Conditions: Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL)
Keywords: Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL) Phase II Acalabrutinib Rituximab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
The main purpose of this research study is to find out if the combination of acalabrutinib and high frequency low dose subcutaneous rituximab is safe and effective in patients who have previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Detailed description:
Despite an array of available therapies, CLL remains an incurable disease. Furthermore, the presence of certain cytogenetic abnormalities and high-risk mutational features predicts for a reduced response to treatment, and as a result, a shorter period of progression-free survival. The development of a well-tolerated more effective, easily administered and limited duration therapy would be a major contribution to the management of CLL and other B cell malignancies.

Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in vitro and in vivo. Acalabrutinib shows improved selectivity for BTK compared with ibrutinib. Functional inhibition of non-target cells (eg, T cells, NK cells, platelets) was not observed for acalabrutinib at clinically relevant concentrations. Rituximab is a chimeric monoclonal antibody targeting CD20 FDA approved for the treatment of CLL/SLL using intravenous or subcutaneous formulations.

Antibody dependent cellular phagocytosis may be optimized using high frequency subcutaneous administration of anti-CD20 monoclonal antibodies. Unlike ibrutinib, acalabrutinib does not cause significant in vitro inhibition of rituximab induced antibody dependent cellular phagocytosis in vitro. The investigator thus proposes that acalabrutinib would be an ideal partner drug with high frequency low dose SQ rituximab in the treatment of CLL and that the combination will increase the efficacy of therapy for CLL patients by decreasing the time to achievement of complete response and allowing for shorter and less toxic therapy.

Arms:
arm 1: Rituximab: administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, Then 50 mg SQ thereafter.

Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1.

* Patients who have attained a complete response who are also MRD negative at cycle 12 will undergo a BM biopsy to confirm CR and MRD negatively. If confirmed, the patient will stop therapy and be followed until disease progression.
* Patients not in a MRD negative CR, will continue acalabrutinib.
* Repeat response assessments (CTs, MRD testing in blood) will be performed at 24 cycles of therapy for those continuing on acalabrutinib. If both negative the patient will undergo a BM biopsy to confirm CR and MRD negativity. If confirmed, the patient will stop therapy and be followed until disease progression. In the absence of a CR or if MRD +, acalabrutinib may be continued until disease progression, unacceptable toxicity or physician/patient discretion.

Interventions: intervention 1: Acalabrutinib intervention 2: Rituximab
Intervention descriptions: intervention 1: 100 mg by mouth twice a day starting on day 8 of cycle 1 intervention 2: Administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, then 50 mg SQ thereafter.

Protocol document:
Prot_SAP_000.pdf: 
Acalabrutinib + low dose SQ Rituximab 
 
Dated: 06OCT2022  
 
 
Page 1 of 59 
NCT03788291 
Protocol version/Date: 06OCT2022  
 
Protocol #: ULYM18086 
 
 
TITLE: Phase II study of acalabrutinib and high frequency low dose subcutaneous rituximab in 
patients with previously untreated CLL/SLL  
 
Study Chair: 
  
 
Paul M. Barr, MD 
 
 
 
 
University of Rochester 
 
 
 
 
601 Elmwood Ave, Box 704 
 
 
 
 
Rochester NY 14642  
 
IND Number: 
 
 
Acalabrutinib:    
 
 
 
 
Rituximab: FDA Approved 
 
Statistician:  
 
 
Andrea Baran, M.S. 
 
Sub-Investigators:  
 
Clive Zent, MD 
 
 
 
 
Carla Casulo, MD 
 
 
 
 
Jonathan Friedberg, MD 
 
 
 
 
Patrick Reagan, MD 
 
 
 
 
Jane Liesveld, MD 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
This document is a confidential communication of the University of Rochester. Acceptance of 
this document constitutes agreement by the recipient that no unpublished information 
contained herein shall be published or disclosed without prior written approval, except that this 
document may be disclosed to the appropriate Institutional Review Boards/ Independent Ethics 
Committees under the condition that they keep it confidential. 
 
 


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 TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................... 6 
1 . INTRODUCTION .............................................................................................................. 12 
1.1 CLL ..................................................................................................................................................... 12 
1.2 B-CELL RECEPTOR SIGNALING ........................................................................................................ 12 
1.3 BTK inhibition in Lymphoid Malignancies ......................................................................................... 13 
1.4 Acalabrutinib (ACP-196) .................................................................................................................... 13 
1.5 High frequency low dose SQ rituximab in CLL .................................................................................. 14 
1.6 Hypothesis ......................................................................................................................................... 15 
2 OBJECTIVES AND ENDPOINTS ............................................................................................ 17 
2.1 Primary Objective .............................................................................................................................. 17 
2.2 Secondary Objectives ........................................................................................................................ 17 
2.3 Exploratory Objectives ...................................................................................................................... 17 
3 ELIGIBILITY CRITERIA ......................................................................................................... 18 
3.1 Inclusion Criteria ............................................................................................................................... 18 
3.2 Exclusion Criteria ............................................................................................................................... 19 
4 Study Design ..................................................................................................................... 21 
4.1 Overview of Study Design ................................................................................................................. 21 
4.2 Registration ....................................................................................................................................... 21 
4.3 Discontinuation from Study Treatment ............................................................................................ 21 
4.4 Criteria for Study termination ........................................................................................................... 22 
5 STUDY ASSESSMENTS AND TREATMENT SCHEDULE ........................................................... 23 
6 Agent Administration ....................................................................................................... 24 
6.1 Guidelines for Rituximab ................................................................................................................... 24 
6.1.1 Dose Preparation and Administration of Rituximab: Intravenous .................................................................................... 25 
6.1.2 Dose Preparation and Administration of Rituximab: Subcutaneous ................................................................................. 26 
6.1.3 Infusion Related Reactions and Infusion Rate Guidance – Rituximab ............................................................................... 27 
6.2 Guidelines for Administration of Acalabrutinib ................................................................................ 28 
6.2.1 Dispensing of acalabrutinib ............................................................................................................................................... 30 
7 Dose Delays/Dose Modifications ....................................................................................... 32 
7.1 Rituximab .......................................................................................................................................... 32 
7.2 Study Drug Modifications ................................................................................................................. 32 
7.2.1 Discontinuation Criteria .................................................................................................................................................... 34 


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7.2.2 Criteria for Ongoing Treatment ......................................................................................................................................... 34 
7.3 Concomitant Medications ................................................................................................................. 34 
7.4 Ordering Rituximab and acalabrutinib .............................................................................................. 35 
8 MEASUREMENT OF EFFECT ............................................................................................... 36 
8.1 Method of Assessment ..................................................................................................................... 36 
8.2 Identification and Measurement of Tumor Lesions and Organomegaly .......................................... 36 
8.2.1 Target Lesions ................................................................................................................................................................... 36 
8.2.2 SPLEEN AND LIVER ............................................................................................................................................................ 37 
8.2.3 Non-Target Lesions ........................................................................................................................................................... 37 
8.3 Definitions of Tumor Response and Progression .............................................................................. 38 
8.4 Complete Response .......................................................................................................................... 38 
8.5 Partial Response ................................................................................................................................ 38 
8.6 Stable Disease ................................................................................................................................... 39 
8.7 Definitive Disease Progression .......................................................................................................... 39 
8.8 Non-Evaluable ................................................................................................................................... 40 
8.9 Lymphocytosis During Therapy ......................................................................................................... 40 
9 STATISTICAL CONSIDERATIONS ......................................................................................... 42 
9.1 Design ................................................................................................................................................ 42 
9.2 Patient Disposition ............................................................................................................................ 42 
9.3 Patient Demographics and Baseline Characteristics ......................................................................... 42 
9.4 Extent of Exposure ............................................................................................................................ 42 
9.5 Efficacy Analyses ............................................................................................................................... 42 
9.6 Statistical Analyses ............................................................................................................................ 42 
10 SAFETY REPORTING......................................................................................................... 44 
10.1 Definition of Adverse Events ........................................................................................................... 44 
10.2 Serious Adverse Events (SAE) .......................................................................................................... 44 
10.3 Expectedness of Adverse Events ..................................................................................................... 45 
10.4 Attribution of Adverse Events ......................................................................................................... 45 
10.5 Recording/Reporting Adverse Events ............................................................................................. 45 
11 CLINICAL DATA COLLECTION ............................................................................................ 49 
11.1 Amendments to the Protocol ......................................................................................................... 49 
11.2 Financial Disclosures and Ethical Considerations ........................................................................... 49 
11.3 IRB and Regulatory approval........................................................................................................... 49 
11.4 Informed Consent ........................................................................................................................... 49 
11.5 Confidentiality ................................................................................................................................. 50 


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11.6 Study Documentation and Storage ................................................................................................. 51 
11.7 Data Collection and Safety .............................................................................................................. 52 
11.8 Publication Policy ............................................................................................................................ 52 
12 Planned correlative analyses ........................................................................................... 53 
13 REFERENCES ................................................................................................................... 55 
Appendix 1.  Known Strong in Vivo Inhibitors or Inducers of CYP3A...................................... 57 
Appendix 2.  Grading scale for hematologic toxicity in CLL studies ........................................ 58 
Appendix 3.  Highly effective methods of contraception ...................................................... 59 
 
 
 
 
 


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A M E N D M E N T S  
 
Version 2.0 (Dated 06 October 2022) of this Protocol is the first amendment to this 
clinical trial and contains the following modifications: 
• The formulation of acalabrutinib has changed. The tablet formulation will be used in all 
paitents going foward; 
• The previous version included peripheral blood sample collection in a 10ml purple top tube 
for lymphocytes, on D1 of cycles 3, 6, 9, 12, 15, 18, 21, 24. This has been changed to 3, 6, 
9, 12, 16, 18, 22, 25 (+/- 4 weeks) to align with patient visits and include flexibility for these 
correlative studies 
• Response assessments are clarified. Following cycles 12 and 24, patients who have 
attained a radiographic complete response will undergo a BM biopsy to confirm CR.  
Patients in CR will also have MRD testing performed on peripheral blood and marrow. 
Patients in CR and undetectable for MRD, will stop therapy and be followed until disease 
progression. Patients not in a MRD negative CR, will continue acalabrutinib. 
• Patient assessments following cycle 24 are clarified. After this point, patients will be 
evaluated as per institutional standards (typically every 3-4 months). Physical exam data, 
vital signs, laboratory values and patient diaries will no longer be collected. Patients 
continuing on acalabrutinib will continue with adverse event assessments at each 
evaluation and be followed for progression and survival events. 


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STUDY SYNOPSIS 
 
Protocol no. 
 
Study Title 
Phase II study of acalabrutinib and high frequency low dose subcutaneous 
rituximab in patients with previously untreated CLL/SLL 
Principle 
Investigator and 
Study Chair 
Paul M. Barr, MD 
Wilmot Cancer Institute, University of Rochester, Rochester NY USA 
Study Site & 
Enrollment 
University of Rochester Medical Center 
40 evaluable patients 
Study Rationale 
Despite an array of available therapies, CLL/SLL remains an incurable disease.  
Furthermore, the presence of certain cytogenetic abnormalities and high-risk 
mutational features predicts for a reduced response to treatment, and as a 
result, a shorter period of progression-free survival.  The development of a 
well-tolerated more effective, easily administered and limited duration 
therapy would be a major contribution to the management of CLL and other B 
cell malignancies.   
 
Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in 
vitro and in vivo. Acalabrutinib shows improved selectivity for BTK compared 
with ibrutinib.  Functional inhibition of non-target cells (eg, T cells, NK cells, 
platelets) was not observed for acalabrutinib at clinically relevant 
concentrations. Rituximab is a chimeric monoclonal antibody targeting CD20 
FDA approved for the treatment of CLL/SLL using intravenous or subcutaneous 
formulations. 
 
Antibody dependent cellular phagocytosis may be optimized using high 
frequency subcutaneous administration of anti-CD20 monoclonal antibodies. 
Unlike ibrutinib, acalabrutinib does not cause significant in vitro inhibition of 
rituximab induced antibody dependent cellular phagocytosis in vitro. We thus 
propose that acalabrutinib would be an ideal partner drug with high frequency 
low dose SQ rituximab in the treatment of CLL and that the combination will 
increase the efficacy of therapy for CLL patients by decreasing the time to 
achievement of complete response and allowing for shorter and less toxic 
therapy.  


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Study Objectives 
Primary objective: 
• 
Define the clinical efficacy as defined by complete remission rate of 
acalabrutinib and high frequency low dose subcutaneous rituximab in 
patients with previously untreated CLL/SLL 
 
Secondary objectives:  
• 
Describe the rate of minimal residual disease (MRD) negativity using 6-
color flow cytometry. 
• 
Define the progression free survival and duration of response in patients 
treated with the combination. 
• 
Determine the safety of acalabrutinib and high frequency low dose 
subcutaneous rituximab in this population. 
Exploratory objectives:  
• 
Determine the effect of high frequency low dose SQ rituximab on circulating 
CLL cell CD20 expression before and after the addition of acalabrutinib. 
• 
Determine the effects of in vivo exposure of circulating target and effector 
cells to acalabrutinib on subsequent in vitro anti-CD20 mAb induced ADCP, 
ADCC and CDC. 
• 
Determine the effect of treatment with acalabrutinib and HFLD SQ 
rituximab on T, B, NK and monocyte immunophenotypes in CLL/SLL patients 
 
Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for 
participation in this study: 
1. Diagnosis of B-cell CLL or SLL, with diagnosis established according to IWCLL 
criteria and documented within medical records. Patients must not have 
received previous CLL/SLL directed therapy 
2. CLL/SLL that warrants treatment consistent with accepted IWCLL criteria for 
initiation of therapy. Any one of the following conditions constitute CLL/SLL 
that warrants treatment:  
a) Evidence of progressive marrow failure as manifested by the onset or 
worsening of anemia and/or thrombocytopenia, or 
b) Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin), 
progressive, or symptomatic splenomegaly, or 
c) Massive (i.e., ≥10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or  
d) Progressive lymphocytosis in the absence of infection, with an increase 
in blood absolute lymphocyte count (ALC) ≥50% over a 2-month period 
or lymphocyte doubling time of <6 months (as long as initial ALC was 
≥30,000/L), or 
e) Autoimmune anemia and/or thrombocytopenia that is poorly 
responsive to corticosteroids or other standard therapy, or 
f) Constitutional symptoms, defined as any one or more of the following 
disease-related symptoms or signs occurring in the absence of evidence 
of infection: 


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i. 
Unintentional weight loss of ≥10% within the previous 6 
months, or 
ii. 
Significant fatigue (≥Grade 2), or 
iii. 
Fevers >100.5°F or 38.0°C for ≥2 weeks, or 
iv. 
Drenching night sweats for >1 month.  
3. Adequate organ system function, defined as follows: 
a) Absolute neutrophil count (ANC) ≥ 0.5 x109/L and platelet count ≥ 
30x109/L 
b) Total bilirubin ≤2.5 times the upper limit of normal (ULN), unless due to 
Gilbert’s disease 
c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 x ULN if no liver involvement or ≤5 x the ULN if known liver 
involvement 
d) Calculated creatinine clearance >30mL/min (as calculated by the 
Cockcroft-Gault formula) 
e) Patients with PT/INR or aPTT ≤ 2xULN. 
4. ECOG performance status ≤ 2, or ≤ 3 if related to CLL. 
5. Male or female ≥ 18 years of age. 
6. Ability to swallow and retain oral medication. 
7. Woman of childbearing potential (WOCBP) who are sexually active must use 
highly effective methods of contraception during treatment and for 2 days 
after the last dose of acalabrutinib and for 12 months following last dose of 
rituximab.  (see Appendix 3 for examples) 
8. Willingness and ability to comply with study and follow-up procedures and 
give written informed consent. 
Exclusion Criteria 
Patients who meet any of the following exclusion criteria are not to be 
enrolled to this study: 
1. Patients receiving cancer therapy  
a. Systemic corticosteroid therapy started prior to study entry is 
allowed as clinically warranted.  Topical or inhaled corticosteroids 
are permitted. 
2. Serologic status reflecting active hepatitis B or C infection. Patients who 
are hepatitis B core antibody (anti-HBc) positive and who are surface 
antigen negative will need to have a negative polymerase chain reaction 
(PCR).  Those who are hepatitis B surface antigen (HbsAg) positive or 
hepatitis B PCR positive will be excluded.  Subjects who are hepatitis C 
antibody positive will need to have a negative PCR result.  Those who are 
hepatitis C PCR positive will be excluded. 
3. Known history of HIV. 
4. Known histological transformation from CLL to an aggressive lymphoma. 
5. Evidence of ongoing systemic bacterial, fungal or viral infection, except 
localized fungal infections of skin or nails. NOTE: Patients may be receiving 
prophylactic antiviral or antibacterial therapies at investigator discretion. 
6. Live virus vaccines within 4 weeks prior to C1D1 or during rituximab 
therapy. 
7. History of anaphylaxis (excluding infusion related reactions) in association 
with previous anti-CD20 administration or acalabrutinib. 


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8. Any severe and/or uncontrolled medical conditions or other conditions 
that could affect their participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure 
(NY Heart Association functional classification III-IV) 
b. Uncontrolled cardiac arrhythmia (Patients with controlled atrial 
fibrillation/flutter are eligible) 
c. Myocardial infarction within 3 months of enrollment 
d. Angina not well-controlled by medication 
e. Poorly controlled or clinically significant atherosclerotic vascular 
disease including cerebrovascular accident (CVA), transient 
ischemic attack (TIA), angioplasty, cardiac/vascular stenting within 
3 months of enrollment.  
f. Active bleeding or history of bleeding diathesis (eg, hemophilia or 
von Willebrand disease).  
g. Any history of intracranial bleed or stroke within 6 months of first 
dose of study drug  
h. Patients with suspected or confirmed PML  
i. 
Patients with malabsorption syndrome or gastrointestinal disease 
that limits absorption of oral medication 
9. Malignancy within 2 years of study enrollment except for adequately 
treated basal, squamous cell carcinoma or non-melanomatous skin cancer, 
carcinoma in situ of the cervix, superficial bladder cancer not treated with 
intravesical chemotherapy or BCG within 6 months, localized prostate 
cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 
months apart with the most recent one being within 4 weeks of study 
entry. 
10. Patients with active uncontrolled autoimmune hemolytic anemia or ITP. 
11. Inability to discontinue use of strong CYP3A inhibitors. Patients taking 
moderate CYP3A inhibitors or strong CYP3A inducers are eligible.  
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (eg, phenprocoumon) within 7 days of first dose of study drug. 
13. Requires treatment with proton pump inhibitors (eg, omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or 
pantoprazole) at study entry.  Subjects receiving proton pump inhibitors 
who switch to H2-receptor antagonists or antacids are eligible for 
enrollment to this study. 
14. Women who are pregnant or breastfeeding. 
Efficacy Endpoints 
The primary objective of the study is to determine the efficacy of acalabrutinib 
and subcutaneous rituximab as defined by complete response rate at 1 year of 
therapy. The complete response rate will be presented with an associated 95% 
two-sided exact binomial confidence interval. 
 
Study Design 
Single center, open label, Phase II trial of acalabrutinib and high frequency low 
dose subcutaneous rituximab in previously untreated CLL patients requiring 
therapy. 


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Premedication  
 
Pre-medicate patients approximately 30 minutes prior to the first dose of 
rituximab (administered IV) and second dose of rituximab (administered 
subcutaneously) with acetaminophen 650 mg (or equivalent), an antihistamine 
(diphenhydramine 50 mg or equivalent). Premedications will be optional prior 
to subsequent subcutaneous doses. Use of anti-pneumocystis (PJP) and 
antiviral prophylaxis is optional.  
Dosing  
Regimen & 
Treatment  
Study Visits 
All cycles will be 28 days. 
Rituximab: administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg 
IV, Then 50 mg SQ thereafter. 
Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1. First dose prior to 
rituximab on day 8. 
• 
Response assessments will be performed prior to the completion of 
cycle 12.  Patients who have attained a radiographic complete 
response will undergo a BM biopsy to confirm CR.  Patients in CR will 
also have MRD testing performed on peripheral blood and marrow. 
Patients in CR and undetectable for MRD, will stop therapy and be 
followed until disease progression. 
• 
Patients not in a MRD negative CR, will continue acalabrutinib. 
• 
Repeat response assessments will be performed at 24 cycles of 
therapy for those continuing on acalabrutinib. Patients in CR and 
undetectable for MRD, will stop therapy and be followed until disease 
progression, .unacceptable toxicity or physician/patient discretion. 
 
SCHEMA 
 
 
 
 
 
 
*If otherwise in CR  
¥ Administered twice weekly, 1st dose of rituximab will be administered 
intravenously, subsequently doses will be administered subcutaneously    
 
 
Correlative 
Experiments 
Study labs (peripheral blood) will be collected immediately before initiation of 
the first dose of rituximab (50 mg IV), at 1 hour and at completion of the 
infusion. Peripheral blood will also be sampled immediately before and 2 
hours after the subcutaneous administration 50 mg of rituximab on days 3, 8, 
Acalabrutinib BID
Rituximab¥ 
x 6 cycles
Acalabrutinib BID x 
6 cycles
CR & MRD-
follow off therapy
No CR or MRD+
Acalabrutinib 
CT 
CT 
BM biopsy*  
MRD*  
(12 cycles) 
CT 
BM biopsy*  
MRD*  
(24 cycles) 


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and 15 of cycle 1, on day 1 of cycles 2-6 of rituximab, at 4 weeks after the 
administration of the last dose of rituximab, and then every 3 months until 24 
months after initiation of therapy (see section 12). These samples will be 
analyzed in the laboratory of Dr. Clive Zent at the University of Rochester.  
 
At the post cycle 12 and/or cycle 24 response assessment, peripheral blood 
and bone marrow samples will be analyzed for MRD  
Statistical 
Considerations 
The complete response rate will be estimated from forty enrolled subjects. An 
associated 95% two-sided confidence interval will be calculated using exact 
binomial methods. We anticipate a CR rate of 20%, which would result in a 
95% two-sided confidence interval with a width of 26.6% (from 9.1% to 35.6%) 
for a sample size of 40 subjects. 
 
 
 
 


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1 . INTRODUCTION 
1.1 CLL/SLL 
In the US, an estimated 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be reported for 
2016 with deaths totaling 4,660 due to the disease according to American Cancer Society estimates 
(American Cancer Society, 2016). Small lymphocytic lymphoma (SLL) is same disease as CLL, 
predominantly affecting the nodal compartment whereas the bone marrow and peripheral blood have a 
higher degree of disease involvement in CLL. CLL affects mainly older adults and is characterized by the 
accumulation of clonal mature B lymphocytes in the blood, bone marrow, and secondary lymphoid 
tissues. CLL is a heterogeneous disease, with several higher risk cytogenetic abnormalities which are 
generally more difficult to treat, including 17p deletion, TP53 gene mutation, and 11q deletion. [1] 
Chemotherapy regimens in combination with monoclonal antibody therapy have historically comprised 
the standard of care for patients with CLL.  Frontline therapy for patients with CLL had consisted of the 
anti-CD20 monoclonal antibody rituximab, in combination with either fludarabine and 
cyclophosphamide, or bendamustine.  Depending on the age and comorbidities of the patient, 
chlorambucil in combination with an anti-CD20 monoclonal antibody is also considered.  In addition to 
rituximab, other anti-CD20 antibodies have also been approved for the treatment of CLL, including 
ofatumumab and obinutuzumab. [2-4] Recently the BTK inhibitor, ibrutinib was approved by the FDA for 
the treatment of patients with CLL in the relapsed or refractory setting or more recently as first-line 
therapy. [5, 6] 
Despite these advancements, CLL remains an incurable disease, and many patients will progress and 
eventually die from their disease or the complications of its therapies such as infection.  Furthermore, 
patients with higher risk cytogenetic abnormalities still present with a less than optimal response to 
approved therapies and shorter duration of response and progression free survival.  As such, there is a 
pressing need for new, innovative, targeted therapies (and novel combinations of these therapies) for 
the treatment of patients with relapsed/refractory CLL. Despite this progress treatment of CLL remains 
suboptimal. Patients do not recover immune competency resulting in complications including infections, 
second malignancies, and autoimmune cytopenias. Currently therapies using B cell receptor pathway 
inhibitors are continued until disease progression or intolerance. About 30% of patients stop therapy 
because of adverse events and a smaller percentage stop because of disease progression.[7] The 
development of a well-tolerated more effective, easily administered and limited duration therapy 
combining a specifically targeted BTK inhibitor and an anti-CD20 mAb would be a major contribution to 
the management of CLL and other B cell malignancies.   
 
1.2 B-CELL RECEPTOR SIGNALING 
Since its discovery, the biological role of the BCR signal transduction pathway has been described, 
including the respective functions of BCR itself, several other tyrosine kinases, tyrosine phosphatases, 
adaptor molecules, lipid-modifying enzymes, modular binding domains, and transcription factors. [8] 
Together, the components of the BCR signaling pathway tell the eloquent story of a signaling cascade 
starting at the level of the BCR and resulting in the activation/modulation of an array of diverse 
intracellular signaling pathways responsible for mounting an effective humoral response by the BCR-
activated B cells. It is now widely accepted that BCR signaling is an important contributor to malignant 
transformation of B lymphocytes. In CLL, there is mounting evidence to support the role of BCR signaling 
as a central component of the oncogenic process. [9] Overall, the accumulated evidence suggests that 


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CLL has powerful addiction to BCR signaling and, hence, supports the concept of BCR signal inhibition as 
a novel treatment approach.  
 
1.3 BTK INHIBITION IN LYMPHOID MALIGNANCIES 
Bruton tyrosine kinase (BTK) is a non-receptor enzyme in the Tec kinase family that is expressed among 
cells of hematopoietic origin, including B-cells, myeloid cells, mast cells, and platelets, where it regulates 
multiple cellular processes including proliferation, differentiation, apoptosis, and cell migration.[10, 11]  
In addition, BTK-dependent activation of mast cells, myeloid cells, and other immunocytes in 
peritumoral inflammatory stroma has been shown to sustain the complex microenvironment needed for 
lymphoid and solid tumors.[12, 13]  Taken together, these findings suggested inhibition of BTK offered 
an attractive strategy for treating B-cell neoplasms. 
1.4 ACALABRUTINIB (ACP-196) 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  The compound 
has 1 stereogenic center and acalabrutinib is the S-enantiomer.  Acalabrutinib is a potent inhibitor of 
BTK in vitro and in vivo and is approved in the US for the treatment of adult patients with MCL who have 
received at least 1 prior therapy.  Pharmacology models have been used to define kinase selectivity of 
acalabrutinib in comparison to other BTK inhibitors, and to investigate functional effects of on-target 
and off-target activities.  Acalabrutinib shows improved selectivity for BTK and does not appreciably 
inhibit non-BTK TEC family kinases, compared with ibrutinib.[14]  Functional inhibition of non-target 
cells (eg, T cells, NK cells, platelets) was not observed for acalabrutinib at clinically relevant 
concentrations. As such, acalabrutinib does not cause significant in vitro inhibition of rituximab induced 
ADCP in vitro (unpublished data from the Zent lab).  We thus propose that acalabrutinib would be an 
ideal partner drug with high frequency low dose SQ rituximab in the treatment of CLL. 
 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a favorable 
nonclinical safety profile. The systemic toxicity of acalabrutinib has been investigated in 6 repeat-dose 
toxicology studies. The NOAEL in the dog was 30 mg/kg/day, which was the highest dose evaluated. 
Pharmacokinetic and pharmacodynamics studies have been conducted in healthy volunteers 
investigating dose-ranging, food-effect, and drug-drug interactions of acalabrutinib dosing for 1 or 2 
days. Minimal low-grade side effects were noted. Median plasma Tmax values were increased in the fed 
state (2.5 hours) relative to the fasted state (0.5 hour). The mean plasma ACP-196 Cmax values 
decreased to 27.3% of the values observed in the fasted state. In contrast, the relative exposure of ACP-
196 (AUC) remained mostly unchanged in both states. The effect of coadministration of a potent 
CYP3A4 inhibitor, itraconazole, on the plasma levels of ACP-196 was also evaluated. The mean plasma 
ACP-196 Cmax values increased 3.7-fold in the presence of itraconazole. The mean plasma AUC0-last, 
AUC0-24, and AUC0-inf values also increased between 4.9- to 5.1-fold in the presence of itraconazole. 
Mean CL/F and Vz/F values decreased in the presence of itraconazole. Additionally, administration of 
the gastric pH modifiers, calcium carbonate or omeprazole, decreased mean Cmax to 25% and 21% and 
AUC to 47% and 43%, respectively, of values obtained with ACP-196 dosed alone. Rifampin dosed at 600 
mg QD for 9 days decreased AUC to 23% of values obtained with ACP-196 dosed alone. 
 
In August of 2022, AstraZeneca informed all sponsors that the new tablet formation of acalabrutinib 
would be used in the future. The tablets consist of acalabrutinib maleate, a salt form of acalabrutinib 
freebase that is used in capsules, and delivers an equivalent dose of acalabrutinib compared to the 


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capsules (100mg). Therefore, the tablets can be switched directly for capsules on a 1:1 basis. This new 
tablet formulation was developed to overcome the interactions between acalabrutinib capsules and acid 
reducing agents (ARAs). Acalabrutinib tablets can be co-administered with all acid reducing agents 
(proton pump inhibitors, H2-receptor antagonists, antacids). Since the formulations are bioequivalent, 
the same safety and efficacy can be expected, with the added benefit for patients who require co-
treatment with PPIs now able to be taking acalabrutinib. 
 
Clinical experience with acalabrutinib has included >3000 trial participants to date, justifying current 
FDA approval of acalabrutinib 100 mg po bid for patients with relapsed mantle cell lymphoma. 
Regarding CLL/SLL, clinical efficacy results are available for a subset of subjects with relapsed CLL. [14] 
One hundred thirty-four subjects were sequentially enrolled and continuously treated with acalabrutinib 
100 to 400 mg once daily in the dose-escalation portion of the study, and 100 mg twice daily in the 
expansion portion. Clinical activity of acalabrutinib was robust. The ORR, including PR and PRL, was 
96.9% based on the efficacy evaluable population. The rate of progression-free survival at 12 months 
and 18 months was 95.4% and 89.6%, respectively. Subjects could be enrolled in the treatment-naive 
subgroup if they did not want to receive chemoimmunotherapy or if they had comorbidities that would 
have precluded chemoimmunotherapy. A total of 99 subjects were treated in the treatment-naive 
subgroup with a median time on study for this population of 24.8 months. The ORR, including PR and 
PRL, was 99.0% based on the efficacy evaluable population. The rate of PFS was 99% at both 12 and 18 
months. 
 
An aggregate safety analysis of acalabrutinib monotherapy was conducted in order to assess safety for 
acalabrutinib-exposed subjects with hematologic malignancies without confounding toxicity from 
combination therapy drugs. The analysis was performed on a 7-study integrated monotherapy 
population. The most commonly reported AEs of any grade were headache (42.3%), diarrhea (40.4%), 
fatigue (24.6%), nausea (23.6%), contusion (23.5%), cough (22.1%), and upper respiratory tract infection 
(21.7). The most frequently reported Grade ≥3 AEs were neutropenia (10.4%), anemia (7.5%), 
pneumonia (6.5%), thrombocytopenia (3.7%), and hypertension (3.1%). Grade 5 AEs were reported for 
27 (4.4%) subjects in the monotherapy population. Of these 27 subjects, 13 (2.1%) subjects had an 
infection event, including 6 (1.0%) subjects with Grade 5 pneumonia, which was the only Grade 5 event 
reported for more than 1 subject. The remaining reported Grade 5 infection events include Aspergillus 
infection, brain abscess, Candida sepsis, lower respiratory tract infection, lung infection, sepsis, and 
septic shock. 
 
Safety data is available combining acalabrutinib with anti-CD20 therapy as well. A phase 1b study of 
acalabrutinib with obinutuzumab in patients with relapsed as well as previously untreated CLL has 
enrolled 45 patients to date. (acalabrutinib investigator brochure 7.1) The most frequently reported 
adverse events were upper respiratory tract infection (68.9%), weight increased (64.4%), diarrhea 
(62.2%), rash maculopapular (62.2%), cough (55.6%), nausea (51.1%), headache (44.4%), infusion related 
reaction (44.4%), contusion (42.2%), dizziness (40.0%), vomiting (40.0%), arthralgia, constipation, 
hypertension, and skin lesion (37.8% each), fatigue (35.6%), decreased appetite, edema peripheral, and 
sinusitis (33.3% each), fall and oral pain (31.1% each), myalgia (28.9%), and dyspepsia and paresthesia 
(26.7% each). The most frequently reported Grade ≥3 AEs were neutrophil count decreased in 11 
(24.4%) subjects, platelet count decreased and syncope in 4 (8.9%) subjects each, and weight increased 
in 3 (6.7%) subjects. There were no Grade 5 (fatal) AEs reported.  
 
1.5 HIGH FREQUENCY LOW DOSE SQ RITUXIMAB IN CLL 


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Unconjugated anti-CD20 mAb are effective and tolerable therapy for CLL and other B cell malignancies 
but rarely achieve complete remission as single agents and are not curative. Anti-CD20 mAb primary kills 
B cells by activating the innate immune system i.e. cell mediated cytotoxicity and complement 
dependent cytotoxicity (CDC). There is appreciable in vivo murine and in vivo primary human cell data 
showing that the primary mechanism of removal of opsonized B cells in the circulation is phagocytosis 
by fixed macrophages in the liver (Kupffer cells) and spleen. [15-23](and unpublished data from Zent lab) 
The mechanism of cellular cytotoxicity in malignant lymphoid tissue is less well understood but could 
involve activation of tumor associated macrophages that converts them from supportive to cytotoxic 
cells. NK cell mediated ADCC has a limited capacity to kill CLL cells in vitro and there is no documented 
cytotoxic role for NK cells in lymphoid tissue. In summary, most anti-CD20 mAb cytotoxicity is mediated 
by the innate immune system via CDC and macrophage ADCP.   
Mechanisms of resistance of B cells to anti-CD20 mAb therapy are not well understood. Circumstantial 
evidence suggests that treatment efficacy is limited by the finite cytotoxic capacity of the innate 
immune system. Studies of complement levels after treatment in patients with circulating B cells 
suggests that depletion of complement is not a major limitation of CDC but are not conclusive. [24, 25] 
Intrinsic resistance to activated complement system generated membrane attack complexes activated 
by anti-CD20 mAb has been demonstrated in vitro. [26, 27] There is limited data on the cytotoxic 
capacity of fixed macrophages in humans and no published data on target B cell resistance to ADCP. An 
important and well documented mechanism of acquired resistance to anti-CD20 mAb therapy is loss of 
CD20 expression by target cells by trogocytosis as recently reviewed. [28] In brief, administration of 
large doses of aCD20 mAb rapidly activates the innate immune cytotoxic mechanism followed by rapid 
loss of cell membrane CD20 (~99%) by the surviving cells. [24] Loss of CD20 occurs by trogocytosis, a 
mechanism of non-lethal removal of membrane bound immune complexes (e.g. CD20-anti-CD20 mAb) 
from target cells by effector cells including macrophages, monocytes, and neutrophils. [29] In clinical 
trials therapy with higher frequency (2-3 x week) lower (20 mg/m2) doses of rituximab did not cause 
significant loss of CD20. [30, 31] These data support further trials of high frequency low dose rituximab 
in the management of CLL and other B cell malignancies.  
Rituximab is FDA approved for the treatment of CLL based on an overall survival benefit when combined 
with standard therapy in the first line setting. [3] Subcutaneously administered rituximab is also 
approved for use in CLL based on non-inferior pharmacokinetics and comparable efficacy. [32-34] 
Additionally, in a randomized phase 3 trial comparing intravenous vs. subcutaneous rituximab, 77% of 
patients preferred subcutaneous administration. [35]  The most common adverse events (≥20%) 
observed in patients with FL include infections, neutropenia, nausea, constipation, cough, and fatigue. 
The most common adverse events (≥20%) observed in patients with DLBCL include infections, 
neutropenia, alopecia, nausea, and anemia. The most common adverse events (≥20%) observed in 
patients with CLL were infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and 
injection site erythema. 
1.6 HYPOTHESIS 
Combined BTK inhibitor and anti-CD20 mAb therapy has been shown to be safe and effective for 
treatment of CLL. [36]  The rationale for use of this combination is the disparate mechanisms of actions 
and assumed differences in tumor cell resistance to cytotoxicity of these drugs. In addition, initiation of 
therapy with BTK inhibitors frequently causes lymphocytosis by mobilizing CLL cells from lymphoid tissue 
into the circulation where they are more susceptible to mAb mediated cytotoxicity. We propose that the 
combination of a BTK inhibitor and kinetically optimized high frequency low dose rituximab therapy will 
increase the efficacy of therapy for CLL by decreasing the time of achievement of complete response 
and allowing for shorter and less toxic therapy.  


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2 OBJECTIVES AND ENDPOINTS 
2.1 PRIMARY OBJECTIVE 
• 
To define the clinical efficacy as defined by complete remission rate of acalabrutinib and high 
frequency low dose subcutaneous rituximab in patients with previously untreated CLL/SLL 
 
2.2 SECONDARY OBJECTIVES 
• 
To describe the rate of MRD negativity using 6-color flow cytometry. 
• 
To define the progression free survival and duration of response in patients treated with the 
combination. 
• 
To determine the safety of acalabrutinib and high frequency low dose subcutaneous rituximab in 
this population. 
2.3 EXPLORATORY OBJECTIVES 
• 
To determine the effect of high frequency low dose SQ rituximab on circulating CLL cell CD20 
expression before and after the addition of acalabrutinib. 
• 
To determine the effects of in vivo exposure of circulating target and effector cells to acalabrutinib 
on subsequent in vitro anti-CD20 monoclonal antibody induced ADCP, ADCC and CDC. 
• 
To determine the effect of treatment with acalabrutinib and HFLD SQ rituximab on T, B, NK and 
monocyte immunophenotypes in CLL/SLL patients 
 
Response and efficacy endpoints will be defined as per the guidelines for the diagnosis, response 
assessment and supportive management of chronic lymphocytic leukemia. [37] 


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3 ELIGIBILITY CRITERIA 
Patients must meet all of the following inclusion criteria and none of the exclusion criteria to be eligible 
for participation in this study. 
3.1 INCLUSION CRITERIA 
Patients must meet all of the following inclusion criteria to be eligible for participation in this study: 
1. Diagnosis of B-cell CLL or SLL, with diagnosis established according to IWCLL criteria and 
documented within medical records. Patients must not have received previous therapy for 
CLL/SLL  
2. CLL/SLL that warrants treatment consistent with accepted IWCLL criteria for initiation of therapy.  
Any one of the following conditions constitutes CLL/SLL that warrants treatment: 
a. Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia, or 
b. Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin), progressive, or 
symptomatic splenomegaly, or 
c. Massive (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy, or 
d. Progressive lymphocytosis in the absence of infection, with an increase in blood absolute 
lymphocyte count (ALC) ≥50% over a 2-month period or lymphocyte doubling time of <6 
months (as long as initial ALC was ≥30,000/L), or 
e. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy, or 
f. Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection: 
i. Unintentional weight loss of ≥10% within the previous 6 months, or 
ii. Significant fatigue (≥Grade 2), or 
iii. Fevers >100.5°F or 38.0°C for ≥2 weeks, or 
iv. Drenching night sweats for >1 month. 
3. Adequate organ system function, defined as follows: 
a. Absolute neutrophil count (ANC) ≥ 0.5x109/L and platelet count ≥ 30x109/L 
b. Total bilirubin ≤2.5 times the upper limit of normal (ULN) unless due to Gilbert’s disease 
c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if no 
liver involvement or ≤5 x the ULN if known liver involvement 
d. Calculated creatinine clearance >30 mL/min (as calculated by the Cockcroft-Gault 
formula) 
e. Patients with PT/INR or aPTT ≤2xULN. 
4. ECOG performance status ≤ 2 unless related to CLL. 
5. Male or female ≥ 18 years of age. 
6. Ability to swallow and retain oral medication. 


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7. Woman of childbearing potential (WOCBP) who are sexually active must use highly effective 
methods of contraception during treatment and for 2 days after the last dose of acalabrutinib and 
for 12 months following last dose of rituximab.  (see Appendix 3 for examples)   
8. Willingness and ability to comply with study and follow-up procedures, and give written informed 
consent. 
3.2 EXCLUSION CRITERIA 
Patients who meet any of the following exclusion criteria are not to be enrolled to this study: 
1.    Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, hormonal therapy, surgery). 
a. Systemic corticosteroid therapy started prior to study entry is allowed as clinically 
warranted.  Topical or inhaled corticosteroids are permitted. 
2. Serologic status reflecting active hepatitis B or C infection. Patients who are hepatitis B core 
antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative 
polymerase chain reaction (PCR).  Those who are hepatitis B surface antigen (HbsAg) positive or 
hepatitis B PCR positive will be excluded.  Subjects who are hepatitis C antibody positive will 
need to have a negative PCR result.  Those who are hepatitis C PCR positive will be excluded. 
3. Known history of HIV. 
4. Known histological transformation from CLL to an aggressive lymphoma. 
5. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized fungal 
infections of skin or nails. NOTE: Patients may be receiving prophylactic antiviral or antibacterial 
therapies at investigator discretion. 
6. Live virus vaccines within 4 weeks prior to C1D1 or during rituximab therapy. 
7. History of anaphylaxis (excluding infusion related reactions) in association with previous anti-
CD20 administration or acalabrutinib. 
8. Any severe and/or uncontrolled medical conditions or other conditions that could affect their 
participation in the study such as: 
a. Symptomatic, or history of documented congestive heart failure (NY Heart Association 
functional classification III-IV) 
b. Uncontrolled cardiac arrhythmia (Patients with controlled atrial fibrillation/flutter are 
eligible) 
c. Myocardial infarction within 3 months of enrollment 
d. Angina not well-controlled by medication 
e. Poorly controlled or clinically significant atherosclerotic vascular disease including 
cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, 
cardiac/vascular stenting within 3 months of enrollment.  
f. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand 
disease).  
g. Any history of intracranial bleed or stroke within 6 months of first dose of study drug  
h. Patients with suspected or confirmed PML  
i. 
Patients with malabsorption syndrome or gastrointestinal disease that limits absorption 
of oral medication 
9. Malignancy within 2 years of study enrollment except for adequately treated basal, squamous 
cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the cervix, superficial 
bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, localized 
prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart 
with the most recent one being within 4 weeks of study entry. 


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10. Patients with active uncontrolled autoimmune hemolytic anemia or ITP. 
11. Inability to discontinue use of strong CYP3A inhibitors. Patients taking moderate CYP3A 
inhibitors or strong CYP3A inducers are eligible. 
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, 
phenprocoumon) within 7 days of first dose of study drug. 
13. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole) at study entry.  Subjects receiving proton pump 
inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this 
study. 


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4 STUDY DESIGN 
 
4.1 OVERVIEW OF STUDY DESIGN 
This is an open label, Phase II trial of acalabrutinib and high frequency low dose subcutaneous rituximab 
in previously untreated CLL patients requiring therapy. Subjects will be recruited from the James P. 
Wilmot Cancer Center, University of Rochester in Rochester, New York. Patients seen in the inpatient or 
outpatient setting with histologically confirmed untreated CLL will be evaluated for this study. 
 
Patients will be treated with the following combination:  
Rituximab: day 1 = 50 mg IV, then 50 mg SQ 2 x weekly for 6 cycles. Note that in the event of a first dose 
infusion reaction, subsequent doses may be given IV if felt necessary by the treating investigator. 
Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1. First dose prior to rituximab on day 8. 
 
• 
Response assessments will be performed prior to the completion of cycle 12.  Patients who have 
attained a radiographic complete response will undergo a BM biopsy to confirm CR.  Patients in 
CR will also have MRD testing performed on peripheral blood and marrow. Patients in CR and 
undetectable for MRD, will stop therapy and be followed until disease progression. 
• 
Patients not in a MRD negative CR, will continue acalabrutinib. 
• 
Repeat response assessments will be performed at 24 cycles of therapy for those continuing on 
acalabrutinib. Patients in CR and undetectable for MRD, will stop therapy and be followed until 
disease progression, unacceptable toxicity or physician/patient discretion. 
 
All cycles will be 28 days. 
 
Patients will be followed until the occurrence of definitive disease progression and may discontinue 
therapy early for unacceptable toxicity or withdrawal from the study due to investigator decision or 
other reasons.  
4.2 REGISTRATION  
Patients registered to the study must sign consent after being informed of the procedures to be followed, 
the experimental nature of the treatment, potential benefits, alternatives, side-effects, risks and 
discomforts.  Patients should begin study treatment within 30 days of consent. 
4.3 DISCONTINUATION FROM STUDY TREATMENT 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
MRD negative CR or CRi at completion of cycle 12 or cycle 24  (MRD negativity is defined as <1 CLL 
cell/10,000) 
• 
Disease progression 
• 
Severe toxicity  
• 
Patient requests to withdraw consent or discontinue treatment 
• 
Pregnancy 


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• 
Inability of the patient to comply with study requirements 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Non-compliance/lost to follow-up 
• 
Investigator discretion 
• 
Study termination 
 
Patients who discontinue from study treatment (for reasons other than progressive disease) will continue 
to be followed for progression.  After withdrawal from protocol treatment, patients should be followed 
for AEs for 30 calendar days after their last dose of study drug. All new AEs occurring during this period 
must be reported and followed until resolution, unless, in the opinion of the investigator, these values are 
not likely to improve because of the underlying disease. In this case the investigators must record his or 
her reasoning for this decision in the patient’s medical records. All patients who have CTCAE Grade 3 or 4 
laboratory abnormalities at the time of withdrawal should be followed until the laboratory values have 
returned to Grade 1 or 2, unless in the opinion of the investigator, it is not likely that these values are to 
improve because of the underlying disease. In this case, the investigator must record his or her reasoning 
for making this decision in the patient’s medical records.  
4.4 CRITERIA FOR STUDY TERMINATION 
This study will be considered terminated when 1 or more of the following conditions are met: 
• 
All subjects have completed all required study visits; 
• 
All subjects have discontinued from the study; 
• 
The University of Rochester Data Safety Monitoring Committee or Institutional Review Board 
(IRB) discontinues the study because of safety considerations. 


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5 STUDY ASSESSMENTS AND TREATMENT SCHEDULE 
Table 5.1 below lists all of the required assessments that should be performed at each study visit.  
TABLE 5.1: STUDY ASSESSMENTS AND TREATMENT SCHEDULE 
 
*1st dose of rituximab will be administered intravenously, subsequently doses will be administered subcutaneously    
 
1 Treatment Administration +/- 1 day window.  Physical Exam, Vital Signs, Hematology and Chem visit days have - 1 day window 
2 Treatment Administration +/- 3 day window.  Physical Exam, Vital Signs, Hematology and Chem visit days have a - 3 day window  
3 Following completion of cycle 24 or upon discontinuation of therapy in the absence of disease progression, patients will be evaluated as per 
institutional standards (typically every 3-4 months). Physical exam data, vital signs, laboratory values and patient diaries will no longer be 
collected. Patients continuing on acalabrutinib will continue with adverse event assessments at each evaluation and be followed for progression 
and survival events. 
4 See section 12 
5 FISH for del17p, del11q, del13q, trisomy 12 will be performed on peripheral blood or marrow within 6 months of C1D1. IGHV, TP53, NOTCH1, 
SF3B1 mutation analysis to be performed at screening (if feasible) unless previously tested. 
6 Baseline CT scan within 60 days prior to Cycle 1/Day 1. CT Scan/Response Assessment +/- 7 day window.  CT Scan/Response assessment end of 
cycle 12 and at the end of cycle 24 for patients continuing on acalabrutinib. Follow up CTs to be done at investigator discretion/ per standard of 
care. CTs at cycle 12 and 24 will not be required if a patient does not have measurable disease at baseline. 
7 Visits every 3 months (+/- 1 month) or as per investigator discretion. Treatment Administration and labs or other assessments +/- 7 day 
window from visit. 
8 Serum or urine pregnancy test prior to Cycle 1 / Day 1 and within 30 days following discontinuation for females of childbearing potential. If 
patient has experienced menopause or no longer has uterus / ovaries this can be omitted.  
9 Bone Marrow sample performed prior to completion of cycle 12 and/or cycle 24 to confirm a complete response / MRD negativity   
10 Flow cytometry of peripheral blood for minimal residual disease assessment is being performed prior to completion of cycle 12 and at cycle 
24 for patients continuing on acalabrutinib. A patient in CR will undergo a bone marrow biopsy to confirm the response. Bone marrow and 
peripheral blood samples will be analyzed and stored in the laboratory of Dr. Richard Burack at the University of Rochester. 
11 Follow-up for SAEs should continue until resolution, stabilization, the subject has withdrawn consent or has been lost to follow-up.  
12 Patients not in a MRD negative complete remission will continue acalabrutinib. 
13Acalabrutinib is dosed twice daily every day, unless treatment is held or discontinued, starting Cycle 1 Day 8.  
14At a minimum, hematology includes white blood cells and differential, hemoglobin, hematocrit, mean corpuscular volume, platelets.  
15At a minimum, chemistry includes sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, glucose, calcium, phosphorus, albumin 
16Chemistry, uric acid and LDH will be repeated 6-8 hours after treatment initiation and as further clinically indicated for patients with a high 
tumor burden, which is defined as having any lymph nodes >10cm or lymph nodes >5cm with an absolute lymphocyte count>25 x109/L 
Cycle = 28 days 
 
Screening 
Cycle 11 
Cycle 
2-62 
Cycle 7-
122 
Cycles 12-
242 
Follow 
up3 
D-28 to -1 
D1 
D3,4  
or 5 
D8 
D15 
D1 
D1 
q3 mo 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
X 
X 
X  
 
Vital signs 
X 
X 
X 
X 
 
X 
X 
X  
 
Hematology14 
X 
X 
X 
X 
X 
X 
X 
X  
 
Chemistry 15 
X 
X16 
 
 
 
X 
X 
X  
 
LDH, Uric acid 
X 
X16 
 
 
 
 
 
 
 
B2mcg 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
X8 
 
 
 
 
 
 
 
 
Hep B/C serology, quant Igs 
X 
 
 
 
 
 
 
 
 
FISH 
X5 
 
 
 
 
 
 
 
 
IGHV, TP53, NOTCH1, SF3B1 
X5 
 
 
 
 
 
 
 
 
CT imaging (neck, chest, 
abdomen, pelvis) 
X6 
 
 
 
 
 
X6 
X6 
 
BM aspirate &biopsy 
 
 
 
 
 
 
X9 
X9 
 
Flow cytometry for MRD  
 
 
 
 
 
 
X10 
(PB/BM) 
X10 
(PB/BM) 
 
Correlative Labs 4 
 
X 
X 
X 
X 
X 
X 
X 
 
Rituximab 50 mg* twice weekly 
 
X* 
X 
X 
X 
X 
 
 
 
Acalabrutinib 100 mg BID 
 
 
 
X13 
X 
X 
X 
X12 
X12 
Response Assessment 
 
 
 
 
 
 
X 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X  
X 11 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X  
 


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6 AGENT GUIDANCE 
6.1 GUIDELINES FOR RITUXIMAB 
• 
Method of Administration: Rituximab will be administered as an intravenous for the first dose.  
• 
Subsequent doses will be subcutaneous. Note that in the event of a first dose infusion reaction, 
subsequent doses may be given IV if felt necessary by the treating investigator. 
• 
Potential Drug Interactions:  No Drug Interactions have been reported to date. 
• 
Pre-medications: Pre-medicate approximately 30 minutes prior to rituximab with an 
antihistamine (oral diphenhydramine 50 mg or equivalent) and oral acetaminophen 650 mg (or 
equivalent). Premedications will be optional prior to subsequent subcutaneous doses. Use of 
anti-pneumocystis (PJP) and antiviral prophylaxis is optional. 
• 
Hypersensitivity and Infusion Reaction Precautions: Medication and resuscitation equipment must 
be available per institutional guidelines prior to first rituximab administration for the emergency 
management of potential anaphylactic reactions.   
• 
Supply: Rituximab intravenous solution (Rituxan® 100 mg/10 mL or 500 mg/50 mL vials) and 
rituximab/hyaluronidase (Rituxan Hycela® rituximab 1400 mg/hyaluronidase 23,400 units per 
11.7 mL vials) will be sourced by study sites from commercially-available supplies.   
• 
Storage and handling: Rituximab intravenous solution and rituximab/hyaluronidase should be 
stored in a refrigerator between 2-8 degrees Celsius (36-46 degrees Fahrenheit).  During storage, 
vials should be kept in their original packaging to protect them from light.  Do not freeze or shake 
vials. 
• 
Potential risks: Treatment with rituximab (a standard treatment modality for this clinical situation) 
may cause serious side effects. While unlikely to occur, some of which can be life-threatening or 
cause death, including the following, listed according to their frequency/risk. Please refer to 
rituximab prescribing information for additional details. 
• 
Contraception recommendations: Woman of childbearing potential (WOCBP) who are sexually 
active must use highly effective methods of contraception during treatment and for 12 months 
following last dose of rituximab.  (see Appendix 3 for examples) 
 
Very Common (≥10% of patients) – The most common side effects (>10%) observed with 
rituximab treatment in patients, include: 
• 
Infusion/Administration related reaction 
• 
Fever 
• 
Chills 
• 
Infection 
• 
Weakness 
• 
Headache 
• 
Abdominal Pain 
• 
Pain 
• 
Low white blood cell counts 
• 
Low platelet count 
• 
Night sweats 


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• 
Rash 
• 
Pruritus (itching) 
• 
Rash and itching at injection site 
• 
Cough 
• 
Runny nose 
• 
Angioedema (swelling, especially around the nose or mouth) 
• 
Nausea 
 
Common (>5-10% of patients) - Common side effects (>5-10%) observed with rituximab 
treatment in patients, include: 
• 
Back pain 
• 
Throat irritation 
• 
Flushing (redness in face or other areas of body) 
• 
Anemia (low hemoglobin) 
• 
Hives (itchy red welts) 
• 
Wheezing 
• 
Shortness of breath 
• 
Sinus infection 
• 
Hyperglycemia (high blood sugar) 
• 
Peripheral edema (swelling of extremities) 
• 
Diarrhea 
• 
Vomiting 
• 
Constipation 
• 
Dizziness 
• 
Anxiety 
• 
Muscle pain 
• 
Joint pain 
• 
Constriction (‘spasm’) of muscles in chest 
• 
Hypotension (low blood pressure)  
• 
Hypertension (high blood pressure) 
 
6.1.1 DOSE PREPARATION AND ADMINISTRATION OF RITUXIMAB: INTRAVENOUS 
PREPARATION 
Per current rituximab prescribing information, final concentration of the intravenous bag of rituximab 
should be between 1-4 mg/mL.  Instructions below will provide an intravenous solution with a final 
concentration of 1 mg/mL.  Sites are discouraged from preparing more concentrated solutions, as it may 
be difficult to properly administer the required dose.  Doses should be prepared under standard aseptic 
conditions following applicable regulatory guidelines.  Do not use rituximab/hyaluronidase for 
preparation of the intravenous cycle 1 day 1 rituximab dose.   
 
Steps for Preparation of 1 mg/mL IV solution 
1. Prepare a 45 mL IV bag of 0.9% sodium chloride 
a. Sites may either pump a bag with 0.9% sodium chloride to a final volume of 45 mL, or 
withdraw overfill from a prefilled bag to achieve a final volume of 45 mL 


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i. Rituximab for IV use is compatible with polyethylene (PE) and polyvinyl chloride 
(PVC) infusion bags 
2. Draw up 5 mL of rituximab intravenous solution for injection (10 mg/mL) into a syringe 
3. Add 5 mL of rituximab to the 45 mL bag of 0.9% sodium chloride 
4. Gently invert the prepared IV bag a few times to mix.  Do NOT shake the bag. 
5. Label according to applicable local, state, and federal regulations 
 
Diluted solutions of rituximab for intravenous infusion should be used immediately.  If unable to use 
immediately, prepared solutions for infusion may be stored for up to 24 hours between 2-8 degrees 
Celsius (36-46 degrees Fahrenheit). 
 
ADMINISTRATION 
After administering appropriate pre-medications, infuse the 50 mg dose intravenously at 25 mg/hr (total 
of 2 hours), modifying if necessary for infusion related reactions (section 6.1.3) 
 
IV doses of rituximab should not be mixed with other solutions.  Bags should not be shaken.  Solutions 
should be administered by IV infusion – do not administer by IV push, IV bolus, or subcutaneously.  If the 
patient develops an infusion reaction, see section 6.1.3.  Permanently discontinue the infusion if the 
patient develops a serious or life-threatening cardiac arrhythmia. 
 
The date of administration of rituximab must be recorded within the eCRF, patient’s medical records, 
and/or in the drug accountability records.  For the purpose of drug accountability and dosing, subjects 
should record the doses missed on a drug diary.  Any error in drug administration should be recorded 
(e.g., missed dose). 
6.1.2 DOSE PREPARATION AND ADMINISTRATION OF RITUXIMAB: SUBCUTANEOUS 
PREPARATION 
Individual 50 mg doses of rituximab/hyaluronidase should be drawn from vials into discrete syringes, 
under standard aseptic conditions and following applicable regulatory guidelines.  At the manufacturer’s 
standard concentration (120 mg/mL), sites will need to draw up 0.42 mL per syringe for each dose.  
Rituximab/hyaluronidase is compatible with polypropylene and polycarbonate syringes, and stainless 
steel transfer and injection needles.  To avoid clogging the needle, do not attach the injection needle 
until immediately before administration. 
 
Doses of rituximab hyaluronidase drawn into syringes should be used immediately.  Doses not used 
immediately may be stored for up to 48 hours between 2-8 degrees Celsius (36-46 degrees Fahrenheit) 
and up to 8 hours at 30 degrees Celsius (86 degrees Fahrenheit) in diffused daylight.  After drawing up 
doses, residual rituximab/hyaluronidase in the source vial should be discarded.  If using a closed system 
transfer device for withdrawal of rituximab/hyaluronidase from source vials, the source vials (not doses 
drawn up) may be kept in a refrigerator for up to 7 days from the time of initial access. 
 
Following successful tolerance of at least one dose of subcutaneous rituximab/hyaluronidase at the 
study site, the site may elect to provide the patient with pre-drawn doses for home administration, with 
the patient’s consent.  Patients receiving pre-drawn doses for home administration should be provided 
with: 
• 
Detailed instructions regarding proper storage, handling, and administration technique 
• 
A prescription for injection needles 
• 
A sharps bin for safe disposal of used needles & syringes 


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• 
Contact information for study personnel, in the event of questions or acute issues 
• 
Information on managing injection reactions 
 
NOTE: If the site provides doses to patients for home administration, no more than two doses may be 
provided at one time.  Doses of rituximab/hyaluronidase are only stable for a maximum of 48 hours 
when stored between 2-8 degrees Celsius (36-46 degrees Fahrenheit) and up to 8 hours at 30 degrees 
Celsius (86 degrees Fahrenheit) in diffused daylight.  Patients should be educated on the importance of 
storing doses in a refrigerator at home.  Doses for home administration should be provided to patients 
in clean, sterile overwraps. 
 
ADMINISTRATION 
NOTE: Patients must have tolerated an IV dose of rituximab before they can be given subcutaneous 
rituximab/hyaluronidase. 
 
Pre-medication is recommended as per section 6.1. 
 
Attach stainless steel injection needle immediately prior to dose administration and inject 
subcutaneously into the abdomen.  Rotate abdominal injection sites with each dose.  Do not inject dose 
into any area appearing red, hard, bruised, tender, or where moles or scars are present.  Do not inject 
doses of other subcutaneous medications at the same site.   
 
6.1.3 INFUSION RELATED REACTIONS AND INFUSION RATE GUIDANCE – RITUXIMAB 
Infusion related reactions, including severe reactions, have been reported with rituximab administration 
in patients with CLL.  Guidelines are provided below for patients who experience such reactions.  
Symptomatic infusion reactions, despite premedication, may be treated at the discretion of the treating 
physician, including but not limited to: oral acetaminophen 650 mg (or equivalent), corticosteroids, 
antihistamines, oxygen, and bronchodilators.   
The following are recommended infusion rate reduction/delay guidelines for patients who experience 
severe Infusion Related Reactions (IRR’s) in which treatment should be interrupted. Final decision for 
infusion rate reduction/delay or discontinuation resides with the treating investigator. 
 
1st or 2nd Infusion Interruption: 
• 
Hold infusion and closely monitored patient, institute symptomatic medical management until 
resolution of IRR symptoms. 
• 
Following the judgment of the Investigator, and provided the patient is stable, the infusion may 
be resumed at ½ the previous rate and escalated at 30 minutes if tolerated. 
• 
If the patient does not experience any further IRR symptoms, infusion may resume. 
3rd Infusion Interruption (same day): 
• 
Discontinue infusion for that day – monitor patient for resolution of all symptoms.  Patient should 
have all vital signs completed as well as any other standard of care procedures completed as 
warranted by the Investigator prior to release of patient from study site. 


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• 
Any remaining diluted product should be discarded. 
If at any time during rituximab treatment, an infusion related reaction is observed, the treating 
investigator may reduce the infusion flow rate at their discretion. 
 
6.2 GUIDELINES FOR ACALABRUTINIB 
• 
Formulation, Packaging, and Storage: Acalabrutinib is manufactured according to current Good 
Manufacturing Practice (cGMP) regulations and will be provided to the investigational site by Acerta 
Pharma/AstraZeneca or designee. It should be stored according to the instructions on the label that is 
affixed to the package containing each respective drug product. Acalabrutinib should be kept in a low-
humidity place at room temperature between 20-25 degrees Celsius (68-77 degrees Fahrenheit).  
Excursions between 15-30 degrees Celsius (59-86 degrees Fahrenheit) are permitted.  The drug product 
is provided as capsules intended for oral administration.  
• 
Supply: Acalabrutinib (Calquence®) will be supplied to sites as 100 mg capsules (60 
capsules/bottle) by Acerta Pharma/AstraZeneca.  Sites approved for study participation will receive an 
initial shipment of of acalabrutinib following site activation. 
• 
Method of Administration:  acalabrutinib will be administered orally twice daily (every 12 hours) 
with or without food. Capsules should be swallowed whole with water; do not break, open, chew, or crush 
capsules. 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 next dose.  If it has been > 3 hours, the dose should not be taken and the subject 
should take the next dose at the scheduled time.  The missed dose will not be made up and must be 
returned to the site at the next scheduled visit.   
• 
Potential Drug Interactions:   
Acalabrutinib is not a strong direct inhibitor or inducer or CYP isoforms; thus, acalabrutinib, at the 
currently used clinical doses, is unlikely to be a perpetrator of a drug-drug interaction at the level of 
inhibition or induction of CYP isoforms.  Acalabrutinib is partially metabolized by CYP3A; its exposure is 
affected when coadministered with strong CYP3A4 inducers or inhibitors.  Consequently, the concomitant 
use of strong inhibitors/inducers of CYP3A4 (see Appendix 1) will be avoided. 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.  
 
The effect of agents that reduce gastric acidity (e.g. proton pump inhibitors or antacids) on 
acalabrutinib capsule absorption was evaluated in a healthy volunteer study.  Results from this 
study indicate that subjects should avoid the use of calcium carbonate-containing drugs or 
supplements and short-acting H2 receptor antagonists for a period of at least 2 hours before 
and 2 hours after taking acalabrutinib capsules.  Use of omeprazole, esomeprazole, 
lansoprazole or any other proton pump inhibitors (eg, lansoprazole, dexlansoprazole, 
rabeprazole, or pantoprazole) while taking acalabrutinib capsules is not recommended due to a 
potential decrease in study drug-related exposure. The new tablet formation was developed to 
overcome the interactions between acalabrutinib capsules and acid reducing agents (ARAs). 
Acalabrutinib tablets can be co-administered with all acid reducing agents (proton pump 
inhibitors, H2-receptor antagonists, antacids). Since the formulations are bioequivalent, the 
same safety and efficacy can be expected, with the added benefit for patients who require co-
treatment with PPIs now able to be taking acalabrutinib, 


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• 
Table 6.2.1: Drug Interactions with acalabrutinib 
Strong CYP3A Inhibitors 
Clinical Impact Co-administration of acalabrutinib with a strong CYP3A inhibitor 
(itraconazole) increased acalabrutinib plasma concentrations  
Increased acalabrutinib concentrations may result in increased toxicity.  
Prevention or 
Management  
Avoid co-administration of strong CYP3A inhibitors with acalabrutinib.  
Alternatively, if the inhibitor will be used short-term, interrupt acalabrutinib  
Moderate CYP3A Inhibitors 
Clinical Impact Co-administration of acalabrutinib with a moderate CYP3A inhibitor may 
increase acalabrutinib plasma concentrations  
Increased acalabrutinib concentrations may result in increased toxicity.  
Prevention or 
Management  
When acalabrutinib is co-administered with moderate CYP3A inhibitors, 
reduce acalabrutinib dose to 100 mg once daily. 
Strong CYP3A Inducers 
Clinical Impact Co-administration of acalabrutinib with a strong CYP3A inducer (rifampin) 
decreased acalabrutinib plasma concentrations  
Decreased acalabrutinib concentrations may reduce acalabrutinib activity.  
Prevention or 
Management  
Avoid co-administration of strong CYP3A inducers with acalabrutinib if 
feasible.  
If a strong CYP3A inducer cannot be avoided, increase the acalabrutinib dose 
to 200 mg twice daily.  
Gastric Acid Reducing Agents 
 
 
 
 
 
 
 
 
 
 
• 
Pre-medications: None 
• 
Prophylaxis: none  
• 
Contraception recommendations: Woman of childbearing potential (WOCBP) who are sexually 
active must use highly effective methods of contraception during treatment and for 2 days after 
the last dose of acalabrutinib.  (see Appendix 3 for examples) 


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• 
Potential risks: Treatment with acalabrutinib may cause serious side effects. While unlikely to 
occur, some of which can be life-threatening or cause death, including the following, listed 
according to their frequency/risk. Please refer to acalabrutinib prescribing information for 
additional details. 
Very common (occurring in at least 10% or more of patients): 
• 
Headache 
• 
Bruising events including bruises, petechiae (pinpoint red or purple spots on the 
• 
skin), and increased tendency to bruise 
• 
Diarrhea (frequent or loose stools) 
• 
Nausea 
• 
Constipation (bowel movements that are infrequent or hard to pass) 
• 
Bleeding 
• 
Vomiting 
• 
Abdominal pain 
• 
Rash 
Common (occurring in at least 1% but less than 10% of patients): 
• 
Nose bleeds 
• 
Severe Bleeding 
6.2.1 DISPENSING OF ACALABRUTINIB 
The investigational product, acalabrutinib capsules for oral administration, is supplied as yellow and 
blue, opaque hard gelatin capsules, with 100 mg of acalabrutinib as the active ingredient.  Each capsule 
also contains compendial inactive ingredients: silicified microcrystalline cellulose, which is composed of 
microcrystalline cellulose and colloidal silicon dioxide, partially pregelatinized starch, sodium starch 
glycolate, and magnesium stearate.  The capsule shell contains gelatin, titanium dioxide, yellow iron 
oxide and indigotine (FD&C Blue 2). 
Starting in October 2022, all patient transitioned to the tablet formation of acalabrutinib. The tablets 
consist of acalabrutinib maleate, a salt form of acalabrutinib freebase that is used in capsules, and 
delivers an equivalent dose of acalabrutinib compared to the capsules (100mg). Therefore, the tablets 
can be switched directly for capsules on a 1:1 basis. This new tablet formulation was developed to 
overcome the interactions between acalabrutinib capsules and acid reducing agents (ARAs). 
Acalabrutinib tablets can be co-administered with all acid reducing agents (proton pump inhibitors, H2-
receptor antagonists, antacids). Since the formulations are bioequivalent, the same safety and efficacy 
can be expected, with the added benefit for patients who require co-treatment with PPIs now able to be 
taking acalabrutinib. 
 
 The following pictures provide side by side comparisons of the two products 
 
 


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Patients should be instructed to return any unused tablets when they return the bottle to the site. Study 
drug compliance should be reviewed with the patient at the beginning of each new treatment cycle and 
as needed.  Missed doses will be documented in the patients’ medical record. 
Before dispensing, the site pharmacist must check that the acalabrutinib is in accordance with the 
product specifications and the validity is within the re-test date. 
The Pharmacist should record the date dispensed and patient’s number and initials, as well as complete 
the accountability forms with information concerning the dispensation of acalabrutinib. 
Acalabrutinib will be self-administered (by the patient).  Tablets should be taken at approximately the 
same time each day with or without food.   Patients should be instructed to swallow the tablets as a 
whole and should not chew or crush them. 
Acalabrutinib capsule is administered BID and taken orally approximately every 12 hours.  The tablets 
should be swallowed intact with water.  Subjects should not attempt to open capsules or dissolve them 
in water.  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 next dose.  If it has been > 3 hours, the dose should not be taken and the 
subject should take the next dose at the scheduled time.  The missed dose will not be made up and must 
be returned to the site at the next scheduled visit. 


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7 DOSE DELAYS/DOSE MODIFICATIONS 
7.1 RITUXIMAB 
No reduction in the dose of rituximab is permitted. 
Supportive care should be considered for any patient who experiences Grade ≥ 2 cytopenias, or Grade ≥ 
1 non-hematologic toxicities.  Use of growth factors (such as G-CSF or pegylated G-CSF) is allowed, per 
ASCO guidelines (http://jop.ascopubs.org/cgi/content/full/2/4/196). A maximum four (4) week delay for 
recovery from toxicity is allowed for both rituximab and acalabrutinib (individually or together) to allow 
recovery of hematologic toxicities to ≤Grade 3 or non-hematologic toxicities to ≤ Grade 2 or to baseline 
level.  If the patient withdraws consent or has documented progression, an end of study visit should be 
completed. 
Dose delay and/or modification guidance is for adverse events considered at least possibly related to the 
study drug.  If cytopenias are deemed related to the underlying disease rather than study drug, dose 
modifications are not required, or are per investigator discretion. If a patient discontinues only one 
study drug, the patient may continue treatment with the other study drug per the protocol.  
7.2 STUDY DRUG MODIFICATIONS 
• 
The actions should be taken for any Grade 4 toxicity or unmanageable Grade 3 toxicity. In 
addition, the actions in Table 7.2.1 should be taken when modification of acalabrutinib dose is 
recommended for specific treatment-related adverse events as listed in Table 7.2.2. 
• 
If the dose of acalabrutinib is reduced, at the Investigator’s discretion, the dose of acalabrutinib 
may be re-escalated after 2 cycles of a dose reduction in the absence of a recurrence of the toxicity 
that led to the reduction. Dose changes must be recorded in the study documentation.  
• 
Dose modifications are for adverse events attributed to study treatment. Dose modifications are 
not required for adverse events unrelated to study treatment.  
• 
Guidance for dose modifications in the event of drug interactions is provided in Table 6.2.1 
 
 
 
TABLE 7.2.1: DOSE MODIFICATION ACTIONS FOR ACALABRUTINIB 
Event Occurrence 
Action 
1st-2nd  
May restart at original dose level (100 mg BID) 
3rd  
Restart at 100 mg daily 
4th  
Discontinue acalabrutinib 
 
 
 
TABLE 7.2.2: STUDY DRUG MODIFICATIONS 
 
Rituximab 
Acalabrutinib 
NCI-CTCAE Grade 
 
Neutropenia 
Grade 3 neutropenia 
Maintain current dose 
Maintain current dose 


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Rituximab 
Acalabrutinib 
Grade 4 neutropenia 
lasting >7 days or 
occurrence of neutropenic 
fever or infection 
Delay rituximab until Grade ≤ 3 and/or 
neutropenic fever or infection is 
resolved; thereafter, resume at full dose.  
If delay is > 4 weeks, discontinue 
rituximab. 
Hold acalabrutinib until recovery of Grade 
≤ 3 or baseline. Follow dose modification 
actions in TABLE 7.2.1. 
Thrombocytopenia 
Grade 3 thrombocytopenia 
Maintain current dose  
Maintain current dose 
Grade 4 thrombocytopenia 
Delay rituximab until Grade ≤ 3; 
thereafter resume at full dose.  If delay is 
> 4 weeks, discontinue rituximab. 
Hold acalabrutinib until recovery of Grade 
≤ 3 or baseline. Follow dose modification 
actions in TABLE 7.2.1. 
Diarrhea (non-infectious) 
Grade 1: increase of <4 
stools per day over baseline 
n/a 
 
Provide antidiarrheal (eg, loperamide) 
and maintain current acalabrutinib dose 
level and schedule.  
Grade 2: increase of 4-6 
stools per day over baseline 
n/a 
  
Provide antidiarrheal (eg, loperamide). 
Withhold acalabrutinib until Grade ≤ 1. 
Resume acalabrutinib at current dose 
level. If rechallenge results in 
recurrence, may resume at initial or 
lower dose level at investigator 
discretion (if applicable). Consider 
addition of anti-inflammatory (eg, 
sulfasalazine, budesonide).  
Grade 3: increase of >7 
stools per day over baseline 
n/a 
 
Provide antidiarrheal (eg, loperamide). 
Withhold acalabrutinib until Grade ≤ 1. 
Resume at lower dose level (if 
applicable). Consider addition of anti-
inflammatory (eg, sulfasalazine, 
budesonide).  
Grade 4: life-threatening 
n/a 
 
Provide antidiarrheal (eg, loperamide). 
Withhold acalabrutinib until Grade ≤ 1. 
May resume at lower dose level (if 
applicable) or discontinue acalabrutinib 
at investigator discretion. Consider 
addition of anti-inflammatory (eg, 
sulfasalazine, budesonide).  
Immune related pneumonitis 
Grade 1 
Withhold 
rituximab 
until 
resolved.  
Resume at full dose or if delay >4 weeks, 
discontinue rituximab 
Maintain current dose. Consider 
pneumocystis prophylaxis 
Grade ≥2 
Discontinue rituximab, consider systemic 
corticosteroids and pneumocystis 
treatment. 
Discontinue acalabrutinib, consider 
systemic corticosteroids and 
pneumocystis treatment. 
Rash or injection site reaction 
Grade 1 
Maintain current dose 
Maintain current dose 
Grade 2 
Withhold rituximab until Grade ≤ 1.  
Resume at full dose or if delay >4 weeks, 
discontinue rituximab. 
Maintain current dose  


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Rituximab 
Acalabrutinib 
Grade 3 or 4 
Withhold rituximab until Grade ≤ 1.  
Resume at full dose or if delay >4 weeks, 
discontinue rituximab. 
Withhold acalabrutinib until Grade ≤ 1, 
consider systemic corticosteroids. Follow 
dose modification actions in TABLE 7.2.1. 
All Other Non-Hematological Adverse Events 
Grade 3 
Withhold rituximab until Grade ≤ 1.  
Resume at full dose or if delay >4 weeks, 
discontinue rituximab. 
Hold acalabrutinib until recovery of Grade 
≤ 1 or baseline. Follow dose modification 
actions in TABLE 7.2.1. 
Grade 4 
Discontinue rituximab. 
Hold acalabrutinib until recovery of Grade 
≤ 1 or baseline. Follow dose modification 
actions in TABLE 7.2.1. 
 
 
7.2.1 DISCONTINUATION CRITERIA 
Regardless of the inciting agent, the following warrant treatment discontinuation: 
• 
Treatment related adverse reactions that are life-threatening. 
• 
Treatment related diarrhea or colitis, grade 4; also administer high-dose systemic corticosteroids. 
• 
Infusion-related reaction, grade 4. 
• 
Treatment related immune-related Pneumonitis, Grade 2 or higher; also administer high-dose 
systemic corticosteroids. 
7.2.2 CRITERIA FOR ONGOING TREATMENT  
Continue treatment as per protocol provided that patient has: 
• 
No intolerable toxicities related to study drug. 
o Treatment may be delayed to recover from toxicity. 
• 
No clinical or radiographic evidence of disease progression.  
• 
Not withdrawn from the study for other reasons. 
7.3 CONCOMITANT MEDICATIONS 
Concomitant use of acalabrutinib with strong CYP3A inhibitors (e.g., ketoconazole, conivaptan, 
clarithromycin, indinavir, itraconazole, lopinavir, ritonavir, telaprevir, posaconazole and voriconazole) is 
not allowed.  
Avoid concomitant use of moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem, 
dronedarone, fluconazole, verapamil) with acalabrutinib if feasible. If a moderate CYP3A inhibitor must 
be used, reduce the acalabrutinib dose to 100 mg once daily. 
Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s 
wort) if feasible. If a strong CYP3A inducer must be used, increase the acalabrutinib dose to 200 mg 
twice daily. 
 


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7.4 ORDERING RITUXIMAB AND ACALABRUTINIB 
Acalabrutinib will be supplied at no charge by Acerta/Astra Zeneca.  
Upon receipt of treatment supplies, the Pharmacist or the appropriate person of the site should update 
the accountability forms.  If any abnormality on the bottles is observed, the Pharmacist or the 
appropriate person must document that on the acknowledgement of receipt and contact that Sponsor 
and/or Sponsor designee. 
Rituximab will be ordered by the trial site via commercial channels. 


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8 MEASUREMENT OF EFFECT 
During the study period, all patients will be evaluated for response by history, examination, CT and/or 
MRI and bone marrow assessment.  After cycle 24, all efficacy assessments should be per investigator 
discretion or standard of care.  All efficacy assessments have a +/- 7 day window.  The determination of 
response and progression will be based on the IWCLL criteria for CLL and SLL patients. [37] 
CT scan is the preferred method of tumor assessment but MRI may be used at the investigator’s 
discretion. The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and throughout the study.  
Patients will remain on study treatment until achievement of MRD negative CR at 12 or 24 months, the 
occurrence of definitive disease progression, unacceptable toxicity, or withdrawal from the study due to 
investigator decision or other reasons. Patients who discontinue from study treatment (either for 
toxicity or physician choice) and have not progressed will continue to be followed for disease 
progression. 
8.1 METHOD OF ASSESSMENT 
In addition to clinical examination, imaging-based evaluation will be used in this study in all patients 
enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI scanning may be 
used at the investigator’s discretion in patients for whom this may be a preferred alternative to CT 
scanning. Contrast-enhanced scanning is preferred, but iodine-containing or gadolinium contrast 
material may be omitted in patients for whom use of a contrast agent would be medically 
contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, radionuclide scans, or tumor markers 
will not be considered for response assessment. 
For radiographic evaluations, the same method of assessment and the same technique (e.g., scan type, 
scanner, patient position, dose of contrast, injection/scan interval) should be used to characterize each 
identified and reported lesion at baseline and during study treatment and follow-up. However, if a 
patient is imaged without contrast at baseline, subsequent assessments should be performed with 
contrast, unless the patient cannot tolerate the contrast. 
8.2 IDENTIFICATION AND MEASUREMENT OF TUMOR LESIONS AND 
ORGANOMEGALY 
8.2.1 TARGET LESIONS 
For patients with measurable adenopathy/disease at baseline, up to 6 lymph nodes should be selected 
as target lesions that will be used to quantitate the status of the disease during study treatment. Ideally, 
the target lesions should be located in disparate regions of the body. Only peripheral nodes need be 
selected as target lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease are 
assessed whenever these sites are involved. 
Target lesions will be measured and recorded at baseline and as per the study assessment schedule. The 
cross-sectional dimensions (the largest cross-sectional diameter, i.e., the LD × LPD) will be recorded (in 
cm) for each target lesion. The product of the perpendicular diameters (PPD) (in cm2) for each target 


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lesion and the sum of the products (SPD) (in cm2) for all target lesions will be calculated and recorded. 
The baseline SPD will be used as references by which objective tumor response will be characterized 
during treatment. The nadir LD of individual lesions and the nadir SPD will be used as references by 
which CLL progression will be characterized. All LD and LPD diameters will be reported in centimeters 
and all PPDs and SPDs will be reported in centimeters squared. 
A nodal mass may be selected as a nodal target lesion if it is both abnormal and measurable at baseline. 
A lymph node lesion is considered abnormal if it has a single diameter that is > 1.5 cm and is considered 
measurable if it has 2 perpendicular diameters that can be accurately measured in cross section with the 
LD being ≥ 1.0 cm and the LPD also being ≥ 1.0 cm. 
At follow-up time points, the LDs for individual lesions and the SPD of all nodal target lesions will be 
considered. Because nodal target lesions that have one or both diameters >0 cm and < 1.0 cm cannot be 
reliably measured, a default value of 1.0 cm will be assigned for each diameter that meets these criteria 
and the resulting PPD will be used in SPD calculations. Based on this convention, a CR may be achieved 
even if an SPD value is >0 cm2 (i.e., if all lymph nodes measure < 1.0 cm2). 
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered progressive 
disease. 
In cases in which a large lymph node mass has split into multiple components, all subcomponents 
regardless of size will be used in calculating the SPD. Progression of the lesion will be based on the SPD 
of sub-components. Lesion sub-components will have the true PPDs calculated. Similarly, lesion sub-
components that are visible but neither abnormal nor measurable will have the default PPD of 1.0 cm2 
(1.0 cm × 1.0 cm) used in calculating the SPD. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual lesion 
can continue to be measured. If the lesions have merged in a way that they can no longer be separated 
by this boundary, the newly merged lesion will be measured bi-dimensionally. 
8.2.2 SPLEEN AND LIVER 
Both the spleen and liver will be assessed by CT/MRI scan and by physical examination on deep 
inspiration at baseline and as per the study assessment schedule. The baseline and nadir values for the 
longest vertical dimension (LVD) of each organ will be used as reference to further characterize the 
objective tumor response of the measurable dimensions of the CLL during treatment. All spleen and liver 
LVD measurements should be recorded in centimeters. 
8.2.3 NON-TARGET LESIONS 
Any other measurable and abnormal nodal lesions not selected for quantitation as target lesions may be 
considered non-target lesions. In addition, non-measurable evidence of CLL such as nodal lesions with 
both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal disease, ascites, pleural or 
pericardial effusions, lymphangitis of the skin or lung, abdominal masses that are not confirmed and 
followed by imaging techniques, cystic lesions, previously irradiated lesions, and lesions with artifacts 
may be considered as non-target disease. 
The presence or absence of non-target disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-target lesions should be recorded. The 
non-target disease at baseline will be used as a general reference to further characterize regression or 


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progression of CLL during assessments of the objective tumor response during treatment. 
Measurements are not required and these lesions should be followed as “present” or “absent”. 
8.3 DEFINITIONS OF TUMOR RESPONSE AND PROGRESSION 
Responses will be categorized by the IRC as CR, CRi, PR, PR-L, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to otherwise 
categorize response status. 
The best overall response will be determined. The best overall response is the best response recorded 
from the start of treatment until disease/recurrence progression (taking as a reference for disease 
progression the smallest measurements recorded since treatment started). Where imaging data are 
available, these data will supersede physical examination data in determining tumor status. 
8.4 COMPLETE RESPONSE 
To satisfy criteria for a CR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
ALC in peripheral blood of <4 x 109/L 
• 
Regression of all target nodal masses to normal size ≤1.5 cm in the LD 
• 
Normal spleen and liver size 
• 
Regression to normal of all nodal non-target disease and disappearance of all detectable 
non-nodal, non-target disease 
• 
Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid cells 
and no lymphoid nodules in a bone marrow sample (the presence of benign reactive nodules is 
still compatible with a CR) 
• 
Absence of constitutional symptoms 
• 
Peripheral blood counts meeting all of the following criteria: 
o ANC >1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF) 
o Platelet count ≥100 x 109/L without need for exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for exogenous 
growth factors (e.g., erythropoietin) 
Patients who fulfill all the criteria for a CR (including bone marrow criteria) but who have a persistent 
anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow that is related to prior or 
ongoing drug toxicity (and not to progressive CLL) will be considered as a CR with incomplete marrow 
recovery (CRi). These patients remain eligible for MRD assessments and will discontinue therapy if 
negative for residual disease (similar to management for patient achieving a CR) 
8.5 PARTIAL RESPONSE 
To satisfy criteria for a PR, all of the following criteria must be met: 
• 
No evidence of new disease 
• 
Change in disease status meeting ≥2 of the following criteria, with 2 exceptions in which only 1 
criterion is needed: 1) only lymphadenopathy is present at baseline; 2) only lymphadenopathy 


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and lymphocytosis are present at baseline. In these 2 cases, only lymphadenopathy must improve 
to the extent specified below:   
o In a patient with baseline lymphocytosis (ALC ≥4 x 109/L), a decrease in peripheral blood 
ALC by ≥50% from baseline or a decrease to <4 x 109/L 
o A decrease by ≥50% from the baseline in the SPD of the target nodal lesions 
o In a patient with enlargement of the liver or spleen at baseline, a decrease by ≥50% from 
baseline  
o A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid nodules 
• 
No target, splenic, liver, or non-target disease with worsening that meets the criteria for definitive 
PD 
• 
Peripheral blood counts meeting 1 of the following criteria: 
o ANC >1.5 x 109/L or >50% increase over baseline without need for exogenous growth 
factors (e.g., G-CSF) 
o Platelet count >100 x 109/L or ≥50% increase over baseline without need for exogenous 
growth factors 
o Hemoglobin >110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (e.g., erythropoietin) 
PR criteria met but without recovery of lymphocytosis = PR-L 
8.6 STABLE DISEASE 
To satisfy criteria for SD, the following criteria must be met: 
• 
No evidence of new disease 
• 
There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient evidence of 
tumor growth to qualify for definitive PD 
8.7 DEFINITIVE DISEASE PROGRESSION 
The occurrence of any of the following events indicates definitive PD: 
• 
Evidence of any new disease: 
o A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD 
o New or recurrent splenomegaly, with a minimum LVD of 14 cm 
o New or recurrent hepatomegaly, with a minimum LVD of 20 cm 
o Unequivocal reappearance of an extra-nodal lesion that had resolved 
o A new unequivocal extra-nodal lesion of any size  
o *New non-target disease (e.g., effusions, ascites, or other organ abnormalities related to 
CLL). 
 
*Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence alone of PD 
unless histologically confirmed. Thus, a declaration of PD should not be made if this is the only 
manifestation of apparently new disease. 
 
• 
Evidence of worsening of target lesions, spleen or liver, or non-target disease: 
o Increase from the nadir by ≥50% from the nadir in the SPD of target lesions 
o Increase from the nadir by ≥50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm 


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o Splenic progression, defined as an increase in splenic enlargement by ≥50% from nadir (with 
a minimum 2 cm increase and a minimum LVD of 14 cm) 
o Hepatic progression, defined as an increase in hepatic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm) 
o Unequivocal increase in the size of non-target disease (e.g., effusions, ascites, or other organ 
abnormalities related to CLL) 
o Transformation to a more aggressive histology (e.g., Richter’s syndrome) as established by 
biopsy (with the date of the biopsy being considered the date of CLL progression if the 
patient has no earlier objective documentation of CLL progression). 
 
• 
Decrease in platelet count or hemoglobin that is attributable to CLL. 
o The current platelet count is <100 x 109/L OR there has been a decrease by >50% from the 
highest on-study platelet count. 
o The current hemoglobin is <100 g/L (10.0 g/dL) OR there has been a decrease by >20 g/L (2 
g/dL) from the highest on-study hemoglobin. 
 
If there is uncertainty regarding whether there is true progression, the patient should continue study 
treatment and remain under close observation pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of worsening CLL 
will not be considered definitive disease progression; in such patients, both CLL- related and non-CLL-
related causes for the constitutional symptoms should be considered. 
Worsening of disease during temporary interruption of study treatment (e.g., for inter current illness) is 
not necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other relevant 
evaluations should be considered in order to document whether definitive disease progression has 
occurred. If subsequent evaluations suggest that the patient has experienced persistent definitive CLL 
progression, then the date of progression should be the time point at which progression was first 
objectively documented. 
8.8 NON-EVALUABLE 
In a patient who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 
• 
There are no images or inadequate or missing images 
• 
Images of the liver and spleen are missing at that time point (with the exception that absence of 
splenic images will not result in an NE designation in a patient known to have undergone 
splenectomy). 
Note: A time-point will be considered to have a response of NE if any target lesion is missing. PD may be 
assigned at any time point regardless of the extent of missing target or non-target lesions. Missing non-
target lesions will not impact the ability to assess for response or disease progression. 
8.9 LYMPHOCYTOSIS DURING THERAPY 
Upon initiation of acalabrutinib, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from 
baseline and above absolute lymphocyte count of 5,000/mcL) may occur. The onset of isolated 
lymphocytosis usually occurs during the first few weeks of acalabrutinib therapy. Patients with 
lymphocytosis should be continued on study drug until the occurrence of definitive disease progression 


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(i.e., disease progression that is manifest by worsening CLL-related signs other than lymphocytosis 
alone), or the occurrence of another reason to discontinue study therapy. Unless related to treatment 
interruption, new or increasing lymphocytosis after 6 months of starting treatment may be considered 
disease progression and should be confirmed as per the response criteria.  


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9 STATISTICAL CONSIDERATIONS 
9.1 DESIGN 
This is a single-arm, single-center prospective study. The complete response rate will be estimated from 
forty enrolled subjects. An associated 95% two-sided confidence interval will be calculated using exact 
binomial methods. We anticipate a CR rate of 20%, which would result in a 95% two-sided confidence 
interval with a width of 26.6% (from 9.1% to 35.6%) for a sample size of 40 subjects. The maximum 
possible width of a 95% confidence interval using 40 subjects would be 32.4%. 
9.2 PATIENT DISPOSITION 
The disposition of patients includes the number and percentage of patients for the following categories: 
patients enrolled, patients treated (safety population), patients in the intent to treat population, and 
patients discontinued from the study. The reasons for study discontinuation will also be summarized in 
this table. Only one primary reason for study discontinuation will be reported in the summary. However, 
all reasons will be presented in the listing. A listing will present data concerning patient disposition. 
9.3 PATIENT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline demographic and clinical characteristics will be summarized as percentages for categorical 
variables and as mean, standard deviation, median, minimum and maximum for continuous measures. 
9.4 EXTENT OF EXPOSURE 
The dose (mg) of study drugs administered, the total number of doses of study drugs, and the duration 
of treatment (number of study cycles) will be summarized with descriptive statistics. The number and 
percentage of patients whose dose is modified at any time will be summarized by each type of 
modification by cycle and overall. The proportion of patients completing each cycle of treatment will be 
summarized. 
9.5 EFFICACY ANALYSES   
All patients included in the study should have a baseline tumor assessment within 60 days prior to Cycle 
1/Day 1. Each patient will be assigned one of the following categories: 1) complete response or 
complete response with incomplete marrow recovery, 2) partial response or partial response with 
lymphocytosis, 3) stable disease, 4) progressive disease, 5) unknown (not assessable, insufficient data).  
9.6 STATISTICAL ANALYSES 
The treated population is defined as all enrolled subjects who received at least 1 dose of study drug. 
Efficacy and safety analysis will be based on this population.  
The CR rate is defined as the proportion of patients with a best overall response of complete response 
with or without marrow recovery. Patients who do not have a tumor response assessment for any 


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reason will be considered non-responders and will be included in the denominator when calculating the 
CR rate.  
The ORR is defined as the proportion of patients with a best overall response of partial response (PR) or 
complete response (CR). Patients who do not have a tumor response assessment for any reason will be 
considered non-responders and will be included in the denominator when calculating the ORR.  
Progression-free survival is defined as the time from treatment initiation until the date of first 
documentation of definitive disease progression or date of death from any cause, whichever occurs first. 
Patients who die without a reported prior progression will be considered to have progressed on the day 
of their death. Patients who did not progress or are lost to follow-up will be censored at the day of their 
last tumor response assessment. The use of a new anticancer therapy prior to the occurrence of PD will 
result in censoring at the date of last tumor response assessment prior to initiation of new therapy. 
The safety population includes all subjects who received at least 1 dose of study treatment. Safety 
evaluations will be based on the incidence, intensity, and type of adverse events, as well as on clinically 
significant changes in the patient’s physical examination, vital signs, and clinical laboratory results. 
Safety variables will be tabulated and presented by study drug actually received. 


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10 SAFETY REPORTING  
10.1 DEFINITION OF ADVERSE EVENTS 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered a 
medicinal product; the untoward medical occurrence does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product (IMP) or other protocol-
imposed intervention, regardless of attribution. 
An adverse event includes the following: 
• 
Signs or symptoms that were not present or observed in the patient prior to the AE reporting 
period and that emerge during the protocol-specified AE reporting period (i.e. TEAEs) 
• 
Complications that occur as a result of protocol-mandated interventions (e.g. invasive 
procedures such as biopsy) 
• 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention 
• 
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 
• 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms, require treatment or further diagnostic tests, or lead to discontinuation or 
delay in treatment, or if it represents a clinically significant change from baseline as determined 
by the investigator 
• 
Progressive disease will not be considered an adverse event. 
Adverse events and laboratory results will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and the severity of adverse events will be graded using the scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Hematologic 
toxicity will be graded by CLL criteria [37] and can be found in Appendix 2.  For adverse events not 
covered by the NCI-CTCAE Version 5.0 grading system, the following definitions will be used: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
10.2 SERIOUS ADVERSE EVENTS (SAE) 
An AE should be classified as an SAE if the following criteria are met: 
o It results in death (i.e. the AE actually causes or leads to death 
o It is life threatening (i.e. the AE, in the view of the investigator, places the patient at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe form, might have 
caused death) 
o It requires or prolongs inpatient hospitalization, but not to include routine hospitalizations for 
neutropenic fevers that do not result in sepsis syndrome and/or ICU transfer 
o It results in persistent or significant disability/incapacity (i.e. the AE results in substantial 


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disruption of the patient’s ability to conduct normal life functions) 
o It results in a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
the investigational product 
o It is considered a significant medical event by the investigator (e.g. may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above).  
Clarification should be made between an SAE and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous. The general term severe is often used 
to describe the intensity (severity) of a specific event; the event itself, however, may be of relatively 
minor medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
usually associated with events that pose a threat to a patient’s life or ability to function. A severe AE 
(Grade 3 or 4) does not necessarily need to be considered serious.  For example, a white blood cell count 
of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered serious.  
Seriousness (not intensity) serves as a guide for defining regulatory reporting obligations. 
10.3 EXPECTEDNESS OF ADVERSE EVENTS 
Expected adverse events are those that have been previously identified as resulting from administration 
of the agents.  For the purposes of this study, an adverse event is considered expected when it appears 
in the investigational brochure, the package insert or is included in the informed consent form as a 
potential risk.  An adverse event is considered unexpected when it varies in nature, intensity or 
frequency from information provided in the current adverse event list, the investigational brochure, the 
package insert, in published medical literature, in the protocol, or is not included in the informed 
consent form as a potential risk. 
10.4  ATTRIBUTION OF ADVERSE EVENTS 
The investigator must attempt to determine if there exists reasonable possibility that an AE or SAE is 
related to the use of the investigational treatment. Attribution of adverse events should be described as 
treatment related or not related.  To ensure consistency of AE and SAE causality assessments, 
investigators should apply the following general guidelines when determining if an AE or SAE is 
treatment-related: 
o Treatment-Related: There is a reasonable causal relationship between the investigational 
treatment and the adverse event.  There is a plausible temporal relationship between the onset 
of the AE and administration of the investigational treatment, and the AE cannot be readily 
explained by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or 
the AE follows a known pattern of response to the investigational treatment; and/or the AE 
abates or resolves upon discontinuation of the investigational treatment or dose reduction and, 
if applicable, reappears upon re-challenge. 
o Not Treatment-Related: There is no reasonable causal relationship between the investigational 
treatment administered and the adverse event. Evidence exists that the AE has an etiology other 
than the investigational treatment (e.g. pre-existing medical condition, underlying disease, 
intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal 
relationship to administration of the investigational treatment.   
 
10.5 RECORDING/REPORTING ADVERSE EVENTS 


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AEs experienced by participants will be collected and reported from initiation of investigational 
treatment (to also include events preceding initiation of study treatment if an AE is at least possibly 
related to withholding medication prohibited by protocol, or a study procedure such as a biopsy), 
throughout the study, and within 30 days after the last dose of study medication. All SAEs regardless of 
grade, severe AEs (i.e. Grade ≥ 3), and events of death will be recorded, regardless of event attribution.  
Baseline disease-related signs and symptoms which are initially recorded as medical history, will 
subsequently be recorded as adverse events during the trial if they worsen in severity or increase in 
frequency.  Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or serious adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to the 
study.  Follow-up for SAEs should continue until resolution, stabilization, the subject has withdrawn 
consent or has been lost to follow-up.  
 
• 
Further AE reporting procedures are as follows: 
• Serious adverse events must be reported to the Study Chair from the first dose of protocol-
indicated treatment up to and including 30 days after administration of the last dose of 
investigational agent. 
• All AEs, regardless of grade, and events of death of any patient during the course of the trial 
will be reported in the case report form, and the investigator will give his or her opinion as 
to the relationship of the adverse event to trial drug treatment. 
• Asymptomatic abnormal laboratory values of Grade 1 or Grade 2 that do not trigger dose 
interruption or modification of protocol-indicated treatment will be deemed not clinically 
significant and are not required to be individually noted or recorded within the study data. 
• Laboratory and vital sign abnormalities are to be recorded as AEs only if they are medically 
relevant as judged by the investigator (e.g. symptomatic, requiring corrective treatment, 
leading to discontinuation of protocol-indicated treatment, and/or fulfilling a seriousness 
criterion). 
• Since this is an investigator-initiated study, the principal investigator, also referred to as the 
study chair, is responsible for reporting SAEs to any regulatory agency and to the study 
chair's data safety monitoring committee (DSMC) and IRB. 
• Fatal and life-threatening SAEs must be reported within 24 hours of the study chair's 
observation or awareness of the event to the DSMC chairperson or designee  
• All other serious (non-fatal/non-life threatening) events must be reported within 4 calendar 
days of the study chair's observation or awareness of the event to the DSMC chairperson or 
designee.  
• The study team should report all SAEs and special situations for patients receiving 
acalabrutinib to Acerta-Pharma per contractual guidelines.  
• The SAE report must include at minimum:  
o Event term(s) 
o Seriousness criteria  
o Intensity of the event(s): Investigator's determination. Intensity for each SAE, including 
any lab abnormalities, will be determined using the NCI CTCAE version 5.0 as a 
guideline, whenever possible.  
o Causality of the event(s): Investigator's determination of the relationship of the event(s) 
to study drug administration. 
• 
Deaths 
All deaths that occur during the protocol-specified AE reporting period, regardless of attribution, 


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will be reported to the appropriate parties. When recording a death, the event or condition that 
caused or contributed to the fatal outcome should be reported as the single medical concept. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, report 
"Unexplained Death." Deaths that occur during the protocol specified adverse event reporting 
period that are attributed by the investigator solely to progression of disease should be 
recorded only in the study CRF. 
 
• 
Hospitalizations for Medical or Surgical Procedures  
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a patient is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
o Hospitalizations for the following reasons do not require reporting: 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for pre-existing conditions that have not worsened 
• 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study 
• 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study 
 
• 
Procedures for Reporting Drug Exposure During Pregnancy 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or until 2 days after the last dose of 
acalabrutinib or 12 months after the last dose of rituximab. Pregnancy should be confirmed with 
a serum pregnancy test. The patient should permanently discontinue protocol-indicated 
treatment. If a woman suspects that she is pregnant while participating in this study, she must 
inform the investigator immediately and study treatment should be withheld until pregnancy is 
confirmed by a serum pregnancy test. If serum pregnancy test is positive, the patient should 
permanently discontinue protocol-indicated treatment.  
The investigator or medical designee should counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until 
conclusion of the pregnancy. All pregnancies of patients taking acalabrutinib or partners of 
patients taking acalabrutinib as well as related outcomes should be reported to Acerta-Pharma 
per contractual guidelines. Any SAEs associated with the pregnancy (e.g. an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported using the SAE form. The pregnancy must be followed for the final 
pregnancy outcome (i.e., delivery, still birth, miscarriage).  
 
• 
Data Safety Monitoring Committee and Institutional Review Board  
Study Investigators will conduct continuous review of data and patient safety.  The Investigator 
will submit quarterly progress reports of these data to the Data Safety Monitoring Committee 
for review.  The review will include for each treatment arm/dose level:  the number of patients 
enrolled, withdrawals, significant toxicities, serious adverse events both expected and 
unexpected, dose adjustments, and responses observed.  The PI maintains a database of all 
adverse events with toxicity grade and information regarding treatment required, 
complications, or sequelae.  The Investigator will submit a copy of the AE spreadsheet along 
with a Progress Report to the Data Safety Monitoring Committee (DSMC) for review. Actual 
review dates will be assigned when the 1st patient is accrued. 


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• 
Any serious adverse event that is serious, related AND unexpected must be reported 
within 5 calendar days to both the DSMC Safety Coordinator and the RSRB (see RSRB 
guidelines).  The DSMC Chair will determine whether further action is required, and when 
patient safety is of concern, an interim meeting may be called. 
• 
Serious adverse events that are related AND expected or unrelated AND unexpected will 
be reported to the DSMC for review at the quarterly meeting.  SAE reports are expected to 
include sufficient detail so that the DSMC can determine the severity, toxicity grade, 
expectedness, treatment required, and a follow up report documenting resolution or if 
there are sequelae.  Serious adverse events that require detailed reports (but not 
necessarily expedited) are expected, related, non-hematologic toxicities of grades 3, 4 or 5. 
The Data Safety Monitoring Committee provides oversight of study progress and safety by 
review of accrual and events at regularly scheduled meetings. The frequency of review is 
determined by the size, risk and complexity of the trial, and is assigned by the Protocol Review 
Committee at the time of their initial review and approval. The Data and Safety Monitoring 
Committee will monitor all adverse event rates utilizing a cumulative spreadsheet listing of all 
events submitted along with progress reports by the PI. All serious adverse events that have 
occurred in the prior 3 months will be reviewed at the regular quarterly meeting of the DSMC in 
order to confirm toxicity grade, expectedness, relatedness, sequelae, follow up required, and 
risk to current or future subjects. 
 
• 
Food and Drug Administration (FDA) 
In this trial, unexpected adverse events believed to be related to investigational therapy will be 
reported to the FDA via MedWatch (using the online form currently available at 
https://www.accessdata.fda.gov/scripts/medwatch/), by telephone 1-800-FDA-1088, or by fax 
1-800-FDA-0178 (using the form currently available at 
http://www.fda.gov/medwatch/report/hcp.htm).   
 
• 
Additional Reporting Requirements for IND  
Events meeting the following criteria need to be submitted to the FDA as expedited IND Safety 
Reports according to the following guidance and timelines: The Study chair is required to notify 
the FDA of any fatal or life-threatening AE that is unexpected and assessed to be possibly, 
probably or definitely related to the investigational agents. An unexpected AE is one that is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with the 
risk information described in the general investigational plan or elsewhere in the current 
application, as amended. Such reports are to be telephoned or faxed to the FDA within 7 
calendar days of first learning of the event. 


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11 CLINICAL DATA COLLECTION  
11.1 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. Acerta-Pharma / Astra Zeneca will be notified of any amendments to the protocol. 
All amendments require review and approval of the Principal Investigator. The written amendment must 
be submitted to the IRB at the investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be reviewed 
and approved by the IRB. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
investigator as applicable, and specifically when an increase to dosing or patient exposure and/or 
patient number has been proposed; or, when the addition or removal of an Investigator is necessitated. 
11.2 FINANCIAL DISCLOSURES AND ETHICAL CONSIDERATIONS 
All investigators will be required to have a signed up-to-date curriculum vitae (CV), current within two 
years, a current copy of their medical license, and a completed FDA form 1572.  
This study will be conducted according to the standards of Good Clinical Practice outlined in the ICH E6 
Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, institutional research 
policies and procedures and any other local applicable regulatory requirement(s). 
11.3 IRB AND REGULATORY APPROVAL 
The study protocol, ICF, IB, available safety information, patient documents, patient recruitment 
procedures, information about payments and compensation available to the patients and 
documentation evidencing the PI’s qualifications must be submitted to the IRB for ethical review and 
approval prior to the study start and in accordance with institutional guidelines. 
The PI/Sponsor and/or designee will follow all necessary regulations to ensure initial and ongoing, IRB 
study review. The PI must submit and, where necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the informed consent document. Investigators will be advised by 
the sponsor or designee whether an amendment is considered substantial or non-substantial and 
whether it requires submission for approval or notification only to an IRB.  Sites must follow institutional 
IRB guidelines for submission requirements. 
If applicable, the PI will notify the IRB within 90 days of the end of the study, or if the study terminates 
early, the PI must notify the IRB within 15 days of the termination. A reason for the early termination 
must be provided (as defined in Directive 2001/20/EC).  
11.4 INFORMED CONSENT 


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Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study, after having been informed of all aspects of the study that are relevant 
to the patient's decision to participate. Informed consent is documented by means of a written, signed, 
and dated informed consent form. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of the 
study. Each consent form must include all of the relevant elements currently required by the responsible 
regulatory authority, as well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the study. Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications of 
participating in this study, the candidate will be asked to give consent to participate in the study by 
signing an informed consent form. A notation that written informed consent has been obtained will be 
made in the patient’s medical record. A copy of the informed consent form, to include the patient’s 
signature, will be provided by the investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study must be obtained. 
11.5 CONFIDENTIALITY  
Confidentiality of patient’s personal data will be protected in accordance with the Health Insurance 
Portability and Accountability Act of 1996 (HIPAA), and national data protection laws. HIPAA regulations 
require that, in order to participate in the study, a patient must sign an authorization from the study 
that he or she has been informed of following: 
• 
What protected health information (PHI) will be collected from patients in this study;  
• 
Who will have access to that information and why;  
• 
Who will use or disclose that information;  
• 
That health information may be further disclosed by the recipients of the information, and that if 
the information is disclosed the information may no longer be protected by federal or state 
privacy laws;  
• 
The information collected about the research study will be kept separate from the patient’s 
medical records, but the patient will be able to obtain the research records after the conclusion 
of the study;  
• 
Whether the authorization contains an expiration date; and  
• 
The rights of a research patient to revoke his or her authorization.  In the event that a patient 
revokes authorization to collect or use his or her PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of patient authorization. For patients 
that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e., that the patient is alive) at the end of their scheduled 
study period.  In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a 
requirement that the investigator and institution permit authorized representatives of the 
Sponsor, the regulatory authorities and the IRB direct access to review the patient’s original 
medical records at the site for verification of study-related procedures and data.   
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients on the CRF or other documents submitted to the Sponsor. This information, together with the 
patient’s date of birth, will be used in the database for patient identification. Patient names or 
addresses will not be entered in the CRF or database. No material bearing a patient’s name will be kept 


Acalabrutinib + low dose SQ Rituximab 
 
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Page 51 of 59 
on file by the Sponsor. Patients will be informed of their rights within the ICF. 
11.6 STUDY DOCUMENTATION AND STORAGE 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated study 
duties and should ensure that all persons assisting in the conduct of the study are informed of their 
obligations. All persons authorized to make entries and/or corrections on the CRFs are to be included on 
this document. All entries in the patient’s CRF are to be supported by source documentation where 
appropriate. Source documents are the original documents, data, records and certified copies of original 
records of clinical findings, observations and activities from which the patient’s CRF data are obtained. 
These can include, but are not limited to, hospital records, clinical and office charts, laboratory, medico-
technical department and pharmacy records, diaries, microfiches, EKG traces, copies or transcriptions 
certified after verification as being accurate and complete, photographic negatives, microfilm or 
magnetic media, X-rays, and correspondence.  
The PI and study staff are responsible for maintaining a comprehensive and centralized filing system 
(Site Study File/SSF or ISF) of all study-related (essential) documentation, suitable for inspection at any 
time by representatives from the Sponsor and/or applicable regulatory authorities. The ISF/SSF must 
consist of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced. The ISF/SSF should contain as a minimum all relevant documents 
and correspondence, including key documents such as the IB and any amendments, protocol and any 
amendments, signed ICFs, IRB approval documents, Financial Disclosure forms, patient identification 
lists, enrollment logs, delegation of authority log, staff qualification documents, laboratory normal 
ranges, records relating to the study drug including accountability records. Drug accountability records 
should, at a minimum, contain information regarding receipt, shipment, and disposition. Each form of 
drug accountability record, at a minimum, should contain PI name, date drug shipped/received, date, 
quantity and batch/code, or lot number for identity of each shipment. In addition, all original source 
documents supporting entries in the CRF must be maintained and be readily available. 
The IRB shall maintain adequate documentation / records of IRB activities for at least 3 years after 
completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other study-
related records for no less than 2 years after the last marketing application has been approved by FDA; 
or, in the event that the marketing application has not been approved by FDA, for no less than 2 years 
after the last shipment / delivery of the drug for investigational use is discontinued and FDA has been 
notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., medical records), all original, signed 
informed consent forms, and copies of all CRFs, SAE Reporting forms, source documents, detailed 
records of treatment disposition, and related essential regulatory documents. The documents listed 
above must be retained by the investigator for as long as needed to comply with national and 
international regulations (generally 2 years after discontinuing clinical development or after the last 
marketing approval). The Sponsor or its representative will notify the investigator(s)/institutions(s) when 
the study-related records are no longer required. 


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Page 52 of 59 
11.7 DATA COLLECTION AND SAFETY 
The study CRF is the primary data collection instrument for the study. An electronic case report form will 
be utilized for the collection of all data and all data will be entered using the English language and 
should be kept current to enable the monitor to review the patients’ status throughout the course of 
the study. 
In order to maintain confidentiality, only study number, patient number, initials, and date of birth will 
identify the patient in the CRF.  If the patient’s name appears on any other document (e.g. laboratory 
report), it must be obliterated on the copy of the document to be supplied to the investigator site and 
replaced instead with the patient number and patient’s initials.  The investigator will maintain a 
personal patient identification list (patient numbers with corresponding patient identifiers) to enable 
records to be identified and verified as authentic. Patient data/information will be kept confidential, and 
will be managed according to applicable local, state, and federal regulations. 
 
11.8 PUBLICATION POLICY 
All information provided regarding the study, as well as all information collected/documented during 
the course of the study, will be regarded as confidential.  
A clinical study report will be prepared upon completion of the study. The PI will disclose the study 
results, in the form of a clinical study report synopsis, to the applicable regulatory authorities within one 
year of the end of the study.  


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Page 53 of 59 
12 PLANNED CORRELATIVE ANALYSES 
At URMC, study labs (peripheral blood) will be collected immediately before initiation of the first dose of 
rituximab (50 mg IV), at 1 hour and at completion of the infusion. Peripheral blood will also be sampled 
immediately before and 2 hours after the subcutaneous administration 50 mg of rituximab on days 3, 8, 
and 15 of cycle 1, on day 1 of cycles 2-6 of rituximab, at 4 weeks after the administration of the last dose 
of rituximab, and then every 3 months until 24 months after initiation of therapy. After collection, these 
samples will be processed and analyzed in the laboratory of Dr. Clive Zent at the University of Rochester.  
 
Acalabrutinib and HFLD SQ rituximab correlative studies specimen requirements 
Cycle 1 
D1  
Cycle 1 
D3 or 4 
or 5 
Cycle 1 
D8 
Cycle 1 
D15 
Cycle 2-6 
D1 
Cycle 9-
24 D1 
5 ml yellow top tube (serum) 
X* 
X# 
X# 
X# 
X 
X*** 
10 ml purple top tube (CLL cells) 
X* 
X# 
X# 
X# 
X##  
10 ml purple top tube 
(lymphocytes) 
X** 
X*** 
X*** 
* Before start of RTX infusion and then at 1 hour and at completion of infusion. All samples need to be 
labeled with the amount /dose of rituximab administered and the time of sample collection. 
Document any interruptions in infusion 
** before start of rituximab infusion 
*** before rituximab on D1 of cycles 3, 6, 9, 12, 16, 18, 22, 25 (+/- 4 weeks) 
# before and 2 hours after rituximab injection  
## before rituximab injection - need to collect 2 tubes (only applies to Cycle 2 D1) 
Window for each sample is +/- 15 minutes.  
 
 
At the post cycle 12 and/or cycle 24 response assessment, peripheral blood and bone marrow samples 
will be analyzed for minimal residual disease in the laboratory of Dr. Richard Burack at the University of 
Rochester. Minimal residual disease in peripheral blood and bone marrow will be evaluated by 6-color 
flow cytometry in attempt to quantify each patient’s depth of remission.  
 
Minimal residual disease processing/transport 
Peripheral blood:  
1. 
Whole blood will be collected in 2 BD CPT tubes [e.g. BD Vacutainer CPT Mononuclear Cell 
Preparation Tube - Sodium Heparin (16x125mm/8mL)] 
2. 
Centrifuge at 1800xg for 30 minutes in a swing bucket centrifuge (not a fixed angle) 
within 24 hours of collection 
3. 
If shipping, place in absorbent sleeve (e.g. Absorb Aqui-pak), then in insulated sealable 
pouch with ambient cold pack (e.g. Koolit gel pack) 
4. 
Send in rigid package, compliant for shipping biological class B materials. Label package 
as “Acalabrutinib rituximab Study” 
Bone marrow: 


Acalabrutinib + low dose SQ Rituximab 
 
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Page 54 of 59 
1. 
Bone marrow will be collected in Sodium Heparin (green top). An aliquot of an original 
specimen is acceptable. 
2. 
If shipping, place in absorbent sleeve (e.g. Absorb Aqui-pak), then in insulated sealable 
pouch with ambient cold pack (e.g. Koolit gel pack) 
3. 
Send in rigid package, compliant for shipping biological class B materials. Label package 
as “Acalabrutinib rituximab Study” 
Ship to: 
Phil Rock, Tissue Bank 
University of Rochester Medical Center 
601 Elmwood Ave. Hematopathology – Room#2.3655A 
Rochester NY 14642 
 
 
Phone: 585-275-3713 
 
 
Fax: 585-276-2390 
 
 
Email: Philip_rock@urmc.rochester.edu 


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Page 55 of 59 
13 REFERENCES 
1. 
Dohner, H., et al., Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J 
Med, 2000. 343(26): p. 1910-6. 
2. 
Eichhorst, B., et al., First-line chemoimmunotherapy with bendamustine and rituximab versus 
fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic 
leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. 
Lancet Oncol, 2016. 
3. 
Fischer, K., et al., Long-term remissions after FCR chemoimmunotherapy in previously untreated 
patients with CLL: updated results of the CLL8 trial. Blood, 2016. 127(2): p. 208-15. 
4. 
Goede, V., et al., Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated 
results of the CLL11 study. Leukemia, 2015. 29(7): p. 1602-4. 
5. 
Burger, J.A., et al., Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N 
Engl J Med, 2015. 373(25): p. 2425-37. 
6. 
Byrd, J.C., et al., Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N 
Engl J Med, 2014. 371(3): p. 213-23. 
7. 
Mato, A.R., et al., Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a 
real world experience. Blood, 2016. 128(18): p. 2199-2205. 
8. 
Dal Porto, J.M., et al., B cell antigen receptor signaling 101. Mol Immunol, 2004. 41(6-7): p. 599-
613. 
9. 
Young, R.M. and L.M. Staudt, Targeting pathological B cell receptor signalling in lymphoid 
malignancies. Nat Rev Drug Discov, 2013. 12(3): p. 229-43. 
10. 
Khan, W.N., Regulation of B lymphocyte development and activation by Bruton's tyrosine kinase. 
Immunologic Research, 2001. 23(2): p. 147-156. 
11. 
Mohamed, A.J., et al., Bruton's tyrosine kinase (Btk): function, regulation, and transformation 
with special emphasis on the PH domain. Immunol Rev, 2009. 228(1): p. 58-73. 
12. 
de Rooij, M.F.M., et al., The clinically active BTK inhibitor PCI-32765 targets B-cell receptor– and 
chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood, 2012. 
119(11): p. 2590-2594. 
13. 
Ponader, S., et al., The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic 
leukemia cell survival and tissue homing in vitro and in vivo. Blood, 2012. 119(5): p. 1182-1189. 
14. 
Byrd, J.C., et al., Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J 
Med, 2016. 374(4): p. 323-32. 
15. 
Uchida, J., et al., The innate mononuclear phagocyte network depletes B lymphocytes through Fc 
receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med, 2004. 
199: p. 1659-1669. 
16. 
Minard-Colin, V., et al., Lymphoma depletion during CD20 immunotherapy in mice is mediated 
by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV. Blood, 2008. 112(4): p. 1205-13. 
17. 
Montalvao, F., et al., The mechanism of anti-CD20-mediated B cell depletion revealed by 
intravital imaging. J Clin Invest, 2013. 123(12): p. 5098-103. 
18. 
Gul, N., et al., Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. 
J Clin Invest, 2014. 124(2): p. 812-23. 
19. 
Gul, N. and M. van Egmond, Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: 
A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer. Cancer Res, 2015. 
75(23): p. 5008-13. 
20. 
Weiskopf, K. and I.L. Weissman, Macrophages are critical effectors of antibody therapies for 
cancer. MAbs, 2015. 7(2): p. 303-10. 


Acalabrutinib + low dose SQ Rituximab 
 
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Page 56 of 59 
21. 
Church, A.K., et al., Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic 
lymphocytic leukaemia cells by autologous macrophages. Clin Exp Immunol, 2016. 183: p. 90-
101. 
22. 
Grandjean, C.L., et al., Intravital imaging reveals improved Kupffer cell-mediated phagocytosis as 
a mode of action of glycoengineered anti-CD20 antibodies. Sci Rep, 2016. 6: p. 34382. 
23. 
Zent, C.S. and M.R. Elliott, Maxed out macs: physiologic cell clearance as a function of 
macrophage phagocytic capacity. FEBS J, 2017. 284(7): p. 1021-1039. 
24. 
Baig, N.A., et al., Induced resistance to ofatumumab-mediated cell clearance mechanisms, 
including complement-dependent cytotoxicity, in chronic lymphocytic leukemia. J Immunol, 
2014. 192: p. 1620-1629. 
25. 
Klepfish, A., et al., Adding fresh frozen plasma to rituximab for the treatment of patients with 
refractory advanced CLL. Qjm, 2008. 101(9): p. 737-40. 
26. 
Baig, N.A., et al., Complement dependent cytotoxicity (CDC) in chronic lymphocytic leukemia 
(CLL): Ofatumumab enhances alemtuzumab CDC and reveals cells resistant to activated 
complement. Leuk Lymphoma, 2012. 53(11): p. 2218-27. 
27. 
Lindorfer, M.A., et al., Real-time analysis of the detailed sequence of cellular events in mAb-
mediated complement-dependent cytotoxicity of B-cell lines and of chronic lymphocytic leukemia 
B-cells. Mol Immunol, 2016. 70: p. 13-23. 
28. 
Taylor, R.P. and M.A. Lindorfer, Fcgamma-receptor-mediated trogocytosis impacts mAb-based 
therapies: historical precedence and recent developments. Blood, 2015. 125(5): p. 762-6. 
29. 
Valgardsdottir, R., et al., Human neutrophils mediate trogocytosis rather than phagocytosis of 
CLL B cells opsonized with anti-CD20 antibodies. Blood, 2017. 129(19): p. 2636-2644. 
30. 
Zent, C.S., et al., The treatment of recurrent/refractory chronic lymphocytic leukemia/small 
lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL 
cells into the circulation. Cancer, 2010. 116(9): p. 2201-7. 
31. 
Aue, G., et al., Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 
expression on tumor cells in patients with chronic lymphocytic leukemia. Haematologica, 2010. 
95(2): p. 329-32. 
32. 
Assouline, S., et al., Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous 
rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a 
phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol, 2016. 3(3): p. 
e128-38. 
33. 
Davies, A., et al., Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for 
first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. 
Lancet Haematol, 2017. 4(6): p. e272-e282. 
34. 
Davies, A., et al., Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma 
(SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol, 2014. 15(3): p. 343-52. 
35. 
Rummel, M., et al., Preference for subcutaneous or intravenous administration of rituximab 
among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: 
results from a prospective, randomized, open-label, crossover study (PrefMab). Ann Oncol, 2017. 
28(4): p. 836-842. 
36. 
Burger, J.A., et al., Safety and activity of ibrutinib plus rituximab for patients with high-risk 
chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol, 2014. 15(10): p. 1090-
9. 
37. 
Hallek, M., et al., iwCLL guidelines for diagnosis, indications for treatment, response assessment, 
and supportive management of CLL. Blood, 2018. 131(25): p. 2745-2760. 


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Page 57 of 59 
 Appendix 1.  Known Strong in Vivo Inhibitors or Inducers of CYP3A 
 
 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ac 
boceprevir 
carbamazepined 
clarithromycinb 
phenytoind 
conivaptinb 
rifampind 
indinavir 
St John's wortd  
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
  
a. 
A strong inhibitor for CYP3A is defined as an inhibitor that increases the AUC of a substrate for CYP3A by ≥ 5-fold. 
b. 
In vivo inhibitor of P-glycoprotein.  
c. 
A strong inducer for CYP3A is defined as an inducer that results in ≥ 80% decrease in the AUC of a substrate for CYP3A. 
d. 
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 13 
November 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.
htm#inVivo 
 


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Appendix 2.  Grading scale for hematologic toxicity in CLL studies 
 
Grade 
Decrease in platelets† or 
Hb‡ (nadir) from 
pretreatment value, % 
Absolute neutrophil 
count/uL§ (nadir) 
0 
No change to 10% 
≥2000 
1 
11%-24% 
≥ 1500 and < 2000 
2 
25%-49% 
≥ 1000 and < 1500 
3 
50%-74% 
≥ 500 and < 1000 
4 
≥75% 
<500 
*Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result of toxicity at any level of 
decrease from pretreatment will be recorded as grade 5. 
 
†Platelet counts must be below normal levels for grades 1 to 4. If, at any level of decrease, the platelet count is <20 x109/L (20 
000/uL), this will be considered grade 4 toxicity, unless a severe or life-threatening decrease in the initial platelet count (eg, 20 x 
109/L [20 000/uL]) was present pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts. 
 
‡Hb levels must be below normal levels for grades 1 to 4. Baseline and subsequent Hb determinations must be performed 
before any given transfusions.  
 
§If the absolute neutrophil count (ANC) reaches < 1 X 109/L (1000/_L), it should be judged to be grade 3 toxicity. Other 
decreases in the white blood cell count, or in circulating neutrophils, are not to be considered because a decrease in the white 
blood cell count is a desired therapeutic endpoint. A gradual decrease in granulocytes is not a reliable index in CLL for stepwise 
grading of toxicity. If the ANC was < 1 X 109/L (1000/uL) before therapy, the patient is not evaluable for toxicity referable to the 
ANC. The use of growth factors such as G-CSF is not relevant to the grading of toxicity, but should be documented. 
 
 
 


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Appendix 3.  Highly effective methods of contraception 
Intrauterine Device Methods 
Hormonal Methods 
Copper T 
Any registered and marketed contraceptive agent 
that contains an estrogen and/or a progestational 
agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents) such as: 
Levonorgestrel-releasing intrauterine system 
     Medroxyprogesterone injections 
 
     Etonogestrel implants 
 
     Hormone shot or injection 
 
     Normal and low dose combined oral pills 
 
     Norrelgestomin EE transdermal system 
  

ICF_001.pdf: 
Page 1 of 12 
CTO # ULYM18086 
STUDY00003231 
Version Date: 17Aug2021 
RSRB Approval Date: 9/16/2021 
Expiration Date: 9/1/2022 
 
 
CONSENT FORM - NCT03788291 
 
Phase II study of acalabrutinib and high frequency low dose subcutaneous rituximab in patients 
with previously untreated CLL/SLL 
 
Principal Investigator: Paul Barr, MD 
 
This consent form describes a research study, what you may expect if you decide to take part and important 
information to help you make your decision. Please read this form carefully. 
 
The study staff will also explain this study to you. Please ask questions about anything that is not clear 
before you agree to participate. You may take this consent form home to think about and discuss with family 
or friends. 
 
Key Information 
• 
Being in this research study is voluntary – it is your choice. 
• 
You are being asked to take part in this study because you have been diagnosed with chronic 
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 
• 
The main purpose of this research study is to find out if the combination of acalabrutinib and frequent 
low dose subcutaneous rituximab is safe and effective in patients who have previously untreated 
CLL/SLL. 
• 
Your participation in the treatment part of the study will last about 2 years. After that, study personnel 
will monitor your health status by checking your medical chart periodically, noting any additional 
treatments you might receive for CLL/SLL. 
• 
Procedures will include documenting your medical history and physical examination, updating 
medications being taken, and doing blood tests before starting the medication. 
• 
There are risks from participating. 
o The most common risk is headache or transient diarrhea with starting acalabrutinib or an 
infusion reaction with the first rituximab administration. 
o One of the most serious risks is an irregular heart rhythm (atrial fibrillation). See the “Risks 
of Participation” section in this consent form for more information. You should discuss these 
risks in detail with the study team. 
• 
We do not know if you will benefit from this research study. It is possible that your condition will 
get better, but it is also possible that there will be no effect on your condition or that your condition 
will get worse. We can use what we learn from this research study to help other people with the same 
disease. 
• 
If you do not want to take part in this study, you may discuss other therapy options with your 
physician. These could include being followed with observation, chemotherapy or ibrutinib. 


Page 2 of 12 
CTO # ULYM18086 
STUDY00003231 
Version Date: 17Aug2021 
RSRB Approval Date: 9/16/2021 
Expiration Date: 9/1/2022 
 
Description of Study Procedures 
 
Before you begin the research study 
 
You will need to have the following exams, tests or procedures to find out if you can be in the research 
study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not 
join the research study. If you have had some of them recently, they may not need to be repeated. This will 
be up to your study doctor. 
 
• 
A medical history, which includes questions about your health, current medications, and any 
allergies. 
• 
Physical exam, which includes vital signs, height, weight, and assessment of disease. 
• 
Performance status, which evaluates how you are able to carry on with your usual activities. 
• 
Blood tests, to measure the numbers and types of cells in your blood, test markers to help better 
understand your CLL disease, test your liver and kidney function, blood clotting, and test for viruses 
in your blood. 
• 
Blood pregnancy test (for women of child bearing potential) 
• 
An assessment of your tumor using CT (Computed Tomography) scan of your chest, abdomen, 
pelvis and neck will be done. This is a tumor assessment to measure the extent of your disease. 
 
If these tests show that you are eligible to participate in the research study, you will begin the study 
treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study. 
 
Study Treatment 
Treatments are repeated every 28 days. Each period of 28 days is called a cycle. 
 
• 
You will start treatment with an IV infusion of rituximab on Day 1. An IV is a small plastic tube 
inserted into a vein in your arm using a needle, the drug will be administered through the tube. 
Afterwards, you will receive rituximab subcutaneous starting on Day 3, 4, or 5 of cycle 1 and then 
twice weekly for 6 cycles. 
• 
You will begin acalabrutinib on Day 8 of cycle 1. Acalabrutinib will be taken twice per day by 
mouth. 
• 
Response assessments including CT will be performed prior to the completion of cycle 12. Based 
on these results at cycle 12, the study doctor will decide if you will undergo a bone marrow biopsy 
to confirm complete remission as well as peripheral and bone marrow testing for minimal residual 
disease (MRD) negativity. 
o 
If remission is confirmed, you will stop therapy and be followed until disease progression. 
o 
If not in a complete remission or MRD remains positive/detectable, you will continue acalabrutinib 
until cycle 24. 
• 
Repeat response assessments will again be performed at 24 cycles of therapy for those continuing 
on acalabrutinib. Based on these results, the study doctor will decide if you will undergo a bone 
marrow biopsy to confirm complete remission and minimal residual disease negativity. 
o 
If remission is confirmed, you will stop therapy and be followed until disease 
progression. 
o 
If not in a complete response or MRD remains positive/detectable, will you will 
continue acalabrutinib at you and your study doctor’s discretion. 
o 
Know that using minimal residual disease testing to guide treatment duration is still 
considered investigational. 


Page 3 of 12 
CTO # ULYM18086 
STUDY00003231 
Version Date: 17Aug2021 
RSRB Approval Date: 9/16/2021 
Expiration Date: 9/1/2022 
 
The table below provides further details of study procedures: 
 
Cycle = 28 days 
Screening 
Cycle 1 
Cycle 
2-6 
Cycle 
7-12 
Cycles 
12-24 
Follow 
up 
D-28 to -1 
D1 
D3,4 
or 5 
D8 
D15 
D1 
D1 
Every 3 
months 
 
Informed Consent 
X 
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
 
Blood Draw 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Test 
X 
 
CT imaging (neck, chest, 
abdomen, pelvis) 
X 
X 
X 
Bone Marrow (BM) 
aspirate & biopsy 
X 
X 
Flow cytometry for 
MRD 
X 
Rituximab 50 mg twice 
weekly 
X 
X 
X 
X 
X 
Acalabrutinib 100 mg 
twice a day 
X 
X 
X 
X 
X 
X 
Response Assessment 
X 
X 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
 
Information about your study participation and study results may be included in your electronic health 
record. If you have concerns about this or to obtain more detail, you should discuss this with the study team. 
 
Number of Subjects 
Approximately 40 subjects will take part in this study. 
 
Risks of Participation 
There are risks to taking part in any research study. One risk is that you may get a study drug that does not 
help treat your disease or that makes your condition or disease worse. Another risk is that there may be side 
effects. 
 
All cancer treatments can have side effects, which can range from mild and reversible to severe, long lasting 
and possibly life-threatening. There is a great deal of variability among side effects of different cancer 
treatments and between individuals. In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the study team immediately if 
you experience any side effects. 
Everyone in the research study will be watched carefully for side effects. You will be monitored during the 
administration of the study drugs to keep track of your blood counts and the function of vital organs, 
particularly the kidneys and liver. If you experience side effects, they may go away after you stop taking 
the study drug. Some side effects can be mild; but others can be long lasting and may never go away. Some 
may be life-threatening or fatal. 


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Since the effect of the study drug(s) taken with other medications may not be known, it is important that 
you tell the research doctor about all prescription and non-prescription drugs, herbal preparations and 
nutritional supplements that you are taking or planning to take. There may also be some foods that you 
should avoid while on this research study and your research doctor will review this information with you. 
 
During the research study, you will be notified of newly discovered side effects or significant findings, 
which may affect your health or willingness to participate. You may be asked to sign a new consent form 
that shows that you have been informed of new information relating to this research study. 
 
Risks Associated with Rituximab: 
Very Common (Equal to or greater than 10% of patients): 
• 
Infusion/Administration related reaction (flushing, decreased blood pressure, rash) 
• 
Fever 
• 
Chills 
• 
Infection 
• 
Weakness 
• 
Headache 
• 
Abdominal Pain 
• 
Pain 
• 
Low white blood cell counts (and associated risk of infection) 
• 
Low platelet count (and associated risk of bleeding) 
• 
Night sweats 
• 
Rash 
• 
Pruritus (itching) 
• 
Rash and itching at injection site 
• 
Cough 
• 
Runny nose 
• 
Angioedema (swelling, especially around the nose or mouth) 
• 
Nausea 
 
Common (1-10% of patients): 
• 
Back pain 
• 
Throat irritation 
• 
Flushing (redness in face or other areas of body) 
• 
Anemia (low hemoglobin leading to fatigue and shortness of breath) 
• 
Hives (itchy red welts) 
• 
Wheezing 
• 
Shortness of breath 
• 
Sinus infection 
• 
Hyperglycemia (high blood sugar causing fatigue, blurry vision in patients with diabetes) 
• 
Peripheral edema (swelling of extremities) 
• 
Diarrhea 
• 
Vomiting 
• 
Constipation 
• 
Dizziness 
• 
Anxiety 


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• 
Muscle pain 
• 
Joint pain 
• 
Constriction (‘spasm’) of muscles in chest 
• 
Hypotension (low blood pressure) 
• 
Hypertension (high blood pressure) 
 
Less Common (less than 1% of patients): 
• 
Progressive multifocal leukoencephalopathy (a brain infection) 
• 
Tumor lysis syndrome (rapid breakdown of the leukemia) 
 
Risks Associated with Acalabrutinib: 
Very Common (Equal to or greater than 10% of patients): 
• 
Infections 
• 
Headache 
• 
Bruising Events including bruises, petechiae (pinpoint red or purple spots on the skin), and increased 
tendency to bruise 
• 
Diarrhea (frequent or loose stools) 
• 
Musculoskeletal pain 
• 
Nausea 
• 
Constipation (bowel movements that are infrequent or hard to pass) 
• 
Bleeding 
• 
Vomiting 
• 
Abdominal pain 
• 
Rash 
• 
Fatigue (feeling tired) 
• 
Joint pain 
• 
Leukopenia (low white blood cells) 
• 
Dizziness 
• 
Second primary malignancy (development of second cancer) 
• 
Anemia (low red blood cells) 
 
Common (1-9% of patients): 
• 
Nose bleeds 
• 
Thrombocytopenia (low platelets) 
• 
Asthenia (lack of energy) 
• 
Atrial fibrillation/flutter (a type of abnormal heart rhythm) 
 
 
Less Common (less than 1% of patients): 
• 
Progressive multifocal leukoencephalopathy (a brain infection) 
• 
Other severe infections 
• 
Irregular heart rhythm (atrial fibrillation) 
• 
Tumor lysis syndrome (rapid breakdown of the leukemia) 
• 
Drug induced liver injury 


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Risks Associated with Bone Marrow Biopsies: 
For this procedure, a numbing drug is injected into the skin over one of your hipbones. A needle is then 
inserted into the hipbones and a small piece of bone is removed. The risks may include: 
• 
Moderate pain and discomfort 
• 
Bleeding at the biopsy site 
• 
Scarring at the biopsy site 
• 
Rarely, an infection at the biopsy site 
• 
Rarely, nerve injury at the biopsy site 
 
Risks Associated with Bone Marrow Aspiration: 
For this procedure, a numbing drug is injected into the skin over the same hipbone. A needle is then inserted 
into the hipbone and a sample of bone marrow fluid is removed. Risks of this procedure are small, but may 
include: 
• 
Pain from the needle sticks 
• 
Pain from aspirating the bone marrow with a syringe 
• 
Bleeding 
• 
Infection 
• 
Local nerve damage 
 
Radiation Risks Associated with Scans and X-Rays: 
While you are in this research study, CT scans may be used to evaluate your disease. The frequency of these 
exams is similar to what you would receive as standard care. In the long term, over many years, there is a 
very low risk of developing a new cancer as a result of the radiological evaluation and treatment for your 
cancer. 
 
This research study involves exposure to radiation from up to 3 CT scans of the chest, abdomen, pelvis and 
neck. Please note that this radiation exposure is required to obtain the desired research information. 
 
 
Risks Associated with Contrast Agents Used During Scans: 
There is a small risk with using a contrast agent that is injected into a vein during the CT scan. The contrast 
agent is a special dye that highlights organs, blood vessels or tissue to make them more visible. Depending 
on the type of contrast agent that is used, it may cause decreased kidney function or worsen kidney function 
in people who already have decreased kidney function. Therefore, we will monitor your kidney function 
closely while you participate in this study. If there is any change in your kidney function, we may have to 
remove you from the study. 
 
Uncommonly, some people have allergic reactions (such as hives and itching) to the contrast agent. Serious 
reactions (for example, drop in blood pressure, difficulty breathing or severe allergic reaction and death) 
are rare. 
 
Reproductive Risks: 
The drugs used in this research study may affect a fetus. The effects of the study drug on a developing baby 
are unknown; therefore while participating in this research study, you should not become pregnant or father 
a baby and should not nurse a baby. 
 
If you are able to have children, you should use a highly effective method of birth control while taking 
study treatment, as well as for 4 weeks after you stop taking study treatment, to prevent pregnancy in either 


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you or your partner. A “highly effective method of birth control” is defined as a method that has a low 
failure rate (i.e. less than 1% per year) when used consistently and correctly and includes implants, 
injectables, birth control pills with two hormones, some intrauterine devices (IUDs), sexual abstinence 
(which is defined as refraining from all aspects of sexual activity) or a sterilized partner. If you are using 
hormonal contraceptives such as birth control pills or devices, a second barrier method of contraception 
(e.g. condoms) must be used. Note: Some birth control pills will not work when you are taking certain 
drugs. If you have any questions about this, please discuss this with the study doctor. 
 
Be aware that you can still become pregnant even if you use highly effective method of birth control. 
 
If you or your partner becomes pregnant during the study or until 2 days after the last dose of acalabrutinib 
or 12 months after the last dose of rituximab, you should immediately inform the study staff. If you become 
pregnant on the study, you must immediately stop taking the study treatment. The Sponsor would like to 
collect information about the birth of your baby even after treatment is stopped. We can provide counseling 
about preventing pregnancy for either male or female study participants. 
 
In addition to the risks listed above, there could be unknown or unexpected side effects associated with the 
use of the study drug. You will be told in a timely manner, verbally and in writing, of any new information, 
findings, or changes to the way the research will be done that might influence your willingness to continue 
your participation in this study. 
 
Risks of study data in the Electronic Health Record 
The study team may be notified if you receive other health care services at URMC or its Affiliates (e.g., 
visit to the emergency room). In addition, the following individuals may know you participated in research 
and may see results of testing conducted for this study: 
• 
Staff at the University of Rochester Medical Center and its Affiliates (e.g., Strong Memorial 
Hospital, Highland Hospital, URMC primary care, specialist physician offices) who have a reason 
to access your electronic health record. 
• 
Health care providers who are involved in your care at a facility that is not part of the University of 
Rochester Medical Center and its Affiliates and who have reason to access your electronic health 
record. 
• 
Individuals who request a copy of information from your health record for activities such as 
treatment or payment (e.g., medical insurance companies, worker’s compensation). 
 
Benefits of Participation 
We do not know if you will benefit from this research study. It is possible that your condition will get better, 
but it is also possible that there will be no effect on your condition or that your condition will get worse. 
We may be able to use what we learn from this research study to help other people with the same disease. 
 
Alternatives to Participation 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
• 
Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but 
instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as 
possible. 


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Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Compensation for Injury 
If you are directly injured by the treatment being studied, or by medical procedures needed because of this 
study, and you receive medical care for the injury, you may need to pay for that care. You will be reimbursed 
for reasonable and necessary medical costs for such care, but you might not be reimbursed for care covered 
and paid for by a third party like your health insurance provider, or costs such as required co-payments or 
deductibles related to that coverage. No other funds have been set aside to pay for such things as lost wages 
or expenses due to a current underlying illness or condition. 
 
If your research injury is paid for by the University, we will collect your name, date of birth, gender, and 
Medicare Health Insurance Claim Number or Social Security Number to determine your Medicare status. 
This information will be used only in accordance with the law. If you are a Medicare beneficiary, 
information about the study you are in, and any payments made related to your injury, will be reported to 
the Centers for Medicare & Medicaid Services (CMS), in accordance with CMS requirements. This 
information will not be used for any other purpose. 
 
Costs 
Acerta Pharma/AstraZeneca will provide the study drug, acalabrutinib, free of charge while you are 
participating in this study. Tests and procedures that are required only for the study, that are not a part of 
your regular medical care, will also be provided at no charge. 
 
Rituximab at this dose and frequency is not standard of care and may not be covered by your insurance, 
you should discuss with your study doctor and insurance company any costs that may be associated with 
receiving this study drug. 
 
You or your insurance company will be billed for any standard medical care given during this research 
study. You will be responsible for any co-pays, insurance deductibles and/or co-insurance required by your 
health insurance carrier for your standard medical care. This standard medical care includes any care that 
you would receive for the treatment of your type of cancer whether you were participating in a study or not, 
such as: 
• Routine clinic visits with your doctor or nurse practitioner 
• Tests (Including but not limited to routine items such as: laboratory blood tests, CT, PET/CT, and/or 
FDG/PET scans, X-rays, lung function, or cardiac testing.) 
• Procedures (Including but not limited to routine items such as: bone marrow biopsies and/or 
aspirates, other tumor biopsies) 
• Medications: other standard medications to treat your cancer. This can include other chemotherapies 
or non-chemotherapy medications used to treat your cancer, and/or medications to treat or prevent 
side-effects. 
 
You may want to talk with your insurance company about its payment policy for standard medical care 
given during a research study prior to enrolling on a research study. Depending on how your insurance 
company processes payments for standard medical care given during a research study, you might have 
unexpected expenses from being in this study. If your insurance company does not pay for your standard 
medical care, you will be billed for those charges. 
 
Ask your study doctor to discuss the specific costs that will or will not be covered by the sponsor. This 
discussion should include who will pay the costs of treating possible side effects. 


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Payments 
You will not be paid for participating in this study. 
 
Financial Interest 
The Investigator, Dr. Barr, receives payment for consulting activities from the Study Sponsor, AstraZeneca. 
Please feel free to ask Dr. Barr or other study staff any questions you may have about his role as a consultant 
for the sponsor. 
 
 
Confidentiality of Records and Authorization to Use and Disclose Information for Research Purposes 
The University of Rochester makes every effort to keep the information collected from you private. In order to 
do so, we will maintain your information in a password protected database where only study investigators and 
coordinators will access. Sometimes, however, researchers need to share information that may identify you with 
people that work for the University. If this does happen we will take precautions to protect the information you 
have provided. Results of the research may be presented at meetings or in publications, but your name will not 
be used. 
 
If you have never received a copy of the University of Rochester Medical Center (URMC) and Affiliates 
Notice of Privacy Practices, please ask the investigator for one. 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information. For example: 
• 
Research records 
• 
Records about phone calls made as part of thisresearch 
• 
Records about your study visits 
• 
Past and present medical records related to the study, including records of external providers that are 
available via your electronic health record at URMC & Affiliates 
• 
Results of medical tests 
 
Who may use and give out information about you? 
• 
The study doctor and the study staff 
• 
URMC and Affiliates 
 
Your information may be given to: 
• 
The Department of Health and Human Services 
• 
The University of Rochester 
• 
The U.S. Food and Drug Administration (FDA) may also need to inspect study records at some point 
during the study or even after it has been completed. In the event that this should occur, every effort 
will be made to keep identifying information about youprivate. 
 
 
 
 
 
 
 
Why will this information be used and/or given to others? 


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• 
To do the research 
• 
To study the results 
• 
To see if the research was done correctly 
 
If the results of this study are made public, information that identifies you will not be used. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over. 
 
How long will this permission be valid? 
This permission will last indefinitely. 
 
May I cancel my permission to use and disclose information? 
Yes. You may cancel your permission to use and disclose your health information at any time. You do this 
by sending written notice to the study doctor. Upon receiving the written notice, the study team will no 
longer use or disclose your health information and you will not be able to stay in this study. Information 
that has already been gathered may need to be used and given to others for the validity of the study. 
 
May I withdraw from the study? 
Yes. If you withdraw your permission to be in the study, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given to others. 
 
Is my health information protected after it has been given to others? 
No. There is a risk that your information will be given to others without your permission. 
 
Future Use of Information/Samples 
Your information might be distributed or used for future research studies without additional informed 
consent. All identifiers will be removed before your information is used or distributed. 
 
Circumstances for Dismissal 
The study doctor may stop you from taking part in this research study at any time if he/she believes it is in 
your best interest; if you do not follow the research study rules; or if the research study is stopped. 
 
Early Termination 
You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to 
stop. He or she will tell you how to stop safely. 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the study treatment 
can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is 
to discuss what follow up care and testing could be most helpful for you. 
 
 
New Study Information 
If we discover any new information that might make you change your mind about continuing in the study, 
we will let you know. 


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Return of Research Results 
In general, we will not give you any individual results from your participation in the study. If we find 
something of urgent medical importance to you, we will inform you, although we expect that this will be a 
very rare occurrence. 
 
Contact Persons 
For more information concerning this research or if you feel that your participation has resulted in any 
research related injury, emotional or physical discomfort, please contact: Dr. Paul Barr at 585-275-5863. 
 
Please contact the University of Rochester Research Subjects Review Board at 265 Crittenden Blvd., CU 
420628, Rochester, NY 14642, Telephone (585) 276-0005 or (877) 449-4441 for the following reasons: 
• 
You wish to talk to someone other than the research staff about your rights as a research 
subject; 
• 
To voice concerns about the research; 
• 
To provide input concerning the research process; 
• 
In the event the study staff could not be reached. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this website at any time. 
 
Voluntary Participation 
Taking part in this study is voluntary. You are free not to take part or to withdraw at any time, for whatever 
reason. No matter what decision you make, there will be no penalty or loss of benefit to which you are 
entitled. In the event that you do withdraw from this study, the information you have already provided will 
be kept in a confidential manner. 


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SIGNATURES/DATES 
After reading and discussing the information in this consent form you should understand: 
• 
Why this study is being done; 
• 
What will happen during the study; 
• 
Any possible risks and benefits to you; 
• 
Other options you may have instead of being in the study; 
• 
How your personal information will be protected; 
• 
What to do if you have problems or questions about this study. 
 
 
Subject Consent 
I have read (or have had read to me) the contents of this consent form and have been encouraged to ask 
questions. I have received answers to my questions. I agree to participate in this study. I have received (or 
will receive) a signed copy of this form for my records and future reference. 
 
 
Subject Name (Printed by Subject) 
 
 
Signature of Subject 
Date 
 
 
Person Obtaining Consent 
I have read this form to the subject and/or the subject has read this form. I will provide the subject with a 
signed copy of this consent form. An explanation of the research was given and questions from the subject 
were solicited and answered to the subject’s satisfaction. In my judgment, the subject has demonstrated 
comprehension of the information. I have given the subject adequate opportunity to read the consent before 
signing. 
 
 
Name and Title (Print) 
 
 
Signature of Person Obtaining Consent 
Date