Inhibition of Anaphylaxis by Ibrutinib
Phase: PHASE2
Conditions: Food Allergy, Anaphylaxis Food
Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
i 
PROTOCOL 
 
 
Study Title: 
Preventing Life-Threatening Allergic Reactions with Ibrutinib, an 
FDA-Approved BTK Inhibitor 
 
Principal Investigator:  
Jacqueline Pongracic, MD  
 
 
 
 
Northwestern Feinberg School of Medicine 
 
 
 
 
Department of Pediatrics and Medicine, Division of Allergy/Immunology 
 
 
 
 
225 E. Chicago Ave, Box 60 
 
 
 
 
Chicago IL, 60611 
 
 
 
 
Phone: (312) 227-6010 
 
 
 
 
Fax: (312) 227-9401 
 
 
 
 
Email: JPongracic@luriechildrens.org 
 
Sub-Investigator(s): 
 
Bruce Bochner, MD 
 
 
 
Department of Medicine, Division of Allergy/Immunology 
 
 
 
 
 
 
Anne Marie Singh, MD 
 
 
 
 
Department of Pediatrics, Division of Allergy/Immunology 
 
 
 
 
 
 
Biostatistician: 
 
Alfred Rademaker, PhD 
 
 
 
 
Northwestern Feinberg School of Medicine 
 
 
 
Department of Preventive Medicine  
 
 
 
680 North Lake Shore Drive. Suite 1400  
 
 
 
Chicago, Illinois 60611 
 
 
 
 
Phone:  (312) 503-2288 
 
 
 
 
Fax: (312) 908-9588 
 
 
 
 
Email: rademaker@northwestern.edu 
 
Study Drug: 
 
 
Ibrutinib (Brand name: Imbruvica®) 
 
Protocol Number: 
 
BB20150924 
 
Version: 
 
 
August 7, 2017 
 
 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
ii 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................................................ 1 
STUDY SCHEMA ....................................................................................................................................... 2 
STUDY SUMMARY .................................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ............................................................................................... 4 
1.1 
Disease Background ................................................................................................................. 4 
1.2 
Study Drug Background and Associated Known Toxicities ......................................................... 4 
1.3 
Rationale ................................................................................................................................... 4 
2.0 
STUDY OBJECTIVES.................................................................................................................... 5 
2.1 
Primary Objective ...................................................................................................................... 5 
2.2 
Secondary Objectives ................................................................................................................ 5 
2.3 
Exploratory Objective .................................................................. Error! Bookmark not defined. 
2.4 
Endpoints .................................................................................................................................. 5 
3.0 
SUBJECT ELIGIBILITY ................................................................................................................. 6 
3.1 
Inclusion Criteria ........................................................................................................................ 6 
3.2 
Exclusion Criteria ...................................................................................................................... 6 
3.3 
Study Stopping Criteria .............................................................................................................. 7 
3.4 
Recruitment ............................................................................................................................... 7 
4.0 
TREATMENT PLAN ...................................................................................................................... 7 
4.1 
Treatment Dosage and Administration ....................................................................................... 7 
4.2 
Toxicities and Dosing Delays ..................................................................................................... 8 
4.3 
Concomitant Medications/Treatments ........................................................................................ 9 
4.4 
Duration of Therapy ................................................................................................................... 9 
4.5 
Duration of Follow Up ................................................................................................................ 9 
4.6 
Subject Replacement ...............................................................................................................10 
5.0 
STUDY PROCEDURES ................................................................................................................10 
5.1 
Screening/Baseline Procedures ................................................................................................10 
5.2 
Procedures During Treatment (Part 1) ......................................................................................11 
5.3 
Procedures During Treatment (Part 2) ......................................................................................12 
5.4 
Follow-up Procedures ...............................................................................................................13 
5.5 
Time and Events Table .............................................................................................................14 
5.6 
Removal of Subjects from Study ...............................................................................................15 
6.0        RESPONSE CRITERIA .................................................................................................................15 
6.1 
Safety/tolerability ......................................................................................................................15 
6.2  
Efficacy ....................................................................................................................................15 
7.0        ADVERSE EVENTS ......................................................................................................................15 
7.1 
Experimental Therapy...............................................................................................................15 
8.0 
ADVERSE EVENT MONITORING ................................................................................................17 
8.1 
Definitions ................................................................................................................................18 
8.2 
Steps to Determine If an Adverse Event Requires Expedited Reporting ....................................19 
8.3 
Reporting Requirements for Adverse Events .............................................................................19 
9.0 
DRUG INFORMATION ..................................................................................................................20 
9.1 
Ibrutinib 140 mg tablets ............................................................................................................20 
9.2       Return and Retention of Study Drug ...........................................................................................21 
10.0 
STATISTICAL CONSIDERATIONS ..........................................................................................21 
10.1 
Study Design/Study Endpoints ..................................................................................................21 
10.2 
Sample Size and Accrual ..........................................................................................................21 
11.0 
STUDY MANAGEMENT ...........................................................................................................21 
11.1 
Conflict of Interest ....................................................................................................................21 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................................22 
11.3 
Data Management and Monitoring/Auditing...............................................................................22 
11.4 
Adherence to the Protocol ........................................................................................................22 
11.5 
Amendments to the Protocol .....................................................................................................23 
11.6  
Confidentiality ...........................................................................................................................23 
11.7 
Provisions to Protect the Privacy Interests of Subjects ..............................................................23 
11.8 
Record Retention .....................................................................................................................24 
11.9 
Obligations of Investigators .......................................................................................................24 
12.0 
REFERENCES .........................................................................................................................24 
13.0 
APPENDIX 1: Pill Diary ...........................................................................................................27 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
1 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ALC 
Absolute Lymphocyte Count 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BAT 
Basophil Activation Test 
BTK 
Bruton’s Tyrosine Kinase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Comprehensive Metabolic Panel 
CRU 
Clinical Research Unit 
SBPC 
Single-blind Placebo-controlled 
DLT 
Dose-Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
EKG 
Electrocardiogram 
FC 
Food Challenge 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IgE 
Immunoglobulin E 
IV (or iv) 
Intravenously 
MCL 
Mantle Cell Lymphoma 
MTD 
Maximum Tolerated Dose 
OFC 
Oral Food Challenge 
PBMCs 
Peripheral Blood Mononuclear Cells 
p.o. 
per os/by mouth/orally 
PST 
Peripheral Blood Testing 
SAE 
Serious Adverse Event 
sIgE 
Surface Immunoglobulin E 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
SPT 
Skin Prick Test 
WBC 
White Blood Cells 
WM 
Waldenstrom’s Macroglobulineia 
 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
2 
This is a phase II open label study on the use of Ibrutinib on the inhibition of food-induced anaphylaxis in 
adults with food allergy.  Ibrutinib (brand name Imbruvica) is currently FDA approved for the treatment of 
mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulineia 
(WM).  We propose to administer this approved drug to adults with food allergy to inhibit anaphylaxis.  
STUDY SCHEMA 
This is open-label study consists of 2 parts.  Part 1 is designed to determine the fewest doses and 
shortest length of time, from two days to up to 7 days, needed for ibrutinib to fully inhibit tests for food 
allergy, and to determine the length of persistence of efficacy after the drug is stopped.  Part 2 is 
designed to determine the ability of ibrutinib, optimally dosed as defined in Part 1, to prevent signs and 
symptoms of anaphylaxis during a food challenge in food-
allergic subjects.    
   
Part 1: At Visit 1, after undergoing informed consent 
subjects will be screened for eligibility (history, skin prick test 
[SPT] to peanut/tree nuts with histamine and saline SPT 
positive and negative controls, respectively, basophil 
activation test [BAT], peanut or tree nut-specific IgE).  30 mL 
of peripheral blood will be collected by a trained phlebotomist 
using standard procedures for BAT, sIgE to peanut/tree nuts 
and components, quantitative immunoglobulins (QUIGs), 
eosinophil and basophil enumeration, as well as screening 
for toxicities (see below).  After this visit, subjects will be given ibrutinib (two 
doses of 420 mg of ibrutinib to start the following day and to be taken orally at 
8am exactly 24 hours apart) and return for Visit 2 to undergo repeat PST and 
phlebotomy for testing preformed in an identical manner to Visit 1. If two 
consecutive doses of 420 mg of ibrutinib given 24 hours apart is insufficient 
to cause >80% inhibition of the SPT and BAT response, subjects will be 
given two additional doses of 420 mg of ibrutinib to continue to take at 8am 
exactly 24 hours apart for two more days, and return for Visit 3 for identical 
repeat testing as in Visits 1 and 2.  If four consecutive doses of 420 mg of 
ibrutinib given 24 hours apart is insufficient to cause >80% inhibition of the 
SPT and BAT response, subjects will be given three additional doses of 420 
mg of ibrutinib to continue to take 24 hours apart for three more 
days, and return for Visit 4 for identical repeat testing as in 
Visits 1, 2 and 3, where based on preliminary data, we expect 
SPT and BAT to be suppressed.  Once both the SPT and BAT 
responses are inhibited, no further ibrutinib doses will be given, 
and subjects will return on a weekly basis until both the peanut/tree nut PST and BAT return to at least 
80% of baseline values.  At this point, Part 1 will have been completed.  At each visit, patients will be 
monitored for toxicities, including CBC, CMP, and pregnancy testing.  Prior to drug initiation and at the 
end of the trial, an EKG will be performed.  
 
Part 2: Visit 1 will be identical to those for Part 1 except that subjects will take a higher dose of ibrutinib 
(560mg daily) for 2 days and a single-blind, placebo-controlled (SBPC) graded food challenge of up to 8 
mg of peanut or tree nut protein, administered over escalating doses, will be performed in a monitored at 
the study site in a clinical research unit (CRU) setting.  Prior to the SBPC food challenge, 30 mL of 
peripheral blood will be collected for BAT, sIgE to peanut and components, as well as for total IgE, 
eosinophil and basophil enumeration.  During the challenge, subjects will be repeatedly assessed for 
signs and symptoms of food-induced anaphylaxis between each dose per food challenge protocol.  This 
visit will establish each subject’s baseline threshold dose for peanut/tree nut reactivity.   
 
Once a confirmed reaction occurs, the food challenge will be terminated and the reaction treated until it 
has resolved. Within 15 minutes of a positive challenge, an additional 10 mL of blood will be drawn for 
mast cell microparticle analysis.  After a minimum of a two week recovery period, each subject will then 
begin taking ibrutinib 560 mg orally daily for 2 days, which is the minimum number of doses that 
Clinical protocol for part 1 (top) and part 2 
(bottom).  + or - = predicted response; ??? = 
question to be answered; * = if needed 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
3 
demonstrate efficacy as determined in Part 1.  Two hours after the final dose, subjects will return to the 
study site for Visit 2, and PST and SBPC food challenges will be repeated to establish each subject’s 
new threshold dose for peanut/tree nut reactivity while on ibrutinib, and with repeat post-challenge blood 
collection for mast cell microparticle analysis.  At this point of the protocol, ibrutinib dosing will be 
stopped.  Follow up visits starting 3 months after cessation of ibrutinib will be conducted to repeat toxicity 
labs and skin testing.   
STUDY SUMMARY 
Title 
Inhibition of Anaphylaxis by Ibrutinib 
 
Protocol Number 
BB20150924 
Phase 
Phase 2 
Methodology 
Open label study to determine dosing and safety of Ibrutinib for the 
treatment of food allergy 
Study Duration 
12 weeks 
Study Center(s) 
Single-center  
Objectives 
Primary:  To determine the shortest amount of time and fewest ibrutinib 
doses required to eliminate food SPT and BAT reactivity and to evaluate 
the effect of pretreatment with ibrutinib on food allergen reactivity in food 
allergic subjects given ibrutinib 420 mg daily for 2-7 doses 
 
Secondary: To determine if a suppressed SPT response to peanut, 
despite normal BAT responses, predicts whether a SBPC food challenge 
will be altered from baseline threshold dose for peanut reactivity. 
Number of Subjects 
12 
Diagnosis and Main 
Inclusion Criteria 
Adults with food-challenge proven food allergy to peanut (or tree nut)will 
be invited to participate.   
Study Product(s), Dose, 
Route, Regimen 
Ibrutinib 420 or 560 mg, PO once daily  
Duration of administration 
2-7 days 
Reference therapy 
There are currently no approved therapies for food allergy 
Statistical Methodology 
Descriptive statistics will be used to determine 80% reduction in allergy 
test size (skin testing) and basophil degranulation during treatment. 
 
 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
4 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Food allergy is a potentially life threatening disease, and its prevalence continues to increase 
despite public health efforts (1,2)  Newer studies have shown that it is less likely that a subject will 
lose their food allergies over time and food allergies can also start in adulthood, so more adults 
now have life-threatening food allergies.  Near fatal and fatal reactions can occur of subjects with 
food allergies and can lead to devastating results (3,4).  Furthermore, the economic burden of 
childhood food allergy is nearly $25 billion per year, including 200,000 emergency department 
trips annually (5).  Despite this significant disease burden, there are currently no approved 
therapies for food allergy.  Standard of care is constant vigilance in avoidance of allergen, and 
use of self-injected epinephrine after a reaction has occurred.  Therefore, there is a large unmet 
need for new therapeutics to prevent serious allergic disease including food allergy and 
anaphylaxis.  Newly FDA approved BTK inhibitors such as ibrutinib (as well as others under 
development (6,7)) may be able to fill this void, and offer a therapy to these subjects.   
1.2 
Study Drug Background and Associated Known Toxicities 
Ibrutinib is a once daily, oral, selective, irreversible small-molecule inhibitor of Bruton’s tyrosine 
kinase (BTK), a key component of B-cell receptor signaling (8,9).  BTK is also essential for FcεRI 
signaling and triggering of mast cells and basophils (10){Iyer, 2011 #10272;Kuehn, 2008 
#10273;MacGlashan, 2011 #8797}.  It is currently FDA approved for the treatment of Mantle Cell 
Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Waldenstrom’s macroglobulinemia 
(WM). 
 
In subjects with recurrent B-cell lymphoma, >90% irreversible occupancy of the BTK active site in 
peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of >/= 2.5 
mg/kg/day.  Ibrutinib is absorbed with a median Tmax of 1-2 hours.  It is metabolized by 
cytochrome P450 and CYP3A, and has a half-life of 4-6 hours.  The majority (80%) is fecally 
excreted.  
 
The approved CLL and WM dose (420 mg orally once daily) has been shown to inhibit allergy test 
responses in cancer subjects receiving this drug by 1 week of treatment (the earliest time point 
examined) in preliminary data from our group.  The 560 mg dose (used for MCL) has similar side-
effect and toxicity profiles as the lower dose.  Initial data from Part 1 suggests that the 420mg 
dose can at least partially (in some cases fully) inhibit skin test responses to peanut and tree nuts 
in allergic subjects after just 2 doses, with minimal side effects and no observed toxicity thus far in 
subjects taking ibrutinib for up to 7 days.  Therefore, we can justify using the higher dose of 560 
mg orally once daily for Part 2 to investigate whether this higher dose can further reduce skin test 
responses beyond what is seen with the lower dose.   
 
In human studies, ibrutinib is metabolized in the liver, and not significantly renally cleared.  In 
healthy volunteers, co-administration with CYP3A inhibitors increased Cmax, and therefore the 
drug will not be concomitantly administered with strong or moderate inhibitors of CYP3A.  Known 
toxicities in cancer subjects receiving ibrutinib chronically include bleeding events (5% of MCL 
subjects), infection (25% of MCL subjects), myelosuppression (41% of subjects), and renal 
toxicity has also been reported.  Ibrutinib is also pregnancy category D.  This underscores our 
goal of finding the fewest possible doses to achieve the anti-allergy effect we are seeking, which 
could be as few as just 2 doses. 
1.3 
Rationale 
There are currently no treatments for food allergy. IgE uniquely arms mast cells and basophils via 
their surface expression of FcεRI in allergy.  Crosslinking of the receptor is known to activate a 
number of SRC-family kinases (e.g., LYN, SYK) required for receptor function. BTK is a key 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
5 
component of FcεRI signaling and triggering of mast cells and basophils.  Since signaling 
mediated by FcεRI aggregation is thought to require the activity of BTK (8,9), MacGlashan et. al. 
(9) tested ibrutinib, formerly known as PCI-32765, for its ability to prevent activation of human 
basophils in vitro. For stimulation with anti-IgE, ibrutinib inhibited CD63, CD203c and CD11b 
upregulation, and release of histamine, LTC4 and IL-4 as well as the cytosolic calcium response 
(IC90 of ≈50 nM).  Ibrutinib did not inhibit basophil activation by FMLP or C5a and did not inhibit 
IL-13 release induced by IL-3, suggesting that BTK is required for IgE-mediated activation of 
human basophils.  We propose to test whether this pharmacology can be exploited in vivo to 
prevent allergic reactions. 
 
Peanut and tree nut allergies are among the most common adult food allergens, and can 
often be the most severe.  Additionally, peanut and tree nut allergies are often life-long.  Young 
adults and adolescents have a higher rate of accidental exposure and mortality as a result of food 
allergies than younger children, so there is an unmet need for therapies directed at food allergy, 
especially in this population.  Therefore, we have chosen peanut and tree nut allergies in an effort 
to investigate a treatment that has the potential to benefit the most individuals with a potentially 
severe allergy.  
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
2.1.1 
To determine if short term administration of ibrutinib to adults with peanut (or tree 
nut) allergy will safely change allergen challenge thresholds 
2.2 
Secondary Objectives  
2.2.1 
To describe the adverse events associated with ibrutinib when administered in a 
short course of 2-7 doses daily 
 
2.2.2 
To determine the minimum number of doses of ibrutinib needed to inhibit testing 
for food allergy (SPT and BAT) 
 
2.2.3 
To determine the length of effect of inhibition of testing for food allergy after the 
drug is stopped (SPT and BAT) 
 
2.2.4 
To determine if 2-7 daily doses of ibrutinib have any impact on blood levels of 
total and food-specific IgE, and numbers of circulating eosinophils and basophils. 
2.3 
Endpoints 
Primary Objective 2.1.1: The highest dose of food allergen that is tolerated in a food 
challenge prior to reaction occurring in a food challenge, both before and while taking 
ibrutinib.  
 
Secondary Objective 2.2.1:  Adverse events, including bleeding, hepatotoxicity and renal 
toxicity will be monitored.  
 
Secondary Objective 2.2.3:  Change in SPT size and percent activation of basophils from 
BAT will be determined. 
 
Secondary Objective 2.2.4:  Change in blood levels of total and food-specific IgE, and 
numbers of circulating eosinophils and basophils. 
 
Exploratory Objective:  Clinical signs and symptom of food allergy reactions will be 
compared among subjects at oral food challenge visit in the study.   

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
6 
3.0 
SUBJECT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled in the study. Study 
procedures may not begin until a subject signs the informed consent form. 
3.1 
Inclusion Criteria 
3.1.1 
History of food allergy to peanut (or tree nut).  
 
3.1.2 
Male or female age ≥ 18 years. 
 
3.1.3 
Positive skin prick testing and basophil activation test to the trigger food(s), either 
peanut and/or tree nut(s). 
 
3.1.4 
Clinical reaction to oral food challenge at baseline (for Part 2 only) 
 
3.1.5 
Adequate organ and marrow function as defined below: 
- leukocytes 
 
≥ 3,000/mcL 
- absolute neutrophil count ≥ 1,500/mcL 
- platelets  
 
≥ 100,000/mcl 
- total bilirubin 
 
within normal institutional limits 
- AST(SGOT)/ALT(SPGT) within normal institutional limits 
- Creatinine  
 
within normal institutional limits 
 
 
3.1.6 
Women of child bearing potential must agree to two forms of highly effective 
contraception (hormonal, device, or barrier method of birth control; abstinence) 
prior to study entry, for the duration of study participation, and for 90 days 
following completion of therapy.  Should a woman become pregnant or suspect 
she is pregnant while participating in this study, she should inform the Principal 
Investigator and her treating physician immediately. 
 
3.1.5.1 A female of child bearing potential is any woman (regardless of sexual 
orientation, having undergone a tubal ligation, or remaining celibate by 
choice) who meets the following criteria: 
 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
 
Has not been naturally postmenopausal for at least 12 consecutive 
months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
 
3.1.7 
Ability to understand and the willingness to sign a written informed consent. 
 
3.1.8 
Ability to clearly understand and speak English at an 8th grade reading level. For 
safety reasons, subjects must speak English due to the anticipated need for clear 
and timely communication with investigators and the study team in emergency 
situations, since the investigators and study team are English speaking. 
3.2 
Exclusion Criteria 
 
3.2.1 
Subjects who have been on immunomodulatory therapies or oral corticosteroids 
within 1 month prior to study participation will be excluded, and those taking 
antihistamines must stop these drugs for one week prior to enrollment and must 
refrain from taking antihistamines during the duration of the study so as not to 
interfere with SPT responses. 
 
3.2.2 
Subjects with symptoms not consistent with type 1 food reactions (atopic 
dermatitis, eosinophilic esophagitis and any other non-IgE-mediated food 
sensitivities) will be excluded. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
7 
 
3.2.3 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to ibrutinib. 
 
3.2.4 
Uncontrolled inter-current illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, beta-blocker use or psychiatric illness/social situations that would 
limit compliance with study requirements. 
 
3.2.5 
Subjects must not be pregnant or nursing due to the potential for congenital 
abnormalities and the potential of this regimen to harm nursing infants. 
 
3.2.6 
Subjects on anticoagulants, anti-platelet therapy, or any other predisposition 
towards bleeding. 
 
3.2.7 
Subjects with history of idiopathic urticaria, dermatographism, idiopathic or 
unexplained anaphylaxis, or anaphylaxis (to foods or otherwise) resulting in 
intubation, prolonged hypotension, or neurological sequelae 
3.3 
Study Stopping Criteria 
The study will be stopped if >50% of patients cannot complete the protocol due to 
toxicities or adverse events.  Toxicities (section 4.2) and adverse events (section 7.0) are 
listed below. Monitoring is described in section 8.0.  
3.4 
Recruitment 
Patients with a diagnosis of peanut or tree nut allergy by a board certified allergist-
immunologist will be identified as potential subjects from the allergy clinics at 
Northwestern University Feinberg School of Medicine. The treating physician will ask 
potential subjects permission to be contacted by study personnel. Potential subjects will 
then be contacted by authorized study personnel and given time to review the study 
information and consider participation.  
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
For Part 1 of the study, we will determine the length of treatment (i.e., the number of daily 
doses) required to inhibit both basophil and food skin test responses.  Preliminary data 
demonstrates that 7 days of treatment will inhibit both basophil and mast cell 
responsiveness to aeroallergens, but have not yet tested shorter time points.  Prior 
studies in cancer subjects suggest that one dose is sufficient to completely inhibit BAT, 
but we propose a minimum of two doses to allow for diffusion and penetration of ibrutinib 
into the skin compartment where our SPT is performed to assess skin mast cell 
responsiveness.  For Part 1, 6 subjects will take ibrutinib 420 mg, by mouth once daily 
(every 24 hours) on an outpatient basis.  After two days, the subject will undergo blood 
testing and SPT to assess basophil and mast cell reactivity.  If both tests are negative, 
Part 1 is completed.  If both tests are not negative, then the subject will take 2 more days 
of ibrutinib (same dose, for a total of 4 doses), and identical testing will be repeated. If 
testing is not negative at day 4, the subject will take 3 more days of ibrutinib (same dose, 
for a total of 7 doses), which is the maximum anticipated number of doses needed to 
suppress both the BAT and SPT.  

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
8 
 
For Part 2 of the study, 6 subjects will take ibrutinib 560 mg once daily by mouth (every 
24 hours) for 2 days, which is the minimum number of days required to cause ≥80% 
inhibition of food SPT and BAT responses as determined in part 1.  Part 2 will last a 
minimum of 3 days. 
 
Dose-limiting toxicity (DLT) includes any grade 3 or 4 hematologic toxicity, grade 3 
hepatotoxicity or increase in creatinine x 2.5 normal limit.  DLT will be monitored at each 
visit, at any time during treatment.   
 
Maximally tolerated dose (MTD) will occur at the point DLT occurs.  Ibrutinib is approved 
as a daily medication for another indication, and we propose to use the drug in adults 
only at its approved oral dosing of 420 or 560 mg daily for a minimum of two days and a 
maximum of 7 days.  Dose limiting events include grade 3 or 4 hematologic events, grade 
3 or 4 hepatotoxicity, AST or ALT >3 times normal range, creatinine > 2.5 times normal 
range.  DLT evaluation will be completed throughout the study, anytime during treatment.  
 
In healthy volunteers, co-administration with CYP3A inhibitors increased Cmax, and 
therefore the drug will not be concomitantly administered with strong or moderate 
inhibitors of CYP3A (for example, “azole” medications and subjects will be advised 
against drinking grapefruit juice). 
4.2 
Toxicities and Dosing Delays 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
subject will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.4).  
 
At each visit, subjects will be monitored for toxicities.  If a subject develops a grade 3 or 4 
hematologic, renal, or hepatotoxicity, the medication will be stopped.  Toxicities with 
grades are listed below.  
 
 
 
Hematological Toxicities: 
 
Hematological Toxicity Dose Reductions for Ibrutinib 
ANC 
Platelets 
Action 
≥ 1,500/L 
100,000/L 
None. 
 
1000-1499/L 
 
75,000-99,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
TBD dose.  
-2nd Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses.  
Clinical protocol for part 1 (left) and part 2 (right). + or - = predicted response;   
??? = question to be answered; * = if needed 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
9 
-3rd Occurrence:  
Discontinue protocol therapy. 
 
500-999/L 
 
50,000-74,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
TBD dose.  
 -2nd Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Do not 
replace missed doses. Restart next treatment at 
TBD dose. 
-3rd Occurrence: Discontinue protocol therapy. 
 
<500/L 
 
<50,000/L 
-1st Occurrence: Hold current dose until ANC ≥ 
1,500/L and platelets ≥ 100,000/L. Restart 
next treatment at TBD dose. 
-2nd Occurrence: Discontinue protocol therapy.  
 
Renal Toxicity:  Creatinine will be monitored per protocol.  Creatinine levels >2.5 times 
the normal limit will result in discontinuation of protocol therapy.   
 
Hepatotoxicity:  Grade 3 hepatotoxicity, or an increase in AST or ALT >3 times upper limit 
of normal will result in discontinuation in protocol therapy.  
4.3 
Concomitant Medications/Treatments 
The following concomitant medications/treatments are not allowed: immunomodulatory 
therapies, oral corticosteroids within 1 month of study participation; those taking 
antihistamines must stop these drugs for one week prior to enrollment and must refrain 
from taking antihistamines during the duration of the study so as not to interfere with SPT 
responses; and any other prior investigational interventions.   
4.4 
Duration of Therapy 
Treatment will continue for a minimum of 2 days and a maximum of 7 days per Part 1 of 
the protocol.  Other reasons the medication may be discontinued include: 
 
Inter-current illness that prevents further administration of treatment; 
 
Unacceptable adverse event(s); 
 
Subject decides to withdraw from the study; or 
 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
4.5 
Duration of Follow Up 
Subjects will be followed until SPT and BAT return to baseline in Part 1, and for up to 6 
months after cessation of ibrutinib treatment in Part 2. Subjects removed from treatment 
for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  
 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. 
The Principal Investigator will be notified.  The reason for study removal and the date the 
subject was removed will be documented in the Case Report Form. The subject will be 
followed-up per protocol.  

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
10 
4.6 
Subject Replacement 
Subjects who withdraw voluntarily from the study, but were tolerating the drug will be 
replaced.  Subjects who drop out or miss doses due to toxicity will not be replaced since 
these subjects will be considered to have experienced a dose limiting toxicity. 
 
 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining written informed consent. Assessments performed for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 14 days prior to start of treatment. 
The screening procedures include: 
5.1.1 Informed Consent 
 
Informed consent will be obtained per IRB and GCP guidelines.  
5.1.2 Medical history 
 
Complete medical and surgical history, history of infections will be obtained.  
5.1.3 Demographics 
 
Age, gender, race, ethnicity will be obtained. 
5.1.4 Review subject eligibility criteria   
Subjects will be screened to ensure they meet inclusion and exclusion criteria, 
including history and prior laboratory testing consistent with a diagnosis of IgE 
mediated food allergy.  
5.1.5 Review previous and concomitant medications 
 
Medications will be reviewed and documented.  
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight and 
basic full physical exam will be performed by study physicians.  
5.1.7 Adverse event assessment 
Baseline adverse events will be assessed. This will include a CMP and CBC, 
EKG.  See section 6 for Adverse Event monitoring and reporting. 
5.1.8 Hematology 
 
Baseline CBC will be performed.  
5.1.9 Blood draw for correlative studies 
 
See Section 9.0 for details. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
11 
5.1.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose, and total bilirubin. 
5.1.11 Pregnancy test (for females of child bearing potential) 
 
See section 3.1.6.1 for definition.  
 
5.1.12 Immunoglobulin levels  
Total quantitative immunoglobulins (QUIGs), including IgG, IgA, IgM, and IgE, as 
well as serum specific IgE for peanut/tree nuts will be monitored  
5.1.13 Spirometry  
To be performed before SBFC if the patient has a history of asthma or exercise-
induced bronchospasm. 
5.2 
Procedures During Treatment (Part 1) 
5.2.1 
Screening visit (Day 0) (Screening visit testing will be completed before 
drug administration) 
 
 
Screening:   
 Physical exam, vital signs 
 CBC 
 CMP 
 Immunoglobulin levels  
 EKG 
 Urine Pregnancy test (if required) 
 
Procedures (to be done only if labs and EKG are within normal limits):  
 Skin-prick testing 
 Basophil activation test 
5.2.2 
Day 2 (or 4 or 7 depending on when skin testing and basophil activation 
test return to baseline) 
 Skin prick testing 
 Basophil activation test 
 Hematology 
 Serum chemistries 
 Immunoglobulin levels  
5.2.3 
After treatment termination (Termination and End of Study visits; time point 
determined when both skin prick testing and basophil activation testing 
return to baseline) 
 Physical exam, vital signs 
 Hematology 
 Serum chemistries 
 Immunoglobulin levels  
 EKG 
 Urine Pregnancy test (if required) 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
12 
5.3 
Procedures During Treatment (Part 2) 
5.3.1 
Screening/Baseline visit (Visit 1) 
 
 
Screening: 
 Physical exam, vital signs 
 Urine Pregnancy test (if required) 
 CBC 
 CMP 
 Immunoglobulin levels  
 EKG 
 Spirometry (only if the subject has a history of asthma)  
 
Procedures (to be done only if labs and EKG are within normal limits) 
 Skin prick testing 
 Basophil activation test 
 SBPC oral food challenge as follows: 
 
All oral food challenges (OFC) shall be performed as single (patient)-blinded, placebo 
controlled food challenges according to standard published guidelines (11, 12).  
Placebo challenge and active challenge will be performed in that order on the same day 
if the subject has no symptoms during the first (placebo) challenge.  If a reaction 
requiring treatment occurs during the first challenge, the next challenge should not be 
performed until the symptoms have subsided. Oral food challenge to peanut or tree nut 
protein will be performed according to standard operating procedure.  At physician 
discretion, based upon history and possible subjective or very mild objective symptoms 
during a challenge, dosing intervals may be extended. 
 
Actions to minimize risk of severe allergic reactions during oral food challenge (OFC): 
Prior to the OFC visit, subjects will be told to contact study staff about asthma and 
seasonal allergy symptoms, fever, acute infections including upper respiratory 
infections, rashes or change in status of chronic medical conditions.  OFCs will be 
rescheduled in the event that any of these occur. Study staff will contact subjects 1-3 
days before the OFC to inquire about recent symptoms. 
 
All OFCs will be conducted in the Clinical Research Unit within the main hospital.  
Intravenous access will be obtained before the OFC begins.  Emergency medications 
(epinephrine, diphenhydramine, cetirizine, albuterol, ranitidine) will be immediately 
accessible in the subject’s room.  All OFCs will be conducted by trained personnel and 
supervised by a clinician with experience in performing OFCs and trained in the 
treatment of anaphylaxis.  Spirometry (assessment of pulmonary function) will be 
performed prior to the onset of the OFC. Vital signs and pulse oximetry will be obtained 
at baseline and prior to each dose of the food allergen and q15 minutes thereafter with 
an observation period of at last 2 hours after the last dose is consumed (longer should a 
reaction occur).  The OFC will begin with a low dose, which will increase incrementally.  
At physician discretion, based upon history and possible subjective or very mild 
objective symptoms during a challenge, dosing intervals may be extended.  The 
procedure will be stopped when clear objective symptoms are noted.  
 
Subjects will be discharged after a period of observation appropriate to the nature of the 
symptoms.  They will receive information regarding possible delayed manifestations 
and home treatment.  All subjects will be provided with an epinephrine auto-injector to 
take home (if they do not have one already) and instructions on how and when to use it. 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
13 
5.3.2 
Visit 2 
 Skin prick testing 
 Basophil activation test 
 CBC 
 CMP 
 Immunoglobulin levels  
 Spirometry (only if the patient has a history of asthma) 
 
 SBPC oral food challenge as follows: 
 
All oral food challenges (OFC) shall be performed as single(patient)-blind, placebo 
controlled food challenges according to standard published guidelines (11, 12).  
Placebo challenge and active challenge will be performed in that order on the same day 
if the subject has no symptoms during the first (placebo) challenge.  If a reaction 
requiring treatment occurs during the first challenge, the next challenge should not be 
performed until the symptoms have subsided. Oral food challenge to peanut or tree nut 
protein will be performed according to standard operating procedure.   
At physician discretion, based upon history and possible subjective or very mild 
objective symptoms during a challenge, dosing intervals may be extended. 
 
Actions to minimize risk of severe allergic reactions during oral food challenge (OFC): 
Prior to the OFC visit, subjects will be told to contact study staff about asthma and 
seasonal allergy symptoms, fever, acute infections including upper respiratory 
infections, rashes or change in status of chronic medical conditions.  OFCs will be 
rescheduled in the event that any of these occur. Study staff will contact subjects 1-3 
days before the OFC to inquire about recent symptoms. 
 
All OFCs will be conducted in the Clinical Research Unit within the main hospital.  
Intravenous access will be obtained before the OFC begins.  Emergency medications 
(epinephrine, diphenhydramine, cetirizine, albuterol, ranitidine) will be immediately 
accessible in the subject’s room.  All OFCs will be conducted by trained personnel and 
supervised by a clinician with experience in performing OFCs and trained in the 
treatment of anaphylaxis.  Spirometry (assessment of pulmonary function) will be 
performed prior to the onset of the OFC. Vital signs and pulse oximetry will be obtained 
at baseline and prior to each dose of the food allergen and q15 minutes thereafter with 
an observation period of at last 2 hours after the last dose is consumed (longer should a 
reaction occur).  The OFC will begin with a low dose, which will increase incrementally.  
At physician discretion, based upon history and possible subjective or very mild 
objective symptoms during a challenge, dosing intervals may be extended.  The 
procedure will be stopped when clear objective symptoms are noted.  
 
Subjects will be discharged after a period of observation appropriate to the nature of the 
symptoms.  They will receive information regarding possible delayed manifestations 
and home treatment.  All subjects will be provided with an epinephrine auto-injector to 
take home (if they do not have one already) and instructions on how and when to use it. 
5.4 
Follow-up Procedures 
Subjects will be followed every month after completion of (or early withdrawal from) study 
treatment until testing returns to baseline. Toxicity monitoring will be repeated (including 
hematology, serum chemistries, QUIGs, ssIgE) at 3 months after cessation of ibrutinib; if 
at this time they are not yet back to baseline, they will be repeated at 6 months.   
 
Physical exam, vital signs 
 
Urine Pregnancy test (if required) 
 
CBC 
 
CMP 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
14 
 
Immunoglobulin levels  
 
Skin prick testing  
 
 
 
 
5.5 
Time and Events Table 
5.4.1. Part 1 
 
Visit 
1 
2 
3a 
4/Early 
Termination 
End-of-
Study 
 
 
Screening 
/ 
Day 0 
Day 2 
Day 4 or 
Day 7 
Every 7 
days until all 
allergy 
testing 
returns to 
baseline 
positive 
Final 
Visit 
when all 
allergy 
testing is 
positive 
Informed 
Consent 
X 
 
 
 
 
Skin prick testing 
X 
X 
X 
X 
 
Basophil 
activation test 
X 
X 
X 
X 
 
History and PE 
X 
 
 
 
X 
Toxicity (include 
DLT) Evaluations 
X 
X 
X 
X 
X 
CBC 
X 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
X 
Urine pregnancy 
testingb 
X 
X 
X 
X 
X 
 
a If required 
 
b Females of child-bearing potential only 
 
5.4.2. Part 2 
 
Visit 
1 
2 
3 
 
 
Screeing / 
Day 0 
Day 2 
Follow up 
(3 and/or 6 
months 
after Visit 
2) 
Informed 
Consent 
X 
 
 
Skin prick testing 
X 
X 
X 
Basophil 
activation test 
X 
X 
 
SBPC food 
challenge 
X 
X 
 
History and PE 
X 
X 
X 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
15 
Toxicity (include 
DLT) Evaluations 
X 
X 
X 
CBC 
X 
X 
X 
CMP 
X 
X 
X 
EKG 
X 
X 
 
Urine pregnancy 
testb 
X 
 
 
 
b Females of child-bearing potential only 
 
5.6 
Removal of Subjects from Study  
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted);  
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; 
5.5.4 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.5 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.6 
Subject becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); or 
5.5.7 
Lost to follow-up. If a research subject cannot be located after a period of 2 
months, the subject may be considered “lost to follow-up.” All attempts to contact 
the subject during the 2 months must be documented. 
6.0        RESPONSE CRITERIA 
6.1 
Safety/tolerability 
Analyses will be performed for all subjects having received at least one dose of study 
drug. CBC, CMP, EKG will be performed on all subjects to monitor for toxicities and 
safety. 
6.2  
Efficacy 
Increase in quantity of food that can be ingested on oral food challenge, decreased skin 
prick tests and decreased basophil activation will be used to assess efficacy of the 
treatment.  
7.0        ADVERSE EVENTS 
7.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Study Agent Prescribing 
Information.  (This drug is currently FDA approved for alternate indications. Sections 
below are from the current package insert).  
7.1.1 
Contraindications 
 
None. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
16 
7.1.2 Special Warnings and Precautions for Use 
Prior studies of ibrutinib adverse events were performed on cancer patients who had 
often failed other treatments, and were treated chronically.  However, Advani et. al. (13) 
reported side effects in a phase 1 study for only 28 days, the shortest duration of 
treatment that has been reported in the literature.  In that study, a total of 56 patients with 
a variety of relapsed B-cell malignancies were treated over seven dosage cohorts (1.25 - 
12 mg/kg/day).  For the cohort receiving dosages closest to the one being used in our 
study (a total of 6 subjects given 5 mg/kg/day, or 420 mg/day for an 81 kg person) the 
most common adverse events were typically grade 1 or 2 in severity.  Grade 3 or 4 
events were infrequent and independent of dose.  Data from this cohort of 6 subjects was 
extracted and reproduced from Table 3 of the Advani et. al. paper below.  For the entire 
cohort of 56 subjects, Grade 3-4 hematologic toxicities included neutropenia (12.5%), 
thrombocytopenia (7.2%) and anemia (7.1%).  According to the authors, no evidence of 
cumulative hematologic or non-hematologic toxicity was observed in patients with 
prolonged dosing, nor was any consistent relationship seen between dose level and 
adverse events.   
 
 
As the subjects enrolled in this study will be generally healthy except for food allergy, and 
on ibrutinib for a much shorter duration (maximum of 7 days, perhaps as little as 2 days), 
we expected adverse events to be milder and less frequent, if at all, compared to prior 
studies of ibrutinib in cancer trials.  However, for completeness, adverse events as 
documented with chronic use are detailed below.  
7.1.2.1 Hemorrhage 
Five percent of patients with MCL had Grade 3 or higher bleeding events 
(subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding 
events including bruising of any grade occurred in 48% of patients with MCL 
treated with 560 mg daily. 
The mechanism for the bleeding events is not well understood. 
7.1.2.2 Infections 
Fatal and non-fatal infections have occurred with ibrutinib therapy. At least 25% 
of patients with MCL had infections Grade 3 or greater NCI Common 
Terminology Criteria for Adverse Events CTCAE) (14). 
7.1.2.3 Myelosuppression 
Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. 
These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%). 
Monitor complete blood counts monthly. 
7.1.2.4 Renal Toxicity 
Fatal and serious cases of renal failure have occurred with ibrutinib therapy. 
Treatment- emergent increases in creatinine levels up to 1.5 times the upper limit 
of normal occurred in 67% of patients and from 1.5 to 3 times the upper limit of 
normal in 9% of patients. Periodically monitor creatinine levels. Maintain 
hydration. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
17 
7.1.2.5 Embryo-Fetal Toxicity 
Based on findings in animals, ibrutinib can cause fetal harm when administered 
to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 
times those reported in patients with MCL receiving the ibrutinib dose of 560 mg 
per day. Reduced fetal weights were observed at lower exposures. Advise 
women to avoid becoming pregnant while taking ibrutinib. If this drug is used 
during pregnancy or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to a fetus. 
7.1.3 
Interaction with other medications 
As stated, metabolism of ibrutinib is inhibited by CYP3A inhibitors.  Patients on 
these medications will be excluded.  
7.1.4 
Adverse Reactions 
As per package insert (15), adverse reactions are listed in Section 7.1.2. Of note, 
patients in the trial references took a larger dose and for much longer duration 
that we propose in this study.  
The most commonly occurring adverse reactions (approx. 20%) were 
thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, 
peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, 
constipation, rash, abdominal pain, vomiting and decreased appetite. 
The most common Grade 3 or 4 non-hematological adverse reactions (approx. 
5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and 
skin infections. 
Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 
560 mg daily occurring at a rate of approx. 10%. 
Ten patients (9%) discontinued treatment due to adverse reactions in the trial 
(N=111). The most frequent adverse reaction leading to treatment 
discontinuation was subdural hematoma (1.8%). Adverse reactions leading to 
dose reduction occurred in 14% of patients. 
Patients with MCL who develop lymphocytosis greater than 400,000/mcL have 
developed intracranial hemorrhage, lethargy, gait instability, and headache. 
However, some of these cases were in the setting of disease progression. 
Forty percent of patients had elevated uric acid levels on study including 13% 
with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 
15% of patients.  
8.0 
ADVERSE EVENT MONITORING 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of Subjects enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during a trial. Additionally, certain adverse events must be reported in an expedited manner 
to allow for optimal monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug/device, will 
be monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse event 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
18 
return to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the changes observed; or 
 
death. 
8.1 
Definitions 
8.1.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
8.1.2  
Severity of Adverse Events 
The severity of an AE is graded as follows: 
 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
 
Severe (grade 3): the event makes the subject unable to perform normal daily 
activities or significantly affects his/her clinical status. 
 
Life-threatening (grade 4): the subject was at risk of death at the time of the 
event. 
 
Fatal (grade 5): the event caused death. 
8.1.3 
Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
8.1.3.1       Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
8.1.3.2       Is life-threatening. 
(the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
19 
8.1.3.3       Requires in-subject hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
8.1.3.4       Results in persistent or significant disability or incapacity. 
8.1.3.5       Is a congenital anomaly/birth defect. 
8.1.3.6       Is an important medical event. 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the subject, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event“. For 
example: allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; convulsions that may not result in hospitalization; development 
of drug abuse or drug dependency. 
8.2 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event. 
 
Step 2: Grade the adverse event. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
8.3 
Reporting Requirements for Adverse Events 
8.3.1 
Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug.  
 
The Northwestern University IRB must be notified within 5 business days of 
any unanticipated problems involving risk to subjects or others (UPIRSO). 
The following events meet the definition of UPIRSO: 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
20 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
7. The FDA should be notified within 7 business days of any unexpected 
fatal or life-threatening adverse event with possible relationship to study 
drug, and 15 business days of any event that is considered: 1) serious, 
2) unexpected, and 3) at least possibly related to study participation. 
8.3.2     Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation- are to be reported annually as part 
of regular data submission. 
8.3.3 
Stopping Rules  
The study will be stopped if >50% of patients cannot complete the protocol due to 
toxicities or adverse events.    
 
9.0 
DRUG INFORMATION 
9.1 
Ibrutinib 140 mg tablets 
 
Other names for the drug(s)/device: Imbruvica® 
 
Classification - type of agent/device: small molecule BTK inhibitor 
 
Mode of action: Ibrutinib forms a covalent bond with a cysteine residue in the BTK active 
site, leading to inhibition of BTK enzymatic activity.  BTK is a signaling molecule of the B-
cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling 
through the B-cell surface receptors results in activation of pathways necessary for B-cell 
trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits 
malignant B-cell proliferation and survival in vivo as well as cell migration and substrate 
adhesion in vitro.  
 
Storage and stability:  Ibrutinib is stored at room temperature and the tablets are 
stable.  
 
Protocol dose: 420 or 560 mg once daily for 2-7 days 
 
Preparation: as supplied from the manufacturer 
 
Route of administration for this study: By mouth 
 
Incompatibilities:  N/A 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
21 
 
Availability: commercially available by prescription.  Medication will be paid for 
through NIH funding, and provided free of charge to subjects.  
 
Side effects: Most common side effects are diarrhea, nausea, fatigue and 
musculoskeletal pain.  Other side effects include myelosuppression, bleeding and 
hepatoxicity.  Please refer to package insert for comprehensive list of side effects.  
 
Nursing implications:  Ibrutinib is category D.  It should not be used in nursing 
mothers.   
 
9.2       Return and Retention of Study Drug 
Study drug will obtained by the research pharmacy at Northwestern Feinberg School of 
Medicine by prescription only.  Study drug will dispensed as needed, until next follow up.  
Therefore, we do not anticipate retention of study drug.  However, if there is unused 
study drug, it will be disposed of in an appropriate manner.  
 
9.2.1 
Compliance will be assessed by subject diary and self-report.   
 
10.0 
STATISTICAL CONSIDERATIONS 
Descriptive statistics will be completed to determine an 80% reduction in skin prick wheal size 
and basophil activation test reactivity (as determined by % inhibition of anti-IgE-induced CD63 
expression).  As this is an open label study, each patient’s responsiveness will be examined 
compared to themselves prior to initiation of treatment.  
10.1 
Study Design/Study Endpoints 
This is an open label study of ibrutnib in 12 food allergic adults to determine the shortest 
amount of time and fewest ibrutinib doses required to eliminate food SPT and BAT 
reactivity and to evaluate the effect of pretreatment with ibrutinib on food allergen 
reactivity in food allergic subjects given ibrutinib 420 or 560 mg daily for 2-7 doses.  
Given the nature of the study, it will be stopped if >50% of patients have a DLT at target 
enrollment.  
10.2 
Sample Size and Accrual 
12 subjects allows 80% power to detect a reduction in skin test positivity rate from 100% 
before treatment to 15% after treatment using a one-sided 0.05 level McNemar’s test.  
Patients will be recruited from the allergy clinics at Northwestern University Feinberg 
School of Medicine with a diagnosis of peanut (or tree nut) allergy by a board certified 
allergist-immunologist.  
 
10.3 
Data Analyses Plans 
As this is an open label trial, descriptive statistics will be used.  Each patient will be 
compared to him/herself prior to beginning treatment and at each time point in the study 
to assess SPT size (parts 1 and 2), BAT response (parts 1 and 2), and OFC threshold 
and response (part 2).   
11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by Northwestern Feinberg School of Medicine.   All investigators will 
follow the University conflict of interest policy. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
22 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a subject’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the 
informed consent discussion. 
11.3 
Data Management and Monitoring/Auditing 
As has been done previously for the phase 1 study of ibrutinib (13), adverse events will 
be monitored throughout treatment and toxicities will be assessed using the National 
Cancer Institute Common Toxicity Criteria for AEs, with its latest version, currently 
version 4.03.   
11.4 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
11.4.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form 
must be completed within five (5) business days of making the change.  
11.4.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
23 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
Protocol Deviations: Deviations should be summarized and reported to the IRB 
at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  
11.5 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
subject, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
11.6  
Confidentiality 
The specimens will be coded and data will be stored in the Allergy-Immunology Research 
Labs, Mezzanine, McGaw Pavilion, or in locked file cabinets and/or on password 
protected computers.  Only the study personnel will have access to the specimens and 
data generated.  The PI and the study team members will be responsible for receipt or 
transmission of the data and specimens. The specimens will be maintained until 
exhausted or until the study ends.  If there are remaining samples at the end of the study, 
any identifying information will be removed from the sample vial and the specimens will 
be treated with 10% bleach and discarded.  Unused portions of the specimens may be 
shared with other members of the University community.  The original data will remain 
with the PI in the Allergy Division.  No PHI will be shared.  
11.7 
Provisions to Protect the Privacy Interests of Subjects 
Certain other people besides the PI and his research team may review the results of the 
study, such as administrative staff members from the Office of Research, Office of 
Research Integrity and members of the Institutional Review Board, and members of the 
Office for Human Research Protections.  There is a slight risk that a subject’s privacy 
might be at risk.  All of the above mentioned people in the respective capacities are 
obligated to protect a subject’s privacy and have training and certification in the 
safeguarding of the patient’s privacy.  All data and results will be maintained in the 
Allergy-Immunology Research Labs, Mezzanine, McGaw Pavilion, in locked file cabinets 
and/or on password protected computers. 
  
To help the subjects feel at ease, these safeguards are outlined in the consent form. 
  
As far as information in medical records, only licensed medical personnel would have 
permission to access the information. 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
24 
 
11.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed subject consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
11.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study subjects. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
12.0 
REFERENCES 
 
1. 
Sicherer SH, Sampson HA. Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment. J 
Allergy Clin Immunol. 2014 Feb;133(2):291–307–quiz308.  
2. 
Branum AM, Lukacs SL. Food allergy among U.S. children: trends in prevalence and 
hospitalizations. NCHS Data Brief. 2008 Oct;(10):1–8.  
3. 
Sampson HA. Fatal food-induced anaphylaxis. Allergy. 1998;53(46 Suppl):125–30.  
4. 
Tejedor Alonso MA, Moro Moro M, Múgica García MV. Epidemiology of anaphylaxis. Clin Exp 
Allergy. 2015 Jun;45(6):1027–39.  
5. 
Gupta R, Holdford D, Bilaver L, Dyer A, Holl JL, Meltzer D. The economic impact of childhood food 
allergy in the United States. JAMA Pediatr. 2013 Nov;167(11):1026–31.  
6. 
Burger JA. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 2014 
Mar;9(1):44–9.  
7. 
Whang JA, Chang BY. Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. 
Drug Discov Today. 2014 Aug;19(8):1200–4.  

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
25 
8. 
Kuehn HS, Swindle EJ, Kim M-S, Beaven MA, Metcalfe DD, Gilfillan AM. The phosphoinositide 3-
kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of 
reactive oxygen species in antigen-stimulated mast cells. J Immunol. 2008 Dec 1;181(11):7706–
12.  
9. 
MacGlashan D, Honigberg LA, Smith A, Buggy J, Schroeder JT. Inhibition of IgE-mediated 
secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor. Int 
Immunopharmacol. 2011 Apr;11(4):475–9.  
10. 
Wechsler JB, Schroeder HA, Byrne AJ, Chien KB, Bryce PJ. Anaphylactic responses to histamine 
in mice utilize both histamine receptors 1 and 2. Allergy. 2013 Oct;68(10):1338–40.  
11. 
Bindslev-Jensen C, Ballmer-Weber BK, Bengtsson U, Blanco C, Ebner C, Hourihane J, Knulst AC, 
Moneret-Vautrin DA, Nekam K, Niggemann B, et al. 2004. Standardization of food challenges in patients 
with immediate reactions to foods--position paper from the European Academy of Allergology and Clinical 
Immunology. 2004 Allergy, 59:690-697. 
 
12. 
Nowak-Wegrzyn A, Assa'ad AH, Bahna SL, Bock SA, Sicherer SH, Teuber SS, Adverse Reactions to 
Food Committee of American Academy of Allergy A, Immunology. 2009. Work Group report: oral food 
challenge testing. J Allergy Clin Immunol, 2009 123:S365-383. 
 
13. 
Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, 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.  
14. 
Common Terminology Criteria for Adverse Events (CTCAE). (Version 4.0, May 28, 2009). National 
Institutes of Health, National Cancer Institute. 
<http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf>.  
 
15. 
IMBRUVICA® - Full Prescribing Information. (Revised: January 2015). U.S. Food and Drug 
Administration. <http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf>. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
26 
 
 
 
 
 
 
 
 

PROTOCOL                                                                                                                                                      Version: Aug 7, 2017 
________________________________________________________________________ 
27 
 
13.0 
APPENDIX 1: Pill Diary