A Phase II Study Using ACP-196 (Acalabrutinib) in Patients With Relapsed/Refractory and Treatment-naïve Deletion 17p CLL/SLL: Pharmacodynamic Assessment of BTK Inhibition and Antitumor Response.
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Sponsor: Acerta Pharma BV

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CLINICAL RESEARCH PROJECT
Protocol #: 15-H-0016
Drug Name: ACP-196 (Acalabrutinib)
IND number: 118717
IND Sponsor: Acerta Pharma, BV
Title:
A Phase II Study Using ACP-196 (Acalabrutinib) in Patients with Relapsed/Refractory and 
Treatment-naïve Deletion 17p CLL/SLL: Pharmacodynamic Assessment of BTK Inhibition and Antitumor 
Response.
Short Title: Acalabrutinib phase II study
Keywords: Acalabrutinib, BTK Inhibitor, Biologic Response Modifier Therapy, CLL, SLL
Principal Investigator:
Company Providing Investigational Drug: Acerta Pharma, BV
Subjects of Study:
Number
Sex
Age-range 
48 evaluable subjects, max. 60 screened
M/F
> 18
Ionizing Radiation for Research:
Yes
Off-Site Project:
No
Multicenter trial:
No
DSMB Involvement:
Yes
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PROTOCOL APPROVAL
Version M
I have carefully read Protocol 15-H-0016 entitled “A phase II study using ACP-196 (acalabrutinib) in
patients with relapsed/refractory and treatment-naïve deletion 17p CLL/SLL: pharmacodynamic 
assessment of BTK inhibition and antitumor response”. I agree to conduct this study as outlined herein and 
in compliance with Good Clinical Practices (GCP) and all applicable regulatory requirements.  
Furthermore, I understand that the Sponsor, Acerta Pharma, BV, and the Institutional Review Board (IRB)/ 
Independent Ethics Committee (IEC) must approve any changes to the protocol in writing before 
implementation.
I agree not to divulge to anyone, either during or after the termination of the study, any confidential 
information acquired regarding the investigational product and processes or methods of Acerta Pharma,
BV.  All data pertaining to this study will be provided to Acerta Pharma, BV.  The policy of Acerta 
Pharma, BV requires that any presentation or publication of study data by clinical investigators be reviewed 
by Acerta Pharma, BV before release, as specified in the protocol.
Principal Investigator’s Signature
Date
Print Name
Confidentiality Statement
This document contains proprietary and confidential information of Acerta Pharma, BV that must not be 
disclosed to anyone other than the recipient study staff and members of the institutional review 
board/independent ethics committee. This information cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of Acerta Pharma, BV.
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PRECIS
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are mature B-cell
malignancies. Patients with relapsed disease and 17p deletion have a particularly aggressive disease 
course. Standard chemoimmunotherapy regimens for patients with relapsed/refractory disease (patients 
who have previously had treatment and need treatment again or patients who did not have a sufficient 
response to therapy) have resulted in few durable remissions. 
B-cell receptor (BCR) activation is a key pathway engaged in the pathogenesis of CLL as well as in the 
interaction of CLL cells with the tumor microenvironment that is required for survival of CLL cells. The 
more aggressive forms of CLL, such as patients with relapsed/refractory disease, are characterized by 
stronger BCR activation. Disruption of tumor microenvironment interactions and inhibition of BCR 
signaling are promising therapeutic strategies in CLL. Bruton tyrosine kinase (BTK) is a key enzyme in 
BCR signaling. Ibrutinib is the first BTK inhibitor that has reached the clinic and is approved as therapy 
for relapsed/refractory CLL. The advent of kinase inhibitors such as ibrutinib has demonstrated 
significantly improved responses as second line therapies as well as improved responses in patients with 
17p deletion compared to responses from standard chemoimmunotherapy regimens with long (more than 
2 years) durable remissions in the majority of patients. 
Acalabrutinib (ACP-196) is an orally available, new molecule that irreversibly inhibits BTK and shows 
encouraging activity and acceptable safety in nonclinical and clinical studies. Acalabrutinib has shown 
efficacy in 3 separate models of lymphoid malignancies. Calquence® has been approved in the United 
States and other markets for the treatment of adult patients with mantle cell lymphoma (MCL) who have 
received at least one prior therapy, CLL, and SLL. We believe that acalabrutinib, a more selective BTK
inhibitor than ibrutinib, is designed to be more potent, more specific, and could overcome limitations 
currently seen with ibrutinib.
This study will investigate the safety and efficacy of acalabrutinib for patients with CLL/SLL who have 
relapsed/refractory disease or treatment-naïve deletion 17p. The primary endpoint is the response to 
acalabrutinib. Biological sampling from lymph nodes, bone marrow, and peripheral blood early during 
treatment will be used to investigate BTK inhibition in the bone marrow and lymph node compartments, 
the main sites for CLL progression in addition to the circulating tumor cells.
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................. 4 
LIST OF TABLES: ..................................................................................................................................................... 7 
1.0 
OBJECTIVES ......................................................................................................................................... 8 
1.1 
PRIMARY OBJECTIVE ........................................................................................................................................... 8 
1.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 8 
1.3 
EXPLORATORY OBJECTIVE .................................................................................................................................... 8 
2.0 
BACKGROUND AND SCIENTIFIC JUSTIFICATION .................................................................................... 8 
2.1 
PATHOPHYSIOLOGY ............................................................................................................................................ 8 
2.2 
EPIDEMIOLOGY AND CLINICAL COURSE OF CHRONIC LYMPHOCYTIC LEUKEMIA ............................................................... 9 
2.3 
DIAGNOSTIC AND PROGNOSTIC CATEGORIES OF CLL/SLL .......................................................................................... 9 
2.4 
INDICATIONS FOR TREATMENT OF CLL ................................................................................................................. 11 
2.5 
TREATMENT OPTIONS FOR CLL/SLL .................................................................................................................... 12 
2.5.1 
Watchful Waiting ..................................................................................................................................... 12 
2.5.2 
First-Line Chemotherapy/Immunotherapy/Chemoimmunotherapy ........................................................ 12 
2.5.3 
Complications of Chemoimmunotherapy ................................................................................................ 13 
2.5.4 
Relapsed or Refractory CLL ...................................................................................................................... 14 
2.5.5 
Stem Cell Transplantation ........................................................................................................................ 15 
2.5.6 
BCR Signaling Inhibitors (Single Agent) .................................................................................................... 15 
2.5.7 
BCR Signaling Inhibitors (Combinations) .................................................................................................. 16 
2.5.8 
Other Options .......................................................................................................................................... 17 
2.6 
ACALABRUTINIB (ACP-196)50............................................................................................................................ 17 
2.6.1 
Distribution .............................................................................................................................................. 18 
2.6.2 
Metabolism and Clearance50 ................................................................................................................... 18 
2.6.3 
Clinical Experience in Chronic Lymphocytic Leukemia ............................................................................. 19 
2.6.4 
Clinical and Scientific Justification for Protocol Design ............................................................................ 19 
3.0 
STUDY DESIGN ................................................................................................................................... 21 
4.0 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ..................................................................................... 24 
4.1 
INCLUSION CRITERIA ......................................................................................................................................... 24 
4.2 
EXCLUSION CRITERIA ........................................................................................................................................ 25 
5.0 
TREATMENT PLAN ............................................................................................................................. 26 
5.1 
DRUG ADMINISTRATION .................................................................................................................................... 26 
5.2 
THERAPY SCHEDULE .......................................................................................................................................... 26 
5.3 
PROPHYLACTIC MEDICATIONS ............................................................................................................................. 26 
5.4 
HOLDING AND DOSE ADJUSTMENTS OF STUDY DRUG ADMINISTRATION IN THE CASE OF TREATMENT-RELATED TOXICITY: .... 26 
5.4.1 
Neutropenia ............................................................................................................................................. 26 
5.4.2 
Thrombocytopenia ................................................................................................................................... 26 
5.4.3 
Nonhematologic Toxicities ....................................................................................................................... 27 
5.5 
HOLDING OF STUDY DRUG ADMINISTRATION ........................................................................................................ 27 
5.5.1 
Surgical Procedures .................................................................................................................................. 27 
5.5.2 
Hepatitis B Virus Reactivation .................................................................................................................. 27 
5.5.3 
Progressive Multifocal Leukoencephalopathy ......................................................................................... 28 
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5.5.4 
Permanent Discontinuation of Study Drug Administration in Case of Treatment-related Adverse 
Events .............................................................................................................................................. 28 
5.6 
SUPPORTIVE CARE (NONINVESTIGATIONAL) .......................................................................................................... 28 
5.7 
PERMITTED AND NONPERMITTED CONCOMITANT MEDICATIONS (INVESTIGATOR’S BROCHURE) ...................................... 28 
5.7.1 
Guideline for Use of CYP Inhibiting and Inducing Drugs .......................................................................... 28 
5.7.2 
Concomitant Use of QT Prolonging Agents .............................................................................................. 29 
5.7.3 
Concomitant Use of Antiplatelet Agents and Anticoagulants ................................................................. 29 
5.8 
SPECIAL INSTRUCTIONS FOR SUBJECTS .................................................................................................................. 29 
5.8.1 
Immunizations ......................................................................................................................................... 29 
5.8.2 
Birth Control ............................................................................................................................................. 29 
5.8.3 
Calcium Carbonate ................................................................................................................................... 29 
6.0 
CLINICAL MONITORING ...................................................................................................................... 29 
6.1 
SCREENING VISIT .............................................................................................................................................. 30 
6.2 
BASELINE TESTING ............................................................................................................................................ 31 
6.3 
ON THERAPY EVALUATIONS ............................................................................................................................... 31 
6.3.1 
Day 1 (C1/D1) Through Day 5 (C1D5) ...................................................................................................... 31 
6.3.2 
On Therapy Evaluations Through 6 Cycles of Treatment ......................................................................... 32 
6.3.3 
Post 6 Cycles of Therapy (Day 28 ± 15-day window unless otherwise noted) .......................................... 33 
6.3.4 
Assessments Every 3 Months (± 15-day window) While on Therapy ....................................................... 34 
6.3.5 
Additional Studies at 12 and 24 Months and Yearly Thereafter (± 30-day window unless otherwise 
noted) .............................................................................................................................................. 34 
6.3.6 
 
 ........................................................................................................................ 35 
6.3.7 
Assessments at Time of Progressive Disease or Suspicion of Progressive Disease .................................. 35 
6.3.8 
Safety Follow-up 30 (+7) Days After the Last Dose of Study Drug (for Subjects Who Remain on 
Study) .............................................................................................................................................. 35 
6.3.9 
Discontinuation Follow-Up ....................................................................................................................... 36 
7.0 
CRITERIA FOR RESPONSE ................................................................................................................... 37 
7.1 
COMPLETE RESPONSE (CR) ................................................................................................................................ 38 
7.2 
PARTIAL RESPONSE (PR) ................................................................................................................................... 38 
7.3 
PROGRESSIVE DISEASE (PD) ............................................................................................................................... 39 
8.0 
ANCILLARY LABORATORY RESEARCH STUDIES .................................................................................... 39 
8.1 
COLLECTION OF SAMPLES .................................................................................................................................. 39 
8.2 
INTENDED USE ................................................................................................................................................ 40 
8.3 
STORAGE, TRACKING AND DISPOSITION OF SAMPLES AND DATA ................................................................................ 40 
8.4 
 ......................................................................................................................................... 41 
9.0 
BIOSTATISTICAL CONSIDERATIONS .................................................................................................... 41 
9.1 
PRIMARY ENDPOINT:  RESPONSE TO ACALABRUTINIB .............................................................................................. 41 
9.2 
SECONDARY ENDPOINTS .................................................................................................................................... 41 
9.3 
 .................................................................................................................................. 42 
9.4 
SAMPLE SIZE ................................................................................................................................................... 42 
9.5 
STATISTICAL METHODS ..................................................................................................................................... 42 
9.6 
STUDY STOPPING RULES .................................................................................................................................... 43 
9.7 
STOPPING RULE FOR MORTALITY ........................................................................................................................ 44 
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9.8 
OFF STUDY CRITERIA (FOR SUBJECT PARTICIPATION) ............................................................................................... 45 
10.0 
DATA AND SAFETY MONITORING ....................................................................................................... 46 
10.1 
ASSESSMENT OF SAFETY .................................................................................................................................... 46 
10.1.1 Definitions ................................................................................................................................................ 46 
10.1.2 Severity .................................................................................................................................................... 47 
10.1.3 Pregnancy ................................................................................................................................................ 47 
10.1.4 Adverse Event and Serious Adverse Event Causality Assessments ........................................................... 48 
10.1.5 Adverse Events of Special Interest ........................................................................................................... 49 
10.1.6 Second Primary Malignancies .................................................................................................................. 49 
10.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS ADVERSE EVENTS ............................................................ 49 
10.3 
 IRB AND CD REPORTING .......................................................................................................... 50 
10.3.1 Serious Events .......................................................................................................................................... 50 
10.3.2 Reporting Period for AEs .......................................................................................................................... 50 
10.3.3 Reporting Requirements for SAEs ............................................................................................................ 50 
10.4 
DATA MANAGEMENT ....................................................................................................................................... 51 
11.0 
HUMAN SUBJECT PROTECTION .......................................................................................................... 52 
11.1 
RATIONALE FOR SUBJECT SELECTION .................................................................................................................... 52 
11.1.1 Predicted distribution by gender, age and race: ...................................................................................... 52 
11.1.2 Special Populations .................................................................................................................................. 52 
11.2 
SERIOUS RISKS ASSOCIATED WITH ACALABRUTINIB TREATMENT ................................................................................ 53 
11.2.1 Hemorrhage ............................................................................................................................................. 53 
11.2.2 Infections ................................................................................................................................................. 54 
11.2.3 Cytopenias ............................................................................................................................................... 54 
11.2.4 Second Primary Malignancies .................................................................................................................. 54 
11.2.5 Atrial Fibrillation ...................................................................................................................................... 55 
11.3 
POTENTIAL FOR DRUG-DRUG INTERACTIONS ......................................................................................................... 55 
11.4 
CONTRAINDICATIONS ........................................................................................................................................ 55 
11.5 
OVERDOSE INSTRUCTIONS ................................................................................................................................. 55 
11.6 
RISKS RELATED TO BLOOD DRAWS ...................................................................................................................... 56 
11.7 
RISKS RELATED TO CT SCAN ............................................................................................................................... 56 
11.8 
RISKS RELATED TO PREGNANCY AND NURSING MOTHERS ........................................................................................ 56 
11.9 
RISKS RELATED TO BONE MARROW BIOPSY ........................................................................................................... 57 
11.10 
RISKS RELATED TO LYMPH NODE BIOPSY .............................................................................................................. 57 
11.11 
RISKS RELATED TO TRANSFUSIONS ....................................................................................................................... 58 
11.12 
RISKS IN RELATION TO BENEFIT ........................................................................................................................... 58 
11.13 
INFORMED CONSENT PROCESSES AND PROCEDURES ............................................................................................... 58 
11.14 
CONFLICT OF INTEREST ...................................................................................................................................... 58 
11.15 
TECHNICAL TRANSFER AGREEMENTS .................................................................................................................... 58 
12.0 
PHARMACEUTICALS ........................................................................................................................... 59 
12.1 
ACALABRUTINIB50 ............................................................................................................................................ 59 
13.0 
REFERENCES ...................................................................................................................................... 62 
APPENDIX A ........................................................................................................................................................ 66 
APPENDIX B ........................................................................................................................................................ 71 
APPENDIX C ........................................................................................................................................................ 73 
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LIST OF TABLES: 
TABLE 1:  RAI STAGING SYSTEM: 10 ........................................................................................................................................ 10 
TABLE 2:  CYTOGENETIC ABNORMALITIES IN CLL14 .................................................................................................................... 11 
TABLE 3:  CRITERIA FOR RESPONSE ........................................................................................................................................ 38 
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1.0
OBJECTIVES 
1.1
Primary Objective
x
To determine the response to acalabrutinib in subjects with chronic lymphocytic leukemia 
(CLL) or small lymphocytic lymphoma (SLL)
1.2
Secondary Objectives
x
Safety and tolerability of acalabrutinib
x
Duration of response to acalabrutinib
o
Time to progression on acalabrutinib
o
Progression-free survival (PFS) and overall survival (OS) on acalabrutinib
x
Explore the biologic effects of once-daily dosing as compared to twice-daily dosing of 
acalabrutinib on CLL tumor cells
x
To measure BTK inhibition and on-target effects of single-agent acalabrutinib in CLL cells in 
lymph node, bone marrow, and blood of subjects with CLL or SLL
1.3
Exploratory Objective 
x
2.0
BACKGROUND AND SCIENTIFIC JUSTIFICATION 
Chronic Lymphocytic Leukemia and/or Small Lymphocytic Lymphoma
The World Health Organization classification of hematopoietic neoplasias describes CLL as a leukemic, 
lymphocytic lymphoma, being only distinguishable from SLL by its leukemic appearance.1 In the National 
Cancer Institute (NCI)-Working Group (WG) guidelines, the diagnosis of CLL requires the presence of at 
least 5 x 109 clonal B lymphocytes/L (5000/μL) in the peripheral blood. The definition of SLL requires the 
presence of lymphadenopathy and/or splenomegaly. Clonal B lymphocytes in the peripheral blood should 
not exceed 5 x 109/L and the diagnosis should be confirmed by histopathologic evaluation of a lymph node 
biopsy when possible.2
Chronic lymphocytic leukemia/SLL cells co-express the T-cell antigen CD5 and B-cell surface antigens 
CD19, CD20, and CD23. The levels of surface immunoglobulin (SIg), CD20, and CD79b are 
characteristically low compared with those found on normal B cells. Each clone of leukemia cells is 
restricted to expression of either kappa or lambda Ig light chains.2
For the purposes of this study, the term “CLL” will encompass both CLL and SLL.
2.1
Pathophysiology 
Chronic lymphocytic leukemia is characterized by a progressive accumulation of functionally incompetent 
lymphocytes. It is believed that antigenic stimulation, along with interactions of accessory cells, cytokines, 
and tumor microenvironment are promoting factors that stimulate proliferation of CLL cells and allows 
them to avoid apoptosis. These effects may differ in distinct CLL/SLL subgroups and thereby lead to the 
heterogeneity seen in clinical outcomes among individual cases. 
Chronic lymphocytic leukemia cells cultured in vitro undergo apoptosis, but they can be rescued by 
coculturing with stromal cells or in presence of soluble factors.3 The tumor-host interactions in vivo were 
recently better defined using gene expression profiling from tumor cells isolated concurrently from 
peripheral blood, bone marrow and lymph node.4 This study identified the lymph node as a key site and 
B-cell receptor (BCR) signaling as a central pathway in CLL pathogenesis. Chronic lymphocytic leukemia
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cells in the lymph node showed up-regulation of gene signatures, indicating BCR and nuclear factor-κB
activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, 
phosphorylation of the spleen tyrosine kinase (Syk) and IκBα, was detected in lymph node derived cells.
Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective 
BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and 
c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the lymph node and 
was correlated with clinical disease progression.4 The BCR is a multimeric complex formed by the 
assembly of SIg homodimer and the noncovalently bound heterodimer Igα/Igβ (CD79a/CD79b). They 
operate through immunoreceptor tyrosine-based activation motifs (ITAM) by linking the antigen-binding Ig 
chains to intracellular tyrosine kinases of the Src-family. BCR signaling induces receptor oligomerization,
Ig α and β phosphorylation and the recruitment and activation of the Syk.5 The downstream signaling 
cascade depends on BTK and phosphoinositide 3-kinase (PI3K).6 These data identify the disruption of 
tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic 
strategies in CLL.
2.2
Epidemiology and Clinical Course of Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia is the most common leukemia of adults in Western countries with an annual 
incidence of 2 to 4.5 per 100,000 in the general population. According to the NCI Surveillance 
Epidemiology and End Results (SEER) data, it is estimated that 14,990 men and women (8,870 men and 
6,120 women) will be diagnosed with CLL. It affects males twice as frequently as females and is a disease 
of older individuals (median age 73.0 years for whites).7 The highest rates of incidence are seen in 
Caucasians followed by African Americans. Lower rates of incidence are seen in Asian and Hispanic 
populations. 
The complications of CLL usually arise from progressive disease. These complications are, but not limited 
to infection, hematologic abnormalities, immune phenomena, secondary cancers, and disease 
transformation. It has been estimated that up to 70% of patients with CLL will develop infections, and 
infections account for about 55% of deaths in patients with CLL. Hematologic abnormalities include 
autoimmune hemolytic anemia (AIHA) in approximately 37% of patients, pure red cell aplasia in 6% of 
patients, and immune mediated thrombocytopenia in 2 to 4% of patients.8 Secondary cancers are noted in 
about 11% of cases such as acute myeloid leukemia and other solid malignancies. Finally, disease 
transformation into other forms or more aggressive lymphomas such as diffuse large B-cell lymphoma and 
Hodgkin’s lymphoma occur in about 5% of cases.9
2.3
Diagnostic and Prognostic Categories of CLL/SLL 
The diagnosis of CLL is based upon a complete blood count with differential, flow cytometry of the 
peripheral blood (to determine the immunophenotype of circulating lymphocytes), and examination of the 
peripheral smear. According to the 2008 update of the National Cancer Institute-sponsored Working Group 
(NCIWG) diagnosis and treatment of CLL2, the following 2 criteria must be met:
x
Absolute B lymphocyte count in the peripheral blood ≥5000/μL (5 x 109/L), with a 
preponderant population of morphologically mature-appearing small lymphocytes
x
Demonstration of clonality of the circulating B lymphocytes by flow cytometry of the 
peripheral blood. A majority of the population should express the following pattern of
monoclonal B-cell markers: extremely low levels of surface membrane immunoglobulins 
(SmIg) and either kappa or lambda (but not both) light chains; expression of B-cell associated 
antigens (CD19, CD20, and CD23); and expression of the T-cell associated antigen CD5.
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The diagnostic criteria for SLL require the presence of lymphadenopathy and/or splenomegaly. 
B lymphocytes in the peripheral blood should not exceed 5 x 109/L and the diagnosis should be confirmed 
by histopathologic evaluation of a lymph node biopsy when possible.
Two prognostic staging systems exist, known as the Rai and Binet staging systems. The Rai staging system 
(Table 1) is based upon the gradual and progressive increase in the body burden of leukemic lymphocytes, 
starting in the blood and bone marrow, progressively involving into lymph nodes followed by spleen and 
liver involvement. This will lead to eventual compromise of bone marrow function.
Table 1: Rai Staging System: 10
Stage
Risk
Manifestations
Median survival (months)
0
Low
Blood and marrow lymphocytosis
120
I
Intermediate
Lymphocytosis and adenopathy
108
II
Intermediate
Lymphocytosis + organomegaly
94
III
High
Lymphocytosis + anemia 
(hemoglobin <11g/dL)
60
IV
High
Lymphocytosis + thrombocytopenia 
(platelets <100K/μL)
60
This system is of great value in stratifying patients with survival curves corresponding to the Rai low-risk, 
intermediate-risk, and high-risk groups, respectively. The Rai staging system was designed to provide 
prognostic information for patient care. However, some patients classified as having early-stage disease 
rapidly progress. For this reason, other prognostic markers such as immunoglobulin variable heavy chain 
(IGHV) genes, Zeta chain associated protein 70 (ZAP 70), and cluster of differentiation 38 (CD38) have 
been identified to further stratify the aggressive nature of a particular patient’s disease status. IGHV genes 
are defined as mutated if there is a greater than 2 percent difference in nucleotide sequence compared with 
germline DNA.11 The unmutated IGHV genes are associated with shorter OS and a higher risk of relapse 
following treatment, including hematopoietic cell transplantation.12 ZAP 70 is a tyrosine kinase normally 
expressed by natural killer (NK) and T cells and is required for normal T-cell receptor signaling. ZAP 70 is 
not normally expressed in B lymphocytes but has been found in a subset of patients with CLL and appears 
to correlate with survival. Abnormal expression of ZAP 70 in CLL B cells is strongly associated with the 
presence of an unmutated IGHV, another poor prognostic factor.13
Chromosomal abnormalities also play an important role in prognostication. The first reports describing 
chromosomal aberrations in CLL cells date back to the late 1970s. The development of fluorescence in situ 
hybridization (FISH) in the late 1980s and early 1990s allowed for a more sensitive detection of 
chromosomal abnormalities. Dohner et al looked at genomic aberrations in CLL and found that the most 
common isolated chromosomal abnormality associated with B-CLL/SLL is deletion of 13q14, which is 
present in up to 64% of cases studied by FISH. This deletion is believed to be a primary event in CLL, as it 
is present in a majority of the tumor cells and is frequently the sole abnormality.14 The prognosis of 
patients with 13q14 abnormalities appears to be significantly better, and is similar to that of patients with a 
normal karyotype.14 In contrast, trisomy 12 is associated with an atypical morphology and 
immunophenotype, a high proliferation rate, and advanced clinical stage, and is thought to confer a worse 
prognosis. Trisomy 12 may be a secondary abnormality since it is typically identified in a minority of the 
tumor cells.14 Other abnormalities that have been associated with a poor prognosis include deletions at 
11q22-2, and deletions of the p53 locus on chromosome 17p13.14 The properties of these cytogenetic 
markers are summarized in Table 2.
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Table 2: Cytogenetic Abnormalities in CLL14
Chromosome
Median overall survival 
(months)
Median time to first 
treatment (months)
Deletion 17p13
32
9
Deletion 11q22-23
79
13
Trisomy 12
114
49
Normal
111
33
Deletion 13q14
133
92
The 17p deletion as a predictor of poor prognosis among patients requiring therapy and is seen in 
approximately 7 to 10% of patients. In a prospective study, Giesler et al used chromosome banding to 
detect abnormalities of chromosome.17 This was associated with poor survival, and it was the only 
cytogenetic finding with independent prognostic value.15 Deletions of 11q have been described in 17 to 
20% of patients. 11q deletions are associated with extensive adenopathy, progressive disease and shorter 
survival in patients under the age of 55.14 Chromosome 11q contains the ataxia telangiectasia mutated 
(ATM) gene and patients who have loss or mutation of both copies of this gene have an even worse OS
associated with impaired cellular response to irradiation and cytotoxic drug exposure in vitro.16 However
this abnormality may be overcome with the use of fludarabine, cyclophosphamide, and rituximab (FCR).17
The prognostic effect of 12q trisomy has been controversial in that some studies have demonstrated 
advanced disease and higher proliferative activity while others have demonstrated similar survival times to 
that of a normal karyotype.18 The 13q abnormalities appear to be associated with a favorable outcome. 
Two studies using FISH found del(13q14) in 45 to 55% of patients.14 These deletions are often associated 
with inactivation of the Rb gene.19 The region of minimal deletion is suspected to harbor a CLL-associated 
tumor suppressor gene. Lack of Rb gene expression occurs in both the early and late stages of CLL.19
Other markers such as lymphocyte doubling time (LDT), bone marrow histologic pattern, and 
β2-microglobulin (B2M) are also useful as an adjunct to IGHV, ZAP 70, CD38, and FISH. The LDT can 
provide an estimation regarding the rate of disease progression. An actual or projected LDT in untreated 
patients <12 months predicts a progressive course and a longer LDT predicts an indolent course.20 The 
pattern of lymphocyte infiltration in the bone marrow can suggest a progressive versus an indolent course.
A diffuse pattern predicts a progressive course and a nondiffuse (interstitial and nodular) pattern predicts a 
more indolent course.21 Finally, the B2M levels correlate with disease stage and tumor burden in patients 
with CLL. B2M may be regulated, at least in part, by exogenous cytokines. The source of these elevated 
cytokines in CLL is unclear, although IL-6, which inhibits apoptosis in CLL cells, may be released from 
vascular endothelium.22
2.4
Indications for Treatment of CLL
Newly diagnosed patients with asymptomatic early-stage disease (Rai 0, Binet A) should be monitored 
without therapy unless they have evidence of disease progression.23 Patients with intermediate (stages I 
and II) and high risk (stages III and IV) according to the modified Rai classification or at Binet stage B or C 
usually benefit from the initiation of treatment.
According to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL), active disease 
should meet one of the following criteria.2
x
Evidence of progressive marrow failure as manifested by the development of, or worsening of, 
anemia and/or thrombocytopenia 
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x
Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly 
x
Massive nodes (i.e., at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy 
x
Progressive lymphocytosis with an increase of more than 50% over a 2-month period or LDT 
of less than 6 months. Lymphocyte doubling time can be obtained by linear regression 
extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an 
observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of less 
than 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define a 
treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy 
other than CLL (e.g., infections) should be excluded. 
x
Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or 
other standard therapy
x
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs: 
a.
Unintentional weight loss of 10% or more within the previous 6 months
b.
Significant fatigue (i.e., Eastern Cooperative Oncology Group [ECOG] performance status 
≤2; inability to work or perform usual activities)
c.
Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of
infection
d.
Night sweats for more than 1 month without evidence of infection
2.5
Treatment Options for CLL/SLL
2.5.1
Watchful Waiting
Immediate treatment is recommended in patients with advanced stage disease, high tumor burden, and 
severe disease-related "B" symptoms. Otherwise, a period of observation is recommended. Asymptomatic 
early-stage disease should be monitored until evidence of disease progression.2 During the observation 
period, patients are periodically monitored with blood counts and assessed for evidence of progressive 
disease through physical examination and assessment of symptoms.
2.5.2
First-Line Chemotherapy/Immunotherapy/Chemoimmunotherapy
Monotherapy
Monotherapy with alkylating agents has served as initial front-line therapy for CLL. Chlorambucil has
been considered the gold standard for CLL for several decades. This drug remains an appropriate option 
for unfit, elderly patients.23 In addition, another agent known as bendamustine was approved by the United 
States (US) Food and Drug Administration (FDA) for the treatment of CLL in 2008. Knauf et al24 studied 
bendamustine compared with chlorambucil in previously untreated CLL patients. Complete response (CR) 
or partial response (PR) was achieved in 68% of the bendamustine-treated patients and 48% of the 
chlorambucil-treated patients. 
Aside from alkylating agents, 3 purine analogs have been used as monotherapy in CLL. These purine 
analogs are fludarabine, pentostatin, and cladribine. Fludarabine is the best studied compound of the 3 in 
CLL. Fludarabine monotherapy produces superior overall response rates (ORR) compared with other 
treatment regimens containing alkylating agent.25 Cladribine and pentostatin monotherapy also produce
better ORR than chlorambucil, but are not as commonly used. 
Immunotherapy
The advent of monoclonal antibodies demonstrated the first forms of targeted therapy for CLL and other 
malignancies. Rituximab was the first monoclonal antibody used as monotherapy in a consolidation setting 
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demonstrates improved PFS.26 Del Poeta et al reported the estimated the PFS to be 73% at 5 years with 
rituximab consolidation. The combination of anti-CD20 monoclonal antibodies with chemotherapy 
(chemoimmunotherapy) for treatment-naïve patients have proven to be very efficacious therapies for CLL 
and will be discussed below.
Chemoimmunotherapy
Alkylating agents and purine analogs have different mechanisms of action and partially nonoverlapping 
toxicity profiles and these 2 modalities, when combined, achieve synergistic effects. With the advent of 
monoclonal antibodies, the addition of combination chemotherapy demonstrated improved responses. The 
combination of FCR resulted in an ORR of 95%, with CR in 72%, nodular partial response (nPR) in 10%, 
PR due to cytopenia in 7%, and PR due to residual disease in 6%. Six-year OS and failure-free survival 
were 77% and 51%, respectively. Median time to progression was 80 months.27 Bendamustine has also 
been combined with rituximab (BR) for patients with untreated CLL. The ORR was 88% with a CR rate of 
23% and a PR in 65%. After a median observation time of 27.0 months, median event-free survival (EFS) 
was 34 months, and 91% of patients were alive.28
The GCLLSG CLL10 trial looked at the comparison of FCR versus BR in untreated patients.29 The ORR
was identical in both arms with 97.8% (p=1.0). The CR rate with FCR was 47.4% compared to 38.1% with 
BR. Progression-free survival was 85.0% at 2 years in the FCR arm and 78.2% in the BR arm. Event-free
survival was 82.6% at 2 years in the FCR arm and 75.7% in the BR arm. There was no difference in OS 
rate for the FCR versus BR arm (94.2% vs 95.8% at 2 years). Several other combinations have been 
investigated, such as cladribine with rituximab, methylprednisolone plus rituximab followed by 
alemtuzumab, fludarabine plus alemtuzumab, or fludarabine and cyclophosphamide and alemtuzumab.
None of these regimens resulted in higher efficacy than FCR.30
Recently, Geode et al31 studied a third-generation monoclonal antibody known as obinutuzumab in 
combination with chlorambucil for previously untreated patients with CLL. As compared with 
chlorambucil monotherapy and rituximab monotherapy, increased response rates and prolonged PFS were 
seen in the combination. The median PFS for combination obinutuzumab plus chlorambucil versus
chlorambucil alone was 27 months and 11 months, respectively. Higher rates of CR were seen in the 
combination obinutuzumab plus chlorambucil than in the rituximab and obinutuzumab combination. The 
combination of obinutuzumab and chlorambucil was given FDA approval in 2013.
2.5.3
Complications of Chemoimmunotherapy
Chemoimmunotherapy in CLL, most notably the FCR regimen can lead to impressive response rates and to 
a median PFS up to 6 years.27 However, late complications after fludarabine and alkylator therapy are
often observed. Twenty percent of patients have a persistent cytopenia (platelet count of <50x109/L and/or 
neutrophil count <109/L). Intergroup study E2997 suggest a 5% incidence of myeloid neoplasia 6 years 
after fludarabine and cyclophosphamide therapy24; the adjusted incidence for myeloid neoplasia rate at 
8 years was 8%. Survival in patients who do not achieve a CR and have disease progression after FCR is 
estimated to be less than 2 years.27 These findings indicate that while FCR leads to a high response rate, it 
also leads to short- and long-term toxicities and likely a more difficult to treat disease at relapse as well.27
In the GCLLSG CLL 10 Trial29 the toxicities of FCR and BR were compared. FCR-treated patients had 
significantly more frequent severe (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 
to 5) adverse events (AEs) during the whole observation period (90.8% vs 78.5%). Severe hematotoxicity 
was especially more frequent in the FCR arm (90.0% vs 66.9%). The higher rate of severe neutropenia 
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(81.7% vs 56.8%) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%) in the FCR 
arm. Treatment-related mortality occurred in 3.9% in the FCR arm and 2.1% in the BR arm.29
In general, the addition of monoclonal antibodies adds another infusion-related toxicity, that is, an allergic 
component, to the drug or a portion of the drug as in the case of rituximab and ofatumumab.
Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with 
rituximab-chlorambucil, but the risk of infection was not increased.31
2.5.4
Relapsed or Refractory CLL
There is no generally agreed upon standard therapy regimen for CLL patients when they relapse. 
Treatment options include the front-line regimen described above. Treatments for relapsed patients need to 
be individualized. Considerations for choosing a certain regimen can be activity towards bulky disease, 
adverse FISH cytogenetics like 17p, physical fitness of patient, or toxicity profile.25
This section will include the most commonly used regimens for relapsed disease.
Repeat chemoimmunotherapy treatment options are usually used as second-line treatment. A phase 2 trial
of FCR in 284 subjects with previously treated CLL (19% fludarabine refractory and 35% rituximab
refractory) reported OR and CR rates of 74% and 30%, respectively. The estimated median PFS and OS
were 21 and 47 months, respectively. On subgroup analysis, subjects with fludarabine-refractory disease,
chromosome 17 abnormalities, or >3 prior treatments had shorter survival rates.32 In addition, a multicenter 
phase II trial of BR in 78 subjects with relapsed or refractory CLL reported an ORR of 59% with a median 
duration of response of 15 months. After a median follow-up of 2 years, the median EFS and OS were 
14.7 and 34 months, respectively.33 Other options include the addition of rituximab plus high-dose
methylprednisolone. A small series of 14 subjects with fludarabine-refractory CLL, 21% of whom had 
previously received rituximab, reported an ORR of 93% with a median time to progression of 15 months.34
Other lymphoma regimens such as EPOCH, CHOP, and CVP with the addition of an anti-CD20 
monoclonal antibody have also been used as therapy for relapsed/refractory disease. These regimens do 
not demonstrate any significant improvement in disease reduction or durable remissions.
Ofatumumab is a second generation anti-CD20 antibody used for relapsed/refractory disease. A phase 2
trial evaluated ofatumumab in 138 subjects with CLL who were either refractory to both fludarabine and
alemtuzumab, or refractory to fludarabine, with lymphadenopathy greater than 5 cm. Subjects had received 
a median of 5 prior therapies. Overall response rates were 58% and 47% in the 2 subject groups, 
respectively. There were no CRs. Median OS was 13.7 and 15.4 months, respectively. The activity of 
ofatumumab appeared to be independent of whether the subjects had previously received the anti-CD20
antibody rituximab.35 The US FDA granted accelerated approval to ofatumumab for the treatment of 
patients with CLL refractory to both fludarabine and alemtuzumab in 2009.
Alemtuzumab is an anti-CD52 monoclonal antibody and has been tested in a phase 3 trial with relapsed or 
refractory CLL (15% percent of whom had received prior fludarabine). These subjects were randomly 
assigned to treatment with either single-agent fludarabine or combination therapy with fludarabine plus
alemtuzumab. Combination therapy resulted in a significantly longer median PFS (24 months vs
17 months).36 Alemtuzumab has activity in cells lacking TP53 function. A retrospective analysis of 
105 subjects with relapsed or refractory CLL treated with alemtuzumab included 35 subjects with 17p 
deletion. When compared with the entire study population, subjects with 17p deletion demonstrated a 
similar ORR (49% vs 43%), median PFS (7.1 vs 7.0 months), but shorter median OS (19.1 vs 
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32.8 months).37 Alemtuzumab is not a commonly used treatment for many patients as there is a higher 
incidence of viral infections associated with treatment. 
These relapsed/refractory regimens are not curative and generally only provide remission for a short period 
of time. In most cases, these regimens are used to bridge patients to the next treatment or aid in tumor 
reduction prior to stem cell transplant. 
2.5.5
Stem Cell Transplantation
Patients with CLL are generally elderly, and due to the relatively benign course of the disease in the 
majority of patients, few are considered for aggressive treatments such as hematopoietic cell 
transplantation. Stem cell transplant remains as the only curative option for CLL. Prognostication and 
transplant-related mortality continue to improve, and this may potentially lead to more CLL patients being 
referred for stem cell transplant. Currently, this option is reserved to those patients with a good 
performance status and with high-risk prognostic factors, namely deletion 17p, and those patients who are 
refractory to prior therapies. Unfortunately, only a small subset of patients meets those criteria.
2.5.6
BCR Signaling Inhibitors (Single Agent)
There are several drugs in development for lymphoid malignancies that interfere with the BCR signaling. 
There are many new drugs in clinical trials that target BCR receptors signaling pathway. These drugs are 
grouped based on the kinase inhibition along the BCR signaling pathway. Many kinase inhibitors are 
currently being studied and are in development. This discussion will focus on Syk inhibitors, BTK
inhibitors, and PI3K inhibitors which have thus had the most study and progress. 
Fostamatinib, an oral Syk inhibitor, was tested in a phase 1/2 study. Friedberg et al found that 6 out of 
11 (55%) subjects with CLL had a PR.38 Common toxicities in these heavily pretreated subjects were 
diarrhea, fatigue, cytopenias, nausea, and hypertension. GS-9973 (entospletinib) is another Syk compound 
was shown to have favorable response in a single-arm, open-label phase 2 study involving subjects with 
relapsed or refractory hematologic malignancies.39 This study enrolled 56 subjects: 32 subjects with 
CLL/SLL and 24 subjects with non-Hodgkin’s lymphoma. Efficacy analysis was available for 22/54 
subjects, which included 13 CLL/SLL subjects. At the week 8 evaluation, all subjects experienced reduced 
tumor bulk: 4 subjects achieved a decrease of >50% in their measurable lymph node disease; 8 had a <50% 
decrease. Thirty of 34 (88%) subjects experienced an AE. Reversible Grade 3 or 4 transaminase elevations
occurred in 4 subjects. There were 2 mortalities in this trial; one from disease progression and another 
from pneumonia, which occurred at day 7 of the trial drug. Trials using combination of GS-9973 and 
idelalisib are ongoing and the results are pending. Other Syk inhibitors include PRT062627 or P505-15
showing promising results in cells line and mouse models. A dose-finding study using P505-15 in healthy 
volunteers has been completed and includes single and multiple dosing regimens.40
The kinase inhibitor ibrutinib targets BTK and has been shown to have activity in CLL. The first BTK 
inhibitor in clinical trials was ibrutinib, which received accelerated approval from the FDA in 
February 2014 for treatment of relapsed/ refractory CLL. The approval was based on favorable clinical 
response on 48 relapsed CLL subjects. The phase 1b/2 multicenter ibrutinib trial reported by Byrd et al. 
involved 85 relapsed CLL subjects in which 51 received 420 mg, and 34 received 840 mg of the drug.41
The ORR was the same in the group that received 420 mg and the group that received 840 mg (71%), and 
an additional 20% and 15% of subjects in the respective groups had a partial response with lymphocytosis 
(PRL). The estimated PFS rate was 75% and the OS rate was 83% at 26 months. The most common side 
effects observed in the clinical study included thrombocytopenia, diarrhea, bruising, neutropenia, anemia, 
upper respiratory tract infection, fatigue, musculoskeletal pain, rash, fever, constipation, peripheral edema, 
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arthralgia, nausea, stomatitis, sinusitis, and dizziness. Other BTK inhibitors in clinical trials include 
AVL-292 (phase 1b). Although ibrutinib demonstrated higher response rates than AVL, it was later found 
out that AVL may have underperformed due to differences in PK; higher doses were required to achieve
improved responses.42
Idelalisib (CAL-101, GS-1101, Zydelig®) is a selective oral inhibitor of the p110δ isoform of PI3Kδ.
Firocari et al reported on a phase 1 study that enrolled 54 subjects with heavily pretreated 
relapsed/refractory CLL treated with continuous once- or twice-daily doses ranging from 50 mg to 350 mg
per dose. After a median of 9 months of drug exposure, an ORR of 39% was observed. Nodal response 
(50% reduction from baseline) was observed in a larger proportion of subjects (81%) who did not meet 
criteria for objective response. Median PFS was 17 months; it increased to 29 months for those receiving 
150 mg twice daily or greater. Dose-limiting toxicities (DLTs) were not observed, and potentially 
treatment-related AEs (fatigue, rash, diarrhea, respiratory tract infections, and reversible increases in 
hepatic transaminases) resulted in discontinuation of treatment in only 7% of subjects. Because PI3Kδ 
influences clonal expansion and differentiation of suppressor T cells, some of these events, particularly 
diarrhea and/or colitis, may represent on-target toxicities of idelalisib.43
Long-term data regarding responses and toxicity are still maturing for kinase inhibitors. Thus far, they 
have shown dramatic responses in the short term but have failed to show deep remissions. Patterns of 
resistance are now emerging. With ibrutinib specifically, recent data have emerged regarding mutations 
that may indicate potential mechanisms of resistance.44
2.5.7
BCR Signaling Inhibitors (Combinations)
Kinase inhibitors have demonstrated very promising response rates and investigators have started using 
kinase inhibitors in combinations with chemotherapy, monoclonal antibodies, and other kinase inhibitors. 
The majority of these studies remain early in accrual and maturity.
Ibrutinib in combination with BR was administered to relapsed/refractory CLL subjects. Barrientos et al 
reported on 30 subjects with relapsed/refractory CLL/SLL who received up to 6 cycles of BR with a 
continuous fixed ibrutinib dose of 420 mg/day. With a median treatment duration of 16 months, the ORR 
was 93% (28/30 subjects, including 5 CRs and 3 nPRs), and 1 additional subject achieved a PRL. The 
most frequently reported treatment-emergent AEs were diarrhea (70%), nausea (66.7%), fatigue (46.7%), 
neutropenia (40%), and upper respiratory tract infection (36.7%). The most frequently reported 
treatment-emergent AEs Grade 3 or higher in severity were neutropenia (40.0%), maculopapular rash and 
fatigue (10.0% each), and thrombocytopenia, febrile neutropenia, and cellulitis (6.7% each). The estimated 
12-month PFS was 90%. Moreover, responses appeared independent of high-risk features.45
Ibrutinib in combination with rituximab enrolled 40 subjects. At a median follow-up of 14 months, 32 of 
40 subjects continued therapy without disease progression. Burger et al looked at 39 subjects who were 
evaluable for response assessment per 2008 IWCLL guidelines; 34 subjects (87%) achieved PR, and 
3 subjects (8%) CRs, accounting for an ORR of 95%. One CR was negative for minimal residual disease
by flow cytometry; the ORR in the 20 subjects with del17p or TP53 mutation was 90% (16 PR, 2 CR). 
Among the 8 subjects that came off of the study, 3 subjects died from unrelated infectious complications 
(2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. 
Two subjects came off of the study because of possibly ibrutinib-related toxicity (1 subdural hematoma, 
1 Grade 3 mucositis), 1 subject had progressive disease, and 1 proceeded to stem cell transplantation.
Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of 
upper respiratory infections) being the most common complication.46
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Byrd et al reported on ibrutinib in combination with ofatumumab for treatment of relapsed CLL/SLL. For 
the 27 enrolled CLL/SLL subjects the ORR, as measured by IWCLL criteria and PFS is 100%, with a 
median follow-up of 9.8 months; 89% of CLL/SLL/prolymphocytic leukemia (PLL) subjects remained on
study and only 1 subject discontinued treatment by proceeding to stem cell transplant. The majority of AEs
were Grade 1 or 2 in severity, and no Grade 3 or 4 infusion reactions, neutropenia, or thrombocytopenia 
were observed.47
Idelalisib has also been studied in combination with rituximab versus rituximab plus placebo. Sharman et 
al demonstrated that the median PFS was 5.5 months in the placebo group and was not reached in the 
idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; p<0.001). Subjects
receiving idelalisib versus those receiving placebo had improved ORR (81% vs 13%; odds ratio, 29.92; 
p<0.001) and OS at 12 months (92% vs 80%; hazard ratio for death, 0.28; p=0.02). Serious AEs occurred 
in 40% of the subjects receiving idelalisib and rituximab and in 35% of subjects receiving placebo and 
rituximab.48
2.5.8
Other Options
The intrinsic apoptotic pathway is often dysregulated in relapsed CLL/SLL due to a deficiency in 
pro-apoptotic proteins such as TP53 and overexpression of anti-apoptotic proteins such as Bcl-2.
Venetoclax is a selective, potent, orally bioavailable, small-molecule Bcl-2 inhibitor that can trigger 
apoptosis. Seymour et al reported 56 subjects who were enrolled with a median time on study of 
10.0 months. Venetoclax showed activity in subjects with relapsed/refractory CLL with a response rate of 
84% for the study population, including 20% CR/CRi. Subjects with high-risk CLL showed similar 
efficacy with a response rate of 82% in del(17p) and 78% in F-refractory disease. The most common AEs 
(all grades, ≥25% of subjects) were diarrhea (46%), neutropenia (43%), fatigue (34%), upper respiratory 
tract infection (29%), and cough (25%). Grade 3/4 AEs occurring in ≥4 of 56 subjects were neutropenia 
(41%), tumor lysis syndrome (TLS) (11%), thrombocytopenia (10%), hyperglycemia (10%), anemia (7%), 
and febrile neutropenia (7%). This study continued enrollment using a revised dosing schedule designed to 
reduce the identified risk of TLS. A phase 2 monotherapy study in subjects with relapsed del(17p) CLL 
has commenced as well as combination studies with either rituximab or obinutuzumab in patients with 
relapsed CLL.49
2.6
Acalabrutinib (ACP-196)50
Calquence® (acalabrutinib) has been approved in the US and other markets for the treatment of adult 
patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, CLL, and SLL.
Mechanism of Action:
Acalabrutinib is a low molecular weight irreversible inhibitor of BTK, which binds covalently to a cysteine 
residue (Cys481) in the front position of the ATP-binding pocket of BTK. BTK inhibition blocks BCR 
signaling and induces apoptosis. Acalabrutinib and its major metabolite, ACP-5862, have limited off-target
kinase activity. The lack of activity against Tec- and Src- family kinases, important for T cells, functioning 
NK cells and platelets, as well as against epidermal growth factor receptor (EGFR), important for epithelial 
cell function, may contribute to the safety and efficacy profile of acalabrutinib. Acalabrutinib has shown 
efficacy in 3 separate models of lymphoid malignancies: follicular cell line xenograft, primary CLL 
xenograft, and spontaneous canine lymphoma. Efficacy data have been evaluated in subjects with CLL, 
including subjects with relapsed/refractory CLL (N=134), treatment-naïve disease (N=99), subjects 
intolerant of ibrutinib (N=33), and subjects with Richter’s or PLL transformation (N=29).
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2.6.1
Distribution
Quantitative whole-body autoradiography was performed on 5 male and 5 female Sprague Dawley rats
after a single oral administration of [14C]-acalabrutinib (4 mg/kg). Rats were sacrificed 0.25, 1, 24, 72,
and 168 hours after compound administration and the concentration of radioactivity was measured in 
tissues by autoradiography/radioluminography. In the period of 0.25 to 24 hours after dosing, although the 
absolute radioactivity numbers went down rapidly, the relative concentrations of [14C]-acalabrutinib in 
various tissues at the individual time points remained similar. The highest radioactivity concentrations 
were present in the small intestinal wall, liver, kidney, blood, adrenal gland, stomach wall, spleen, lacrimal 
glands, and pancreas. Low or no radioactivity was observed in the brain, spinal cord, or lens of the eye. 
Overall, the in vivo retention studies showed that acalabrutinib is effectively excreted by rats and that no 
retention was observed 7 days after administration. The mean in vitro protein binding ratios of 
acalabrutinib at final concentrations of 1 and 10 μmol/L were 83.0% and 79.2% for fasted male mouse 
plasma, 86.6% and 93.4% for fasted male rat plasma, 73.8% and 68.3% for fasted male dog plasma, 88.5% 
and 86.0% for fasted male monkey plasma, and 97.5% and 91.9% for fasted male human plasma,
respectively.
2.6.2
Metabolism and Clearance50
Metabolism
The biotransformation of acalabrutinib has been evaluated in rat and dog with characterization of 
metabolites in bile and urine following oral and intravenous (IV) administration. Parent drug 
GSH-conjugation and subsequent enzymatic degradation of the glutathione moiety to the glycine-cysteine 
(Gly-Cys) conjugates by removal of the glutamic acid and Cys conjugates by subsequent removal of the 
glycine were the major biotransformation pathways noted in rat bile and urine. GSH-conjugation in 
combination with oxidation of acalabrutinib was also observed. For all of the glutathione-type metabolites, 
the position of the GSH, Gly-Cys and Cys was indicated at the butynyl moiety. In the pooled 1- to 8-hour 
rat plasma samples, very low levels of parent drug and the parent-Cys conjugate were detected along with 
trace levels of the CysGly- and the oxidized GSH-conjugate. After IV administration of acalabrutinib to 
dogs, the metabolites detected in urine, bile, and plasma were qualitatively comparable to those observed in 
rats. In line with metabolism in the rat, GSH conjugation with subsequent metabolism of the glutathione 
moiety appeared to be the major metabolic pathway. In both rat and dog body fluids, minor polar 
metabolites were detected with unresolved structure elucidation.
To characterize the cytochrome P450 (CYP) isoforms responsible for the metabolism of acalabrutinib, CYP 
reaction phenotyping for acalabrutinib was examined in 2 different in vitro systems, human liver 
microsomes and recombinant CYP isoforms, BactosomesTM. Additional studies were performed in a 
human liver microsomal system with specific chemical inhibitors of individual CYP isoforms. Inhibition 
of acalabrutinib metabolism by specific CYP3A4/5 inhibitors (ketoconazole and troleandomycin) indicate 
that CYP3A4/5 is the predominant CYP isoform responsible for metabolism of acalabrutinib. Other
specific chemical inhibitors for CYP1A2, CYP2E1, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 
had minimal effect on the metabolic consumption of acalabrutinib in human liver microsomes.
Collectively, these results suggest that the CYP-mediated metabolism of acalabrutinib is catalyzed 
primarily by CYP3A4/5.
In vitro metabolism studies evaluated the inhibition properties of acalabrutinib on the 7 major CYP 
isoforms. Acalabrutinib did not appreciably inhibit CYP1A2, CYP2B6, CYP2C19 (IC50 > 100 μM), or 
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CYP2C8 (IC50 = 37 μM), CYP2C9 (IC50 = 28 μM), or CYP3A4/5 with IC50 values that ranged from 57 μM 
(testosterone as substrate) to 69 μM (midazolam as substrate). Examination of time-dependent inhibition of 
CYP3A4/5 in human liver microsomes showed that acalabrutinib has the potential to serve as a 
time-dependent inhibitor of CYP3A4/5 isoforms with a shift in IC50 vales from 69 μM to 16 μM 
(midazolam as substrate) or 57 μM to 13 μM (testosterone as substrate) upon preincubation of 
acalabrutinib. In a similar manner, acalabrutinib has the potential to serve as a time-dependent inhibitor of 
CYP2C8 and CYP2C9 isoforms with a shift in IC50 values from 37 μM to 18 μM, and a shift in IC50 values 
from 28 μM to 14 μM, respectively. Furthermore, modeling of the direct CYP inhibition in vitro data 
(FDA 2012) suggests minimal potential for acalabrutinib to increase the area under the concentration-time
curve (AUC) of a CYP3A4 substrate—an oral dose of 450 mg of acalabrutinib is projected to yield a R1 
value = 1.07. In a similar manner, acalabrutinib is not expected to increase exposure of co-administered 
therapeutics that are substrates for other CYP isoforms.
The potential of acalabrutinib (up to 50 μM; a concentration 119-fold greater than an estimated human Cmax
for a dose of 100 mg; Cmax = 420 nM) to induce CYP isoforms was evaluated in 3 cryopreserved 
preparations of cultured human hepatocytes from 3 donor livers. Hepatocytes were treated with varying 
concentrations of acalabrutinib (0.01, 0.05, 0.1, 0.5, 1, 5, 10, or 50 μM) or 1 of 3 known human CYP 
inducers, namely, omeprazole (50 μM), phenobarbital (750 μM), and rifampin (20 μM). Under the 
conditions of this study, where the positive controls caused anticipated and appropriate increases in CYP 
enzyme expression, treatment of all 3 cultured human hepatocytes with up to 50 μM acalabrutinib caused
concentration-dependent increases (>2.0-fold and >20% of the positive control, up to 32.9-fold change) in 
CYP1A2 mRNA levels, and in at least 1 of the 3 hepatocyte preparations tested, treatment at 50 μM 
acalabrutinib increased (>2.0-fold and/or ≥20% of the positive control) CYP2B6 and 3A4 mRNA levels 
(up to 2.9- and 2.44-fold, respectively). At lower concentrations, acalabrutinib caused an approximately 
2-fold induction of CYP1A2 mRNA at concentrations (1 μM) that are greater than 2-fold the estimated 
Cmax of (420 nM) of acalabrutinib in humans after an oral dose of 100 mg. Furthermore, at an acalabrutinib
concentration of 5 μM, the increase in CYP1A2 mRNA was less than 12% of the positive control, 
omeprazole. Therefore, acalabrutinib is not anticipated to be strong inducer of CYP1A2 in humans. In a 
similar manner, at concentrations (10 μM) that are >20-fold the estimated Cmax of acalabrutinib (420 nM) in 
humans after an oral dose of 100 mg, no notable induction was observed of CYP2B6 and CYP3A4 
(<2.0-fold and <20% of the positive control). Therefore, acalabrutinib is not anticipated to be a strong 
inducer of CYP isoforms in humans.
Excretion
Recovery of radioactivity from 6 individual human subjects who received an oral microtracer dose of 
[14C]-acalabrutinib was essentially complete within 96 hours post dose with total radioactivity recovery of 
95.7% (4.5% coefficient of variation [CV]). Radioactivity excretion in feces was 77.5% to 86.9% of dose 
and excretion in urine was 10.3% to 14.7% of dose.
2.6.3
Clinical Experience in Chronic Lymphocytic Leukemia
For detailed information on the clinical experience for acalabrutinib, please refer to the acalabrutinib 
Investigator Brochure. 
2.6.4
Clinical and Scientific Justification for Protocol Design
The use of combined therapy with purine analogs and monoclonal antibodies as first-line CLL therapy has 
significantly improved patient outcomes. About 10% of CLL patients do not respond to first-line 
fludarabine-based therapies or have only short-lived responses. The advent of kinase inhibitors has 
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demonstrated significantly improved response to second-line therapies as compared to standard 
chemoimmunotherapy regimens. 
Gene expression profiling has allowed for investigating the effect of the microenvironment on CLL cells in 
vivo.52 BCR activation is a key pathway engaged in the tumor microenvironment and the more aggressive 
form of CLL is characterized by stronger BCR activation in vivo. These data identify the disruption of 
tumor microenvironment interactions and inhibition of BCR signaling as promising therapeutic strategies in 
CLL. BTK is a key enzyme in BCR signal transduction and mutational inactivation of BTK prevents 
B-cell maturation. Pharmacologic inhibition of BTK blocks BCR signaling.53 Ibrutinib was the first BTK 
inhibitor to reach the clinic and was recently approved as second-line therapy for CLL.
This phase 2 study will investigate acalabrutinib, a novel BTK inhibitor, for patients with CLL/SLL.
Patients with relapsed refractory disease will be enrolled. 
The development of novel BTK inhibitors considering the success of ibrutinib is justified from the 
experience with second- and third-generation tyrosine kinase inhibitors for chronic myeloid leukemia. The 
availability of different inhibitors for the same target has been shown to benefit patients in terms of 
choosing between therapies with different side effects and probably also different efficacy profiles.
Furthermore, acalabrutinib has been shown in nonclinical and patient studies to have a different PK profile 
with lower protein binding than ibrutinib, and a higher availability for BTK inhibition.50 Also,
acalabrutinib has shown a more narrow specificity for BTK inhibition than ibrutinib, which also targets 
tyrosine protein kinase (ITK) in T cells.54 The specificity for BTK inhibition without ITK inhibition may 
be especially important as ibrutinib-mediated ITK inhibition has been shown to abrogate FcR-stimulated
NK cell function.55
Thus, acalabrutinib, which does not inhibit ITK, may prove to show higher efficacy in combination 
approaches with monoclonal antibodies as in studies currently ongoing for ibrutinib. These differences are 
expected to give acalabrutinib a different profile in terms of both safety and efficacy compared to ibrutinib. 
These expected differences may thus turn out to be important for clinical use of BTK inhibitors in both 
single-agent therapy and for combination therapy where additive side effects due to off-target side effects 
of different kinase inhibitors could be significant.
Selection of the acalabrutinib treatment regimen (including starting dose, dose modifications, schedule, 
duration, and conditions of administration) for this study has been based primarily on safety, exposure, and 
activity profiles from animal studies in mice and dogs.56,57 Phase 1 to 3 clinical studies involving CLL/SLL 
subjects with refractory/relapsed disease are currently ongoing. Pharmacodynamic results from Study 
ACE-CL-001 (described in Section 2.6.3) suggest BTK resynthesis occurs in malignant B cells within 
24 hours.  While all dosages evaluated in Study ACE-CL-001 showed full BTK occupancy 4 hours after 
dosing, the 100-mg twice daily dose cohort showed full target coverage over 24 hours (≥97% BTK 
occupancy at 4 and 24 hours).  The 100-mg twice daily regimen is expected to provide acalabrutinib 
PK/pharmacodynamic correlation within 4 hours of dosing.
The following specific issues have been considered in the study design:
x
The dose of acalabrutinib of 200 mg once daily is within the dose range (100 mg to 400 mg
once daily and 100 mg to 200 mg twice daily) with no DLTs observed in any dose cohort in the 
phase 1 study. Full target inhibition and clinical responses have been seen in both 100 mg and 
175 mg dose cohorts. A 200-mg daily dose therefore provides a safe dose that is expected to 
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be at least 2-fold above what is needed for full target inhibition and is the recommended dose 
for this phase 2 study.
x
Due to the short half-life of acalabrutinib, testing 2 dosage regimens (twice daily vs once daily)
and measuring the drug occupancy in different compartments (peripheral blood, bone marrow,
and lymph nodes) will provide important information about mechanisms of action for a 
covalent inhibitor and guide future dosage regimens for both single-agent and combination 
trials. After the completion of 6 dosing cycles and associated procedures, subjects in the 
once-daily dosing cohort will be permitted to switch to twice-daily dosing at the investigator’s 
discretion.
x
Treatment until the occurrence of disease progression or unacceptable toxicity with a targeted 
agent is appropriate and follows the paradigm of imatinib administration for chronic 
myelogenous leukemia. This study design will provide further information regarding duration 
of response and drug safety during chronic administration.  Recent in vitro studies show that 
acalabrutinib is only moderately cytotoxic, making it likely that continued dosing is required.
Prolonged therapy thus offers study participants the potential for maximum benefit from 
treatment.
x
Dose modifications described in the protocol are chosen to balance concerns for subject safety 
with the need to achieve antitumor activity. 
x
Studying previously treated CLL/SLL is justifiable as the side effect profile of the drug is 
favorable compared to chemoimmunotherapy. Given the experience with ibrutinib, the side 
effect profile would not be expected to be significantly different than that of ibrutinib. The 
vast majority of patients benefit from the treatment. If observed responses and side effect 
profile are beneficial, this study could serve as a platform to develop an early intervention 
study as well as further combination approaches with other kinase inhibitors.
x
Enrolling subjects with relapsed disease into a trial of an agent with a different PK and 
specificity profile from ibrutinib that still targets the underlying pathogenic BCR pathway in 
CLL is reasonable. 
x
As acalabrutinib is able to mobilize CLL cells out of the lymph node, studying the tumor 
microenvironment of the lymph node prior to and during treatment will further our 
understanding of the role of signaling events in the lymph node for CLL/SLL pathogenesis.
Obtaining blood, bone marrow, and lymph node biopsies before and during treatment is 
feasible, safe, and tolerable. Assessing the degree of BTK inhibition in different anatomic 
compartments and the resultant effect on tumor biology will help advance treatment options for 
these patients.
x
In an effort to build quantitative understanding of the relationship between acalabrutinib and 
ACP-5862 concentration, BTK receptor occupancy, and biomarkers included in this study, 
sparse acalabrutinib plasma concentrations will be collected at time points through 4 hours post 
dose, to further understanding of the contribution of both acalabrutinib and the metabolite 
ACP-5862 to drug activity.
3.0
STUDY DESIGN 
This is a phase 2 single center trial. It is an open-label study of acalabrutinib in subjects with CLL or SLL 
with a lead-in period for pharmacodynamic assessment.  Subsequently, subjects will receive acalabrutinib
continuously until disease progression or development of drug-related toxicity.
For pharmacodynamic assessment during the lead-in period, subjects will receive acalabrutinib for 3 days 
followed by study drug hold for a portion of the research sampling at different intervals from last dose.
Study drug will be restarted after completion of research sampling. 
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Subjects will be enrolled onto 2 different study arms based on the presence or absence of superficial 
lymphadenopathy: 
x
Arm A will enroll approximately 32 subjects with superficial lymphadenopathy, who will 
undergo lymph node biopsy to assess pharmacodynamic endpoints
x
Arm B will enroll approximately 16 subjects (with or without lymphadenopathy) who will 
undergo bone marrow biopsy to assess pharmacodynamic endpoints.  
If Arm A completes accrual before Arm B, then all remaining subjects will be enrolled into Arm B.
In each Arm, subjects will be randomized to receive 1 of 2 dosing regimens: 1) acalabrutinib, 200 mg once 
daily; or 2) acalabrutinib, 100 mg twice daily. Thus, up to 24 subjects will receive acalabrutinib 200 mg
once daily and up to 24 subjects will receive acalabrutinib 100 mg twice daily. Randomization will be 
provided by the Clinical Center Pharmacy, ID MRS section.
In Arm A (subjects willing and able to undergo superficial lymph node biopsies), tissue samples will be 
collected according to the following schedule: 
x
A1a) acalabrutinib, 200 mg once daily:  lymph node biopsy (Day 3) 4 hours after the last dose; 
x
A1b) acalabrutinib, 200 mg once daily:  lymph node biopsy (Day 4) 24 hours after the last dose. 
x
A2a) acalabrutinib, 100 mg q12 hours: lymph node biopsy (Day 4) 12 hours after the last dose; 
x
A2b) acalabrutinib, 100 mg q12 hours: lymph node biopsy (Day 5) 36 hours from last dose.
In Arm B (subjects willing and able to undergo bone marrow biopsies), tissue samples will be collected 
according to the following schedule: 
x
B1c) acalabrutinib, 200 mg daily: bone marrow biopsy (Day 3) 4 hours after the last dose; 
x
B2c) acalabrutinib, 100 mg q12 hours: bone marrow biopsy (Day 4) 12 hours from last dose. 
For all 6 cohorts, peripheral blood samples will be collected at the time that biopsies are done, i.e., on day 3 
4 hours post dose (peak level), on day 4 (trough level), and on day 5 (trough level plus 24 hours off drug).
On day 6, after all sampling is complete, subjects resume continuous treatment until disease progression or 
limiting side effects.  
Subjects in once-daily cohorts will be permitted, at the investigator’s discretion, to transition to twice-daily 
dosing after 6 cycles of acalabrutinib.
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                Screening
1         2         
3          4        
5
     6
Study Specimen Schedule
Study drug held after Day 3 and resumed on Day 6 after completion of research specimens.
Study Arm A (up to 32 subjects willing and able to undergo superficial lymph node biopsies):
1a) Lymph node biopsy:
(Day 3) 4 hours after the last dose
1b) Lymph node biopsy:
(Day 4) 24 hours after the last dose
2a) Lymph node biopsy:
(Day 4) 12 hours after the last dose
2b) Lymph node biopsy:
(Day 5) 36 hours from last dose
Study Arm B (up to 16 subjects willing and able to undergo bone marrow biopsies):
1c) Bone marrow biopsy:
(Day 3) 4 hours after the last dose
2c) Bone marrow biopsy:
(Day 4) 12 hours from last dose
Up to 48 
Relapsed/Refractory 
CLL/SLL Patients
Acalabrutinib
Cohort 1a, 1b, 1c: 200 mg daily
Cohort 2a, 2b, 2c: 100 mg Q12h
(28 Day Cycles to 6 Mo)
Continue Treatment: 200 mg
daily or 100 mg Q12h 
Off Treatment: 
Progressive 
Disease
Off Treatment: 
Intolerable Side 
Effects
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Cohort
A1a
(lymph node)
A1b
(lymph node)
A2a
(lymph node)
A2b
(lymph node)
B1c
(bone 
marrow)
B2c
(bone marrow)
Drug dose
200 mg once 
daily
200 mg once 
daily
100 mg twice
daily
100 mg twice
daily
200 mg once 
daily
100 mg twice
daily
At
baseline
Bone marrow 
biopsy, lymph 
node biopsy
Bone marrow 
biopsy, lymph 
node biopsy
Bone marrow 
biopsy, lymph 
node biopsy
Bone marrow 
biopsy, lymph 
node biopsy
Bone marrow 
biopsy
Bone marrow 
biopsy
Cycle 1, 
Day 3
Lymph node 
biopsy 4 hrs 
post dose
Bone marrow 
biopsy 4 hrs 
post dose
Cycle 1, 
Day 4
Lymph node 
biopsy 24 hrs 
post dose
Lymph node 
biopsy 12 hrs 
post dose
Bone marrow 
biopsy 12 hrs 
post dose
Cycle 1, 
Day 5
Lymph node 
biopsy 36 hrs 
post dose
End of 
cycle 6
Bone marrow 
biopsy. Lymph 
node biopsy 
when indicated.
Bone marrow 
biopsy. Lymph 
node biopsy 
when indicated.
Bone marrow 
biopsy. Lymph 
node biopsy 
when indicated.
Bone marrow 
biopsy. Lymph 
node biopsy 
when indicated.
Bone marrow 
biopsy.
Bone marrow 
biopsy.
At 12 
months 
from start 
of drug
Bone marrow 
biopsy.
Bone marrow 
biopsy.
Bone marrow 
biopsy.
Bone marrow 
biopsy.
Bone marrow 
biopsy.
Bone marrow 
biopsy.
After 12 
months
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Bone marrow 
biopsy and/or 
lymph node 
biopsy when 
indicated.
Indicated means:  a lymph node biopsy may be requested for work-up of persistent disease.  A bone marrow biopsy may be 
requested to confirm complete response by International Workshop on Chronic Lymphocytic Leukemia criteria.  
In subjects with progressive disease bone marrow and/or lymph node biopsy may be done as part of the work-up as clinically 
indicated.
4.0
ELIGIBILITY ASSESSMENT AND ENROLLMENT
4.1
Inclusion Criteria
1.
Men and women 18 years of age and older with histologically confirmed disease as defined by 
the following: 
x
CLL:  clonal B-lymphocytosis ≥5,000 cells/PL or SLL:  lymphadenopathy with the 
tissue morphology of CLL but that are not leukemic, <5,000 cells/PL. 
x
Immunophenotypic profile or immunohistochemistry read by an expert pathologist as 
consistent with CLL. This will include CD5, CD19, and CD20 expression by the CLL 
cells typically also with CD23 expression, but CD23 negative cases may be included if 
there is no t11;14 translocation present. 
2.
Active disease as defined by at least one of the following (IWCLL consensus criteria):
x
Weight loss ≥10% within the previous 6 months  
x
Extreme fatigue  
x
Fevers of greater than 100.5ºF for ≥2 weeks without evidence of infection 
x
Night sweats for more than 1 month without evidence of infection 
x
Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia and/or thrombocytopenia 
x
Massive or progressive splenomegaly 
x
Massive nodes or clusters or progressive lymphadenopathy 
x
Progressive lymphocytosis with an increase of >50% over a 2-month period, or an 
anticipated doubling time of less than 6 months 
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x
Compensated autoimmune hemolysis 
3.
Relapsed/refractory CLL/SLL, or treatment-naïve subjects with deletion 17p, TP53 mutations, 
or NOTCH-1 mutation.
4.
ECOG performance status of ≤2
5.
Absolute neutrophil count (ANC) >500/μL, platelets >30,000/μL
6.
Female subjects who are sexually active and able to bear children must agree to use highly 
effective methods of contraception during the study and for 2 days after the last dose of study 
drug.
7.
Willing and able to participate in all required evaluations and procedures in this study protocol 
including swallowing capsules without difficulty and serial biopsies
8.
Ability to understand the purpose and risks of the study and provide signed and dated informed 
consent and authorization to use protected health information (in accordance with national and 
local subject privacy regulations)
4.2
Exclusion Criteria
1.
Radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or investigational 
products in the 4 weeks prior to study drug administration
2.
Richter’s transformation
3.
Autoimmune hemolytic anemia or thrombocytopenia requiring steroid therapy
4.
Steroids ≥20 mg prednisone or equivalent for more than 3 days within the last 3 months.
5.
Impaired hepatic function: total bilirubin ≥1.5 x upper limit of normal (ULN) (unless due to 
Gilbert's syndrome), aspartate amino transferase (AST)/alanine aminotransferase (ALT)
≥2.5 x institutional ULN, unless due to infiltration of the liver
6.
Impaired renal function: estimated glomerular filtration rate (eGFR) ≤50 as determined by 
CKD-EPI equation
7.
Life-threatening illness, medical condition, or organ system dysfunction which, in the 
investigator's opinion, could compromise the subject's safety, interfere with the absorption or 
metabolism of acalabrutinib oral (PO), or put the study outcomes at undue risk
8.
Concomitant immunotherapy, chemotherapy, radiotherapy, corticosteroids (at dosages 
equivalent to prednisone >20 mg/day), or experimental therapy
9.
Active hepatitis B or hepatitis C infection   
10. HIV infection 
11. Female subjects: current pregnancy or unwilling to utilize effective contraceptive methods or 
refrain from pregnancy if of childbearing potential or currently breastfeeding 
12. Psychiatric illness/social situations that would limit the subject’s ability to tolerate and/or 
comply with study requirements.
13. Unable to understand the investigational nature of the study or give informed consent.
14. Individuals <18 years old 
15. Known hypersensitivity to any component of acalabrutinib 
16. Any prior therapy with other BTK inhibitors
17. Requires systemic anticoagulation with coumadin (warfarin)
18. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ 
cervical cancer, or other cancer from which the subject has been disease free for ≥2 years or 
which will not limit survival to <2 years.
19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection 
of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, 
or partial or complete bowel obstruction
20. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including 
radiation
21. History of stroke or intracranial hemorrhage within 6 months before signing the treatment 
consent form
22. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of signing the treatment 
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consent form, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or left ventricular ejection fraction (LVEF) ≤40%
23. Requires treatment with strong or moderate CY3A4/5 inhibitors (unless no alternative is 
available)
5.0
TREATMENT PLAN 
5.1
Drug Administration
Acalabrutinib is an orally administered product. Acalabrutinib will be administered with or without food.
Acalabrutinib administration will take place in the outpatient facility of the 
clinical center or at the subject’s home. The drug dose is 200 mg PO daily (Cohort 1a, 1b, 1c) or 
100 mg q12 hours (Cohorts 2a, 2b, 2c). Subjects in the once-daily dosing cohorts will be permitted, at the 
investigator’s discretion, to transition to twice-daily dosing after completing 6 cycles of acalabrutinib.  Use
of proton pump inhibitors, H2 receptor antagonists, or antacids while taking acalabrutinib has the potential 
to decrease acalabrutinib exposure. If treatment with a gastric acid reducing agent is required, consider 
using a H2-receptor antagonist (2 hours after acalabrutinib) or antacid (2 hours before or 2 hours after 
acalabrutinib). Avoid co-administration with proton pump inhibitors.  Subjects will take study drug at
approximately the same times each day.
5.2
Therapy Schedule
All cycles will be 28 (±5) days long.
5.3
Prophylactic Medications
x
Allopurinol 300 mg PO once daily at the discretion of the Principle Investigator (PI) (Cycle 1 
only)
x
Bactrim DS PO once daily 3 times per week (or alternative agent in case of sulfa allergy) at the 
discretion of the PI
x
Acyclovir 800 mg PO twice daily at the discretion of the PI
5.4
Holding and Dose Adjustments of Study Drug Administration in the Case of 
Treatment-Related Toxicity:
5.4.1
Neutropenia
x
Grade 4 ANC (<500/μL) for >7 days deemed related to study drug
Occurrence
Action
1st – 2nd
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level:
Filgrastim or Peg-filgrastim at the discretion of the PI
3rd
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at 1 dose level 
lower (100 mg once daily)
4th
Discontinue acalabrutinib
5.4.2
Thrombocytopenia
x
Grade 4 platelets (<75% decrease from baseline) deemed related to study drug
Occurrence
Action
1st – 2nd
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level
3rd
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at 1 dose level 
lower (100 mg once daily).
4th
Discontinue acalabrutinib
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5.4.3
Nonhematologic Toxicities
x
Grade 3 nonhematological toxicity deemed related to study drug (despite optimal supportive 
care)
Occurrence
Action
1st – 2nd
Hold acalabrutinib until recovery to Grade 1 or baseline; may restart at original 
dose level. 
3rd
Hold acalabrutinib until recovery to Grade 1 or baseline; restart at 1 dose level 
lower (100 mg once daily).
4th
Discontinue acalabrutinib
x
Subjects experiencing a second occurrence of Grade 3 diarrhea, constitutional symptoms, 
readily reversible metabolic events, or infection may be restarted at the same dose when the 
toxicity resolves to Grade 1 or baseline.
Other Grade 1-2 nonhematologic toxicities thought related to drug do not necessitate holding of 
acalabrutinib, as long as the AE is not a toxicity as detailed in Section 5.5 are encountered. Supportive 
measures as appropriate should be taken to minimize side effects. An interruption of study drug 
administration is permissible.
5.5
Holding of Study Drug Administration
5.5.1
Surgical Procedures 
BTK inhibition might affect platelet aggregation, therefore:
Consider the benefit-risk of withholding acalabrutinib for 3 days presurgery and postsurgery depending 
upon the type of surgery and the risk of bleeding. 
5.5.2
Hepatitis B Virus Reactivation
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated with acalabrutinib.
Therefore, subjects with a history of hepatitis B virus (HBV) infection (HBV core antibody positive) will
be referred to a physician with expertise in managing hepatitis B for antiviral prophylaxis. Subjects who 
receive HBV prophylaxis are eligible for participation in the study. After the start of study drug, subjects 
should be monitored every 3 months with a quantitative polymerase chain reaction (PCR) test for HBV 
DNA. Monitoring every 3 months should continue until 12 months after last dose of acalabrutinib.
Any subject with a rising viral load (above lower limit of detection:  approximately 10 IU/mL) should 
discontinue study treatment and pre-emptively be treated with a nucleoside analog (i.e., lamivudine) for at 
least 12 months after the last treatment cycle of therapy or be referred to a specialist such as a 
gastroenterologist for management.  This may not be relevant in all participating countries.  As intravenous 
immunoglobulins (IVIG) may cause false positive hepatitis serology, monthly PCR testing is not required 
in subjects who are currently receiving or received prophylactic IVIG within 3 months before study 
enrollment and have a documented negative anti-HBc test before the initiation of IVIG therapy.  PCR 
testing should be performed when clinically indicated (e.g., in the setting of rising transaminase levels),
(see Section 11.2.2).
Subjects who are anti-HBc positive should have a quantitative PCR test every 3 months during treatment 
and every 3 months thereafter for 12 months after the last dose of any study drug.  Subjects who are 
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receiving antiviral prophylaxis should have a quantitative PCR monthly for the first 3 months and then 
every 3 months thereafter for 12 months after last dose of any study drug.
The household members of subjects who develop HBV reactivation will be counseled and advised to be 
screened for HBV with their primary care doctors.
5.5.3
Progressive Multifocal Leukoencephalopathy
If progressive multifocal leukoencephalopathy (PML) is suspected, hold further treatment with 
acalabrutinib treatment until a diagnosis of PML is excluded.  If a diagnosis of PML is confirmed, 
permanently discontinue acalabrutinib.
5.5.4
Permanent Discontinuation of Study Drug Administration in Case of Treatment-related 
Adverse Events
x
Serious or life-threatening cardiac arrhythmias (Grade 3 or 4)
x
Severe infection (requiring vasopressor support >24 hours, or intubation)
x
Hepatitis B viral load above the lower limit of detection
x
Confirmed diagnosis of PML
x
Any Grade 4 toxicity excluding readily reversible metabolic or laboratory abnormalities or 
hematologic toxicities 
x
Progressive disease as defined in Section 7.3
x
Pregnancy or unwillingness to use highly effective method of contraception
Subjects who will not be able to receive further study drug administration will be followed for safety and 
after resolution of the event will continue to be followed at regular intervals and will undergo reassessment 
of disease as outlined in Sections 6.0 and 7.0.
5.6
Supportive Care (Noninvestigational)
x
Growth Factors: Filgrastim or pegfilgrastim may be used at the PI’s discretion in subjects
with neutropenia.
x
Blood Products: Subjects will be transfused with packed red blood cells and platelets as 
clinically indicated.  All required blood products will be irradiated prior to transfusion.  
x
Anti-infective Agents: Anti-infective agents will be used as indicated for treatment of 
intercurrent infections.
x
Pneumocystis pneumonia (PCP) prophylaxis: PCP prophylaxis is not mandatory but will be 
offered. Typically, prophylaxis will be with TMP/SMX. Subjects who are allergic to sulfa 
drugs may be given an alternative agent, at the discretion of the PI.
5.7
Permitted and Nonpermitted Concomitant Medications (Investigator’s Brochure)
Subjects may continue most medications they were prescribed prior to study enrollment for co-morbid 
conditions. We ask subjects to report all medications and over the counter drugs they are taking. 
5.7.1
Guideline for Use of CYP Inhibiting and Inducing Drugs
Avoid co-administration of strong CYP3A inhibitors with acalabrutinib (see APPENDIX B).  
Alternatively, if the inhibitor will be used short-term, interrupt acalabrutinib.  When acalabrutinib is 
administered with moderate CYP3A inhibitors, reduce acalabrutinib dose to 100 mg once daily.  Avoid 
co-administration of strong CYP3A inducers with acalabrutinib (see APPENDIX B).  If a strong CYP3A 
inducer cannot be avoided, increase the acalabrutinib dose to 200 mg twice daily.
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5.7.2
Concomitant Use of QT Prolonging Agents
No compound induced changes in the mean, diastolic or systolic arterial blood pressure, heart rate and the 
length of the heart rate corrected QT interval (QTc) could be detected during 24-hour recording patterns in
healthy subjects administered acalabrutinib in therapeutic (100 mg) or supratherapeutic (400 mg) doses. 
(HV-005). Acalabrutinib may be given with other medications that may cause prolonged QTc.
5.7.3
Concomitant Use of Antiplatelet Agents and Anticoagulants
Due to potential bleeding complications associated with other BTK inhibitors, subjects who require 
anticoagulation with warfarin will not be allowed to start treatment with acalabrutinib unless the 
anticoagulation drug has been changed. With other forms of anticoagulation acalabrutinib should be 
monitored carefully and subjects should be observed closely for signs and symptoms of bleeding.
5.8
Special Instructions for Subjects
5.8.1
Immunizations
Live vaccines are contraindicated in this subject population. Subjects who would like to receive other 
routine nonattenuated vaccinations will be allowed to do so. Subjects will be advised not to receive live 
viral vaccines. The ability to generate an immune response to any vaccine following administration of 
acalabrutinib has not been studied.
5.8.2
Birth Control
Female subjects with reproductive potential who are sexually active must use highly effective methods of 
contraception during the study and for 2 days after the last dose of acalabrutinib.  Examples of highly 
effective methods of contraception are listed in Section 11.8.
5.8.3
Calcium Carbonate
Subjects should be instructed to 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.  Use of omeprazole or esomeprazole or any other long-acting proton pump inhibitors while 
taking acalabrutinib is not recommended due to a potential decrease in acalabrutinib exposure.
6.0
CLINICAL MONITORING 
Samples will be ordered and tracked through the 
. Should a 
 screen not be available, the 
 will be completed and will 
accompany the specimen and be filed in the medical record. 
All evaluations under Section 6.0 where research blood is required for tumor mutations, blood may be 
redrawn and sent to the testing company if there are problems with the sample.
Subjects with a history of HBV infection should be monitored as described in Section 5.5.2.
Subjects with known history of hepatitis C virus (HCV) infection or who are hepatitis C antibody-positive 
should be tested for HCV RNA during Screening and at Cycle 6.  No further testing beyond Cycle 6 is 
necessary if PCR results are negative.
Cases of PML have been reported in patients treated with acalabrutinib. Signs and symptoms of PML may 
include cognitive and behavioral changes, language disturbance, visual disturbance, sensory deficits,
weakness, and coordination and gait difficulties. If PML is suspected, hold further treatment with 
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acalabrutinib until a diagnosis of PML is excluded.  A diagnostic evaluation may include, but is not limited 
to:
x
Neurology consultation
x
Brain magnetic resonance imaging (MRI)
x
PCR analysis for John Cunningham Virus DNA in cerebrospinal fluid
If PML is confirmed, permanently discontinue acalabrutinib.
Subjects should be monitored for increases in liver biochemistry indicating potential Hy’s law (PHL) or 
Hy’s law (HL).  The investigator is responsible for determining whether a subject meets PHL criteria at any 
point during the study.  See APPENDIX C for the process to be followed in identifying and reporting cases 
of PHL and HL.
6.1
Screening Visit
Written informed consent will be obtained from all subjects by the investigator or his/her designee before 
any protocol specific procedures are carried out.
Screening Visit will include the following:
x
Complete medical history
x
Physical examination
x
Concomitant medication review
x
ECOG performance evaluation
x
Complete blood count with differential
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and lactate dehydrogenase (LDH)
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
Reticulocyte count
x
Coagulation panel (PT, PTT)
x
C-reactive protein (CRP)
x
Iron studies (ferritin, transferrin, iron)
x
Folate, Vitamin B12
x
Beta-2 microglobulin 
x
Haptoglobin
x
Direct antiglobulin test (DAT)
The following results from other 
IRB approved protocols that subjects may have participated in or 
outside results may be used as part of the screening laboratory tests for this study:
x
Flow cytometry panel for CLL (may be done on blood and/or bone marrow and/or lymph node) or 
immunohistochemistry of lymph node or bone marrow demonstrating CLL/SLL.  Results obtained 
within the past 12 months prior to signing the treatment consent form are acceptable.
x
In treatment-naïve subjects, interphase FISH cytogenetics for deletion 17p13 within 3 months of 
signing the treatment consent form
x
Viral serologies for hepatitis B and C, HIV 1/2 within 1 month of signing treatment consent form. 
For individuals with a positive hepatitis B core antibody, HBV DNA PCR will be performed to 
screen for subclinical infection within 3 months of signing the treatment consent form.
x
For females of childbearing potential, 2 negative pregnancy tests sensitive to 50 mIU/mL. 
(Negative tests to be completed 2-4 weeks apart.)
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x
Complete staging computed tomography (CT) of the neck, chest, abdomen and pelvis within 3 
months prior to signing treatment consent. Intravenous and PO contrast will be used unless the 
subject has a contrast allergy or impaired renal function.
x
Electrocardiogram (ECG) within 3 months prior to signing treatment consent
6.2
Baseline Testing
Screening results may be used as baseline. Baseline tests will be obtained within 1 month prior to starting 
study drug, unless noted otherwise:
x
Laboratory results from other 
IRB approved protocols that subjects may have participated in or 
outside reports may be accepted:
x
For females of childbearing potential, pregnancy test sensitive to 50 mIU/mL or less
x
IGHV mutation analysis where possible (as this test does not change with time, any prior report is 
acceptable)
x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and deletion 
17p13 within 3 months prior to starting study drug
x
Bone marrow aspirate and biopsy within 3 months of starting treatment
x
x
Lymph node biopsy within 3 months of signing treatment consent form (per investigator discretion)
6.3
On Therapy Evaluations 
6.3.1
Day 1 (C1/D1) Through Day 5 (C1D5)
Adverse events will be continually monitored. Assessments for PML will be completed as clinically 
indicated throughout the study.
 
Day 1 (C1/D1):  To be drawn before the first dose (may be drawn up to 3 days before the first dose):
x
For females of childbearing potential, pregnancy test sensitive to 50 mIU/mL or less
x
Complete blood count with differential
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH 
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
Reticulocyte count
x
Beta-2 microglobulin 
x
CRP
x
Coagulation panel (PT, PTT)
x
Serum free light chains, quantitative immunoglobulins
x
Serum protein electrophoresis with immunofixation
x
Lymphocyte phenotyping (T, B, NK)
x
Day 3 (C1/D3): To be drawn before study drug intake
x
Complete blood count with differential
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Day 3 (C1/D3): To be drawn 4 hours after study drug intake (± 2 hours)
x
Complete blood count with differential
x
x
Subjects in cohort A1a will have a lymph node biopsy 4 hours after study drug intake 
(± 2 hours).*
x
Subjects in cohort B1c will have a bone marrow (BM) biopsy 4 hours after study drug intake 
(± 2 hours).*
 
Day 4 (C1/D4):
x
Complete blood count with differential
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH 
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
Reticulocyte count
x
Beta-2 microglobulin 
x
CRP
x
x
Subjects in cohort A1b (24 hours (± 2 hours) post dose) and A2a (12 hours (± 2 hours) post 
dose) will have a lymph node biopsy for research.*
x
Subjects in cohort B2c (12 hours ± 2 hours) will have BM biopsy for research.*
Day 5 (C1/D5):
x
Complete blood count with differential
x
LDH
x
Beta-2 microglobulin 
x
x
Subjects in cohort A2b (36 hours ±2 hours post dose) will have a lymph node biopsy for 
research.*
*All attempts will be made to obtain research lymph node biopsies and bone marrow biopsies within the 
given time frame. However, due to unanticipated factors in the clinical center work flow (emergency 
procedures in interventional radiology, staffing issues in procedure unit) we will allow specimens to be 
obtained outside the specified window.
6.3.2
On Therapy Evaluations Through 6 Cycles of Treatment
Evaluations will be completed at the
at Cycle 1 Day 14 (± 3 days) and then for Cycle 1 through 
Cycle 5 (Day 28 ± 5 days). A cycle is defined as 4 weeks (28 days). The following assessments will be 
completed:
x
Interval history and physical examination
x
Concomitant medication review 
x
ECOG performance status evaluation 
x
Adverse events
x
Complete blood count with differential
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
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x
CRP
x
HBV DNA quantitative PCR (subjects with history of HBV infection only, every 
3 months)
x
HCV RNA quantitative PCR at Cycle 6 (subjects with a history of hepatitis C only)
x
Beta-2 microglobulin 
x
Repeat pregnancy test if applicable in women of child bearing potential (except day 14).
x
Additional blood draws, procedures, or imaging are (Day 28 ± 5-day window):
x
C2/D28: Lymphocyte phenotyping (T, B, NK) 
x
C2/D28: Complete staging CT of the neck, chest, abdomen and pelvis will be obtained.
IV and PO contrast will be used unless the subject has a contrast allergy or impaired renal 
function.
x
C3/D28: Serum free light chains
6.3.3
Post 6 Cycles of Therapy (Day 28 ± 15-day window unless otherwise noted)
x
Interval history and physical examination
x
Concomitant medication review 
x
ECOG performance status evaluation 
x
Adverse Events
x
Complete blood count with differential
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH 
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
Reticulocyte count
x
Coagulation panel (PT, PTT)
x
Serum free light chains, quantitative immunoglobulins
x
Serum protein electrophoresis with immunofixation
x
CRP
x
HBV DNA Quantitative PCR* (subjects with history of HBV infection only)
x
Beta-2 microglobulin 
x
Haptoglobin
x
DAT
x
Lymphocyte phenotyping (T, B, NK)
x
Repeat pregnancy test (women of child bearing potential) 
x
Peripheral blood flow cytometry panel for CLL may be obtained 
x
Staging CT of the neck, chest, abdomen and pelvis. IV and PO contrast will be used unless 
the subject has a contrast allergy or impaired renal function.
x
Bone marrow biopsy and aspirate. Bone marrow flow cytometry panel for CLL may be 
performed.
x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and 
deletion 17p13 may be obtained.
x
x
Lymph node biopsy may be obtained within 4 months of the “post 6 cycles of therapy” 
visit at the discretion of the PI; if lymph node biopsy performed, then lymph node flow 
cytometry panel for CLL may be obtained.
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x
*Every 3 months, HBV DNA quantitative PCR testing should be performed locally as needed for subjects
with a history of HBV infection.
6.3.4
Assessments Every 3 Months (± 15-day window) While on Therapy
x
Interval history and physical examination
x
Adverse events
x
Concomitant medication review 
x
ECOG performance status evaluation 
x
Complete blood count with differential 
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH
x
Hepatic Panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
CRP
x
Coagulation panel (PT/PTT) if clinically indicated
x
HBV DNA quantitative PCR (subjects with history of HBV infection only)
x
HCV RNA quantitative PCR (only for subjects with a history of hepatitis C infection with 
positive results at Cycle 6)
x
Beta-2 microglobulin 
x
Repeat pregnancy test if applicable (women of child bearing potential)
x
Reticulocyte count
x
Serum-free light chains, quantitative immunoglobulins
x
Haptoglobin
x
DAT
x
x
Lymphocyte phenotyping (T, B, NK) may be collected.
x
Epstein-Barr virus (EBV)/cytomegalovirus (CMV) PCR may be obtained.
6.3.5
Additional Studies at 12 and 24 Months and Yearly Thereafter (± 30-day window unless 
otherwise noted)
x
Lymphocyte phenotyping (T, B, NK)
x
Staging CT of the neck, chest, abdomen and pelvis. IV and PO contrast will be used unless 
the subject has a contrast allergy or impaired renal function.
x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and 
deletion 17p13 may be obtained.
x
HBV DNA quantitative PCR (subjects with history of HBV infection only)
x
Peripheral blood flow cytometry panel for CLL may be done.
x
Bone marrow biopsy and aspirate should be performed 3 months ± 15-days after the 
subject meets CT and hematologic criteria for CR.
x
When a bone marrow biopsy and aspirate is performed, a flow cytometry panel for CLL 
may be obtained.
x
Lymph node biopsy may be obtained within 4 months of the 12, 24 or yearly visit at the 
discretion of the PI.
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x
When a lymph node biopsy is performed a flow cytometry panel for CLL may be obtained.
x
x
6.3.6
6.3.7
Assessments at Time of Progressive Disease or Suspicion of Progressive Disease
x
Interval history and physical examination
x
Adverse events
x
Concomitant medication review 
x
ECOG performance status evaluation 
x
Complete blood count with differential 
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
CRP
x
Coagulation panel (PT/PTT) if clinically indicated
x
HBV DNA quantitative PCR (subjects with history of HBV infection only)
x
Beta-2 microglobulin 
x
Serum-free light chains, quantitative immunoglobulins
x
Lymphocyte phenotyping (T, B, NK) - yearly
x
Staging CT of the neck, chest, abdomen and pelvis. IV and PO contrast will be used unless 
the subject has a contrast allergy or impaired renal function.
x
PET scan as clinically indicated
x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and 
deletion 17p13 may be obtained.
x
Peripheral blood flow cytometry panel for CLL may be obtained.
x
Bone marrow biopsy and aspirate, bone marrow flow cytometry panel for CLL may be 
obtained.
x
Lymph node biopsy (if accessible), flow cytometry panel for CLL may be obtained.
x
x
6.3.8
Safety Follow-up 30 (+7) Days After the Last Dose of Study Drug (for Subjects Who Remain 
on Study)
x
Interval history and physical examination
x
Adverse events
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x
Concomitant medication review 
x
ECOG performance status evaluation 
x
Complete blood count with differential 
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
CRP
x
Coagulation panel (PT/PTT) if clinically indicated
x
HBV DNA quantitative PCR (subjects with history of HBV infection only)
x
Beta-2 microglobulin 
x
Serum free light chains, quantitative immunoglobulins
x
Lymphocyte phenotyping (T, B, NK) - yearly
x
Staging CT of the neck, chest, abdomen, and pelvis, as clinically indicated. IV and PO 
contrast will be used unless the subject has a contrast allergy or impaired renal function.
x
PET scan as clinically indicated
x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and 
deletion 17p13 may be obtained.
x
Peripheral blood flow cytometry panel for CLL may be obtained.
x
Bone marrow biopsy and aspirate, bone marrow flow cytometry panel for CLL may be 
obtained.
x
Lymph node biopsy (if accessible), flow cytometry panel for CLL may be obtained.
x
x
6.3.9
Discontinuation Follow-Up
The following will be completed every 6 months (± 30-day window) for subjects who discontinue study 
drug for reasons other than progression or start of an alternate anticancer therapy.  Assessment conducted 
will be based on investigator discretion and disease status.
x
If progressive disease is suspected, see Section 6.3.7
x
Interval history and physical examination
x
ECOG performance status evaluation 
x
Complete blood count with differential 
x
Acute Care Panel (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen)
x
Mineral panel (phosphorus, magnesium, albumin, and calcium)
x
Total protein, uric acid, and LDH
x
Hepatic panel (alkaline phosphatase, ALT, AST, total bilirubin, and direct bilirubin)
x
Coagulation panel (PT/PTT) if clinically indicated
x
CRP
x
HBV DNA quantitative PCR (subjects with history of HBV infection only)
x
Beta-2 microglobulin 
x
Serum free light chains, quantitative immunoglobulins
x
Lymphocyte phenotyping (T, B, NK) 
x
Staging CT of the neck, chest, abdomen and pelvis. IV and PO contrast will be used unless 
the subject has a contrast allergy or impaired renal function as clinically indicated.
x
PET scan as clinically indicated
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x
Interphase FISH cytogenetics for deletion 13q14, trisomy 12, deletion 11q22-23, and 
deletion 17p13
x
Peripheral blood flow cytometry panel for CLL 
x
Bone marrow biopsy and aspirate, bone marrow flow cytometry panel for CLL 
x
Lymph node biopsy (if accessible), flow cytometry panel for CLL 
x
7.0
CRITERIA FOR RESPONSE
Responses for spleen and lymphadenopathy will be primarily assessed using CT scans. In the absence of a 
CT scan, assessment by physical exam may be substituted.
Response assessments will be made by IWCLL 2008 guidelines2 incorporating the 2012 and 2013 
clarifications for subjects treated with kinase inhibitors.59 Response includes CR, PR, and PRL (Table 3).
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Table 3: Criteria for Response 
Response
CR
PRF
PRLF
PDG
Group A
LymphadenopathyA
None >1.5cm
Decrease 
≥50%
Decrease ≥50%
Increase ≥50% or 
any new lesion 
>1.5 cm
Splenomegaly/hepatomegalyB
None
Decrease 
≥50%
Decrease ≥50%
Increase ≥50% or 
new splenomegaly 
or hepatomegaly
Blood lymphocytesC
<4000/μL
Decrease 
≥50% 
Increase or <50% 
decrease 
Increase ≥50% 
and ≥5,000/μL 
B lymphocytes
Bone marrowD
Normocellular, <30% 
lymphocytes, no 
B-lymphoid nodules. 
Not applicable
Not applicable
Not applicable
Group BE
Platelet count
>100,000/μL
>100,000/μL 
or increase 
≥50% 
>100,000/μL or 
increase ≥50% 
Decrease ≥50% 
secondary to CLL
Hemoglobin
>11.0g/dL
>11.0 g/dL or 
increase ≥50% 
>11.0 g/dL or 
increase ≥50% 
Decrease ≥50% 
secondary to CLL
Neutrophils
>1,500/μL
>1,500/μL or 
increase ≥50% 
> 1,500/μL or 
increase ≥50%
Not applicable
CR = complete response; CRi = CR with incomplete blood count recovery CT = computed tomography; PD = progressive 
disease; PR = partial response; PRL = partial response with lymphocytosis
A Sum of the products of up to 6 lymph nodes as evaluated by CT scans.  In the absence of a CT scan assessment by physical 
exam may be substituted. 
B Splenomegaly assessed by CT scan.  In the absence of a CT scan assessment by physical exam may be substituted.  New 
splenomegaly or hepatomegaly is assessed by physical exam. 
C Subjects with treatment-related lymphocytosis remain on study unless associated with other signs of progressive disease.  
Treatment-related lymphocytosis may occur at the start of treatment or at any time when resuming treatment after a dose 
interruption. 
D Complete response requires confirmation with bone marrow biopsy.  In the absence of a confirmatory bone marrow biopsy the 
response can be classified as CRu.  In case of a hypocellular marrow the response can be classified as CRi.  
E PR or PRL, at least 1 Group B criterion has to be met.  CR, all criteria in A and B must be met.  In subjects meeting Group A 
criteria for CR but not Group B, the response can be classified as CRi. 
F PR and PRL criteria refer to changes from baseline.  
G PD criteria refer to changes from baseline in subjects who never responded and to changes from best response (nadir) in 
subjects who responded.
7.1
Complete Response (CR)
x
Is defined as meeting all criteria in A and B. 
x
Meet all criteria in A and B but bone marrow confirmation is pending: unconfirmed complete 
response (CRu).
x
Meet all criteria in A but bone marrow is hypocellular, or criteria in B are not met: complete
response with incomplete blood count recovery (CRi).
7.2
Partial Response (PR)
x
Is defined by 2 criteria in Group A if abnormal before therapy and at least 1 Group B criterion.
x
In subjects with just 1 involved Group A site (e.g., lymphadenopathy in a subject with SLL), the 
response is PR when the criterion for that site is met.
x
If criteria for PR, except for a decrease in the number of blood lymphocytes by 50% or more from 
the value before therapy, are met, then assessment will be PRL.
x
SLL subjects need to have both ALC >50% and ALC >5K to be PRL.
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7.3
Progressive Disease (PD)
Progressive disease is defined by at least one of the following criteria when occurring in the absence of a 
confounding process (e.g., infection), and that is maintained or continues to progress over a period of at 
least 3 months:
x
Progressive lymphocytosis ≥50% from nadir, confirmed due to expansion of CLL cells by flow 
cytometry (≥5,000 B lymphocytes/μL)
x
or an increase ≥50% in the sum of the products of at least 2 lymph nodes with at least 1 lymph 
node >1.5 cm in greatest diameter
x
or the appearance of a new pathologic lymph node >1.5 cm in greatest diameter
x
or new onset splenomegaly or hepatomegaly on physical exam, or other new CLL organ infiltrates
x
or an increase ≥50% in splenomegaly or hepatomegaly
x
or the progression or development of cytopenia (excluding autoimmune cytopenia), as documented 
by a decrease of hemoglobin levels by >2 g/dL, or by a decrease of platelet counts by >50%, if a 
marrow biopsy supports a disease-related etiology.
Other criteria for PD include:
x
Transformation to a more aggressive histology (e.g., Richter syndrome). Whenever possible, this 
diagnosis should be established by lymph node biopsy.
A rise of the lymphocyte count at the beginning of therapy or resumption of therapy after a period of drug 
hold in absence of other indications of progressive disease will not be considered as evidence of 
progressive disease because this type of agent does typically lead to a mobilization of tumor cells into the 
peripheral blood.
8.0
ANCILLARY LABORATORY RESEARCH STUDIES
8.1
Collection of Samples
Blood samples: A volume not to exceed 550 mL of peripheral blood will be requested during the initial 
8-week period.  
Lymphapheresis:
Lymphapheresis may also be collected in subjects with lymphocytosis that 
persists at 6 months, 12 months, yearly thereafter, and at progression of disease.
Bone marrow biopsies and aspirate:
Lymph node biopsies: An excisional or core lymph node biopsies may be obtained pretreatment and at a 
timepoint during cycle 1. 
PBMC sample: At a single on-treatment visit, six 10-mL NaHep tubes of peripheral blood may be
collected (see Section 6.3.6).
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8.2
Intended Use
These specimens will not be used for diagnostic purposes. 
The translational and correlative endpoints of the study require analysis of tumor samples from blood, bone 
marrow, and lymph node for occupancy of BTK and impact of kinase inhibition on the tumor cells.
The assessment of BTK inhibition as a pharmacodynamic endpoint and the ability of acalabrutinib to 
occupy and inactivate BTK will be conducted at Acerta Pharma, BV.
x
8.3
Storage, Tracking and Disposition of Samples and Data
Storage: All samples at
will be stored in the laboratory of 
. Samples collected will 
be de-identified prior to storage in the laboratory of the Principal Investigator following current 
 
Policy. Efforts to ensure protection of subject information include:
x
Each sample is assigned a unique number. 
x
Vials holding subject samples are labeled with the sequential laboratory accession ID number that 
does not contain any personal identifier information.
x
An electronic database is used to store subject information related to the coded samples.
x
The laboratory is located in a controlled access building and laboratory doors are kept locked. 
Visitors to the laboratory are required to be accompanied by laboratory staff at all times.
x
Hard copy records or electronic copies of documents containing subject information are kept in the 
locked laboratory or other controlled access locations.
Tracking: Samples will be ordered and tracked through the 
.  Should a 
 
not be available, the 
will be completed and will accompany the specimen and be 
filed in the medical record.  Samples will not be sent outside 
 without IRB notification and an executed 
MTA or CTA. 
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End of study procedures: Samples from consenting subjects will be stored until they are no longer of
scientific value or if a subject withdraws consent for their continued use, at which time they will be 
destroyed. 
Loss or destruction of samples: Should we become aware that a major breech in our plan for tracking and 
storage of samples has occurred, the IRB will be notified.
8.4
   
x
9.0
BIOSTATISTICAL CONSIDERATIONS
9.1
Primary Endpoint:  Response to Acalabrutinib
The best response to treatment will be determined according to IWCLL 2008 criteria incorporating 2012
and 2013 clarifications pertaining to subjects treated with kinase inhibitors. Response includes CR, PR, 
and PRL.
9.2
Secondary Endpoints
x
Safety and tolerability of once daily and twice-daily dosing of acalabrutinib
x
Response and duration of response
o
Time to progression on acalabrutinib
o
Progression-free survival and OS on acalabrutinib
x
Degree of inhibition of BTK assessed using a specific probe assay in tumor samples collected on 
acalabrutinib (blood, bone marrow, and lymph node), and after 2 and 6 months of continued dosing 
(blood and bone marrow).
x
On-treatment effects on tumor biology of CLL cells in blood, bone marrow, and lymph nodes 
including proliferation (Ki67), activation (flow cytometric markers such as CD38, CD69, CD86), 
and gene expression.
x
Clonal dynamics on treatment assessed using FISH cytogenetics and gene sequencing for somatic 
mutations.
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x
Shifts in cellular and humoral immunity on treatment (e.g., immunoglobulin levels, changes in 
T-cell subsets).
9.3
Exploratory Endpoint
x
9.4
Sample Size
The study will enroll 44 subjects evaluable for response to complete the primary endpoint.  Subjects 
receiving at least 6 months of therapy for whom CR assessment as detailed in Section 7.0 will be 
considered evaluable for response.  The subjects in 2 different dosing cohorts are pooled to evaluate the 
primary endpoint of response: Cohort 1. acalabrutinib 200 mg once daily; and Cohort 2. acalabrutinib
100 mg twice daily.  Each dosing cohort will include 22 subjects. To account for subjects discontinuing 
participation before having completed 6 months on treatment, we will enroll up to 4 additional subjects.  
Thus, up to 48 subjects may be started on study drug. To account for screening failures, up to 12 additional 
subjects may be screened for protocol. Up to 60 subjects will sign the screening consent and up to 48 will 
sign the standard consent to start treatment, with the intention of accruing 44 evaluable subjects.
For pharmacodynamics studies, we aim to have at least 6 subjects donating paired tumor samples 
pretreatment and on-treatment in each cohort for a total of 36 subjects.
9.5
Statistical Methods
The planned analyses will include descriptive statistics on the proportions of ORs. The response 
probabilities will be estimated using the sample proportions and their inferences including confidence 
intervals and hypotheses testing will be evaluated using Binomial distributions, and, if appropriate, normal 
approximations.  The duration of response, OS, and the PFS time will be analyzed using appropriate 
nonparametric tools in survival analysis such as Kaplan-Meier estimates taking consideration of random 
censoring.  
In addition, methods based on survival analysis, cumulative incidence rates, and other competing risk 
models will be used to evaluate the treatment effects.  Graphical tools will be used to display the 
appropriate estimates (i.e., estimated proportions and Kaplan-Meier curves) and their corresponding 95% 
confidence intervals. Methods based on multiple regression, analysis of variance, logistic regression and 
nonparametric regression will also be employed if deemed appropriate.
Response rate and survival will also be reported on an intention-to-treat basis.
As a secondary analysis, the efficacy and safety profiles of 2 dosing cohorts will be compared. The effect 
on the possible dosing reduction due to AEs will be examined and adjusted. Appropriate methods will be 
used to examine missing patterns and handle the missing data in the analysis as deemed appropriate.
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9.6
Study Stopping Rules  
The study will be monitored to ensure that the occurrence of a specified set of treatment-related serious 
AEs that occur during the treatment period does not substantially exceed an anticipated rate. The following 
specified treatment-related serious AEs determined to be probably or definitely related to therapy will be
considered for early stopping of the study 
1.   AEs resulting in death
2.   Severe infection requiring vasopressor >24 hours or intubation 
3.   Any Grade 4 toxicity excluding
x
Readily reversible metabolic or laboratory abnormalities
x
Hematologic toxicities
We anticipate the rate of these specified treatment-related serious AEs within the 6 month period 
(completion of primary endpoint) to be 15% or less. Since the 2 dosing cohorts do not differ in total dose, 
we will monitor the treatment-related serious AEs in the 2 dosing cohorts together. Following Geller et al. 
(2003), our stopping rule is determined by a Bayesian approach. The stopping boundary for an experiment 
is reached if the Bayesian posterior probability that the true probability of developing one or more of the 
specified treatment-related serious AEs exceeds this benchmark rate of 15% is at least 90%. We take our 
prior distribution to be a beta distribution so that our prior clinical opinion is worth 20% of the weight we 
will place on the new data. This gives prior parameters alpha = 1.35, beta = 7.65. Hence when we make 
decisions about stopping the study, the data from the study will dominate over the prior opinion.  We begin 
monitoring the treatment-related serious AEs when 3 subjects are evaluable for treatment-related serious 
AEs within the 6 months.  
Number of subjects in the 
experiment
Stop if the number of subjects who have 
developed any of the specified treatment-
related serious adverse events reaches:
≤ 5
3
≤ 10
4
≤ 15
5
≤ 20
6
≤ 26
7
≤ 31
8
≤ 36
9
≤ 42
10
≤ 47
11
≤48
12
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We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 48 independent Bernoulli trials, each had a probability p for having 
treatment-related serious AEs and q=1-p for not having treatment-related serious AEs and compared the
treatment-related serious AEs outcomes with the above stopping boundary to determine whether the study 
was stopped.  We repeated the simulation 100,000 times and computed the proportion of stopped studies 
(i.e., “number of stopped studies”/100,000) which were stopped using the above stopping rule.  The 
following table summarizes the proportions of stopped studies under a number of scenarios for p:
Probability of TRSAE = p
0.10
0.15
0.20
0.25
0.30
Proportion of Stopped Studies
3.8%
18.8%
47.2%
75.5%
91.8%
Average number of subjects
46.7
42.8
35.4
26.7
19.4
Average number TRSAEs
4.7
6.4
7.1
6.7
5.8
TRSAE = treatment-related serious adverse event
These results suggest that our stopping rule has a low probability stopping a study when the proportion of 
treatment-related serious AEs is below the benchmark value of 15%, and the probability of stopping a study 
is high when the true proportion of treatment-related serious AEs exceeds this benchmark value. Based on 
these results, we believe that our Bayesian stopping rule has satisfactory statistical properties. 
9.7
Stopping Rule for Mortality
In addition, we have a stopping rule for treatment-related mortality (TRM; death that are probably or 
definitely related to the protocol regimen).  We anticipate the TRM rate within 1 year to be 5% or less.
Using the same Bayesian approach, the stopping boundary is reached if the Bayesian posterior probability 
that the true probability of developing TRM’s exceeds 5% is at least 90%.  We take our prior distribution to 
be a beta distribution with parameters (α, β) = (0.45, 8.55). This indicates that the relative weight we place 
on our prior opinion is approximately 20% of the weight we will place on the results of the new study.  The 
following table summarizes the threshold numbers for stopping the study based on above Bayesian 
approach.
Number of 
subjects in the 
experiment
Stop if the number of subjects 
who have TRMs reaches:
≤ 2
2
≤ 20
3
≤ 33
4
< 47
5
48
6
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 48 independent Bernoulli trials, each had a probability p for having TRM and 
q=1-p for not having TRM and compared the TRM outcomes with the above stopping boundary to 
determine whether the study was stopped.  We repeated the simulation 100,000 times and computed the 
proportion of stopped studies (i.e., “number of stopped studies”/100,000) which were stopped using the 
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above stopping rule.  The following table summarizes the proportions of stopped studies under a number of 
scenarios for p:
Probability of TRM = p
0.03
0.05
0.07
0.10
0.15
0.20
Proportion of Stopped Studies
3.5%
14%
30.8%
58.6%
88.3%
97.9%
Average number of subjects
47.1
44.6
40.7
33.4
22.7
16
Average number TRMs
1.4
2.2
2.9
3.4
3.4
3.2
These results suggest that our stopping rule has a low probability stopping a study when the proportion of 
TRM is below the benchmark value of 5%, and the probability of stopping a study is high when the true 
proportion of TRM exceeds this benchmark value. Based on these results, we believe that our Bayesian 
stopping rule has satisfactory statistical properties. 
9.8
Off Study Criteria (for Subject Participation)
Subject choice: Subjects may be removed from the study at their request.  The risks of withdrawing will 
be discussed, as will alternative treatment options. Subjects who opt to withdraw from the protocol will be 
strongly encouraged to continue to have laboratory tests (complete blood count, chemistries) monitored for
1 month after study withdrawal for their safety.  
PI Decision: Subjects will be taken off study for:
x
Initiation of nonprotocol treatment
x
Significant PD or a concomitant condition that would make the subject ineligible for further 
protocol participation. Subjects who meet criteria of PD and are continuing to gain clinical benefit 
from therapy may be able to temporarily remain on acalabrutinib after discussion with the medical 
monitor. 
x
Reactivation of HBV infection
x
Pregnancy or initiation of breast feeding
x
Subject becomes significantly noncompliant with study drug administration, study procedures, or 
study requirements, which might increase risk or substantially compromise the interpretation of 
study results.
Completion of the study: Subjects will be followed indefinitely until an off-study criterion is met or the 
study is closed to further follow-up care.
Subjects who discontinue study drug for reasons other than disease progression or start of alternative 
anticancer therapy will be followed approximately every 6 months (± 30 days) until disease progression or 
start of alternative anticancer therapy, whichever comes first.  
Subjects or the partner of a subject who becomes pregnant will be followed for the duration of the 
pregnancy and birth of the offspring.
Once protocol participation is complete, the subject will be referred back to his or her referring physician, 
consented to the 
 for consideration for 
standard therapy or evaluated for eligibility for another 
 protocol, depending on what is considered 
to be in the best interest of the subject.
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Subjects who are still on treatment at the end of the study and deriving clinical benefit from acalabrutinib 
treatment may continue treatment.  At the time of the final data cutoff (DCO) and database closure, subjects 
who remain in this study may be transitioned to a separate rollover study or remain within this study for 
continued access to study drug.  Once all active subjects are eligible to continue to receive acalabrutinib 
and after database closure, this study would be considered closed.  There will be no further data collection 
other than reporting of SAEs per Section 10.2.  Access within this study will enable continued treatment 
with visit assessments per standard of care, whereas the separate rollover study will enable treatment 
continuation with visit assessments and data collection per the rollover study protocol.
10.0
DATA AND SAFETY MONITORING
Principal Investigator: Accrual, efficacy and safety data will be monitored by the Principal Investigator:
IRB: Prior to implementation of this study, the protocol and the proposed subject
consent and assent forms will be reviewed and approved by the properly constituted Institutional Review 
Board (IRB) operating according to 45 CFR 46. This committee will approve all amendments to the 
protocol or informed consent and conduct continuing annual review so long as the protocol is open to 
accrual or sample and/or data analysis continues.  Accrual and safety data will also be monitored and 
reviewed annually by the IRB.
Quality assurance and control monitoring will be consistent with the 
Quality Assurance and Quality Control Policy.
 DSMB: The 
 Data Safety and Monitoring Board (DSMB) will review the protocol, 
progress report, accrual, efficacy and safety data at 6- or 12-month intervals as scheduled.  All AEs and 
serious adverse events (SAEs) observed during the clinical trial and for which there is a relationship with 
the use of acalabrutinib or the conduct of the study will be reported to the DSMB at the regularly scheduled 
DSMB meeting. The DSMB may recommend early termination of the study for considerations of safety 
and efficacy.
Acerta Pharma, BV (Sponsor): An annual progress report, any amendments to the protocol, and any 
change in the status of the protocol will be forwarded to:  
In addition, regular communication with the Sponsor occurs to discuss study progress, obtain investigator 
feedback and exchange, and discuss "significant safety events" (i.e., AEs leading to dose reductions, related 
SAEs, and deaths).  
10.1
Assessment of Safety
10.1.1 Definitions
Please refer to 
 for 
current definitions.
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10.1.2 Severity
Definitions found in the CTCAE v4.03 will be used for grading the severity (intensity) of nonhematologic
AEs:
x
Grade 1 (mild AE) – experiences which are usually transient, requiring no special treatment, and 
not interfering with the subject’s daily activities
x
Grade 2 (moderate AE) – experiences which introduce some level of inconvenience or concern to 
the subject, and which may interfere with daily activities, but are usually ameliorated by simple 
therapeutic measures
x
Grade 3 (severe AE) – experiences which are disabling; unacceptable or intolerable, significantly 
interrupt the subject’s usual daily activity, and require systemic drug therapy or other treatment
x
Grade 4 (life-threatening AE) – experiences which cause the subject to be in imminent danger of 
death
x
Grade 5 (death related to AE) – experiences which result in subject death
The grading scale for hematologic toxicity in subjects with CLL is in the table below.
Grading Scale for Hematologic Toxicity in CLL2
Grade1
Decrease in platelets2 or
hemoglobin3 (nadir) from 
pretreatment value
Absolute neutrophil count/μL4
(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
ANC = absolute neutrophil count; CLL = chronic lymphocytic leukemia; G-CSF = granulocyte colony-
stimulating factor; WBC = white blood cell
1.
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 reported as Grade 5.
2.
Platelet counts must be below normal levels for Grades 1 to 4.  If, at any level of decrease, the platelet 
count is < 20 x 109/L (20,000/μL), this will be considered Grade 4 toxicity, unless a severe or life-
threatening decrease in the initial platelet count (e.g., < 20 x 109/L [20,000/μL]) was present 
pretreatment, in which case the patient is not evaluable for toxicity referable to platelet counts.
3.
Hemoglobin levels must be below normal levels for Grades 1 to 4. Baseline and subsequent hemoglobin 
determinations must be performed before any given transfusions. The use of erythropoietin is irrelevant 
for the grading of toxicity but should be documented.
4.
If the ANC reaches < 1 x 109/L (1000/μL), it should be judged to be Grade 3 toxicity. Other decreases in 
the WBC count, or in circulating neutrophils, are not to be considered because a decrease in WBC 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/μL) 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.
10.1.3 Pregnancy
Subjects will be advised to immediately inform the investigator if the subject or subject’s partner becomes 
pregnant from the time of consent to 2 days after the last dose of study drug.  Any female subjects receiving 
acalabrutinib who become pregnant must immediately discontinue study drug.  The investigator will
counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.  
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The investigator should report all pregnancies and pregnancies in the partners of subjects within 24 hours 
using the Pregnancy Report Form Part I.  This form should be faxed or emailed to Acerta Pharma, BV Drug 
Safety.  Any pregnancy-associated SAE must be reported using the SAE report form, according to the usual 
timelines and directions for SAE reporting.
Any uncomplicated pregnancy that occurs with the subject or with the partner of a treated subject during 
this study will be reported. All pregnancies and partner pregnancies that are identified during or after this 
study, wherein the estimated date of conception is determined to have occurred from the time of consent to 
2 days after the last dose of acalabrutinib will be reported, followed to conclusion, and the outcome 
reported.
Monitoring of the pregnancy should continue until conclusion of the pregnancy at which point the 
Pregnancy Report Form Part II must be completed and submitted to Acerta Pharma, BV Drug Safety.  If a 
viable baby is born, then at 2 months postpartum the Pregnancy Report Form Part III must be completed 
and submitted.
Pregnancy itself is not regarded as an AE unless there is suspicion that the investigational product under 
study may have interfered with the effectiveness of a contraceptive medication. Likewise, elective 
abortions without complications are not considered AEs. Any SAEs associated with pregnancy (e.g.,
congenital abnormalities/birth defects/spontaneous miscarriages or any other serious events) must
additionally be reported as such using the SAE report form. 
10.1.4 Adverse Event and Serious Adverse Event Causality Assessments
The relationship of AEs and SAEs to the study drug will be assessed by means of the question: ‘Is there a 
reasonable possibility that the event may have been caused by the study drug?’  Answer Yes or No. 
The following descriptions below help to guide the assessment of causality:
No = There is no reasonable possibility that the event may have been caused by study drug. The AE:
x
May be judged to be due to extraneous causes such as disease or environment or toxic factors
x
May be judged to be due to the subject’s clinical state or other therapy being administered
x
Is not biologically plausible
x
Does not reappear or worsen when study drug is re-administered
x
Does not follow a temporal sequence from administration of study drug
Yes = There is a reasonable possibility that the event may have been caused by study drug. The AE:
x
Follows a temporal sequence from administration of study drug
x
Is a known response to the study drug based on clinical or preclinical data
x
Could not be explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other therapy administered to the subject
x
Disappears or decreases upon cessation or reduction of dose of study drug
x
Reappears or worsens when study drug is re-administered
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10.1.5 Adverse Events of Special Interest
The following are adverse events of special interest (AESIs) and must be reported to the sponsor 
expeditiously (see Section 10.2 for reporting instructions), irrespective of regulatory seriousness criteria or 
causality: 
x
Ventricular arrhythmias (e.g., ventricular extrasystoles, ventricular tachycardia, ventricular 
arrhythmia, ventricular fibrillation)
10.1.6 Second Primary Malignancies
Adverse events for malignant tumors reported during a study should generally be assessed as SAEs.  If no 
other seriousness criteria apply, the “Important Medical Event” criterion should be used.  In certain 
situations, however, medical judgment on an individual event basis should be applied to clarify that the 
malignant tumor event should be assessed and reported as a nonserious AE.  For example, if the tumor is 
included as medical history and progression occurs during the study but the progression does not change 
treatment and/or prognosis of the malignant tumor, the AE may not fulfill the attributes for being assessed 
as serious, although reporting of the progression of the malignant tumor as an AE is valid and should occur.  
Also, some types of malignant tumors, which do not spread remotely after a routine treatment that does not 
require hospitalization, may be assessed as nonserious; examples in adults include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.
x
The above instruction applies only when the malignant tumor event in question is a new malignant 
tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is being treated 
by the investigational product under study and is not the development of new or progression of 
existing metastasis to the tumor under study).  Malignant tumors that—as part of normal, if rare, 
progression—undergo transformation (e.g., Richter's transformation of B cell chronic lymphocytic 
leukemia into diffuse large B cell lymphoma) should not be considered a new malignant tumor.
10.2
Documenting and Reporting of Adverse and Serious Adverse Events
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation time points during the 
study.  All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, clinically significant laboratory test, or other means 
will be recorded in the subject’s medical record and eCRF, with the exception of laboratory values that are 
not associated with clinical symptoms.  Those will only be captured in the subject’s medical records.
Reporting serious, unexpected adverse reactions (SUSARs) to IRB:
An SAE may qualify for mandatory expedited reporting to regulatory authorities if the SAE is attributable 
to the investigational product and is not listed in the current acalabrutinib Investigator Brochure (i.e., an 
unexpected event).  In this case, Acerta Pharma, BV Drug Safety/Designee will forward a formal 
notification describing the SUSAR to all investigators. The investigators should follow the local 
institutional requirements of reporting SUSARs to IRB.
Reference Safety Information (RSI):
For the purpose of reporting adverse events (AEs) and serious adverse events (SAEs), the acalabrutinib 
Investigator Brochure contains the Reference Safety Information (RSI) for acalabrutinib.
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10.3
IRB and CD Reporting
10.3.1 Serious Events
Expedited Reporting:
Events requiring expedited reporting will be submitted to the IRB per 
 
Reports to the IRB at the time of Continuing Review:
The investigator or designee will refer to 
 to determine IRB 
reporting requirements.
Reports to the CD:
The investigator or designee will refer to
guidelines to 
determine CD reporting requirements and timelines.
10.3.2 Reporting Period for AEs
After the signing of the informed consent form (ICF) and prior to the first dose of study drug, all SAEs
must be reported.  After the first dose of study drug, all AEs/SAEs, irrespective of attribution of causality
must be reported.  
All AEs must be reported until 30 days after the last dose of study drug or the start of new anticancer 
therapy (whichever comes first).  After this period, investigators should report any SAEs and other AEs of 
concern that are believed to be related to prior treatment with study drug.
All SAEs which occur during the reporting period should be followed to resolution or until the investigator 
assessed the subject as stable or until the subject is lost to follow-up or withdraws consent.  
Resolution/stable means the subject has returned to baseline state of health of the investigator does not 
expect any further improvement or worsening of the event. 
10.3.3 Reporting Requirements for SAEs 
IRB: Please see Section 10.3.1 above.
Acerta Pharma, BV:
x
The SAE should be reported within 24 hours of discovery of the event or information via 
electronic data capture (EDC) on the AE/SAE eCRF.
x
If after hours, or if the EDC is not available, fax an SAE Reporting Form within 24 hours of 
the discovery of the event or information to fax number or email below and then enter the SAE 
on the AE/SAE eCRF when EDC is available (Note: All SAEs must be reported via EDC even 
if initial notification to Acerta Pharma, BV is via fax or email on the SAE Reporting Form).
Acerta Pharma, BV Drug Safety Contact Information
x
Drug Safety queries will be issued in EDC and the site is expected to address queries within a 
reasonable time period (e.g., 24-48 hours).
The following may not be reported to the IRB immediately:
x
A standard procedure for protocol therapy administration
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x
The administration of blood or platelet transfusion
x
A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling, 
or biomarker blood sampling)
x
Prolonged hospitalization for technical, practical, or social reasons in the absence of an AE
x
A procedure planned before entry into the study
10.4
Data Management
Authorized study site personnel will complete eCRFs designed for this study according to the completion 
guidelines that will be provided by the sponsor.  The investigator will ensure that the eCRFs are accurate, 
complete, legible, and completed within 5 days of each subject’s visit (unless required earlier for SAE 
reporting).  The investigator will ensure that source documents that are required to verify the validity and 
completeness of data transcribed on the eCRFs are never obliterated or destroyed.  Data will be abstracted 
from Clinical Center progress notes as well as from progress notes forwarded from the subjects’ home 
physician that have been uploaded into the electronic medical record. Laboratory data from 
 and from 
referring home physicians will be entered into the system. 
We will maintain the confidentiality of identifiable private information collected in this Clinical Trial and 
protect the privacy of the individual human subjects. All human subjects’ personally identifiable 
information (PII) as defined in accordance with the Health Insurance Portability and Accountability Act 
(HIPAA), eligibility and consent verification will be recorded in 
 and a database provided by 
Acerta Pharma, BV. Primary data containing individually identifiable information obtained during the 
conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply 
with 
 information security standards. Neither individual personal identifiers nor the key linking coded 
data to individuals will be released to Acerta Pharma, BV without prior IRB approval and an executed 
or MTA.  The 
may provide clinical 
specimens and data (blood, bone marrow, lymph node, serum or plasma) for the analysis of BTK inhibition 
in tumor samples, as well as tumor samples or derivatives thereof (cells, DNA, RNA, protein) to Acerta
Pharma, BV under this study.  Identifiable data will not be sent outside 
without prior IRB approval or 
appropriate conditions for disclosure outlined in the executed 
or MTA.
End of study procedures: Data will be stored in locked cabinets and in a password protected database 
until it is no longer of scientific value. 
Loss or destruction of data: Should we become aware that a major breech in our plan to protect subject
confidentiality and trial data has occurred, the IRB will be notified.
Publication policy: Given the research mandate of 
, subject data including the results of testing 
and responses to treatment will be entered into an 
-authorized and controlled research database. Any 
future research use will occur only after appropriate human subject protection institutional approval such as 
prospective 
 IRB review and approval or an exemption from the 
10.5
Protocol Monitoring
Representatives of Acerta Pharma, BV or its designee will monitor this study until completion.  Monitoring 
will be conducted through personal visits with the investigator and site staff as well as any appropriate 
communications by mail, fax, email, or telephone.  The purpose of monitoring is to ensure compliance with 
the protocol and the quality and integrity of the data.  This study is also subject to reviews or audits.
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Every effort will be made to maintain the anonymity and confidentiality of all subjects during this clinical 
study.  However, because of the experimental nature of this treatment, the investigator agrees to allow the 
IRB/IEC, representatives of Acerta Pharma, BV, its designated agents, and authorized employees of the 
appropriate regulatory agencies to inspect the facilities used in this study and, for purposes of verification, 
allow direct access to the hospital or clinic records of all subjects enrolled into this study.  This includes 
providing by fax, email, or regular mail de-identified copies of radiology, pathology, and/or laboratory 
results when requested by the sponsor.  A statement to this effect will be included in the informed consent 
and permission form authorizing the use of protected health information.
11.0
HUMAN SUBJECT PROTECTION 
The investigator(s) accept their responsibilities for protecting the rights and welfare of human research 
subjects and will permit, with reasonable advance notice and at reasonable times, the designated research 
monitors to monitor the conduct of the research, as well as to audit source documents to the extent 
necessary to verify compliance with FDA Good Clinical Practice and the approved protocol.
11.1
Rationale for Subject Selection
11.1.1 Predicted distribution by gender, age and race:
Chronic lymphocytic leukemia is a rare neoplasm that comprises a substantial proportion of all leukemia in 
middle-aged persons and is the most common type among elderly persons in Western populations.  
Epidemiologic studies suggest that distribution by gender will be 66% males and 33% females.13 This 
trend appears to be lost with age.  Chronic lymphocytic leukemia is more common in Caucasian and 
African-American populations but rare in Hispanics and very rare in the Asian population. This study will 
be open to all subjects who fit the inclusion criteria and provide informed consent to protocol participation. 
We would predict that distribution should be comparable to that seen on the 
screening protocol as follows:
x
by gender: 33% females; 66% males
x
by age: ages 23-79, median 60  
x
by race: 2% Asian, 11% Black, 8% Hispanic, 79% White
11.1.2 Special Populations 
Justification for exclusion of children: Chronic lymphocytic leukemia is uncommon in patients less than 
45 years of age and is virtually unknown in patients less than 20 years of age. At the time of diagnosis, 
more than 95% of patients are 45 years old and above.7 Chronic lymphocytic leukemia may also be, 
biologically, a different disease in children.  Ibrutinib has not been studied in human subjects under 
18 years of age. For these reasons, individuals <18 years old have been excluded from protocol 
participation. 
Justification for exclusion of pregnant women: There are no clinical studies that were done on pregnant 
women, and it is unknown whether acalabrutinib or its metabolites are excreted in human milk. In 
addition, it is highly unlikely that a woman of premenopausal age will present with CLL or SLL at the 
Clinical Center. CLL/SLL is a malignancy of B cells that predominantly affects the elderly population. 
Diagnosis is typically made in adults over the age of 50 and more than half of the people with CLL/SLL are 
over the age of 70.
Justification for exclusion of subjects with impaired hepatic or renal function: In dedicated hepatic 
impairment studies (ACE-HI-001 and ACE-HI-102), subjects with normal liver function (N=6), 
acalabrutinib exposure (AUC) was increased by 21.9-fold, 1.5-fold, and 5.3-fold in subjects with mild 
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(Child-Pugh A; N=6), moderate (Child-Pugh B; N=6), and severe (Child-Pugh C; N=8) hepatic 
impairment, respectively. To minimize risks, subjects enrolled in this study must have AST and ALT 
levels <2.5 x the institutional ULN.
Acalabrutinib has not been formally studied in subjects with renal impairment.  To minimize risks, subjects
enrolled in this study must have an eGFR >50. 
Justification for exclusion of cognitively impaired subjects: Cognitively impaired and institutionalized 
persons will not participate in this study.  Subjects must be able to provide informed consent and 
understand and comply with the treatment plan and follow-up.
Recruitment: The study will be listed on the clinicaltrials.gov.  If recruitment goals are not met, a 
recruitment plan will be developed by the 
.
Payment for participation: $0 – Subjects will not be compensated for their participation in this study.
There is no payment for the blood samples obtained for research.
Reimbursement for protocol participation travel, food, and lodging will be consistent with 
 guidelines.  
For travel from home: Travel from home for the first 
visit will not be reimbursable. If the subject
consents to protocol participation travel home following the first visit will be reimbursable. Subjects will 
be reimbursed 100% of government rate for travel once the subject has been determined eligible to 
participate and signs consent.
Local travel (car/taxi/shuttle/train/bus): Subjects will be reimbursed for local train/bus and/or shuttle 
costs consistent with 
guidelines.  Car mileage will be reimbursed $0.41/mile when the distance from 
home is greater than 30 miles. Reimbursement for mileage less than 30 miles from home is not provided.
Subjects will not be reimbursed for rental car cost beyond the car mileage rate. Taxi will be paid only 
when medically necessary and authorized by the PI.
Meals: Subjects will not be reimbursed for meals.
Lodging: Will be consistent with 
guidelines.  
11.2
Serious Risks Associated with Acalabrutinib Treatment
The acalabrutinib Investigator Brochure contains the Reference Safety Information for acalabrutinib.
11.2.1 Hemorrhage
Serious hemorrhagic events occurred in clinical trials been reported by subjects treated with acalabrutinib.
The mechanism for hemorrhage is not well understood.  Subjects receiving antithrombotic agents may be at 
increased risk of hemorrhage. Use caution with antithrombotic agents and consider additional monitoring 
for signs of bleeding when concomitant use is medically necessary.  Consider the benefit-risk of 
withholding acalabrutinib for at least 3 days presurgery and postsurgery. Subjects with hemorrhage should 
be managed per institutional guidelines with supportive care and diagnostic evaluations as clinically 
indicated.
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11.2.2 Infections
Serious infections (bacterial, viral, and fungal) , including fatal events, have occurred in clinical studies
with acalabrutinib.  The most frequent reported Grade ≥3 infection was pneumonia (preferred term).  
Across the acalabrutinib clinical development program (including subjects treated with acalabrutinib in 
combination with other drugs), cases of hepatitis B virus reactivation, aspergillosis, and PML have 
occurred.
Consider prophylaxis in patients who are at increased risk for opportunistic infections. Subjects should be 
monitored for signs and symptoms of infection and treated as medically appropriate. Subjects with 
infection events should be managed according to institutional guidelines with maximal supportive care and 
diagnostic evaluations as clinically indicated. 
Hepatitis B Virus Reactivation
Cases of HBV reactivation have occurred in clinical studies with acalabrutinib. Subjects who are HBV 
core antibody-positive or have a known history of HBV infection should be monitored every 3 months with 
a quantitative PCR test for HBV DNA.  Monitoring should continue every 3 months until 12 months after 
last dose of acalabrutinib. 
Any subject with a rising viral load (above lower limit of detection) should discontinue study drug and have 
antiviral therapy instituted and a consultation with a physician with expertise in managing hepatitis B.  
Insufficient data exist regarding the safety of resuming acalabrutinib in subjects who develop HBV 
reactivation.
Progressive Multifocal Leukoencephalopathy
Cases of PML have occurred in clinical studies with acalabrutinib.  Signs and symptoms of PML may 
include cognitive and behavioral changes, language disturbances, visual disturbances, sensory deficits, 
weakness, and coordination and gait difficulties.
If PML is suspected, hold further treatment with acalabrutinib treatment until PML is excluded.  
A diagnostic evaluation may include (but is not limited to):
x
Neurologic consultation
x
Brain MRI
x
PCR analysis for John Cunningham virus DNA in cerebrospinal fluid
If PML is confirmed, permanently discontinue acalabrutinib.
11.2.3 Cytopenias
Grade 3 or 4 events of cytopenias, including neutropenia, anemia, and thrombocytopenia have occurred in 
clinical studies with acalabrutinib.  Monitor blood counts as specified in Section 6.0 and as medically 
appropriate.  Please refer to Section 5.4 for study drug modification guidance.  Subjects with cytopenias 
should be managed according to institutional guidelines or as clinically indicated.
11.2.4 Second Primary Malignancies
Second primary malignancies, including solid tumors and skin cancers, have been reported in patients 
treated with acalabrutinib.  The most frequent second primary malignancy was skin cancer (basal cell 
carcinoma). Subjects should be monitored for signs and symptoms of malignancy. Subjects who develop a
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second primary malignancy should be managed according to institutional guidelines with diagnostic 
evaluations as clinically indicated, and it may be necessary for subjects to permanently discontinue study 
treatment. Continuation of acalabrutinib treatment should be discussed with the medical monitor.  
11.2.5 Atrial Fibrillation
Atrial fibrillation or flutter has occurred in clinical studies with acalabrutinib particularly in subjects with 
cardiac risk factors including hypertension, diabetes mellitus, acute infections, and a previous history of 
atrial fibrillation.  Monitor for symptoms of atrial fibrillation and atrial flutter (e.g., palpitations, dizziness, 
syncope, chest pain, dyspnea) and obtain an ECG as appropriate.  Subjects with atrial fibrillation should be 
managed per institutional guidelines with supportive care and diagnostic evaluations as clinically indicated.
11.3
Potential for Drug-Drug Interactions
Based on available nonclinical and clinical data, acalabrutinib is metabolized by CYP3A, GSTM1/M2 and 
amide hydrolysis.  CYP3A-mediated oxidation appears to be the major route of metabolism in humans.  
Nonclinical CYP interaction studies data indicate that acalabrutinib is very unlikely to cause clinical 
drug-drug interactions through alteration of the metabolism of drugs that are substrates for CYP enzymes.
Agents That May Increase Acalabrutinib Plasma Concentrations (CYP Isoform Inhibitors)
Acalabrutinib may be metabolized by CYP3A4.  Therefore, any medications that are strong inhibitors of 
CYP3A4 should be avoided.
Agents That May Decrease Acalabrutinib Plasma Concentrations (CYP Isoform Inducers)
Acalabrutinib may be metabolized by CYP3A4. Therefore, any medications that are strong inducers of 
CYP3A4 should be avoided.
Acalabrutinib absorption may be lower in individuals being treated with proton pump inhibitors, 
histamine 2 (H2) receptor antagonists, or antacids.
11.4
Contraindications
Acalabrutinib is contraindicated in subjects with clinically significant hypersensitivity to any of the
compound’s structural components. 
11.5
Overdose Instructions
Study drug overdose is the accidental or intentional use of the drug in an amount higher than the dose being 
studied.  An overdose or incorrect administration of study drug is not an AE unless it results in untoward 
medical effects.  Any study drug overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF. 
All AEs associated with an overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.  If the associated AE fulfills serious criteria, the event should be reported to the 
sponsor immediately (i.e., no more than 24 hours after learning of the event). 
For overdoses associated with a SAE, the standard reporting timelines apply.
For any subject experiencing an acalabrutinib overdose (as defined above), observation for any 
symptomatic side effects should be instituted, and vital signs, biochemical and hematologic parameters 
should be followed closely (consistent with the protocol or more frequently, as needed).  Appropriate 
supportive management to mitigate adverse effects should be initiated.  If the overdose ingestion of 
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acalabrutinib is recent and substantial, and if there are no medical contraindications, use of gastric lavage or 
induction of emesis may be considered.
The medical monitor must be contacted if a study drug overdose occurs.
11.6
Risks Related to Blood Draws
No major risks are involved with blood draws. Minor complications including bleeding, pain, bruising, 
inflammation, and hematoma formation at the site of blood draws. Vasovagal reactions or infections may 
rarely occur.
11.7
Risks Related to CT Scan
Computed tomography, sometimes called CT scan, uses special x-ray equipment to obtain image data from 
different angles around the body and then uses computer processing of the information to show a cross-
section of body tissues and organs. Oral and/or IV contrast agents will be used and are usually well
tolerated. However, some subjects will experience allergic reactions to IV contrast. To lower the risk of 
allergic reactions, low allergenic contrast agents are administered at 
 clinical center.  In addition,
subjects will be advised that approximately 2 to 7% of subjects who receive contrast agents will experience 
a temporary reduction in kidney function lasting up to 2 weeks following infusion and that in rare 
instances, permanent renal damage can result from the use of the IV contrasting agent. Therefore, in 
subjects with impaired kidney function, we will not use IV contrast.
The amount of radiation subjects will receive from the research scans in this study is 7.0 rem for the first 
year, which is above the guideline of 5 rem (or 0.5 rem in children) per year allowed for research subjects 
by the 
.  After the first year, subjects will receive 3.5 rem of radiation 
annually.  All female subjects will receive pregnancy testing prior to radiation exposure.
11.8
Risks Related to Pregnancy and Nursing Mothers
There are no clinical studies in pregnant women, and it is unknown whether acalabrutinib or its metabolites 
are excreted in human milk. Therefore, women of childbearing potential who are sexually active must use 
highly effective methods of contraception during the study and for 2 days after the last dose of 
acalabrutinib.
Women will be considered of nonreproductive potential if they are either: 
1.
Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause);
in women <45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient); 
OR
2.
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening; 
OR
3.
Have a congenital or acquired condition that prevents childbearing.
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Examples of highly effective methods of contraception are defined below‡:
x
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation, which may be oral, intravaginal, or transdermal
x
Progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, 
injectable, or implantable
x
Intrauterine device or intrauterine hormone-releasing system
x
Bilateral tubal occlusion (a surgical procedure that prevents the egg from being fertilized)
x
Vasectomy of a female subject’s male partner (with medical assessment and confirmation of vasectomy 
surgical success)
x
Sexual abstinence† (only if refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments)
†Abstinence (relative to heterosexual activity) can only be used as the sole method of contraception if it 
is consistently employed during the entire period of risk associated with the study treatments as the 
subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and 
IECs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, and postovulation methods) 
and withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not 
acceptable methods of contraception. Female and male condom should not be used together as an 
effective method of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not 
qualify as an acceptable method of contraception for subjects participating at sites in this 
country/region.
Subjects should promptly notify the investigator if they, or their partner, become pregnant during this 
study, or within 2 days after the last dose of acalabrutinib.  If a female subject becomes pregnant during the 
treatment period, she must discontinue acalabrutinib immediately.  Pregnancy in a female subject or a male 
subject’s partner must be reported (see Section 10.1.3).  
Developmental and reproductive toxicology studies in rats have not identified acalabrutinib-related
toxicities for fertility, reproductive success, embryofetal development or embryofetal survival.  In rabbits, 
at dose levels which resulted in maternal toxicities skeletal variations were associated with reductions in 
fetal weights.  In rat reproductive study, dystocia (prolonged/difficult labor) was observed.
11.9
Risks Related to Bone Marrow Biopsy
The anesthetic can cause some temporary stinging and burning. A pulling sensation and discomfort may be 
felt as the marrow is withdrawn, and sometimes, very infrequently a nerve may be injured during the 
procedure causing pain. Although rare, there is a potential for bleeding at the site and local infection. 
Bleeding can be stopped by applying local pressure, and infection can be treated with antibiotics. 
Another risk associated with this procedure is allergic reactions.
11.10
Risks Related to Lymph Node Biopsy 
Lymph nodes are part of the immune system. They are found in the neck, behind the ears, in the armpits, 
and in the groin. A lymph node biopsy removes lymph node tissue to be looked at under a microscope for 
signs of cancer.  There are several ways to do a lymph node biopsy. 
x
A fine or core needle aspiration biopsy puts a thin needle into the lymph node and removes 
cells to look at. Subjects will feel only a quick sting from the local anesthesia used to numb the 
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skin and may feel some pressure from the biopsy needle. After a core needle biopsy, the site 
may be tender for 2 to 3 days.
x
An open biopsy makes a cut in the skin and removes the lymph node. General anesthesia may 
be required. For 1 to 2 days, subjects may feel tired and have a mild sore throat from the tube 
that was used to help them breathe during the biopsy.  Throat lozenges and gargling with warm 
salt water will be recommended. After the open biopsy, the biopsy site may feel tender, firm, 
swollen, and/or bruised. Subjects may be advised not do any heavy lifting or other activities 
that stretch or pull the muscles around the area.  Subjects will be instructed on wound care and 
timing of suture removal.
Another risk associated with this procedure is allergic reactions.
11.11
Risks Related to Transfusions 
Some risks with the transfusion with blood and /or blood products include fever or allergic reactions. 
These risks are uncommon and are usually mild, but on rare occasions may be severe or life threatening.
Extremely rare risks include infections with viruses, such as hepatitis or HIV or serious incompatibility 
reactions. 
11.12
Risks in Relation to Benefit
The benefits to the adult subject could be a reduction or a disappearance of the CLL/SLL resulting in an 
improved quality of life, a decreased susceptibility to infections, and foremost a significant improvement in 
survival time.  Potentially, treatment with other therapies could also be avoided or postponed.
11.13
Informed Consent Processes and Procedures
The investigational nature and research objectives of this trial, the procedure and its attendant risks and 
discomforts will be carefully explained to the subject and a signed informed consent document will be 
obtained prior to entry onto this study.
At any time during participation in the protocol, should new information become available relating to risks, 
AEs, or toxicities, this information will be provided orally or in writing to all enrolled or prospective 
subject participants.  Documentation will be provided to the IRB and if necessary, the informed consent 
amended to reflect relevant information.
Note: Effective January 21, 2019, a witness to the signature of the written long form research consent at an 
 site (whether initially approved by an IRB before or after January 21, 2019) is no longer a 
requirement.
11.14
Conflict of Interest
Acerta Pharma, BV is providing the acalabrutinib for this study to 
without charge. No 
 
investigator involved in this study receives any payment or other benefits from Acerta Pharma, BV. The PI
assures that each associate investigator received a copy of the 
’s Guide to preventing conflict of 
interest. No members of the research team reported a potential conflict of interest.  
11.15
Technical Transfer Agreements
The protocol has the following associated 
:
x
Between
, and Acerta Pharma, BV
The protocol is associated with the following MTA:
x
Between 
and 
 will 
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provide de-identified RNA and DNA samples collected under this protocol for sequencing 
and analysis. 
12.0
PHARMACEUTICALS
12.1
Acalabrutinib50
Background Information: Note for more detailed and comprehensive background information please 
refer to the acalabrutinib IB.
Investigational Product Name and Description: Acalabrutinib is (S)-4-(8-amino-3-(1-but-2-
ynoylpyrrolidin-2-yl)-imidazo[1,5-α]pyrazin-1-yl)-N-(pyridin-2-yl)-benzamide. Acalabrutinib is a more
selective and irreversible small-molecule inhibitor of BTK than ibrutinib, currently under investigation.
When formulated, the investigational product is acalabrutinib capsule. Molecular weight: 465.5 g/mole.
Acalabrutinib is a white to yellow solid. 
BTK in lymphoma and B-cell malignancies: The role of BTK in BCR signaling is well established by 
the existence of the human genetic immunodeficiency disease X-linked agammaglobulinemia (XLA), and 
the mouse genetic immunodeficiency disease X-linked immunodeficiency, both caused by a mutation in the 
BTK gene. These genetic diseases are characterized by reduced BCR signaling and a failure to generate 
mature B cells.  The BTK protein is expressed in most hematopoietic cells with the exception of T cells and 
NK cells, but the selective effect of BTK mutations suggests that its primary functional role is in antigen 
receptor signaling in B cells.
Several lines of evidence suggest that signaling through the BCR is necessary to sustain the viability of 
B-cell malignancies.  First, expression of a functional BCR is maintained throughout lymphoma 
progression even as the nonexpressed immunoglobulin heavy chain (IgH) is involved in oncogenic 
translocations and despite prolonged treatment of tumor cells with anti-idiotype therapy.  In addition, 
selective knockdown of BCR components by RNA interference results in apoptosis in multiple B cell 
lymphoma cell lines4. The inhibitor ibrutinib in these same studies also promoted apoptosis in these cells.
Ibrutinib (Imbruvica®), a first-generation oral, small-molecule BTK inhibitor has been developed for the 
treatment of patients with B-cell malignancies and was recently approved in the US for treatment of MCL.
While highly potent in inhibiting BTK, ibrutinib has also shown in vitro activity against other kinases with 
a cysteine in the same position as Cys481 in BTK to which the drug covalently binds. For example,
ibrutinib inhibits EGFR, while acalabrutinib does not.  In addition, ibrutinib is a substrate for CYP3A4/5 
and CYP2D6, which increases the possibility of drug-drug interactions. These liabilities support the 
development of alternative BTK inhibitors for use in the therapy of lymphoid cancers.
Acalabrutinib is a selective BTK inhibitor with greater selectivity and better physiochemical properties than 
the BTK inhibitors currently in development. Acerta Pharma, BV is developing acalabrutinib for the 
treatment of patients with B-cell malignancies. Calquence® has been approved in the US and other markets 
for the treatment of adult patients with MCL who have received at least one prior therapy, CLL, and SLL.
Toxicology: 
Acalabrutinib has been evaluated in Good Laboratory Practice (GLP) repeat-dose general toxicity studies 
with dosing durations up to 6 months in rats and 9 months in dogs.  In vitro and in vivo safety 
pharmacology and toxicology studies with acalabrutinib have demonstrated a favorable nonclinical safety 
profile.  Results from acalabrutinib general toxicity studies show that dose levels ≤100 mg/kg/day are well 
tolerated in mice and rats, and dose levels ≤30 mg/kg/day are well tolerated in dogs.  
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In addition, developmental and reproductive toxicity has been evaluated in studies of acalabrutinib in rats 
and rabbits.  No effects of acalabrutinib on fertility, in male rats at exposures 18-times, or in female rats at 
exposures 16-times the acalabrutinib exposure in patients at the recommended dose of 100 mg twice daily, 
embryofetal development (EFD) or survival were observed.  In an EFD study in rabbits, oral administration 
of acalabrutinib during the period of organogenesis, at an exposures 4-times the AUC in patients at 100 mg
twice daily, produced maternal toxicity and resulted in decreased fetal body weights and delayed skeletal 
ossification. Acalabrutinib produced no maternal toxicity and no evidence of teratogenicity or fetal 
development, growth, or survival at an exposure approximately equivalent to the human exposure at the 
recommended dose. In a prenatal and postnatal development study in rats, oral administration of 
acalabrutinib from gestation day 6 through lactation day 12, was associated with dystocia 
(prolonged/difficult labor) at exposures ≥ 4-times the clinical exposure at the recommended dose of 100 mg
twice daily.
Please refer to acalabrutinib IB for additional details.
Pharmacokinetics: 
Acalabrutinib has a short PK half-life with a long-lasting pharmacodynamic effect due to covalent binding 
to BTK.  In a first-in-human study in healthy subjects, acalabrutinib plasma time to maximum 
concentration (Tmax) values were between 0.5 and 1.0 hour for all dose cohorts (2.5 mg twice daily to 
100 mg once daily), and mean half-life ranged from 0.97 to 2.1 hours.  Acalabrutinib has an absolute oral 
bioavailability of 25%, is best taken with water, can be taken with or without food, and does not 
accumulate in plasma upon repeat-dose administration.  Based on population PK analysis, acalabrutinib PK 
was linear over the 75 to 250 mg dose range.  Variability in exposure to acalabrutinib is mainly due to a 
combination of gastric pH-dependent absorption and predominantly cytochrome P450 (CYP)3A-mediated 
metabolism.
Clinical Studies:
For information on acalabrutinib clinical experience, please refer to the acalabrutinib IB.
Indication:
Acalabrutinib is a low molecular weight irreversible inhibitor of BTK, which binds covalently to a cysteine 
residue (Cys481) in the front position of the ATP-binding pocket of BTK. Acerta Pharma, BV is
developing acalabrutinib for the treatment of patients with cancer.  Calquence® has been approved in the 
US and other markets for the treatment of adult patients with MCL who have received at least one prior 
therapy, CLL, and SLL (see Section 2.6).
Formulation, Packaging, and Storage: 
Acalabrutinib will be provided in white, high-density polyethylene bottles with induction-sealed liner. 
Each bottle contains 30 capsules (100 mg of acalabrutinib per capsule). Investigational product should be 
kept in a secure place under appropriate storage conditions as stated on clinical study label.
Dosage and Administration: 
Investigators are prohibited from supplying acalabrutinib to any subjects not properly enrolled in this study 
or to any physicians or scientists except those designated as sub-investigators on FDA Form 1572.  The 
investigator must ensure that subjects receive acalabrutinib only from personnel who fully understand the 
procedures for administering the drug.
At any given monthly visit, only enough acalabrutinib for 1 cycle should be dispensed. In cases where 
there are subject scheduling conflicts, additional doses of acalabrutinib may be given to accommodate visits 
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within the 5-day window. At the post 6-month assessment and every additional clinic visit a 3-month 
supply of study drug will be given. Extra doses of acalabrutinib may be given to accommodate visits 
within the ±15-day window and must be given from the same batch. 
The dose for this study is based on the phase 1 experience with acalabrutinib in CLL described in 
Section 2.6.4.  Acalabrutinib 100 mg twice daily or 200 mg once daily is intended to be administered orally 
with 8 ounces (approximately 240 mL) of water. The capsules should be swallowed intact and subjects
should not attempt to open capsules or dissolve them in water.  
Each dose of acalabrutinib should be taken at approximately the same time each day. If a dose is missed, it 
can be taken up to 6 hours after the scheduled time for subjects taking acalabrutinib once daily and up to 
3 hours after the scheduled time for subjects taking acalabrutinib twice daily.  All subjects should return to 
the normal schedule the following day.  If it has been greater than the allowed time, the dose should not be 
taken, and the subject should take the next dose at the scheduled time the next day.  The missed dose will 
not be made up and must be returned to the site at the next scheduled visit. 
Supply: 
The drug product acalabrutinib is manufactured by Acerta Pharma, BV.
Shipping:
Accountability Procedures:  
Drug accountability records will be maintained for all clinical supplies. Any empty and partially used vials 
and clinical trial supplies will be destroyed locally according to the institution’s standard operating 
procedures for drug destruction.  The pharmacy will maintain detailed documentation of the number and 
identification of vials which are destroyed, and copies of these documents will be provided to the sponsor 
and Acerta Pharma, BV.  Disposition of all unused boxes of study drug will be carried out according to
instructions provided by the sponsor and/or Acerta Pharma, BV at the end of the study after drug 
accountability is performed by the study monitor.
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13.0
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40.
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lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk)
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Byrd JC, Furman RR, Coutre S, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib 
(PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment 
Naive (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small 
Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New 
and Updated Results of 116 Patients in a Phase Ib/II Study. ASH Annual Meeting Abstracts 
2012;120:189-.
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Evans E, Tester R, Aslanian S, et al. Clinical Development of AVL-292; A Potent, Selective 
Covalent Btk Inhibitor for the Treatment of B Cell Malignancies. ASH Annual Meeting Abstracts 
2011;118:3485-.
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Fiorcari S, Brown WS, McIntyre BW, et al. The PI3-kinase delta inhibitor idelalisib (GS-1101) 
targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and 
marrow stromal cells. PLoS One 2013;8:e83830.
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Lymphocytic Leukemia (CLL) Developing Resistance To BTK Inhibition. Blood 2013;122:866.
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Barrientos JC, Barr PM, Flinn I, et al. Ibrutinib In Combination With Bendamustine and Rituximab 
Is Active and Tolerable In Patients With Relapsed/Refractory CLL/SLL: Final Results Of a Phase 
1b Study. Blood 2013;122:525.
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Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic 
Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients. Blood 
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Byrd JC. A phase Ib/II study evaluating activity and tolerability of BTK inhibitor PCI-32765 and 
ofatumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma 
(CLL/SLL) and related diseases. ASCO 2012.
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Fuhrman RR, Sharman JP, Coutre SE, et al. A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study Evaluating the Efficacy and Safety of Idelalisib and Rituximab for Previously 
Treated Patients with Chronic Lymphocytic Leukemia (CLL). Blood 2013;122:LBA-6.
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Davids MS, Pagel JM, Kahl BS, et al. Bcl-2 Inhibitor ABT-199 (GDC-0199) Monotherapy Shows 
Anti-Tumor Activity Including Complete Remissions In High-Risk Relapsed/Refractory (R/R) 
Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL). Blood 
2013;122:872.
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homing to follicles. Curr Top Microbiol Immunol 1999;246:87-92.
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Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765
blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell
malignancy. Proc Natl Acad Sci U S A 2010;107:13075-80.
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Herishanu Y, Perez-Galan P, Liu D, et al. The lymph node microenvironment promotes B-cell 
receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic 
leukemia. Blood 2011;117:563-74.
53.
Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) 
has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 
2013;31:88-94.
54.
Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of 
ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013;122:2539-49.
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Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell–
mediated cytotoxicity. Blood 2014;123:1957-60.
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Gardner H. ACP-196: A second generation Btk inhibitor demonstrates biologic activity in a canine 
model of B-cell non-Hodgkin lymphoma. AACR Abstract 2014.
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57.
Niemann C. The novel Bruton’s tyrosine kinase inhibitor ACP-196 shows in vivo efficacy against 
human chronic lymphocytic leukemia cells xenografted to the NSG mouse model. AACR Abstract 
2014.
58.
Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-
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in chronic lymphocytic leukemia. J Clin Oncol 2012 30:2820-2822.
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APPENDIX A
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APPENDIX B
EXAMPLES OF CO-ADMINISTERED DRUGS THAT NEED ADDITIONAL CONSIDERATION
The lists of drugs in these tables are not exhaustive.  Any questions about drugs not on this list should be 
addressed to the medical monitor of this study.
Strong Inhibitors of CYP3A
Moderate inhibitors of CYP3A
boceprevir
aprepitant
clarithromycina
cimetidine
cobicistata
ciprofloxacin
conivaptana
clotrimazole
danoprevir and ritonavirb
crizotinib
diltiazema
cyclosporine
elvitegravir and ritonavirb
dronedaronea
idelalisib
erythromycin
indinavir and ritonavirb
fluconazole
itraconazolea
fluvoxamine
ketoconazole
imatinib
lopinavir and ritonavira,b
tofisopam
nefazodone
verapamila
nelfinavira
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir)b
posaconazole
ritonavira, b
saquinavir and ritonavira, b
telaprevira
tipranavir and ritonavira, b
troleandomycin
voriconazole
a.
Inhibitor of P-glycoprotein.
b.
Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in clinical practice.
Caution should be used when extrapolating the observed effect of ritonavir alone to the effect of combination 
regimens on CYP3A activities.
After discontinuation of the strong CYP3A inhibitor, wait 3 days before resuming venetoclax or acalabrutinib. 
Strong Inducers of CYP3A
Moderate inducers of CYP3A
carbamazepine
bosentan
enzalutamide
efavirenz
mitotane
etravirine
phenytoin
modafinil
rifampin
St. John’s worta
a.
The effect of St. John’s wort varies widely and is preparation dependent.
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P-gp Inhibitors
BCRP inhibitors
Narrow therapeutic index P-gp 
substrates
amiodarone
curcumin
digoxin
carvedilol
cyclosporine A
everolimus
clarithromycin
eltrombopag
sirolimus
dronedarone
itraconazole
lapatinib
lopinavir and ritonavir
propafenone
quinidine
ranolazine
ritonavir
saquinavir and ritonavir
telaprevir
tipranavir and ritonavir
verapamil
Source: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Web 
link Accessed 18 July 2018: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm093664.htm#inVivo
Bile acid sequestrants
Proton pump inhibitors
H2-receptor antagonists
cholestyramine
dexlansoprazole
cimetidine
colestipol
esomeprazole
famotidine
colesevelam
lansoprazole
nizatidine
omeprazole
ranitidine
rabeprazole
pantoprazole
Source: FDA Established Pharmacologic Class Text Phrase. Web link accessed 18 July 2018:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/lawsactsandrules/ucm
428333.pdf
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APPENDIX C
ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER BIOCHEMISTRY AND 
EVALUATION OF HY’S LAW
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately report potential 
Hy’s law (PHL) cases and Hy’s law (HL) cases.  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver biochemistry.  The 
investigator is responsible for determining whether a subject meets PHL criteria at any point during the 
study. All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local laboratory 
evaluations even if collected outside of the study visits (e.g., PHL criteria could be met by an elevated ALT 
from a central laboratory and/or elevated total bilirubin from a local laboratory).  The investigator will also 
review AE data (e.g., for AEs that may indicate elevations in liver biochemistry) for possible PHL events.
The investigator participates with the sponsor in the review and assessment of cases meeting PHL criteria 
to agree whether HL criteria are met.  HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury (DILI) caused by the investigational 
medicinal product (IMP). The investigator is responsible for recording data pertaining to PHL/HL cases 
and for reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
DEFINITIONS
Potential Hy’s Law (PHL)
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN at any point during the study after the start 
of study drug, irrespective of an increase in alkaline phosphatase.
Hy’s Law (HL)
AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN, where no reason other than the IMP can be 
found to explain the combination of increases (e.g., elevated alkaline phosphatase indicating cholestasis, 
viral hepatitis, or another drug).
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on the same day) 
the elevation in total bilirubin, but there is no specified timeframe within which the elevations in 
transaminases and total bilirubin must occur.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
Laboratory data must be comprehensively reviewed for each subject to identify laboratory values meeting 
the following criteria:
x
ALT ≥3 x ULN
x
AST ≥3 x ULN
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x
Total bilirubin ≥2 x ULN
When the identification criteria are met from central or local laboratory results, the investigator will 
perform the following:
x
Notify the sponsor representative/medical monitor by telephone and report the PHL case as 
an SAE of Potential Hy’s law: seriousness criteria “important medical event” and causality 
assessment “yes/related” or in accordance with the clinical study protocol as appropriate. 
x
Request a repeat of the test (new blood draw) without delay
x
Complete the appropriate unscheduled laboratory eCRF module(s) 
x
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the clinical study protocol, as applicable
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study medical monitor
and the investigator will review available data, to agree whether there is an alternative explanation for 
meeting PHL criteria other than DILI caused by the IMP and to ensure that timely analysis and reporting to 
health authorities within 15 calendar days from the date PHL criteria were met.   
Where there is an agreed alternative explanation for the ALT or AST and total bilirubin elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently whether the 
AE meets the criteria for an SAE:
x
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
x
If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE
accordingly with the new information (reassessing event term; causality and seriousness 
criteria) following the sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and total bilirubin elevations 
other than the IMP, then:
x
Send updated SAE (report term “Hy’s law”) according to the sponsor’s standard processes 
o
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
o
Because there is no alternative explanation for the HL case, a causality assessment 
of “related” should be assigned
If there is an unavoidable delay of over 15 calendar days in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative explanation 
until such time as an informed decision can be made:
x
Provide any further update to the previously submitted SAE of PHL (report term now 
“Hy’s law case”), ensuring causality assessment is related to IMP and seriousness criteria 
is medically important, according to clinical study protocol process for SAE reporting.
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x
Continue follow-up and review according to the agreed plan.  After the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report 
following the clinical study protocol process, according to the outcome of the review.
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S LAW
This section is applicable when a subject meets PHL criteria on study treatment and has already met PHL 
criteria at a previous on study treatment visit. The requirement to conduct follow-up, review, and 
assessment of a repeat occurrence(s) of PHL is based on the nature of the alternative cause identified for 
the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being met and 
answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study (e.g., chronic or progressing malignant disease, severe infection, or liver
disease)?
o
If the answer is No:
Follow the process described in “Potential Hy’s Law Criteria Met” in this Appendix for 
reporting PHL as an SAE.
o
If the answer is Yes:
Determine if there has been a significant change in the subject’s condition compared with 
when PHL criteria were previously met. Note:  A “significant” change in the subject’s 
condition refers to a clinically relevant change in any of the individual liver biochemistry 
parameters (ALT, AST, or total bilirubin) in isolation or in combination or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a 
significant change will be at the discretion of the investigator; this may be in consultation 
with the study medical monitor if there is any uncertainty. 
o
If there is no significant change, no action is required
o
If there is a significant change, follow the process described in “Potential Hy’s Law Criteria 
Met” in this Appendix for reporting PHL as an SAE
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LABORATORY TESTS
The list below represents a comprehensive list of follow-up tests that may aid in assessing PHL/HL. 
Test results used to assess PHL/HL should be recorded on the appropriate eCRF. 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV
IgM and IgG anti-HBc
HbsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA
Other viral infections
IgM and IgG anti-CMV
IgM and IgG anti-HSV
IgM and IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin 
(CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab 
(Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
Reference
FDA Guidance for Industry (issued July 2009) Drug-induced liver injury: Premarketing clinical evaluation 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf
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