Acalabrutinib in CLL and MCL Patients Subjected to Allogeneic Hematopoietic Stem Cell Transplantation (alloSCT)
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia, Chronic Graft-versus-host-disease, Mantle Cell Lymphoma, Adverse Event, Response Rate
Sponsor: Polish Lymphoma Research Group

 
 
 
  
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PROTOCOL Ver 1.5 
TITLE: 
Acalabrutinib in CLL and MCL patients subjected to 
allogeneic hematopoietic stem cell transplantation 
(alloSCT) 
PROTOCOL NUMBER: 
PLRG12 
 
STUDY DRUG: 
Acalabrutinib (ACP-196) 
 
EUDRAC NUMBER: 
2018-003465-33 
Study Coordinator and 
Principal Investigator 
 
Prof. Wojciech Jurczak MD, PhD  
Department of Hematology, Kopernika 17,  
31-501 Kraków, Poland 
E-mail: Wojciech.Jurczak@uj.edu.pl 
Trial Editorial Board 
And Co-
investigator(s): 
 
Prof. Iwona Hus MD, PhD  
Department of Clinical Transplantology,  
Medical University of Lublin 
Prof. Anna Czyż MD, PhD 
Department of Hematology, Blood Neoplasms and Bone 
Marrow Transplantation, Wroclaw Medical University  
SPONSOR: 
PLRG – Polish Lymphoma Research Group 

 
 
 
  
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TABLE OF CONTENTS 
1.0 
BACKGROUND INFORMATION ....................................................................... 19 
1.1 
Relapsing/ refractory CLL and (MCL) ................................................................. 19 
1.2 
Bruton Tyrosine Kinase Inhibition in CLL and MCL ............................................ 21 
1.3 
Acalabrutinib (ACP-196) .................................................................................... 21 
1.3.1 
Mechanism of Action ........................................................................... 22 
1.3.2 
Safety Pharmacology .......................................................................... 22 
1.3.3 
Drug-drug Interaction Potential ............................................................ 22 
1.4 
Clinical Experience – acalabrutinib .................................................................... 22 
1.4.1 
Clinical Efficacy in CLL and MCL ......................................................... 22 
1.4.2 
Adverse Events  .................................................................................. 22 
1.4.3 
Warnings and Precautions .................................................................. 24 
1.4.3.1 
Hemorrhage ........................................................................ 24 
1.4.3.2 
Infection ............................................................................... 25 
1.4.3.3 
Cytopenias .......................................................................... 25 
1.4.3.4 
Second Primary Malignancies ............................................. 25 
1.4.3.5 
Atrial Fibrillation ................................................................... 25 
2.0 
STUDY OBJECTIVES ....................................................................................... 25 
2.1 
Primary Objective: .............................................................................................. 25 
2.2 
Secondary Objective(s): ..................................................................................... 26 
2.3 
Exploratory Objective(s) ..................................................................................... 26 
3.0 
STUDY DESIGN ................................................................................................ 26 
3.1 
Study Parameters .............................................................................................. 27 
3.1.1 
Efficacy Parameters ............................................................................ 27 
3.1.2 
Safety Parameters ............................................................................... 28 
3.1.3 
Exploratory Parameters……………………………………………………28                 
3.2 
Rationale for Study Design and Dosing Regimen .............................................. 31 
3.3 
Selection of Study Population ............................................................................ 33 
3.3.1 
Inclusion Criteria .................................................................................. 33 

 
 
 
  
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3.3.2 
Exclusion Criteria ................................................................................ 34 
3.3.3 
Enrollment  Procedures ....................................................................... 36 
3.4 
Study Drug ......................................................................................................... 36 
3.4.1 
Premedications.................................................................................... 36 
3.4.2 
Formulation, Packaging, and Storage .................................................. 36 
3.4.3 
Administration of Study Drug ............................................................... 37 
3.5 
Study Treatment Schedule ................................................................................. 37 
3.6 
Duration of Therapy ........................................................................................... 37 
3.7 
Dosing Delays and Modifications ....................................................................... 38 
3.8 
Concomitant Therapy ......................................................................................... 39 
3.8.1 
Permitted Concomitant Therapy .......................................................... 39 
3.8.2 
Prohibited or Restricted Concomitant Therapy .................................... 42 
3.9 
Precautions ........................................................................................................ 42 
3.9.1 
Dietary Restrictions ............................................................................ .42 
3.9.2 
Drug-drug Interactions ......................................................................... 42 
3.9.3 
Reproductive Toxicity .......................................................................... 43 
3.9.4 
Overdose Instructions.......................................................................... 44 
3.10 
Withdrawal of Subjects From Study Treatment .................................................. 44 
3.11 
Removal from study ........................................................................................... 45 
3.12 
Data and Safety Monitoring ................................................................................ 45 
4.0 
STUDY ACTIVITIES AND ASSESSMENTS ...................................................... 45 
4.1 
Description of Procedures .................................................................................. 46 
4.1.1 
Informed Consent ................................................................................ 46 
4.1.2 
Medical History .................................................................................... 46 
4.1.3 
Adverse Events ................................................................................... 46 
4.1.4 
Concomitant Medications and Therapy ............................................... 46 
4.1.5 
Confirmation of Eligibility ..................................................................... 47 
4.1.6 
ECOG Performance Status ................................................................. 47 
4.1.7 
Physical Examination, Vital Signs, Height & Weight ............................ 47 

 
 
 
  
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4.1.8 
Electrocardiogram ............................................................................... 47 
4.1.9 
Urine or Serum Pregnancy Test .......................................................... 47 
4.1.10 
Hematology ......................................................................................... 48 
4.1.11 
Serum Chemistry ................................................................................. 48 
4.1.12 
Hepatitis B and C Testing .................................................................... 48 
4.1.13     Additional clinical tests and procedures………………………………….49          
4.1.14 
Biomarker Studies ............................................................................... 49 
4.1.15 
Tumor Assessments ............................................................................ 50 
4.1.16 
Study Drug Accountability ................................................................... 50 
4.2 
Assessment of Response to Treatment ............................................................. 50 
4.3 
Treatment Termination and Safety Follow-up Visits ........................................... 50 
4.4 
Follow-up for Progression and Survival .............................................................. 51 
4.4.1 
PFS as an Endpoint: Discontinuation Follow-up .................................. 51 
4.4.2 
OS as an Endpoint: Long-term Follow-up ............................................ 51 
4.5 
Missed Evaluations ............................................................................................ 51 
5.0 
STATISTICAL METHODS OF ANALYSIS ......................................................... 52 
5.1 
General Considerations ..................................................................................... 52 
5.2 
Rationale for Sample Size .................................................................................. 53 
5.3 
Analysis Populations .......................................................................................... 54 
5.4 
Missing Data Handling ....................................................................................... 54 
5.5 
Endpoint Data Analysis ...................................................................................... 54 
5.5.1 
Efficacy Endpoints ............................................................................... 54 
5.5.2 
Safety Endpoints ................................................................................. 54 
5.5.3       Exploratory Endpoints……………………………………………………...55 
5.5.4 
Study Treatment Administration and Compliance ................................ 55 
5.5.5 
Analysis of Efficacy Parameters .......................................................... 55 
2.5.5.1 
Primary Efficacy Endpoint .................................................... 55 
2.5.5.2 
Secondary Efficacy Endpoint ............................................... 55 
5.5.6 
Biomarker Analyses ............................................................................ 56 

 
 
 
  
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6.0 
ASSESSMENT OF SAFETY .............................................................................. 56 
6.1 
Definitions .......................................................................................................... 56 
6.1.1 
Adverse Events ................................................................................... 56 
6.1.2 
Serious Adverse Event ........................................................................ 58 
6.1.3 
Severity ............................................................................................... 59 
6.2 
Documenting and Reporting of Adverse and Serious Adverse Events ............... 59 
6.2.1 
Adverse Event Reporting Period ......................................................... 59 
6.2.2 
Assessment of Adverse Events ........................................................... 59 
6.2.3 
Pregnancy ........................................................................................... 60 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events ......... 61 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse Events....... 61 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ......... 61 
7.1 
Institutional Review Board and Independent Ethics Committee.......................... 62 
7.2 
Informed Consent and Protected Subject Health Information Authorization ....... 62 
7.3 
Subject Screening Log ....................................................................................... 63 
7.4 
Case Report Forms ............................................................................................ 63 
7.5 
Investigational Study Drug Accountability .......................................................... 63 
7.6 
Record Retention ............................................................................................... 63 
8.0 
REFERENCES .................................................................................................. 64 
APPENDICES ............................................................................................................... 67 
 
 
IN-TEXT FIGURES  
 
Figure 1-2.  BCR signaling pathway …………………………………………………………21 
Figure 3-1.  Study Schema ............................................................................................27 
 
 
 
LIST OF APPENDICES 

 
 
 
  
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Appendix 1.  Schedule of Assessments .........................................................................68 
Appendix 2.  Performance Status Scores ......................................................................70 
Appendix 3.  Known Strong in Vivo Inhibitors or Inducers of CYP3A .............................71 
Appendix 4.  Adverse Event Assessment of Causality ...................................................72 
Appendix 5 IWCLL Response evaluation (according to Hallek)…………………………..73 
 
 
 
 

 
 
 
  
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ABBREVIATIONS 
 
 
 
AE 
adverse event 
AESI 
AIHA 
alloSCT 
ASCO 
ASCT 
adverse events of special interest 
autoimmune hemolytic anemia 
allogeneic stem cell transplantation 
American Society of Clinical Oncology 
autologous stem cell transplantation 
Akt 
ALC 
protein kinase b 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
anti-HBc 
anti-HBs 
aPTT 
absolute neutrophil count 
hepatitis B core antibody 
hepatitis B surface antibody  
Activated Partial Thromboplastin Time 
AST 
ATG 
ATP 
aspartate aminotransferase 
antithymocyte globulin 
adenosine triphosphate 
Bcl-2 
BCR 
BCRi 
BFR 
B cell lymphoma 2 
B-cell receptor 
B-cell receptor inhibitors 
bendamustine, fludarabine, rituximab 
BID 
BM 
twice per day (dosing) 
bone marrow 
BP 
blood pressure 
BTK 
Bruton tyrosine kinase 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CD 
cluster of differentiation (cell surface marker) 

 
 
 
  
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CFR 
Code of Federal Regulations 
CI 
CI 
calcineurin inhibitor 
cumulative incidence 
CIs 
confidence intervals 
CLL 
chronic lymphocytic leukemia 
CR 
CrCl 
complete response (remission) 
creatinine clearance 
CRF 
CSA 
case report form 
cyclosporine 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome p450 
DCR 
DLI 
disease control rate 
donor lymphocyte infusion 
DLT 
DNA 
dose-limiting toxicity 
deoxyribonucleic acid 
DOR 
EBMT 
EBV 
duration of response 
European Group for Blood and Marrow Transplantation 
Ebstein-Barr virus 
ECG 
Electrocardiogram 
ECOG 
FCM 
Eastern Cooperative Oncology Group 
flow cytometry 
EFS 
EMA 
EMCLN 
ESMO 
FCR 
event-free survival 
European Medicine Agency 
European MCL Network 
European Society of Medical Oncology 
fludarabine, cyclophosphamide, rituximab 
FDA 
FISH 
Food and Drug Administration 
fluorescence in situ hybridization 

 
 
 
  
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F 
FCM 
fludarabine 
flow cytometry 
GvHD 
GRFS 
graft versus host disease 
GvHD-free and relapse-free survival 
HBV 
HBsAg 
hepatitis B virus 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
HLA 
human immunodeficiency virus 
human leukocyte antigens 
HSCT 
HTC-CI 
hematopoietic stem cel transplantation 
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) 
ICF 
informed consent form 
IEC 
INR 
IgVH 
independent ethics committee 
international normalized ratio 
immunoglobulin heavy chain gene variable region 
Ig 
Immunoglobulin 
IRB 
institutional review board 
irRECIST 
Itk 
IWCLL 
immune-related response criteria 
interleukin-2 inducible T-cell kinase 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
IVIG 
ITP 
intravenous or intravenously 
intravenous immunoglobulin 
idiopathic thrombocytopenic purpura 
LDH 
lactate dehydrogenase 
MCL 
Mantle Cell Lymphoma 
MedDRA 
MRD 
MRI 
Medical Dictionary for Regulatory Activities 
Minimal Residual Disease 
magnetic resonance imaging 
MTD 
maximum tolerated dose 

 
 
 
  
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NCCN 
NCI 
National Comprehensive Cancer Network 
National Cancer Institute 
NHL 
Non Hodgkin lymphoma 
NK 
NKT 
NPT 
NRM 
MTX 
natural killer (cells) 
natural killer T cell  
non-protocol anti-tumor therapy 
non-relapse mortality 
methotrexate 
HYHA 
New York Heart Association Functional Classification 
ORR 
overall response rate 
OS 
PB 
overall survival 
peripheral blood 
PBMC 
PBSC 
PCR 
peripheral blood mononuclear cells 
peripheral blood stem cells 
polymerase chain reaction 
PFS 
PI3K 
progression-free survival 
phosphoinositide 3-kinase 
PD 
pharmacodynamic, pharmacodynamics, or progressive disease 
P-gp 
p-glycoprotein 1 (transporter) 
PI3K 
phosphatidylinositol-3 kinase 
PK 
PLRG 
pharmacokinetic or pharmacokinetics 
Polish Lymphoma Research Group 
PR 
RIC 
RR 
RNA 
partial response (remission) 
reduced-intensity conditioning 
response rate 
ribonucleic acid 
QD 
once per day (dosing) 
QTc 
R 
corrected QT interval 
rituximab 

 
 
 
  
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RECIST 
RI 
RIC 
R/R 
Response Evaluation Criteria in Solid Tumors 
relapse incidence 
reduced intensity conditioning 
relapsed/refractory 
SAE 
serious adverse event 
SD 
sIg 
stable disease or standard deviation 
surface immunoglobulin 
SUSAR 
suspected unexpected serious adverse reaction 
Syk 
spleen tyrosine kinase 
TAAE 
TEAE 
Th 
treatment associated adverse events 
treatment emergent adverse events 
T helper cell 
TBI 
total body irradiation 
Treg 
Txk 
TT 
regulatory T cells 
T cell X chromosome kinase 
treatment termination 
ULN 
upper limit of normal 
WHODRUG 
WOCBP 
World Health Organization Drug Dictionary 
Women of childbearing potential 
 

 
 
 
  
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STUDY SYNOPSIS 
Study Title: 
Acalabrutinib in CLL and MCL patients subjected to allogeneic 
hematopoietic stem cell transplantation (alloSCT) 
Protocol Number: 
PLRG12 
Study Drug: 
ACALABRUTINIB (ACP-196)  
Phase: 
Phase II 
Comparator: 
N/A 
Study Centers: 
Subjects will be enrolled in 6 PLRG centers in Poland 
Study Objectives: 
Primary Objective(s): 
• 
Safety:  
- 
adverse event (AE) incidence 
- 
serious adverse event (SAE) incidence 
• 
Response to therapy:  
- 
partial and complete remission rate (PR and CR),  
- 
minimum residual disease CR (MRD CR) rate assessed 
by flow cytometry in peripheral blood (PB) and bone 
marrow (BM) 
Secondary Objective(s): 
• 
relapse incidence (RI),  
• 
non-relapse mortality (NRM),  
• 
progression free survival (PFS),  
• 
overall survival (OS), 

 
 
 
  
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Exploratory Objective(s): 
• 
acute and chronic graft versus host disease (GvHD) 
incidence,   
• 
GvHD-free and relapse-free survival (GRFS),  
• 
cytometric assessment of immune cell populations: T cell 
subsets (CD4+ T cells, CD8+ T cells, Th1, Th2, Th17, T 
regulatory cells), NK cells, NKT cells and normal B cells, B-
regulatory cells 
Study Design: 
In this trial II phase multicenter trial we plan to use acalabrutinib 
before and after allogeneic hematopoietic stem cell transplantation 
(alloSCT) with reduced intensity conditioning (RIC) in patients with 
refractory/relapsed MCL and CLL with poor prognostic factors. 
Acalabrutinib will be used before alloSCT with the intention to reduce 
tumor burden and after transplant to augment disease control. Since 
chronic GvHD is mediated by activated B lymphocytes, we also 
speculate that the drug as a BTK inhibitor may reduce the severity 
and incidence of chronic graft-versus-host disease (GvHD) after 
alloSCT, as it was shown for ibrutinib.  
Best response to therapy and safety issues will be the primary target 
of this small trial (25 transplanted pts).  
 
We hypothesize that this treatment will improve the efficacy of the 
alloSCT – this issue will be addressed by serial minimal residual 
disease (MRD) evaluation in peripheral blood and bone marrow. This 
treatment strategy could significantly improve the outcome of poor 
prognosis MCL and CLL patients. 

 
 
 
  
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Efficacy and Safety 
Parameters: 
Efficacy parameters:  
- 
partial and complete remission rate (PR and CR),  
- 
minimum residual disease CR (MRD CR) rate assessed 
by flow cytometry in peripheral blood (PB) and bone 
marrow (BM) 
- 
relapse incidence (RI),  
- 
non-relapse mortality (NRM),  
- 
progression free survival (PFS),  
- 
duration of response (DOR) 
- 
overall survival (OS), 
- 
GvHD-free and relapse-free survival (GRFS),  
 
Safety parameters:  
- 
adverse event (AE) incidence 
- 
serious adverse event (SAE) incidence 
Pharmacodynamic, 
Pharmacokinetic and 
Biomarker 
Parameters: 
N/A 
 
Sample Size: 
40 patients will be enrolled, and  approximately 25 patients will 
respond to therapy and undergo allogeneic Stem Cell Transplant.  
Inclusion Criteria: 
1. Men and women ≥ 18 years of age. 
2. Relapsing / refractory BTK-inhibitors naïve CLL patients 
meeting IWCCL criteria for requiring treatment:  
a. after 1-4 therapy lines if del 17 or p53 mutation in 
>10% of analyzed CLL cells (PB or BM) or 
b. after 2-4 therapy lines if high risk CLL (refractory or 
less than 24 months response to the last 
immunochemotherapy) or 

 
 
 
  
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3. Relapsing / refractory BTK-inhibitors naïve MCL patients 
with measurable disease or bone marrow involvement 
revealed in trephine biopsy or 
4. Patients fulfilling criteria 2 or 3, when ibrutinib therapy was 
initiated, responding to therapy 
5. Patient qualified for allo SCT procedure by the transplant 
center participating in the trial with identified sibling donor or 
initiated Poltransplant search for matched unrelated donor.  
6. Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1 
7. Woman of childbearing potential (WOCBP) who are 
sexually active must use highly effective methods of 
contraception during treatment and for 2 days after the last 
dose of acalabrutinib and for 6 months after the transplant 
procedure if performed. Males who are sexually active must 
use highly effective methods of contraception during 
treatment and for 6 months after the transplant procedure if 
performed.   
8. Willing and able to participate in all required evaluations 
and procedures in this study protocol including swallowing 
capsules without difficulty. 
9. Ability to understand the purpose and risks of the study and 
provide signed and dated informed consent and 
authorization to use protected health information. 
Exclusion Criteria: 
1. Patients failing 5 or more previous therapy lines 
2. Prior malignancy (or any other malignancy that requires active 
treatment), 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 ≥ 5 
years 
3. Clinically significant cardiovascular disease such as 
uncontrolled or symptomatic arrhythmias, congestive heart 
failure, or myocardial infarction within 6 months of screening, or 

 
 
 
  
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any Class 3 or 4 cardiac disease as defined by the New York 
Heart Association Functional Classification (NYHA).  Subjects 
with controlled, asymptomatic atrial fibrillation during screening 
can enroll on study. 
4. Malabsorption syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small 
bowel that is likely to affect absorption, symptomatic 
inflammatory bowel disease, partial or complete bowel 
obstruction, or gastric restrictions and bariatric surgery, such as 
gastric bypass. 
5. Impaired hepatic function (as indicated by any of the following):  
a. Serum total bilirubin > 2.5 x upper limit of normal 
(ULN)  
b. Alanine amino transferase and/or aspartate amino 
transferase > 2.5 x ULN  
c. Alkaline phosphatase > 2.5 x ULN  
6. Impaired renal function: serum creatinine > 2.5 x ULN  
7. Other concurrent serious diseases that increase Hematopoietic 
Cell Transplantation-Comorbidity Index (HCT-CI) > 4 
8. Central nervous system involvement with CLL 
9. Known history of drug-specific hypersensitivity or anaphylaxis 
to study drug (including active product or excipient 
components).  
10. Active bleeding, history of bleeding diathesis (eg, hemophilia or 
von Willebrand disease). 
11. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP 
(idiopathic thrombocytopenic purpura). 
12. Presence of a gastrointestinal ulcer diagnosed by endoscopy 
within 3 months before screening. 
13. Requiring or receiving a strong cytochrome P450 3A4 
(CYP3A4) inhibitor/inducer (see appendix 3 for a complete list) 

 
 
 
  
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14. Requiring or receiving anticoagulation with warfarin or 
equivalent vitamin K antagonists (eg, phenprocoumon) within 7 
days of first dose of study drug.  
15. Requiring proton pump inhibitors (e.g., omeprazole, 
esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or 
pantoprazole).  Subjects receiving proton pump inhibitors who 
switch to H2-receptor antagonists or antacids are eligible for 
enrollment to this study. 
16. Prothrombin time/INR or aPTT (in the absence of Lupus 
anticoagulant) > 2x ULN. 
17. History of significant cerebrovascular disease or event, 
including stroke or intracranial hemorrhage, within 6 months 
before the first dose of study drug. 
18. Major surgical procedure within 30 days of first dose of study 
drug.  Note:  If a subject had major surgery, they must have 
recovered adequately from any toxicity and/or complications 
from the intervention before the first dose of study drug.   
19. Known history of infection with HIV or any active uncontrolled 
systemic infection 
20. Hepatitis B or C serologic status: subjects who are hepatitis B 
core antibody (anti-HBc) positive and who are surface antigen 
negative will need to have a negative polymerase chain 
reaction (PCR).  Those who are hepatitis B surface antigen 
(HbsAg) positive or hepatitis B PCR positive will be excluded.   
Subjects who are hepatitis C antibody positive will need to have 
a negative PCR result.  Those who are hepatitis C PCR positive 
will be excluded. 
21. ANC < 500/µl, Platelets < 20 000/µl, and hemoglobin < 8 g/dl 
22. Breastfeeding or pregnant.  
23. Concurrent participation in another therapeutic clinical trial. 

 
 
 
  
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Dose Regimen/Route 
of Administration: 
Acalabrutinib is provided as hard 100 mg gelatin capsules for oral 
administration approximately every 12 hours. 
Concomitant 
Medications: 
Prohibited Concomitant Therapy 
• 
strong cytochrome P450 3A4 (CYP3A4) inhibitors/inducers 
• 
any protein pomp inhibitors, any vitamin K antagonists or 
any other anti-cancer medications, excluding used in 
transplant conditioning 
Study duration: 
01.03.2019-31.10.2022 

 
 
 
  
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1.0 
BACKGROUND INFORMATION 
1.1 
R/R CLL AND MCL 
Chronic lymphocytic leukemia (CLL) is the most common leukemia diagnosed in adults in 
western societies with a year incidence of–4.8 - 5/100 000 [1] [2]. Clinical course of CLL 
is highly heterogeneous, indolent in some patients, while aggressive with resistance to the 
therapy and short overall survival in the others. Poor prognosis in patients with CLL is 
associated with the presence of 17p deletion/TP53 mutation or/and short response (less 
than 24 – 36 months) to immunochemotherapy [3].  The clinical importance of 17p 
deletion/TP53 mutation is associated with chemo-refractoriness [4]. As the results of CLL8 
study shown, in patients treated with FCR protocol (fludarabine, cyclophosphamide, 
rituximab) as the first line therapy, progression-free survival (PFS) was only 11.3 months 
and overall survival (OS) was 33 months as compared to 56.8 and not reached in the 
whole patients group [5] [6]. Significant improvement in the outcome of patients with 17p 
del/TP53 mutation came with the introduction of the novel small molecule agents into CLL 
therapy, such as B-cell receptor inhibitors (BCRi), such as ibrutinib, Bruton Tyrosine 
Kinase (BTK) inhibitor and idelalisib, phosphoinositide 3-kinase (PI3K) delta inhibitor and 
Bcl-2 antagonist (venetoclax). In relapsed/refractory patients with 17p deletion treated with 
ibrutinib PFS median was up to 26 – 40 months and OS up to 57 months Ibrutinib is 
reimbursed in Poland in this patients group. Idelalisib is also an efficient option in these 
patients [7], however with higher toxicity (pneumonitis, colitis, transaminasemia, 
infections) [8], it is not reimbursed in Poland. BCRi therapy is also efficient in heavily 
pretreated fludarabine refractory patients [9] [10]. Though BCRi treatment altered the 
therapeutic landscape of CLL, the disease cannot be cured with small molecules that allow 
to maintain disease control without inducing deep response since partial response is 
observed in most patients. After four-year follow-up, CLL progression is observed in about 
19% of patients treated with ibrutinib [11]. The preferred therapeutical option for this group 
is venetoclax that results in response in 70% of patients progressing during ibrutinib 
therapy [12]. Median PFS in patients treated with venetoclax after BCRi failure was not 
reached, in contrast to immunochemotherapy where it is was only 5 months [13]. 
Venetoclax is not reimbursed in Poland. Moreover, the optimal therapeutic option for 
patients with CLL progression on venetoclax is not established. That is why allogeneic 
stem cell transplantation, that offers a curative option and has the potential to improve the 
natural course of poor-risk CLL should be considered in patients with high-risk disease, 

 
 
 
  
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even in the era of novel therapies [14]. The concern for fully myeloablative allo-SCT in 
CLL is high toxicity and treatment related mortality (TRM). This is significantly lower when 
reduced-intensity conditioning (RIC) which is used that is currently recommended in CLL 
[15]. The efficacy of RIC allo-SCT is resonated by the T cell-mediated graft-versus 
leukemia effect that could eliminate the leukemic clone (usually over a period of 3-6 
months) [16]. Event-free survival (EFS) five years after RIC allo-SCT was 35% – 45% and 
OS 50-70% confirming the curative potential but showing also the need for improvement. 
We hypothesize that acalabrutinib could be used both for bridging to alloSCT and after 
the procedure to augment disease control. Ibrutinib was shown to be effective before 
alloSCT and did not appear to adversely affect engraftment, GVHD risk, and NRM as 
reported by the Chronic Malignancy and the Lymphoma Working Parties of the EBMT 
(European Group of Blood and Bone Marrow Transplantation). Treatment with ibrutinib in 
patients relapsed after alloSCT resulted in minimal residual disease eradication in 36% of 
patients [17]. Moreover, ibrutinib was approved by the FDA for the treatment of adult 
patients with chronic GvHD, as it reduces severity of chronic GvHD symptoms in patients 
refractory to prior GvHD treatment [18]. These data suggest that using BCR inhibitors in 
patients after alloSCT could improve the outcome of patients with high-risk CLL. There is 
one ongoing clinical study with ibrutinib used before and after transplantation 
[NCT02869633]. There is so far no data on acalabrutinib in this setting. 
Mantle cell lymphoma (MCL) is a relatively rare subtype of NHL with an incidence of 0.5 
cases per 100,000 person-years, a male-to-female ratio of 2.3-2.5:1, and a median age at 
diagnosis of close to 70 years [19]. The relatively early development of resistance to 
immune-chemotherapy implies the necessity of therapy intensification already in the first 
line approach, including wherever possible intermediate cytarabine doses followed by 
autologous stem cell consolidation (ASCT) and rituximab maintenance [20]. Prognosis of 
MCL patients relapsing/ refractory to the first line therapy is poor. Although acalabrutinib 
increases RR and PFS compared to Ibrutinib in R/R MCL [21], majority of the patients will 
develop resistance to any subsequent regimens [22].  Therefore, offering an allogeneic 
transplant procedure to patients responding to BTK inhibitors, is fully justified, as it may 
be potentially curative.  
1.2 
BRUTON TYROSINE KINASE INHIBITION IN CLL AND MCL 
Bruton tyrosine kinase (BTK) is a non-receptor enzyme in the Tec kinase family that is 
expressed among cells of hematopoietic origin, including B-cells, myeloid cells, mast 

 
 
 
  
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cells, and platelets, where it regulates multiple cellular processes including proliferation, 
differentiation, apoptosis, and cell migration (Khan 2001, Mohamed 2009, Bradshaw 
2010). Bruton tyrosine kinase (BTK) is a key component of the signalosome that forms 
as part of the BCR pathway cascade, and is critical for the transduction and amplification 
of signals from the BCR (Figure 1.2) [23] [24]. When antigen binds the membrane 
immunoglobulin portion of the BCR, the resulting conformational change induces 
phosphorylation of the immunoreceptor tyrosine-based action motifs, causing the 
recruitment of BTK and other signalosome components. BTK is named after the 
pediatrician Ogden Bruton, who first described a case of X-linked agammaglobulinemia, 
a primary immunodeficiency that has since been linked to mutations in the BTK gene 
[25]. The essential role of BTK in MCL cell activation, proliferation and survival makes its 
inhibition a compelling therapeutic strategy. 
 
 
Figure 1-2  BCR signaling pathway  
1.3 
ACALABRUTINIB (ACP-196) 
Acalabrutinib is an imidazopyrazine analogue with a molecular weight of 465.5 g/mol.  
The compound has 1 stereogenic center and acalabrutinib is the S-enantiomer.  
Acalabrutinib is orally bioavailable in humans and is suitable for formulating in capsules. 

 
 
 
  
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Acalabrutinib is approved in the US for the treatment of adult patients with MCL who 
have received at least 1 prior therapy.  It is also being evaluated for the treatment of 
patients with other B-cell malignancies.     
1.3.1 
Mechanism of Action 
Acalabrutinib is a potent inhibitor of BTK in vitro and in vivo.  Pharmacology models have 
been used to define kinase selectivity of acalabrutinib in comparison to other BTK 
inhibitors, and to investigate functional effects of on-target and off-target activities.  
Acalabrutinib shows improved selectivity for BTK compared with ibrutinib [26].  
Functional inhibition of non-target cells (e.g., T cells, NK cells, platelets) was not 
observed for acalabrutinib at clinically relevant concentrations. 
1.3.2 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with acalabrutinib have demonstrated a 
favorable nonclinical safety profile; for detailed information on the safety pharmacology 
of acalabrutinib, refer to the Investigator’s Brochure.   
1.3.3 
Drug-drug Interaction Potential 
For more detailed information on drug-drug interaction potential for acalabrutinib, refer to 
the Investigator’s Brochure. Please refer to Section “Concomitant Therapy” for guidance 
on drugs that may cause drug-drug interactions. 
1.4 
CLINICAL EXPERIENCE – ACALABRUTINIB 
For more detailed information on the clinical experience for acalabrutinib, please refer to 
the Investigator’s Brochure.   
1.4.1 
Clinical Efficacy in CLL and MCL 
Acalabrutinib is a highly selective, potent inhibitor of BTK [27] [28]. Acalabrutinib has a 
butynamide moiety that covalently binds Cys-481 in the ATP binding pocket of BTK, 
thereby blocking BCR signaling through BTK [26]. The US Food and Drug Administration 
(FDA) granted accelerated approval to acalabrutinib on October 31, 2017 for the 
treatment of patients with MCL who have received at least one prior therapy [21]. 
Acalabrutinib is also in clinical development for the treatment of other hematological 
malignancies, including chronic lymphocytic leukemia (CLL) and is included in the US 
National Comprehensive Cancer Network (NCCN) guidelines as a treatment option for 

 
 
 
  
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relapsed or refractory CLL. For further details please refer to section 5.3.1 of the 
Investigator’s Brochure.  
1.4.2 
Adverse Events  
There are no data on Acalabrutinib safety in the post-transplant patients. An aggregate 
safety analysis of acalabrutinib monotherapy was conducted in order to assess safety for 
acalabrutinib-exposed subjects with hematologic malignancies without confounding 
toxicity from combination therapy drugs.  The analysis was performed on a 7-study 
integrated monotherapy population ‘INT-7’, which consisted of treated subjects in 5 
acalabrutinib monotherapy studies (15-H-0016, ACE-CL-001, ACE-LY-002, ACE-LY-
004, ACE-WM-001) and treated subjects in the acalabrutinib monotherapy treatment 
arms of 2 additional combination studies (ACE-LY-003 and ACE-MY-001).  As of the 03 
September 2017 data extraction date, the pooled INT-7 population represented 
614 acalabrutinib-exposed subjects with a median exposure of 21.9 months (range, 0.03 
to 42.4 months).  Overall, the safety of monotherapy acalabrutinib in subjects with 
hematologic malignancies has been acceptable in the integrated analysis.  An overview 
of AEs for this population is presented in Table 1.4.2.. 
Table 1.4.2.    Overview of treatment-emergent adverse events of the INT-7 All 
Monotherapy Population 
Adverse Event Category 
N=614 
n (%) 
Any treatment-emergent adverse events 
  
   Any grade 
609 (99.2) 
   Grade ≥3 
334 (54.4) 
Any adverse event related to acalabrutinib 
  
   Any grade 
459 (74.8) 
   Grade ≥3 
128 (20.8) 
Any serious adverse events 
256 (41.7) 
Adverse events leading to study drug discontinuation 
44 (7.2) 
Grade 5 (fatal) adverse event 
27 (4.4) 
INT-7 studies include 15-H-0016, ACE-CL-001, ACE-LY-002, ACE-LY-003, ACE-LY-
004, ACE-MY-001, and ACE-WM-001. 
Note: A subject with multiple severity grades for a given adverse event was counted 
once under the maximum severity. 
Data as of 03 Sep 2017. 
  

 
 
 
  
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Almost all subjects (609 [99.2%]) had at least 1 AE, and about half (334 [54.4%]) had at 
least 1 Grade ≥3 AE.  The most commonly reported AEs of any grade were headache 
(42.3%), diarrhea (40.4%), fatigue (24.6%), nausea (23.6%), contusion (23.5%), cough 
(22.1%), and upper respiratory tract infection (21.7).  The most frequently reported 
Grade ≥3 AEs were neutropenia (10.4%), anemia (7.5%), pneumonia (6.5%), 
thrombocytopenia (3.7%), and hypertension (3.1%).   
Treatment-related AEs were reported for 459 (74.8%) subjects, and 128 (20.8%) 
subjects had Grade ≥3 treatment-related AEs.  The most frequently reported treatment-
related AEs of any grade were headache (29.5%), diarrhea (17.4%), contusion (14.5%), 
nausea (9.3%), fatigue (7.5%), petechiae (7.5%), neutropenia (7.0%), arthralgia (5.9%), 
and dizziness (5.0%).  The most frequently reported treatment-related Grade ≥3 AEs 
was neutropenia (6.8%). 
1.4.3 
Warnings and Precautions 
1.4.3.1 
Hemorrhage 
Serious hemorrhagic events, including central nervous system, respiratory, and 
gastrointestinal hemorrhage, have been reported in clinical trials with acalabrutinib; 
some of these bleeding events resulted in fatal outcomes.  Grade 3 or higher bleeding 
events, including gastrointestinal, intracranial, and epistaxis have been reported in 2% of 
patients. Overall, bleeding events including bruising and petechiae of any grade 
occurred in approximately 50% of patients with hematological malignancies. 
The mechanism for hemorrhage is not well understood.  Acalabrutinib may further 
increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant 
therapies and patients should be monitored for signs of bleeding.  Consider the benefit-
risk of withholding acalabrutinib for 3-7 days pre- and post-surgery depending on the 
surgery and the risk of bleeding.   
 
1.4.3.2 
Infection 
Serious infections (bacterial, viral or fungal), including fatal events and opportunistic 
infections, have been reported in clinical studies with acalabrutinib.  The most frequently 
reported Grade 3 or 4 infection was pneumonia.  Across the acalabrutinib clinical 
development program (including subjects treated with acalabrutinib in combination with 
other drugs), cases of hepatitis B virus (HBV) reactivation (resulting in liver failure and 

 
 
 
  
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death in 1 case) and cases of progressive multifocal leukoencephalopathy have 
occurred in subjects with hematologic malignancies.  Monitor patients for signs and 
symptoms of infection and treat as medically appropriate. 
1.4.3.3 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias including neutropenia, anemia, and 
thrombocytopenia have occurred in clinical studies with acalabrutinib.   Subjects should 
be closely monitored as appropriate. 
1.4.3.4 
Second Primary Malignancies 
Events of second primary malignancies, including non-skin carcinomas, have been 
reported in clinical studies with acalabrutinib.  The most frequently reported second 
primary malignancy was skin cancer.  Advise protection from sun exposure.  
1.4.3.5 
Atrial Fibrillation 
Events of atrial fibrillation/flutter have been reported in clinical studies with acalabrutinib, 
particularly in subjects with cardiac risk factors, hypertension, diabetes mellitus, acute 
infections, and a previous history of atrial fibrillation. 
The mechanism for atrial fibrillation is not well understood.     
2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE: 
• 
Safety:  
- 
adverse event (AE) incidence 
- 
serious adverse event (SAE) incidence 
• 
Response to therapy:  
- 
partial and complete remission rate (PR and CR),  
- 
minimum residual disease CR (MRD CR) rate assessed by flow 
cytometry in peripheral blood (PB) and bone marrow (BM) 
2.2 
SECONDARY OBJECTIVE(S): 
▪ 
relapse incidence (RI),  
▪ 
non-relapse mortality (NRM),  
▪ 
progression free survival (PFS),  
▪ 
overall survival (OS), 

 
 
 
  
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2.3 
EXPLORATORY OBJECTIVE(S) 
▪ 
acute and chronic graft versus host disease (GvHD) incidence,   
▪ 
GvHD-free and relapse-free survival (GRFS), cytometric 
assessment of immune cell populations: T cell subsets (CD4+ T 
cells, CD8+ T cells, Th1, Th2, Th17, T regulatory cells), NK cells, 
NKT cells and normal B cells, B-regulatory cells 
 
3.0 
STUDY DESIGN 
In this phase II multicenter trial we plan to use acalabrutinib before and after allogeneic 
hematopoietic stem cell transplantation (alloSCT) with reduced intensity conditioning 
(RIC) in patients with refractory/relapsed MCL and CLL with poor prognostic factors. 
Acalabrutinib will be used before alloSCT with the intention to reduce tumor burden and 
after transplant to augment disease control. Since chronic GvHD is mediated by activated 
B lymphocytes, we also speculate that the drug as a BTK inhibitor may reduce the severity 
and incidence of chronic graft-versus-host disease (GvHD) after alloSCT, as it was shown 
for ibrutinib.  
Feasibility and safety issues will be the primary target of this small trial (25 transplanted 
pts). TEAE and SAE of acalabrutinib in patients after alloSCT that was not previously 
assessed. 
We hypothesize that this treatment will improve the efficacy of the alloSCT – this issue 
will be addressed by serial minimal residual disease (MRD) evaluation in peripheral 
blood and bone marrow. This treatment strategy could significantly improve the outcome 
of poor prognosis MCL and CLL patients. The study schema is provided below (Figure 
3-1). 

 
 
 
  
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Figure 3-1.  Study Schema 
 
3.1 
STUDY PARAMETERS 
3.1.1 
Efficacy Parameters 
Partial and complete remission rate (PR and CR) will be assessed, based on medical 
history, clinical examination, laboratory assessment and imaging studies. Assessments 
will be done at the study entry, before the transplant and subsequently 1, 3, 6 & 9, 12, 15 
and 18 months after allo SCT procedure. Imaging studies will be done on the study 
entry, at 3 months, before the transplant if Acalabrutinib was administered for more than 3 
months, on re-initiating of acalabrutinib (which is 1-3 months after the transplant), at the end 
of post - transplant acalabrutinib therapy, 18 months after the transplant and any time when 
investigator will suspect PD. In Patients who would not be transplanted imaging studies will 
be performed on the study entry,  at 3 months, at 6 months, and later any time when 
investigator will have suspect  PD. 
Response in CLL and MCL patients is defined according to the standard IWCLL criteria 
updated in 2018 [29] and Cheson Criteria [30] [31] respectively. Additionally, for the 
purpose of the protocol in  PR patients the maximal diameter of lymph nodes < 5 cm is 
required, since lymphadenopathy    5 cm was recognized as a major predictor in 
relapse in CLL patients treated with ASCT after nonmyeloablative conditioning [32].  
Imaging studies will be based on CT scans.  

 
 
 
  
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Additionally, minimum residual disease CR (MRD CR) rate will be assessed by flow 
cytometry. In this study, we plan to evaluate MRD using flow cytometry (FCM), first in 
peripheral blood (PB) and in case of negativity in bone marrow (BM) in a central 
laboratory certified for MRD assessment at the following time points: will be performed at 
the study entry, before the transplant and subsequently 1, 3, 6 & 9, 12, 15 and 18  
months after allo SCT procedure.  
Relapse incidence (RI), non-relapse mortality (NRM), progression free survival (PFS), 
and overall survival (OS) are regarded as secondary targets and will be based on local 
investigators assessment.  
 
 
3.1.2 
Safety Parameters 
The safety of acalabrutinib will be characterized by the type, frequency, severity, timing 
of onset, duration, and relationship to study drug of any treatment-emergent AEs or 
abnormalities of laboratory tests; SAEs; or AEs leading to discontinuation of study 
treatment or death.  
For consistency of interpretation, AEs and laboratory results will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA), and the severity of AEs will be 
graded using the Common Terminology Criteria for Adverse Events (CTCAE), Version 
4.03 or higher.  Standard definitions for seriousness will be applied (see Section 6.1). 
 
3.1.3 
Exploratory Parameters 
 
Since the incidence and severity of GvHD may be altered by acalabrutinib usage, acute 
and chronic graft versus host disease (GvHD) incidence and GvHD-free and relapse-
free survival (GRFS) are regarded as exploratory parameters. hey will be assessed 
according to Statistical Guidelines for EBMT by M. Labopin and S. Iaobelli and GRFS 
definition according to Holtan et al [33]. 
Donor chimerism analysis will be routinely performed at 1, 3, 6, 9 and 12 months post-
alloSCT on peripheral blood; then every 3 months during follow-up period. For patients 
with progressive mixed chimerism confirmed on 2 subsequent tests done 2 weeks apart 

 
 
 
  
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the intervention will consist of calcineurin inhibitor (CI) taper. For patients with relapse or 
decreasing donor chimerism DLI is allowed as per institutional protocol. Chimerism 
analysis will be routinely performed (for time-points see the table) at the local labs. 
 
Evaluation of immune cell populations, at the study entry, at 3 months, 6 months, at the 
time of transplant, then every three months for the following 18 months using FCM, such 
as T cell subsets (CD4+ T cells, CD8+ T cells, Th1, Th2, Th17, T regulatory cells), NK 
cells, NKT cells and normal B cells, B-regulatory cells as well as immunoglobulin levels 
(IgG, IgA, IgM). (for time-points see the table).  
Additionally, frozen cells for future assessment will be collected.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table  3.1.3. Summary of Study Assesments: 
 
 
Screening 
Treatment period 
TT 
SFU 
FU 
Before alloSCT 
At 
alloSCT 
After 
alloSCT 
Study month 
-1 - 0 
1 
2 3 4 
5 
6 
 
1,3,6,9 
 
 
12,15,18 
Physical 
examination 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
x 

 
 
 
  
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Medical history, 
including AE, 
SAE data 
collection 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
 
Rai staging 
x 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
performance 
status 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
(pulse, BP, 
temp.) 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
Urine or serum 
pregnancy test 
x 
 
 
 
 
 
 
x 
12 months 
after 
alloSCT 
 
 
 
FBC 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
x 
U&E and LFT1 
x 
x 
x x x 
x 
x 
x 
x 
x 
x 
 
HBV, HCV, HIV 
serology2 
x 
 
 
 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins 
(IgG, IgM, IgA) 
x 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
ß2-microglobulin 
x 
 
 
 
 
 
 
 
 
 
 
 
Coombs test 
x 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis 
x 
 
 
 
 
 
 
 
 
 
 
 
FISH panel, p53 
mutation status* 
x 
 
 
 
 
 
 
 
 
 
 
 
IgVH mutation 
status* 
x 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
evaluation 
(imaging studies) 
x 
 
 
x 
 
 
x 
x 
see 3.1.1 
for details 
 
 
 

 
 
 
  
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MRD 
assessment by 
flow cytometry* 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
Chimerism 
 
 
 
 
 
 
 
 
Until full 
donor 
chimerism 
 
 
 
Immune 
parameters 
evaluation by 
flow cytometry* 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
Blood samples 
for additional 
assessments 
x 
 
 
x 
 
 
x 
x 
x 
 
 
x 
TT, treatment termination visit (within 7 days of the last dose of study drug);  SFU, safety 
follow-up visit (30+/-7 days the last dose of study drug), FU, follow-up visits 
(*) – procedures performed by the central lab.  
(1) – U&E and LFT include: calcium, chloride magnesium, phosphate/phosphorus, 
potassium, sodium ALT, AST,  total bilirubin albumin, alkaline phosphatase, , 
bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, lactate dehydrogenase 
(LDH),total protein, and uric acid.   
 
(2) – hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), anti-
HBc, and HCV antibody 
 
3.2 
RATIONALE FOR STUDY DESIGN AND DOSING REGIMEN 
According to current guidelines of European Society of Medical Oncology (ESMO), in 
CLL patients with 17p deletion/TP53 mutation as well as in the patients with refractory 
CLL or short remission BCR inhibitors are recommended as preferred therapy. 
Venetoclax is recommended in patients who are unsuitable to BCRi or after BCRi failure. 
In both groups of patients, allogeneic stem cell transplantation should be considered 
[ESMO].  Options for R/R patients with MCL are even more limited. Although both 
ibrutinib and acalabrutinib are registered in this setting, PFS is moderate and the therapy 
for BTK inhibitor resistant patients is an undisputable unmet medical need.   We 

 
 
 
  
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hypothesize that acalabrutinib might be efficient treatment reducing tumor burden before 
alloSCT and used after the transplantation might improve the results of the procedure, 
both in terms of disease control and influence on GvHD incidence The rationale for this 
hypothesis are the clinical data on ibrutinib. Acalabrutinib is a next generation more 
selective BTK inhibitor with promising safety and efficacy profiles in patients with 
relapsed CLL and MCL [27] [21]. There is no data on safety or efficacy of acalabrutinib in 
patients after alloSCT. 
 
Disease status in patients with CLL/ MCL treated with acalabrutinib after alloSCT will be 
evaluated by MRD assessment. MRD negativity in CLL is defined as detection of less 
than one leukemic cell per 10 000 leukocytes in peripheral blood (PB) or bone marrow 
(BM) [29]. In patients treated for CLL, MRD negativity following therapy was shown to be 
a strong independent predictor for PFS and OS irrespective of the type and line of 
treatment, achievement of CR and pre-treatment patients characteristics [34]. What is 
more, MRD negativity was found to have a higher prognostic value than achievement of 
complete clinical response (CR) [35]. In patients with CLL undergoing alloSCT, MRD 
negativity 12 months after transplantation was associated with significantly longer event-
free survival (EFS), PFS and OS [36] [37]. MRD eradication can be achieved several 
months after alloSCT, probably because the onset of graft-versus-leukemia effect is not 
immediate. It has been suggested that kinetics rather than a single MRD assessment is 
more meaningful. Elimination of MRD in BM has higher negative predictive value for 
predicting subsequent relapse risk than in PB. Therefore, for treatment delivered with 
curative intent, like allo-SCT, it would be likely essential to evaluate MRD in BM. 
According to EMA guidelines MRD status should be determined around 3 months after 
the end of therapy and patients should be first screened for eradication in PB and if 
negativity is shown, this should be confirmed in BM [www.ema.europa.eu]. Evaluation of 
MRD is currently not recommended for routine clinical practice, but is considered as an 
important endpoint surrogate for PFS in clinical trials [1] where both PR and CR should 
be categorized as MRD+ or MRD- [38]. Standardized protocols of MRD evaluation in 
CLL with sensitivity of ≥ 4x10-4 are either multiparameter (four-color or more) flow 
cytometry (FCM) or allele- specific oligonucleotide PCR [39]. There is no specific method 
to be used as both are considered as appropriate.  

 
 
 
  
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MRD monitoring in MCL patients will be adapted according to European MCL Network 
(EMCLN) experience [40].  
 
3.3 
SELECTION OF STUDY POPULATION 
3.3.1 
Inclusion Criteria 
Eligible subjects will be considered for inclusion in this study if they meet all of the 
following criteria:  
1. Men and women ≥ 18 years of age. 
2. Relapsing / refractory BTK-inhibitors naïve CLL patients meeting IWCCL criteria 
for requiring treatment:  
a. after 1-4 therapy lines if del 17 or p53 mutation in >10% of analyzed CLL 
cells (PB or BM) or 
b. after 2-4 therapy lines if high risk CLL (refractory or less than 24 months 
response to the last immunochemotherapy) or 
3. Relapsing / refractory BTK-inhibitors naïve MCL patients with measurable 
disease or bone marrow involvement revealed in trephine biopsy or 
4. Patients fulfilling criteria 2 or 3, when ibrutinib therapy was initiated, responding 
to therapy 
5. Patient qualified for allo SCT procedure by the transplant center participating in 
the trial with identified sibling donor or initiated Poltransplant search for matched 
unrelated donor.  
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
7. Woman of childbearing potential (WOCBP) who are sexually active must 
use highly effective methods of contraception during treatment and for 2 
days after the last dose of acalabrutinib and for 6 months after the 
transplant procedure if performed. Males who are sexually active must use 
highly effective methods of contraception during treatment and for 6 
months after the transplant procedure if performed.   
8. Willing and able to participate in all required evaluations and procedures in this 
study protocol including swallowing capsules without difficulty. 

 
 
 
  
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9. Ability to understand the purpose and risks of the study and provide signed and 
dated informed consent and authorization to use protected health information. 
 
3.3.2 
Exclusion Criteria 
Subjects will be ineligible for this study if they meet any of the following criteria: 
1. Patients failing 5 or more previous therapy lines 
2. Prior malignancy (or any other malignancy that requires active treatment), 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 ≥ 5 
years 
3. Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of 
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart 
Association Functional Classification, or corrected QT interval (QTc) > 480 msec 
at screening.  Subjects with controlled, asymptomatic atrial fibrillation during 
screening can enroll on study. 
4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, 
or resection of the stomach or small bowel that is likely to affect absorption, 
symptomatic inflammatory bowel disease, partial or complete bowel obstruction, 
or gastric restrictions and bariatric surgery, such as gastric bypass. 
5. Impaired hepatic function (as indicated by any of the following):  
a. Serum total bilirubin > 2.5 x upper limit of normal (ULN)  
b. Alanine amino transferase and/or aspartate amino transferase > 2.5 x 
ULN  
c. Alkaline phosphatase > 2.5 x ULN  
6. Impaired renal function: serum creatinine > 2.5 x ULN  
7. Other concurrent serious diseases that increase Hematopoietic Cell 
Transplantation-Comorbidity Index (HCT-CI) > 4 
8. Central nervous system involvement with CLL 
9. Known history of drug-specific hypersensitivity or anaphylaxis to study drug 
(including active product or excipient components).  

 
 
 
  
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10. Active bleeding, history of bleeding diathesis (eg, hemophilia or von Willebrand 
disease). 
11. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic 
thrombocytopenic purpura). 
12. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months 
before screening. 
13. Requiring or receiving a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer 
(see appendix 3 for a complete list) 
14. Requiring or receiving anticoagulation with warfarin or equivalent vitamin K 
antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.  
15. Requiring proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, 
dexlansoprazole, rabeprazole, or pantoprazole).  Subjects receiving proton pump 
inhibitors who switch to H2-receptor antagonists or antacids are eligible for 
enrollment to this study. 
16. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x 
ULN. 
17. History of significant cerebrovascular disease or event, including stroke or 
intracranial hemorrhage, within 6 months before the first dose of study drug. 
18. Major surgical procedure within 7 days of first dose of study drug.  Note:  If a 
subject had major surgery, they must have recovered adequately from any 
toxicity and/or complications from the intervention before the first dose of study 
drug.   
19. Known history of infection with HIV or any active uncontrolled systemic infection 
20. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody 
(anti-HBc) positive and who are surface antigen negative will need to have a 
negative polymerase chain reaction (PCR).  Those who are hepatitis B surface 
antigen (HbsAg) positive or hepatitis B PCR positive will be excluded.  Subjects 
who are hepatitis C antibody positive will need to have a negative PCR 
result.  Those who are hepatitis C PCR positive will be excluded. 
21. ANC < 500/µl, Platelets < 20 000/µl, and hemoglobin < 8 g/dl 
22. Breastfeeding or pregnant.  
23. Concurrent participation in another therapeutic clinical trial. 

 
 
 
  
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3.3.3 
Enrollment Procedures 
After the subject has signed and dated the Informed Consent Form (ICF), all screening 
procedures have been completed, and eligibility has been confirmed, the subject can be 
enrolled into the study.  
3.4 
STUDY DRUG 
3.4.1 
Premedication 
No specific premedication or supporting medications are required in conjunction with 
acalabrutinib administration. 
3.4.2 
Formulation, Packaging, and Storage 
Acalabrutinib, the investigational product, acalabrutinib capsules for oral administration, 
is supplied as yellow and blue, opaque hard gelatin capsules, with 100 mg of 
acalabrutinib as the active ingredient.  Each capsule also contains compendial inactive 
ingredients: silicified microcrystalline cellulose, which is composed of microcrystalline 
cellulose and colloidal silicon dioxide, partially pregelatinized starch, sodium starch 
glycolate, and magnesium stearate.  The capsule shell contains gelatin, titanium dioxide, 
yellow iron oxide and indigotine (FD&C Blue 2). 
Acalabrutinib will be provided in white, high-density polyethylene bottles.   
Refer to the acalabrutinib Investigator’s Brochure for additional information regarding the 
drug product to be used in this trial. 
3.4.3 
Administration of Study Drug  
Acalabrutinib capsule is administered BID and taken orally approximately every 12 
hours.  The capsules should be swallowed intact with water.  Subjects should not 
attempt to open capsules or dissolve them in water.  Acalabrutinib can be taken with or 
without food. 
If a dose is missed, it can be taken up to 3 hours after the scheduled time with a return 
to the normal schedule with the next dose.  If it has been > 3 hours, the dose should not 
be taken and the subject should take the next dose at the scheduled time.  The missed 
dose will not be made up and must be returned to the site at the next scheduled visit. 

 
 
 
  
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Guidance on co-administration of acalabrutinib with agents that affect gastric pH is 
provided in Section 3.9.2. 
3.5 
STUDY TREATMENT SCHEDULE 
Acalabrutinib 100 mg will be administered orally twice daily, every day (for details and 
explanations see below).  
 
3.6 
DURATION OF THERAPY 
Acalabrutinib will be administered for 3-6 months before the intended alloSCT. Patients 
with CR or PR (defined by Cheson and IWCLL criteria  + limfadenpathy < 5 cm)   after 
initial BTK inhibitor will proceed to alloSCT, donor availability and their general status 
permitting. After restarting acalabrutinib after the transplant procedure (see details 
below) it will be administered for further 9 months. In patients who do not have an 
acceptable donor acalabrutinib will be administered until disease progression or 
unacceptable toxicity.  
 
Post-HSCT acalabrutinib treatment initiation  
Acalabrutinib will be initiated 30-90 days after (*) the procedure for 9 months in patients 
who will fulfill the following criteria:   
- 
ANC  ≥ 1000/µl and platelet count ≥ 50 000/µl  
- 
ECOG 0-2  
- 
adequate renal function: serum creatinine < 2 x ULN OR creatinine clearance 
(calculated clearance permitted) ≥ 40 mL/min  
- 
total bilirubin =< 2.5 x upper limit of normal (ULN)  
- 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 
x upper limit of normal (ULN)  
Patients can not have:  
- 
active systemic infection  
- 
active uncontrolled grade 3-4 gastrointestinal or liver acute GvHD  
- 
any life-threatening illness, medical condition, or organ system dysfunction 
which, in the investigator's opinion, could compromise the subject's safety 
after HSCT 
- 
clinically significant active bleeding 

 
 
 
  
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Acalabrutinib will be continued for 9 months in the absence of disease progression, 
worsening symptoms of GvHD or unacceptable toxicity.  
(*) – Acalabrutinib may be re-started earlier after the transplant if patients do not achieve 
clinical CR or experience early progression after the transplant 
 
3.7 
DOSING DELAYS AND MODIFICATIONS 
Subjects should be followed closely for AEs or laboratory abnormalities that might 
indicate acalabrutinib-related toxicity.  If a subject experiences a treatment-related 
toxicity or other intolerable AE during the course of therapy, then acalabrutinib should be 
withheld, as necessary, until the AE resolves or stabilizes to an acceptable degree.  
Dose modifications for the following treatment-emergent toxicities are provided in Table 
3-X: 
• 
Grade 4 neutropenia (< 500/µL) for > 7 days (neutrophil growth factors are 
permitted per American Society of Clinical Oncology (ASCO) guidelines [Smith 
2006] and use must be recorded on the case report form [CRF]). 
• 
Grade 3 thrombocytopenia in presence of significant bleeding. 
• 
Grade 4 thrombocytopenia.  
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, if persistent despite optimal 
antiemetic and/or anti-diarrheal therapy. 
• 
any Grade 4 active systemic infection or unmanageable G3 (including, among 
the others  CMV and EBV) 
• 
Any other Grade 4 toxicity or unmanageable Grade 3 toxicity. 
 

 
 
 
  
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Table 3-7: Drug Modification Actions for Acalabrutinib 
Occurrence 
Action 
1st – 2nd 
Hold acalabrutinib until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level 
3rd 
Hold acalabrutinib until recovery to Grade ≤ 1 or baseline; restart at one 
dose level lower (100 mg QD) 
4th 
Discontinue acalabrutinib 
 
As appropriate, certain laboratory abnormalities may warrant more frequent monitoring 
(eg, once per week) until abnormalities have recovered to Grade ≤ 1.  If acalabrutinib is 
reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even 
if there is minimal or no toxicity with the reduced dose.  However, if the AE resolves to 
Grade ≤1 or if the subject tolerates a reduced dose of acalabrutinib for ≥ 4 weeks then 
the dose may be increased to the next higher dose level, at the discretion of the 
investigator.  Such re-escalation may be particularly warranted if further evaluation 
reveals that the AE that led to the dose reduction was not treatment-related.  The 
maximum dose of acalabrutinib is 100 mg BID. Any other clinically important events 
where dose delays may be considered appropriate must be discussed with the Principal 
Investigator.   
 
3.8 
CONCOMITANT THERAPY 
3.8.1 
Permitted Concomitant Therapy 
Transplant procedure: 
A. Acceptable donors: 
• 
HLA-identical sibling 
• 
HLA matched (HLA-A, -B, -C, -DR, -DQ i.e. 10/10) unrelated donor 
• 
Unrelated donor with single HLA mismatch 
• 
Haploidentical family donor 
 

 
 
 
  
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B. Source of stem cell  
• 
For alloSCT from HLA-identical sibling or HLA matched (10/10 or 9/10) 
unrelated donor: preferably PBSC 4-6 x 10/6 CD34+/kg recipient's body 
weight. 
• 
For HSCT from haploidentical donors: according to institutional protocol  
C. Conditioning before alloSCT from HLA-identical sibling or matched  (10/10 or 
9/10) unrelated donor. Investigators may choose to use reduced intensity 
conditioning based on either bendamustine or TBI, both in combination with 
fludarabine and rituximab 
BFR: 
• 
Bendamustine 130 mg/m2 infused iv over 60 min daily on days −5 to − 3 
• 
Fludarabine 30 mg/m2 iv daily on days -5 to -3  
• 
Rituximab 375 mg/m2 iv on day -6 
TBI/F/R: 
• 
Fludarabine 30 mg/m2 i.v. daily on days -5 to -3 
• 
TBI 4 Gy on day -1 or 0 
• 
Rituximab 375 mg/m2 iv on day -6 
D. Conditioning before HSCT from haploidentical family donors 
• 
Cyclophosphamide 14.5 mg/kg i.v.daily on days -6 and -5 
• 
Fludarabine 30mg/m2 i.v.daily on days -6, -5, -4, -3 and -2 
• 
TBI 2 Gy on day -1 
GvHD prophylaxis:   
A. For alloSCT from HLA-matched sibling donor 
• 
Tacrolimus iv/po or CSA iv/po starting on day -2 per institution standard 
• 
MTX  10  mg/m2  on day +1, 5 mg/m2 iv on days +3, +6, optionally +11 
• 
Rituximab 375 mg/m2*  i.v on day +1, +8  
**Rituximab dose escalation to 500 mg/m2 is allowed  

 
 
 
  
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Tacrolimus/CSA taper will be initiated at +100 - +180 days after alloSCT in patients with 
no active GvHD. Tacrolimus/CSA doses wil be tapered earlier and more  rapidly in 
patients with persistent/progressive disease and no GvHD. 
 
B. For alloSCT from HLA-matched (10/10 or 9/10) unrelated donor  
• 
ATG: Thymoglobuline 1.5 mg/kg daily i.v. on days -2, -1 (total dose 3.0 mg 
/kg) or ATG Neovi (Fresenius) 10 mg/kg i.v. daily on days -2, -1 
• 
Tacrolimus iv or p.o. or CSA iv or p.o.starting on day -2  
• 
MTX  10 mg/m2 i.v. on day +1, 5 mg/m2 p.o. on days +3, +6, +11 
• 
Rituximab 375  mg/m2 iv on days +1 and +8 
*Rituximab dose escalation to 500 mg/m2 is allowed  
Tacrolimus/CSA taper will be initiated at +100 - +180 days after alloSCT in 
patients with no active GvHD. Tacrolimus/CSA doses will be tapered earlier and 
more  rapidly in patients with persistent/progressive disease and no GvHD. 
 
C. For HSCT from family haploidentical donor or optionally for alloSCT from HLA-
mismatched (9/10, except for mismatch regarding HLA-DQB1) unrelated donor  
• 
Cyclophosphamide 50 mg/kg i.v. on days +3, +4 
• 
Tacrolimus p.o. or i.v.  starting on day +5  
• 
Mycophenolate mofetil 3 x 15 mg/kg p.o. or i.v. on days from +5 to +35 
Tacrolimus taper will be initiated at +120 - +150 days after alloSCT and should 
be tapered off by day +150- +180 days after alloSCT in patients with no active 
GvHD. Tacrolimus doses will be tapered more rapidly in patients with 
persistent/progressive disease and no GvHD. 
 
Supportive care:  
Patients will receive supportive care with antibiotics, antifungals, antivirals and 
immunizations after alloSCT according to institutional guidelines 
 

 
 
 
  
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3.8.2 
Prohibited or Restricted Concomitant Therapy 
Any (other than mentioned in 3.8.1) chemotherapy, anticancer immunotherapy, 
experimental therapy, or radiotherapy are prohibited. 
Warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) are prohibited. 
The concomitant use of strong inhibitors/inducers of CYP3A4 (see Appendix 3) should 
be avoided when possible (see Section 3.9.2).  If a subject requires a strong CYP3A 
inhibitor while on study, monitor the subject closely for potential toxicities.  For additional 
information on drugs with potential drug-drug interactions, refer to Section 3.9.2. 
  
3.9 
PRECAUTIONS 
3.9.1 
Dietary Restrictions 
Acalabrutinib can be taken with or without food.    
3.9.2 
Drug-drug Interactions 
At the systemic exposure levels expected in this study, acalabrutinib inhibition of CYP 
metabolism is not anticipated. 
However, acalabrutinib is metabolized by CYP3A.  Concomitant administration of 
acalabrutinib with a strong CYP3A and P-glycoprotein (P-gp) inhibitor, itraconazole 
increased exposure by approximately 5-fold.  Conversely, concomitant administration of 
acalabrutinib with a strong CYP3A inducer, rifampin decrease acalabrutinib exposure 
and could reduce efficacy.  Consequently, the concomitant use of strong 
inhibitors/inducers of CYP3A (see Appendix 3) should be avoided when possible.   
If medically justified, subjects may be enrolled if such inhibitors or inducers can be 
discontinued or alternative drugs that do not affect these enzymes can be substituted 
within 7 days before first dose of study drug.  If a subject requires a strong CYP3A4 
while on study, the subject should be monitored closely for any potential toxicities. 
The effect of agents that reduce gastric acidity (eg, proton pump inhibitors or antacids) 
on acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004).  
Results from this study indicate that subjects should avoid the use of calcium 
carbonate-containing drugs or supplements for a period of at least 2 hours before and at 
least 2 hours after taking acalabrutinib.  Use of omeprazole, esomeprazole, lansoprazole 

 
 
 
  
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or any other proton pump inhibitors while taking acalabrutinib is not recommended due 
to a potential decrease in study drug exposure.  However, the decision to treat with 
proton-pump inhibitors during the study is at the investigator’s discretion, with an 
understanding of the potential benefit to the subject’s gastrointestinal condition and a 
potential risk of decreased exposure to acalabrutinib. 
Although the effect of H2-receptor antagonists (such as famotidine or ranitidine) on 
acalabrutinib absorption has not been evaluated, if treatment with an H2-receptor 
antagonist is required, the H2-receptor antagonist should be taken approximately 
2 hours after an acalabrutinib dose. 
3.9.3 
Reproductive Toxicity 
The potential for acalabrutinib to be excreted in breast milk of nursing mothers is 
unknown. 
For results of acalabrutinib nonclinical reproductive toxicity studies, including definitive 
embryofetal development studies, please refer to the Investigator’s Brochure. 
Women of childbearing potential (WOCBP) who are sexually active must use highly 
effective methods of contraception throw-out the trial and 6 months after the last dose of 
BTK inhibitor.  For male subjects with a pregnant or non-pregnant WOCBP partner, no 
contraception measures are required. Please refer to the Investigator’s Brochure for 
detailed definitions for WOCBP and highly effective methods of contraception. 
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 as outlined in Section 6.2.4.   
3.9.4 
Overdose Instructions 
Clinical information relevant to overdose is not available. For results from nonclinical 
overdose studies in rats and dogs, please refer to the Investigator’s Brochure. 
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. 

 
 
 
  
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All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the CRF and reported to Sponsor under the same timelines as an SAE.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the CRF.  If the associated AE fulfills serious criteria, Investigators should 
report the event to the Sponsor within 24 hours using the SAE Reporting Form. The 
Sponsor should report any SAEs to the IRB and Regulatory Authorities per institutional 
and/or regulatory guidelines, and to Acerta-Pharma per contractual guidelines. 
In the event of subject ingestion of more than the recommended acalabrutinib dosage, 
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 acalabrutinib is 
recent and substantial, and if there are no medical contraindications, use of gastric 
lavage or induction of emesis may be considered. 
3.10 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
The investigator may withdraw any subject from study treatment, if, in the investigator’s 
opinion, it is not in the subject’s best interest to continue.  
Any subject has the right to withdraw from the study at any time.  In addition, subjects 
may be withdrawn from study treatment for the following reasons: 
• 
Study treatment should be discontinued in the event of a toxicity lasting 
> 28 days, unless reviewed and approved by the investigator.   
• 
Any subject who starts new chemotherapy or chemoimmunotherapy for the 
treatment of disease being studied, becomes pregnant or breastfeeding, is 
significantly noncompliant, should be withdrawn from study treatment. 
Subjects who discontinue study therapy will continue to be followed on study for 
follow-up of safety and survival unless they withdraw consent for further follow-up.  Thus, 
all subjects receiving ≥ 1 dose of study drug will be followed during the immediate post-
therapy and long-term follow-up assessments unless the subject withdraws consent for 
such follow-up to be conducted. 
3.11 
REMOVAL FROM STUDY 
Reasons for removal of a subject from the study are: 

 
 
 
  
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• 
Subject’s withdrawal of consent from study 
• 
Decision by sponsor 
• 
Subject lost to follow-up 
• 
Death 
3.12 
DATA AND SAFETY MONITORING 
This trial will be monitored in accordance with the Sponsor’s Pharmacovigilance 
procedures.  Adverse events, AESIs, and SAEs will be reviewed internally as part of 
ongoing safety surveillance.   
Quarterly conference calls with the investigators and applicable site staff will be 
conducted to discuss study progress, obtain investigator feedback and exchange, and 
discuss "significant safety events" (ie, AEs leading to dose reductions, related SAEs, 
and deaths).  
4.0 
STUDY ACTIVITIES AND ASSESSMENTS 
The schedule of events is provided in Appendix 1.  Descriptions of the scheduled 
evaluations are outlined below and complete information on study drug and dosing is 
provided in Section 3.4. 
Before study entry, throughout the study, and at the follow-up evaluation, various clinical 
and diagnostic laboratory evaluations are outlined.  The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments.  
Clinical evaluations and laboratory studies may be repeated more frequently if clinically 
indicated. 
4.1 
DESCRIPTION OF PROCEDURES 
4.1.1 
Informed Consent 
The subject must read, understand and sign the ICF approved by the institutional review 
board or independent ethics committee (IRB/IEC), confirming his or her willingness to 
participate in this study before initiating any screening activity that is not standard of 
care.  Subjects must also grant permission to use protected health information, if 
required by local regulations. A copy of the informed consent form, including patient’s 
signature, will be provided by the investigator to the patient. If the amendment to the 

 
 
 
  
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protocol substantially alters the trial design or the potential risks to the patients, the 
patient’s consent to continue participation in the trial must be obtained.  
 
4.1.2 
Medical History 
Collect and record the subject’s complete history through review of medical records and 
by interview performed at screening.  Medical history includes clinically significant 
diseases, surgeries, cancer history (including prior cancer therapies and procedures), 
reproductive status, smoking history, use of alcohol and drugs of abuse. Concurrent 
medical signs and symptoms must be documented to establish baseline severities.  A 
disease history, including the date of initial diagnosis and list of all prior anticancer 
treatments, and responses and duration of response to these treatments, also will be 
recorded. 
4.1.3 
Adverse Events 
The accepted regulatory definition for an AE is provided in Section 6.1.  Important 
additional requirements for reporting SAEs are explained in Section 6.2. 
4.1.4 
Concomitant Medications and Therapy 
Document all concomitant medications and procedures from within 21 days before the 
start of study drug administration through 30 days after the last dose of study drug. 
4.1.5 
Confirmation of Eligibility 
Subject eligibility for enrollment will be assessed per Section 3.3.3.  All screening 
procedures, unless otherwise indicated, should be completed within 8 days of the first 
dose of study drug. 
4.1.6 
ECOG Performance Status 
The ECOG performance index is provided in Appendix 2. 
4.1.7 
Physical Examination, Vital Signs, Height & Weight 
The screening physical examination will include, at a minimum, the general appearance 
of the subject, height (screening only) and weight, and examination of the skin, eyes, 
ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous 

 
 
 
  
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system, and lymphatic system.  As a part of the tumor assessment, a full physical 
examination should be performed to assess the extent of disease involvement. The 
exam should also include the evaluation of presence and degree of enlarged lymph 
nodes, hepatomegaly, and splenomegaly.  
Vital signs (blood pressure, pulse, and body temperature) will be assessed after the 
subject has rested in the sitting position for at least 5 minutes. 
4.1.8 
Electrocardiogram  
12-lead electrocardiogram (ECG) is required in all patients at screening and from then  
when clinically indicated. Subjects should be in supine position and resting for at least 
10 minutes before any study-related ECGs. Include study specific schedule for ECGs. 
4.1.9 
Urine or Serum Pregnancy Test 
Pregnancy tests will be required only for women of childbearing potential.   
All women of childbearing potential will have a serum or urine pregnancy test at 
screening, 14 days prior first dosing, at transplant and at the end of acalabrutinib 
exposure and at specified subsequent visits. Positive urine pregnancy test should be 
confirmed by serum test. 
4.1.10 
Hematology 
Hematology studies must include complete blood count (CBC) with differential including, 
but not limited to white blood cell count, hemoglobin, hematocrit, platelet count, ANC, 
and absolute lymphocyte count (ALC).    
4.1.11 
Serum Chemistry 
Chemistry will include albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood 
urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), magnesium, phosphate/phosphorus, potassium, sodium, total bilirubin, total 
protein, and uric acid.  If an unscheduled ECG is done at any time, then an electrolyte 
panel (ie, calcium, magnesium, and potassium) must be done to coincide with the ECG 
testing. 
 

 
 
 
  
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4.1.12 
Hepatitis B and C Testing 
Hepatitis serology testing must include hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (anti-HBs), anti-HBc, and HCV antibody.  In addition, any subjects 
testing positive for any hepatitis serology must have PCR testing during screening and 
on study (see Appendix 1 and exclusion criterions #20).     
Subjects who are anti-HBc positive should have quantitative PCR testing for HBV DNA 
performed during screening and monthly thereafter as per institutional practices.  Any 
subject with a rising viral load (above lower limit of detection) should discontinue study 
drug and have antiviral therapy instituted and a consultation with a physician with 
expertise in managing hepatitis B.  As 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 (eg, in the setting of rising transaminase levels).  
Subjects with a known history of hepatitis C or who are hepatitis C antibody positive 
should be tested for HCV RNA performed during screening  
 
4.1.13 
Additional clinical tests or procedures 
 
• 
Quantitative immunoglobulins (IgG, IgA and IgM) should be evaluated at 
the study entry and then every 3 months  
• 
Coombs test (indirect and direct) should be performed at screening and 
repeated if necessary 
• 
Β2-microglobulin should be evaluated at the study entry 
• 
Molecular cytogenetics FISH (17p-deletion, 13q deletion, trisomy 12) and 
p53 mutation analysis (TP53 mutation) at screening and at progression 
 
Patients must have documented B-CLL according the NCI criteria. B-CLL cells co-
express the T-cell antigen CD5 and B-cell antigen (CD20 and CD23). The levels of 
surface immunoglobulins (sIg, CD20 and CD79b are characteristically low compared 
with those found on normal C-cells. Each B-cell is monoclonal with regard to expression 
of either κ or λ. 
 

 
 
 
  
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4.1.14 
Biomarker Studies 
Blood samples will be used for further characterization of circulating tumor cells, 
lymphocyte and myeloid cell subsets.   
Evaluation of immune cell populations, at the study entry, at 3 months, at the time of 
transplant, then every three months for the following 18 using FCM, such as T cell subsets 
(CD4+ T cells, CD8+ T cells, Th1, Th2, Th17, T regulatory cells), NK cells, NKT cells and 
normal B cells, B-regulatory cells as well as immunoglobulin levels (IgG, IgA, IgM). (for 
time-points see the table Appendix 1) 
MRD using FCM, first in PB and in case of its negativity in BM in a laboratory certified for 
MRD assessment (for time-points see the table, BM analysis if required should be 
performed together with PB analysis at the next scheduled patient visit) 
Chimerism analysis will be routinely performed (for time-points see the table in Appendix 
1) at the local labs. Additional exploratory studies may include somatic mutation in IgVH 
and IgVH3-21 usage in previously untreated population. 
4.1.15 
Tumor Assessments 
A pretreatment computerized tomography (CT) scan with contrast (unless 
contraindicated) is required of the neck, chest, abdomen, and pelvis and any other 
disease sites within 30 days before the first dose of study drug.  
On-treatment CT scans with contrast (unless contraindicated) of the neck, chest, 
abdomen, and pelvis and any other disease sites will be done for tumor assessments 
every 3 months (± 10 days) until 18th month after alloSCT, or more frequently at 
investigator discretion.  At all other visits, tumor assessments will be done by physical 
exam and laboratory results. 
In patients with severe renal insufficiency at screening use CT contrast according to 
local practice. If necessary, use MRI scan. CT without contrast is not recommended 
except for patients who develop renal insufficiency during treatment. It is obligatory to 
use the same imaging technique for all tumor evaluation. 
When progressive disease is detected by physical examination in the absence of any 
objective hematological progression, a CT scan of involved nodes will be performed. In 

 
 
 
  
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addition, CT scans may be performed at any time at the investigator discretion, if 
clinically indicated. 
4.1.16 
Study Drug Accountability 
See Section 7.5. 
4.2 
ASSESSMENT OF RESPONSE TO TREATMENT 
Response assessments will be evaluated based on International Workshop on Chronic 
Lymphocytic Leukemia (IWCLL) and revised Cheson criteria for MCL for Treatment and 
Tumor Response Criteria (refer to Appendix 5). 
4.3 
TREATMENT TERMINATION AND SAFETY FOLLOW-UP VISITS 
A treatment termination (TT) visit is required for safety assessments for any subjects 
who permanently discontinue study drug for any reason, including disease progression.  
The TT visit should be scheduled within 7 days of the last dose of study drug, if possible, 
and is not required for subjects who discontinue from the study within 10 days of a 
scheduled study visit.   
Each subject should be followed until the safety follow-up (SFU) visit at 30 (+ 7) days 
after his or her last dose of study drug to monitor for resolution or progression of AEs 
and to document the occurrence of any new events, regardless of whether the subject 
receives a new anticancer therapy or demonstrates disease progression within this 
timeframe.  Subjects who withdraw consent for study treatment should still be 
encouraged to complete the SFU assessments, but these assessments cannot be 
mandated if subject consent for further study participation is withdrawn.  If the TT visit 
and the SFU visit coincide, then these can be combined into 1 visit.  After TT there will 
be three follow-up visits at months +12, +15, +18. The Schedule of Assessments 
(Appendix 1) describes the procedures required for the TT, SFU and FU visits. 
4.4 
FOLLOW-UP FOR PROGRESSION AND SURVIVAL 
4.4.1 PFS as an Endpoint: Discontinuation Follow-up 
Each subject should be followed until disease progression or the start of alternative 
anticancer therapy.  If neither of these has occurred at the time of the 30-day SFU visit, 
discontinuation follow-up (DFU) visits should occur approximately every 3 months until 
disease progression or next anticancer treatment.  

 
 
 
  
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4.4.2 OS as an Endpoint: Long-term Follow-up 
Once subjects progress or start use of alternative anticancer therapy—for all subjects 
who have not withdrawn consent—they will be contacted approximately every 3 months 
by clinic visit or telephone, to assess survival and the use of alternative anticancer 
therapy until death or lost to follow up. 
4.5 
MISSED EVALUATIONS 
Missed evaluations should be rescheduled and performed as close to the original 
scheduled date as possible.  An exception is made when rescheduling becomes, in the 
investigator’s opinion, medically unnecessary or unsafe because it is too close in time to 
the next scheduled evaluation.  In that case, the missed evaluation should be 
abandoned. 
5.0 
STATISTICAL METHODS OF ANALYSIS  
5.1 
GENERAL CONSIDERATIONS 
This is a Phase 2, single-arm trial designed to assess the safety and efficacy of 
acalabrutinib in subjects with CLL and MCL undergoing allo SCT.    
The severity of AEs (adverse events), TEAEs (treatment emerge adverse events) and 
SAEs (severe adverse events) will be described according to Common Terminology 
Criteria for Adverse Events (CTCAE v4.3 or higher). 
An AE summary table will present the number of events, number of patients and the 
percentage of patients having AEs, SAEs, TEAEs and TEAEs that led to study 
discontinuation 
Tabulation of summary statistics, graphical presentation and statistical analyses will be 
performed using appropriate statistical software. Continuous, quantitative variable 
summaries will include the number of patients (N) (with non-missing values/valid cases), 
mean and standard deviation. 
Categorical, qualitative variable summaries will include the frequency and percentage of 
patients/entries, who/which are in particular categories.  
The assumed overall type I error rate/significance level for the primary and secondary 
efficacy parameters is 5%, two-sided. Two-sided confidence limits will be evaluated at 

 
 
 
  
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95%, p-values from inferential tests comparing patient cohorts/patient subgroups will be 
compared to 5%.  
Missing values will not be substituted by estimated values. All statistical evaluations will 
be based in valid cases except for procedures described for calculating response rates 
or in case of censoring within Kaplan-Meier methodology. In case of incomplete start or 
stop dates of AEs or concomitant medication appropriate conservative imputation 
methods will be specified in the statistical analysis plan (SAP). 
Baseline values will be defined as the last pre-administration observation used for 
calculating post-administration changes from baseline. 
    
5.2 
RATIONALE FOR SAMPLE SIZE 
 
Summing up, for our study the sample size is sufficient to reach the difference close to 
20%-25% with statistical power between 80%-90% and alpha = 5%.  
 
We used the article by Hern [41]  containing sample size tables for phase II of clinical trials 
based on the exact binomial distribution. We decided to use it because the Fleming’s 
procedure  based on a normal approximation is technically incorrect for small clinical trials 
like ours. Table below shows the part of the table from [41]  adequate for our study.  
 
 
 
 

 
 
 
  
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In the table above p0 is the highest level of efficacy (proportion in control group), p1 – 
minimal required level of efficacy (proportion in the intervention group). The trial tests the 
null hypothesis H0: P ≤ p0 against the alternative hypothesis H1: P ≥p1. Red box shows the 
proper lines. If we assume 20% difference in the response rate (p1 = 80%) then we need 
45 patient among whom 33 will be healthy after the treatment with alpha = 5% and 
statistical power = 90%. Higher difference e.g. 25% (p1 = 85%) requires 27 patients in the 
trial with 21 patient healthy after the treatment (alpha = 5% and statistical power = 90%).  
The green box shows the sample size similar to our study (n = 35) with difference equal 
to 20% and alpha = 5% with statistical power = 80%.  
5.3 
ANALYSIS POPULATIONS 
All efficacy and safety analysis will be performed using the treated population, which 
consists of all subjects who receive any amount of study treatment.  The analysis of 
MRD negative CR will only include subjects who have achieved complete response. 
5.4 
MISSING DATA HANDLING 
No imputation of values for missing data will be performed except that missing or partial 
start and end dates for AEs and concomitant medication will be imputed according to 
prespecified, conservative imputation rules.  Subjects lost to follow-up (or drop out) will 
be included in statistical analyses to the point of their last evaluation. 
5.5 
ENDPOINT DATA ANALYSIS 
5.5.1 
Efficacy Endpoint(s) 
The primary efficacy endpoints include overall response rate (ORR), complete response 
(CR) rate, and minimal residual disease (MRD) negative CR rate.  
Secondary endpoints include relapse incidence (RI), non-relapse mortality (NRM), 
progression free survival (PFS), overall survival (OS), duration of response (DOR). 
5.5.2 
Safety Endpoint(s) 
 
All safety variables will be analyzed for the safety population. The safety population 
includes all patients who will receive at least one dose of study medication. Incidence 
rates of AEs Grade  3 will be presented two-sided 95% Clopper Pearson Cis. 
All AE will be assessed according to the NCI-CTCAE, v5.0 grading system. 

 
 
 
  
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AE will be summarized according to the primary system-organ class (SOC) and within 
each SOC. 
AE grade 3 or higher, AEs related to acalabrutinib, AEs leading to treatment interruption 
or discontinuation, AEs of special interest and SAE will will be analyzed in a similar way 
to all AEs. Cause of death will be also summarized and listed. 
The number of patients prematurely discontinued from the treatment with corresponding 
reason for discontinuation will be summarized and listed. Discontinuation form the study 
will be also summarized and listed.  
Descriptive statistics will be presented for cumulative study medication doses, dose 
modifications and duration of exposure. 
ECG will be analyzed descriptively. 
Laboratory parameters, hematology and serum chemistry will be presented in shift 
tables of NCI-CTCAE, V5.0 grade at baseline versus worst grade during treatment 
period. The summary of laboratory parameters, presented by means, standard deviation, 
maximum and minimum will be also presented. Selected laboratory parameters will be 
also graphically presented over time, including ALT, AST and bilirubin. 
ECOG performance status will be summarized over time. 
5.5.3 
Exploratory Endpoints 
Immune cell populations will be presented as percentages and absolute values. The 
summary of immune parameters, presented by means, standard deviation, maximum 
and minimum will be presented. Selected laboratory parameters will be also graphically 
presented over time. The Wilcoxon paired test will be used to compare the results before 
during and after therapy. The Spearman rank correlation coefficient will be used in 
correlation tests. 
Cumulative incidence functions will be used to estimate aGvHD and cGvHD incidence in 
a competing risks setting, with death and relapse considered as competing events. 
Descriptive statistics will be presented for  donor chimerism evaluation. 
 
5.5.4 
Study Treatment Administration and Compliance 
Descriptive information will be provided regarding the number of acalabrutinib doses 
prescribed, the total number of doses taken, the number of days of treatment, and the 
number and timing of prescribed dose delay, reductions and interruptions.   

 
 
 
  
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For each subject, acalabrutinib compliance will be described in terms of the proportion of 
study drug actually taken. 
5.5.5 
Analysis of Efficacy Parameters 
Definitions for efficacy endpoints, are standard 
5.5.5.1 
Primary Efficacy Endpoint 
All primary endpoints will be analyzed in a descriptive way. Exact 95% CIs will be 
calculated for the objective response rate using Blythe-Still-Casella method. 
5.5.5.2 
Secondary Efficacy Endpoint 
PFS is defined as the time from first dose to documented disease progression, or death 
from any cause, whichever occurs first.  Data for subjects who are still alive and free 
from progression at the time of data cutoff date, lost to follow-up, have discontinued the 
study, or have initiated non-protocol anti-tumor therapy (NPT) will be censored on last 
assessment (or, if no post-baseline tumor assessment, at the time of first dose plus 1 
day).  Duration of PFS will be estimated using Kaplan-Meier methodology.  Approximate 
95% CIs for median duration of PFS will be computed using the formula proposed by 
Brookmeyer and Crowley.  
OS is defined as the time from first dose to death from any cause.  Data for subjects who 
are still alive at the time of data cutoff date, lost to follow-up, have discontinued the study 
(or, if no post-baseline assessment, at the time of first dose plus 1 day) will be censored 
at the date last known to be alive. Duration of OS will be estimated using Kaplan-Meier 
methodology.  Approximate 95% CIs for median duration of OS will be computed using 
the formula proposed by Brookmeyer and Crowley.  
For GRFS events are defined as grade 3-4 acute GVHD, chronic GVHD requiring 
systemic therapy, relapse, or death from any other reason. Duration of GRFS will be 
estimated using Kaplan-Meier methodology.  Approximate 95% CIs for median duration 
of GRFS will be computed using the formula proposed by Brookmeyer and Crowley.  
The RI and NRM will be calculated using cumulative incidence (CI) curves in a 
competing risks setting, death in remission being treated as a competing event to 
relapse. To estimate CI of acute or chronic GVHD, relapse and death will be considered 
competing events. 
 

 
 
 
  
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5.5.6 
Biomarker Analyses 
Additional PD, PK, and biomarker analyses may be performed, as deemed appropriate. 
Correlations between subject characteristics and outcome measures and correlations 
among outcomes measures will be explored using regression models or other 
appropriate techniques. 
6.0 
ASSESSMENT OF SAFETY 
Safety assessments will consist of monitoring and recording, AEs, and SAEs; 
measurements of protocol-specified hematology, clinical chemistry, urinalysis, and other 
laboratory variables; measurement of protocol-specified vital signs; and other protocol-
specified tests that are deemed critical to the safety evaluation of the study drug(s). 
6.1 
DEFINITIONS 
6.1.1 
Adverse Events 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational product, regardless of attribution.  This 
includes the following: 
• 
AEs not previously observed in the subject that emerge during the 
protocol-specified AE reporting period, including signs or symptoms associated 
with CLL, MCL or GvHD that were not present before the AE reporting period 
(see Section 4.3). 
• 
Pre-existing medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
• 
Abnormal laboratory values considered clinically significant by the investigator 
should be reported as an AE.   

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

 
 
 
  
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cannot be determined as exclusively due to the progression of the underlying 
malignancy, or if they do not fit the expected pattern of progression for the 
disease under study. 
If there is any uncertainty about an AE being due only to the disease under 
study, it should be reported as an AE or SAE. 
Symptomatic deterioration may occur in some subjects. Symptomatic deterioration is 
when progression is evident in the subject’s clinical symptoms and the investigator may 
elect not to perform further disease assessments.  If there is any uncertainty about an 
AE being due only to the disease under study, it should be reported as an AE or SAE.  
6.1.2 
Serious Adverse Event 
The terms “severe” and “serious” are not synonymous.  Severity (or intensity) refers to 
the grade of an AE (see below).  “Serious” is a regulatory definition and is based on 
subject or event outcome or action criteria usually associated with events that pose a 
threat to a subject’s life or functioning.  Seriousness (not severity) serves as the guide 
for defining regulatory reporting obligations from the Sponsor to applicable regulatory 
authorities. 
An AE should be classified as an SAE if it meets any 1 of the following criteria: 
• 
It results in death (ie, the AE actually causes or leads to death). 
• 
It is life-threatening (ie, the AE, in the view of the investigator, places the 
subject at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (ie, the AE results in 
substantial disruption of the subject’s ability to conduct normal life 
functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational product. 
• 
It is considered a significant medical event by the investigator based on 
medical judgment (eg, may jeopardize the subject or may require 
medical/surgical intervention to prevent 1 of the outcomes listed above). 

 
 
 
  
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6.1.3 
Severity 
Definitions found in the CTCAE version 4.03 or higher will be used for grading the 
severity (intensity) of AEs.  The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each referenced AE.  Should a subject experience any AE 
not listed in the CTCAE, the following grading system should be used to assess severity: 
• 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no 
special treatment, and not interfering with the subject’s daily activities 
• 
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 
• 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, 
significantly interrupt the subject’s usual daily activity, and require systemic 
drug therapy or other treatment 
• 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the 
subject to be in imminent danger of death 
• 
Grade 5 (Death related to AE) – experiences which result in subject death] 
6.2 
DOCUMENTING AND REPORTING OF ADVERSE AND SERIOUS 
ADVERSE EVENTS 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or 
reported during the study, as outlined in the prior sections, are recorded on the CRF.  
6.2.1 
Adverse Event Reporting Period 
The AE reporting period for this study begins when the subject receives the first dose of 
study drug and ends with the 30 days of the last acalabrutinib dose.  An exception to this 
reporting period is any AE occurring due to a protocol-defined screening procedure.  If 
any SAE occurs beyond 30 days after the last dose of acalabrutinib AND it is assessed 
by the investigator as related to acalabrutinib, it must be reported as an SAE. 
6.2.2 
Assessment of Adverse Events 
Investigators will assess the occurrence of AEs and SAEs at all subject evaluation 
timepoints during the study.  All AEs and SAEs whether volunteered by the subject, 

 
 
 
  
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discovered by study personnel during questioning, or detected through physical 
examination, or other means, will be recorded in the subject’s medical record and on the 
AE CRF.  
Disease progression itself is not considered an AE; however, signs and symptoms of 
disease progression may be reported as AEs if they cannot be determined as 
exclusively due to progression. 
Each recorded AE or SAE will be described by its diagnostic term, duration (eg, start and 
end dates), severity, regulatory seriousness criteria, if applicable, suspected relationship 
to the study drug (see following guidance), and any actions taken.  The relationship of 
AEs to the study drug will be assessed by means of the question: ‘Is there a reasonable 
possibility that the event may have been caused by the study drug?’ per FDA guidance 
on safety reporting requirements (FDA Guidance 2012).  
See Appendix 4 for more detail on assessing relationship. 
6.2.3 
Pregnancy 
 
 
Investigators should report all pregnancies and pregnancies in the partners of subjects 
to the Sponsor within 24 hours. The Sponsor should report all occurrences to the IRB 
and Regulatory Authorities per institutional and/or regulatory guidelines, and to Acerta 
Pharma per contractual guidelines.  
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  [2-day 
guidance applicable to acalabrutinib monotherapy only] after the last dose of study 
medication or 6 months after the alloSCT will be reported, followed to conclusion, and 
the outcome reported. 
Subjects should be instructed to immediately notify the investigator of any pregnancies.  
Any female subjects receiving study drug who become pregnant must immediately 
discontinue study drug [guidance applicable to acalabrutinib monotherapy only].  The 

 
 
 
  
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investigator should counsel the subject, discussing any risks of continuing the pregnancy 
and any possible effects on the fetus. 
6.2.4 
Expedited Reporting Requirements for Serious Adverse Events 
Investigators should report all SAEs to the Sponsor within 24 hours using the SAE 
Reporting Form. The Sponsor should report all SAEs to the IRB and Regulatory 
Authorities per institutional and/or regulatory guidelines, and to Acerta Pharma per 
contractual guidelines.  
Whenever possible, SAEs should be reported by diagnosis term not as a constellation of 
symptoms.  All deaths should be reported with the primary cause of death as the AE 
term, as death is typically the outcome of the event, not the event itself.  The primary 
cause of death on the autopsy report should be the term reported.   
If study drug is discontinued because of an SAE, this information must be included in the 
SAE report. 
 
6.2.5 
Type and Duration of Follow-up of Subjects after Adverse Events 
All AEs and SAEs that are encountered during the protocol-specified AE reporting period 
should be followed to resolution, or until the investigator assesses the subject as stable,  
or the subject is lost to follow-up or withdraws consent. 
 
 
7.0 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
The Sponsor retains the right to terminate the study and remove all study materials from 
a study site at any time.  Specific circumstances that may precipitate such termination 
are: 
• 
Unsatisfactory subject enrollment with regard to quality or quantity 
• 
Significant or numerous deviations from study protocol requirements, such as 
failures to perform required evaluations on subjects and maintain adequate study 
records 
• 
Inaccurate, incomplete and/or late data recording on a recurrent basis 

 
 
 
  
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• 
The incidence and/or severity of AEs in this or other studies indicating a potential 
health hazard caused by the study treatment 
7.1 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS 
COMMITTEE 
The investigator will submit this protocol, the informed consent, current Investigator’s 
Brochure, and any other relevant supporting information (eg, all advertising materials) to 
the appropriate IRB/IEC for review and approval before study initiation. Amendments to 
the protocol must also be approved by the IRB/IEC and local regulatory agency, as 
appropriate, before the implementation of changes in this study. 
This clinical study was designed and will be implemented in accordance with the 
protocol, the International Conference on Harmonisation (ICH) Harmonised Tripartite 
Guidelines for Good Clinical Practices, applicable local regulations (including US Code 
of Federal Regulations (CFR) Title 21 and European Directive 2001/20/EC), and the 
ethical principles laid down in the Declaration of Helsinki. 
7.2 
INFORMED CONSENT AND PROTECTED SUBJECT HEALTH 
INFORMATION AUTHORIZATION 
The investigator, or designee, must explain to each subject the purpose and nature of 
the study, the study procedures, the possible adverse effects, and all other elements of 
consent as defined in § 21 Code of Federal Regulations (CFR) Part 50, and other 
applicable national and local regulations governing informed consent form.  Each subject 
must provide a signed and dated informed consent before enrollment into this study.  In 
the case of a subject who is incapable of providing informed consent, the investigator (or 
designee) must obtain a signed and dated informed consent form from the subject’s 
legal guardian.  Signed consent forms must remain in each subject’s study file and be 
available for verification by study monitors at any time. 
In accordance to individual local and national subject privacy regulations, the 
investigator or designee must explain to each subject that for the evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with regulatory agencies and IRBs/IECs. It is the investigator’s or designee’s 
responsibility to obtain written permission to use protected health information from each 
subject, or if appropriate, the subject’s legal guardian.  If a subject or subject’s legal 
guardian withdraws permission to use protected health information, it is the investigator’s 

 
 
 
  
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responsibility to obtain the withdrawal request in writing from the subject or subject’s 
legal guardian and to ensure that no further data will be collected from the subject.  Any 
data collected on the subject before withdrawal will be used in the analysis of study 
results. 
7.3 
SUBJECT SCREENING LOG 
The investigator will keep a record that lists all subjects considered for enrollment 
(including those who did not undergo screening) in the study.  For those subjects 
subsequently excluded from enrollment, record the reason(s) for exclusion. 
7.4 
CASE REPORT FORMS 
Authorized study site personnel will complete CRFs designed for this study according to 
the completion guidelines that will be provided.  The investigator will ensure that the 
CRFs are accurate, complete, legible, and completed promptly.    
7.5 
INVESTIGATIONAL STUDY DRUG ACCOUNTABILITY 
Acalabrutinib capsules must be kept in a limited access cabinet or space.  The study 
drug must not be used outside the context of the protocol.   
7.6 
RECORD RETENTION 
The investigator and other appropriate study staff are responsible for maintaining all 
documentation relevant to the study.  Mandatory documentation includes copies of study 
protocols and amendments, each Form FDA 1572, IRB/IEC approval letters, signed 
ICFs, drug accountability records, SAE information, subject files (source documentation) 
that substantiate entries in CRFs, all relevant correspondence and other documents 
pertaining to the conduct of the study. 
The investigator shall retain study records in accordance with institutional and/or 
national/local regulations, whichever is longer. 

 
 
 
  
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8.0 
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Clin Oncol, 2007. 25(5): p. 579-86. 
32. 
Sorror, M.L., et al., Long-term outcomes among older patients following 
nonmyeloablative conditioning and allogeneic hematopoietic cell 
transplantation for advanced hematologic malignancies. JAMA, 2011. 
306(17): p. 1874-83. 
33. 
Holtan, S.G., et al., Composite end point of graft-versus-host disease-free, 
relapse-free survival after allogeneic hematopoietic cell transplantation. 
Blood, 2015. 125(8): p. 1333-8. 

 
 
 
  
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34. 
Owen, C., et al., Use of minimal residual disease assessment in the 
treatment of chronic lymphocytic leukemia. Leuk Lymphoma, 2017. 
58(12): p. 2777-2785. 
35. 
Kovacs, G., et al., Minimal Residual Disease Assessment Improves 
Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia 
(CLL) Who Achieve Partial Response: Comprehensive Analysis of Two 
Phase III Studies of the German CLL Study Group. J Clin Oncol, 2016. 
34(31): p. 3758-3765. 
36. 
Dreger, P., et al., Allogeneic stem cell transplantation provides durable 
disease control in poor-risk chronic lymphocytic leukemia: long-term 
clinical and MRD results of the German CLL Study Group CLL3X trial. 
Blood, 2010. 116(14): p. 2438-47. 
37. 
Algrin, C., et al., Flow cytometry minimal residual disease after allogeneic 
transplant for chronic lymphocytic leukemia. Eur J Haematol, 2017. 98(4): 
p. 363-370. 
38. 
Hallek, M., Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk 
stratification, and treatment. Am J Hematol, 2015. 90(5): p. 446-60. 
39. 
Thompson, P.A. and W.G. Wierda, Eliminating minimal residual disease 
as a therapeutic end point: working toward cure for patients with CLL. 
Blood, 2016. 127(3): p. 279-86. 
40. 
Hoster, E. and C. Pott, Minimal residual disease in mantle cell lymphoma: 
insights into biology and impact on treatment. Hematology Am Soc 
Hematol Educ Program, 2016. 2016(1): p. 437-445. 
41. 
A'Hern, R.P., Sample size tables for exact single-stage phase II designs. 
Stat Med, 2001. 20(6): p. 859-66. 
 

 
 
 
  
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APPENDICES

 
 
 
 
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Appendix 1.  Schedule of Assessments 
 
Screening 
Treatment period 
Before alloSCT 
At alloSCT 
After alloSCT 
Study month 
-1 - 0 
1 
2 
3 
4 
5 
6 
 
1,3,6,9,12,15,18 
Physical 
examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Medical history, 
including AE, 
SAE data 
collection 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rai staging 
x 
 
 
 
 
 
 
 
 
ECOG 
performance 
status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs 
(pulse, BP, 
temp.) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
 
 
Urine or serum 
pregnancy test 
x 
 
 
 
 
 
 
x 
12 months after 
allo-SCT 
FBC 
x 
x 
x 
x 
x 
x 
x 
x 
x 
U&E and LFT1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HBV, HCV, HIV 
serology2 
x 
 
 
 
 
 
 
 
 
Serum 
immunoglobulins 
(IgG, IgM, IgA) 
x 
 
 
x 
 
 
x 
x 
x 
ß2-microglobulin 
x 
 
 
 
 
 
 
 
 
Coombs test 
x 
 
 
 
 
 
 
 
 
Urine analysis 
x 
 
 
 
 
 
 
 
 
FISH panel, p53 
mutation status* 
x 
 
 
 
 
 
 
 
 

 
 
 
 
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IgVH mutation 
status* 
x 
 
 
 
 
 
 
 
 
Tumor 
evaluation 
(imaging 
studies) 
x 
 
 
x 
 
 
x 
x 
see 3.1.1 for 
details 
MRD 
assessment by 
flow cytometry* 
x 
 
 
x 
 
 
x 
x 
x 
Chimerism 
 
 
 
 
 
 
 
 
Until full donor 
chimerism 
Immune 
parameters 
evaluation by 
flow cytometry* 
x 
 
 
x 
 
 
x 
x 
x 
Blood samples 
for additional 
assessments 
x 
 
 
x 
 
 
x 
x 
x 
 (*) – procedures performed by the central lab.  

 
 
 
 
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(1) – U&E and LFT include: calcium, chloride magnesium, phosphate/phosphorus, 
potassium, sodium ALT, AST,  total bilirubin albumin, alkaline phosphatase, , 
bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, lactate dehydrogenase 
(LDH),total protein, and uric acid.   
 
(2) – hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), anti-
HBc, and HCV antibody 
 
 

 
 
 
 
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Appendix 2.  Performance Status Scores  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able 
to carry out work of a light or sedentary nature, eg, light house 
work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours 
4 
Completely disabled.  Cannot carry on any self-care. Totally 
confined to bed or chair 
5 
Dead 
As published in Am J Clin Oncol: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
Credit: Eastern Cooperative Oncology Group Chair: Robert Comis, MD 
Available at: http://www.ecog.org/general/perf_stat.html.  Accessed 23 August 2013. 
 
 
 
 

 
 
 
 
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Appendix 3.  Known Strong in Vivo Inhibitors or Inducers of CYP3A 
Strong Inhibitors of CYP3Aa 
Strong Inducers of CYP3Ad 
boceprevir 
carbamazepinee 
clarithromycinb 
phenytoine 
conivaptinb 
rifampine 
indinavir 
St John's worte  
itraconazoleb 
 
ketoconazoleb 
 
lopinavir/ritonavirb (combination drug) 
 
mibefradilc 
 
nefazodone 
 
nelfinavir 
 
posaconazole 
 
ritonavirb 
 
saquinavir 
 
telaprevir 
 
telithromycin 
 
voriconazole 
 
  
a. A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate by ≥ 
5-fold. 
b. In vivo inhibitor of P-glycoprotein. 
c. Withdrawn from the United States market because of safety reasons. 
d. A strong inducer is defined as an inducer that results in ≥ 80% decrease in the AUC 
of a substrate. 
e. In vivo inducer of P-glycoprotein.   
Note: The list of drugs in these tables is not exhaustive.  Any questions about drugs 
not on this list should be addressed to the Sponsor of the protocol. 
Source: FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers . Web link Accessed 11 June 2015: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm#inVivo 

 
 
 
 
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Appendix 4.  Adverse Event Assessment of Causality 
 
Is there a reasonable possibility that the event may have been caused by study drug?  
No___ Yes___ 
The descriptions provided below will help guide the principal investigator in making the 
decision to choose either “yes” or “no”: 
No = There is no reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
may be judged to be due to extraneous causes such as disease or environment 
or toxic factors 
• 
may be judged to be due to the subject’s clinical state or other therapy being 
administered 
• 
is not biologically plausible 
• 
does not reappear or worsen when study drug is re-administered 
• 
does not follow a temporal sequence from administration of study drug 
Yes = There is a reasonable possibility that the event may have been caused by study 
drug. 
The adverse event: 
• 
follows a temporal sequence from administration of study drug 
• 
is a known response to the study drug based on clinical or preclinical data 
• 
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 
• 
disappears or decreases upon cessation or reduction of dose of study drug 
• 
reappears or worsens when study drug is re-administered 
 

 
 
 
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Appendix 5 IWCLL Response evaluation (according to Hallek) 
 
Definition of response, relapse and refractory disease  
Assessment of response should include a careful physical examination and evaluation of 
the blood and bone marrow. The timing of response assessment for therapies with a 
defined treatment duration (such as chemoimmunotherapeutic approaches) should be at 
least 2 months after completion of therapy. To define the response to therapy, two 
groups of parameters need to be assessed and documented: parameters of group A 
assess the lymphoid tumor load and constitutional symptoms, while parameters of group 
B assess the hematopoietic system (Table).  
For continued therapies or treatment strategies that contain a maintenance phase, the 
assessment of response should be performed at least 2 months after patients achieve 
their maximum response or at a time point that is predefined in the protocol; in this case, 
it is not necessary to interrupt therapy for response assessment. Maximum response 
can be defined as a treatment phase where no additional improvement is seen during at 
least 2 months of therapy. In clinical trials, any response (e.g. CR, PR) should be 
sustained for at least 2 months prior to using this response in the assessment. In 
addition, where appropriate, a further assessment of response (i.e. marrow assessment) 
may be performed at least 2 months after the patient has cleared minimal residual 
disease from the peripheral blood.  
1. Complete remission (CR) requires all of the following criteria (Table 4):  
1.1. Peripheral blood lymphocytes (evaluated by blood and differential count) below 
4.000/μl (4x10
9
/L).  
1.2. Absence of significant lymphadenopathy by physical examination. In clinical trials, a 
CT scan of the neck, abdomen, pelvis and thorax is desirable if previously abnormal. 
Lymph nodes should be < 1,5 cm in longest diameter. Once this is determined, further 
imaging should not be required until disease progression is apparent by clinical 
examination or on blood testing.  
1.3. No splenomegaly or hepatomegaly by physical examination. In clinical trials, a CT 

 
 
 
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scan of the abdomen should be performed at response assessment and should show no 
evidence for lymphadenopathy and splenomegaly. We propose to use a recent 
consensus response cutoff for splenomegaly of 13 cm in cranio-caudal length.96,97 
However, the persistence of splenomegaly may not correlate with outcome.96 The 
quantitative determination of hepatomegaly seems more difficult; changes such as focal 
or disseminated hepatic nodules support liver involvement.  
1.4. Absence of disease-related constitutional symptoms. 5.1.5. Blood counts above the 
following values:  
1.5.1. Neutrophils 1.500/μL. 5.1.5.2. Platelets 100.000/μL. 5.1.5.3. Hemoglobin 
11,0 g/dL (without red blood cell transfusions).  
1.6. Minimal residual disease assessment.  
In clinical trials aimed at maximizing the depth of remission, the presence of minimal 
residual disease (MRD) after therapy should be assessed (see section 5.9.). The 
sensitivity of the method used to evaluate for MRD should be reported, as should be the 
tissue studied (blood or marrow). The proportion of patients achieving undetectable 
MRD should be reported with the total number of patients treated with the specific 
therapy as the denominator (not as a proportion of responders or those in complete 
remission).  
1.7. For patients in clinical trials (Table 3): a bone marrow aspirate and biopsy should be 
performed if clinical and laboratory results listed in 5.1.1 to 5.1.5 demonstrate that a CR 
may have been achieved. To define a CR, the cytological or pathological evaluation of 
the bone marrow smear or biopsy must be at least normocellular for age, without 
evidence for typical CLL lymphocytes by morphological criteria. This evaluation is not 
based on a flow cytometry- based MRD assessment (see section 9).  
In a clinical trial, the time point of marrow biopsy should be defined by the protocol. For 
example, in patients receiving chemo(immuno)therapy, the time point of marrow biopsy 
is typically 2 months post therapy.  
When performing marrow biopsies in clinical trials, lymphoid nodules can be found that 
may reflect residual disease.98,99 These nodules may be recorded as “nodular PR”. 

 
 
 
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Immunohistochemistry may be performed to define whether the nodules are comprised 
primarily of T cells, of B cells other than CLL cells or of CLL cells. If nodules are not 
composed of CLL cells, a CR can be documented provided all other criteria are met. If 
the marrow is hypocellular, a repeat determination should be performed after 4 weeks or 
later, when peripheral blood counts have recovered. However, this time interval should 
not exceed 6 months after the last treatment. In cases, where a marrow biopsy was 
obtained at baseline, a comparison of pre- versus post-therapy biopsies should be 
performed. In general practice, the use of a marrow biopsy for evaluating a CR is at the 
discretion of the physician.  
In clinical trials aimed at maximizing the response rate, the quality of the response 
should be assessed in the marrow for MRD by highly sensitive molecular based assays 
or immunophenotyping (see section 5.9.).  
1.8. Some patients fulfill all the criteria for a CR (including the marrow examinations 
described in 5.16), but have a persistent anemia, thrombocytopenia or neutropenia 
apparently unrelated to CLL, but related to drug toxicity. These patients should be 
considered as a different category of remission, CR with incomplete marrow recovery 
(CRi). For the definition of this category, CRi, the marrow evaluation (see 5.1.7) should 
be performed with scrutiny and not show any clonal disease infiltrate. In clinical trials, 
CRi patients should be monitored prospectively to determine whether their outcome 
differs from that of patients with detectable residual disease or with non-cytopenic CR.  
2. To define a partial remission (PR), at least one parameter of group A and one 
parameter of group B need to improve, if previously abnormal (see Table 4 and sections 
5.2.1-5). If only one parameter of both groups A and B was abnormal prior to therapy, 
only 1 needs to improve. Constitutional symptoms persisting for more than 1 month 
should be recorded.  
2.1. A decrease in the number of blood lymphocytes to 50% or less from the value prior 
to therapy.  
2.2. Reduction in lymphadenopathy compared to baseline (by cross-sectional imaging 
scans in clinical trials or by palpation in general practice) as defined by:  
2.2.1 A decrease in lymph node size by 50% or more in  

 
 
 
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• 
the sum of the products of the same enlarged lymph nodes selected at 
baseline as assessed by imaging (an established number in clinical trials 
of lymph nodes has been up to 6).   
• 
and the sum of longest diameters of the same enlarged lymph nodes 
selected at baseline as assessed by physical exam (an established 
number in clinical trials of lymph nodes has been a maximum of 6).  
2.2.2 No increase in any lymph node, and no new enlarged lymph node (diameter 1,5 
cm). For small lymph nodes (longest diameter < 1,5 cm), an increase of < 25% is not 
considered to be significant.  
2.3. A regression of 50% of the extent of enlargement of the spleen below the costal 
margin defined by palpation, or normalization in size. When assessed by CT, scan 
spleen size must have regressed by 50% in length beyond normal.96 A persistence of 
splenomegaly post therapy may have limited influence on outcome in CLL.96  
2.4. A regression of 50% of the extent of enlargement of the liver below the costal 
margin defined by palpation, or normalization in size. Given the impact of numerous 
medical conditions, liver size by physical examination or by CT scan is not a reliable 
measure of hepatic involvement by CLL and should only be counted if hepatomegaly is 
clearly attributable to lymphoid involvement.  
2.5. The blood count should show one of the following results:  
2.4.1. Platelet counts greater than 100.000/μL or 50% improvement over baseline.  
2.4.2. Hemoglobin greater than 11,0 g/dL or 50% improvement over baseline without red 
blood cell transfusions or erythropoietin support.  
3. Progressive disease (PD) during or after therapy is characterized by at least one of 
the following, when compared to nadir values (Table 4):  
3.1. Lymphadenopathy: Progression of lymphadenopathy is often discovered by physical 
examination and should be recorded at regular intervals. In CLL, the use of imaging (CT 
scans) usually does not add much information for the detection of progression or 
relapse.100 Disease progression occurs, if one of the following events below is 

 
 
 
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observed:  
• Appearance of any new lesion such as enlarged lymph nodes ( 1,5 cm), 
splenomegaly, hepatomegaly or other organ infiltrates. Transient increases of 
lymph node size during treatment with novel inhibitors may occur and should not 
be counted as PD.   
• An increase by 50% or more in greatest determined diameter of any previous site ( 
1,5 cm).   
3.2. An increase in the spleen size by 50% or more or the de novo appearance of 
splenomegaly. In the setting of splenomegaly, the splenic length must increase by 50% 
of the extent of its prior increase beyond baseline (e.g., a 15-cm spleen must increase to 
16 cm). If no prior splenomegaly was observed at baseline or if splenomegaly has 
resolved with treatment, the spleen must increase by at least 2 cm from baseline.   
3.3. An increase in the liver size of 50% of the extent enlargement of the liver below the 
costal margin defined by palpation, or the de novo appearance of hepatomegaly. Given 
the impact of numerous medical conditions, liver size by physical examination or by CT 
scan is not a reliable measure of hepatic involvement by CLL and should only be 
counted if hepatomegaly is clearly attributable to lymphoid involvement.   
3.4. An increase in the number of blood lymphocytes by 50% or more with at least 5.000 
B- lymphocytes per μL. Certain therapies (for example kinase inhibitors) may cause 
lymphocytosis. In the setting of therapy with such agents, an increase in blood 
lymphocyte count, by itself, does not uniformly indicate an increased tumor burden, but 
may reflect re- distribution of leukemia cells from lymphoid tissues to the blood. This 
should be pre-defined in the protocol of clinical trials for therapies where re-distribution 
of disease occurs. In such cases, increased lymphocytosis alone is not a sign of 
treatment failure or progressive disease.  
.3.5. Transformation to a more aggressive histology (Richter syndrome or Richter 
transformation). The diagnosis of Richter transformation should be established by lymph 
node or other tissue biopsy.  
3.6. Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) directly 

 
 
 
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attributable to CLL and unrelated to autoimmune cytopenias.  
3.6.1 During therapy: cytopenias may occur as a side effect of many therapies and 
should be assessed according to Table 5. During therapy, cytopenias cannot be used to 
define disease progression. Each protocol should define the amount of drug(s) to be 
administered with such cytopenias.  
3.6.2. Post treatment: The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of Hb levels by 2 g/dl or to < 10 g/dl, or by a 
decrease of platelet counts by 50% or to < 100.000/μl, which occurs at least 3 months 
after treatment, defines disease progression, if the marrow biopsy is consistent with the 
cytopenia due to increased marrow infiltration of clonal CLL cells and is not considered a 
treatment related toxicity.  
4. Stable disease: Patients who have not achieved a CR or a PR, and who have not 
exhibited PD, will be considered to have stable disease (which is equivalent to a non-
response).  
5. Treatment failure: Responses that should be considered clinically beneficial include 
CR and PR; all others (e.g. stable disease, non-response, progressive disease, or death 
from any cause) should be rated as a treatment failure.  
6. Time to next treatment, progression-free survival, event-free survival, and overall 
survival.  
“Progression-free survival” (PFS) is defined as the interval between the first treatment 
day (in phase III trials: day of randomization for intent-to-treat analysis) to the first sign of 
disease progression or death from any cause.  
“Event-free survival” (EFS) is defined as the interval between the first treatment day (in 
phase III trials: day of randomization for intent-to-treat analysis) to the first sign of 
disease progression or start of a new treatment or withdrawal from the trial due to 
toxicity or death (whichever occurs first).  
“Overall survival” (OS) is defined as the interval between the first treatment day (in 
phase III trials: day of randomization for intent- to-treat analysis) to death. “Time to next 
treatment” is defined as interval between the first treatment day until the patient starts an 

 
 
 
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alternative therapy for progressive CLL.  
Please note that the response duration may be assessed during therapy for continuous 
treatment, in particular with oral agents, as well as after the end of treatment, in 
particular with chemo(immuno)therapy. Study protocols should provide detailed 
specifications of the planned time points for the assessment of the treatment response 
under continuous therapy. Response durations of less than six months are not 
considered clinically relevant (see refractory disease, 8.).  
7. Relapse  
Relapse is defined as evidence of disease progression (see 3) in a patient who has 
previously achieved the above criteria of a CR or PR (5.1-5.2) for a period of 6 or more 
months.  
8. Refractory disease  
Refractory disease is defined as treatment failure (as defined in 5.5) or as progression 
within 6 months from the last dose of therapy.  
9. Minimal residual disease  
The complete eradication of the leukemia is a desired endpoint. Use of sensitive 
multicolor flow cytometry, PCR, or next-generation sequencing can detect minimal 
residual disease (MRD) in many patients who achieved a complete clinical response. 
Prospective clinical trials have provided substantial evidence that therapies that are able 
to eradicate MRD usually result in an improved clinical outcome. The techniques for 
assessing MRD have undergone a critical evaluation and have become well 
standardized. Six-color flow cytometry (MRD flow), allele-specific oligonucleotide PCR or 
high-throughput sequencing using the ClonoSEQ assay are reliably sensitive down to a 
level of less than one CLL cell in 10.000 leukocytes.108 Refinement and harmonization 
of these technologies has established that a typical flow cytometry-based assay 
comprises a core panel of six markers (i.e. CD19, CD20, CD5, CD43, CD79b and 
CD81). As such, patients will be defined as having undetectable MRD (MRD- neg) 
remission if they have blood or marrow with less than one CLL cell per 10.000 
leukocytes. The blood generally can be used for making this assessment, as the marrow 
will have detectable CLL when it is also found in the peripheral blood. However, there 

 
 
 
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are therapies that preferentially clear the blood but not the marrow (such as monoclonal 
antibodies). Therefore, it may be important to confirm that the marrow aspirate also is 
MRD-neg when the blood is found to be MRD-neg. Clinical trials aimed at maximizing 
the depth of remissions should include at least one test to assess for MRD, because the 
lack of leukemia persistence using these sensitive tests has a strong, positive prognostic 
impact. The report should be clear as to whether blood and/or marrow have been 
assessed and should report the proportion of MRD-neg patients on an intent-to-treat 
basis using the total number of patients in that treatment arm as the denominator (not 
those assessed or those who responded to treatment).  
Table Appendix 5  - Response definition after treatment for CLL patients  
Group  
PARA-
METER  
CR  
PR  
PD  
 
SD  
A  
   
Lymph 
nodes  
None 1,5 cm  
Decrease 50% 
(from baseline) 1)  
  
Increase 50% 
from baseline or 
from response  
Change of - 
49% to 
+49%  
Liver 
and/or 
spleen 
size*  
Spleen size < 13 
cm; liver size 
normal  
Decrease 50% 
(from baseline)  
  
Increase 50% 
from baseline or 
from response  
  
Change of - 
49% to 
+49%  
Constitutio
nal 
symptoms  
None  
Any  
Any  
 
Any  
Circulating 
lymphocyt
e count  
Normal  
Decrease 50% 
from baseline  
Increase 50% 
over baseline  
Change of - 
49% to 
+49%  
B  
     
Platelet 
count  
100.000/μl  
  
100.000/μl or 
increase 50% 
over baseline  
   
Decrease of 
50% from 
baseline 
secondary to 
CLL  
Change of - 
49 to +49%  
Hemoglobi
n  
11,0 g/dl 
(untransfused and 
without 
erythropoietin)  
11 g/dl or 
increase 50% 
over baseline  
   
Decrease of 2 
g/dl from 
baseline 
secondary to 
Increase < 
11,0 g/dl or 
< 50% over 
baseline, or 
decrease < 

 
 
 
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CLL  
2 g/dl  
Marrow  
Normocellular, no 
CLL cells, no B- 
lymphoid nodules.  
Presence of CLL 
cells, or of B- 
lymphoid 
nodules, or not 
done  
Increase of CLL 
cells by 50% 
on successive 
biopsies  
No change 
in marrow 
infiltrate  
 
 
1) Sum of the products of 6 or less lymph nodes (as evaluated by CT scans and physical 
exam in clinical trials, or by physical exam in general practice).  
 
 
Table 6. Response Definitions for Clinical Trials [31]