performed.
Secondary Endpoints and Methods
Conditional on the positive result of primary endpoint, select key secondary endpoints will be 
tested.  The SAP will describe Type I error control for the secondary outcomes.
INV-assessed PFS
INV-assessed PFS is defined as time from randomization until disease progression (assessed 
by the Investigator per IWCLL 2008 criteria) or death from any cause, whichever occurs first.  
Analysis methods for INV-assessed PFS will be similar to those described for PFS as assessed 
by the IRC per IWCLL 2008 criteria.
INV-assessed ORR
INV-assessed ORR is defined as the proportion of subjects who achieve a CR, CRi, nPR, or PR 
over the course of the study per Investigator assessment.  Subjects who do not have any 
postbaseline response assessment will be considered to be nonresponders. 
ORR will be compared between treatment arms using the Cochran-Mantel-Haenszel chi-square 
test, adjusted for randomization stratification factors.

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IRC-assessed ORR
IRC-assessed ORR will be summarized and analyzed similarly to INV-assessed ORR.
OS
OS is defined as the time from date of randomization until date of death due to any cause. 
Subjects who have not died by the analysis DCO date will be censored at the last date known to
be alive before the cutoff date.  Subjects known to be alive or dead after the DCO date will be 
censored at the DCO date.  The analysis methods for OS will be similar to those described for 
PFS.
PRO Measures
The FACIT-Fatigue PRO endpoint was analyzed through Amendment 5.0 only.  FACIT-Fatigue 
will be collected as scheduled in Appendix 1, Appendix 2, Appendix 3, and Appendix 4.  The 
baseline score is defined as the last score collected on or before first dose of study drug.  Total 
score and change from baseline in total score at each postbaseline assessment time point will 
be assessed. 
INV- and IRC-assessed DOR
DOR is defined as the time from the first documentation of objective response to the earlier time 
of disease progression (assessed by the Investigator or IRC per IWCLL 2008 criteria) or death 
from any cause.  The same censoring rules and analysis methods will be applied as described 
for PFS. 
Time to Next Treatment 
TTNT is defined as the time from randomization to institution of nonprotocol-specified treatment 
for CLL.  The analysis methods for TTNT will be similar to those described for PFS.  For 
crossover patients, TTNT should be defined as time from initial treatment of acalabrutinib to 
institution of nonprotocol-specified treatment for CLL.
CCI
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CCI

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12.8 
Safety Analyses 
Safety data will be summarized for the safety population.  The baseline value for the safety 
analysis is defined as the value collected at the time closest to and before the start of study drug 
administration. 
Adverse Events 
AEs will be graded by the Investigator according to the National Cancer Institute (NCI) CTCAE 
v4.03 for nonhematologic and hematologic AEs.  Each AE verbatim term will be coded to a 
system organ class and a preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Treatment-Emergent Adverse Events 
All TEAEs will be summarized by treatment arm.  AE incidence rates will also be summarized by 
severity and relationship to study drug.  In addition, TEAEs with onset during the first 6 months 
(i.e., 24 weeks or 198 days) of study treatment will be similarly summarized since the treatment 
for Arm B is 9 IV doses over 24 weeks or until disease progression. 
Grade 3 or Grade 4 TEAEs; TEAEs leading to permanent study drug treatment discontinuation; 
TEAEs leading to dose modification; serious TEAEs; and TEAEs resulting in death will be 
summarized by treatment arm. 
For subjects who received crossover acalabrutinib therapy, all TEAEs collected in the 
treatment-emergent period of crossover acalabrutinib therapy will be summarized separately. 
Clinical Laboratory Tests 
Data Summary Methods: 
For gradable parameters, a summary of worst postbaseline toxicity grade will be provided in the 
treatment-emergent period and during the first 6 months of treatment by treatment arm and 
worst toxicity grade (any Grade and Grade 3/4).  The difference in percentages will be 
displayed.  Only subjects whose grades worsened are counted in the numerator of percentage 
calculation while the denominator is all subjects in each treatment arm. 
Analysis of Lymphocytosis: 

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For all subjects with baseline and any postbaseline ALC measurements, summaries of ALC at 
peak will be provided by treatment arm. 
Treatment-related lymphocytosis is defined as an ALC > 5000 cells per microliter and an 
increase above baseline.  The number of subjects with at least one occurrence of lymphocytosis 
will be summarized.  For subjects with lymphocytosis, resolution of lymphocytosis is defined as 
1) a decrease of ALC value to the baseline level or lower, or 2) an achievement of ALC value 
WKDWLVEHORZȝ/ZKLFKHYHU occurs first.  The following analyses will be conducted for 
subjects with lymphocytosis by treatment arm:  ALC at peak and time to peak ALC for subjects 
who have lymphocytosis will be summarized with descriptive statistics. 
Duration of lymphocytosis is defined as the duration of time from the earliest date on which the 
ALC value met the lymphocytosis criteria at a postbaseline assessment to the earliest date on 
which a subsequent ALC value met the resolution criteria. 
Analysis of Serum Immunoglobulins 
Serum immunoglobulins (IgA, IgG and IgM) are collected as scheduled in Appendix 1 to 
Appendix 4.  For each variable, descriptive statistics will be presented at each scheduled 
postbaseline assessment by treatment arm.  Subjects who received IV immunoglobulin on the 
study will be excluded from the summary for IgG. 
ECOG Performance Status 
The ECOG performance status will be collected as scheduled in Appendix 1 to Appendix 4.  The 
ECOG performance status grade ranges from 0 to 5.  Descriptive statistics will be provided for 
each visit over time. 
Vital Signs and Weight 
Body temperature, heart rate (beats/min), systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), and weight will be collected for this study.  Those parameters will be 
collected as scheduled in Appendix 1 to Appendix 4.  For each parameter, descriptive statistics 
will be provided over time. 

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13
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
13.1
Direct Access to Source Data/Documents
Study Monitoring
Representatives of Acerta Pharma or its designee will monitor this study until completion.  The 
purpose of monitoring is to ensure compliance with the protocol and the quality and integrity of 
the data.  This study is also subject to reviews or audits.
Every effort will be made to maintain the anonymity and confidentiality of all subjects during this 
clinical study.  However, because of the experimental nature of this treatment, the Investigator 
agrees to allow the IRB/IEC, representatives of Acerta Pharma, its designated agents, and 
authorized employees of the appropriate regulatory agencies to inspect the facilities used in this 
study and, for purposes of verification, allow direct access to the hospital or clinic records of all 
subjects enrolled into this study.  This includes providing by fax, email, or regular mail 
de-identified copies of radiology, pathology, and/or laboratory results when requested by the 
Sponsor.  A statement to this effect will be included in the informed consent and permission 
form authorizing the use of protected health information.
Audits and Inspections
Authorized representatives of Acerta, a regulatory authority, an IEC or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an Acerta 
audit or inspection is to systematically and independently examine all study-related activities 
and documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the International 
Council for Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator 
should contact Acerta immediately if contacted by a regulatory agency about an inspection.
Institutional Review Board and Independent Ethics Committee
The Investigator will submit this protocol, the informed consent, Acalabrutinib Investigator 
Brochure, and any other relevant supporting information (e.g., all advertising materials) to the 
appropriate IRB/IEC for review and approval before study initiation.  A signed protocol approval 
page; a letter confirming IRB/IEC approval of the protocol and informed consent; and a 
statement that the IRB/IEC is organized and operates according GCP guidelines and the 
applicable laws and regulations; must be forwarded to Acerta Pharma before screening 
subjects for the study.  Additionally, sites must forward a signed Form FDA 1572 (Statement of 

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Investigator) to Acerta Pharma before screening subjects for study enrollment.  Amendments to 
the protocol must also be approved by the IRB/IEC and local regulatory agency, as appropriate, 
before the implementation of changes in this study.
13.2
Quality Control and Quality Assurance
Sponsor shall implement and maintain quality control and quality assurance procedures to 
ensure that the study is conducted and data are generated, documented and reported in 
compliance with the protocol, GCP, and applicable regulatory requirements. This study shall be 
conducted in accordance with the provisions of the Declaration of Helsinki (October 2008) and 
all revisions thereof, and in accordance with FDA regulations (21 Code of Federal Regulations 
[CFR] Parts 11, 50, 54, 56, and 312, Subpart D – Responsibilities of Sponsors and 
Investigators) and with the ICH guidelines on GCP (ICH E6).
13.3
Ethics
Ethical Conduct of the Study
This clinical study was designed and will be implemented in accordance with the protocol, the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local 
regulations (including United States Code of Federal Regulations Title 21 and European 
Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki 
(October 2008).
Written Informed Consent
A copy of the IRB/IEC-approved informed consent must be forwarded to Acerta Pharma for 
regulatory purposes.  The Investigator, or designee (designee must be listed on the Study 
Personnel Responsibility/Signature Log), must explain to each subject the purpose and nature 
of the study, the study procedures, the possible adverse effects, and all other elements of 
consent as defined in § 21CFR Part 50, and other applicable national and local regulations 
governing informed consent.  Each subject must provide a signed and dated informed consent 
before study participation.  If allowed by the protocol, a legal representative may sign the ICF for 
a subject incapable of giving consent.  Signed consent forms must remain in each subject’s 
study file and be available for verification by study monitors at any time.
In accordance to individual local and national patient privacy regulations, the Investigator or 
designee must explain to each subject that for the evaluation of study results, the subject’s 

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protected health information obtained during the study may be shared with Acerta Pharma and 
its designees, regulatory agencies, and IRBs/IECs.  As the study Sponsor, Acerta Pharma will 
not use the subject’s protected health information or disclose it to a third party without applicable 
subject authorization.  It is the Investigator’s or designee’s responsibility to obtain written 
permission to use protected health information from each subject, or if appropriate, the subject’s 
legal guardian.  If a subject or subject’s legal guardian withdraws permission to use protected 
health information, it is the Investigator’s responsibility to obtain the withdrawal request in writing 
from the subject or subject’s legal guardian and to ensure that no further data will be collected 
from the subject.  Any data collected on the subject before withdrawal will be used in the 
analysis of study results.
13.4
Data Handling and Recordkeeping
Subject Screening Log
The Investigator must keep a record that lists all subjects considered for enrollment (including 
those who did not undergo screening) in the study.  For those subjects subsequently excluded 
from enrollment, record the reason(s) for exclusion.
CRFs
Authorized study site personnel (see Section 13.8) will complete CRFs designed for this study 
according to the completion guidelines that will be provided as part of the clinical database.  The 
Investigator will ensure that the CRFs are accurate, complete, legible, and completed promptly.  
Refer to Section 13.4.4 for record retention requirements. 
Inspection of Records
Acerta or designee will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct.
Retention of Records
The Investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed ICFs, drug 
accountability records, SAE information transmitted to Acerta Pharma, subject files (source 

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documentation) that substantiate entries in CRFs, all relevant correspondence and other 
documents pertaining to the conduct of the study. 
An Investigator shall retain records for a period of at least 2 years after the date the last 
marketing application is approved for the drug for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication, until 2 years after the investigation is discontinued and regulatory authorities have 
been notified.  The Investigator must notify Acerta Pharma and obtain written approval from 
Acerta Pharma before destroying any clinical study records at any time.  Acerta Pharma will 
inform the Investigator of the date that study records may be destroyed or returned to Acerta 
Pharma. 
Acerta Pharma must be notified in advance of, and Acerta Pharma must provide express written 
approval of, any change in the maintenance of the foregoing documents if the Investigator 
wishes to move study records to another location or assign responsibility for record retention to 
another party.  If the Investigator cannot guarantee the archiving requirements set forth herein 
at his or her study site for all such documents, special arrangements must be made between the 
Investigator and Acerta Pharma to store such documents in sealed containers away from the 
study site so that they can be returned sealed to the Investigator for audit purposes. 
13.5 
Protocol Amendments 
Acerta Pharma will initiate any change to the protocol in a protocol amendment document.  The 
amendment will be submitted to the IRB/IEC together with, if applicable, a revised model ICF.  If 
the change in any way increases the risk to the subject or changes the scope of the study, then 
written documentation of IRB/IEC approval must be received by Acerta Pharma before the 
amendment may take effect.  Additionally under this circumstance, information on the increased 
risk and/or change in scope must be provided to subjects already actively participating in the 
study, and they must read, understand, and sign any revised ICF confirming willingness to 
remain in the trial. 
13.6 
Publication Policy 
Authorship, in general, will follow the recommendations of the International Committee of 
Medical Journal Editors (International Committee of Medical Journal Editors 2014). 

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13.7 
Clinical Trial Insurance 
Clinical trial insurance has been undertaken according to the laws of the countries where the 
study will be conducted.  An insurance certificate will be made available to the participating sites 
at the time of study initiation. 
13.8 
General Investigator Responsibilities 
The principal Investigator must ensure that: 
1. He or she will conduct or supervise the study. 
2. His or her staff and all persons who assist in the conduct of the study clearly understand 
their responsibilities and have their names included in the Study Personnel 
Responsibility/Signature Log. 
3. The study is conducted according to the protocol and all applicable regulations. 
4. The protection of each subject’s rights and welfare is maintained. 
5. Signed and dated informed consent and, when applicable, permission to use protected 
health information are obtained from each subject before conducting nonstandard of care 
study procedures.  If a subject or subject’s legal guardian withdraws permission to use 
protected health information, the Investigator will obtain a written request from the 
subject or subject’s legal guardian and will ensure that no further data be collected from 
the subject. 
6. The consent process is conducted in compliance with all applicable regulations and 
privacy acts. 
7. The IRB/IEC complies with applicable regulations and conducts initial and ongoing 
reviews and approvals of the study. 
8. Any amendment to the protocol is submitted promptly to the IRB/IEC. 
9. Any significant protocol deviations are reported to Acerta Pharma and the IRB/IEC 
according to the guidelines at each study site. 
10. CRF pages are completed promptly. 
11. All Investigational New Drug (IND) Safety Reports/SUSAR Reports are submitted 
promptly to the IRB/IEC. 
12. All SAEs are reported to the Study Representative within 24 hours of knowledge via the 
clinical database and to the IRB/IEC per their requirements. 
 
 

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14 
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lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and 
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Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with 
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points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2. 
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Eichhorst B, Robak T, Montserrat E, et al.  Chronic lymphocytic leukaemia: ESMO Clinical 
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Fayers PM, Aaronson NK, Bjordal K, et al, on behalf of the EORTC Quality of Life Group. The 
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Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide 
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Furman RR, Sharman JP, Coutre SE, et al.  Idelalisib and rituximab in relapsed chronic 
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Reporting, Editing and Publication of Scholarly Work in Medical Journals 2014 Dec.  Available 
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Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. 
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immunocompromised patients. Cochrane Database Syst Rev. 2014 Oct 1;10:CD005590. 
Wiestner A. The role of B-cell receptor inhibitors in the treatment of patients with chronic 
lymphocytic leukemia. Haematologica 2015 Dec;100(12):1495-507. 
Wierda W O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, 
and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005 
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ZYDELIG® [prescribing information].  Foster City, CA: Gilead Sciences, Inc.; 2016. 
 
 
 

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15 
APPENDICES 
 

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Appendix 1. Schedule of Assessments – Acalabrutinib Treatment 
 
Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT Visitc 
SFU 
Visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 6 Cycle 7 
Q12W starting at 
Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
1 
8 
15 
1 
15 
1 
15 
1 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
Study Drug 
Administration 
 
 
 
 
 
 
 
 
 
 
x 
ARM A 
Acalabrutinib 
100 mg BID PO 
 
Continuous Twice-Daily Dosing 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & 
randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examh   
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
Weight 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 
Vital signsi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 
ECG 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO assessmentsk 
 
x 
 
 
x 
 
x 
 
x 
Q24W starting at 
Cycle 13 (e.g., Cycles 
13, 19)l 
 
 
 
Q24W 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
Adverse eventsm  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum pregnancy testn 
x 
xo 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
HIV testing (for study 
sites in Germany) 
xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologyq 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT Visitc 
SFU 
Visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 6 Cycle 7 
Q12W starting at 
Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
1 
8 
15 
1 
15 
1 
15 
1 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
HBV PCRr 
x 
 
 
 
x 
 
x 
 
x 
QM through Cycle 19, 
then Q12W thereafter 
 
 
 
QM/ 
Q12W, as 
appropriate 
QM/  
Q12W, as 
appropriate 
 
HCV PCRs 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics and FISH 
panel 
x 
 
 
 
 
 
 
 
xt 
 
 
xu 
xu 
 
 
 
CMV testingv 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyw 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ANC, ALC, 
PLT, Hgb 
(within 7 days 
of  CT) 
x 
x 
x 
 
 
Coagulation testsx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistryy 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
Urinalysisz 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins, 
T/B/NK/monocyte 
counts 
 
x 
 
 
 
 
Cycle 3 
only 
 
x 
Q24W starting at 
Cycle 13 (e.g., Cycles 
13, 19)l 
 
 
 
Q24W 
 
 
ȕ2-microglobulin 
 
x 
 
 
 
 
Cycle 3 
only 
 
x 
Q24W starting at 
Cycle 13 (e.g., Cycles 
13, 19)l 
 
 
 
Q24W 
 
 
CT/MRI scanscc 
xdd 
 
 
 
 
 
 
 
 
 
xee,ff 
 
 
x 
 
 
Overall response 
assessment 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Bone marrow biopsy and 
aspirategg 
x 
 
 
 
 
 
 
 
 
 
To confirm CR 
 
 
As clinically 
indicated 
 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT Visitc 
SFU 
Visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 6 Cycle 7 
Q12W starting at 
Cycle 10 (e.g., 
Cycles 10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
1 
8 
15 
1 
15 
1 
15 
1 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
MRD assessmenthh 
 
 
 
 
 
 
 
 
 
 
At time of bone 
marrow 
biopsy/post CR 
 
 
 
 
 
New anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Abbreviations:  AE=adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis 
B surface antibody; aPTT = activated partial thromboplastin time; BID = twice daily; BTK = Bruton tyrosine kinase; CBC = complete blood count; 
CMV = cytomegalovirus; CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; FISH = fluorescence in situ hybridization; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C 
virus; Hgb = hemoglobin level; HIV = human immunodeficiency virus; IGHV = immunoglobulin heavy-chain variable; INR = international normalized ratio; 
IVIG = intravenous immunoglobulins; MRD  PLQLPDOUHVLGXDOGLVHDVH3&5 SRO\PHUDVHFKDLQUHDFWLRQ3/&Ȗ SKRVSKROLSDVH&JDPPD3/7 SODWHOHWFRXQW
PO = oral; PRO = patient reported outcomes; Q12W = every 12 weeks; Q24W = every 24 weeks; QM = every month; TT = treatment termination; SAE=serious 
adverse event; SFU = safety follow-up. 
Footnotes for ACE-CL-309 Schedule of Study Activities for Acalabrutinib Monotherapy: 
a. 
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated. 
b. 
Subjects will have visits on Days 1, 8 and 15 of Cycle 1, on Days 1 and 15 of Cycles 2 to 6, on Day 1 of Cycle 7, and on Day 1 of every third cycle 
thereafter, starting with Cycle 10; each cycle is 28 days.  There is no restriction on maximum treatment allowed with acalabrutinib.   
c. 
A treatment termination (TT) visit is required for subjects who permanently discontinue treatment early for any reason, including disease progression.  A 
30-day (+ 7 days) SFU visit after the last dose of all study drugs is required when subjects discontinue all study drugs.  The TT visit should be performed 
within 7 days of the last dose of all study drugs, if possible, and is not required for subjects who discontinue from study treatment within 10 days of a 
scheduled study visit or if the TT visit would be performed within 14 days of the SFU visit.  In addition to the TT visit, each subject should be followed until 
the SFU visit at 30 (+ 7) days after his or her last dose of all study drugs to monitor for resolution or progression of AEs and to document the occurrence of 
any new events, regardless of whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   
d. 
Each subject should be followed until disease progression.  If disease progression has not occurred at the time of the 30-day SFU visit, post-treatment 
disease follow-up visits should occur approximately every 3 months (12 weeks) until disease progression, regardless of whether the subject receives a new 
anticancer therapy.  During this period, subjects will be followed for disease progression via CT/MRI scans, complete blood count (CBC) with differential, 
physical exams, serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).   
e. 
Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately every 3 months (12 weeks) by clinic visit or 
telephone, to assess survival until death or lost to follow-up. 
f. 
After the final data cutoff, for subjects who are still on treatment and deriving clinical benefit, all procedures and assessments will be performed as standard 
of care. For continued access to study drug, see Section 7.3.  All AEs, SAEs, irrespective of attribution of causality, and periodic laboratory results will be 
collected and recorded in the subject’s medical records.  Only the SAEs will be reported to the sponsor using a paper form. 

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g. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second on 
treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 
7 days of CT/MRI scans.  Bone marrow biopsies/aspirates to confirm a CR must be done within 8-12 weeks of the CT/MRI scan which showed CR. 
h. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination 
of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  
 
   
i. 
Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position.   
j. 
6XEMHFWVVKRXOGEHLQVXSLQHSRVLWLRQDQGUHVWLQJIRU 10 minutes before the baseline ECG.  
k. 
Through Amendment 5.0 PRO endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the PRO endpoints will not be collected. 
l. 
After Cycle 7 Day 1, PRO assessments (through Amendment 5.0), serum immunoglobulins, ȕ2-microglobulin, and T/B/NK/monocyte counts should be 
collected every 12 weeks at Cycle 10 and Cycle 13, and every 24 weeks thereafter. 
m. 
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.  After the end of the protocol-defined AE reporting period (see Section 11.8.1), only SAEs or other AEs of 
concern that are believed to be related to prior treatment with study drug are required to be collected.   
n. 
Serum pregnancy testing, per the Schedule of Assessments, will be required only for women of childbearing potential.  More frequent pregnancy testing 
than delineated in the Schedule of Assessments may be done if required by local regulatory authorities. 
o. 
This serum pregnancy test is to be performed on Cycle 1 Day 1 (- 3 days). 
p. 
For study sites in Germany: Screening peripheral blood samples to be sent to a central vendor to be tested for seropositivity for HIV-1 antibody, HIV-2 
antibody, and if positive, reactivity for the HIV-specific p24 antigen.  
q. 
Hepatitis serology must include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis 
C (HCV) antibody.  In addition, any subjects testing positive for any hepatitis serology must have polymerase chain reaction (PCR) testing (see exclusion 
criterion #16). 
r. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and monthly during treatment Cycles 2 
through 19.  After Cycle 19, monitoring will occur every 3 months.  HBV monitoring should continue until 12 months after last dose of study drug(s).  Any subject 
with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with a physician with 
expertise in managing hepatitis B. As intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, PCR testing monthly is not required in 
subjects who are currently receiving or received prophylactic IVIG within 3 months before study enrollment and have a documented negative anti-HBc test 
before the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., in the setting of rising transaminase levels).  
s. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA performed during screening.  No further 
testing beyond screening is necessary if PCR results are negative. 
t. 
If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit.  
u. 
Peripheral blood samples will be taken at screening and at disease progression (if the progression peripheral blood sample is not taken at the TT visit, then 
it can be drawn at the SFU visit).   
v. 
CMV testing at screening must include serologic testing for CMV immunoglobulin G (CMV IgG), CMV IgM, and CMV DNA PCR testing.  Subjects must have 
a result for CMV DNA PCR which is below the lower limit of quantitation at screening.  Subjects assigned to Arm B must have monthly CMV DNA PCR 
testing while on treatment.  Monthly monitoring for CMV should continue by CMV DNA PCR testing for Arm B subjects until 12 months after the last dose of 
idelalisib or bendamustine, including the crossover period.  The screening CMV serologies will be advisory only, to guide Investigators in assessing risk of 
new infection or reactivation of CMV while on study. 
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w. 
Hematology includes CBC with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, absolute neutrophil 
count (ANC), and absolute lymphocyte count (ALC). 
x. 
Coagulation tests at screening include Prothrombin time/INR and aPTT. 
y. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen 
(BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to 
coincide with the ECG testing.  
z. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
aa. 
 
bb. 
 
cc. 
Radiologic imaging by CT with contrast is required and must include the pelvis, abdomen, chest, and neck (and any other disease area).  Subjects who are 
intolerant to intravenous (IV) CT contrast agents will have CT scans performed with oral contrast.  MRI may be used for imaging assessments if a contrast 
CT scan is contraindicated or unobtainable.  CT/MRI scan can be performed up to 7 days before response evaluation. 
dd. 
Pretreatment radiologic tumor assessment should be performed within 30 days before the first dose.  Subjects who have standard of care CT/MRI results 
may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was done within 30 days of first dose and was acquired in 
accordance with the guidelines outlined in Section 11.1.22. 
ee. 
Bone marrow and radiologic assessments are both required for confirmation of a CR.  Testing for minimal residual disease (bone marrow aspirate) will be 
done on subjects with confirmed CRs.  Clinical assessments of tumor response should be done at every visit.  A central radiology vendor will be used to 
collect and store images for Independent Review Committee (IRC) review.  
ff. 
In cases where cytopenic progression is suspected, a bone marrow aspirate or biopsy must be performed to distinguish autoimmune and drug-related 
cytopenias.  In cases where Richter’s transformation is suspected (e.g., rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a 
ORZSODWHOHWFRXQWDQGHOHYDWHGVHUXP/'+FDOFLXPDQGȕPLFURJOREXOLQOHYHOVGLagnosis should be confirmed by biopsy of lymph nodes, bone marrow, 
or involved organs.  Pathology analyses will be done at a central laboratory for confirmation of Richter’s transformation.  If a whole body PET-CT scan is 
obtained by the Investigator as an ancillary diagnostic tool, the results of this scan should be captured in the EDC as an unscheduled visit (these scans are 
not required, as biopsy of the affected site is diagnostic and sufficient for confirmation). 
gg. 
A bone marrow aspirate and biopsy wLOOEHGRQHDWVFUHHQLQJRUPRQWKVEHIRUHHQUROOPHQWWRFRQILUP&5DQGDVFOLQLFDOO\LQGLFDWHGGXULQJWKH
post-treatment disease follow-up period. 
hh. 
For subjects on acalabrutinib monotherapy, if the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that 
CR has been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample to evaluate MRD should be done between 8-12 weeks 
from the time of supportive clinical assessments including CT/MRI imaging of suspected CR. 
 
 
 
 
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Appendix 2. Schedule of Assessments – Idelalisib/Rituximab Treatment 
 
Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT visitc 
SFU 
visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 
6 
Cycle 7 
Q12W starting 
at Cycle 10 
(e.g., Cycles 
10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
 
1 
8 
15 
1 
15 
1 
15 
1 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
 
 
x 
ARM 
B 
Idelalisib 150 mg BID 
PO 
 
 
Continuous Twice-Daily Dosing 
 
 
 
 
 
 
 
Rituximab IV (first 
dose 375 mg/m2; 
500 mg/m2 
subsequently) 
 
x 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examh    
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
Weight 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 
Vital signsi 
x 
x 
x 
x 
x 
x 
x 
x  
x 
x 
 
x 
x 
 
 
 
ECG 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO assessmentsk 
 
x 
 
 
x 
 
x 
 
x 
Q24W starting at 
Cycle 13 (e.g., 
Cycles 13, 19)l 
 
 
 
Q24W 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
Adverse eventsm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum pregnancy testn 
x 
xo 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
HIV testing (for study sites in 
Germany) 
xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT visitc 
SFU 
visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 
6 
Cycle 7 
Q12W starting 
at Cycle 10 
(e.g., Cycles 
10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
 
1 
8 
15 
1 
15 
1 
15 
1 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
Hepatitis serologyq 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV PCRr 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRs 
x 
 
 
 
x 
 
x 
 
x 
QM through 
Cycle 19, then 
Q12W thereafter 
 
 
 
QM/ 
Q12W, as 
appropriate 
QM/ 
Q12W, as 
appropriate 
 
CMV testingt 
x 
 
 
 
x 
 
x 
 
x 
QM 
 
 
QM 
QM 
QM 
 
Cytogenetics and FISH panel 
x 
 
 
 
 
 
 
 
xu 
 
 
xv 
xv 
 
 
 
Hematologyw 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ANC, ALC, 
PLT, Hgb 
(within 7 days 
of  CT) 
x 
x 
x 
 
 
Coagulation testsx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistryy 
x 
x 
x 
x 
x 
x 
x 
Cycle 
3 only 
x 
x 
 
x 
x 
x 
 
 
Urinalysisz 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulins, 
T/B/NK/monocyte counts 
 
x 
 
 
 
 
Cycle
 3 
only 
 
x 
Q24W starting at 
Cycle 13 (e.g., 
Cycles 13, 19)l 
 
 
 
Q24W 
 
 
ȕ2-microglobulin 
 
x 
 
 
 
 
Cycle
 3 
only 
 
x 
Q24W starting at 
Cycle 13 (e.g., 
Cycles 13, 19)l 
 
 
 
Q24W 
 
 
CT/MRI scanscc 
xdd 
 
 
 
 
 
 
 
 
 
xee,ff 
 
 
x 
 
 
Overall response assessment 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Bone marrow biopsy and 
aspirategg 
x 
 
 
 
 
 
 
 
 
 
To confirm CR 
 
 
As clinically 
indicated 
 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT visitc 
SFU 
visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 
6 
Cycle 7 
Q12W starting 
at Cycle 10 
(e.g., Cycles 
10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
 
1 
8 
15 
1 
15 
1 
15 
1 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
MRD assessmenthh 
 
 
 
 
 
 
 
 
 
 
At time of bone 
marrow 
biopsy/post CR 
 
 
 
 
 
New anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Abbreviations:  AE = adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; aPTT = activated 
partial thromboplastin time; anti-HBs = hepatitis B surface antibody; BTK = Bruton tyrosine kinase; CBC = complete blood count; CMV = cytomegalovirus; 
CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; FISH = fluorescence in situ hybridization; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Hgb = hemoglobin level; 
HIV = human immunogenicity virus; IGHV = immunoglobulin heavy-chain variable; INR = international normalized ratio;  IV = intravenous; IVIG = intravenous 
immunoglobulin; MRD = minimal residual disease; PCR = SRO\PHUDVHFKDLQUHDFWLRQ3/&Ȗ = phospholipase C gamma; PLT = platelet count; PO = oral; 
PRO = patient reported outcomes; Q12W = every 12 weeks; Q24W = every 24 weeks; QM = every month; TT = treatment termination; SAE = serious adverse 
event; SFU = safety follow-up. 
Footnotes for ACE-CL-309 Schedule of Study Activities for Idelalisib in Combination With Rituximab: 
a. 
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated. 
b. 
Subjects will have visits on Days 1, 8, and 15 of Cycle 1, on Days 1 and 15 of Cycles 2 to 6, on Day 1 of Cycle 7, and on Day 1 of every third cycle 
thereafter, starting with Cycle 10; each cycle is 28 days.  Rituximab is to be administered for a maximum of 8 infusions (6 cycles).  Idelalisib treatment will 
continue until disease progression or unacceptable toxicity.     
c. 
A treatment termination (TT) visit is required for subjects who permanently discontinue treatment early for any reason, including disease progression.  A 
30-day (+ 7 days) SFU visit is required after subjects receive their last dose of all study drugs.  The TT visit should be performed within 7 days of the last 
dose of all study drugs, if possible, and is not required for subjects who discontinue from study treatment within 10 days of a scheduled study visit or if the 
TT visit would be performed within 14 days of the SFU visit.  In addition to the TT visit, each subject should be followed until the SFU visit at 30 (+ 7) days 
after his or her last dose of all study drugs to monitor for resolution or progression of AEs and to document the occurrence of any new events, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   
d. 
Each subject should be followed until disease progression.  If disease progression has not occurred at the time of the 30-day SFU visit, post-treatment 
disease follow-up visits should occur approximately every 3 months (12 weeks) until disease progression, regardless of whether the subject receives a new 
anticancer therapy.  During this period, subjects will be followed for disease progression via CT/MRI scans, complete blood count (CBC) with differential, 
physical exams, serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).   
e. 
Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately every 3 months (12 weeks) by clinic visit or 
telephone, to assess survival until death or lost to follow-up. 

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f. 
After the final data cutoff, for subjects who are still on treatment and deriving clinical benefit, all procedures and assessments will be performed as standard 
of care. For continued access to study drug, see Section 7.3.  All AEs, SAEs, irrespective of attribution of causality, and periodic laboratory results will be 
collected and recorded in the subject’s medical records.  Only the SAEs will be reported to the sponsor using a paper form. 
g. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second on 
treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 7 
days of CT/MRI scans.  Bone marrow biopsies/aspirates to confirm a CR must be done within 8-12 weeks of the CT/MRI scan which showed CR. 
h. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination 
of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed 
physical exams are done thereafter.   
i. 
Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position. 
j. 
6XEMHFWVVKRXOGEHLQVXSLQHSRVLWLRQDQGUHVWLQJIRU 10 minutes before the baseline ECG.  
k. 
Through Amendment 5.0 PRO endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the PRO endpoints will not be collected.  
l. 
After Cycle 7 Day 1, PRO assessments (through Amendment 5.0), serum immunoglobulins, ȕ2-microglobulin, and T/B/NK/monocyte counts should be 
collected every 12 weeks at Cycle 10 and Cycle 13, and every 24 weeks thereafter. 
m. 
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.  After the end of the protocol-defined AE reporting period (see Section 11.8.1), only SAEs or other AEs of 
concern that are believed to be related to prior treatment with study drug are required to be collected.   
n. 
Serum pregnancy testing, per the Schedule of Assessments, will be required only for women of childbearing potential.  More frequent pregnancy testing 
(either urine or serum) than delineated in the Schedule of Assessments may be done if required by local regulatory authorities. 
o. 
This serum pregnancy test is to be performed on Cycle 1 Day 1 (-3 days).  
p. 
For study sites in Germany: Screening peripheral blood to be sent to a central vendor to be tested for seropositivity for HIV-1 antibody, HIV-2 antibody, and if 
positive, reactivity for the HIV-specific p24 antigen.   
q. 
Hepatitis serology must include hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and 
hepatitis C (HCV) antibody.  In addition, any subjects testing positive for any hepatitis serology must have PCR testing (see exclusion criterion #16). 
r. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA performed during screening.  No further 
testing beyond screening is necessary if PCR results are negative. 
s. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month during treatment 
Cycles 2 through 19.  After Cycle 19, monitoring will occur every 3 months. HBV monitoring should continue until 12 months after last dose of study drug(s).  
Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a consultation with 
a physician with expertise in managing hepatitis B.  As intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, PCR testing every 
month is not required in subjects who are currently receiving or received prophylactic IVIG within 3 months before study enrollment and have a documented 
negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., in the setting of rising 
transaminase levels).    
t. 
CMV testing at screening must include serologic testing for CMV immunoglobulin G (CMV IgG), CMV IgM, and CMV DNA PCR testing.  Subjects must have 
a result for CMV DNA PCR which is below the lower limit of quantitation at screening.  Subjects assigned to Arm B must have monthly CMV DNA PCR 
testing while on treatment.  Monthly monitoring for CMV should continue by CMV DNA PCR testing for Arm B subjects until 12 months after the last dose of 
idelalisib or bendamustine, including the crossover period.  The screening CMV serologies will be advisory only, to guide Investigators in assessing risk of 
new infection or reactivation of CMV while on study. 
u. 
If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 

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v. 
Peripheral blood samples will be taken at screening and at disease progression (if the progression peripheral blood sample is not taken at the TT visit, then 
it can be drawn at the SFU visit).   
w. 
Hematology includes CBC with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, absolute neutrophil 
count (ANC), and absolute lymphocyte count (ALC). 
x. 
Coagulation tests at screening include Prothrombin time/INR and aPTT. 
y. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen 
(BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to 
coincide with the ECG testing. 
z. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
aa. 
 
 
bb. 
 
cc. 
Radiologic imaging by CT with contrast is required and must include the pelvis, abdomen, chest, and neck (and any other disease area).  Subjects who are 
intolerant to intravenous (IV) CT contrast agents will have CT scans performed with oral contrast.  MRI may be used for imaging assessments if a contrast 
CT scan is contraindicated or unobtainable.  CT/MRI scan can be performed up to 7 days before response evaluation. 
dd. 
Pretreatment radiologic tumor assessment should be performed within 30 days before the first dose.  Subjects who have standard of care CT/MRI results 
may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was done within 30 days of first dose and was acquired in 
accordance with the guidelines outlined in Section 11.1.22. 
ee. 
Bone marrow and radiologic assessments are both required for confirmation of a CR.  Testing for minimal residual disease (bone marrow aspirate) will be 
done on subjects with confirmed CRs.  Clinical assessments of tumor response should be done at every visit.  A central radiology vendor will be used to 
collect and store images for Independent Review Committee (IRC) review.  
ff. 
In cases where cytopenic progression is suspected, a bone marrow aspirate or biopsy must be performed to distinguish autoimmune and drug-related 
cytopenias. In cases where Richter’s transformation is suspected (e.g., rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a 
low platelet count; and HOHYDWHGVHUXP/'+FDOFLXPDQGȕPLFURJOREXOLQOHYHOVGLDJQRVLs should be confirmed by biopsy of lymph nodes, bone marrow, 
or involved organs. Pathology analyses will be done at a central laboratory for confirmation of Richter’s transformation.  If a whole body PET-CT/MRI scan is 
obtained by the Investigator as an ancillary diagnostic tool, the results of this scan should be captured in the EDC as an unscheduled visit (these scans are 
not required, as biopsy of the affected site is diagnostic and sufficient for confirmation). 
gg. 
A bone marrow aspirate and biopsy will EHGRQHDWVFUHHQLQJRUPRQWKVEHIRUHHQUROOPHQWWRFRQILUP&5DQGDVFOLQLFDOO\LQGLFDWHGGXULQJWKH
post-treatment disease follow-up period. 
hh. 
For subjects on treatment with idelalisib plus rituximab, if the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations 
suggest that CR has been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample to evaluate MRD should be done no earlier 
than between 8-12 weeks after the completion of rituximab treatment (e.g., earliest bone marrow biopsy would be start of Cycle 9).  For subjects who 
completed all treatment, if the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that CR has been 
achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample to evaluate MRD should be done between 8-12 weeks from the time of 
supportive clinical assessments including CT/MRI imaging of suspected CR. 
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Appendix 3. Schedule of Assessments – Bendamustine/Rituximab Treatment 
 
Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT visitc 
SFU visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study Drugf 
Days 
 
Cycle 1 
Cycles 2 to 6 
Assessed 
Q12W/Q24Wg 
 
30 days after 
last dose 
Q12W 
Q12W 
 
 
 
1 
2 
8 
15 
1 
2 
 
 
 
 
 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
x 
ARM B 
Bendamustine  
70 mg/m2 IVh 
 
x 
x 
 
 
x 
x 
 
 
 
 
 
 
Rituximab IV (first dose 
375 mg/m2; 500 mg/m2 
subsequently) 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility & randomize 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exami    
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
 
 
ECOG PS 
x 
x 
 
 
 
x 
 
 
x 
x 
 
 
 
Weight 
x 
x 
x 
 
x 
x 
x 
 
x 
x 
 
 
 
Vital signsj 
x 
x 
x 
x 
x 
x 
x  
 
x 
x 
 
 
 
ECG 
xk 
 
 
 
 
 
 
 
 
 
 
 
 
PRO assessmentsl 
 
x 
 
 
 
xm 
 
 
 
 
Q12W/ 
Q24W, as 
appropriatem 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
Adverse eventsn 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum pregnancy testo 
x 
xp 
 
 
 
x 
 
 
x 
x 
 
 
 
HIV testing (for study sites in 
Germany) 
Xq 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologyr 
x 
 
 
 
 
 
 
 
 
 
 
 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT visitc 
SFU visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study Drugf 
Days 
 
Cycle 1 
Cycles 2 to 6 
Assessed 
Q12W/Q24Wg 
 
30 days after 
last dose 
Q12W 
Q12W 
 
 
 
1 
2 
8 
15 
1 
2 
 
 
 
 
 
 
HBV PCRs 
x 
 
 
 
 
x 
 
 
 
 
QM/ 
Q12W, as 
appropriate 
QM/ 
Q12W, as 
appropriate 
 
HCV PCRt  
x 
 
 
 
 
 
 
 
 
 
 
 
 
CMV testingu 
x 
 
 
 
 
x 
 
 
 
QM 
QM 
QM 
 
Cytogenetics and FISH panel 
x 
 
 
 
 
 
 
 
xv 
xv 
 
 
 
Hematologyw 
x 
x 
x 
x 
x 
x 
 
ANC, ALC, PLT, 
Hgb (within 7 days 
of  CT) 
x 
x 
x 
 
 
Coagulation testsx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistryy 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
x 
 
 
Urinalysisz 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulins, 
T/B/NK/monocyte counts 
 
x 
 
 
 
Cycle 3 onlym 
 
 
 
 
Q12W/ 
Q24W, as 
appropriatem 
 
 
ȕ-microglobulin 
 
x 
 
 
 
Cycle 3 onlym 
 
 
 
 
Q12W/ 
Q24W, as 
appropriatem 
 
 
CT/MRI scansdd 
xee 
 
 
 
 
 
 
xff,gg 
 
 
x 
 
 
Overall response assessment 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Bone marrow biopsy and 
aspiratehh 
x 
 
 
 
 
 
 
To confirm CR 
 
 
As clinically 
indicated 
 
 
MRD assessmentii 
 
 
 
 
 
 
 
At time of bone 
marrow biopsy/post 
CR 
 
 
 
 
 
New anticancer therapy 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
x 
 
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Abbreviations:  AE=adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis 
B surface antibody; aPTT = activated partial thromboplastin time; BTK = Bruton tyrosine kinase; CBC = complete blood count; CR = complete remission 
(response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; FISH = fluorescence 
in situ hybridization; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; Hgb = hemoglobin level; HIV = human immunogenicity 
virus; IGHV = immunoglobulin heavy-chain variable; INR = international normalized ratio; IV = intravenous; IVIG = intravenous immunoglobulin; MRD = minimal 
residual disease; PCR = polymerase cKDLQUHDFWLRQ3/&Ȗ SKRVSKROLSDVH&JDPPD3/7 SODWHOHWFRXQW32 RUDO352 SDWLHQWUHSRUWHGRXWFRPHV
Q12W = every 12 weeks; Q24W = every 24 weeks; QM = every month; TT = treatment termination; SAE = serious adverse event; SFU = safety follow-up. 
Footnotes for ACE-CL-309 Schedule of Study Activities for Bendamustine in Combination With Rituximab: 
a. 
Screening tests should be performed within 30 days before the first administration of study drug, unless otherwise indicated. 
b. 
Subjects will have visits on Days 1, 2, 8, and 15 of Cycle 1, on Days 1 and 2 of Cycles 2 to 6, and on Day 1 of the next 12-week visit regardless of whether 
the subject is on study drug.  Each cycle is 28 days.  Bendamustine in combination with rituximab is to be administered for a maximum of 6 cycles.  
c. 
A treatment termination (TT) visit is required for subjects who permanently discontinue treatment early for any reason, including disease progression.  A 
30-day (+ 7 days) SFU visit is required after subjects receive their last dose of all study drugs.  The TT visit should be performed within 7 days of the last 
dose of all study drugs, if possible, and is not required for subjects who discontinue from study treatment within 10 days of a scheduled study visit or if the 
TT visit would be performed within 14 days of the SFU visit.  In addition to the TT visit, each subject should be followed until the SFU visit at 30 (+ 7) days 
after his or her last dose of all study drugs to monitor for resolution or progression of AEs and to document the occurrence of any new events, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   
d. 
Each subject should be followed until disease progression.  If disease progression has not occurred at the time of the 30-day SFU visit, post-treatment 
disease follow-up visits should occur approximately every 3 months (12 weeks) until disease progression, regardless of whether the subject receives a new 
anticancer therapy.  During this period, subjects will be followed for disease progression via CT/MRI scans, complete blood count (CBC) with differential, 
physical exams, serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).   
e. 
Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately every 3 months (12 weeks) by clinic visit 
or telephone, to assess survival until death or lost to follow-up. 
f. 
After the final data cutoff, for subjects who are still on treatment and deriving clinical benefit, all procedures and assessments will be performed as standard 
of care. For continued access to study drug, see Section 7.3.  All AEs, SAEs, irrespective of attribution of causality, and periodic laboratory results will be 
collected and recorded in the subject’s medical records.  Only the SAEs will be reported to the sponsor using a paper form. 
g. 
Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second 
on treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  For bendamustine-treated subjects, the 
second radiologic tumor assessment will occur at the next 12-week interval (± 14 days) regardless of whether the subject is on study drug.  Hematology 
results must be done within 7 days of CT/MRI scans.  Bone marrow biopsies/aspirates to confirm a CR must be done within 8-12 weeks of the CT/MRI 
scan which showed suspected CR. 
h. 
Accommodations should be made in the event of doses of bendamustine held or delayed due to toxicity to permit a full six cycles to be received, wherever 
possible.  A maximum of 6 cycles can be administered.  See further instructions for data entry in such cases in the eCRF guidelines. 
i. 
The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and 
examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  
Symptom-directed physical exams are done thereafter.   
j. 
Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position. 
k. 
6XEMHFWVVKRXOGEHLQVXSLQHSRVLWLRQDQGUHVWLQJIRU 10 minutes before the baseline ECG.  
l. 
Through Amendment 5.0 PRO endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the PRO endpoints will not be collected. 

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m. For bendamustine-WUHDWHGVXEMHFWVVHUXPLPPXQRJOREXOLQVȕ-microglobulin, and T/B/NK/monocyte counts will be collected 16 weeks after Cycle 3 (e.g., 
SFU visit), every 12 weeks for the next 2 visits, and every 24 weeks thereafter.  After Cycle 6, PRO assessments (through Amendment 5.0) will be 
conducted at the next monthly visit (e.g., SFU visit), every 12 weeks for the next 2 visits, and then every 24 weeks thereafter. 
n. 
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.  After the end of the protocol-defined AE reporting period (see Section 11.8.1), only SAEs or other 
AEs of concern that are believed to be related to prior treatment with study drug are required to be collected.   
o. 
Serum pregnancy testing, per the Schedule of Assessments, will be required only for women of childbearing potential.  More frequent pregnancy testing 
(either urine or serum) than delineated in the Schedule of Assessments may be done if required by local regulatory authorities. 
p. 
This serum pregnancy test is to be performed on Cycle 1 Day 1 (-3 days).  
q. 
For study sites in Germany: Screening peripheral blood to be sent to a central vendor to be tested for seropositivity for HIV-1 antibody, HIV-2 antibody, and 
if positive, reactivity for the HIV-specific p24 antigen.  
r. Hepatitis serology must include hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and 
hepatitis C (HCV) antibody.  In addition, any subjects testing positive for any hepatitis serology must have PCR testing (see exclusion criterion #16). 
s. 
Subjects who are anti-HBc positive should have a quantitative PCR test for HBV DNA performed during screening and every month during treatment 
Cycles 2 through 19.  After Cycle 19, monitoring will occur every 3 months.  HBV monitoring should continue until 12 months after last dose of study 
drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted and a 
consultation with a physician with expertise in managing hepatitis B.  As intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, 
PCR testing every month is not required in subjects who are currently receiving or received prophylactic IVIG within 3 months before study enrollment and 
have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., in the 
setting of rising transaminase levels). 
t. 
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive should be tested for HCV RNA performed during screening.  No further 
testing beyond screening is necessary if PCR results are negative. 
u. 
CMV testing at screening must include serologic testing for CMV immunoglobulin G (CMV IgG), CMV IgM, and CMV DNA PCR testing.  Subjects must 
have a result for CMV DNA PCR which is below the lower limit of quantitation at screening. Subjects assigned to Arm B must have monthly CMV DNA 
PCR testing while on treatment.  Monthly monitoring for CMV should continue by CMV DNA PCR testing for Arm B subjects until 12 months after the last 
dose of idelalisib or bendamustine, including the crossover period.  The screening CMV serologies will be advisory only, to guide Investigators in assessing 
risk of new infection or reactivation of CMV while on study. 
v. 
Peripheral blood samples will be taken at screening and at disease progression (if the progression peripheral blood sample is not taken at the TT visit, then 
it can be drawn at the SFU visit).   
w. Hematology includes CBC with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, absolute neutrophil 
count (ANC), and absolute lymphocyte count (ALC). 
x. 
Coagulation tests at screening include Prothrombin time/INR and aPTT. 
y. 
Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen 
(BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to 
coincide with the ECG testing. 
z. 
Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
aa. 
 
 
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bb. 
 
cc. If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 
dd. Radiologic imaging by CT with contrast is required and must include the pelvis, abdomen, chest, and neck (and any other disease area).  Subjects who are 
intolerant to intravenous (IV) CT contrast agents will have CT scans performed with oral contrast.  MRI may be used for imaging assessments if a contrast 
CT scan is contraindicated or unobtainable.  CT/MRI scan can be performed up to 7 days before response evaluation. 
ee. Pretreatment radiologic tumor assessment should be performed within 30 days before the first dose.  Subjects who have standard of care CT/MRI results 
may use these results in lieu of the Screening CT/MRI required for this study, provided the CT/MRI was done within 30 days of first dose and was acquired 
in accordance with the guidelines outlined in Section 11.1.22. 
ff. 
Bone marrow and radiologic assessments are both required for confirmation of a CR.  Testing for minimal residual disease (bone marrow aspirate) will be 
done on subjects with confirmed CRs.  Clinical assessments of tumor response should be done at every visit.  A central radiology vendor will be used to 
collect and store images for Independent Review Committee (IRC) review.  
gg. In cases where cytopenic progression is suspected, a bone marrow aspirate or biopsy must be performed to distinguish autoimmune and drug-related 
cytopenias. In cases where Richter’s transformation is suspected (e.g., rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; 
a low platelet count; and HOHYDWHGVHUXP/'+FDOFLXPDQGȕPLFURJOREXOLQ levels), diagnosis should be confirmed by biopsy of lymph nodes, bone 
marrow, or involved organs. Pathology analyses will be done at a central laboratory for confirmation of Richter’s transformation.  If a whole body 
PET-CT/MRI scan is obtained by the Investigator as an ancillary diagnostic tool, the results of this scan should be captured in the EDC as an unscheduled 
visit (these scans are not required, as biopsy of the affected site is diagnostic and sufficient for confirmation). 
hh. A bone marrow aspiraWHDQGELRSV\ZLOOEHGRQHDWVFUHHQLQJRUPRQWKVEHIRUHHQUROOPHQWWRFRQILUP&5DQGDVFOLQLFDOO\LQGLFDWHGGXULQJWKe 
post-treatment disease follow-up period. 
ii. 
For subjects on bendamustine plus rituximab, if the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest 
that CR has been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample to evaluate MRD should be done no earlier than 
between 8-12 weeks after the completion of the bendamustine plus rituximab treatment, or, if treatment has already been completed, no earlier than 
between 8-12 weeks from the time of the supportive clinical assessments that suggest CR. 
 
 
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Appendix 4. Schedule of Assessments – Crossover 
 
Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT Visitc 
SFU Visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 6 Cycle 7 
Q12W 
starting 
at 
Cycle 10 
(e.g., 
Cycles 
10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
 
1 
8 
15 
1 
15 
1 
15 
1 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
Study Drug 
Administration 
 
 
 
 
 
 
 
 
 
 
x 
Crossover Acalabrutinib 
100 mg BID 
 
Continuous Twice-Daily Dosing 
 
 
 
 
 
 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examh   
x 
x 
 
 
x 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
ECOG PS 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
Weight 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 
Vital signsi 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
 
 
ECG 
xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRO assessmentsk 
 
x 
 
 
x 
 
x 
 
x 
Q24W starting 
at Cycle 13 
(e.g., Cycles 
13, 19)l 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
Adverse eventsm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
Serum pregnancy test n 
x 
xo 
 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
 
HIV testing (for study sites 
in Germany) 
x p 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serologyq 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV PCRr 
x 
 
 
 
x 
 
x 
 
x 
QM through 
Cycle 19, then 
Q12W 
thereafter 
 
 
 
QM/ 
Q12W, as 
appropriate 
QM/ 
Q12W, as 
appropriate 
 
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Screeninga 
Treatment Phaseb 
Response 
Evaluation 
TT Visitc 
SFU Visitc 
Post-treatment 
Disease 
Follow-upd 
Survival 
Follow-upe 
Continued 
Access to 
Study 
Drugf 
Days 
 
Cycle 1 
Cycle 2 
Cycles 3 to 6 Cycle 7 
Q12W 
starting 
at 
Cycle 10 
(e.g., 
Cycles 
10, 13, 16) 
Assessed 
Q12W/ 
Q24Wg 
 
30 days 
after last 
dose 
Q12W 
Q12W 
 
1 
8 
15 
1 
15 
1 
15 
1 
 
Study Windows 
- 30 days 
 
± 3 days 
± 3 days 
± 3 days 
± 3 days 
± 14 days 
 
+ 7 days 
± 7 days 
± 7 days 
 
HCV PCR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV testings 
x 
x 
 
 
x 
 
x 
 
x 
QM 
 
 
x 
QM 
QM 
 
Cytogenetics and FISH 
panel 
x 
 
 
 
 
 
 
 
xt 
 
 
xu 
xu 
 
 
 
Hematologyv 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
ANC, ALC, 
PLT, Hgb 
(within 7 days 
of CT) 
x 
x 
x 
 
 
Serum chemistryw 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
Urinalysisx 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulins, 
T/B/NK/monocyte counts 
 
x 
 
 
 
 
Cycle 3 
only 
 
x 
Q24W starting 
at Cycle 13 
(e.g., Cycles 
13, 19)l 
 
 
 
Q24W 
 
 
ȕ-microglobulin 
 
x 
 
 
 
 
Cycle 3 
only 
 
x 
Q24W starting 
at Cycle 13 
(e.g., Cycles 
13, 19)l 
 
 
 
Q24W 
 
 
CT/MRI scansaa 
xbb 
 
 
 
 
 
 
 
 
 
xcc,dd 
 
 
x 
 
 
Overall response 
assessment 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
Bone marrow biopsy and 
aspiratecc 
 
 
 
 
 
 
 
 
 
 
To confirm CR 
 
 
As clinically 
indicated 
 
 
MRD assessmentee 
 
 
 
 
 
 
 
 
 
 
At time of bone 
marrow 
biopsy/post CR 
 
 
 
 
 
Survival status and new 
anticancer therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
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Abbreviations:  AE=adverse event; ALC = absolute lymphocyte count; ANC = absolute neutrophil count; anti-HBc = hepatitis B core antibody; BID = twice daily; 
BTK = Bruton tyrosine kinase; CR = complete remission (response); CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; FISH = fluorescence in situ hybridization; HBV = hepatitis B virus; HCV = hepatitis C virus; Hgb = hemoglobin level; 
HIV = human immunodeficiency virus; IGHV = immunoglobulin heavy-chain variable; IVIG = intravenous immunoglobulin; MRD = minimal residual disease; 
PCR = SRO\PHUDVHFKDLQUHDFWLRQ3/&Ȗ SKRVSKROLSDVH&JDmma; PLT = platelet count; PO = oral; PRO = patient reported outcomes; Q12W = every 12 weeks; 
Q24W = every 24 weeks; QM = every month; TT = treatment termination; SAE = adverse event; SFU = safety follow-up. 
Footnotes for ACE-CL-309 Schedule of Study Activities for Crossover to Acalabrutinib Monotherapy: 
a. Screening tests should be performed within 30 days before the administration of study drug, unless otherwise indicated.  However, screening hematology and 
serum chemistry tests do not need to be repeated if they had been done at a prior study visit within 10 days of crossing over (i.e., receiving acalabrutinib).  
Cytogenetics and FISH panel, serum immunoglobulins and genetic and molecular prognostic factors do not need to be repeated if they had been done at a prior 
study visit within 30 days of crossing over (i.e., receiving acalabrutinib). 
b. Subjects will have visits on Day 1 of every third cycle, starting with Cycle 1; each cycle is 28 days.  There is no restriction on maximum treatment allowed with 
acalabrutinib.   
c. A treatment termination (TT) visit is required for subjects who permanently discontinue treatment early for any reason, including disease progression.  A 30-day 
(+ 7 days) SFU visit after the last dose of all study drugs is required when subjects discontinue all study drugs.  The TT visit should be performed within 7 days 
of the last dose of all study drugs, if possible, and is not required for subjects who discontinue from study treatment within 10 days of a scheduled study visit or if 
the TT visit would be performed within 14 days of the SFU visit.  In addition to the TT visit, each subject should be followed until the SFU visit at 30 (+ 7) days 
after his or her last dose of all study drugs to monitor for resolution or progression of AEs and to document the occurrence of any new events, regardless of 
whether the subject receives a new anticancer therapy or demonstrates disease progression within this timeframe.   
d.  Each subject should be followed until disease progression.  If disease progression has not occurred at the time of the 30-day SFU visit, post treatment disease 
follow-up visits should occur approximately every 3 months (12 weeks) until disease progression, regardless of whether the subject receives a new anticancer 
therapy.  During this period, subjects will be followed for disease progression via CT/MRI scans, complete blood count (CBC) with differential, physical exams, 
serum chemistry, and bone marrow biopsy and aspirate (as clinically indicated).   
e. Once subjects progress—for all subjects who have not withdrawn consent—they will be contacted approximately every 3 months (12 weeks) by clinic visit or 
telephone, to assess survival until death or lost to follow-up. 
f. After the final data cutoff, for subjects who are still on treatment and deriving clinical benefit, all procedures and assessments will be performed as standard of 
care. For continued access to study drug, see Section 7.3.  All AEs, SAEs, irrespective of attribution of causality, and periodic laboratory results will be collected 
and recorded in the subject’s medical records.  Only the SAEs will be reported to the sponsor using a paper form. 
g.  Response evaluations will be done every 12 weeks (± 14 days) with the first on-treatment radiologic assessment occurring on Cycle 4 Day 1, the second on 
treatment scan on Cycle 7 Day 1, and so on through Cycle 25, and then every 24 weeks (± 14 days) thereafter.  Hematology results must be done within 7 days 
of CT/MRI scans.  Bone marrow biopsies/aspirates to confirm a CR must be done within 8-12 weeks of the CT/MRI scan which showed CR. 
h.  The screening physical examination will include, at a minimum, the general appearance of the subject, height (screening only) and weight, and examination of 
the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, lymphatic system, and nervous system.  Symptom-directed 
physical exams are done thereafter.   
i. Vital signs (blood pressure, pulse, and temperature) will be assessed after the subject has rested in the sitting position.   
j.  6XEMHFWVVKRXOGEHLQVXSLQHSRVLWLRQDQGUHVWLQJIRU 10 minutes before the baseline ECG.  
k. Through Amendment 5.0 PRO endpoints were collected and analyzed; with the adaptation of Amendment 6.0, the PRO endpoints will not be collected. 
l. After Cycle 7 Day 1, PRO assessments (through Amendment 5.0), serum immunoglobulins, ȕ2-microglobulin, and T/B/NK/monocyte counts should be 
collected every 12 weeks at Cycle 10 and Cycle 13, and every 24 weeks thereafter. 

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m. 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.  After the end of the protocol-defined AE reporting period (see Section 11.8.1), only SAEs or other AEs of concern 
that are believed to be related to prior treatment with study drug are required to be collected.   
n.  Serum pregnancy testing, per the Schedule of Assessments, will be required only for women of childbearing potential.  More frequent pregnancy testing (either 
urine or serum) than delineated in the Schedule of Assessments may be done if required by local regulatory authorities. 
o. This serum pregnancy test is to be performed on Cycle 1 Day 1 (- 3 days). 
p. For study sites in Germany: Screening peripheral blood to be sent to a central vendor to be tested for seropositivity for HIV-1 antibody, HIV-2 antibody, and if 
positive, reactivity for the HIV-specific p24 antigen. 
q. Hepatitis serology must include hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), hepatitis B core antibody (anti-HBc), and hepatitis C 
(HCV) antibody.  In addition, any subjects testing positive for any hepatitis serology must have PCR testing (see exclusion criterion #16).  
r. Subjects who are hepatitis B core antibody (anti-HBc) positive should be monitored every month with a quantitative polymerase chain reaction (PCR) test for 
HBV DNA during treatment Cycles 2 through 19.  After Cycle 19, monitoring will occur every 3 months.  HBV monitoring should continue until 12 months after 
last dose of study drug(s).  Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have antiviral therapy instituted 
and a consultation with a physician with expertise in managing hepatitis B.  As intravenous immunoglobulins (IVIG) may cause false positive hepatitis serology, 
PCR testing every month is not required in subjects who are currently receiving or received prophylactic IVIG within 3 months before study enrollment and have 
a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR testing should be performed when clinically indicated (e.g., in the setting of 
rising transaminase levels).     
s. During crossover, monthly monitoring for CMV should continue by CMV DNA PCR testing for previously treated Arm B subjects until 12 months after the last 
dose of idelalisib or bendamustine. 
t. If these samples are damaged during collection or shipment, they should be redrawn at any subsequent visit. 
u. Peripheral blood samples will be taken at screening and at disease progression (if the progression peripheral blood sample is not taken at the TT visit, then it 
can be drawn at the SFU visit). 
v. Hematology includes complete blood count (CBC) with differential including, but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, 
absolute neutrophil count (ANC), and absolute lymphocyte count (ALC). 
w. Serum chemistry: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, blood urea nitrogen (BUN), 
calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total protein, and 
uric acid.  If an unscheduled ECG is done at any time, then an electrolyte panel (i.e., calcium, magnesium, and potassium) must be done to coincide with the 
ECG testing.  
x. Urinalysis: pH, ketones, specific gravity, bilirubin, protein, blood, and glucose.   
y. 
 
 
  
z. 
 
aa. Radiologic imaging by CT with contrast is required and must include the pelvis, abdomen, chest, and neck (and any other disease area).  Subjects who are 
intolerant to intravenous (IV) CT contrast agents will have CT scans performed with oral contrast.  MRI may be used for imaging assessments if a contrast CT 
scan is contraindicated or unobtainable.  CT/MRI scan can be performed up to 7 days before response evaluation. 
bb. CT/MRI scans that showed disease progression from Arm B can be used for the crossover screening CT/MRI scan, if obtained within 30 days prior to crossover 
dosing Cycle 1 Day 1.    
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cc. Bone marrow and radiologic assessments are both required for confirmation of a CR.  Testing for minimal residual disease (bone marrow aspirate) will be done 
on subjects with confirmed CRs.  Clinical assessments of tumor response should be done at every visit.  A central radiology vendor will be used to collect and 
store images for Independent Review Committee (IRC) review. 
dd. In cases where cytopenic progression is suspected, a bone marrow aspirate or biopsy must be performed to distinguish autoimmune and drug-related 
cytopenias. In cases where Richter’s transformation is suspected (e.g., rapidly progressive B symptoms; bulky lymphadenopathy; organomegaly; anemia; a low 
SODWHOHWFRXQWDQGHOHYDWHGVHUXP/'+FDOFLXPDQGȕPLFURJOREXOLQOHYHOVGLDJQRVLVVKRXOGEHFRQILUPHGE\ELRSV\RIO\Pph nodes, bone marrow, or 
involved organs.  Pathology analyses will be done at a central laboratory for confirmation of Richter’s transformation.  If a whole body PET-CT/MRI scan is 
obtained by the Investigator as an ancillary diagnostic tool, the results of this scan should be captured in the EDC as an unscheduled visit (these scans are not 
required, as biopsy of the affected site is diagnostic and sufficient for confirmation). 
ee. For subjects on acalabrutinib monotherapy, if the subject’s physical examination findings, laboratory evaluations, and radiographic evaluations suggest that CR 
has been achieved, a confirmatory bone marrow biopsy/aspirate and peripheral blood sample to evaluate MRD should be done between 8-12 weeks from the 
time of supportive clinical assessments including CT/MRI imaging of suspected CR. 
 
 

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Appendix 5. Known Strong in Vivo Inhibitors or Inducers of CYP3A 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ad 
boceprevir 
carbamazepinee 
clarithromycinb 
phenytoine 
conivaptinb 
rifampine 
indinavir 
St John's worte  
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradilc 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the area under the concentration-time curve 
$8&RIDVXEVWUDWHIRU&<3$E\-fold. 
b. 
In vivo inhibitor of P-glycoprotein. 
c. 
Withdrawn from the United States market because of safety reasons. 
d. 
A strong inducer for CYP3A is defined as an LQGXFHUWKDWUHVXOWVLQGHFUHDVHLQWKH$8&RIDVXEVWUDWHIRU
CYP3A. 
e. 
In vivo inducer of P-glycoprotein.   
 
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs not on this list should be 
addressed to the medical monitor of the protocol. 
Source: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Web link 
Accessed 11 June 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm#inVivo 
 
 

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Appendix 6. Performance Status Scores 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, e.g., light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
ZRUNDFWLYLWLHV8SDQGDERXWPRUHWKDQRIZDNLQJKRXUV 
3 
Capable of only limited self-care, confined to bed or chair more 
WKDQRIZDNLQJKRXUV 
4 
Completely disabled.  Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 

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Appendix 7.
FACIT-Fatigue

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Appendix 8. 
 
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CCI

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Appendix 9. 
 
CCI
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CCI

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Appendix 10. Response Assessment Criteria (modified from Hallek 2008) – IWCLL 
Criteria (as updated for persistent lymphocytosis in Cheson 2012) 
Response 
Lymphocytes 
Bone Marrow 
Physical Exama 
(Nodes, Liver, 
Spleen) 
Peripheral Blood 
CR* 
Lymphocytes < 4 x 109/L 
 
Normocellular 

lymphocytes 
No B-lymphoid 
nodules 
Normal (e.g., no 
lymph nodes > 1.5 
cm) 
ANC > 1.5 x 109/Lb 
Platelets > 100 x 
109/Lb 
Hemoglobin > 11.0 
g/dL (untransfused)b 
Cri 
Lymphocytes < 4 x 109/L 
 
Hypocellular 

lymphocytes 
No B-lymphoid 
nodules 
Normal (e.g., no 
lymph nodes > 1.5 
cm) 
Persistent anemia, 
thrombocytopenia, or 
neutropenia related to 
drug toxicity 
nPR 
CR with the presence of lymphoid nodules in the bone marrow which reflect residual 
disease.   
PR* 
Lymphocytes < 5 x 109/L  
Or 
GHFUHDVHIURP
baseline 
 
Not assessed 
UHGXFWLRQLQ
lymphadenopathyc 
and/or in spleen or 
liver enlargement 
ANC > 1.5 x 109/L 
Or 
Platelets > 100 x 109/L 
or 
 LPSURYHPHQW
over baselineb 
Or 
Hemoglobin > 11.0 
JG/RU
improvement over 
baseline 
(untransfused)b 
PRL* 
/\PSKRF\WHV[9/L 
AND 
GHFUHDVHIURP
baseline 
 
Not assessed 
UHGXFWLRQLQ
lymphadenopathyc 
and/or in spleen or 
liver enlargement 
ANC > 1.5 x 109/L 
Or 
Platelets > 100 x 109/L 
or 
 LPSURYHPHQW
over baselineb 
Or 
Hemoglobin > 11.0 
JG/RU
improvement over 
baseline 
(untransfused)b 
SD 
Absence of PD and failure to achieve at least a PR 

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Response 
Lymphocytes 
Bone Marrow 
Physical Exama 
(Nodes, Liver, 
Spleen) 
Peripheral Blood 
PD* 
/\PSKRF\WHV
increase over baseline, 
ZLWK
B lymphocytes/μL 
 
Not assessed 
(except to 
confirm PD as 
assessed by 
progressive 
cytopenias) 
Appearance of any 
new lesion or de novo 
appearance of 
hepatomegaly or 
splenomegaly 
Or 
,QFUHDVHLQ
lymphadenopathy 
Or 
,QFUHDVHLQ
hepatomegaly 
Or  
,QFUHDVHLQ
splenomegaly 
Platelets decrease of 
IURPEDVHOLQH
secondary to CLL 
Or 
Hemoglobin decrease 
of > 2 g/dL from 
baseline secondary to 
CLL 
Abbreviations:  ANC = absolute neutrophil count; CLL= chronic lymphocytic leukemia; CR = 
complete remission (response); CRi = CR with incomplete bone marrow recovery; nPR = nodular 
partial remission; PD = progressive disease; PR = partial remission (response); PRL = partial 
remission (response) with lymphocytosis; SD = stable disease. 
*CR:  all of the above CR criteria have to be met, and patients have to lack disease-related constitutional 
symptoms; PR: at least two of the above PR criteria for lymphadenopathy, splenomegaly, hepatomegaly, 
or lymphocytes plus one of the criteria for ANC, platelets or hemoglobin have to be met; PRL: presence of 
O\PSKRF\WRVLVSOXVUHGXFWLRQLQO\PSKDGHQRSDWK\DQGRULQVSOHHQRUOLYHUHQODUJHPHQWSOXVRQH
of the criteria for ANC, platelets or hemoglobin have to be met; PD: at least one of the above PD criteria 
has to be met, or transformation to a more aggressive histology (e.g., Richter’s syndrome).  For PD as 
assessed by progressive cytopenias, a bone marrow biopsy is required for confirmation.  Note:  Isolated 
elevation of treatment-related lymphocytosis by itself will not be considered PD unless patient becomes 
symptomatic from this per Cheson 2012. 
a 
Computed tomography (CT) scan of abdomen, pelvis, and thorax may be used if previously abnormal 
b 
Without need for exogenous growth factors 
c 
,QWKHVXPSURGXFWVRIO\PSKQRGHVRULQWKHODUJHVWGLDPHWHURIWKHHQODUJHGO\PSKQRGHV) detected before 
therapy and no increase in any lymph node or new enlarged lymph nodes 
 
 

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Appendix 11. Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  No___ 
Yes___ 
The descriptions provided below will help guide the principal Investigator in making the decision 
to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
x 
may be judged to be due to extraneous causes such as disease or environment or 
toxic factors 
x 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
x 
is not biologically plausible 
x 
does not reappear or worsen when study drug is re-administered 
x 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study drug. 
The adverse event: 
x 
follows a temporal sequence from administration of study drug 
x 
is a known response to the study drug based on clinical or preclinical data 
x 
could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject 
x 
disappears or decreases upon cessation or reduction of dose of study drug 
x 
reappears or worsens when study drug is re-administered 
 
 

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Appendix 12. Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law 
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER BIOCHEMISTRY AND 
EVALUATION OF HY’S LAW  
 
INTRODUCTION 
This Appendix describes the process to be followed to identify and appropriately report 
potential Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets 
PHL criteria at any point during the study.  All sources of laboratory data are appropriate 
for the determination of PHL and HL events; this includes samples taken at scheduled 
study visits and other visits, including central and all local laboratory evaluations, even if 
collected outside of the study visits (e.g., PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The 
investigator will also review adverse event (AE) data (e.g., for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events. 
The investigator participates with the sponsor in the review and assessment of cases 
meeting PHL criteria to agree whether HL criteria are met.  HL criteria are met if there is 
no alternative explanation for the elevations in liver biochemistry other than drug-induced 
liver injury (DILI) caused by the investigational medicinal product (IMP).  The investigator 
is responsible for recording data pertaining to PHL/HL cases and for reporting AEs and 
serious adverse events (SAEs) according to the outcome of the review and assessment 
in line with standard safety-reporting processes.   
DEFINITIONS 
Potential Hy’s Law  
$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1DWDQ\SRLQWGXULQJWKHVWXG\
after the start of study drug, irrespective of an increase in alkaline phosphatase.  
Hy’s Law 
$67RU$/7[8/1WRJHWKHUZLWKWRWDOELOLUXELQ[8/1ZKHUHQRUHDVRQRWKHUWKDQ
the IMP can be found to explain the combination of increases (e.g., elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, or another drug).   

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For PHL and HL, the elevation in transaminases must precede or be coincident with (i.e., 
on the same day) the elevation in total bilirubin, but there is no specified timeframe 
within which the elevations in transaminases and total bilirubin must occur. 
IDENTIFICATION OF POTENTIAL HY’S LAW CASES 
Laboratory data must be comprehensively reviewed by the investigator for each subject 
to identify laboratory values meeting the following criteria: 
x 
$/7[8/1 
x 
$67[8/1 
x 
7RWDOELOLUXELQ[8/1 
When the identification criteria are met from central or local laboratory results, the 
investigator will perform the following: 
x 
Notify the sponsor representative/medical monitor by telephone and report the 
PHL case as an SAE of Potential Hy’s law: seriousness criteria “Important 
medical event” and causality assessment “yes/related” or in accordance with the 
clinical study protocol as appropriate. 
x 
Request a repeat of the test (new blood draw) without delay 
x 
Complete the appropriate unscheduled laboratory electronic Case Report Form 
(eCRF) module(s)  
x 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the clinical study protocol, as applicable 
 
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES 
The instructions in this section should be followed by the investigator for all cases where 
PHL criteria are met. 
As soon as possible after the biochemistry abnormality is initially detected, the study 
medical monitor and the Investigator will review available data, to agree whether there is 
an alternative explanation for meeting PHL criteria other than DILI caused by the IMP 

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and to ensure that timely analysis and reporting to health authorities within 15 calendar 
days from the date PHL criteria were met.    
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin 
elevations, a determination of whether the alternative explanation is an AE will be made 
and, subsequently, whether the AE meets the criteria for an SAE: 
x 
If the alternative explanation is not an AE, record the alternative explanation on 
the appropriate eCRF. 
x 
If the alternative explanation is an AE/SAE, update the previously submitted PHL 
SAE accordingly with the new information (reassessing event term, causality, 
and seriousness criteria) following the sponsor’s standard processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and total 
bilirubin elevations other than the IMP, then: 
x 
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard 
processes:  
o The “Medically Important” serious criterion should be used if no other serious 
criteria apply. 
o Because there is no alternative explanation for the HL case, a causality 
assessment of “related” should be assigned. 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until an informed decision can be made: 
x 
Provide any further update to the previously submitted SAE of PHL (report term 
now “Hy’s law case”), ensuring causality assessment is related to IMP and 
seriousness criteria are medically important, according to clinical study protocol 
process. 
x 
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are still met.  Update the previously submitted PHL 
SAE report following the clinical study protocol process, according to the 
outcome of the review. 

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ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW 
This section is applicable when a subject meets PHL criteria while receiving study 
treatment and has already met PHL criteria at a previous on-study treatment visit.  The 
requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous 
occurrence.   
The investigator should determine the cause for the previous occurrence of PHL and 
answer the following question: 
Was the alternative cause for the previous occurrence of PHL determined to be 
the disease under study (e.g., chronic or progressing malignant disease, severe 
infection, or liver disease)? 
x 
If the answer is No: 
Follow the process described in “Potential Hy’s Law Criteria Met” in this 
Appendix for reporting PHL as an SAE. 
x 
If the answer is Yes:  
Determine whether there has been a significant change in the subject’s 
condition compared with the previous occurrence of PHL.  Note:  A 
“significant” change in the subject’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST, 
or total bilirubin) in isolation or in combination or a clinically relevant 
change in associated symptoms.  The determination of whether there has 
been a significant change will be at the discretion of the investigator; this 
may be in consultation with the study medical monitor if there is any 
uncertainty. 
o If there is no significant change, no action is required. 
o If there is a significant change, follow the process described in 
“Potential Hy’s Law Criteria Met” in this Appendix for reporting 
PHL as an SAE. 
 
LABORATORY TESTS 
The list below represents a comprehensive list of follow-up tests that may aid in 
assessing PHL/HL.   
Test results used to assess PHL/HL should be recorded on the appropriate eCRF. 

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Additional standard chemistry and 
coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgM and IgG anti-HCV 
HCV RNA 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin 
(CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab 
(Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
 
Reference 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing 
clinical evaluation 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM174090.pdf 
 

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Appendix 13. Management of Study Procedures During Pandemic 
 
This appendix consolidates guidance for subject safety and ongoing access to medical 
care and investigational product during the global COVID-19 pandemic.  The measures 
detailed below will be implemented across Acerta Pharma studies on a temporary basis 
until the pandemic is considered resolved by governmental and public health 
organizations, as applicable. 
Regardless of the guidance below, please consider public health advice in your local 
market and individual risk/benefit in treatment decisions for patients at your study site 
during the pandemic.  Please also consider logistical requirements such as the ability of 
patients to travel to the study site, accessibility of public transport, etc. 
If the patient is unable or unwilling to visit the study site due to COVID-19 related 
reasons, investigators may ask enrolled patients to use healthcare facilities local to the 
patient to ensure safety and efficacy measures are done per protocol.  If a study 
assessment is not done at either the site or a facility local to the patient, then its absence 
should be documented as a protocol deviation.  Any protocol deviations resulting from 
the COVID-19 situation should be recorded and prefixed with COVID-19. 
Study Subject Participation 
Conduct of Telephone Visits 
Due to the current pandemic, it is conceivable that not all subject visit commitments may 
be able to be fulfilled.  If a subject is unable or unwilling to attend a study visit, 
adaptation of the onsite visit to a telephone visit is recommended to ensure continuity of 
study care (as an interim measure; e.g., telephone contacts instead of visits, shipping 
study medication to the subject).  Priority should be given to maintaining ongoing safety 
follow-up (even if this is conducted by telephone contacts).  Study sites should speak 
with their site monitor before performing a telephone visit so he or she may provide 
guidance regarding logistics that may need consideration.  Also, study sites should 
speak with the site monitor if the subject cannot attend more than one onsite visit in 
succession, because multiple incomplete visits may have the potential to impact 
evaluation of study endpoints. 

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Acalabrutinib Dose Modification Recommendation for COVID-19 
The sponsor recognizes that coronavirus 2019-nCoV (COVID-19) presents an increased 
risk for all patients.  Due to the potential impact of COVID-19 on multiple organ systems, 
the sponsor recommends the following dose modification and management plan for 
patients with confirmed or suspected COVID-19 while receiving treatment with 
acalabrutinib.  
First and foremost, the following safety reporting guidelines are required: 
All confirmed or suspected COVID-19-related adverse events (AEs) must be recorded in 
the eCRF. All dose modifications should be based on the worst Common Terminology 
Criteria for Adverse Events (CTCAE) grade.  All interruptions or modifications must be 
recorded on the AE and drug administration eCRFs.  The CTCAE general grading 
criteria should be used to evaluate COVID-19. 
If an event is suspected to be COVID -19 infection, the sponsor recommends 
interrupting acalabrutinib and testing for COVID-19 per local guidance. 
x 
If COVID-19 is ruled out, standard clinical practice and the study protocol 
procedures should be followed regarding any dose modifications required for 
management of severe infections. 
x 
If COVID-19 is confirmed or diagnosis is suspected after evaluation, COVID-19 
infection should be managed per local guidance until the subject achieves full 
recovery, defined as no signs or symptoms. 
In case of COVID-19 positivity, the investigator must determine the risk and benefit of 
interruption versus continuation of acalabrutinib and whether to resume it at full or 
modified doses or discontinue treatment. 
Please contact the study medical monitor for further discussion. 
Comparator Drugs or Drugs used in Combination with Acalabrutinib: 
x 
Please refer to guidance from the manufacturer. 

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Drug-drug interactions (DDI) may occur with some of the drugs being used as best 
supportive care (e.g., drugs that are strong inducers or inhibitors of cytochrome P450 
[CYP]3A). Guidance is provided below: 
Drug-Drug Interaction Guidance for Investigators with Subjects Enrolled in an 
Acalabrutinib Clinical Study who are COVID-19 Positive: 
x 
The potential combination with chloroquine or 8-8-OH-chloroquine (8-OH-CHQ) 
and azithromycin are not predicted to have a pharmacokinetic DDI with 
acalabrutinib.  However, both agents are known to cause cardiovascular risk of 
QT-prolongation.  Therefore, the risk/benefit of initiating 8-OH-CHQ + 
azithromycin should be discussed with the medical monitor.  
x 
Many antivirals and antibiotics are considered strong CYP3A4 inhibitors or 
inducers and are therefore likely to cause complex DDIs with acalabrutinib.  The 
risk-benefit balance of acalabrutinib use in the setting of COVID-19 treatment 
should be discussed between the investigator and the medical monitor.  
x 
Remdesivir is rapidly metabolized to a pharmacologically active metabolite, 
GS-443902.  Based on published and publicly available data, remdesivir does 
not appear to inhibit CYP isoforms and will likely not interact in a meaningful way 
with drug transport systems.  Remdesivir does not prolong QTc interval.  
x 
Systemic steroids and acalabrutinib may impair the ability of the body to fight 
infection; it is best to avoid high-dose systemic steroids while taking 
acalabrutinib. 
x 
The study protocol and investigator brochure should be referenced for other DDI 
information. 
COVID-19 Specific Data Entry Instructions for Investigational Sites 
Adverse Event Recording: 
Currently no changes to normal data capture procedures are required for COVID-19 
data in the eCRF.  For subjects who have confirmed or who are suspected of having 
coronavirus infection, the infection should be documented as an AE or serious adverse 
event (SAE), in line with instructions for safety reporting documented in the clinical study 

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protocol.  Either “COVID-19 Confirmed” or “COVID-19 Suspected” should be used 
when reporting the event as follows: 
x 
If test is positive, “COVID-19 confirmed” should be recorded in the AE field. 
x 
If test is negative, AE/SAE signs and symptoms and/or other diagnosis should be 
recorded in the AE field(s). 
x 
If test is not available and signs and symptoms, as judged by the investigator, are 
highly suspicious of COVID-19 infection, record “COVID-19 suspected” in the AE 
field. 
Details of any testing or procedure to determine the status of COVID-19 infection should 
be documented on the Concomitant Procedure Form if available or on the appropriate 
eCRF page in the study. 
For fatal SAEs, the Death Information Form, End of Study Treatment Form, and Study 
Exit Form should be completed. 
Study Treatment Recording: 
If an AE or SAE is associated with COVID-19, the investigator should determine whether 
the subject’s treatment with investigational product should continue, be interrupted, or be 
discontinued in accordance with the clinical study protocol. 
For dosing interruptions, where applicable, the following guidelines should be used: 
Related to AE:  
x 
On the Dose Administration Forms(s), dose change/missed should be indicated 
with AE as the reason. The dosing stop date must correlate to the AE/SAE 
start/stop dates. 
Related to Logistics:  
x 
For subjects who have missed a study treatment due to an inability to travel to 
the clinic or for some other logistical reason, on the Dose Administration Form(s) 
dose change/missed should be indicated with Other as the reason, and “Logistic” 
as Other, Specify. 
If these options are not available in the eCRF, then either dose discontinuation should 
be recorded (if permanently stopped) or a protocol deviation should be recorded, 
prefixed COVID19. 

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For dosing discontinuations, where applicable, the dosing discontinuation guidelines 
should be followed, and the End of Treatment Form(s) completed. 
Capturing telephone contacts with subjects: 
If a telephone visit is substituted for an onsite study visit, the following are guidelines for 
data capture: 
1. If the visit is specified as a phone visit as per protocol, no additional action is 
required. 
2. If the visit is listed as on-site but the subject will be contacted by phone, data 
should be completed as per a normal visit (i.e., using the relevant eCRF pages to 
capture a phone Visit Date, and any possible assessment that can be obtained 
remotely should be captured, such as AEs, study drug administration and/or 
concomitant medications, and any additional safety information).  All 
assessments that cannot be performed should be marked as not done or eCRF 
inactivated/marked Blank.  A protocol deviation should be recorded in the clinic 
notes prefixed COVID19 detailing the use of a phone visit in place of an onsite 
visit. 
3. If the visit requires procedures which cannot be performed via telephone contact 
(e.g., MRI or CT Scan), this should be discussed with the site monitor because 
this procedure may impact primary efficacy or safety analyses. 
 
Acalabrutinib Site-to-Subject Drug Shipment Instructions During Pandemic Containment 
or in Case of Force Majeure 
If a subject is definitively unable to physically go to the study site or unable to be 
represented by a third person because of pandemic containment or other force majeure, 
the study site's pharmacy may ship the study drug to the home of the subject following 
approval by the sponsor. 
For such a shipment, the following conditions must be met: 

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x 
The sponsor is responsible for delivery of the study drug to the study site. Any 
shipments made from the site to the subject will be the responsibility of the study 
site. 
x 
The subject is informed about the shipment method, confirms the address for 
receipt of the drug, and agrees that his or her personal information (i.e., name 
and address) may be given to a professional carrier. 
x 
The pharmacy securely packages the drug for shipment. 
x 
A professional carrier is used by the pharmacy to ship the drug securely and 
maintain chain of custody, with evidence provided. Acalabrutinib must be stored 
and shipped at room temperature (15°C to 30°C). The professional carrier must 
ensure that temperature monitoring is conducted for all shipments. 
x 
To respect patient confidentiality, the carrier should only be given the name and 
address of the subject. The sponsor should not receive any personal information 
about the patient. 
x 
A procedure is defined with the carrier to confirm the receipt of the drug by the 
subject and that it is received in good condition. 
x 
The site contacts the subject to confirm the receipt and integrity of the drug and 
gives instructions about the drug administration. 
x 
The pharmacy completes its accountability with each shipment made directly to a 
subject. 
 

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: ace-cl-309-csp-amend-8
Document Title:
ACE-CL-309 Clinical Protocol Amendment 8 Global
Document ID:
Doc ID-004368267
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
02-Jun-2021 02:13 UTC
Content Approval
28-May-2021 08:03 UTC
Management Approval
02-Jun-2021 02:14 UTC
Management Approval
28-May-2021 17:47 UTC
Management Approval
01-Jun-2021 19:53 UTC
Management Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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