A Phase 2 Study of Ibrutinib as Neoadjuvant Therapy in Patients With Localized Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Washington University School of Medicine

 
 
 
A PHASE 2 STUDY OF IBRUTINIB AS NEOADJUVANT THERAPY IN PATIENTS 
WITH LOCALIZED PROSTATE CANCER 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol Number:  201808057 
Version Date: 05 November 2021 
 
Principal Investigator:  
Russell K. Pachynski, M.D. 
 
Phone: (314) 286-2341 
E-mail: rkpachynski@wustl.edu  
 
 
 
 
 
 
Sub-Investigators 
 
 
 
Modality 
Gerald Andriole, M.D. 
 
 
Medical Oncology 
Arnold Bullock, M.D. 
 
 
Medical Oncology 
Robert Figenshau, M.D. 
 
 
Medical Oncology 
Eric Kim, M.D. 
 
 
 
Medical Oncology 
Eric Knoche, M.D.  
 
 
Medical Oncology 
Joel Picus, M.D. 
 
 
 
Medical Oncology 
 
Bruce Roth, M.D. 
 
 
 
Medical Oncology 
Yu Tao, Ph.D. 
 
 
 
Biostatistics 
 
 
 
 
 
 
Study Drug:  
 
Ibrutinib 
 
IND#: 
127936 
IND Sponsor: 
Russell K. Pachynski, M.D. 
NCT#: 
NCT02643667 
Funded by: 
 
 
Pharmacyclics 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 

 
Version 11/05/2021  
Page 2 of 65 
A PHASE 2 STUDY OF IBRUTINIB AS NEOADJUVANT THERAPY IN PATIENTS 
WITH LOCALIZED PROSTATE CANCER 
 
Protocol Revision History 
Version 1.0 
 
08/10/15 
Version 1.1 
 
03/08/16 
Version 2.0 
 
04/02/18 
Version 3.0 
 
05/03/18 
Version 3.1 
 
05/30/18 – not submitted 
Version 3.2 
 
06/15/18 – not submitted 
Version 3.3 
 
07/02/18 – not submitted 
Version 3.4 
 
08/01/18 
Version 4.0 
 
10/16/18 
Version 5.0 
 
05/17/19 
Version 6.0 
 
12/30/19 
 
 
 
 
Version 7.0 
 
03/22/21 
Version 8.0 
 
11/05/2021 

 
Version 11/05/2021  
Page 3 of 65 
Abstract 
Title 
A phase 2 study of ibrutinib as neoadjuvant therapy in patients with 
localized prostate cancer 
Patient population 
Prostate cancer patients scheduled for radical prostatectomy (RP) 
Rationale for Study 
30-40% of patients who undergo RP with curative intent for their localized 
prostate cancer experience relapse of their disease. Thus, improved 
therapeutic approaches are needed in this patient population. Enhancing 
the patient’s anti-tumor immune response prior to surgery may improve 
long-term outcomes following RP. 
 
Tumor-infiltrating B cells are increased in prostate cancer tissue, and high 
intra-tumoral density of B cells correlate with higher stage of disease and 
greater potential for recurrence or progression (Woo JR et al, 2014). 
Unpublished data from UCSF’s laboratory have shown that T cells within 
the prostate that are associated with B cell aggregates lack T cell activation 
markers. Recently, preclinical studies showed that ibrutinib, a potent 
inhibitor of Bruton’s tyrosine kinase (BTK) but also an inhibitor of 
interleukin-2 inducible T-cell kinase (ITK) enhances T-cell mediated 
antitumor immunity when combined with PD-L1 blockade (Sagiv-Barfi I et 
al, 2015).  
 
Btk has also been found to be overexpressed in prostate cancer cells, 
which correlates with cancer grade, and the knockdown of Btk expression 
inhibits the growth of prostate cancer cells in vitro (Guo W et al, 2014). 
Therefore, inhibition of Btk may also have direct anti-tumor activity in 
prostate cancer. In this study, the immunomodulatory and cytotoxic effects 
of ibrutinib will be studied in patients with localized prostate cancer in the 
neoadjuvant setting. 
Primary Objective 
• 
To assess safety in patients with localized prostate cancer. 
• 
To characterize B and T cell infiltration within prostate tissue of men 
with localized prostate cancer treated with neoadjuvant ibrutinib, and 
to compare B and T cell infiltration to a reference population of 
untreated patients who underwent RP. 
Secondary Objectives 
• 
To characterize changes in the frequency and number of circulating B 
and T cells induced by neoadjuvant ibrutinib in patients with localized 
prostate cancer. 
• 
To determine the cytotoxic effect and clinical benefit (pathologic T0 at 
time of RP) of neoadjuvant ibrutinib in men with localized prostate 
cancer. 
Exploratory Objectives 
• 
To examine Btk expression in prostate tumor cells and tumor-
infiltrating B cells. 
• 
To determine the impact of neoadjuvant ibrutinib on PD-L1 expression 
in prostate cancer cells and tumor-infiltrating lymphocytes (TILs). 
• 
To determine the effects of neoadjuvant ibrutinib on T and B cell 
repertoire within the tumor and blood. 
 
 
 
 
 

 
Version 11/05/2021  
Page 4 of 65 
Study Design 
This is a phase 2 study of neoadjuvant ibrutinib in men with localized 
prostate cancer undergoing RP as their initial locally directed therapy with 
curative intent. In the safety lead-in phase, a cohort of 6 patients will be 
treated with ibrutinib 840 mg/d x 4 weeks to assess safety and adverse 
events (AEs). If no more than 2 out of 6 patients experience dose limiting 
toxicities (DLT), the study will continue accruing. DLTs will be assessed 
during the safety lead-in phase only, during treatment with ibrutinib and the 
period prior to RP.  To assess the immune response following neoadjuvant 
treatment, tissue from RP specimen will be compared to tissue from core 
biopsy specimen obtained prior to treatment, with each subject serving as 
his own control. Immune infiltration will also be compared to a reference 
cohort of 12 patients who had undergone RP, matched to the study 
population using the UCSF CAPRA-S score. 
Number of patients 
Three patients were enrolled at UCSF in an 840 mg/d x 2 weeks cohort; 
no DLTs occurred.  At WUSM, a safety lead-in of 6 patients will be accrued 
at the 840 mg/d x 4 week dose level. In the event that no DLTs are 
encountered, an additional 18 patients will be enrolled for a total of 24 
patients at the 840 mg/d x 4 week dose level. A full safety assessment will 
be carried out after the first 10 patients have completed the phase 2 study 
(6 in the safety lead-in + 4), and accrual will be suspended if 3 or more of 
these 10 patients experience grade 3 or 4 treatment-related toxicity.  
 
If RP is delayed over 12 days after the last dose of ibrutinib therapy (i.e. 
from scheduling delay of RP), a replacement patient will be accrued. The 
maximum number of allowed replacement patients is 4 (see Section 12.4). 
Duration of Therapy 
All patients will receive ibrutinib for 4 weeks prior to RP. RP will be 
performed 7 to 12 days after the last dose of ibrutinib. 
Duration of Follow up 
All patients will be followed for 4 weeks after RP. 
Duration of study 
The study will conclude when the last patient has completed his 4–week 
follow-up after RP. The anticipated duration of study is 18-24 months. All 
treatment related adverse events will be followed until resolution or 
stabilization to grade <2. 
Study Drugs 
Ibrutinib, also known as PCI-32765 and marketed under the name 
Imbruvica, is a small molecule irreversible Btk inhibitor that has shown 
clinical efficacy in B cell malignancies by blocking BCR signaling. Btk 
inhibitors may prove to be efficacious for other cancers where B cells and 
BTK signaling contribute necessary mechanisms for tumor growth, 
including immunomodulatory mechanisms. The dose of 840 mg x 4 weeks 
has been established as safe in solid tumors. 
 
The dose level for the phase 2 study is 840 mg/d x 4 weeks. In the event 
that DLTs are encountered in 2 or more of the initial 6 patients, dose de-
escalation with cohort of 6 per dose level are as follows: 
Level -1: 840mg x 2 weeks 
Level -2: 560mg x 2 weeks 

 
Version 11/05/2021  
Page 5 of 65 
Safety Assessments 
Safety will be assessed by reviewing adverse events (AEs), laboratory 
evaluations, and by physical examination. The NCI CTCAE v4.03 will be 
used. All AEs and serious AEs (SAEs) that occur on study drug or within 
30 days after the last dose of study drug, will be recorded on case report 
forms (CRFs) from enrollment through 4 weeks post-surgery.  
 
The study will be halted if 4 of the first 4, or 5 of the first 9, or 6 of the first 
14, or 7 of the first 18, or 8 of the first 23, or if the 9th non-hematological 
toxicity is observed before the last patient has completed the trial. Accrual 
will be stopped and the event will be reviewed by the Data Safety and 
Monitoring Board if a grade 5 non-hematological toxicity is observed. 
Efficacy Assessments 
For the primary endpoints, toxicities will be assessed according to NCI 
CTCAE v.4.03 and changes in B cell infiltration within prostate tissue 
between core biopsy and RP specimen will be quantified using 
immunohistochemistry (IHC). A positive result is considered to be >2 fold 
decrease in the number of B cell infiltration. 
 
For the secondary endpoints, immune subsets including B and T cells will 
be analyzed in the blood via flow cytometry, and in the core biopsy and RP 
specimens via IHC. 
Unique Aspects of this 
Study 
This is the first study to evaluate the safety of ibrutinib and its effect on B 
cell infiltration in the neoadjuvant setting for patients with localized prostate 
cancer. The secondary and exploratory objectives will enhance our 
understanding of the immunomodulatory and cytotoxic effects of Btk 
inhibition in prostate cancer. Findings may justify further exploration of 
ibrutinib in prostate cancer, including combinational therapy in advanced 
prostate cancer. 
 
 
 

 
Version 11/05/2021  
Page 6 of 65 
 
List of Abbreviations 
5-HT 
5-hydroxytryptamine (serotonin) 
ADL 
activity of daily living 
ADT 
androgen deprivation therapy 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
B-CLL 
B-cell chronic lymphocytic leukemia 
BCR 
B-cell receptor 
Breg 
B regulatory cells  
BSA 
body surface area 
BTK 
Bruton’s tyrosine kinase 
BUN 
blood urea nitrogen 
CAPRA 
Cancer of the Prostate Risk Assessment 
CBC 
complete blood cell (count) 
CHR 
Committee on Human Research (UCSF IRB) 
CpG 
cytosine-phosphate-guanine 
CNS 
central nervous system 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CrCl 
creatinine clearance 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTL 
cytotoxic T lymphocyte  
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CTMS 
Clinical Trial Management System 
CYP 
cytochrome P450 
DFS 
disease-free survival 
DL 
dose level 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose limiting toxicity 
D2 
dopamine receptor D2 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
EC50 
median effective concentration 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FL 
follicular lymphoma 
GCP 
Good Clinical Practice 
g/dL 
gram per deciliter 
Hb 
Hemoglobin 
HBcAb 
Hepatitis B core antibody  
HBeAg 
Hepatitis B “e” antigen 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 

 
Version 11/05/2021  
Page 7 of 65 
List of Abbreviations 
HBV 
hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HED 
human equivalent dose 
HGB 
Hemoglobin 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure  
IC50 
concentration that inhibits a process by 50% 
ICH 
International Conference on Harmonization 
IHC 
immunohistochemistry  
IND 
investigational new drug application 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LHRH 
luteinizing hormone releasing hormone 
LLN 
lower limit of normal 
LMWH 
low molecular weight heparin 
MCL 
Mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mL 
milliliter  
MM 
multiple myeloma 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
nM 
nanomolar 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
non-small cell lung carcinoma 
ORR 
overall response rate 
OTC 
over the counter 
PBMC 
peripheral blood mononuclear cells 
PD 
disease progression 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PK 
pharmacokinetics 
Plt 
platelet (count) 
PML 
progressive multifocal encephalopathy 
PO 
Per os (by mouth, orally) 
PR 
partial response 
RP 
radical prostatectomy 
PRC 
Protocol Review Committee (UCSF) 
PSA 
prostate specific antigen 
pT0 
pathologic complete response 
PT 
prothrombin time  
PTT 
partial thromboplastin time 
QOL 
Quality of Life 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cell (count) 

 
Version 11/05/2021  
Page 8 of 65 
List of Abbreviations 
SAE 
serious adverse events  
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SIP-T 
sipuleucel-T 
SLL 
small lymphocytic lymphoma 
SJS 
Stevens-Johnson Syndrome  
t1/2 
half-life 
TCR 
T-cell receptor  
TILs 
tumor infiltrating lymphocytes 
Tmax 
time to maximum concentration 
TPC 
Tissue Procurement Core 
ULN 
upper limit of normal 
μL 
microliter 
WBC 
white blood cell (count) 
WM 
Waldenstrom’s macroglobulinemia 
 
 
 
 

 
Version 11/05/2021  
Page 9 of 65 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 

 
Version 11/05/2021  
Page 10 of 65 
Table of Contents 
Abstract 
3 
List of Abbreviations ....................................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................... 12 
1.1 
Background on Indication ................................................................................... 12 
1.2 
Ibrutinib ............................................................................................................... 12 
1.3 
Rationale for the Proposed Study ........................................................................ 20 
1.4 
Rationale for Study Design ................................................................................. 21 
1.5 
Correlative Studies .............................................................................................. 21 
2 
OBJECTIVES AND ENDPOINTS OF THE STUDY ........................................................... 22 
2.1 
Objectives ............................................................................................................ 22 
2.2 
Endpoints of the Study ........................................................................................ 22 
3 
STUDY DESIGN ................................................................................................................ 23 
3.1 
Characteristics ..................................................................................................... 23 
3.2 
Number of Subjects ............................................................................................. 24 
3.3 
Eligibility Criteria ................................................................................................ 24 
3.4 
Duration of Therapy ............................................................................................ 26 
3.5 
Duration of Follow Up ........................................................................................ 26 
4 
REGISTRATION PROCEDURES...................................................................................... 27 
4.1 
Confirmation of Patient Eligibility ...................................................................... 27 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ................ 27 
4.3 
Assignment of UPN ............................................................................................. 27 
4.4 
UCSF Patients ..................................................................................................... 27 
5 
STUDY DRUGS ................................................................................................................. 27 
5.1 
Ibrutinib ............................................................................................................... 27 
6 
TREATMENT PLAN .......................................................................................................... 28 
6.1 
Dosage and Administration ................................................................................. 28 
6.2 
Dose Modifications for an Individual Patient Regardless of Dose Cohort ......... 30 
6.3 
Monitoring and Toxicity Management ................................................................ 31 
7 
REGULATORY AND REPORTING REQUIREMENTS ..................................................... 35 
7.1 
Sponsor-Investigator Reporting Requirements ................................................... 36 
7.2 
Exceptions to Expedited Reporting ..................................................................... 39 
8 
STUDY PROCEDURES AND OBSERVATIONS .............................................................. 39 
8.1 
Schedule of Procedures and Observations .......................................................... 39 
8.2 
Schedule of Study Procedures and Assessments ................................................. 43 
8.3 
Usage of Concurrent/Concomitant Medications ................................................. 44 
8.4 
Dietary Restrictions ............................................................................................. 44 
8.5 
Prohibited Medications/Therapies ....................................................................... 45 
8.6 
Restricted Medications ........................................................................................ 45 
8.7 
Guidelines for Ibrutinib Management with Surgeries and Procedures ............... 46 
9 
REPORTING AND DOCUMENTATION OF RESULTS ..................................................... 46 
9.1 
Evaluation of Activity ......................................................................................... 46 
9.2 
Evaluation of Safety ............................................................................................ 47 

 
Version 11/05/2021  
Page 11 of 65 
10 
DATA AND SAFETY MONITORING ................................................................................. 48 
11 
DATA SUBMISSION SCHEDULE ..................................................................................... 48 
11.1 
Adverse Event Collection in the Case Report Forms .......................................... 49 
12 
STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS ........................... 49 
12.1 
Study Endpoints .................................................................................................. 49 
12.2 
Study Design ....................................................................................................... 49 
12.3 
Sample Size and Power Estimate ........................................................................ 49 
12.4 
Replacement Policy ............................................................................................. 50 
12.5 
Stopping Rules .................................................................................................... 50 
12.6 
Analyses Plans ..................................................................................................... 51 
12.7 
Reference Population .......................................................................................... 52 
12.8 
Evaluation of Safety ............................................................................................ 53 
12.9 
UCSF’s Data ........................................................................................................ 53 
13 
REFERENCES .................................................................................................................. 54 
APPENDIX 1: PERFORMANCE STATUS CRITERIA .............................................................. 56 
APPENDIX 2: Prohibited and Restricted Medications .............................................................. 57 
APPENDIX 3:  SPECIMEN COLLECTION ............................................................................... 58 
APPENDIX 4:  CHILD-PUGH SCORE ...................................................................................... 59 
APPENDIX 5: Definitions for Adverse Event Reporting .............................................................. 60 
APPENDIX 6: Reporting Timelines ............................................................................................... 0 
 
 
 

 
Version 11/05/2021  
Page 12 of 65 
1 
INTRODUCTION 
 
1.1 
Background on Indication 
 
Prostate cancer is the most common malignancy and the second leading cause of cancer-
related death in men in Western countries. In the United States, 233,000 new cases were 
diagnosed and nearly 30,000 men died from prostate cancer in 2014 (Siegel R et al, 2014). 
While surgery and radiotherapy are potentially curative treatments in patients with 
localized prostate cancer, treatment failure rates reach 35-40% (Han M et al, 2001; Kuban 
DA et al, 2003). Neoadjuvant androgen deprivation therapy (ADT) in combination with 
surgery or radiation have been investigated to reduce treatment failure rates (Goldenberg 
SL et al, 1996; Van Poppel H et al, 1995). While these studies have shown that 
neoadjuvant ADT decreases the proportion of patients with positive margins at surgery, 
neoadjuvant ADT has not translated into significant benefit in meaningful clinical endpoints 
such as progression-free survival (PFS) or overall survival (Scolieri MJ et al, 2000). 
Neoadjuvant therapy thus remains an investigational approach. 
 
The clinical efficacy of immunotherapies in the treatment of advanced human 
malignancies, and the positive impact on survival of sipuleucel-T (Sip-T) in men with 
advanced prostate cancer (Kantoff PW et al, 2010) has led to the investigation of the role 
of immunotherapy in the neoadjuvant setting. In a recently completed phase II study of 
neoadjuvant Sip-T for localized prostate cancer (Fong L et al, 2014), patients received 3 
infusions of Sip-T at 2 week intervals beginning 6-7 weeks prior to RP. Neoadjuvant Sip-
T was safe and tolerable, and did not impact surgery.  Importantly, significant increases in 
CD3+ and CD4+ T cells were observed in the prostatectomy specimens, suggesting that 
a tumor-specific immune response can be induced via this approach. 
 
While cancer immunotherapies have largely been focused at inducing T cell mediated 
anti-cancer immune response, with strategies including cancer vaccines and immune 
checkpoint blockade, B cells have recently been increasingly appreciated to play an 
inhibitory role on antitumor immune responses. B regulatory cells (Bregs) secrete the anti-
inflammatory cytokine IL-10 and inhibit cytotoxic T lymphocyte (CTL) activity. In addition, 
a significant role for B cells as promoters of tumorigenesis is their ability to inhibit TH1 and 
cytotoxic CD8+ T cell mediated anti-tumor immunity (Gunderson AJ et al, 2013). Targeting 
B cells in cancers in which B cells contribute necessary mechanisms for tumor growth may 
therefore prove to be a tractable strategy. 
 
1.2 
Ibrutinib 
 
Ibrutinib is a first-in-class, orally administered, potent inhibitor of Bruton’s tyrosine kinase 
(BTK), a mediator of critical B-cell signaling pathways implicated in the pathogenesis of 
B-cell malignancies. Ibrutinib (IMBRUVICA®) is approved for the treatment of (1) mantle 
cell lymphoma (MCL) in patients who have received at least one prior therapy, (2) chronic 
lymphocytic leukemia (CLL) in patients who have received at least one prior therapy, (3) 
CLL in patients with 17p deletion, (4) Waldenström’s Macroglobulinemia, (5) marginal 
zone lymphoma (MZL) in patients who required systemic therapy and have received at 
least one prior anti-CD20-based therapy, and (6) adult patients with chronic GVHD after 
failure of one or more lines of systemic therapy. Ibrutinib covalently binds to the cysteine-
481 amino acid of BTK and inhibits various processes, including ERK signaling, NF-κB 
DNA binding, cytosine-phosphate-guanine (CpG)-mediated CLL-cell proliferation, and 

 
Version 11/05/2021  
Page 13 of 65 
tumor-cell migration. At concentrations relevant to exposure levels in patients, ibrutinib 
demonstrates remarkable selectivity in the inhibition of BCR signaling over TCR signaling. 
 
1.2.1 Nonclinical studies: Ibrutinib 
 
1.2.1.1 
Pharmacokinetics and Metabolism 
 
Following oral administration of ibrutinib at doses ranging from 420 to 840 
mg/day, exposure to ibrutinib increased proportionally with substantial 
intersubject variability. The mean terminal plasma elimination half-life (t1/2) 
of ibrutinib ranged from 4 to 6 hours, with a median time to maximum 
plasma concentration (Tmax) of 1 to 2 hours. Despite the doubling in mean 
systemic exposure when dosed with food, the favorable safety profile of 
ibrutinib allows dosing with or without food. Ibrutinib is extensively 
metabolized primarily by cytochrome P450 (CYP) 3A4-mediated metabolic 
pathways. The on-target effects of metabolite PCI-45227 are not 
considered clinically relevant. Steady-state exposure of ibrutinib and PCI-
45227 was less than 2-fold of first dose exposure implying non-clinically 
relevant accumulation. About 8% of ibrutinib is excreted in the urine. 
Ibrutinib exposure is not altered in patients with creatinine clearance (CrCl) 
> 30 mL/min. Patients with severe renal impairment or patients on dialysis 
have not been studied. Following single dose administration, the AUC of 
ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh 
class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) 
hepatic impairment compared to subjects with normal liver function. A 
higher proportion of Grade 3 or higher adverse reactions were reported in 
patients with B-cell malignancies (CLL, MCL and WM) with mild hepatic 
impairment based on NCI organ dysfunction working group (NCI-ODWG) 
criteria for hepatic dysfunction compared to patients with normal hepatic 
function.   
 
For the most up to date and comprehensive pharmacokinetics (PK) and 
product metabolism information regarding ibrutinib, please refer to the 
current IB. 
 
1.2.1.2 
Toxicology 
 
In safety pharmacology assessments, no treatment-related effects were 
observed in the central nervous system or respiratory system in rats at any 
dose tested. Further, no treatment-related corrected QT interval (QTc) 
prolongation effect was observed at any tested dose in a cardiovascular 
study using telemetry-monitored dogs.  
 
Based on data from rat and dog including general toxicity studies up to 13 
weeks duration, the greatest potential for human toxicity with ibrutinib is 
predicted to be in lymphoid tissues (lymphoid depletion) and the 
gastrointestinal tract (soft feces/diarrhea with or without inflammation). 
Additional toxicity findings seen in only one species with no observed 
human correlate in clinical studies to date include pancreatic acinar cell 
atrophy (rat), minimally decreased trabecular and cortical bone (rat) and 
corneal dystrophy (dog).  

 
Version 11/05/2021  
Page 14 of 65 
 
In vitro and in vivo genetic toxicity studies showed that ibrutinib is not 
genotoxic. In a rat embryo-fetal toxicity study ibrutinib administration was 
associated with fetal loss and malformations (teratogenicity) at ibrutinib 
doses that result in approximately 6 times and 14 times the exposure 
(AUC) in patients administered the dose of 560 mg daily, respectively.  
 
1.2.1.3 Pharmacology 
 
Ibrutinib was evaluated in vitro for its ability to inhibit purified BTK and 
selected members of the closely related Tec and Src/Ab1 family kinases. 
The concentration that inhibits kinase activity by 50% (IC50) for BTK and 
other kinases are listed in Table 1.2.1. With only a few exceptions, a 10-
fold or greater selectivity was demonstrated for BTK relative to the off-
target kinases. 
 
Table 1.2.1 Median IC50 Values of Ibrutinib toward Selected Tec and 
Src/Ab1 Family Kinases 
Kinase 
Median IC50 (nM) 
Selectivity for BTK 
Btk* 
0.39 
1.0 
ErbB4/HER4* 
0.64 
1.6 
Blk* 
0.94 
2.4 
Bmx/Etk* 
1.10 
2.8 
Fgr 
2.86 
7.3 
Txk* 
2.87 
7.4 
Lck 
3.49 
9.0 
Yes/YES1 
3.94 
10 
Tec* 
5.49 
14 
Csk 
6.17 
16 
EGFR* 
7.80 
20 
Brk 
10.10 
26 
Itk* 
11.70 
30 
Hck 
16.98 
44 
ErbB2/HER2* 
21.57 
55 
JAK3* 
21.90 
56 
 
*Kinases labeled with an asterisk (*) have a cysteine in the active site 
representing a possible target for covalent binding with ibrutinib.  
 
A cellular signal transduction assay conducted to investigate ibrutinib 
inhibition of BCR signaling showed concentration-dependent inhibition of 
autophosphorylation of BTK by ibrutinib (IC50 = 11nM), phosphorylation of 
the physiological substrate of BTK, PLCγ (IC50 = 29nM), and 
phosphorylation of a further downstream kinase, ERK (IC50 = 13nM). The 

 
Version 11/05/2021  
Page 15 of 65 
phosphorylation of Syk, which functions upstream or in parallel to BTK, was 
not affected (Honigberg et al, 2010).  
 
Ibrutinib inhibited the proliferation of DLBCL patient derived cell lines with 
a median effective concentration (EC50) of 1 or 2nM. Ibrutinib reduced 
proliferation of primary CLL cells at concentrations of 500nM and 1000nM. 
Nonclinical primary pharmacodynamics studies have shown that orally 
administered ibrutinib inhibits tumor growth in human tumor xenograft 
murine models. Maximum ibrutinib growth inhibition of OCI-Ly10 xenograft 
tumors (81% to 140%) occurred with a once-daily oral gavage dose of 
12mg/kg/day. 
 
Based on preclinical data, the blockade of BCR signaling pathway by 
ibrutinib in CLL has 2 major effects: (1) direct induction of apoptosis and 
(2) inhibition of cell homing and migration to chemokines and subsequent 
adhesion to cellular substrates (Herman et al, 2011; de Rooij et al, 2012). 
In preclinical models, ibrutinib caused a transient early lymphocytosis and 
profoundly inhibited CLL progression, as assessed by weight, development 
of hepatomegaly, and survival. Similarly, in human subjects with CLL, 
ibrutinib 
clinical 
activity 
(resolution 
of 
lymphadenopathy 
and/or 
organomegaly) was accompanied by a transient increase in lymphocyte 
counts, which presumably is due to an egress of tissue-resident CLL cells 
into the blood. 
 
No treatment-related effects were observed in rat in vivo central nervous 
system (CNS) and respiratory safety pharmacology studies. No treatment-
related QT interval corrected for heart rate (QTc) prolongation effect was 
observed in a cardiovascular study in telemetry-monitored dogs. However, 
oral administration of ibrutinib in dogs at dose levels of 24mg/kg or more 
was associated with increased PR interval, lowered heart rate and QTc 
shortening, with a no-observed-adverse-effect level (NOAEL) of 24 
mg/kg/day. 
 
1.2.2 Clinical studies: Ibrutinib 
 
In healthy subjects and in patients with B-cell malignancies, ibrutinib is readily 
absorbed, with a median time to maximum concentration (Tmax) of 1 to 2 hours and 
half-life of 4 to 6 hours. Exposure increases proportionally with dose. Ibrutinib is 
primarily metabolized by cytochrome P450, CYP3A. Strong and moderate 
inhibitors of CYP3A, as well as strong CYP3A inducers should be avoided (See 
Section 7.6 for restricted medications). Ibrutinib is rapidly cleared mainly in the 
form of metabolites, and is eliminated primarily via feces with ~80% recovered 
mostly within 2 days.  
 
In the current clinical development program, ibrutinib is being evaluated in over 26 
ongoing and 9 completed company-sponsored clinical studies in healthy 
volunteers and in subjects with recurrent B-cell lymphomas, including chronic 
lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell 
lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma 
(DLBCL), multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM), and 
marginal zone lymphoma (MZL). As of data cutoff date of April 6, 2014, safety data 

 
Version 11/05/2021  
Page 16 of 65 
from nonrandomized studies are available for 1,204 subjects treated with single 
agent ibrutinib (1,061 subjects plus 143 healthy volunteers) and for 136 subjects 
treated with ibrutinib combinations with immunotherapy and/or chemotherapy. In 
addition, one randomized comparator-controlled phase 3 study of ibrutinib 
monotherapy in subjects with CLL/SLL has undergone primary analysis in which 
195 subjects received ibrutinib and 191 subjects received ofatumumab. Seven 
additional phase 3 trials (1115, CLL3001, CLL3002, MCL3001, MCL3002, 
DBL3001 and FLR3001) in subjects with CLL/SLL or non-Hodgkin’s lymphoma 
(NHL) are ongoing. 
 
The clinical benefit of ibrutinib was first demonstrated in a phase 1 dose-escalation 
study of ibrutinib in subjects with recurrent B-cell lymphomas with overall response 
rates (ORRs) ranging from 85.7% in subjects with CLL/SLL and MCL to 33.3% in 
subjects with DLBCL. These findings were further demonstrated in subsequent 
phase 2 studies in subjects with previously treated MCL or CLL/SLL, and a 
randomized, comparator-controlled phase 3 pivotal study in subjects with 
previously treated CLL/SLL. Activity was also demonstrated in other histologies 
(FL, DLBCL, WM, FL, MZL, MM) and with combination therapy (fludarabine, 
cyclophosphamide, rituximab; bendamustine + rituximab; and ofatumumab). 
 
In pooled safety data for subjects treated with ibrutinib monotherapy in 11 
nonrandomized studies (1102, 1117, 1112 [crossover only], 1104, MCL2001, 
MCL4001, 1106, 1111, FLR2002, 04753, and JPN-101) with a median duration of 
treatment of 5.1 months (range 0.0 to 30.3 months), the most frequently reported 
treatment-emergent adverse events in >10% of subjects were diarrhea (35.9%), 
fatigue (28.6%), nausea (20.2%), cough (17.5%), and anemia (15.2%). The most 
frequently reported treatment-emergent adverse events related to ibrutinib in >5% 
of subjects were diarrhea (25.5%), fatigue (16.0%), nausea (11.7%), neutropenia 
(9.1%), and thrombocytopenia (8.2%). The most common treatment-emergent 
grade 3 or 4 AEs in >2% of subjects were neutropenia (10.7%), thrombocytopenia 
(6.2%), pneumonia (5.7%), anemia (5.5%), fatigue (2.9%), hypertension (2.7%) 
and atrial fibrillation (2.6%). Among the 1,061 subjects in the pooled analysis of 
monotherapy studies, 9.4% discontinued ibrutinib therapy due to an adverse event. 
The most frequently reported AEs leading to treatment discontinuation included 
infection (e.g., pneumonia [0.9%] and septic shock [0.4%]), disease progression 
(0.6%), 
acute 
renal 
failure 
(0.4%), 
respiratory 
failure 
(0.4%), 
and 
thrombocytopenia (0.4%). No subjects discontinued ibrutinib treatment due to 
diarrhea. Fatal AEs were reported in 9.9% of subjects. The most frequently 
reported fatal AEs included progressive disease, pneumonia (1.2%), sepsis 
(0.6%), respiratory failure (0.5%), cardiac arrest (0.4%), and plasma cell myeloma 
(0.4%). 
 
Safety data are available for one phase 3 randomized comparator controlled 
(ibrutinib vs. ofatumumab) study of ibrutinib monotherapy in subjects with CLL/SLL 
(ibrutinib: 195 subjects, ofatumumab: 191 subjects). As of Nov 6, 2013 data cutoff, 
the median exposure of ibrutinib was 8.6 months (range: 0.2 to 16.1). The most 
frequent treatment-emergent adverse events in >10% subjects were diarrhea 
(47.7%), fatigue (27.7%), nausea (26.2%), pyrexia (23.6%), anemia (22.6%), and 
neutropenia (21.5%). The most common treatment-emergent adverse events in 
>5% subjects were diarrhea (32.8%), nausea (15.9%), neutropenia (13.3%), 
arthralgia (11.3%), petechiae (11.3%), and fatigue (9.7%). The most common 

 
Version 11/05/2021  
Page 17 of 65 
treatment-emergent grade 3 or 4 AEs in >2% subjects were neutropenia (16.4%), 
pneumonia (6.7%), thrombocytopenia (5.6%), and anemia (4.6%). In this study, 
8.2% of subjects receiving ibrutinib discontinued study treatment due to an adverse 
event. The most frequently reported AE leading to study discontinuation in the 
ibrutinib arm was pneumonia. Fatal AEs were reported for 6.2% of subjects 
receiving ibrutinib. The most common AEs leading to death were pneumonia 
(1.5%), CLL disease progression (1.0%), and sepsis (1.0%).  
 
In pooled safety data for 143 healthy subjects receiving ibrutinib monotherapy in 7 
clinical studies (CLL1001, CLL1002, CLL 1004, CLL 1006, CLL 1008, CLL 1010, 
and CLL 10113), treatment-emergent adverse events were reported by 26.6% of 
subjects. The most frequently reported AEs by preferred term were headache 
(8.4%), diarrhea (6.3%), and abdominal pain (3.5%). No treatment-emergent 
grade 3 or 4 adverse events, SAEs, or fatal AEs were reported in healthy subjects. 
No healthy subjects discontinued study treatment due to AEs. 
 
Based on currently available data, ibrutinib has an acceptable safety profile as 
monotherapy and when combined with chemoimmunotherapy or immunotherapy. 
No maximum tolerated dose (MTD) was reached in the first-in-human (FIH) study 
(04753) using intermittent dosing cohorts up to 12.5mg/kg/day and continuous 
dosing of 560mg or with combination therapies (up to 560mg). Data from the 
randomized, comparator-controlled phase 3 pivotal study also demonstrated the 
safety and tolerability of ibrutinib in subjects with previously treated CLL/SLL when 
compared with ofatumumab.  
 
Based on positive early phase 1 and 2 data, the FDA granted Breakthrough 
Therapy Designation to ibrutinib as monotherapy for previously treated MCL, for 
WM and for CLL/SLL. In June 2014, ibrutinib (Imbruvica) was approved in the 
United States for the treatment of patients with MCL, and those with CLL, who 
have received at least 1 prior therapy.  
 
A full list of completed and ongoing clinical studies with ibrutinib as well as 
investigator sponsored trial studies with ibrutinib can be found in the investigator’s 
brochure (IB).  
 
Integrated safety data from a total of 1,523 subjects with B-cell malignancies 
treated with ibrutinib monotherapy in 17 studies that have completed primary 
analysis or final analysis included in the CSR as of the 31 July 2017 cutoff date for 
the current IB update in B-cell malignancies are summarized below.  
  
The most frequently reported treatment-emergent adverse events (TEAEs) in 
subjects receiving ibrutinib as monotherapy (N = 1,523): 
 
 

 
Version 11/05/2021  
Page 18 of 65 
 
Most frequently reported 
TEAEs >10% a 
Most frequently reported Grade 
3 or 4 TEAEs >2% a  
Most frequently reported 
Serious TEAEs >1% b  
Diarrhea 
Neutropenia 
Pneumonia 
Fatigue 
Pneumonia 
Atrial fibrillation 
Nausea 
Thrombocytopenia 
Pyrexia 
Cough 
Anemia 
Febrile neutropenia 
Pyrexia 
Hypertension   
Sepsis 
Anemia  
Diarrhea  
Cellulitis 
Upper respiratory tract infection 
 Neutropenia  
Atrial fibrillation 
Fatigue 
Pleural effusion 
Dyspnoea 
Oedema peripheral 
Neutrophil count decreased 
Urinary tract infection 
Thrombocytopenia    
Febrile Neutropenia 
Lung infection 
Muscle spasms 
Hyponatraemia 
Abdominal pain 
Constipation 
Hypokalaemia 
Acute kidney injury 
Arthralgia 
 
Amaemia 
Vomiting 
 
Respiratory failure 
Decrease appetite 
 
 
Dyspnoea 
 
 
Headache 
 
 
Pneumonia 
 
 
Rash 
 
 
Hypertension 
 
 
Abdominal pain 
 
 
Back pain 
 
 
Contusion 
 
 
Dizziness 
 
 
a Source is Table 5 of IB (v11), b Source is Table 6 of IB (v11) 
 
1.2.2.1 
Risks 
 
Bleeding-related Events   
There have been reports of hemorrhagic events in subjects treated with 
ibrutinib, both with and without thrombocytopenia. These include minor 
hemorrhagic events such as contusion, epistaxis, and petechiae; and 
major hemorrhagic events, some fatal, including gastrointestinal bleeding, 
intracranial hemorrhage, and hematuria. 
 
Initially, subjects were excluded from participation in specific ibrutinib 
Phase 2 and 3 studies if they required warfarin or other vitamin K 
antagonists. Warfarin or other vitamin K antagonists should not be 
administered concomitantly with ibrutinib unless specified in the protocol. 
Supplements such as fish oil and vitamin E preparations should be avoided 
In an in vitro platelet function study, inhibitory effects of ibrutinib on 
collagen-induced platelet aggregation were observed. Use of ibrutinib in 
subjects requiring other anticoagulants or medications that inhibit platelet 
function may increase the risk of bleeding. See Section 7.3.1 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy and/or 
supplements. Ibrutinib should be held at least 3 to 7 days pre- and post-
surgery, depending upon the type of surgery and the risk of bleeding. See 
Section 7.7 for guidance on ibrutinib management with surgeries or 
procedures. Patients with congenital bleeding diathesis have not been 
studied.  

 
Version 11/05/2021  
Page 19 of 65 
 
Infections  
Infections (including sepsis, bacterial, viral, or fungal infections) were 
observed in subjects treated with ibrutinib. Some of these infections have 
been associated with hospitalization and death. Consider prophylaxis 
according to standard of care in subjects who are at increased risk for 
opportunistic infections. Although causality has not been established, 
cases of progressive multifocal leukoencephalopathy (PML) and hepatitis 
B reactivation have occurred in subjects treated with ibrutinib. Subjects 
should be monitored for signs and symptoms (fever, chills, weakness, 
confusion, vomiting and jaundice) and appropriate therapy should be 
instituted as indicated. 
 
Cytopenias  
Treatment-emergent 
Grade 
3 
or 
4 
cytopenias 
(neutropenia, 
thrombocytopenia, and anemia) were reported in subjects treated with 
ibrutinib. Monitor complete blood counts monthly.  
 
Interstitial Lung Disease (ILD) 
Cases of interstitial lung disease (ILD) have been reported in subjects 
treated with ibrutinib. Monitor subjects for pulmonary symptoms indicative 
of ILD. If symptoms develop, interrupt ibrutinib and manage ILD 
appropriately. If symptoms persist, consider the risks and benefits of 
ibrutinib treatment and follow the protocol dose modification guidelines as 
needed. 
 
Atrial Fibrillations  
Atrial fibrillation and atrial flutter have been reported in subjects treated with 
ibrutinib, particularly in subjects with cardiac risk factors, acute infections, 
and a previous history of atrial fibrillation. Periodically monitor subjects 
clinically for atrial fibrillation. Subjects who develop arrhythmic symptoms 
(e.g., palpitations, lightheadedness) or new onset of dyspnea should be 
evaluated clinically, and if indicated, have an ECG performed. For atrial 
fibrillation which persists, consider the risks and benefits of ibrutinib 
treatment and follow the protocol dose modification guidelines. 
  
Tumor Lysis Syndrome 
Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects 
at risk of tumor lysis syndrome are those with high tumor burden prior to 
treatment. Monitor subjects closely and take appropriate precautions. 
 
Non-melanoma Skin Cancer 
Non-melanoma skin cancers have occurred in subjects treated with 
ibrutinib. Monitor subjects for the appearance of non-melanoma skin 
cancer.  
 
Diarrhea  
Diarrhea is the most frequently reported non-hematologic AE with ibrutinib 
monotherapy and combination therapy. Other frequently reported 
gastrointestinal events include nausea, vomiting, and constipation. These 
events are rarely severe and are generally managed with supportive 

 
Version 11/05/2021  
Page 20 of 65 
therapies including antidiarrheals and antiemetics. Subjects should be 
monitored carefully for gastrointestinal AEs and cautioned to maintain fluid 
intake to avoid dehydration. Medical evaluation should be made to rule out 
other etiologies such as Clostridium difficile or other infectious agents. 
Should symptoms be severe or prolonged follow the protocol dose 
modification guidelines. 
 
Rash 
Rash has been commonly reported in subjects treated with either single 
agent ibrutinib or in combination with chemotherapy. Most rashes were mild 
to moderate in severity. Isolated cases of severe cutaneous adverse 
reactions (SCARs) including Stevens-Johnson syndrome (SJS) have been 
reported in subjects treated with ibrutinib. Subjects should be closely 
monitored for signs and symptoms suggestive of SCAR including SJS. 
Subjects receiving ibrutinib should be observed closely for rashes and 
treated symptomatically, including interruption of the suspected agent as 
appropriate. 
In 
addition, 
hypersensitivity-related 
events 
including 
erythema, urticaria, and angioedema have been reported. 
 
Hypertension 
Hypertension has been commonly reported in subjects treated with 
ibrutinib. Monitor subjects for new onset of hypertension or hypertension 
that is not adequately controlled after starting ibrutinib. Adjust existing anti-
hypertensive medications and/or initiate anti-hypertensive treatment as 
appropriate. 
 
1.3 
Rationale for the Proposed Study 
 
Immunotherapy is an attractive strategy in the treatment of advanced human malignancies 
due to its potential to induce durable clinical responses and its low toxicity profile. 
Sipuleucel-T is the first FDA approved cancer vaccine for the treatment of patients with 
metastatic castrate resistant prostate cancer (CRPC) (Kantoff PW et al, 2010). Immune 
checkpoint antibodies targeting PD-1 and/or CTLA-4 have gained approval for the 
treatment of advanced melanoma and squamous NSCLC, and shows promise in a variety 
of other solid malignancies. While cancer immunotherapies have largely been focused at 
inducing T cell mediated anti-cancer immune response, B cells have recently been 
increasingly appreciated to play an inhibitory role on antitumor immune responses.  
 
Ibrutinib is a potent inhibitor of BTK, which mediates critical B-cell signaling pathways and 
is critical to the survival of malignant B cells. Tumor-infiltrating B cells are increased in 
prostate cancer tissue, and high intra-tumoral density of B cells correlates with higher 
stage of disease and greater potential for recurrence or progression (Woo JR et al, 2014). 
Unpublished data from our laboratory have shown that T cells within the prostate that are 
associated with B cell aggregates lack T cell activation markers. BTK also has inhibitory 
activity on other kinases including ITK, and essential enzyme in TH2 cells. Inhibition of 
BTK can therefore not only inhibit B cells but also potentially shift the balance between 
TH1 and TH2 cells and enhance antitumor immune response. Indeed, Ibrutinib has recently 
been shown to enhance anti-PD-L1 mediated antitumor activity in preclinical models of 
lymphoma, breast and colon cancer (Sagiv-Barfi I et al, 2015). We hypothesize that 
intratumoral B cells suppress anti-tumor immune responses in prostate cancer, and 
predict that ibrutinib reduces the frequency of intratumoral B cells and enhances 

 
Version 11/05/2021  
Page 21 of 65 
the recruitment and expansion of tumor-reactive T cells into the prostate.  
 
BTK has also been found to be overexpressed in prostate cancer cells, and its expression 
level correlates with cancer grade. Furthermore, knockdown of BTK expression inhibits 
the growth of prostate cancer cells in vitro (Guo W et al, 2014). We hypothesize that BTK 
not only has immunomodulatory effects but also may have direct anti-tumor activity 
in prostate cancer that overexpress BTK. The goals of this study are to study the 
immunomodulatory and cytotoxic effects of ibrutinib in patients with localized prostate 
cancer in the neoadjuvant setting. These findings may justify further exploration of ibrutinib 
in prostate cancer, including combination therapy in advanced prostate cancer. 
 
1.4 
Rationale for Study Design 
 
This study will evaluate the immunologic and cytotoxic changes induced by ibrutinib in 
prostate tissues compared to pretreatment biopsies. Three patients were enrolled at the 
840 mg/d x 2 weeks dose level at UCSF and no DLTs were seen.  A safety lead-in 
consisting of 6 patients will be enrolled at the 840 mg/d x 4 weeks dose level to evaluate 
the safety and tolerability of ibrutinib administered for 4 weeks preoperatively in patients 
scheduled for RP. If fewer than 2 DLTs are seen, an additional 18 patients will be treated 
with ibrutinib at the 840 mg/d x 4 weeks dose level before undergoing RP. 
 
The safety profile of ibrutinib is well established from multiple studies in subjects treated 
with single agent ibrutinib (1061 subjects with B cell malignancies, 143 healthy subjects). 
Ibrutinib is generally well tolerated, and treatment related adverse events are generally 
manageable. The rationale for studying ibrutinib at dose of 840mg is that the dose of 
ibrutinib required for activity in solid malignancies via immune modulation and/or direct 
cytotoxicity may be higher than 560mg, the dose currently approved for hematologic 
malignancies. In the phase 1 study of ibrutinib in relapsed or refractory B-cell NHL and B-
cell CLL, MTD was not reached after dose escalation form 2.5mg/kg/day to 12.5mg/kg/day 
(Advani RH et al. J Clin Oncol 2012). The phase 1b/2 study of ibrutinib in 
relapsed/refractory CLL or small lymphocytic lymphoma showed similar efficacy and 
toxicity profiles of ibrutinib administered at 420mg and 840mg (Byrd JC, et al. N Engl J 
Med 2013). Recently, interim data from an open label phase 2 study of ibrutinib combined 
with dexamethasone in relapsed/refractory multiple myeloma showed manageable 
toxicities at a dose up to 840mg (Vij R et al. ASH 2014). We therefore believe that the 
dose of ibrutinib 840mg will be well tolerated in patients with localized prostate cancer.  
 
1.5 
Correlative Studies 
 
This study aims to evaluate the immunomodulatory and cytotoxic effects of ibrutinib in 
prostate cancer patients by comparing their pre-treatment prostate biopsy tissue to post-
treatment prostatectomy tissue. Specifically, immunohistochemistry and genomic analysis 
will be carried out to analyze the following: 
1. Characterize the tumor and immune cell subsets 
2. Explore the location of tumor infiltration lymphocytes (e.g., tumor center, tumor and 
benign tissue interface) 
3. Characterize BCR and TCR clonality and diversity 
4. Examine PD-L1 expression in tumor and immune-infiltrating immune cells 
5. Examine Btk expression in B cells and tumor cells 
6. Assess rate of downstaging and pT0 rate 
7. Assess rate of PSA decline 

 
Version 11/05/2021  
Page 22 of 65 
 
In addition, serum and blood will be analyzed to characterize circulating immune cell 
subsets in response to treatment. 
 
 
2 
OBJECTIVES AND ENDPOINTS OF THE STUDY 
 
2.1 
Objectives 
 
2.1.1 Primary Objectives 
 
1. To assess safety in patients with localized prostate cancer. 
2. To characterize B and T cell infiltration within prostate tissue of men with 
localized prostate cancer treated with neoadjuvant ibrutinib, and to compare B 
and T cell infiltration to a reference population of untreated patients who 
underwent RP. 
 
2.1.2 Secondary Objectives 
 
1. To characterize changes in the frequency and number of circulating B and T 
cells induced by neoadjuvant ibrutinib in patients with localized prostate 
cancer. 
2. To determine the cytotoxic effect and clinical benefit of neoadjuvant ibrutinib in 
men with localized prostate cancer. 
 
2.1.3 Exploratory Objectives 
 
1. To examine Btk expression in prostate tumor cells and tumor-infiltrating B cells 
at baseline before neoadjuvant ibrutinib treatment and at RP after treatment. 
2. To determine the impact of neoadjuvant ibrutinib on PD-L1 expression in 
prostate cancer cells and tumor-infiltrating lymphocytes (TILs). 
3. To determine the effects of neoadjuvant ibrutinib on T and B cell repertoire 
within the tumor and blood. 
 
2.2 
Endpoints of the Study 
 
2.2.1 Primary Endpoints 
 
The primary endpoint of the safety-run in part is adverse events (AEs), especially 
dose limiting toxicity (DLT), as defined in Section 6.1.4.  
 
The primary endpoint of the phase II study include: the change in infiltration of 
CD20+ B cells, IL-10+ B cells, CD3+ T cells, CD8+ cytotoxic T cells, effector 
CD4+FOXP3- T cells, and CD4+FOX3+ T regulatory cells in pre-treatment biopsy, 
RP tissue, and reference RP tissue quantitated by immunohistochemistry (IHC). 
Patients will be considered to have a positive response if there is >2 fold decrease 
from pre-treatment to post-treatment, or considered to have a negative response 
if there is <2 fold decrease. The proportion of patients who have “positive” 
responses will be evaluated. 
 

 
Version 11/05/2021  
Page 23 of 65 
2.2.2 Secondary Endpoints 
 
The changes in the frequency and number of circulating CD19+ B cells, 
CD25highCD27highCD86high B regulatory cells, and CD3+, CD8+, CD4+FOXP3- and 
CD4+FOXP3+ T cells induced by neoadjuvant ibrutinib in patients with localized 
prostate cancer by flow cytometry. Patients will be considered to have a positive 
response if there is >2 fold decrease from pre-treatment to post-treatment, or 
considered to have a negative response if there is <2 fold decrease. The proportion 
of patients who have “positive” responses will be evaluated. 
 
The proportion of patients who achieve >50% PSA decline, pathologic down-
staging and/or pathologic T0 at RP after neoadjuvant ibrutinib in men with localized 
prostate cancer. 
 
2.2.3 Exploratory Endpoints 
 
To examine Btk expression in prostate tumor cells and tumor-infiltrating B cells in 
pre-treatment and post-RP tissue via immunohistochemistry with anti-Btk 
antibody. 
 
To examine the change in PD-L1 expression in prostate cancer cells and tumor-
infiltrating 
lymphocytes 
induced 
by 
neoadjuvant 
ibrutinib 
via 
immunohistochemistry with anti-PD-L1 antibody. 
 
To determine the change in T and B cell repertoire within the tumor and blood with 
neoadjuvant ibrutinib via deep sequencing of VDJ regions of TCRs and BCRs. 
 
 
3 
STUDY DESIGN 
 
3.1 
Characteristics 
 
This is a single center phase 2 open label study starting with a safety lead-in ibrutinib 
administered as neoadjuvant therapy in patients with localized prostate cancer. We 
believe that the dose of ibrutinib 840mg x 4 weeks will be well tolerated in patients with 
localized prostate cancer based on current trial data on ibrutinib but to ensure safety, we 
will start with a safety run-in. Previously at UCSF, 3 patients were enrolled to the 840 mg/d 
x 2 weeks dose level.  No DLTs were observed.  Beginning at WUSM, patients will be 
enrolled at the dose level of 840 mg/d x 4 weeks.  If there are fewer than 2 DLTs, the 
Phase II dose expansion study will open and enroll up to an additional 18 patients to be 
treated with ibrutinib 840mg PO daily for 4 weeks.  
If there are ≥2 DLTs in the safety lead-in, dosing will be de-escalated as follows: 
- 
Level -1: 840 mg/d x 2 weeks, followed by de-escalation if ≥ 2 DLTs to Level -2 
- 
Level -2: 560 mg/d x 2 weeks 
 
In each enrolled patient, neoadjuvant ibrutinib therapy will be followed by radical 
prostatectomy (RP) performed 7 to 12 days after the last dose of ibrutinib. Pre-treatment 
and RP tissue will be evaluated for immunologic characterization, Btk expression and 
pathologic response. The proportion of patients achieving ≥ 50% PSA decline will be 
assessed. Serum will also be obtained to characterize circulating immune response. All 
patients will be followed clinically for 4 weeks after RP to monitor for adverse events. 

 
Version 11/05/2021  
Page 24 of 65 
 
3.2 
Number of Subjects 
 
The safety lead-in part requires 6 patients at the 840 mg/d x 4 weeks dose level. The 
phase II study will require a total of 24 patients (6 in the safety lead-in plus an additional 
18). A sequential stopping rule is in place during Phase II (see Section 12.5).  
If RP is delayed to over 12 days after the last dose of ibrutinib therapy (i.e. from scheduling 
delay of RP), a replacement patient will be accrued. The maximum number of allowed 
replacement patients is 4 (see Section 12.4).  
 
To date, 3 patients have been enrolled and treated at UCSF (PI: L Fong) in Phase I/Cohort 
I (840 mg x 2 weeks) with no DLTs noted to date.   
 
3.3 
Eligibility Criteria 
 
Patients must have baseline evaluations performed prior to the first dose of study drug 
and must meet all inclusion and exclusion criteria. In addition, the patient must be 
thoroughly informed about all aspects of the study, including the study visit schedule and 
required evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient prior to enrollment. The following 
criteria apply to all patients enrolled onto the study unless otherwise specified. 
 
3.3.1 Inclusion Criteria 
 
1. 18 years of age or older 
2. ECOG performance status 0 or 1 
3. Histologically documented adenocarcinoma of the prostate 
4. Patients must be suitable for and willing to undergo a radical prostatectomy at 
the completion of study therapy. 
5. Adequate bone marrow function, defined as: 
o WBC >2,500 cells/mm3 
o ANC >1,500 cells/mm3 
o Hemoglobin >9 mg/dL 
o Platelet count >100,000 cells/mm3 
6. Adequate renal function, defined as serum creatinine <2 mg/dL or CrCl >30 
mL/min 
7. Adequate liver function, defined as: 
o AST and ALT <2.5x institutional ULN 
o Serum bilirubin <1.5x institutional ULN 
8. Adequate coagulation function, defined as normal PT/INR and PTT 
9. Ability to understand and willingness to sign a written informed consent 
document 
10. Available evaluable archival tumor tissue for correlative studies including 
assessment of immune infiltration and Btk expression is required. If archival 
tissue is unavailable, patients must be willing to undergo repeat prostate 
biopsy. Tissue is considered sufficient for correlative endpoint analyses if they 
are obtained from at least 2 prostate cores and consist of at least 15 unstained 
slides from the largest tumor volume and/or highest Gleason score. The 
availability of archival tissue or consent for repeat prostate biopsy is required 
for study eligibility; determination of tissue sufficiency is not required for study 

 
Version 11/05/2021  
Page 25 of 65 
eligibility. 
11. The effects of ibrutinib on the developing human fetus is unknown. Men treated 
or enrolled on this protocol must agree to use adequate contraception prior to 
the study, for the duration of the study participation, and for 3 months after 
completion of treatment. 
 
3.3.2 Exclusion Criteria 
 
1. Patients with neuroendocrine or small cell features are not eligible. 
2. Any evidence of metastatic disease. Pre-operative staging will be undertaken 
per urologic standard of care. 
3. Any prior use of hormonal therapy, including: 
o GNRH agonists or GNRH antagonists (e.g., leuprorelin, degarelix) 
o Antiandrogens (e.g., bicalutamide, flutamide, nilutamide) 
o Novel androgen-directed therapies (e.g., abiraterone, enzalutamide) 
o Any estrogen containing compounds 
o 5-alpha reductase inhibitors (e.g., finasteride, dutasteride) 
o PC-SPES or PC-x products. Other herbal therapies or supplements will be 
considered by the Principle Investigator on a case by case basis based on 
their potential for hormonal or anti-cancer therapies. 
4. Chemotherapy ≤ 21 days prior to first administration of study treatment and/or 
monoclonal antibody ≤ 6 weeks prior to first administration of study treatment 
5. Prior radiation therapy for prostate cancer 
6. Prior exposure to BTK inhibitors 
7. Prior investigational therapy for prostate cancer 
8. Patients may not receive any other concurrent investigational agents while on 
study. 
9. Use of systemic steroid therapy within 28 days of study screening. Patients on 
inhaled or topical steroids are eligible. 
10. Concurrent systemic immunosuppressive therapy within 21 days of the first 
dose of study drug. 
11. Major surgery requiring the use of general anesthetic within 4 weeks of study 
enrollment 
12. HIV, active hepatitis B (HBV) or active hepatitis C (HCV) 
o Patients with past HBV infection or resolved HBV infection, defined as the 
presence of hepatitis B core antibody (HBc Ab) and absence of hepatitis B 
surface antigen (HBsAg) are eligible. HBV DNA must be obtained in these 
patients prior to day 1 of ibrutinib therapy, but detection of HBV DNA in 
these patients will not exclude study participation. 
o Patients positive for HCV antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
13. Inability to swallow capsules or presence of malabsorption syndromes, disease 
significantly affecting gastrointestinal function, history of resection of the 
stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative 
colitis, or partial or complete small obstruction. 
14. Currently active, clinically significant cardiovascular disease, such as 
uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by 
the New York Heart Association Function Classification; or a history of 
myocardial infarction, unstable angina, or acute coronary syndrome within 6 
months prior to screening. 
15. Uncontrolled concurrent illness, or any underlying medical condition, which in 

 
Version 11/05/2021  
Page 26 of 65 
the Principal Investigator’s opinion will make the administration of ibrutinib 
hazardous or obscure the interpretation of adverse events. 
16. Recent infection requiring systemic treatment that was completed within 14 
days prior to the first dose of study drug 
17. Concurrent active malignancy other than non-melanoma skin cancers. Patients 
are considered to be free of active malignancy if they have completed curative 
therapy and have a <30% risk of relapse. 
18. History of congenital bleeding diathesis. 
19. Known bleeding disorders (e.g. von Willebrand’s disease or hemophilia). 
20. Concomitant use of anticoagulants including warfarin, other Vitamin K 
antagonists, and enoxaparin.  
21. Subjects who received a strong or moderate cytochrome P450 (CYP) 3A4 
inhibitor within 7 days prior to the first dose of ibrutinib or patients who require 
treatment with a strong or moderate cytochrome P450 (CYP) 3A inhibitor. 
22. Vaccination with live, attenuated vaccines within 4 weeks of first dose of study 
drug. 
23. Patients on anti-platelet agents including clopidogrel and glycoprotein IIb/IIIa 
inhibitors. Aspirin is allowed, but should be held before surgery according to 
standard practices. 
24. Currently active, clinically significant hepatic impairment Child-Pugh class B or 
C according to the Child-Pugh classification 
25. Any life-threatening illness, medical condition, or organ system dysfunction 
that, in the investigator’s opinion, could compromise the subject’s safety or put 
the study outcomes at undue risk. 
26. Unresolved toxicities from prior anti-cancer therapy, defined as having not 
resolved to CTCAE v 4.03 grade 0 or 1 or to the levels dictated in the eligibility 
criteria with the exception of alopecia. 
 
3.3.3 Inclusion of Minorities 
 
Members of all races and ethnic groups are eligible for this trial. 
 
3.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may continue until: 
• 
Administration of all planned doses is completed 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
Significant patient non-compliance with protocol 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 
3.5 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after radical prostatectomy. Patients removed from 
study for unacceptable treatment related adverse event(s) will be followed until resolution 
or stabilization of all treatment related adverse events to grade 2 or lower. 
 
 

 
Version 11/05/2021  
Page 27 of 65 
4 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name, and your institution name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
UCSF Patients 
 
The 3 patients enrolled at UCSF will be registered to the Siteman Cancer Center OnCore 
database, and UCSF will provide study data to the Washington University study team. 
 
 
5 
STUDY DRUGS 
 
5.1 
Ibrutinib 
 
Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. 
All formulation excipients are compendial and are commonly used in oral formulations. 
Refer to the ibrutinib Investigator's Brochure for a list of excipients.  
 
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles 
with labels bearing the appropriate label text as required by governing regulatory agencies. 
All study drug will be dispensed in child-resistant packaging.  
 

 
Version 11/05/2021  
Page 28 of 65 
Refer to the Pharmacy Manual/site investigational product manual for additional guidance 
on study drug storage, preparation and handling. 
 
Study drug labels will contain information to meet the applicable regulatory requirements. 
 
5.1.1 Classification 
 
Cytotoxic drug: molecular targeted cytotoxic drug 
 
5.1.2 Mechanism of Action 
 
Ibrutinib is a potent (IC50 0.39nM) orally bioavailable small-molecule inhibitor of 
Bruton’s tyrosine kinase (BTK). With only a few exceptions, a 10-fold or greater 
selectivity was demonstrated for BTK relative to off-target kinases. Upon oral 
administration, Ibrutinib binds to cysteine 481 of BTK and irreversibly inhibits BTK 
activity, thereby preventing both B-cell activation and B-cell mediated signaling. 
BTK is a member of the src-related BTK/Tec family of cytoplasmic tyrosine kinases 
that is required for B cell receptor signaling, plays a key role in B cell maturation, 
and is overexpressed in a number of B-cell malignancies. The expression of BTK 
in other tumors has also been associated with increased proliferation, including 
prostate cancer and breast cancer (Guo W et al, 2014; Eifert C et al, 2013).  
 
5.1.3 Contraindications 
 
Ibrutinib is contraindicated in subjects with clinically significant hypersensitivity, 
including anaphylactic and anaphylactoid reactions to the compound itself or to the 
excipients in its formulation. 
 
5.1.4 Availability 
 
Ibrutinib will be supplied by Pharmacyclics Inc. 
 
5.1.5 Storage and handling 
 
Ibrutinib capsules should be stored according to the storage conditions indicated 
on the label. The recommended storage condition for ibrutinib capsules is 15oC to 
25oC (59oF to 77oF) with excursions permitted to 30oC (86oF). 
 
 
6 
TREATMENT PLAN 
 
6.1 
Dosage and Administration 
 
Ibrutinib is administered orally once daily on an outpatient basis at a dose of 840 mg. The 
capsules are to be taken around the same time each day with 8 ounces (approximately 
240 mL) of water, with or without food. The capsules should be swallowed intact and 
subjects should not attempt to open capsules or dissolve them in water. The use of strong 
CYP3A inhibitors/inducers, and grapefruit and Seville oranges should be avoided for the 
duration of the study.  Examples of inhibitors, inducers, and substrates can be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 

 
Version 11/05/2021  
Page 29 of 65 
 
If a dose is not taken at the scheduled time, it can be taken as soon as possible on the 
same day with a return to the normal schedule the following day. The subject should not 
take extra capsules to make up the missed dose. 
 
The first dose will be delivered in the clinic on Day 1, after which subsequent dosing is 
typically on an outpatient basis. Ibrutinib will be dispensed to subjects in bottles at each 
visit. Study drug may not be shipped to the subject without approval from PCYC and may 
not be dispensed to anyone other than the subject. Unused ibrutinib dispensed during 
previous visits must be returned to the site and drug accountability records updated at 
each visit. Returned capsules must not be redispensed to anyone. 
 
6.1.1 Overdose  
 
There is no specific experience in the management of ibrutinib overdose in patients. 
No maximum tolerated dose (MTD) was reached in the Phase 1 study in which 
subjects received up to 12.5 mg/kg/day (1,400 mg/day). Healthy subjects were 
exposed up to single dose of 1680 mg. One healthy subject experienced reversible 
Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. 
Subjects who ingest more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment. 
 
Refer to Section 10 for further information regarding special reporting situations as 
a result of overdose.  
 
6.1.2 Regimen Description 
Study Drug 
Premedication; precautions 
Route 
Schedule 
Ibrutinib 
No premedication required 
Oral 
      Days 1-28 
 
Ibrutinib is supplied in 140mg capsules. Patients in the safety lead-in will be treated 
at a dose of 840 mg PO daily x 4 weeks.  If fewer than 2 DLTs are observed, 
patients will continue to be treated at that dose level.  If ≥ 2 DLTs are observed, 
dose de-escalation is required.  The first reduction will be to Level -1 (840 mg/d x 
2 weeks) and the second reduction (if ≥ 2 DLTs are observed at Level -1) will be 
to Level -2 (560 mg/d x 2 weeks).  
 
6.1.3 Other Modalities or Procedures 
 
Blood samples for PSA and for immune assays will be collected at baseline, before 
RP, and after RP. Radical prostatectomy will be performed at Washington 
University, at least 7 days but not more than 12 days following the last scheduled 
dose of ibrutinib (Day 36 to 41; See Table 6.1). Information including WBC count 
prior to surgery, amount of blood loss during surgery and/or any post-operative 
complication(s) will be included in the safety analysis. As there is a potential for 
loss of immune cell infiltration within the prostate tissue after >12 days of not 
receiving ibrutinib, any patient who undergoes RP after 12 days from the last dose 
of ibrutinib will be included in the final analysis; however, an additional patient will 
be accrued as replacement. This will keep the treatment uniform in order to 

 
Version 11/05/2021  
Page 30 of 65 
evaluate for immune response. The maximum number of allowed replacement 
patients is 4.  
 
Standard institutional practices for the care and treatment of surgical patients will 
be followed before, during, and after each patient’s RP. Patients will be informed 
in the written consent that radical prostatectomy may be delayed due to adverse 
events resulting from study treatment, at the discretion of the investigator and 
performing surgeon.   
 
6.1.4 Dose Limiting Toxicities 
 
Each patient in the safety lead-in will be assessed periodically for the development 
of any toxicity as outlined in Section 7 Study Procedures and Observations. 
Toxicity will be assessed according to the NCI CTCAE v4.0.  Dose adjustments 
will be made according to the system showing the greatest degree of toxicity.  
 
Dose de-escalation in this study will be based on the occurrence of dose-limiting 
toxicities (DLTs) that occur during the duration of ibrutinib therapy and the period 
after the last dose of ibrutinib until the day of surgery. DLTs will be defined as any 
of the following that are attributable to ibrutinib. 
• 
Any grade 4 toxicity, including hematologic toxicities with the exception of 
lymphocytosis. Lymphocytosis, in the absence of clinical symptoms, is 
excluded from DLT, as this may be considered an on-target 
pharmacodynamics effect of BTK inhibition. 
• 
Any grade 3 toxicity. 
• 
Any recurrence of the same grade 3 toxicity. 
• 
Any delay of RP due to study-drug related toxicity. 
• 
Any complications of RP (e.g., bleeding, delayed wound healing) deemed 
to be related to study drug. 
 
The dose of study drug should be modified according to the dose modification 
guidelines, including any of the following toxicities: 
• 
Grade 4 ANC (<500/mm3) for more than 7 days.  
• 
Grade 3 thrombocytopenia (<50,000/mm3) in the presence of clinically 
significant bleeding events. 
• 
Grade 4 thrombocytopenia (<25,000/mm3)). 
• 
Grade 3 or 4 nausea, vomiting, or diarrhea if persistent, despite optimal 
anti-emetic and/or anti-diarrheal therapy. 
 
Patients who experience a DLT may be removed from protocol therapy and 
undergo RP at the discretion of the operating surgeon. 
 
6.2 
Dose Modifications for an Individual Patient Regardless of Dose 
Cohort 
 
If a patient experiences any CTCAE v4.0 grade 4 toxicity attributed to treatment, ibrutinib 
must be discontinued. If a patient experiences any CTCAE v4.0 grade 3 toxicity attributed 
to treatment, ibrutinib must be held until resolution of the toxicity to grade 1 or the patient’s 
baseline, at which time the patient may resume ibrutinib at 50% of the starting dose. If the 
patient experiences recurrence of the same grade 3 toxicity while on 50% reduced dose, 

 
Version 11/05/2021  
Page 31 of 65 
ibrutinib must be discontinued. If a grade 3 toxicity does not resolve to grade 1 or the 
patient’s baseline within 2 weeks of holding therapy, ibrutinib must be discontinued.  
   
Ibrutinib Dose Modifications According to Toxicity 
Event 
Management 
Any grade 4 toxicity attributed to 
treatment 
Discontinue ibrutinib 
Any grade 3 toxicity attributed to 
treatment 
Hold ibrutinib until < grade 1, then 
resume ibrutinib at 50% starting dose 
Recurrence of the same grade 3 toxicity 
while on half dose 
Discontinue ibrutinib 
Grade 3 toxicity not resolving to < grade 
1 within 2 weeks 
Discontinue ibrutinib 
 
Clinical judgment of the treating physician should guide the management plan of each 
patient based on individual benefit/risk assessments.  
  
6.2.1 Dose Modification for Hepatic Impaired Subjects 
 
Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher 
while on study should be managed per standard dose modification guidelines. 
Ibrutinib is metabolized in the liver and therefore subjects with clinically significant 
chronic hepatic impairment at the time of Screening (Child- Pugh class C) are 
excluded from study participation. Concomitant use of strong CYP inhibitors is not 
permitted in subjects with chronic hepatic impairment. Refer to Appendix D for 
Child-Pugh classification. Please refer to the table below for dose modifications 
due to hepatic impairment. 
 
Dose Modification Guidance for Hepatic Impaired Subjects 
 
Child Pugh class A 
(Mild hepatic impairment) * 
Child Pugh Class B 
(Moderate hepatic 
impairment) ** 
Child Pugh class C  
(Severe hepatic 
impairment)  
Ongoing at time 
of enrollment  
Develops 
during study  
Develops during study  
Develops during study  
Ibrutinib 
Dose 
(daily)  
280 mg  
280mg 
140 mg  
Hold until improves to 
moderate [Class B] or better) 
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In the event 
that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity until resolution. 
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until resolution.  
 
6.3 
Monitoring and Toxicity Management 
 
Each patient receiving ibrutinib will be evaluated for safety. The safety parameters include 
all laboratory tests and hematological abnormalities, physical findings, and spontaneous 
reports of adverse events reported to the investigator by patients. 
 
We will monitor for potential adverse effects including but not limited to fatigue, 
dehydration, cytopenias, leukocytosis, diarrhea, nausea, vomiting, signs and symptoms 
of infection including pneumonia, as well as skin disorders including rash.  

 
Version 11/05/2021  
Page 32 of 65 
 
Acute toxicity will be managed by supportive care and/or delay of dose. Further 
management will depend upon the judgment of the treating clinician and may include dose 
reduction. Guidelines for dose modification and management of anticipated adverse 
events are summarized in Table 5.3.1. 
 
Criteria for dose adjustments and management of ibrutinib related toxicities 
Toxicity and Intensity 
Dose Modification and Suggestions for Management  
Fatigue (very common) 
Grade 1 (relieved by rest) 
Ensure adequate caloric intake and assess volume status. Rule out 
other causes of fatigue including anemia. Avoid prescription of 
steroids (e.g., Prednisone or Dexamethasone) which has 
immunomodulatory effects and may affect study endpoints. 
Grade 2 (not relieved by rest, 
limiting instrumental ADL) 
Ensure adequate caloric intake and assess volume status. Rule out 
other causes of fatigue including anemia. Avoid prescription of 
steroids (e.g., Prednisone or Dexamethasone) which has 
immunomodulatory effects and may affect study endpoints. If fatigue 
is not resolved to < grade 1 with supportive management, reduce the 
starting dose of ibrutinib by 140mg. 
Grade 3 (not relieved by rest, 
limiting self care ADL) 
Ensure adequate caloric intake and assess volume status. Rule out 
other causes of fatigue including anemia. Avoid prescription of 
steroids (e.g., Prednisone or Dexamethasone) which has 
immunomodulatory effects and may affect study endpoints. Hold 
ibrutinib dosing until fatigue is resolved to < grade 2, at which time 
restart dose at 50% of the starting dose. 
Diarrhea (very common) 
Grade 1 (increase of <4 stools per 
day over baseline) 
Consider Clostridium difficile testing if clinically indicated. The patient 
should be monitored carefully to ensure maintenance of fluid intake 
to avoid dehydration. Manage with supportive therapy including 
antidiarrheals. 
Grade 2 (increase of 4-6 stools 
per day over baseline) 
Patient should be evaluated by the treating clinician or other 
physicians including history and physical exam. Infectious work-up 
include Clostridium difficile and other suspected organisms should 
be obtained. The patient should be monitored carefully to ensure 
maintenance of fluid intake to avoid dehydration. If infectious work-
up is negative, patient should be managed with supportive therapy 
including antidiarrheals. If symptoms are prolonged (e.g.,, >2 weeks) 
and do not improve with supportive management, reduce the starting 
dose of ibrutinib by 140mg.  
Grade 3 (increase of >7 stools per 
day over baseline; incontinence; 
hospitalization indicated) 
Hospitalization with management per standard institutional practices. 
Rule out Clostridium difficile. Hold ibrutinib until diarrhea < grade 1, 
then resume ibrutinib at 50% of the starting dose. 
Grade 4 (Life-threatening 
consequences; urgent intervention 
indicated) 
Urgent hospitalization and medical management per standard 
institutional practices. Discontinue ibrutinib therapy.  
Nausea/Vomiting (very common) 
Grade 1 (loss of appetite without 
alteration in eating habits; 1-2 
episodes of vomiting in 24 hours) 
5-HT3 antagonists (e.g., Ondansetron), D2 antagonists (e.g., 
Prochlorperazine), or other antiemetic, alone or in combination can 
prevent nausea in the majority of patients. Avoid prescription of 
steroids (e.g., Prednisone or Dexamethasone) which has 

 
Version 11/05/2021  
Page 33 of 65 
Toxicity and Intensity 
Dose Modification and Suggestions for Management  
immunomodulatory effects and may affect study endpoints. 
Grade 2 (oral intake decreased 
without significant weight loss, 
dehydration or malnutrition; 3-5 
episodes of vomiting in 24 hours) 
Implement one or more combinations of antiemetics. Avoid 
prescription of steroids (e.g., Prednisone or Dexamethasone) which 
has immunomodulatory effects and may affect study endpoints. 
Grade 3 (inadequate oral caloric 
or fluid intake; tube feeding, TPN 
or hospitalization indicated; >6 
episodes of vomiting in 24 hours) 
Hospitalization and supportive management including hydration and 
caloric intake per standard institutional practices. Hold ibrutinib until 
nausea < grade 1, then resume ibrutinib at 50% of the starting dose 
after adequate fluid and caloric intake are achieved. Avoid steroids 
(e.g., Prednisone or Dexamethasone) which has immunomodulatory 
effects and may affect study endpoints. 
Cough (very common) 
Grade 1 (mild symptoms, 
nonprescription intervention 
indicated) 
Symptomatic management with OTC cough suppressants (e.g., 
Robitussin). 
Grade 2 (moderate symptoms, 
medical intervention indicated; 
limiting instrumental ADL) 
Chest imaging as clinically indicated to rule out pneumonia. Trial of 
prescription cough suppressants (e.g., Benzonatate). If symptoms 
are prolonged (e.g., >2 weeks) and do not improve, reduce the 
starting dose of ibrutinib by 140mg. 
Grade 3 (severe symptoms; 
limiting self care ADL) 
Chest imaging as clinically indicated to rule out pneumonia. 
Hospitalization if clinically indicated. Hold ibrutinib until cough < 
grade 1, and any reversible causes (e.g., pneumonia) are fully 
treated. Then resume ibrutinib at 50% of the starting dose. 
Pneumonia (very common) 
Grade 2 (moderate symptoms; 
oral intervention indicated) 
Oral antibiotic, antifungal or antiviral as clinically indicated. Chest 
imaging if clinically indicated. If symptoms are prolonged (e.g., >2 
weeks) and do not improve, reduce ibrutinib starting dose by 140mg. 
Grade 3 (IV intervention indicated; 
radiologic, endoscopic or 
operative intervention indicated) 
Hospitalization for infectious work-up and management including 
imaging and endoscopic or operative intervention per standard 
institutional practices. IV antibiotic, antifungal and/or antiviral per 
standard institutional practices. Hold ibrutinib until pneumonia is fully 
treated, then resume at 50% of the starting dose. 
Grade 4 (life-threatening 
consequences; urgent intervention 
indicated) 
Hospitalization and management including IV antibiotics, antifungal 
and/or antiviral per standard institutional practices. Discontinue 
ibrutinib. 
Maculopapular rash (very common) 
Grade 1 (<10% BSA covered with 
or without symptoms) 
Continue dose level of ibrutinib. Review medications for other 
potential drug etiologies and discontinue agent(s) as appropriate. 
Use topical or oral antihistamines for symptomatic relief. Topical 
corticosteroids may be used if clinically indicated. Avoid systemic 
corticosteroids which has systemic immunomodulatory effects and 
may affect study endpoints. 
Grade 2 (10-30% BSA covered 
with or without symptoms; limiting 
instrumental ADL) 
Review medications for other potential drug etiologies and 
discontinue suspected agent(s) as appropriate. Use topical or oral 
antihistamines for symptomatic relief. Topical corticosteroids may be 
used if clinically indicated. Avoid systemic corticosteroids which has 
systemic immunomodulatory effects and may affect study endpoints. 
If symptoms are prolonged (e.g., >2 weeks) and do not improve, 
reduce the starting dose of ibrutinib by 140mg. 

 
Version 11/05/2021  
Page 34 of 65 
Toxicity and Intensity 
Dose Modification and Suggestions for Management  
Grade 3 (>30% BSA covered with 
or without symptoms; limiting self 
care ADL) 
Review medications for other potential drug etiologies and 
discontinue suspected agent(s) as appropriate. Use topical or oral 
antihistamines for symptomatic relief. Topical corticosteroids may be 
used if clinically indicated. Avoid systemic corticosteroids which has 
systemic immunomodulatory effects and may affect study endpoints.  
Hold ibrutinib until rash < grade 1, and then resume at 50% of the 
starting dose. 
Anemia (very common) 
Grade 1 (Hb <LLN-10.0 g/dL) 
Maintain ibrutinib dose level. Assess for evidence of gastrointestinal 
bleeding. 
Grade 2 (Hb <10.0-8.0 g/dL) 
Assess for evidence of gastrointestinal bleeding. Hold ibrutinib until 
anemia is resolved to < grade 1, at which time resume ibrutinib at 
140mg lower than the starting dose. 
Grade 3 (Hb <8.0 g/dL, transfusion 
indicated) 
Transfuse PRBC per standard institutional practices. Hold ibrutinib 
until anemia < grade 1, and then resume at 50% of the starting dose. 
Red blood cell growth factors (erythropoietin) are permitted per 
institutional policy and in accordance with the ASCO guidelines. 
Short doses of steroids for autoimmune cytopenias are permitted for 
<14 days at doses that do not exceed 100 mg per day of prednisone 
or equivalent. 
Thrombocytopenia (very common) 
Grade 1 (Plt <LLN- 75,000/mm3) 
Check manual blood smear to rule out pseudothrombocytopenia. 
Maintain ibrutinib dose level.  
Grade 2 (Plt <75,000-50,000/mm3) 
Check manual blood smear to rule out pseudothrombocytopenia. 
Hold ibrutinib until thrombocytopenia is resolved to < grade 1, at 
which time resume at 140mg lower than the starting dose. 
Grade 3 (Plt <50,000-25,000/mm3) 
Check manual blood smear to rule out pseudothrombocytopenia. 
Hold ibrutinib until thrombocytopenia < grade 1, and then resume at 
50% of the starting dose. Platelet transfusions may be given if 
clinically indicated (e.g., bleeding). 
Grade 4 (Plt <25,000/mm3) 
Check manual blood smear to rule out pseudothrombocytopenia. 
Discontinue ibrutinib. Platelet transfusions may be given if clinically 
indicated (e.g., bleeding or Plt <10,000/mm3). Short courses of 
steroids for autoimmune cytopenias are permitted for <14 days at 
doses that do not exceed 100mg per day of prednisone or 
equivalent. 
Neutropenia (very common) 
Grade 1 (ANC <LLN-1,500/mm3) 
Maintain ibrutinib dose level. Avoid the use of growth factors due to 
potential interference with immune effects of ibrutinib and study 
endpoints. 
Grade 2 (ANC <1,500-1,000/mm3) 
Hold ibrutinib until neutropenia is resolved to < grade 1, at which 
time resume at 140mg lower than the starting dose. Avoid the use of 
growth factors due to potential interference with immune effects of 
ibrutinib and study endpoints. 
Grade 3 (ANC <1000-500/mm3) 
Hold ibrutinib until neutropenia is resolved to < grade 1, at which 
time resume at 50% of the starting dose. Avoid the use of growth 
factors due to potential interference with immune effects of ibrutinib 
and study endpoints. 
Grade 4 (ANC <500/mm3) 
Discontinue ibrutinib. Growth factors such as filgrastim or 

 
Version 11/05/2021  
Page 35 of 65 
Toxicity and Intensity 
Dose Modification and Suggestions for Management  
pegfilgrastim may be used per institutional policy and in accordance 
with the ASCO guidelines. 
Febrile neutropenia (common) 
Grade 3 (ANC <1000/mm3 with a 
single temp  >38.3oC (101 F) or a 
sustained temp of >38oC (100.4 F) 
for >1 hour 
Urgent admission and management including IV antibiotics per 
standard institutional practices. Hold ibrutinib until neutropenia is 
resolved to < grade 1 and any evident infection is adequately 
treated, then resume ibrutinib at 140mg lower than the starting dose. 
Avoid the use of growth factors due to potential interference with 
immune effects of ibrutinib and study endpoints. 
Grade 4 (life-threatening 
consequences; urgent intervention 
indicated) 
Discontinue ibrutinib. Urgent admission and management including 
IV antibiotics per standard institutional practices. Growth factors may 
be used if clinically indicated. 
Leukocytosis (common) 
Grade 3 (ANC >100,000/mm3) 
Admit patient for close monitoring including CBC and signs and 
symptoms of leukostasis. Hold ibrutinib until ANC normalizes, at 
which time resume ibrutinib at 50% of the starting dose. 
Grade 4 (clinical manifestations of 
leukostasis; urgent intervention 
indicated) 
Discontinue ibrutinib. Supportive care including hydration and/or 
cytoreduction per standard institutional practices. 
Other ibrutinib-related AEs 
Grade 1 or 2 
Maintain dose level and initiate standard supportive care. If grade 2 
toxicity does not improve to < grade 1 with optimal supportive care, 
reduce ibrutinib dose by 140mg. 
Grade 3 
Hold ibrutinib until resolve to < grade 1, then reduce dose by 50%. 
Grade 4 
Discontinue ibrutinib.  
Frequency category is based on the following: 
• 
Very common: anticipated >10% 
• 
Common: anticipated >1% and <10% 
Notes: 
• 
All dose modifications should be based on the worst preceding toxicity. 
• 
If a patient requires a dose interruption of >14 days due to a study drug related toxicity, the patient 
must be discontinued from the study. 
• 
Patients who discontinue the study for a study related AE must be followed at least once a week for 
28 days and subsequently at 28 day intervals until resolution or stabilization of the event, whichever 
comes first. 
 
 
7 
REGULATORY AND REPORTING REQUIREMENTS 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. Please refer to Appendix 5 for definitions and Appendix 6 for a grid of reporting 
timelines. 
 
Adverse events will be tracked from the start of study treatment through 30 days after the end of 
treatment. All adverse events must be recorded on the toxicity tracking case report form (CRF) 
with the exception of: 
• 
Baseline adverse events, which shall be recorded on the medical history CRF 
• 
Adverse events related to prostatectomy 
 
Refer to the data submission schedule in Section 11 for instructions on the collection of AEs in 

 
Version 11/05/2021  
Page 36 of 65 
the EDC. 
Reporting requirements for Washington University study team may be found in Section 7.1.   
7.1 
Sponsor-Investigator Reporting Requirements 
 
7.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
7.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The Sponsor-Investigator is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to  qasmc@wustl.edu. Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
7.1.3 Reporting to Pharmacyclics  
 
All SAEs and AESIs (initial and follow-up information) will be reported on a 
MEDWATCH form 3500A or Suspect Adverse Event Report (CIOMS Form 1, IRB 
Reporting form) and sent via email (AEintakePM@pcyc.com) or fax (408) 215-
3372 to Pharmacyclics Drug Safety, or designee, within 15 days of the event. 
Pharmacyclics may request follow-up and other additional information from the 
sponsor Investigator. 
 
Pharmacyclics Inc. 
995 E Arques Ave  
Sunnyvale, CA 94085 
Fax (408) 215-3372 
EMAIL: drugsafety@pcyc.com 
 
Significant new information regarding an ongoing SAE and the resolution must be 
provided promptly to Pharmacyclics Inc. on the SAE form MEDWATCH 3500A. 
 
7.1.3.1 
Pregnancy 
 
Before study enrollment, subjects must agree to take appropriate measures 
to avoid pregnancy of a sexual partner. However, should a pregnancy 

 
Version 11/05/2021  
Page 37 of 65 
occur in the partner of a study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the 
infant until 30 days old will be requested. 
 
A subject must immediately inform the Investigator if his partner becomes 
pregnant from the time of consent to 90 days after the last dose of study 
drug. The Investigator should counsel the subject, discussing any risks of 
continuing the pregnancy and any possible effects on the fetus.   
 
Although pregnancy itself is not regarded as an adverse event, the 
outcome will need to be documented. Any pregnancy occurring in a 
subject’s partner from the time of first dose up until to 90 days after the last 
dose of study drug must be reported. Any occurrence of pregnancy must 
be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting 
timelines of learning of the event. All pregnancies will be followed for 
outcome, which is defined as elective termination of the pregnancy, 
miscarriage, or delivery of the fetus. For pregnancies with an outcome of 
live birth, the newborn infant will be followed until 30 days old by completing 
the Pregnancy Report Form Part II and this must be reported to 
Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. Any 
congenital anomaly/birth defect noted in the infant must be reported as a 
serious adverse event. 
 
7.1.3.2 
Other Malignancies 
 
All new malignant tumors including solid tumors, skin malignancies and 
hematologic malignancies will be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including 
post-progression follow-up for overall survival. 
 
7.1.3.3 
Adverse Events of Special Interest (AESI) 
 
Specific adverse events, or groups of adverse events, will be followed as 
part of standard safety monitoring activities by the Sponsor. These events 
(regardless of seriousness) should be reported on the Serious Adverse 
Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, 
or designee, within 15 days of awareness.  
 
7.1.3.1.3 
Major Hemorrhage 
 
Major hemorrhage is defined as any of the following:  
 
1. Any treatment-emergent hemorrhagic adverse events of Grade 
3 or higher*.   
2. Any treatment-emergent serious adverse events of bleeding of 
any grade 
3. Any treatment-emergent central nervous system hemorrhage / 
hematoma of any grade 
 
*All hemorrhagic events requiring transfusion of red blood cells 
should be reported as grade 3 or higher AE per CTCAE v4.03. 

 
Version 11/05/2021  
Page 38 of 65 
 
Events meeting the definition of major hemorrhage will be captured 
as an event of special interest according to Section 10.4.3 above. 
 
7.1.4 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the Washington University principal investigator to report to the 
FDA as follows: 
 
• 
Report any unexpected fatal or life-threatening suspected adverse 
reaction (refer to Appendix 5 for definitions) no later than 7 calendar 
days after initial receipt of the information. 
• 
Report a suspected adverse reaction that is both serious and 
unexpected (SUSAR, refer to Appendix 5) no later than 15 calendar 
days it is determined that the information qualifies for reporting. Report 
an adverse event (refer to Appendix 5) as a suspected adverse reaction 
only if there is evidence to suggest a causal relationship between the 
drug and the adverse event, such as:  
o A single occurrence of an event that is uncommon and known 
to be strongly associated with drug exposure  
o One or more occurrences of an event that is not commonly 
associated with drug exposure but is otherwise uncommon in 
the population exposed to the drug 
o An aggregate analysis of specific events observed in a clinical 
trial that indicates those events occur more frequently in the 
drug treatment group than in a concurrent or historical control 
group 
• 
Report any findings from epidemiological studies, pooled analysis of 
multiple studies, or clinical studies that suggest a significant risk in 
humans exposed to the drug no later than 15 calendar days after it is 
determined that the information qualifies for reporting. 
• 
Report any findings from animal or in vitro testing that suggest 
significant risk in humans exposed to the drug no later than 15 calendar 
days after it is determined that the information qualifies for reporting.  
• 
Report any clinically important increase in the rate of a serious 
suspected adverse reaction of that listed in the protocol or IB within 15 
calendar days after it is determined that the information qualifies for 
reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA Form 
3500A or in an electronic format that FDA can process, review, and archive.  Study 
teams must notify the Siteman Cancer Center Protocol Development team of each 
potentially reportable event within 1 business day after initial receipt of the 
information, and must bring the signed 1571 and FDA Form 3500A to the Siteman 
Cancer Center Protocol Development team no later than 1 business day prior to 
the due date for reporting to the FDA. 

 
Version 11/05/2021  
Page 39 of 65 
Each notification to FDA must bear prominent identification of its contents (“IND 
Safety Report”) and must be transmitted to the review division in the Center for 
Drug Evaluation and Research (CDER) or in the Center for Biologics Evaluation 
and Research (CBER) that has responsibility for review of the IND.  Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such (“Follow-up IND Safety 
Report”). 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 
include: 
• 
planned hospitalizations 
• 
hospitalizations < 24 hours 
• 
respite care 
• 
events related to disease progression 
 
 
Events that do not require expedited reporting must still be captured in the EDC. 
8 
STUDY PROCEDURES AND OBSERVATIONS 
 
8.1 
Schedule of Procedures and Observations 
 
The study-specific assessments are detailed in this section. Screening assessments must 
be performed within 28 days prior to the first dose of investigational product. Any results 
falling outside of the reference ranges may be repeated at the discretion of the 
investigator. All on-study visit procedures are allowed a window of +/- 3 days unless 
otherwise noted. Treatment or visit delays for public holidays or weather conditions do not 
constitute a protocol violation. 
 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the subject and a copy 
will be filed in the medical record. The original will be kept on file with the study records.   
 
8.1.1 Pretreatment Period 
 
8.1.1.1 
Informed Consent 
 
Before initiation of any screening procedures, each prospective subject will 
be provided a verbal, in-depth explanation of the study, requested to read 
the Institutional Review Board (IRB) approved informed consent form (ICF), 
and encouraged to ask questions. The Investigator must ensure that each 
subject understands how the study will be conducted and how they will 
participate if they so choose. The subject shall be given sufficient time to 

 
Version 11/05/2021  
Page 40 of 65 
properly consider the information and to make an informed decision 
regarding consent. Once all questions have been answered and the 
Investigator is assured that the subject understands the implications of 
study participation, the subject will be asked to provide written consent to 
participate in the study by signing the ICF. The Investigator will document 
the informed consent process in the subject’s medical chart or progress 
notes and will provide a copy of the signed ICF to the subject. 
 
8.1.1.2 
Screening Assessments  
 
The Screening procedures and assessments must be completed within 28 
days of the first day of ibrutinib. 
• 
Physical examination 
• 
Vital signs 
• 
Complete medical history 
• 
Documentation of disease assessment 
• 
ECOG Performance status 
• 
Baseline concomitant medications taken within 28 days of Day 1 
• 
Complete blood count (CBC) with differential and platelet count 
• 
Blood chemistry assessment, including alkaline phosphatase, 
aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), total bilirubin, calcium, phosphorus, blood urea nitrogen 
(BUN), creatinine, total protein, albumin, glucose, potassium, 
sodium, chloride, bicarbonate, lactate dehydrogenase (LDH) 
• 
Coagulation assessment, including prothrombin time, partial 
thromboplastin time, international normalized ratio (PT/PTT/INR) 
• 
PSA 
• 
Hepatitis B surface antigen, anti-HBc antibody and anti-HBs 
antibody. In patients who have positive serology for the anti-HBc 
antibody, HBV DNA should be collected prior to Cycle 1, Day 1. 
• 
HCV serology (anti-HCV antibody) 
• 
HIV screening in accordance with national and/or institutional 
guidelines 
• 
Serum collection in eight 10mL EDTA tubes for immune analyses 
to be sent to the TPC at Washington University  
• 
Electrocardiogram (ECG) 
• 
Pre-treatment tissue for correlative studies. If adequate tissue is 
available from a prior biopsy or surgery, samples will be requested 
from the hospital or clinic pathology department. If adequate tissue 
from a prior biopsy is not available, a prostate biopsy is required to 
participate in the study. There must be a minimum of 3 days 
between prostate biopsy and start of study drug. 
 
8.1.2 Treatment Period 
 
8.1.2.1 
Study Procedures, Week 1, Day 1 
 
• 
Physical examination 
• 
Vital signs 

 
Version 11/05/2021  
Page 41 of 65 
• 
ECOG performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including alkaline phosphatase, AST, 
ALT, total bilirubin, calcium, phosphorus, BUN, creatinine, total 
protein, 
albumin, 
glucose, 
potassium, 
sodium, 
chloride, 
bicarbonate, LDH 
• 
PSA 
 
8.1.2.2 
Study Procedures, Week 2, Day 8  
 
• 
Telephone Visit  
o Evaluation of adverse events 
o Concomitant medications 
o Other pertinent interval history 
• 
CBC with differential and platelet count (not required to be 
completed at Washington University, but results must be 
communicated to the CRC within protocol window) 
 
8.1.2.3 
Study Procedures, Week 3, Day 15 
 
• 
Physical examination 
• 
Vital signs 
• 
ECOG performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including alkaline phosphatase, 
AST, ALT, total bilirubin, calcium, phosphorus, BUN, creatinine, 
total protein, albumin, glucose, potassium, sodium, chloride, 
bicarbonate, LDH 
 
8.1.2.4 
Study Procedures, Week 4, Day 22  
 
• 
Telephone visit  
o Evaluation of adverse events 
o Concomitant medications 
o Other pertinent interval history 
• 
CBC with differential and platelet count (not required to be 
completed at Washington University, but results must be 
communicated to the CRC within protocol window) 
 
8.1.2.5 
Study Procedures, Week 5, Day 29  
 
• 
Physical examination 
• 
Vital signs 
• 
ECOG performance status 
• 
Evaluation of adverse events 

 
Version 11/05/2021  
Page 42 of 65 
• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including alkaline phosphatase, AST, 
ALT, total bilirubin, calcium, phosphorus, BUN, creatinine, total 
protein, 
albumin, 
glucose, 
potassium, 
sodium, 
chloride, 
bicarbonate, LDH 
• 
PSA 
• 
Serum collection in eight 10mL EDTA tubes for immune monitoring 
to be sent to the TPC at Washington University  
 
RP will be performed 7 to 12 days after the last dose of ibrutinib 
(between Week 6, Day 36 and Day 41). 
 
8.1.3 Post-RP/Follow Up Visit (Week 10, Day 64):  
 
Patients will be followed approximately 4 weeks after RP. The following procedures 
will be performed at the follow up Visit: 
• 
Physical examination 
• 
Vital signs 
• 
ECOG performance status 
• 
Evaluation of adverse events 
• 
Concomitant medications 
• 
CBC with differential and platelet count 
• 
Blood chemistry assessment, including alkaline phosphatase, AST, ALT, 
total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate, LDH 
• 
PSA 
• 
Serum collection in eight 10mL EDTA tubes for immune monitoring to be 
sent to the TPC at Washington University  
 
8.1.4 Long Term Follow-up Procedures 
 
The study will conclude when all enrolled patients have been followed 4 weeks 
after RP. All treatment related adverse events will be followed until resolution or 
stabilization to grade <2. 
 
8.1.5 Discontinuation of Therapy 
 
The Investigator will withdraw a patient whenever continued participation is no 
longer in the patient’s best interests. Reasons for withdrawing a patient include, 
but are not limited to, disease progression, the occurrence of an adverse event or 
a concurrent illness, a patient’s request to end participation, a patient’s non-
compliance or simply significant uncertainty on the part of the investigator that 
continued participation is prudent. There may also be administrative reasons to 
terminate participation, such as concern about a patient’s compliance with the 
prescribed treatment regimen. 
 
 

 
Version 11/05/2021  
Page 43 of 65 
 
8.2 
Schedule of Study Procedures and Assessments 
Study Day/Visit Day 
Screening  
D-28 to 0 
+/- 3 days 
Week 1 
D1 +/- 3 
days 
Week 2 
D8 +/- 3 
days 
Week 3 
D15 +/- 3 
days 
Week 4 
D22 +/- 3 
days 
Week 5 
D29 +/- 3 
days 
RP  
D36 to 
D417 
Post-RP 
Follow Up 
Visit +/- 3 
days8 
Informed consent 
X 
 
 
 
 
 
Radical Prostatectomy 
 
AE assessment 
 
X 
X6 
X 
X6 
X 
X 
Concomitant medications 
X 
X 
X6 
X 
X6 
X 
X 
Pre-treatment prostate biopsy 
tissue available 
X 
 
 
 
 
 
 
Treatment/Drug 
Administration 
 
 
 
 
 
 
 
Ibrutinib 
 
Oral daily, D1 to D28 
 
 
Clinical procedures 
 
 
 
 
 
 
 
Telephone visit 
 
 
X6 
 
X6 
 
 
Physical exam 
X 
X 
 
X 
 
X 
X 
Vital signs 
X 
X 
 
X 
 
X 
X 
Medical history 
X 
 
 
 
 
 
 
Disease assessment 
X9 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
X 
 
X 
X 
Laboratory procedures 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X6 
X 
X6 
X 
X 
Blood chemistry + LDH1 
X 
X 
 
X 
 
X 
X 
Glucose 
X 
X 
 
X 
 
X 
X 
Coagulation2 
X 
 
 
 
 
 
 
PSA 
X 
X 
 
 
 
X 
X 
Hepatitis B and C3 
X 
 
 
 
 
 
 
HIV4 
X 
 
 
 
 
 
 
Immune monitoring5 
X 
 
 
 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
Imaging procedures 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
1. Blood chemistry assessment includes alkaline phosphatase, AST, ALT, total bilirubin, calcium, phosphorus, BUN, creatinine, total protein, albumin, potassium, 
sodium, chloride, bicarbonate, and LDH. 
2. Coagulation assessment includes PT, PTT and INR. 
3. Serum hepatitis assessment includes HBsAg, HBsAb, HBcAb, and anti-HCV antibody. 
4. HIV screening with ELISA based assay. 
5. Refer to Appendix 3. 
6. Obtained during telephone visits; CBC may be done at a local lab. 
7. 7-12 days after the last dose of ibrutinib 
8. Week 10, Day 64 
9. Window for disease assessment is up to 60 days prior to enrollment  
 
 

 
Version 11/05/2021  
Page 44 of 65 
8.3 
Usage of Concurrent/Concomitant Medications 
 
Supportive medications in accordance with standard practice (such as for emesis, 
diarrhea, etc.) are permitted.  Use of neutrophil growth factors (filgrastim and 
pegfilgrastim) or red blood cell growth factors (erythropoietin) is permitted per institutional 
policy and in accordance with the ASCO guidelines (Smith 2006).  Transfusions may be 
given in accordance with institutional policy.  
 
Short courses (≤14 days) of steroid treatment for non-cancer related medical reasons (e.g, 
joint inflammation, asthma exacerbation, rash, antiemetic use and infusion reactions) at 
doses that do not exceed 100 mg per day of prednisone or equivalent are permitted. 
 
Treatment for autoimmune cytopenias are permitted for <14 days at doses that do not 
exceed 100 mg per day of prednisone or equivalent. 
 
Concomitant use of ibrutinib and drugs that inhibit or induce CYP3A should be recorded 
on the CRF. Use of medications that inhibit platelet function and may increase the risk of 
bleeding (e.g. Aspirin) should be recorded on the CRF. Use of any medications that may 
have immunosuppressive effects should be recorded on the CFR. 
 
All AEs and serious AEs (SAEs) that occur on study drug or within 30 days after the last 
dose of study drug, will be recorded on case report forms (CRFs) from enrollment through 
4 weeks post-surgery.  
 
8.3.1 Antiplatelet Agents and Anticoagulants 
 
Use ibrutinib with caution in subjects requiring anticoagulants or medications that 
inhibit platelet function. In an in vitro platelet function study, inhibitory effects of 
ibrutinib on collagen-induced platelet aggregation were observed. Supplements 
such as fish oil and vitamin E preparations should be avoided during treatment 
with ibrutinib. Bleeding events of any grade, including bruising and petechiae, 
occurred in subjects treated with ibrutinib. Ibrutinib should be held at least 3 to 7 
days pre- and post-surgery depending upon the type of surgery and the risk of 
bleeding (see Section 7.7). Subjects with congenital bleeding diathesis have not 
been studied. 
 
Subjects requiring the initiation of therapeutic anticoagulation therapy (e.g., atrial 
fibrillation), consider the risks and benefits of continuing ibrutinib treatment. If 
therapeutic anticoagulation is clinically indicated, treatment with ibrutinib should be 
held and not be restarted until the subject is clinically stable and has no signs of 
bleeding. Subjects should be observed closely for signs and symptoms of bleeding.  
No dose reduction is required when study drug is restarted. 
 
8.4 
Dietary Restrictions 
 
Ibrutinib can be taken with or without food at approximately the same time each day. Avoid 
grapefruit and Seville oranges during ibrutinib treatment as these contain moderate 
inhibitors of CYP3A. Patients should also avoid supplements such as fish oil and vitamin 
E preparations as they can cause an interaction with ibrutinib.  
 

 
Version 11/05/2021  
Page 45 of 65 
8.5 
Prohibited Medications/Therapies 
 
The following should not be administered at any time during the study. 
• 
Any investigational product other than ibrutinib. 
• 
Systemic corticosteroid with the exception of a short course of steroids for the 
management of treatment related autoimmune cytopenias). Topical and inhaled 
steroids are allowed. 
• 
Anticoagulant including warfarin or other vitamin K antagonists and lower 
molecular weight heparin (LMWH) including enoxaparin. 
• 
With the exception of aspirin, anti-platelet agents (e.g., clopidogrel, glycoprotein 
IIb/IIIa inhibitors) are not allowed. 
• 
Vaccine therapy including influenza vaccination. However, COVID-19 vaccines 
may be allowed at discretion of investigator. 
• 
Hormone therapy including LHRH agonists, antiandrogens (e.g., bicalutamide, 
flutamide, nilutamide), and 5-α-reductase inhibitors (e.g., finasteride, dutasteride) 
• 
Radiation therapy may not be initiated until after RP.  
 
Should subjects receive one or more of the above medications or therapies, they will 
remain on study and will continue to receive safety evaluations. Following RP, subjects 
may receive hormone therapy or radiation therapy as deemed appropriate by their medical 
professional.  
 
8.6 
Restricted Medications 
 
Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.  
 
Concomitant use of ibrutinib and drugs that strongly or moderately inhibit CYP3A can 
increase ibrutinib exposure and should be avoided. Strong inhibitors of CYP3A (e.g., 
ketoconazole, intraconazole, clarithromycin, telithromycin, nefazadone) and moderate 
inhibitors (e.g., voriconazole, erythromycin, aprepitant, ciprofloxacin, Diltiazem, 
fluconazole, verapamil) should be avoided. If the benefit outweighs the risk and a strong 
CYP3A inhibitor must be used, reduce the ibrutinib dose to 140mg or withhold treatment 
temporarily (for 7 days or less). If a moderate CYP3A inhibitor must be used, reduce 
ibrutinib treatment to 140mg for the duration of the inhibitor use. No dose adjustment is 
required in combination with mild inhibitors. Monitor patient closely for toxicity and follow 
dose modification guidance as needed.  
 
After discontinuation of a CYP3A inhibitor, resume previous dose of ibrutinib. 
 
Administration of ibrutinib with rifampin, a strong CYP3A inducer, decreases ibrutinib 
plasma concentrations by approximately 90%. Avoid concomitant use of strong CYP3A 
inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John’s wort). Consider 
alternative agents with less CYP3A induction. For further information, please refer to the 
current version of the IB and examples of inhibitors, inducers, and substrates can be found 
at http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised 
and should be checked frequently for updates. 
 
Any medications known to cause QT prolongation should be used with caution; periodic 
ECG and electrolyte monitoring should be considered. 
 

 
Version 11/05/2021  
Page 46 of 65 
A standard list of prohibited and restricted medications is provided in Appendix 2. 
 
8.7 
Guidelines for Ibrutinib Management with Surgeries and Procedures 
 
Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following 
guidance should be applied to the use of ibrutinib in the perioperative period for subjects 
who require surgical intervention or an invasive procedure while receiving ibrutinib. 
 
8.7.1 Minor Surgical Procedures 
 
For minor procedures (such as a central line placement, skin or needle biopsy, lumbar 
puncture (other than shunt reservoir access), thoracentesis, or paracentesis) ibrutinib 
should be held for at least 3 days prior to the procedure and should not be restarted for at 
least 3 days after the procedure. For bone marrow biopsies that are performed while the 
subject is on ibrutinib, it is not necessary to hold ibrutinib.  A minimum of 3 days between 
prostate biopsy and start of study drug is required for patients who undergo prostate 
biopsy. 
 
8.7.2 Major Surgical Procedures 
 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention (except for emergency procedures) 
and should be held at least 7 days after the procedure and restarted at the discretion of 
the investigator when the surgical site is reasonably healed without serosanguineous 
drainage or the need for drainage tubes. 
 
 
9 
REPORTING AND DOCUMENTATION OF RESULTS 
 
9.1 
Evaluation of Activity 
 
9.1.1 Characterization of PBMCs using flow cytometry 
 
The number and frequency of immune cell subsets in the peripheral blood, before, 
during and after ibrutinib therapy will be assessed. Fluorochrome-labeled 
antihuman antibodies, including antibodies to CD19, CD25, CD27, CD86, CD3, 
CD8, CD4, CD25, and FOXP3 will be used. Flow cytometry will be performed in 
either the Immunomonitoring Lab (IML) or Pachynski Lab in the Center for Human 
Immunology and Immunotherapy Programs (CHiiPs) at Washington University. 
 
9.1.2 Characterization of immune infiltration within prostate tissue 
 
The effect of ibrutinib on the number of infiltrating B cells and T cells will be 
assessed by immunohistochemistry with antibodies to CD20, IL-10, CD3, CD8, 
CD4, and FoxP3. Prostate tumor tissue from diagnostic core biopsy specimens 
and post-treatment prostatectomy tissue specimens will be analyzed. Infiltrate will 
be scored by the number of cells/µm2; thus, the number of inflammatory cells will 
be normalized to the unit area. For each patient, the change in the number of 
immune cell infiltration from the pre-treatment biopsy to post-treatment 
prostatectomy tissue specimens will be represented by the ratio of post-treatment 

 
Version 11/05/2021  
Page 47 of 65 
prostatectomy versus pre-treatment biopsy tissue specimen. IHC for immune 
infiltration will be performed in the Pachynski Lab at Washington University. 
 
9.1.3 Characterization of Circulating and Intratumoral T and B cells 
via TCR and BCR sequencing 
 
Next-generating sequencing (NGS) of the VDJ region of T-cell receptors (TCRs) 
and B-cell receptors (BCRs) will be utilized to define the TCR and BCR repertoire 
in the blood and tumor tissue before and after ibrutinib therapy. This approach 
allows the tracking of T and B cell clones in the blood and tissue over time to 
assess their expansion and migration. TCR and BCR sequencing will be carried 
out by Sequenta, Inc. 
 
9.1.4 PD-L1 Expression in Tumor and Tumor-Infiltrating 
Lymphocytes  
 
The expression level of PD-L1 on tumor and tumor-infiltrating lymphocytes (TILs) 
will be examined using immunohistochemistry on diagnostic core biopsy 
specimens and post-treatment prostatectomy tissue specimens. The expression 
level of PD-L1 will be graded by an expert pathologist to determine the impact of 
neoadjuvant ibrutinib on PD-L1 expression in prostate cancer cells and TILs. IHC 
for PD-L1 will be performed in the Pachynski Lab at Washington University. 
 
9.1.5 Btk expression 
 
The expression level of Btk on prostate cancer tissue from core biopsy before 
surgery will be examined using immunohistochemistry with anti-Btk antibody 
(Santa Cruz Inc., Santa Cruz, CA, USA; sc-1107). IHC for total Btk and phospho-
Btk will be performed in or the Pachynski Lab at Washington University. 
 
9.1.6 PSA  
 
The utility of a decline in PSA as a marker of response to neoadjuvant therapies is 
not well defined. However, the proportion of patients with PSA response, defined 
as >50% PSA decline, will be reported. 
 
9.1.7 Pathologic Response  
 
The proportion of patients with down-staging of disease by Gleason score will be 
reported. The proportion of patients with pathologic complete response (pT0) at 
the time of prostatectomy will be reported. 
 
9.2 
Evaluation of Safety 
 
The following will be collected to evaluate safety:  
• 
Adverse events (including SAEs and deaths)  
• 
Physical examinations  
• 
Vital signs  
• 
ECOG performance status  
• 
Laboratory test results 

 
Version 11/05/2021  
Page 48 of 65 
 
Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and 
modified criteria for hematologic adverse events. 
 
10 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
For phase I dose escalation studies, Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC). For phase II 
or dose expansion cohorts of a phase I study, the Principal Investigator will review all patient data 
at least every six months, and provide a semi-annual report to the QASMC. This report will 
include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
• 
History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years 
• 
Expected accrual end date and accrual by cohort 
• 
Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• 
Measures of efficacy (phase I studies only if efficacy is objective of the protocol) 
• 
Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• 
Power analysis and/or interim analysis (if described in the protocol) 
• 
Summary of toxicities separated by cohorts with the number of dose-limiting toxicities 
indicated 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 
11 
DATA SUBMISSION SCHEDULE 
 

 
Version 11/05/2021  
Page 49 of 65 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical and Surgical 
History 
Prior to starting treatment 
Concomitant Medications 
Form 
Toxicity Form 
Continuous 
PSA Form 
Baseline, Week 1, Week 5, Post-RP Follow-Up Visit 
Research Blood Form 
Baseline, Week 5, Post-RP Follow-Up Visit 
Treatment Summary Form 
Completion of treatment 
RP Form 
Time of surgery 
Progression Form 
Time of disease progression 
MedWatch Form 
See Section 7.0 for reporting requirements 
Death Form 
At time of death 
 
11.1 Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac 
arrest), report as a grade 5 event under that AE.  Participant death must also be 
recorded on the Death Form. 
 
12 
STATISTICAL CONSIDERATIONS AND EVALUATION OF RESULTS 
 
12.1 Study Endpoints 
 
See Section 2.4 for study endpoints. 
 
12.2 
Study Design 
 
This is a single center phase 2 open label study of neoadjuvant ibrutinib in patients with 
localized prostate cancer. 
 
12.3 Sample Size and Power Estimate 
 
For this phase 2 study, the primary endpoint is the change of B cells between the pre-
treatment biopsy and post-treatment RP specimen. Each patient’s response to 
neoadjuvant ibrutinib will be a binary classification. Patients will be considered to have a 

 
Version 11/05/2021  
Page 50 of 65 
“positive” response if there is >2 fold decrease in the number of B cells, or considered to 
have a “negative” response if there is <2 fold decrease in the number of B cells. The 
accrual of 18 patients to the phase 2 trial and incorporation of 6 patients who received 
ibrutinib at MTD in the safety lead-in (a total of 24 evaluable subjects) will be sufficient to 
determine whether 20% or more of the cohort achieves this 2 fold decrease in B cells, 
compared to a null response of 5% or less of a reference group of patients who underwent 
RP without neoadjuvant treatment. This comparison has a power of 0.818 at a significance 
level of 0.044 based on a one-sided binomial exact test. If 4 more evaluable patients show 
a “positive” response, the treatment achieves the expected “response” rate of 20%.  
 
The safety-run in will require 6 patients (with a potential for 6-12 more if dose de-escalation 
is required). The Phase II study will require a total of 24 patients on MTD and thus 18 
additionally enrolled patients besides the 6 on MTD during the safety lead-in. 
 
12.4 Replacement Policy 
 
All patients who receive a dose of ibrutinib will be analyzed for safety and efficacy. 
Subjects who discontinue from study participation prior to receiving any dose of study 
therapy may be replaced. Subjects who have received any dose of study therapy will not 
be replaced for the safety and efficacy endpoints. Patients removed from study for 
unacceptable treatment related adverse event(s) will be followed until resolution or 
stabilization of all treatment related AEs to grade 2 or lower. However, they will not be 
replaced.  Patients enrolled during the safety lead-in who discontinue treatment during the 
DLT observation period for reasons other than a DLT will need to be replaced for DLT 
purposes. 
 
Because there is a potential for loss of immune cell infiltration within the prostate tissue 
after >12 days of not receiving ibrutinib, any patient who undergoes RP after 12 days from 
the last dose of ibrutinib (i.e. from scheduling delay of RP) will be included in the final 
analysis; however, an additional patient will be accrued as replacement. This will keep the 
treatment uniform in order to evaluate for immune response. The maximum number of 
allowed replacement patients for delayed RP is 4.  
 
12.5 Stopping Rules 
 
If ≥2 patients experience DLTs during the safety lead-in, then the dose of ibrutinib will be 
reduced as follows: 
- 
Level -1 840 mg/d x 2 weeks; if ≥ 2 of 6 DLTs are observed at Level -1, dosing will be 
de-escalated to Level -2 
- 
Level -2 560 mg/d x 2 weeks  
 
If ≥2 patients experience DLTs at Level -2, then the study will be terminated for lack of 
safety. 
 
Toxicity is continuously monitored for all patients.  
 
12.5.1 Non-hematological Toxicity and plans for data and safety 
monitoring 
 
Early stopping of the Phase II phase of the trial will be based on unacceptable non-
hematological toxicity. Approximately less than 15% of patients are expected to 

 
Version 11/05/2021  
Page 51 of 65 
experience grade 3 and up toxicity and a non-hematological toxicity rate of 30% or 
more would definitely be unacceptable. Based on the sequential probability ratio 
test (SPRT) with 80% power and a 0.05 significance level, the study will be halted 
if 4 of the first 4, or 5 of the first 9, or 6 of the first 14, or 7 of the first 18, or 8 of the 
first 23, or if the 9th non-hematological toxicity is observed before the last patient 
has completed the trial. Accrual will be stopped and the event will be reviewed by 
the Data Safety and Monitoring Board if a grade 5 non-hematological toxicity is 
observed.  
 
12.6 Analyses Plans 
 
12.6.1 Analysis Population 
 
All patients who receive a dose of ibrutinib will be analyzed for safety and efficacy. 
Subjects who discontinue from study participation prior to receiving any dose of 
study therapy may be replaced after discussion with the Study Monitor. Subjects 
who have received any dose of study therapy will not be replaced.  
 
Demographic and baseline characteristics will be summarized by each cohort and 
overall. In general, frequency distribution and percentage will be used to 
summarize categorical measurements, while mean with standard deviation and 
median with range will be used to describe symmetric and skewed continuous 
measurements, respectively. Univariate analysis among variables will be 
assessed using the two-sample t-test, Wilcoxon-rank-sum test, Chi-square test, as 
appropriate. 
 
12.6.2 Analysis of Primary Endpoints 
 
12.6.2.1 
Safety 
 
SAEs and non-SAEs will be summarized by descriptive statistics. 
 
12.6.2.2 
Intratumoral Immune Infiltration 
 
For all subjects, immune cell subsets and localization will be summarized 
by changes from baseline to after treatment. Patients will be considered to 
have a positive response if there is >2 fold decrease in the number of B 
cells, or considered to have a negative response if there is <2 fold decrease 
in the number of B cells. The proportion of patients who have “positive” 
responses will be reported, with 95% confidence intervals. Descriptive 
statistics will be used to describe pre-treatment biopsy immune infiltration, 
post-treatment RP immune infiltration, and immune infiltration of reference 
RP tissue. 
 
12.6.3 Analysis of Secondary Endpoints 
 
12.6.3.1 
Circulating immune subsets 
 
For each patient, flow cytometry of circulating immune cell subsets will also 
be performed on pre-treatment blood and again after RP. Established flow 

 
Version 11/05/2021  
Page 52 of 65 
cytometry panels will examine B cell and T cell populations. Immune cell 
quantification will be summarized by changes from baseline to after 
treatment using descriptive statistics.  Furthermore, paired Wilcox on 
signed-rank test will be applied to test the pre-post treatment changes.  
When available, immune cells digested from resected tumor tissues will 
also be assessed by flow cytometry. 
 
12.6.3.2 
Cytotoxic effects and clinical benefits: rate of 
downstaging, pT0 rate, >50% PSA decline (phase II) 
 
Point estimates and 95% confidence intervals of pathologic T0 rate at the 
time of RP will be obtained for phase 2 subjects treated with ibrutinib. 
Pathologic T0 rate at the time of RP will be compared with the null 
hypothesis rate separately by using binomial test.  
 
12.6.4 Analysis of Exploratory Endpoints 
 
12.6.4.1 
Assessment of Btk expression  
 
Btk expression on tumor tissue from pre-treatment biopsies, RP 
specimens, and any other tumor biospecimens obtained will be evaluated 
immunohistochemically and graded as low, intermediate or high. 
Frequency distribution and percentage will be used to summarize Btk 
expression by pre- and post- treatment. In addition, Kappa statistics will be 
used to test if there is any change of Btk expression from pre-treatment 
biopsy to post-treatment RP tissue.  
 
12.6.4.2 
Assessment of PD-L1 expression  
 
PD-L1 protein expression on tumor tissue from pre-treatment biopsies, RP 
specimens, and any other tumor biospecimens obtained will be evaluated 
immunohistochemically and scored on a scale of 0, 1, 2, or 3. We will 
categorize tumors based on the frequency of tumor cells or of immune cells 
staining positively for PD-L1 as follows: IHC 0: <1%, IHC 1: 1-<5%, IHC 2: 
5-<10% and IHC 3: >10%. Frequency distribution and percentage will be 
used to summarize PD-L1 protein expression by pre- and post- treatment.  
Furthermore, McNemar's test will be used to assess the impact of the 
treatment on PD-L1 expression by considering IHC estimates of >10% as 
being positive.  
 
12.6.4.3 
TCR and BCR deep sequencing  
 
For each individual dose level, and for the phase II cohort the change in 
tumor-infiltrating BCR and TCR between pre-treatment and post-RP after 
treatment will be assessed by calculating the number of unique clonotypes, 
read depth and Shannon diversity index. Repertoire overlap and change 
between sequencing experiments will be measured using Baroni-Urbani 
and Buser overlap index and Morisita’s distance, respectively.  
 
12.7 Reference Population 
 

 
Version 11/05/2021  
Page 53 of 65 
As discussed in the introduction (Section 1.1), in a prior study of neoadjuvant Sipuleucel-
T, a negative control was felt to be important to be confident that the observed changes in 
the study population were due to treatment effect since the effect of systemic Sip-T 
administration on localized prostate cancer was unknown. Therefore, a group of 12 
patients who had undergone RP at UCSF without any neoadjuvant therapy, were selected 
prior to undergoing any tissue analyses, and were matched to the study population using 
the UCSF CAPRA-S score for preoperative risk stratification - were used as a negative 
control. These patients were selected from the surgical population at UCSF who provided 
separate, written consent to the use of their RP specimens for research purposes. 
 
Similarly, in this study, a cohort of 12 patients not treated with any neoadjuvant therapy 
will be used as a negative control, since the effect of neoadjuvant ibrutinib in prostate 
cancer tissue is unknown. Patients will be selected from the RP population at UCSF or 
Washington University who provided separate, written consent to the use of their RP 
specimens for research purposes, and will be matched to the phase II study population 
using the UCSF CAPRA-S score for preoperative risk stratification. This analysis will 
provide confidence that the changes observed in the prostates of treated patients are due 
to neoadjuvant treatment effect. These 12 patients will not otherwise be included in the 
analyses as delineated in 12.6.  
 
12.8 Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study drug.  
The study will use the NCI CTCAE v4.0. 
 
12.9 UCSF’s Data 
 
Data from the first three patients enrolled at UCSF will be shared with Washington 
University under a Data Use Agreement and analyzed under the auspices of this study. 
 
 
 
 

 
Version 11/05/2021  
Page 54 of 65 
 
13 
REFERENCES 
 
Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has 
significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013 Jan 
1;31(1):88-94. PubMed PMID: 23045577. 
 
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK and ibrutinib in relapsed chronic lymphocytic 
leukemia. N Engl J Med. 2013 Jul 4;369(1):34-42. PubMed PMID: 23782158. 
 
De Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- 
and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012 Mar 
15;119(11):2590-4. PubMed PMID: 22279054. 
 
Eifert C, Wang X, Kokabee L, et al. A novel isoform of the B cell tyrosine kinase BTK protects breast 
cancer cells from apoptosis. Genes Chromosomes Cancer. 2013 Oct;52(10):961-75. PubMed PMID: 
23913792. 
 
Fong L, Carroll P, Weinberg V, et al. Activated lymphocyte recruitment into the tumor microenvironment 
following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst. 2014 Sep 
24;106(11).pii.dju268. PubMed PMID: 25255802. 
 
Goldenberg SL, Klotz LH, Srigley J, et al. Randomized, prospective, controlled study comparing radical 
prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. 
Canadian Urologic Oncology Group. J Urol. 1996 Sep;156(3):873-7. PubMed PMID: 8709351. 
 
Gunderson AJ, Coussens LM. B cells and their mediators as targets for therapy in solid tumors. Exp Cell 
Res. 2013 Jul 1;319(11):1644-9. PubMed PMID: 23499742. 
 
Guo W, Liu R, Bhardwaj G, et al. Targeting Btk/Etk of prostate cancer cells by a novel dual inhibitor. Cell 
Death Dis 2014 Sep 4;5:e1409. PubMed PMID: 25188519. 
 
Han M, Partin AW, Pound CR, et al. Long-term biochemical disease-free and cancer-specific survival 
following anatomic radical retropubic prostatectomy. The 15-year John Hopkins experience. Urol Clin 
North Am. 2001 Aug;28(3):555-65. PubMed PMID: 11590814. 
 
Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic 
target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 
2011 Jun 9;117(23):6287-96. PubMed PMID: 21422473. 
 
Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell 
activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci. 
2010 Jul 20;107(29):13075-80. PubMed PMID: 20615965. 
 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate 
cancer.N Engl J Med. 2010 Jul 29;363(5):411-22. PubMed PMID: 20818862. 
 
Kuban DA, Thames HD, Levy LB, et al. Long-term multi-institutional analysis of stage T1-T2 prostate 
cancer treated with radiotherapy in the PSA era. Int J Radiat Oncol Biol Phys. 2003 Nov 15;57(4):915-28. 
PubMed PMID: 14575822. 
 
Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. 
Chem Med Chem 2007; 2(1):58–61. PubMed PMID: 17154430 
 

 
Version 11/05/2021  
Page 55 of 65 
Sagiv-Barfi I, Kohrt HE, Czerwinski DK, et al. Therapeutic antitumor immunity by checkpoint blocakde is 
enhanced by ibrutinib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U.S.A. 2015; 112(9):E966-72. 
PubMed PMID: 25730880. 
 
Satterthwaite AB, Witten ON. The role of Bruton’s tyrosine kinase in B-cell development and function: a 
genetic perspective. Immunol Rev. 2000 Jun;175:120-7. PubMed PMID: 10933597. 
 
Scolieri MJ, Altman A, Resnick MI. Neoadjuvant hormonal ablative therapy before radical prostatectomy: 
a review. Is it indicated? J Urol. 2000 Nov;164(5):1465-72. PubMed PMID: 11025684. 
 
Siegel R, Ma J, Zou Z, Jamal A. Cancer statistics, 2014. CA Cancer J Clin 2014 Jan-Feb;64(1):9-29. 
PubMed PMID: 24399786. 
 
Van Poppel H, De Ridder D, Elgamal AA, et al. Neoadjuvant hormonal therapy before radical 
prostatectomy decreases the number of positive surgical margins in stage T2 prostate cancer: interim 
results of a prospective randomized trial. The Belgian Uro-Oncological Study Group. J Urol. 1995 
Aug;154(2 Pt 1):429-34. PubMed PMID: 7541860. 
 
Vij R, Huff CA, Bensinger WI, et al. Ibrutinib, single agent or in combination with dexamethasone, in 
patients with relapsed or refractory multiple myeloma (MM): preliminary phase 2 results. Blood 2014 (ASH 
Annual Meeting Abstract 31). 
 
Woo JR, Liss MA, Muldong MT, et al. Tumor infiltrating B-cells are increased in prostate cancer tissue. J 
Transl Med 2014 Jan 30;12-30. Pubmed PMID: 24475900. 
 
 

 
Version 11/05/2021  
Page 56 of 65 
APPENDIX 1: 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g.,, light housework, 
office work) 
2 
In bed < 50% of the time 
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 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 
 
 
 

 
Version 11/05/2021  
Page 57 of 65 
 
APPENDIX 2: 
Prohibited and Restricted Medications 
Generic name 
Trade/Brand name (if applicable) 
 
 
Bicalutamide 
Casodex 
Carbamazepine 
Tegretol 
Celecoxib 
Celebrex 
Ciprofloxacin 
Cipro 
Clarithromycin 
Biaxin 
Clopidogrel 
Plavix 
Dexamethasone 
Decadron 
Diltiazem 
Cardizem 
Enoxaparin 
Lovenox 
Finasteride 
Proscar 
Fluconazole 
Diflucan 
Flutamide 
Eulexin 
Itraconazole 
Onmel, Sporanox 
Ketoconazole 
 
Nilutamide 
Nilandron 
Phenytoin 
Dilantin 
Prednisone 
Sterapred 
Rifampin 
Rifadin 
Telithromycin 
Ketek 
Verapamil 
Calan 
Warfarin 
Coumadin 
 
Notes:  
1. This list is not meant to be all-inclusive.  
2. Any medications known to cause QT prolongation should be used with caution. Periodic 
ECG and electrolyte monitoring should be considered. 
 
 

 
Version 11/05/2021  
Page 58 of 65 
APPENDIX 3: 
 SPECIMEN COLLECTION 
 
A: For tissue analyses:  
Paired pre- and post- treatment tumor tissue specimens will be collected in all patients and 
analysis will be performed per section 8.  Specimens will be processed initially through the 
Tissue Procurement Core Facility. 
 B: For blood analyses:   
All patients will have 8 (eight) 10mL tubes of blood specimens collected at baseline, at the end 
of ibrutinib therapy, and after RP.  The collection will be divided into 60 mL in 6 EDTA tubes for 
PBMCs for immune monitoring and 20 mL in 2 EDTA tubes for plasma for cytokines.: 
 
These specimens will be transported at room temperature to the Tissue Procurement Core 
Facility where they will processed using their SOPs to obtain plasma and PBMCs. 
 
 
 
 
 
 
 

 
Version 11/05/2021  
Page 59 of 65 
APPENDIX 4: 
 CHILD-PUGH SCORE 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/L (mg/dL) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/L (g/dL) 
>35 (>3.5) 
28-35 (2.8-3.5) 
<28 (<2.8) 
PT INR 
<1.7 
1.71-2.30 
>2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
 
Source:  
1. Child CG, Turcotte JG. “Surgery and portal hypertension”. In Child CG. The liver and 
portal hypertension. Philadelphia:Saunders. 1964. pp. 50-64.   
2. Pugh RN, Murray-Lyon IM, Dawson L, Pietroni MC, Williams R . “Transection of te 
oesophagus for bleeding oesophageal varices”.  The British journal of surgery, 1973;60: 
646-9. 
 
 

 
Version 11/05/2021  
Page 60 of 65 
APPENDIX 5: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website. 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 

 
Version 11/05/2021  
Page 61 of 65 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

 
Version 11/05/2021  
Page 0 of 65 
APPENDIX 6: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Pharmacyclics 
Serious AND unexpected 
suspected adverse reaction 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
Report no later than 15 
calendar days after the event 
Unexpected fatal or life-
threatening suspected 
adverse reaction 
 
 
Report no later than 7 
calendar days after initial 
receipt of the information 
Report no later than 15 
calendar days after the event 
Unanticipated problem 
involving risk to 
participants or others 
Report within 10 working 
days.  If the event results in 
the death of a participant 
enrolled at WU/BJH/SLCH, 
report within 1 working day. 
Report via email after IRB 
acknowledgment 
 
 
Major deviation 
Report within 10 working 
days.  If the event results in 
the death of a participant 
enrolled at WU/BJH/SLCH, 
report within 1 working day. 
 
 
 
A series of minor deviations 
that are being reported as a 
continuing noncompliance 
Report within 10 working 
days.   
 
 
 

 
Version 11/05/2021  
Page 1 of 65 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Pharmacyclics 
Protocol exception 
Approval must be obtained 
prior to implementing the 
change 
 
 
 
Clinically important 
increase in the rate of a 
serious suspected adverse 
reaction of that list in the 
protocol or IB 
 
 
Report no later than 15 
calendar days after it is 
determined that the 
information qualifies for 
reporting 
 
Complaints 
If the complaint reveals an 
unanticipated problem 
involving risks to 
participants or others OR 
noncompliance, report 
within 10 working days.  If 
the event results in the death 
of a participant enrolled at 
WU/BJH/SLCH, report 
within 1 working day.  
Otherwise, report at the time 
of continuing review. 
 
 
 
Breach of confidentiality 
Within 10 working days. 
 
 
 
Incarceration 
If withdrawing the 
participant poses a safety 
issue, report within 10 
working days.   
 
 
 

 
Version 11/05/2021  
Page 2 of 65 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
Pharmacyclics 
 
If withdrawing the 
participant does not 
represent a safety issue and 
the patient will be 
withdrawn, report at 
continuing review. 
Pregnancy/Other 
Malignancies/AESIs 
 
 
 
Report no later than 15 days 
of learning of the event 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
FDA 
 
Adverse event or SAE that does not 
require expedited reporting 
If they do not meet the definition of 
an unanticipated problem involving 
risks to participants or others, report 
summary information at the time of 
continuing review 
Adverse events will be reported in 
the toxicity table in the DSM report 
which is typically due every 6 
months. 
The most current toxicity table from 
the DSM report is provided to the 
FDA with the IND’s annual report. 
Minor deviation 
Report summary information at the 
time of continuing review. 
 
 
Complaints 
If the complaint reveals an 
 
 

 
Version 11/05/2021  
Page 3 of 65 
unanticipated problem involving 
risks to participants or others OR 
noncompliance, report within 10 
working days.  If the event results 
in the death of a participant enrolled 
at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at 
the time of continuing review. 
Incarceration 
If withdrawing the participant poses 
a safety issue, report within 10 
working days.   
 
If withdrawing the participant does 
not represent a safety issue and the 
patient will be withdrawn, report at 
continuing review.