Conditions: Chronic Lymphocytic Leukemia
Keywords: Lymphocytic Leukemia CLL Blood disease White blood cells Bone marrow disease Immunotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the impact of sequential overlapping treatment with PD-1 monoclonal antibody (mAb), pembrolizumab/MK-1375, followed by ibrutinib on endogenous immune function in previously untreated, high-risk CLL patients. Immune function will be evaluated through various laboratory correlative tests.

Detailed description:

Arms:
arm 1: Treatment with pembrolizumab and ibrutinib and follow-up period of up to 24 months.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib is a small-molecule inhibitor of BTK.

Interventions: intervention 1: Pembrolizumab intervention 2: Ibrutinib
Intervention descriptions: intervention 1: Pembrolizumab will be administered intravenously (IV) at 200 mg every 3 weeks for 1 year and up to 2 years. intervention 2: Ibrutinib will be administered orally once daily at approximately the same time each day at the dose of 420 mg daily (3 capsules of 140 mg daily).

Protocol document:
Prot_SAP_000.pdf: 
Phase II Trial of Ibrutinib and PD-1 Blockade in High Risk Chronic Lymphocytic 
Leukemia to Improve Immune Function. 
 
NCT03514017 
 
Version 3.2 
August 10, 2018 


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Phase II Trial of Ibrutinib and PD-1 Blockade in High Risk Chronic Lymphocytic 
Leukemia to Improve Immune Function.  
Protocol Identifying Number: MCC 19199 
Principal Investigator: Julio C. Chavez, MD  
IND #: 136298 
Funded by:  
Merck & Co, Inc. 
Janssen Pharmaceuticals, Inc. 
 
Version Number: v01 Dated 19 May 2017 
v1.2 Dated 05 September 2017 
v02 Dated 08 January 2018 
v03 Dated 23 April 2018 
v3.1 Dated 21 May 2018 
v3.2 Dated 10 August 2018 
 
 
 


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Table of Contents 
LIST OF ABBREVIATIONS ......................................................................................................vi 
STATEMENT OF COMPLIANCE ............................................................................................vii 
STUDY SUMMARY ................................................................................................................ viii 
SCHEMATIC OF STUDY DESIGN .........................................................................................xi 
1 
KEY ROLES ............................................................................................................... 1 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 2 
2.1 
BACKGROUND INFORMATION ............................................................................... 2 
2.2 
RATIONALE................................................................................................................ 5 
Rationale for the Trial and Selected Subject Population ...................................................... 5 
2.3 
POTENTIAL RISKS AND BENEFITS ......................................................................... 7 
2.3.1 
KNOWN POTENTIAL RISKS ................................................................................. 7 
2.3.2 KNOWN POTENTIAL BENEFITS ......................................................................... 9 
3 
OBJECTIVES AND PURPOSE ................................................................................10 
4 
STUDY DESIGN AND ENDPOINTS .......................................................................11 
4.1 
DESCRIPTION OF THE STUDY DESIGN .................................................................11 
4.2.1 PRIMARY ENDPOINT ..........................................................................................12 
4.2.2 SECONDARY ENDPOINTS ..................................................................................12 
4.2.3 EXPLORATORY ENDPOINTS ..............................................................................13 
5 
STUDY ENROLLMENT AND WITHDRAWAL ......................................................13 
5.1 
PARTICIPANT INCLUSION CRITERIA ......................................................................13 
5.2 
PARTICIPANT EXCLUSION CRITERIA .....................................................................14 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ..........................................15 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION .................................................16 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION .....................................16 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION ..............17 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ...................................17 
6 
STUDY AGENT .........................................................................................................17 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .................................................17 
6.1.1 ACQUISITION ......................................................................................................18 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING ...................18 
6.1.3 PRODUCT STORAGE AND STABILITY ...........................................................19 
6.1.4 PREPARATION ...................................................................................................19 
6.1.5 DOSING AND ADMINISTRATION .....................................................................19 
6.1.6 ROUTE OF ADMINISTRATION .........................................................................20 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE .........................20 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS ...........................................20 
6.1.9 DURATION OF THERAPY ..................................................................................25 
6.1.10 TRACKING OF DOSE ..........................................................................................25 


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6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ...........................................26 
7 
STUDY PROCEDURES AND SCHEDULE .............................................................26 
7.1 
STUDY PROCEDURES ..........................................................................................26 
7.1.1 
Overview ..............................................................................................................26 
7.1.2 Informed Consent ..............................................................................................26 
7.1.3 Inclusion/Exclusion Criteria ..................................................................................26 
7.1.4 
Medical History .....................................................................................................26 
7.1. 
4        Concomitant Medications Review ...............................................................27 
7.1. 
5       Post-Study Anticancer Therapy Status ........................................................27 
7.1. 
6       Adverse Event Review ................................................................................27 
7.1. 
7       Full Physical Exam ......................................................................................27 
7.1. 
8 Directed Physical Exam.....................................................................................27 
7.1. 
9       Vital Signs ...................................................................................................27 
7.1. 
10       Eastern Cooperative Oncology Group (ECOG) Performance Status .........27 
7.1. 
11       Assessment of Disease .............................................................................27 
7.1.12     Laboratory Procedures/Assessment .................................................................28 
7.1. 
13       Correlative Studies Blood Sampling ..........................................................28 
7.1.14        Laboratory Safety Evaluations........................................................................28 
7.1.15        Tumor Imaging ...............................................................................................28 
7.1.16      Bone Marrow Biopsy ........................................................................................28 
7.2  
RESEARCH BLOOD SPECIMEN PREPARATION, HANDLING, AND STORAGE
 .............................................................................................................................28 
7.3 
STUDY SCHEDULE .................................................................................................29 
7.3.1 SCREENING ........................................................................................................29 
7.3.2 ENROLLMENT/BASELINE ..................................................................................30 
7.3.3 FOLLOW-UP ........................................................................................................34 
7.3.4 
FINAL STUDY VISIT .........................................................................................34 
7.3.6 
UNSCHEDULED VISIT .....................................................................................35 
7.3.7 
SCHEDULE OF EVENTS TABLE .....................................................................35 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ...........37 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES .................................................38 
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES .38 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ..................38 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ............38 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ................39 
8 
ASSESSMENT OF SAFETY ...................................................................................39 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ........................................................39 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) ....................................................39 
8.1.1.1   Merck Definition of an Overdose and Reporting of Overdose ......................................39 
8.1.1.2 Reporting of Pregnancy and Lactation to Merck and Janssen. ........................................40 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) ................................42 


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8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS .............................................42 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT .......................................................43 
8.2.1 
SEVERITY OF EVENT........................................................................................43 
8.2.2 RELATIONSHIP TO STUDY AGENT ................................................................43 
8.2.3 EXPECTEDNESS ................................................................................................44 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP ............................................................................................................44 
8.4 
REPORTING PROCEDURES ...................................................................................44 
8.4.1 
ADVERSE EVENT REPORTING ......................................................................44 
8.4.2 SERIOUS ADVERSE EVENT REPORTING ......................................................45 
8.4.3 UNANTICIPATED PROBLEM REPORTING .......................................................46 
8.4.4 
EVENTS OF SPECIAL INTEREST ...................................................................46 
8.5 
STUDY HALTING RULES .........................................................................................47 
8.6 
SAFETY OVERSIGHT ..............................................................................................48 
9 
CLINICAL MONITORING .........................................................................................48 
10 
STATISTICAL CONSIDERATIONS ..........................................................................48 
10.1 STATISTICAL AND ANALYTICAL PLANS ............................................................48 
10.2 DESCRIPTION OF STATISTICAL METHODS .......................................................48 
10.2.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) ............................48 
10.2.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) ..........................................49 
10.2.4 EXPLORATORY ANALYSES .............................................................................50 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .....50 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................50 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................50 
13.1 ETHICAL STANDARD ..............................................................................................51 
13.2 INSTITUTIONAL REVIEW BOARD .........................................................................51 
13.3 INFORMED CONSENT PROCESS .............................................................................51 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS ..............................................................................................51 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION .........................................51 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY .....................................................51 
13.5 FUTURE USE OF STORED SPECIMENS .................................................................52 
14 
DATA HANDLING AND RECORD KEEPING ........................................................52 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .........................52 
14.2 STUDY RECORDS RETENTION ...............................................................................52 
14.3 PROTOCOL DEVIATIONS .........................................................................................52 
14.4 PUBLICATION AND DATA SHARING POLICY .....................................................52 
15 
STUDY ADMINISTRATION ....................................................................................52 
15.1 STUDY LEADERSHIP ...............................................................................................52 
16 
CONFLICT OF INTEREST POLICY ......................................................................52 
17 
LITERATURE REFERENCES ................................................................................52 


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APPENDIX ...............................................................................................................................52 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in Chronic 
Lymphocytic Leukemia  
Protocol <#> 
 
LIST OF ABBREVIATIONS 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BTK 
Bruton’s tyrosine kinase 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Science 
CLL 
Chronic Lymphocytic Leukemia 
CMP 
Clinical Monitoring Plan 
CR 
Complete response 
CRF 
Case Report Form 
DSMB 
Data Safety Monitoring Board 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICH E6 
International Conference on Harmonisation Guidance for Industry, Good Clinical 
Practice: Consolidated Guidance 
IGVH 
Immunoglobulin Heavy Chain Variable Region Genes 
IND 
Investigational New Drug Application 
IRB 
Investigational Review Board 
IRR 
Infusion Related Reaction  
ISO 
International Organization for Standardization 
IV 
Intravenous 
iwCLL 
International Workshop on Chronic Lymphocytic Leukemia 
mAb 
Monoclonal Antibody 
MCC 
Moffitt Cancer Center 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PD 
Progressive Disease 
PD-1 
Programmed cell death protein 1 
PDB 
PD1:PDL1 blockade 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PR 
Partial Response 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
TH1 
T Helper Cell 1 
TLS 
Tumor Lysis Syndrome 
UP 
Unanticipated Problem 


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STATEMENT OF COMPLIANCE 
 
 
The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on 
the Protection of Human Subjects (45 CFR Part 46). The Principal Investigator will assure that 
no deviation from, or changes to the protocol will take place without prior agreement from the 
sponsor and documented approval from the Institutional Review Board, except where necessary 
to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed of 
their obligation to meet the above commitments. 
 
 
Principal Investigator:    
 
Print/Type Name 
 
 
Signed:    
 Date: 
 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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STUDY SUMMARY 
 
 
Title: 
Phase II Trial of Ibrutinib and PD-1 Blockade in High Risk Chronic 
Lymphocytic Leukemia to Improve Immune Function.  
 
Précis: 
Study intends to evaluate the impact of sequential overlapping treatment with 
PD-1 monoclonal antibody (mAb), pembrolizumab/MK-1375, followed by 
ibrutinib on endogenous immune function in previously untreated, high-risk 
CLL patients. Immune function will be evaluated through various laboratory 
correlative tests.  
 
Objectives: 
Primary 
1. Assessment of the complete response of CLL to therapeutic intervention 
(defined per current iWCLL 2008 response criteria) 
2. Time to response of CLL to therapeutic intervention (defined as time to 
achievement of response according to iWCLL 2008 criteria). 
 
Secondary Objectives:  
1. Assessment of the overall response rate (CR + PR) defined by the 
iWCLL 2008 criteria. 
2. Restoration of immune response as measured by: 
a. Decreased markers of T-cell exhaustion 
b. Increased of quantitative immunoglobulin levels and subtype 
2. Safety and toxicity of the combination 
3.  Progression free survival (PFS) 
4. Incidence of Richter’s transformation 
 
Exploratory objectives 
1. Alterations in T lymphocyte function, including changes in: 
 
a. 
TH1:TH2 polarization, and TReg:TH17 distributions 
b. 
Markers of T cell exhaustion and/or inhibition 
c. 
Alterations in distribution of naïve vs. memory  
d. 
Cellular activation and cell-mediated cytotoxic capacity 
 
 
 
 
2. 
Alterations in B lymphocyte function, including changes in: 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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a.  Serum anti-pneumococcal antibody titers in response to Prevnar 
vaccination 
b. 
Quantitative serum immunoglobulin levels and subtyping 
c. 
Fc-receptor (FcR) expression patterns  
 
 
 
 
3. 
Alterations in global systemic cytokine patterns: 
Includes IFN-γ, TNF-α, IL-2, IL-4, IL-10, IL-6, IL-17A, allowing 
discrimination between TH1, TH2, and TH17 profiles (described in 
Section 4.2.2.2) 
 
 
 
 
Endpoint: 
Primary Endpoint: 
 
1. Assessment of the complete response to the therapeutic intervention 
2. Time to response to CLL to the therapeutic intervention 
Secondary Endpoints:  
 
1. Assessment of overall response rate (ORR) [CR + CR]  
2. Restoration of immunosuppression: 
a. Decreased markers of T-cell exhaustion 
b. Improvement of the levels of quantitative immunoglobulins 
3. Safety and Toxicity of the combination 
4. Progression free survival (PFS) 
5. Incidence of Richter’s transformation 
 
Exploratory Endpoints 
 
1. Alterations of T-cell function: We postulate that there will be increased 
polarization towards TH1 compartment cells, which will be associated with 
increased cellular immunity. PD-1 blockage will increase TH1 mediated anti-
tumor response. Alterations in B-cell function: Combination of BTK and PD-1 
inhibition will restore B-cell function 
2. Alterations in cytokine profile (as defined in Section 4.2.2.2) 
3. Evaluation of toxicity and safety of the combined therapy: In order to 
minimize toxicity, pembrolizumab will started 6 weeks prior to ibrutinib 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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Population: 
Sample size of 25 subjects, male and female, over 18 years of age, 
performance status ECOG 0 or 1 who are patients at Moffitt Cancer 
Center.  Minority enrollment will be encouraged. 
 
  
 
Phase: 
Phase II 
 
Number of Sites 
Moffitt Cancer Center 
enrolling participants: 
 
Description of Study 
 
Agents: 
Pembrolizumab (anti-PD1, mAb) 200 mg IV every 3 weeks for a total of  
 
51 weeks. Ibrutinib (BTK inhibitor) 420 mg by mouth starting at week 6 
for a duration of up to 51 weeks.. 
 
Study Duration: 
Three to four years. 
 
Participant Duration: 
Two years.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SCHEMATIC OF STUDY DESIGN 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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Principal Investigator: 
Julio C. Chavez, MD  
 
 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr. SRB-2 
Tampa, FL 33612 
 
 
 
 
813-745-8172 
 
 
 
 
Julio.C.Chavez@moffitt.org                                    
 
Statistician: 
Brooke L. Fridley, PhD 
Chair, Department of Biostatistics and 
Bioinformatics 
Moffitt Cancer Center 
12902 Magnolia Dr.  
Tampa, FL 33612 
813-745-1461 
Brooke.Fridley@moffitt.org 
 
Research Scientist: 
Eva Sahakian, PhD 
Moffitt Cancer Center  
12902 Magnolia Dr.  SRB-2 
Tampa, FL 33612 
813-745-8439 
Eva.Sahakian@moffitt.org 
 
Clinical Research Nurse: 
Elyce Turba, MSN, RN, OCN 
Moffitt Cancer Center 
 
 
12902 Magnolia Dr. FOB 3 
 
 
 
Tampa, FL 33612 
 
 
 
 
813-745-1706 
Elyce.Turba@moffitt.org 
 
1 
KEY ROLES 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
Chronic Lymphocytic Leukemia  
Protocol <#> 
 
 
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With an age-adjusted incidence of 4.1/100,000 inhabitants in the United States, chronic lymphocytic 
leukemia (CLL) is the most common type of leukemia in western countries. More than 15,000 newly 
diagnosed cases and 4,500 deaths are currently estimated annually[1].. The median age at diagnosis is 
between 67 and 72 years[2]. More male than female patients (1.7:1) are affected [2-4]. Because the 
incidence rate increases with age, the prevalence and mortality of CLL are likely to increase due to the 
demographic changes associated with an aging population over the next decades. 
Moreover, the proportion of younger patients with early stage CLL and minimal symptoms seems to 
increase due to more frequent blood testing [5]. CLL is characterized by clonal proliferation and 
accumulation of mature, typically CD5-positive B cells within the blood, bone marrow, lymph nodes, 
and spleen[6]. It has recently been reported that in CLL the capacity to generate clonal B cells might be 
acquired at the hematopoietic stem cell (HSC) stage, suggesting that the primary leukemogenic event in 
CLL might involve multipotent, self-renewing HSCs[7]. The leukemic transformation is initiated by 
specific genetic alterations causing the deletion of specific micro-RNA genes and increasing the 
resistance of B cells towards apoptosis [8]. Deletions on the long arm of chromosome 13, specifically 
involving band 13q14 (del(13q14)), represent the single most frequently observed cytogenetic aberration 
in CLL, occurring in approximately 55% of all cases. An isolated del(13q14) is typically characterized 
by a benign course of the disease. Deletions of the long arm of chromosome 11 (del(11q)) can be found 
in ~25% of chemotherapy-naive patients with advanced disease stages and in 10% of patients with early 
stage disease[9, 10]. Deletions of the short arm of chromosome 17 (del(17p)) are found in 5%−8% of 
chemotherapy-naive patients. These deletions almost always include band 17p13 where the prominent 
tumor suppressor gene TP53 is located. Patients with CLL carrying a del(17p) clone show marked 
resistance against genotoxic chemotherapies that cannot be overcome by the addition of anti-CD20 
antibodies in the context of state-of-the art chemoimmunotherapy [11]. Mutations of TP53 are found in 
4%−37% of patients with CLL and have been associated with poor prognosis (ultra-high risk) in a 
number of studies [12]. The presence of an IgVH unmutated status is also associated to shorter time to 
therapy and worse progression free survival (PFS). 
The recently reported whole genome sequencing projects in CLL have revealed a number of recurrent 
somatic gene mutations that occur in parallel to the above mentioned structural genomic aberrations. 
These include the genes NOTCH1, MYD88, TP53, ATM, SF3B1, FBXW7, POT1, CHD2, and others 
[10, 13]. 
More than 50% of CLL patients are asymptomatic at diagnosis and require no treatment. Symptoms 
appear as the disease progresses. Treatment is initiated when a patient’s disease becomes symptomatic 
or progressive as defined by the international workshop on Chronic Lymphocytic Leukemia (iwCLL) 
updated guidelines for diagnosis and treatment of CLL[14]. 
Chronic lymphocytic leukemia (CLL) is associated with well-characterized profound immune 
dysregulation associated with an aberrantly dominant TH2 polarization [15, 16] often contributing 
significantly to morbidity and mortality in patients afflicted with this disease.  Yet, humoral immunity is 
also impaired, as evidenced by compromised responses to vaccine challenge [17-19].  Vaccine efficacy 
against S. pneumoniae is dramatically diminished in CLL patients, demonstrating a more imposing 
refractoriness against polysaccharide antigens [17].  Although rarely curable, CLL typically follows an 
indolent course over many years.  However, infection remains a prominent and frequent challenge in the 
management of CLL, and represents a leading cause of mortality in CLL.  Immune dysfunction seen in 
CLL patients also likely contributes to the overall disease pathogenesis as progressive dysregulation 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
BACKGROUND INFORMATION 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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impairs the natural anti-tumor immune response that might otherwise contain if not eradicate the 
malignant clonal population [20].   
Immune modulators have begun to change our approach to many malignancies.  Monoclonal antibodies 
targeting the checkpoint inhibitor interaction, PD-1:PD-L1, are a new addition to our immunotherapeutic 
arsenal, demonstrating impressive clinical benefit in melanoma, lung cancer and promising early results 
in other solid tumor malignancies as well[21-26]  PD-L1, expressed on a wide variety of cells including 
many tumor cells delivers an inhibitory signal to T cells through PD-1 which potently suppresses 
cellular immunity[27].  Thus, through blockade of the PD-1:PD-L1 axis, anti-tumor immune responses 
can be reconstituted.  Importantly, PD-L1 has been implicated as one of several inhibitory signals 
incorporated into the dysfunctional T cell immune synapse leading to the defective immunity seen in 
CLL patients. [26, 27] 
Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), an intrinsically important 
enzyme in the B cell activation signaling cascade [28, 29].  Ibrutinib has demonstrated therapeutic 
efficacy in several lymphoid malignancies with response rates as high as ~70% in relapsed or refractory 
CLL, and is currently indicated for the treatment of patients with CLL who have received at least one 
line of therapy, with del17p as initial therapy, Waldenstrom’s macroglobulinemia and MCL who have 
received at least one prior therapy[30-32].  Accelerated approval in MCL was granted based on overall 
response rate [33].  Continued approval for this indication may be contingent upon verification of 
clinical benefit in confirmatory trials. Interestingly, Ibrutinib also disrupts IL-2-inducible Kinase (ITK) 
signaling in T lymphocytes resulting in alteration of T cell receptor (TCR) signaling, particularly 
impeding maturation of TH2-type responses while leaving TH1-type responses relatively intact, and thus 
repolarizing responses toward more potent cellular immunity[34].  In the setting of CLL, in which 
immune dysfunction is widely felt to result from aberrantly dominant TH2 polarization, Ibrutinib 
potentially offers a second therapeutic benefit, not only directly targeting CLL B cells through inhibition 
of BTK, but also reengaging a potent anti-tumor response[34].  
Recognizing that CLL-associated immune dysfunction predisposes these patients to overwhelming 
infections that significantly impact survival, we hypothesize that ibrutinib, in addition to targeting the 
malignant clonal B cell population directly, will redirect the endogenous T cell responses and reverse the 
established immune dysregulation.  Furthermore, we believe that a rational combination of ibrutinib with 
PD-1:PD-L1 blockade, targeting an inhibitory mechanism implicated in CLL-associated immune 
dysfunction, will elicit a more global impact on the systemic immunity, reengaging both anti-tumor 
immune responses as well as improve general immunologic health. 
Pharmaceutical and Therapeutic Background 
Pembrolizumab 
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2. Pembrolizumab is currently FDA approved for the first-line treatment of metastatic wild 
type EGFR and ALK non-small lung cancer (NSCLC) that express high PD-L1 expression [Tumor 
Proportion Score (TPS) > 50%], for metastatic NSCLC with progression on or after platinum containing 
chemotherapy with TPS > 1% expression of PD-L1, for metastatic EGFR or ALK rearrangement 
NSCLC with progression after EGFR and/or ALK inhibitors, for unresectable or metastatic melanoma 
and for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after progression to 
platinum-containing chemotherapy. 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades [15, 35].  Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies [16-19, 
21].  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 


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regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid 
tumors[36]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control 
[37, 38].  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions[37, 39].  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (PD-L1 and/or PD-L2)[40]. PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail 
which is responsible for the binding of signaling molecules[40, 41].  The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM)[40].  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade[40, 42].  The mechanism by which PD-1 down modulates 
T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins[40, 43].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells[44].  
Expression has also been shown during thymic cells, T regs and Natural Killer cells [44].  Expression 
has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells [45, 46].  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors [38, 47].  Both ligands are type I transmembrane receptors containing both 
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no 
known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, 
most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments [43, 48].  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen 
unwarranted T-cell function in peripheral tissues [17, 19, 38] .  Although healthy organs express little (if 
any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma [49].  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention [38, 50, 51]. 
Ibrutinib 
PCI-32765 (ibrutinib) is a first-in-class selective, irreversible small molecule inhibitor of Bruton’s 
tyrosine kinase (BTK) currently indicated for the treatment of patients with CLL/Small Lymphocytic 
Lymphoma (SLL) who have received at least 1 prior line of therapy, CLL.SLL with 17p deletion, mantle 
cell lymphoma who have received at least one prior therapy, marginal zone lymphoma (MZL) who 
require therapy and have received at least one least one prior anti-CD20 based therapy,  Waldestrom 
Macroglobulinemia, and chronic graft versus host disease (cGVHD) after failure of one or more lines of 
systemic therapy. Ibrutinib is being co-developed by Pharmacyclics, Inc. and Janssen Biotech, INC. 
“PCI-32765” and “ibrutinib” refer to the same molecule; hereafter, “ibrutinib” will be used. 
The investigational drug product is an oral formulation in a hard gelatin capsule form containing 
micronized ibrutinib. For the most comprehensive nonclinical and clinical information regarding the 
efficacy and safety of ibrutinib, refer to the latest version of the US package insert. 
B cells are lymphocytes with multiple functions in the immune response, including antigen presentation, 
antibody production, and cytokine release. B cells express cell surface immunoglobulins  comprising  
the  BCR,  which  is  activated  by  binding  to  antigen.   Antigen binding induces receptor aggregation 


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and the clustering and activation of multiple tyrosine kinases, which in turn activate further downstream 
signaling pathways [29]. 
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic mutation, 
is tightly regulated. It is thought that B-cell lymphomas and CLL result from mutations acquired during 
normal B-cell development[28]. Several lines of evidence suggest that signaling through the BCR is 
necessary to sustain the viability of B-cell malignancies [52-54]. 
The role of BTK in BCR signal transduction is demonstrated by the human genetic immunodeficiency 
disease X-linked agammaglobulinemia and the mouse genetic disease X-linked immunodeficiency, both 
caused by a mutation in the BTK gene. These genetic diseases are characterized by reduced BCR 
signaling and a failure to generate mature B cells. The BTK protein is expressed in most hematopoietic 
cells with the exception of T cells and natural killer cells, but the selective effect of BTK mutations 
suggests that its primary functional role is as an antigen receptor signaling in B cells[55].  In vitro, PCI-
32765 inhibits purified BTK and selected members of the kinase family with 10-fold specificity 
compared with non-BTK kinases [56, 57]. 
In patients with recurrent B cell lymphoma >90% occupancy of the BTK active site in peripheral blood 
mononuclear cells was observed up to 24hrs after ibrutinib doses of >= 2.5mg/kg/day (>= 175mg/day 
for average weight of 70kg).   
Ibrutinib is absorbed after oral administration with a median Tmax of 1-2 hours.  Ibrutinib exposure 
increases with doses up to 840mg.  The steady-state AUC (mean +/- standard deviation) observed in 
patients at 560mg is 953 +/- 705 ng.h/ml and in patients at 420mg is 680 +/- 517 ng.h/mL.  
Administration with food increased ibrutinib Cmax and AUC by approximately 2 to 4- and 2-fold, 
respectively, compared with administration of ibrutinib after overnight fast. 
 
For the most comprehensive nonclinical and clinical information regarding in vitro and in vivo 
preclinical activity and toxicology of ibrutinib, refer to the latest version of the PCI-32765 Investigator’s 
Brochure. Refer to the Investigator’s Brochure for Preclinical and Clinical data for Pembrolizumab and 
the US Package Insert for IMBRUVICA (Ibrutinib). 
 
 
 
 
Rationale for the Trial and Selected Subject Population 
Patients with untreated high-risk CLL (defined as presence of del17p or TP53, del11q or ATM mutation, 
unmutated IGVH or mutated IGVH with 3.21 phenotype)) have an unmet need as they tend to progress 
rapidly and develop resistance to standard therapies. There is growing evidence that disease progression 
is likely related to genetic evolution, manifested as disruption of the clonal architecture of CLL.  
Although the current recommendation is to consider “watch” and “wait” approach as the best 
management for asymptomatic patients, it has been long debated whether that should be applied for 
high-risk CLL patients. This indication is based on experience with alkylator-only therapy, however 
novel therapies appear less toxic and more tolerable [58]. There is evidence that deferring treatment in 
high-risk patients may be detrimental due to a more aggressive course of disease and that patients with 
clonal evolution into high-risk features may fare even worse prognosis [59]. There have been prior 
attempts to treat early stage high-risk CLL patients with FCR with EFS benefit, although not OS 
improvement [60]. However, it should be noted that usually high-risk CLL (especially 17p deletion) are 
fludarabine-resistant and novel agents, such as ibrutinib, can overcome this situation. Per CLL-IPI score 
the HR(hazard ratio) of 17p deletion/TP53 mutated was 4.2 with a 5-year OS of 63% (score of 4). If a 
2.2 
RATIONALE 


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patient has presence of 17p del/TP53 mutation, unmutated IGVH and age older >65 (CLL-IPI score of 
7) the 5-year OS will be 23% thus, there is a potential role of early intervention for this high-risk 
features CLL population [61]. Given the great activity of ibrutinib in high-risk CLL, especially in 17p 
deletion, there is potential role of this drug in early stage high-risk CLL patients. This was already 
shown with great activity, good tolerance and improvement in quality of life [62]. Given the potential 
synergistic effect of ibrutinib in combination checkpoint blockade, its translation to clinical use under a 
controlled clinical trial is supported and potentially beneficial [63]. 
Since treatment naïve CLL patients may have a more preserved immune system, there should be a better 
efficacy of immune checkpoint inhibitors such as anti PD-1, to restore immune dysfunction and obtain a 
better anti-tumor response.   
The therapeutic combination of PD1:PDL1 blockade (PDB) and ibrutinib can improve the severe 
immune function classically associated with CLL, thereby improving disease-related morbidity and 
mortality in high-risk, previously untreated patients. 
 
The combination of ibrutinib and PD-1 inhibitor was already studied in 2 trials in B-cell malignancies, 
including CLL. In a phase I clinical trial of patients with refractory non-Hodgkin’s lymphomas and CLL 
full doses of ibrutinib and nivolumab were given with acceptable toxicity. There were no DLTs with the 
doses administered [64]. A phase II clinical trial (there was no dose escalation) demonstrated the 
efficacy and safety of the combination ibrutinib at 420 mg and nivolumab at the standard doses of 3 
mg/kg in refractory/relapsed CLL patients [65]. Even though these studies were conducted with a 
different PD-1 antibody, we do not expect a different toxicity profile with pembrolizumab. There is 
currently a phase II study of the combination of ibrutinib and pembrolizumab in advanced melanoma at 
the standard doses without going to dose-escalation (NTC03021460). 
 
1. The combination of PDB and ibrutinib will reverse T cell dysfunction commonly seen in CLL 
patients, potentiating more robust anti-infective and anti-tumor immune responses. 
2. The combination of PBD and ibrutinib will restore protective humoral responses in CLL patients.  In 
particular, immunologic restoration will improve responses and protection against pneumococcal 
infection which represent a significant cause of morbidity and mortality. 
 3. The combination of PDB and ibrutinib can have a synergistic effect on the response rate. 
 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical activity of 
single agent pembrolizumab.  The dose escalation portion of this trial evaluated three dose levels, 1 
mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors.  All three dose levels were well tolerated and no dose-limiting toxicities were observed.  This 
first in human study of pembrolizumab showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been 
identified to date. The dose 10.0 mg/kg Q2W, the highest dose tested in PN00. Data from other clinical 
studies within the pembrolizumab program has shown that a dose of 2mg/kg of pembrolizumab in a 
every three weeks schedule may be sufficient for target engagement and clinical activity. More recently 
a flat dose of 200mg every three weeks was shown to be equally effective. The differences in exposure 
for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are well within 
the established exposure margins of 0.5 – 5.0 for pembrolizumab in the melanoma indication.  
 
For the present trial, a 200mg flat dose every three weeks will be used. 
 
Ibrutinib will be administered at the FDA-approved dose of 420 mg once daily orally for CLL. 
 
 


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A. Ibrutinib 
As previously described, ibrutinib is approved for the treatment of patients with relapsed/refractory CLL 
and patients with CLL with del 17p. The most common adverse events (> 20%) in patients with CLL 
treated with ibrutinib are neutropenia, thrombocytopenia, diarrhea, anemia, fatigue, upper respiratory 
infection, skin rashes, nausea and pyrexia (see IMBRUVICA package insert for most current and full 
listing of possible risks). 
 
• 
Hemorrhage: Fatal bleeding events have occurred in patients treated with ibrutinib. Grade 3 or 
higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal 
bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with 
fatalities occurring in 0.3% of patients in clinical trialsBleeding events of any grade, including 
bruising and petechiae, occurred in 44% of patients treated with ibrutinib. The mechanism for the 
bleeding events is not well understood.  
o For any planned surgery or invasive procedure requiring sutures or staples for closure, ibrutinib 
should be held at least 7 days prior to the intervention 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 serosanguinous drainage or the need for drainage tubes. 
o For planned minor procedures (such as a central line placement, needle biopsy, 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 for these procedures. 
o For emergency procedures, ibrutinib should be held after the procedure until the surgical site is 
reasonably healed, for at least 7 days after the urgent surgical procedure, or at the discretion of 
the investigator. 
• 
Infections: Fatal and non-fatal infections have occurred with ibrutinib therapy. Grade 3 or greater 
infections occurred in 24% of patients in clinical trials. Cases of progressive multifocal 
leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP)have occurred in patients 
treated with ibrutinib. Evaluate patients for fever and infections and treat appropriately per current 
guidelines. Prophylaxis according to standard of care should be considered in patients who are at 
increased risk for opportunistic infections. 
• 
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (24%,  
thrombocytopenia (range, 8%), and anemia (3%) based on laboratory measurements occurred in 
patients treated with single agent ibrutinib. Monitor complete blood counts at least monthly.  
• 
Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with ibrutinib therapy. 
Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater 
atrial fibrillation and atrial flutter occurred in 4% of patients. These events have occurred 
particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous 
history of cardiac arrhythmias. Periodically monitor patients clinically for cardiac arrhythmias. 
Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, 
syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it 
persists, consider the risks and benefits of ibrutinib treatment and follow dose modification 
guidelines 
• 
Hypertension: Hypertension (range, 12%) has occurred in patients treated with ibrutinib with a 
median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset 
hypertension or hypertension that is not adequately controlled after starting ibrutinib. Adjust existing 
anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.  
• 
Second Primary Malignancies: Other malignancies (9%) including non-skin carcinomas (2%) have 
occurred in patients treated with ibrutinib. The most frequent second primary malignancy was non-
melanoma skin cancer (6%).  
2.3 
POTENTIAL RISKS AND BENEFITS 
2.3.1 
KNOWN POTENTIAL RISKS 


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• 
Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with ibrutinib 
therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor 
patients closely and treat as appropriate.  
• 
Embryo-Fetal Toxicity: Based on findings in animals, ibrutinib can cause fetal harm when 
administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during 
the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that 
were 2-20 times higher than those reported in patients with MCL, CLL/SLL or WM. Advise women 
to avoid becoming pregnant while taking ibrutinib and for 1 month after cessation of therapy. 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. 
 
B. Pembrolizumab 
Pembrolizumab does not have a current indication for CLL. It is currently approved for unresectable or 
metastatic melanoma, metastatic NSCLC, metastatic HNSCC and refractory Hodgkin lymphoma. Most 
adverse reactions (> 20% of patients) were consistent with fatigue, pruritus, decreased appetite, skin 
rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation and nausea (KEYTRUDA package 
insert). Of clinical importance are the immune-related adverse events: 
 
• 
Immune mediated pneumonitis: Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving 
pembrolizumab, including grade 1 (0.8%), grade 2 (1.3%), grade 3 (0.9%), grade 4 (0.3%), and 
grade 5 (0.1%) pneumonitis. The median time to onset was 3.3 months (range: 2 days to 19.3 
months), and the median duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) 
of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose 
corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a 
corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior 
thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). 
Pneumonitis led to discontinuation of pembrolizumab in 36 (1.3%) patients. Pneumonitis resolved in 
55 (59%) of the 94 patients.  
• 
Immune-mediated colitis: Colitis occurred in 48 (1.7%) of 2799 patients receiving pembrolizumab, 
including grade 2 (0.4%), grade 3 (1.1%), and grade 4 (<0.1%) colitis. The median time to onset was 
3.5 months (range: 10 days to 16.2 months), and the median duration was 1.3 months (range: 1 day 
to 8.7+ months). Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of 
the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 1 day to 5.3 
months) followed by a corticosteroid taper. Colitis led to discontinuation of pemrbolizumab in 15 
(0.5%) patients. Colitis resolved in 41 (85%) of the 48 patients. 
• 
Immune-mediated hepatitis: Hepatitis occurred in 19 (0.7%) of 2799 patients receiving 
pembrolizumab, including grade 2 (0.1%), grade 3 (0.4%), and grade 4 (<0.1%) hepatitis. The 
median time to onset was 1.3 months (range: 8 days to 21.4 months), and the median duration was 
1.8 months (range: 8 days to 20.9+ months). Thirteen (68%) of the 19 patients received systemic 
corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median duration of 5 days 
(range: 1 to 26 days) followed by a corticosteroid taper. Hepatitis led to discontinuation of 
pembrolizumab in 6 (0.2%) patients. Hepatitis resolved in 15 (79%) of the 19 patients. 
• 
Immune mediated endocrinopathies: Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving 
pembrolizumab, including grade 2 (0.2%), grade 3 (0.3%), and grade 4 (<0.1%) hypophysitis. The 
median time to onset was 3.7 months (range: 1 day to 11.9 months), and the median duration was 
4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) of the 17 patients received systemic 
corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Hypophysitis led to 
discontinuation of pembrolizumab in 4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 
patients. 
• 
Thyroid disorders: Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving 
pembrolizumab, including grade 2 (0.8%) and grade 3 (0.1%) hyperthyroidism. The median time to 
onset was 1.4 months (range: 1 day to 21.9 months), and the median duration was 2.1 months 
(range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of pembrolizumab in 2 
(<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients. Hypothyroidism 


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occurred in 237 (8.5%) of 2799 patients receiving pembrolizumab, including grade 2 (6.2%) and 
grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to 18.9 
months), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism 
led to discontinuation of pembrolizumab in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) 
of the 237 patients. The incidence of new or worsening hypothyroidism was higher in patients with 
HNSCC occurring in 28 (15%) of 192 patients receiving pembrolizumab, including grade 3 (0.5%) 
hypothyroidism. Of these 28 patients, 15 had no prior history of hypothyroidism. Thyroiditis 
occurred in 16 (0.6%) of 2799 patients receiving pembrolizumab, including Grade 2 (0.3%) 
thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months). 
• 
Immune-mediated Nephritis and renal dysfunction: Nephritis occurred in 9 (0.3%) of 2799 patients 
receiving pembrolizumab, including grade 2 (0.1%), grade 3 (0.1%), and grade 4 (<0.1%) nephritis. 
The median time to onset was 5.1 months (range: 12 days to 12.8 months), and the median duration 
was 3.3 months (range: 12 days to 8.9+ months). Eight (89%) of the 9 patients received systemic 
corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median duration of 15 days 
(range: 3 days to 4.0 months) followed by a corticosteroid taper. Nephritis led to discontinuation of 
pembrolizumab in 3 (0.1%) patients. Nephritis resolved in 5 (56%) of the 9 patients 
• 
Infusion-related reactions:  Acute infusion reactions (which can include cytokine release syndrome, 
angioedema, or anaphylaxis) are different from allergic/hypersensitive reactions, although some of 
the manifestations are common to both AEs.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia 
(joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, 
lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); Nausea; 
Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor 
pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting. Pembrolizumab can cause severe or life-threatening infusion-related reactions and has 
been reported in 6 (0.2%) out of 2799 patients that received the drug.  
• 
Embryo-fetal toxicity: Based on its mechanism of action, pembrolizumab can cause fetal harm when 
administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with 
maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this 
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the 
patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly 
effective contraception during treatment with pembrolizumab and for 4 months after the last dose of 
the drug. 
• 
Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. Trough 
levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, 
a subset analysis was performed in the patients with a concentration of pembrolizumab below the 
drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with 
pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every two 
or three weeks, 26 (2.0%) of 1289 evaluable patients tested positive for treatment-emergent anti-
pembrolizumab antibodies. Among the 26 patients who tested positive for treatment emergent anti-
pembrolizumab antibodies, only 4 patients were tested for neutralizing antibodies and one was 
positive. There was no evidence of an altered pharmacokinetic profile or increased infusion 
reactions with anti-pembrolizumab binding antibody development. The detection of antibody 
formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the 
observed incidence of antibody (including neutralizing antibody) positivity in an assay may be 
influenced by several factors including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease. For these reasons, comparison of 
incidence of antibodies to pembrolizumab with the incidences of antibodies to other products may 
be misleading. 
 
 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 


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In February 2014, ibrutinib was the first BTK inhibitor FDA approved for clinical use for the treatment of 
patients with CLL who had relapsed after at least one prior line of therapy or presence of 17p deletion. The 
indication was extended to patients with CLL 17p deletion as first line therapy and patients unfit for 
chemotherapy (older than 65 years old). Ibrutinib has received full approval for use in CLL/SLL.   
 
Pembrolizumab is currently approved for metastatic/advanced melanoma, recurrent or metastatic NSCLC, 
recurrent or metastatic HNSCC and refractory classical Hodgkin Lymphoma. Pembrolizumab does not have 
current approval for CLL at this time. However activity of pembrolizumab has been documented in CLL and 
Richter’s transformation with overall clinical responses and minimal toxicity. 
 
As mentioned in the rationale, there is an opportunity of the drug combination to correct the immune 
dysfunction typical of patients with CLL. Restoration of immune function could lead to improvement of the 
antitumor response and immunity against infections. In addition, treating high risk CLL early may have 
beneficial effects on long term survival. 
 
 
 
Objective:  
This is designed as a phase II study intended to evaluate the impact of sequential overlapping treatment 
with PD-1 monoclonal antibody (mAb), pembrolizumab/MK-1375, followed by ibrutinib on endogenous 
immune function in previously untreated, high-risk CLL patients (defined as presence of del17p or TP53, 
del11q or ATM mutation, unmutated IGVH or mutated IGVH with 3.21 phenotype) with absolute 
lymphocyte count >20,000 but without meeting iwCLL criteria to start therapy. 
 
Primary Objectives: 
1. Assessment of the complete response (CR) of CLL to therapeutic intervention (defined per 
current iWCLL 2008 response criteria) 
 
2. Time to response of CLL to therapeutic intervention (defined as time to achievement of 
response according to iWCLL 2008 criteria). 
 
 
 
Secondary Objectives 
1. Assessment of the overall response rate (ORR) [CR + PR) per iWCLL 2008 response criteria 
2. Restoration of immune response as measured by: 
a. Decreased markers of T-cell exhaustion 
b. Increased of quantitative immunoglobulin levels and subtype 
2. Safety and toxicity of the combination 
3.  Progression free survival (PFS) 
4. 3. 
Incidence of Richter’s transformation (defined as transformation of CLL into an aggressive 
lymphoid/histiocytic histology including well defined World Health Organization 2008 subtypes). Richter’s 
transformation should be biopsy proven 
 
 
Exploratory Objectives: 
3 
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1. 
Alterations in T lymphocyte function, including changes in: 
 
a.  TH1:TH2 polarization, and TReg:TH17 distributions 
b. Markers of T cell exhaustion and/or inhibition 
c. Alterations in distribution of naïve vs. memory  
d. Cellular activation and cell-mediated cytotoxic capacity 
2. 
Alterations in B lymphocyte function, including changes in: 
a. Serum anti-pneumococcal antibody titers in response to Prevnar vaccination 
b. Quantitative serum immunoglobulin levels and subtyping 
c. Fc-receptor (FcR) expression patterns  
3. 
Alterations in global systemic cytokine patterns: Includes IFN-γ, TNF-α, IL-2, IL-4, IL-10, IL-6, 
IL-17A, allowing discrimination between TH1, TH2, and TH17 profiles (described in Section 
4.2.2.2) 
 
Hypothesis for Primary and Secondary Objectives:   
The therapeutic combination of PD1:PDL1 blockade (PDB) and ibrutinib can improve the severe immune 
dysfunction classically associated with CLL, thereby improving disease-related morbidity and mortality in 
high-risk, previously untreated patients. 
 
A. The combination of PDB and ibrutinib will reverse T cell dysfunction commonly seen in CLL patients, 
potentiating more robust anti-infective and anti-tumor immune responses. 
 
B. The combination of PBD and ibrutinib will restore protective humoral responses in CLL patients.  In 
particular, immunologic restoration will improve responses and protection against pneumococcal 
infection which represent a significant cause of morbidity and mortality. 
 
C. The combination of PDB and ibrutinib can have a synergistic effect on the response rate. 
 
 
 
 
 
Trial Design 
The trial is an open-label, single arm phase II study to be conducted only at the Moffitt Cancer Center. 
Anticipated accrual will be 25 subjects.  One of the secondary endpoint of this study is reconstitution of 
immune function, using response to pneumococcal vaccination as a clinical surrogate representation of 
global immune function.  The study is designed to test the null hypothesis that, in high risk CLL 
(defined as presence of del17p or TP53, del11q or ATM mutation, unmutated IGVH or mutated IGVH 
with 3.21 phenotype) patients who do not require treatment of CLL and receive PD-1:PD-L1 blockade 
along with ibrutinib, challenge with the 7-valent pneumococcal vaccine will elicit an immunologic 
response <40%, defined as the generation of detectable antibody responses to >6 antigens. Our specified 
alternative hypothesis is that vaccination in the context of PD-1 blockade and ibrutinib will elicit on 
immunologic response >60% with 90% power.   
4 
STUDY DESIGN AND ENDPOINTS 
4.1 
DESCRIPTION OF THE STUDY DESIGN 


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Protocol <#> 
 
 
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Overall treatment Schema:  All intravenous treatments will be administered at the outpatient Moffitt 
Cancer Center Infusion Center.  The patients will receive a combination of IV pembrolizumab (anti-
PD1) and oral ibrutinib according to the scheduled depicted in Figure 1.  Briefly, patients will receive 
pembrolizumab on a 3-week interval schedule for a total of at least 51 weeks (it could be extended for 
up to 2 years if clinical benefit per investigator); starting with week 6, patients will additionally start 
daily oral ibrutinib which will be continued through 54 weeks of ibrutinib therapy. The rationale of 
starting pembrolizumab first is to avoid overlapping toxicity of ibrutinib and the anti-PD1 antibody. 
Biomarker Research 
Immune Monitoring Laboratory Correlates: 
 
1. 
Global Immune function will be assessed in terms of serum cytokine patterns.  Patient sera will be 
evaluated by flow cytometric means using cytokine bead arrays to measure serum cytokine levels 
quantitatively.  The cytokine panel will include IFN-γ, TNF-α, IL-2, IL-4, IL-10, IL-6, IL-17A, allowing 
discrimination between TH1, TH2, and TH17 profiles.  
2. 
T cell function will be assessed for changes in multiple characteristics including memory formation, 
TH-polarity, markers of exhaustion, and activation via flow cytometric analysis. Naïve and memory sub-
populations will be defined according to expression of CD45RA, CD62L, CCR5 and CCR7.  TH-
polarization, including TH1, TH2, TH17 and TReg subsets, will be determined by intracellular cytokine 
and FoxP3 profiles.  Changes in T cell exhaustion phenotype will be tracked in terms of surface 
expression of several well-defined markers, including CD160, CD200R, CD244, CD272, CD274, 
CD279, as well as the intracellular markers Lag3 and Tim3.  Alterations in cellular activation will be 
measured in terms of phosphorylation of critical T cell signaling pathways, STAT 1, 3 and 5, as well as 
by surface expression of CD107a, correlating to secretory/cytotoxic activity.   
3. 
Humoral immunity will be monitored in terms of quantitative serum immunoglobulin levels as well 
as IgG subtyping by ELISA assay.  FcR subtype utilization patterns will also be evaluated by flow 
cytometric means to identify potential alterations in cellular interpretation of antibody-mediated 
signaling. 
4.  Evaluation of MRD by 4-color flow cytometry. It will be performed in patients who achieved CR 
and PR per iwCLL criteria. If CBC with differential demonstrates the normalization of WBC to normal 
limits with no evidence of lymphocytosis, a peripheral blood sample will be obtained (within 14 days) to 
determine the MRD status of the CLL in peripheral blood by multiparameter flow cytometry. If MRD is 
negative, a confirmation of MRD status in the bone marrow will be performed at the discretion of the 
investigator. 
5. 
Peripheral blood to collect DNA and RNA will be stored for future assessments. 
 
 
 
 
 
1. Complete response (CR)  to the therapeutic intervention 
2. Time to response to CLL to the therapeutic intervention 
 
 
 
 
 
1. Overall response rate (ORR) [CR + PR] 
2. Restoration of immune response as measured by: 
4.2 
STUDY ENDPOINTS 
4.2.1 
PRIMARY ENDPOINT 
4.2.2 
SECONDARY ENDPOINTS 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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a. Decreased markers of T-cell exhaustion 
b. Increased of quantitative immunoglobulin levels and subtype 
2. Safety and toxicity of the combination 
3.  Progression free survival (PFS) 
4. Incidence of Richter’s transformation 
 
 
 
 
1. Alterations of T-cell function: We postulate that there will be increased polarization 
towards TH1 compartment cells, which will be associated with increased cellular 
immunity. PD-1 blockage will increase TH1 mediated anti-tumor response.  
2. Alterations in B-cell function: Combination of BTK and PD-1 inhibition will restore 
B-cell function 
3. Alterations in cytokine profile (as defined in Section 4.2.2.2) 
4. Evaluation of toxicity and safety of the combined therapy: In order to minimize 
toxicity, pembrolizumab will started 6 weeks prior to ibrutinib 
 
 
 
 
 
 
      Patients must meet all of the following criteria to be eligible for study entry: 
 
1. Have high risk CLL which includes one or more of the following characteristics: 
a. 17p deletion by FISH or TP53 by NGS. 
b. 11q deletion or ATM mutation by NGS. 
c. IgVH unmutated or IgVH mutated 3.21 phenotype by NGS assay 
2. Have documented previously untreated CLL according to IWCLL criteria. 
a. Monoclonal B cells that are clonally co-expressing at least 1 B-cell marker on flow cytometry: 
1) CD19  
2) CD20  
3) CD5 
 
b. Prolymphocytes may comprise no more than 55% of blood lymphocytes 
3. Be willing and able to provide written informed consent/assent for the trial. 
4.2.3 
EXPLORATORY ENDPOINTS 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
PARTICIPANT INCLUSION CRITERIA 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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4. Be greater than 18 years of age on day of signing informed consent.  
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Demonstrate adequate organ function as defined in Table 1. 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥11 g/dL  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥ 25 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Negative serum pregnancy test within 3 days prior to receiving the first dose of study medication for a 
female subject of childbearing potential. Subjects of childbearing potential are those who have not 
been surgically sterilized or have not been free from menses for > 1 year. Women who are pregnant or 
breastfeeding are ineligible for this study. 
8. Female subjects of childbearing potential must be willing to use 2 methods of highly effective 
contraception, be surgically sterile, or abstain from heterosexual activity for the course of the study 
through 30 days and 90 days after the last dose of study medication for ibrutinib and pembrolizumab, 
respectively (Reference Section 5.7.2).  Male subjects must agree to use an adequate method of 
contraception starting with the first dose of study therapy through 90 days after the last dose of study 
therapy. Men must agree to not donate sperm during and after the study. 
9. Is able to take oral medication and is willing to adhere to the medication regimen.  
 
 
Any of the following is a criterion for exclusion from the study: 
 
1. Is currently participating in or has participated in a study of an investigational agent or using an 
investigational device within 4 weeks of the first dose of treatment. 
2. Has had any treatment for CLL including any investigational agent, chemotherapy, mAb, anti-PD-1, 
anti-PDL-1, or anti-CTLA-4.  
3. Meets iwCLL criteria to start therapy (Appendix A).  
5.2 
PARTICIPANT EXCLUSION CRITERIA 


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4. Transformation of CLL to aggressive NHL (Richter’s transformation or pro-lymphocytic leukemia) 
5. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
6. Has an active autoimmmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires systemic 
steroids or immunosuppressive agents including subjects with uncontrolled autoimmune hemolytic 
anemia or immune thrombocytopenia. Subjects with vitiligo or resolved childhood asthma/atopy would 
be an exception.  Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome will not be excluded from the study. 
7. Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
8. Has an active infection requiring systemic therapy. 
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject’s participation for the full duration of the 
trial, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.   
10. Subjects with a history of a different malignancy are ineligible unless they have been disease free for 
1 year and considered low risk for relapse, except for: cervical cancer in situ, ductal carcinoma in 
situ, localized prostate cancer with no detectable disease by imaging studies, and non-melanoma 
skin cancers which are eligible at any time.  
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 90 days after the last 
dose of trial treatment.  
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is 
detected). 
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Patients who had 
pneumococcal vaccination within 6 months from starting trial will not be eligible for the study. 
16. Major surgery or a wound that has not fully healed within 4 weeks of first dose. 
17. History of stroke or intracranial hemorrhage within 6 months prior to first dose. 
18. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). 
19. Requires chronic treatment with strong CYP3A inhibitors. 
20. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, 
congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 
(moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association 
Functional Classification. 
 
 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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Protocol <#> 
 
 
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Recruitment of the 25 participants for this trial will occur from new or established patients treated at the 
Hematology Clinic at Moffitt Cancer Center. Screen failure is anticipated to be less than 10%. The target 
accrual is expected to be reached in 18-24 months. All faculty members in the Lymphoma Section will be 
sub-investigators on the trial. They will be trained on the trial design, study agents, and eligibility criteria. 
This will equip each investigator to discuss the trial with potential participants as appropriate. The trial 
will be listed on the Moffitt Cancer Center website (www.moffitt.org) for the availability of local 
physicians to refer patients who could be eligible for the trial.  
 
All investigators will be made aware of the emphasis to enroll women and minorities. The design of the 
trial and eligibility criteria are not restrictive relative to women and minorities. As stated in the 
background section of the protocol, CLL affects more males than females (1.7:1) [2-4]. The clinical 
research team for this trial has experience with recruiting in another frontline investigator-initiated trial 
(MCC16622). Of the 45 participants accrued, 15 were women. The sex, ethnicity, and race of each 
participant on this trial will be captured in the Oncore electronic data base for reporting purposes.  
 
Median age at diagnosis of CLL patients is between 67 and 72 years [2]. Therefore, strategies for 
retention of elderly participants must be considered. Older adults may have medical conditions that cause 
them to drop out if side effects are severe or interact with medical treatment for comorbidities [58]. They 
are often concerned with cost of travel or distance to the study site. Moffitt Cancer Center has the unique 
barrier to enrollment of patients who may decline participation or want to discontinue as they live in 
Florida only during the winter months. Researchers have examined patient satisfaction in older adults and 
determined having continuity in staff and frequent visits increases the sense of being treated in a thorough 
manner [58]. This relationship building promotes retention. Potential participants will be assessed prior to 
screening for any perceived barriers related to the clinical trial process. Referrals will be made to a social 
worker, supportive care services, financial services, or the research nurse to address barriers prior to 
consent. Once consented, the participant will have contact with the research nurse at a minimum of every 
three to four weeks during treatment for the duration of the 12 month treatment process.  
 
 
 
 
 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of 
the investigator should any untoward effect occur that may jeopardize participant safety.  In addition, a 
subject may be withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.   
 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• 
Unacceptable adverse events 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Administrative reasons 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
Chronic Lymphocytic Leukemia  
Protocol <#> 
 
 
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The End of Treatment and Follow-up visit procedures are listed in Section 7.3.7 (schedule of events) and 
Section 7.3 (Visit Requirements).  After the end of treatment, each subject will be followed until 90 days after 
the end of pembrolizumab infusions and 30 days after the last dose of ibrutinib.(serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  The last dispensing of 
ibrutinib will occur at week 51 and dosing will continue for an additional 3 weeks. Subjects who discontinue 
for reasons other than progressive disease will have post-treatment follow-up for disease status and toxicity up 
to 30 days after stopping ibrutinib and 90 days after stopping pembrolizumab.  Follow-up rules will apply 
unless participant initiates a non-study cancer treatment, withdraws consent, or becomes lost to follow-up 
(unsuccessful attempts to contact for 3 months).  After documented disease progression each subject will be 
followed by telephone every 12 weeks for overall survival until death, withdrawal of consent, or the end of the 
study, whichever occurs first. 
 
 
 
 
Every effort will be made to maintain contact with a subject who withdraws early. If the subject remains at 
MCC for further care, clinic visits may be tracked and the condition of the subject followed. If the subject is 
not continuing care at MCC, contact information will be updated at the end of treatment visit, including 
accurate phone numbers, and email address. The importance of the follow-up period for AEs and SAEs will 
be stressed to the subject. 
 
Replacement of participants who screen fail or drop out prior to completing 9 weeks of treatment are 
permitted to be replaced in order to meet the accrual goal of this study.  
 
 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to investigator, funding agency, the IND/IDE sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the PI will promptly inform the IRB and 
will provide the reason(s) for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to 
subjects 
4. Plans to modify or discontinue the development of the study drug 
5. Determination of futility 
In the event Merck or Janssen decide to no longer supply study drug, ample notification will be provided so 
that appropriate adjustments to subject treatment can be made. 
 
 
 
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
6 
STUDY AGENT 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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Protocol <#> 
 
 
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Investigational products for this trial will be supplied by Merck & Co, Inc. (pembrolizumab) and Janssen 
Pharmaceuticals, Inc. (ibrutinib).  
 
Pembrolizumab 
An order form supplied by Merck will be utilized. The form will have instructions on how to order. Pharmacy 
will complete the quantity needed and the shipment address. Orders will require 7 business days to arrive on 
site.  
 
Ibrutinib 
Ibrutinib will be shipped from Janssen as bottles of capsules. For the initial supply, the Janssen trial manager 
will make arrangements for shipment of bottles expected to be used in the first one to two months, dependent 
on planned enrollment. Future re-orders will be submitted using a drug request form supplied by Janssen. 
Order forms will be submitted by email to the team email address (IIS-BIO-VIRO-GCO@its.jnj.com) printed 
on the order form.  Allow 7 business days for drug to arrive on site.  
 
 
 
 
IBRUTINIB 
 
Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Ibrutinib is a small-molecule inhibitor of BTK. 
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. It 
is a white to off-white solid with the empirical formula C25H24N6O2 and a molecular weight 440.50. 
Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. 
Ibrutinib capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib 
as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, 
magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, 
titanium dioxide and black ink. Each white opaque capsule is marked with “ibr 140 mg” in black ink. 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
The white opaque 140 mg capsules marked with “ibr 140 mg” in black ink are available in white HDPE 
bottles with a child-resistant closure: 
• 
90 capsules per bottle: NDC 57962-140-09  
 
PEMBROLIZUMAB 
 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate 
molecular weight of 149 kDa. Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on 
T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occur in some 
tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance 
of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction 
with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the 
anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased 
tumor growth. 
Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in 
efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks in patients with 
6.1.1 
ACQUISITION 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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Protocol <#> 
 
 
Moffitt Cancer Center Protocol Template – v3.2 2018-08-10 
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NSCLC 
Pembrolizumab injection will be provided as a sterile, preservative-free, clear to slightly opalescent, colorless 
to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of 
pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is 
formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
 
 
 
 
IBRUTINIB 
Store bottles at room temperature 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 
30°C (59°F to 86°F). Retain in original package until dispensing. 
 
PEMBROLIZUMAB 
Pembrolizumab for injection (lyophilized powder): carton containing one 50 mg single-dose vial (NDC 
0006- 3029-02). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). 
Pembrolizumab injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-dose vial 
(NDC 0006-3026-02). Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to 
protect from light. Do not freeze. Do not shake. 
 
 
 
 
IBRUTINIB 
N/A 
 
PEMBROLIZUMAB 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance 
with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in the table below: 
 
Table Product descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
Pembrolizumab is provided as a liquid solution (100 mg/vial) in Type I glass vials intended for single use 
only. 
The liquid drug product are a clear to opalescent solutions, essentially free of visible particles. The liquid 
product is intended for IV administration. The liquid drug product can be further diluted with normal saline or 
5% dextrose in the concentration range of 1 to 10 mg/mL in intravenous (IV) containers made of polyvinyl 
chloride (PVC) or non-PVC material. Reconstituted vials should be immediately used to prepare the infusion 
solution in the IV bag and the infusion solution should be immediately administered. Diluted pembrolizumab 
solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of infusion. In addition, IV bags 
can be stored at 2 to 8°C for up to a cumulative time of 20 hours. This recommendation is based on up to 24 
hours of room temperature and up to 24 hours of refrigerated stability data of diluted pembrolizumab 
solutions in the IV bags. 
 
 
 
IBRUTINIB 
Ibrutinib will be administered orally once daily at approximately the same time each day at the dose of 420 
6.1.3 
PRODUCT STORAGE AND STABILITY 
6.1.4 
PREPARATION 
6.1.5 
DOSING AND ADMINISTRATION 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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mg daily (3 capsules of 140 mg daily). Capsules will be swallowed whole with water. Capsules shall not be 
opened, broken or chew. 
 
PEMBROLIZUMAB 
Pembrolizumab will be administered intravenously at 200 mg every 3 weeks 
 
 
IBRUTINIB 
Ibrutinib is only indicated for oral administration 
 
PEMBROLIZUMAB 
Pembrolizumab will be administered as is approved route of administration (IV) 
 
 
 
IBRUTINIB 
The starting dose will be the recommended for chronic lymphocytic leukemia at 420 mg daily (three capsules 
daily orally). There will be no escalation schedule of ibrutinib in this study.  
 
PEMBROLIZUMAB 
The starting dose of pembrolizumab will be at the recommended of 200 mg IV every 3 weeks. There will be 
no dose escalation of pembrolizumab in this study. 
 
 
 
GENERAL MANAGEMENT OF DOSE ADJUSTMENT S/MODIFICATIONS WITH IBRUTINIB 
AND/OR PEMBROLIZUMAB 
 
Below is the table for general management/adjustments of ibrutinib and pembrolizumab for hematologic and 
non-hematologic adverse events. 
 
If study treatment is held for an adverse event and the subject is approved to resume treatment, the subject 
will resume with the timepoint at which the treatment was held.  
 
Toxicity 
Grade 
Dose Modification 
Toxicity 
Management 
Agent to be 
considered for 
dose 
modification  
Thrombocytopenia 
(Unless it is related to CLL 
bone marrow involvement) 
1,2 
N/A 
N/A 
Ibrutinib 
Pembrolizumab 
3 (Platelets < 
50 000 
cells/mm3 
[50x109]) 
Ibrutinib: 
No dose modification required 
Pembrolizumab: 
No dose modification required 
Monitor 
CBC/differential 
at least weekly 
Platelet 
transfusions are 
permitted per 
AABB guidelines 
6.1.6 
ROUTE OF ADMINISTRATION 
6.1.7 
STARTING DOSE AND DOSE ESCALATION SCHEDULE 
6.1.8 
DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 


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4 (Platelets < 
25 000 
cells/mm3 
[50x109]) 
Ibrutinib: 
If thrombocytopenia resolves to ≤ 
Grade 1 (platelets ≥75,000 cells 
/mm3 [75 × 109/L] or baseline, 
restart the dose. If toxicity recurs, 
reduce dose by 140 mg. If toxicity 
persists following two dose 
reductions, discontinue ibrutinib  
 
Pembrolizumab: 
Decision to discontinue will 
depend upon clinical situation and 
per clinical investigator’s 
judgment and in consultation with 
Supporting company 
Monitor 
CBC/differential 
at least weekly 
Platelet 
transfusions are 
permitted per 
AABB guidelines 
Neutropenia 
(Unless it is related to CLL 
bone marrow involvement) 
1,2 
N/A 
N/A 
Ibrutinib  
Pembrolizumab 
3 ANC < 1000 
cells/m3 
[1x109]) 
Ibrutinib 
Hold ibrutinib if Grade 3 
associated with infection or fever 
(temperature ≥ 38.5°C)  
If neutropenia resolves to ≤ Grade 
1 (ANC ≥1500 /mm3 [≥1.5 × 
10
9
/L]) or baseline, restart the 
dose. If toxicity recurs, reduce 
dose by 140 mg. If toxicity 
persists following 2 dose 
reductions, discontinue the drug 
Pembrolizumab 
Hold pembrolizumab until 
resolution to ≤ Grade 1 or 
baseline  
For AEs that downgrade to ≤ 
Grade 2 within 7 days or resolve 
to ≤ Grade 1 or baseline within 14 
days, resume IP/study regimen 
administration at next scheduled 
dose. Otherwise, discontinue 
pembrolizumab  
 
Monitor 
CBC/differential 
at least weekly 
Use of myeloid 
growth factors 
(MGF) are 
permitted per 
ASCO or NCCN 
guidelines 
4 ANC < 500 
cells/m3 
[1x109])  
Ibrutinib 
Hold ibrutinib for Grade 4  
If neutropenia resolves to ≤ Grade 
1 (ANC ≥1500 /mm3 [≥1.5 × 
10
9
/L]) or baseline, restart the 
dose. If toxicity recurs, reduce 
dose by 140 mg. If toxicity 
persists following 2 dose 
reductions, discontinue the drug 
Pembrolizumab 
Decision to discontinue will 
depend upon clinical situation and 
per clinical investigator’s 
judgment and in consultation with 
supporting company 
Monitor 
CBC/differential 
at least weekly 
Use of myeloid 
growth factors 
(MGF) are 
permitted per 
ASCO or NCCN 
guidelines 
Non-Hematological 
1 
N/A 
 
Pembrolizumab 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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toxicity (non-immune 
related toxicity) 
2 
Pembrolizumab 
Hold drug until resolution to 
Grade < 1 toxicity or baseline 
Ibrutinib 
No dose interruption is needed 
Ibrutinib 
3 or 4 
Pembrolizumab 
Hold drug until resolution to 
Grade < 1 toxicity or baseline 
For AEs that downgrade to ≤ 
Grade 2 within 7 days or resolve 
to ≤ Grade 1 or baseline within 14 
days, resume IP/study regimen 
administration at next scheduled 
dose. Otherwise, discontinue 
pemrbolizumab 
For Grade 4 AEs the decision to 
discontinue will depend upon 
clinical situation and per clinical 
investigator’s judgment and in 
consultation with supporting 
company 
Ibrutinib 
Hold Ibrutinib 
If toxicity resolves to ≤ Grade 1 
or baseline, restart the dose. If 
toxicity recurs, reduce dose by 
140 mg. If toxicity persists 
following two dose reductions, 
discontinue ibrutinib  
 
 
 
 
 
 
 
 
 
IBRUTINIB DOSE MODIFICATIONS 
Interrupt ibrutinib therapy for any Grade 3 or greater non-hematological toxicities, Grade 3 or greater 
neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity 
have resolved to Grade 1 or baseline (recovery), ibrutinib therapy may be reinitiated at the starting dose. If 
the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg 
may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue 
ibrutinib.  
Recommended dose modifications are described below: 
 
Toxicity occurrence 
Withhold/Discontinue 
ibrutinib? 
First 
Restart at 420 mg daily 
Second 
Restart at 280 mg daily 
Third 
Restart at 140 mg daily 
Forth 
Discontinue ibrutinib 
 
MANAGEMENT/SUPPORTIVE CARE OF IMMUNE RELATED ADVERSE EVENTS RELATED TO 
PEMBROLIZUMAB 


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Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an adverse event 
of unknown etiology, associated with drug exposure and is consistent with an immune phenomenon.  irAEs 
may be predicted based on the nature of the pembrolizumab compound, its mechanism of action, and 
reported experience with immunotherapies that have a similar mechanism of action.  Special attention 
should be paid to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly after the first 
dose or several months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes prior to labeling an adverse event as an irAE.  Information on how to identify and evaluate 
irAEs has been developed and is included in the Event of Clinical Interest and Immune-Related Adverse 
Event Guidance Document located in the Administrative Binder.  Subjects who develop a Grade 2 or higher 
irAE should be discussed immediately with the Sponsor.   
It is not expected that ibrutinib will cause immune related AEs. 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in the table below 
 
irAE 
Withhold/Discontinue 
pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab 
Discontinue 
if 
unable 
to 
reduce corticosteroid dose to < 
10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
 
Management of specific irAEs 
 
Pneumonitis: 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional anti-inflammatory 
measures, as needed. 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration. 
 
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal 
pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and 
ileus). 
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion. For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose oral steroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks 
 
Type 1 diabetes mellitus 
If new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 hyperglycemia 
associated with metabolic acidosis or ketonuria. 


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Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and C-
peptide. 
 
Hypophysitis: 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered. 
 
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function 
(at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for 
clinical signs and symptoms of thyroid disorders. 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated 
per standard of care. 
Grade 3-4 hyperthyroidism 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
Hepatic: 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
Treat with IV or oral corticosteroids 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over no less 
than 4 weeks 
 
Renal Failure or Nephritis: 
For Grade 2 events, treat with corticosteroids. 
For Grade 3-4 events, treat with systemic corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
 
Management of Pembrolizumab Infusion Related Reactions (IRR): 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. Management of IRR are recommended based on Moffitt 
institutional policies. Below is a table of general recommendations. 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov 
 
 
 
 
 
The duration of ibrutinib therapy will be up to 51 weeks. 
The duration of therapy of pembrolizumab will be up to 51 weeks. Pemrbolizumab dosing could be extended 
for up to 2 years if clinical benefit per investigator. 
Patients will be considered evaluable if they complete at least 9 weeks or three infusions of pembrolizumab. 
 
 
 
For ibrutinib there will be a Patient Compliance Pill Diary for oral medications provided to the subject when 
6.1.9 
DURATION OF THERAPY 
6.1.10 
TRACKING OF DOSE 


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each new supply of ibrutinib is dispensed. 
For pembrolizumab there will be documentation in the patient’s electronic medical record of dosing and a 
pharmacy dispensing/accountability log to determine the adherence. 
 
 
 
 
 
The study drugs will be stored in the Moffitt Investigational Pharmacy Department. There will be an 
accountability log for each drug. Any unused study drug will be destroyed on site per Investigational 
Pharmacy standard procedures. 
 
 
 
 
 
 
The Schedule of Events - Section 7.3.7 summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the PI and/or Merck or Janssen 
for reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive 
in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional consent be 
obtained from the subject.  In these cases, such evaluations/testing will be performed in accordance with 
those regulations. 
 
 
 
Prior to any study procedure, informed consent must be obtained and documented by the subject’s dated 
signature or by the subject’s legally acceptable representative’s dated signature on a consent form. The 
dated signature of the person conducting the consent discussion must also appear on the consent form.  
 
 
 
 
Prior to any trial treatment, all inclusion and exclusion criteria will be reviewed and signed by the PI or 
Sub-Investigator to ensure the subject qualifies for the trial.  
 
 
 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed that is considered to be clinically significant 
by the Investigator.  Details regarding the disease for which the subject has enrolled in this study will be 
recorded separately and not listed as medical history.   
 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
7 
STUDY PROCEDURES AND SCHEDULE 
7.1 
STUDY PROCEDURES 
7.1.1 
Overview 
7.1.2 
Informed Consent 
7.1.3 
Inclusion/Exclusion Criteria 
7.1.4 
Medical History 


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The investigator or qualified designee will record medication, if any, taken by the subject starting at 
screening until end of trial treatment.  All medications related to reportable SAEs and ECIs should be 
recorded as defined in the SAE section of the protocol. 
 
 
 
The investigator or qualified designee will review all new CLL anti-neoplastic therapy initiated after the 
last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after the last 
dose of trial treatment, the Safety Follow-up visit must occur before the first dose of the new therapy.  
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up. 
 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or worsening 
AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse events will 
be collected from the time of consent , and will continue every 3 weeks during treatment. For adverse 
event collection after treatment discontinuation, see Section 8.3. 
  
 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  A full physical 
exam should be performed during screening,  
 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.   
 
 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Schedule of Events 
(Section 7.3.7).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
 
 
The investigator or qualified designee will assess ECOG status (see Appendix B) as specified in the 
Schedule of Events.   
 
 
Assessment of response (ORR) is a primary end point and will be reported using the latest Response 
Criteria Guidelines per the International Working Group of CLL. (Appendix C) 
7.1. 4        Concomitant Medications Review 
 
7.1. 5       Post-Study Anticancer Therapy Status 
7.1. 6       Adverse Event Review 
7.1. 7       Full Physical Exam 
7.1. 8 
Directed Physical Exam 
7.1. 9       Vital Signs 
S
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7.1. 10       Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
7.1. 11       Assessment of Disease 


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Details regarding specific laboratory procedures/assessments to be performed in this trial are provided in 
the Schedule of Events.  Tests specific to screening include hepatitis B and C panel, HIV evaluation at 
screening, serum B-HCG as defined, PT/INR and aPTT, urinalysis, CLL specific testing (ZAP-70, B-2 
microglobulin, IgVH mutation, FISH), T3, free T4, and TSH. 
 
 
Blood samples will be collected pre-dose on Day 1, Week 6, Week 21, and end of ibrutinib therapy for 
immune testing per Schedule of Events. They will be performed at investigator’s discretion if early 
study termination. For sampling requirements, see Section 7.2. 
 
 
 
Laboratory testing for safety will be performed at time points per Schedule of Events. These tests 
include CBC/differential and CMP (albumin, BUN, creatinine, alkaline phosphatase, ALT, AST, CO2, 
calcium, chloride, glucose, potassium, sodium, total bilirubin, total protein, LDH). Additional safety 
evaluations for tumor lysis syndrome (LDH, uric acid, phosphorus, Creatinine and BUN) will occur as 
defined in the Schedule of Events. 
 
 
 
Tumor imaging will consist of CT scan of the neck, chest, abdomen and pelvis. CT scan will be done at 
screening (if not done within 3 months prior to consent). Response assessments will be done at week 12 
(+/-3 days), week 24 (+/-3 days), and after 51 weeks of ibrutinib. If the subject discontinues treatment 
early or progression of disease is suspected, CT will be done at the discretion of the investigator. 
Imaging during follow-up will be performed per investigator discretion.  
 
 
A bone marrow biopsy will be performed at screening (if not performed within 30 days), after the end of 
pembrolizumab and ibrutinib therapy (28-35 days after week 51). If subject discontinues treatment early 
or progression of disease is suspected, a bone marrow biopsy will be done at the discretion of the 
investigator. During follow-up, bone marrow biopsies will be performed per investigator discretion.  
 
 
 
Blood samples for correlative studies will be collected at baseline (prior to first dose of study drug), at week 
9, week 12, and end of ibrutinib treatment. Peripheral blood will be utilized with an estimated volume of 50 
cc collected in five green top tubes.  
1. Preparation of Samples 
Whole blood samples in 5 green top tubes (10ml/tube) will be received in the laboratory of Eva Sahakian, 
PhD. Plasma will be isolated by centrifugation of the green top tubes for 5min at 1500rpm and 
lymphocyte isolation will be performed using Ficol gradient isolation for the purpose of immune testing.  
  
2. Sample Storage 
For storage, plasma will be held in 1.5 ml aliquots and placed in a -20C freezer. Lymphocytes will be 
frozen using 90% FBS and 10% DMSO and placed in a -80C freezer for short term storage. Long term 
storage of lymphocytes will be conducted utilizing liquid nitrogen.  
 
3. Long-Term Use of Samples 
      7.1.12     Laboratory Procedures/Assessment 
7.1. 13       Correlative Studies Blood Sampling 
     7.1.14        Laboratory Safety Evaluations 
     7.1.15        Tumor Imaging 
     7.1.16      Bone Marrow Biopsy 
7.2  RESEARCH BLOOD SPECIMEN PREPARATION, HANDLING, AND STORAGE 
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Any isolated plasma and lymphocytes will be stored for the duration of the trial utilizing the short term 
method above and will be tested per protocol parameters outlined in Section 4.1. With the subject’s 
permission, any samples remaining at the end of the trial will be placed in long term storage for use in 
future research. If any subject does not agree, that subject’s remaining samples will be destroyed at the 
final closure of the trial. 
 
4. Procedure for Clinical Trial Staff 
The following procedure is recommended to be used for collaboration with the Research Science 
Lab: 
a. Notify the Research lab at least 2 days prior to the collection, using the template below. 
Email to alex.achille@moffitt.org and cc eva.sahakian@moffitt.org 
Follow up with a phone message to x6335. 
b. Prepare a plastic bag with 5 green top tubes (tubes obtained from Dr. Sahakian’s lab). Attach 
label to tubes with MCC #, subject MRN, and date of collection. Each bag will have a label 
attached with the MCC #, subject MRN, DOB, initials, date/time of collection. Label should 
have research lab contact information. (“Contact extension 6335 or pager 256-4415 for pick-
up”). 
c. Deliver bag of tubes to the Blood Draw area the day prior to collection.  
 
 
 
 
Screening Visit (Day -28 to -1)  
 
• 
Obtain and review medical history to determine eligibility based on inclusion/exclusion criteria. 
• 
Written informed consent to be obtained prior to any screening procedures 
• 
Review medications history (including over-the-counter drugs, vitamins, herbs, alcohol) to 
determine eligibility based on inclusion/exclusion criteria.  
• 
Perform physical examination needed to determine eligibility based on inclusion/exclusion 
criteria 
• 
Vital signs measurements Evaluation of ECOG performance status 
• 
Twelve-lead ECG 
• 
Serum beta-human chorionic gonadotropin (β-hCG) pregnancy test for women of childbearing 
potential 
• 
Clinical laboratory testing including urinalysis, serum chemistry, hematology, viral serology 
(Hepatitus B, Hepatitis C, and HIV serology), β-2microglobulin, baseline thyroid function tests 
(T3, T4, and TSH) and coagulation parameters. Clinical assessments performed as part of the 
subject’s routine clinical evaluation and not specifically for this study need not be repeated after 
signed informed consent has been obtained provided the assessments fulfill the study 
requirements and are performed within 28 days of starting study treatment. 
• 
Peripheral blood samples for ZAP-70, IgVH mutational status, and FISH only required if they 
have not ever been performed. 
• 
Evaluation of disease status through disease-related symptoms and radiological examinations by 
CT scans. Results of radiologic assessments obtained prior to signing the informed consent as part 
of the subject's standard of care may be used for this study if performed within 3 months before 
date of consent. Subsequent assessments performed throughout the study must use the same 
method of assessment per subject. 
7.3 
STUDY SCHEDULE 
7.3.1 
SCREENING 


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• 
Bone marrow biopsy including flow cytometry and FISH testing for CLL (if not performed within 
30 days of consent). 
 
 
 
 
 
7.3.2.1 
Baseline Visit (Week 0) 
 
• 
Verify subject still meets inclusion/exclusion criteria. 
• 
Review results of serum pregnancy test, if applicable.  
 
• 
History and assessment to include directed physical examination, vital signs, and 
concomitant medication review. Assess and record baseline symptoms prior to study drug 
administration. 
• 
ECOG performance status assessment 
• 
CBC with differential 
• 
Chemistry profile (ALT, AST, alkaline phosphatase, total bilirubin, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Tumor lysis syndrome evaluation (TLS) using BUN, creatinine, phosphorus, potassium, 
LDH, uric acid results.  
• 
Blood for correlatives studies 
• 
Study drug administration (initiation of pembrolizumab IV).  
7.3.2.2 
Week 1 and 2 
• 
Serum chemistry profile and TLS evaluation by laboratory tests. TLS evaluation will 
occur on days 1-3 from initiation of therapy. 
• 
Review of tests and assessment for TLS by the investigator or qualified designee.  
7.3.2.3 
Week 3 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
7.3.2 
ENROLLMENT/BASELINE 


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• 
TLS evaluation 
• 
Study drug administration (pembrolizumab). 
7.3.2.4  
Week 6 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
TLS evaluation 
• 
Blood for correlative studies 
• 
Prevnar 13 vaccination 
• 
Study drug administration (pembrolizumab and start of ibrutinib by mouth daily for up to 
12 months). Medications may be administered in any order on days of infusions. 
• 
Provide pill diary and instruct subject on the recording of data on diary. 
7.3.2.5  
Week 7 and 8 
• 
Serum chemistry profile and TLS evaluation by laboratory tests. 
• 
Review of tests and assessment for TLS by the investigator or qualified designee.  
7.3.2.6  
Week 9 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Study drug administration (pembrolizumab and ibrutinib).  


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• 
Provide pill diary  
• 
Serum chemistry profile and TLS evaluation by laboratory tests. 
• 
Review of tests and assessment for TLS by the investigator or qualified designee.  
7.3.2.7  
Week 10 
• 
Serum chemistry profile and TLS evaluation by laboratory tests. 
• 
Review of tests and assessment for TLS by the investigator or qualified designee.  
7.3.2.8  
Weeks 12, 15, 18, 21 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Study drug administration (ibrutinib and pembrolizumab).  
• 
CT scan week 12. 
• 
Blood for correlatives studies week 21 
• 
Provide pill diary.  
7.3.2.9 
Week 24  
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Tumor imaging (CT scans). 


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• 
Study drug administration (ibrutinib and pembrolizumab).  
• 
Provide pill diary 
7.3.2.10 
Every 3 Weeks from Week 24 (up to 51 weeks of treatment)  
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Tumor imaging as clinically indicated per investigator  
• 
Study drug administration (ibrutinib).  
• 
Provide pill diary 
7.3.2.11 
End of Treatment Visit (0-7 days after last dose, includes early termination) 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Blood for correlative studies (at investigator’s discretion if early termination) 
• 
Bone marrow biopsy (if early termination, at the discretion of the investigator) 
• 
Tumor Imaging (at the investigator discretion) 
• 
Collect remaining bottles of ibrutinib and final pill diary.  
7.3.2.12  
Safety Follow-Up Visit (30-35 days after last dose of study treatment) 
• 
Directed physical examination, vital signs and brief review of systems. 


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• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
 
 
 
Follow-Up Visits (every 12 weeks +/- 7 days after Safety Visit up to 12 months) 
 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Survival status and anti-cancer therapy status 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
 
 
 
When it is determined the patient will end treatment under this study, an End of Treatment (EOT) Visit 
will be carried out. A Final Study Visit will occur at the next regularly scheduled 12 week Follow-Up 
Visit after trial closure is confirmed. This visit is to discuss study closure with the subject. Any AE that is 
ongoing will be considered ongoing at the Final Study Visit.  
 
• 
Directed physical examination, vital signs and brief review of systems. 
• 
Medication reconciliation. 
• 
Toxicity/ AE assessment 
• 
ECOG performance status assessment.  
• 
Hematology (hemoglobin, HCT, RBC, WBC with differential [neutrophils, bands, 
lymphocytes, monocytes, eosinophils and basophils) 
7.3.3 
FOLLOW-UP 
7.3.4 
FINAL STUDY VISIT 


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35 
 
• 
Chemistry (ALT, AST, alkaline phosphatase, total bilirubin, LDH, calcium, bicarbonate, 
sodium, potassium, chloride, creatinine, BUN, total protein and albumin) 
• 
Provide final instructions to the subject and inform subject if results will be available or 
any planned presentation or publication of study data.   
 
 
 
 
 
Any visit not included on the Schedule of Events Table that includes examination in the Moffitt 
hematology clinic, inpatient hospitalization, laboratory evaluations or management of adverse events, will 
be considered an Unscheduled Visit. It will be documented in the subject’s medical record and included 
on the adverse event log. Adverse event or serious adverse event data will be collected in Oncore. No 
separate Oncore form for an unscheduled visit will used to collect additional data. 
 
 
 
All visits beginning at 
week 0  
may be performed within 
+/- 3 days  
Screening 
(day  
-28 to -1) 
 
Week  
0 
Week 
1 
2 
3 
6 
7 
 
 
 
 
8 
9 
10 
12 
15 
18 
21 
24-51 
(every 
3 
weeks) 
EOT 
Visit 
30 days 
 post  
EOT 13 
Follow-
up14 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
 
 
X X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prevnar 13 vaccination 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
administration 2 
 
X  
 
 
X  X  
 
 
X 
#4 
 
X 
X 
X 
X 
X 
 
 
 
Ibrunitib dosing 2 
 
 
 
 
 
X 
X X X 
X 
X 
X 
X 
X 
X 
 
 
 
Post-study anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Review Adverse Events1 
 
X 
 
 
X X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical 
Examination 
 
X 
 
 
X X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (temp, pulse, 
resp, BP)/ Weight 
X 
X 
 
 
X X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
Status 
X 
X 
 
 
X X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B and C Panel, 
HIV AB/AG combo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Serum 
Beta-HCG3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology4 
X 
X 
 
 
X X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic 
panel (CMP)5 
X 
X 
X 
X X X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLS evaluation6 
 
X 
X 
X X X 
X X X 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for: 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.6 
UNSCHEDULED VISIT 
7.3.7 
SCHEDULE OF EVENTS TABLE 


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All visits beginning at 
week 0  
may be performed within 
+/- 3 days  
Screening 
(day  
-28 to -1) 
 
Week  
0 
Week 
1 
2 
3 
6 
7 
 
 
 
 
8 
9 
10 
12 
15 
18 
21 
24-51 
(every 
3 
weeks) 
EOT 
Visit 
30 days 
 post  
EOT 13 
Follow-
up14 
 
ZAP-70, IgHV mutational 
status,  
FISH for CLL7 
Peripheral blood for: B-2 
microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, T4 and TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging10 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
week 
24 
only 
X 
 
 
Bone marrow biopsy11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Correlative Studies Blood 
Collection12 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
1 Baseline symptoms will be assessed and recorded on day 1. Adverse event data will be captured from the time of consent. Events will 
be reviewed and assessed on days of the clinic visits for physical examinations. Additional safety evaluation will be performed 30 days 
from last dose of ibrutinib and 90 days from pembrolizumab. 
2 Pembrolizumab infusions will be every 3 weeks (+/- 3 days) for 51 weeks. Ibrutinib will be dispensed every 3 weeks on the day of the 
pembrolizumab infusion. The last dispensing of ibrutinib will occur at week 51 and dosing will continue for an additional 3 weeks. A 
pill diary will be provided to participants with every dispensing of ibrutinib supply. Pill diary from previous dispensing will be 
reviewed for accountability. 
3 Serum pregnancy test will be performed on females of childbearing potential (FCBP). A FCBP is considered when a sexually mature 
female: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 
consecutive months.    
4 Hematology will consist of CBC and differential with platelet counts. CBC/differential will be performed at day 1, week 0,1,2 after 
starting pembrolizumab and then weekly for the first month on ibrutinib (weeks 6, 7, 8, 9, 10). Starting at week 12, CBC/diff will be 
performed on days of the clinic visits for physical examinations/drug administration. Further CBCs with differential will be performed 
per physician discretion.  
5 CMP includes: sodium, potassium, chloride, CO2, calcium, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
total bilirubin, AST/SGOT, ALT/SGPT, LDH. Subjects will have CMP , week 0, 1, 2 after starting pembrolizumab and then weekly for 
the first month on ibrutinib (weeks 6, 7, 8, 9, 10). Starting at week 12, CMP will be performed on days of the clinic visits for physical 
examinations/drug administration. Further CMPs will be performed per investigator discretion. 
6 TLS (tumor lysis syndrome) laboratory assessment will include: BUN, creatinine, phosphorus, potassium, LDH, uric acid. TLS 
laboratory evaluation will occur at days 1-3 of week 0  weeks 1 and 2 after starting pembrolizumab and then weekly for the first month 
on ibrutinib (weeks 6, 7, 8, 9, 10). Further TLS assessments will depend on clinical condition and/or at investigator discretion. 
7Peripheral blood samples for ZAP-70, IgVH mutational status, and FISH testing will be done ONLY if not ever performed. Previous 
results must be available in the medical record for determination of eligibility.  
10 Tumor imaging will consist of CT of the neck, chest, abdomen and pelvis that will be performed at screening, if not done within 3 
months prior to study entry. Response assessment will be done at week 12, week 24, and end of 51 weeks of treatment. CT scans may 
be performed at different intervals at investigator discretion (i,e. suspicion of progressive disease). Imaging studies post treatment 
discontinuation will be performed per investigator discretion (including end of treatment imaging assessment). 
11 Bone marrow biopsy will be performed at screening (if not performed within 30 days) and after the end of pembrolizumab and 
ibrutinib therapy (28-35 days after week 51).  If subject discontinues treatment early or progression of disease is suspected, a bone 
marrow biopsy will be per investigator discretion. During follow-up, bone marrow biopsies will be performed per investigator 
discretion.  
12 Correlative studies. Please refer to Section 4.1 for biomarkers to be studied. They will be performed at baseline (prior to first dose of 
study drug), at week 6, week 21, and end of ibrutinib treatment. See Section 7.2 for correlative sample collection procedure. They will 
be performed at investigator’s discretion if early study termination 


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13 Safety follow-up will be 90 days after the end of pembrolizumab treatment (may be at the regularly scheduled monthly visit that is 
nearest to 90 days if continuing on ibrutinib treatment) and 30 days post discontinuation of ibrutinib treatment. If the subject 
discontinues early, safety follow up must occur before first dose of the next therapy. 
14 Follow-up after a subject has discontinued trial treatment will be every 12 weeks for 12 months.  
 
 
 
 
 
All patients should be maintained on the same medications throughout the study period, as medically feasible. 
The investigator should instruct the patient to notify the study staff about any new medications he/she takes 
after the start of the study drug. All medications (other than study drug) and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the patient starts treatment with study 
drug must be recorded: 
 
• 
Administration of pegfilgrastim or filgrastim following initiation of protocol therapy is at investigator’s 
discretion for all patients; 
• 
Administration of erythropoietin or darbopoietin is allowed; 
• 
Patients must be instructed not to take any additional medications (including herbal supplements and 
over-the-counter products) during the trial without prior consultation with the investigator. All 
medications taken within 30 days of screening should be recorded. If concomitant therapy must be 
added or changed, the reason and name of the drug/therapy should be recorded; 
• 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the patient 
are allowed, including drugs given prophylactically (e.g. antiemetics or steroids), with the following 
exceptions: 
• 
CYP3A Inhibitors/Inducers o Ibrutinib is metabolized primarily by CYP3A. Avoid co-administration 
with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.  
o Strong inhibitors of CYP3A (e.g., ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, 
clarithromycin, telithromycin, itraconazole, nefazadone, or cobicistat) should be avoided 
o If a strong CYP3A inhibitor must be used in the short term, ibrutinib will be held for the duration of 
inhibitor use. Subjects will be monitored more closely for signs of ibrutinib toxicity (at the 
investigator’s discretion). No dose adjustment is required in combination with mild inhibitors. 
o Grapefruit and Seville oranges should be avoided during ibrutinib treatment, as these contain moderate 
inhibitors of CYP3A 
o Avoid use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin, and St. John’s Wort). 
Consider alternative agents with less CYP3A induction. 
o Dose modifications of ibrutinib are recommended when used concomitantly with posaconazole, 
voriconazole and moderate CYP3A inhibitors.  
o Refer to package insert for a complete chart of recommended dose modifications for use with CYP3A 
inhibitors.  
o A comprehensive list of inhibitors, inducers, and substrates may be found at 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. This website is continually revised and should be 
checked frequently for updates. 
 
 
Anti-platelet Agents and Anticoagulants: 
o Warfarin or vitamin K antagonists should not be administered concomitantly with ibrutinib. 
o Supplements such as fish oil and vitamin E preparations should be avoided. Use ibrutinib with caution 
in subjects requiring other anticoagulants or medications that inhibit platelet function. Subjects with 
congenital bleeding diathesis have not been studied. For guidance on ibrutinib and the use of 
anticoagulants during procedures/surgeries see Section 5.3. 
o Patients who need to be on anticoagulant therapy during treatment with ibrutinib should be treated with 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 


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low molecular weight heparin as the preferred therapy. 
o 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. 
 
 
 
Not Applicable 
 
 
 
See Section 7.4 
 
 
 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase of 
this trial: (except for ibrutinib at 420mg and pembrolizumab as they are part of the trial) 
o Anti-cancer systemic chemotherapy or biological therapy  
o Immunotherapy not specified in this protocol 
o Chemotherapy not specified in this protocol 
o Investigational agents other than pembrolizumab or ibrutinib 
o Radiation therapy. Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed after consultation with Sponsor.   
o Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed..  
o Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of corticosteroids 
may be approved after consultation with the Principal Investigator.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments 
for clinical management should be removed from the trial.  Subjects may receive other medications that the 
investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications, which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
 
 
Tumor lysis syndrome 
It will follow our Moffitt Cancer Center institutional standards for TLS prophylaxis. All patients with high 
tumor burden (WBC > 25 000 and/or bulky disease [masses or lymphadenopathy greater than 7.5cm) must be 
treated with allopurinol (or alternative) starting 12 to 24 prior to the first infusion of pembrolizumab. TLS 
prophylaxis medications may be discontinued at the investigator discretion. 
 
Anti-infectives prophylaxis 
If clinically indicated, antiviral, antifungal, antiparasitic (such as Pneumocystis Jiroveci pneumonia) and/or 
antibacterial may be considered but it Is not mandated in this study. 
 
7.5 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 


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Prevnar 13 vaccination 
For standard evaluation of immunogenicity the Pneumococcal 13-valent Conjugate Vaccine (Prevnar 13) will 
be utilized. Patients will receive Prevnar 13 n week 6 day 1 (if not given in the prior 8 weeks). The dose will 
be the standard 0.5 mg single dose prefilled syringe administered by intramuscular (IM) route 
 
  
 
 
 
 
 
 
 
If it is determined that the patient continuing to receive clinical benefit from the trial at the end of the study. 
The treating physician will work with the patient’s insurance in order to obtain ibrutinib 
 
 
 
 
 
 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or worsening 
AEs as specified in the Schedule of Events and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period. The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
v5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
Merck and Janssen products include any pharmaceutical product, biological product, diagnostic agent or 
protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck or Janssen 
for human use.  
 
8.1.1.1   Merck Definition of an Overdose and Reporting of Overdose  
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose exceeding the 
prescribed dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab 
should be discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a product, the adverse event(s) 
is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of a product meeting the protocol definition of overdose is taken without any associated clinical 
symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
8 
ASSESSMENT OF SAFETY 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 


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Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” All 
reports of overdose with and without an adverse event must be reported within 24 hours Merck Global 
Safety (See SAE Section 8.1.2). 
 
8.1.1.2 Reporting of Pregnancy and Lactation to Merck and Janssen.  
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported 
to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 
90 days of completing the trial or 30 days following cessation of treatment.  All subjects and female 
partners of male subjects who become pregnant must be followed to the completion/termination of the 
pregnancy. Any subject who becomes pregnant during the study, must be promptly withdrawn from the 
study and discontinue further study treatment. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, congenital anomaly, 
ectopic pregnancy, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events).  If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours of their knowledge of the event to Janssen using the 
Serious Adverse Event Form and to Merck Global Safety (See Section 8.1.2).  Because the effect of the 
Janssen medicinal product on sperm is unknown, pregnancies in partners of male subjects exposed to a 
Janssen medicinal product will be reported by the Investigator within 24 hours of their knowledge of the 
event using the Serious Adverse Event Form. Depending on local legislation, this may require prior 
consent of the partner. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.  
 
8.1.1.3  Event of Clinical Interest for Pembrolizumab 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be recorded as such on the Adverse Event case report form and reported within 24 hours to Merck 
Global Safety (See Section 8.1.2). 
 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, (as defined in Section 8.1.1.1 - Definition of an Overdose)   
     that is not associated with clinical symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and 
an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing. 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event should be 
reported as an ECI within 24 hours to Merck Global Safety (See Section 8.1.2) 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and Immune-
Related Adverse Event Guidance Document.”  This document provides guidance regarding 
identification, evaluation and management of ECIs and irAEs.  Additional ECIs are identified in this 
guidance document and also need to be reported within 24 hours to Merck Global Safety.   
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and 
subjects should be asked for signs and symptoms suggestive of an immune-related event.  Subjects who 
develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then additional testing 


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should be performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to 
be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to the 
Merck’s product, must be reported within 24 hours to Merck Global Safety (See Section 8.1.2). 
 
8.1.1.4   Event of Clinical Interest for Ibrutinib 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC. is actively monitoring 
as a result of a previously identified signal (even if non-serious). These adverse events are: 
• 
Major Hemorrhage 
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in severity or that 
results in 1 of the following: intraocular bleeding causing loss of vision, the need for a transfusion of 2 
or more units of red cells or an equivalent amount of whole blood, hospitalization, or prolongation of 
hospitalization. 
• 
Intracranial Hemorrhage 
Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, epidural 
hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be captured as an event 
of special interest. 
• 
Other Malignancies  
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study treatment and 
during any protocol-specified follow-up periods including post-progression follow-up for overall 
survival. 
Any Adverse Event of Special Interest that is to be reported to Janssen Scientific Affairs should be recorded 
on a Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs (see Section 8.4.2) 
within 24 hours of knowledge of the event. 
 
 
8.1.1.5   Janssen Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s name, initials 
or address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssen medicinal product 
• 
an adverse event, outcome, or certain special situations 
 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action taken, 
outcome, (if available) 
• 
Janssen protocol ID 
 


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8.1.1.6    Janssen Product Quality Complaints (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a potential quality 
issue during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage or 
distribution of the product, or delivery system.  Not all PQCs involve a subject.  Lot and batch numbers 
are of high significance and need to be collected whenever available.  Examples of PQC include but not 
limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
8.1.1.7 Janssen Special Reporting Situations 
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen medicinal product 
• 
Medication error involving a Janssen medicinal product (with or without patient exposure to the 
Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from Janssen Scientific 
Affairs, LLC perspective, they are treated in the same manner as adverse events. Special situations 
should be recorded on the Adverse Event page of the CRF. 
 
 
AEs and suspected adverse reactions are considered "serious" if, in the view of either the 
investigator or sponsor, they result in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
 
 
 
 
Unanticipated problems (UPs) involving risks to participants or others to include, in general, 
any incident, experience, or outcome that meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS 


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population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
 
All AEs of unknown etiology associated with pembrolizumab or ibrutinib exposure should be 
evaluated to determine if it is possibly an event of clinical interest (ECI) or UP.  
 
 
 
 
 
All AEs will be graded using the CTCAE 5.0 criteria.  
 
For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity. 
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
 
 
 
 
For all collected AEs, the investigator will evaluate the participant and will determine the AE’s causality 
based on temporal relationship and his/her clinical judgment. The degree of certainty about causality will 
be graded using the categories below. 
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the drug, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
8.2.1 
SEVERITY OF EVENT 
8.2.2 
RELATIONSHIP TO STUDY AGENT 


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concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
 
 
The PI will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
 
 
 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews with study participants presenting for medical care, or upon review by a study monitor. All 
AEs, including local and systemic reactions not meeting the criteria for SAEs, will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of event. All AEs occurring during 
the study must be documented appropriately, regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system 
throughout the study. 
 
Changes in the severity of AEs will be documented to allow an assessment of the duration of the event at 
each level of severity to be performed. AEs characterized as “intermittent” require documentation of 
onset and duration of each episode in the medical record. 
 
Adverse events for the purpose of this study will be reported from the time period beginning when the 
consent form is signed until 90 days after the end of pembrolizumab infusions and 30 days after the last 
dose of ibrutinib. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or stabilization are 
achieved. Any AE present at the time of final study closure will be considered ongoing.  
 
 
 
Adverse event documentation will be performed by entry into the Moffitt OnCore electronic database. 
Reporting of adverse events to the FDA for IND renewal will occur annually by a report obtained from 
the AEs collected in OnCore.  Reporting to Merck and Janssen will be as noted in the section on AEs of 
special interest.  
 
8.2.3 
EXPECTEDNESS 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
8.4 
REPORTING PROCEDURES 
8.4.1 
ADVERSE EVENT REPORTING 


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All AEs will be documented on a paper log with columns for the replication of the fields in the OnCore 
AE data form. The treating physician/investigator will review the log for accuracy and assign CTCAE 
grade and the attribution of a study agent to the AE.  
 
Adverse events for the purpose of this study will be reported from the time period beginning when the 
consent form is signed until study drug discontinuation per the following guidelines:  
1. Pembrolizumab- 90 days following cessation of treatment or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier.  
2. Ibrutinib- 30 days following cessation of treatment 
 
 
 
 
Merck: For the time period beginning when the consent form is signed until treatment allocation, any 
serious adverse event, or follow up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study that occurs to any subject must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be excluded 
from the trial, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier, any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study, whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. 
 
Janssen: For the time period beginning when the consent form is signed until 30 days after cessation of 
ibrutinib, all serious adverse events will be reported within 24 hours to Janssen Scientific Affairs. 
Any adverse event classified as an SAE, will be reported by the appropriate research staff to the 
following within 24 hours of knowledge of the event.  
 
1. 
To the Protocol Monitoring Committee via entry into the OnCore data base 
2. 
To the IRB as required by the Chesapeake IRB reporting criteria 
3. 
Janssen Scientific Affairs 
Preferred- electronically via Janssen SECURE email IIS-BIO-VIRO-GCO@its.jnj.com 
For business continuity purposes, if SECURE email if non-functional: 
a. Fax- 1-866-451-0371 (retain confirmation receipt) 
b. Telephone- if neither email nor fax are functional- 902-405-2671 
 
4. 
Merck Global Safety 
Attn: Worldwide Product Safety 
Fax: 215-993-1220 
 
 
 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
Merck Safety or Janssen Scientific Affairs and should be provided as soon as possible. The study sponsor 
will be responsible for notifying FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 


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the information. 
 
 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP 
report form. It is the site investigator’s responsibility to report UPs to their IRB and to the study sponsor. 
The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• 
UPs that are SAEs will be reported to the IRB and to the study sponsor within 24 hours of 
the investigator becoming aware of the event. 
• 
Any other UP will be reported to the IRB and to the study sponsor within 2 business days of the 
investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures) and the supporting agency head (or designee), within 7 days of the 
IRB’s receipt of the report of the problem from the investigator.  
 
 
 
8.4.4.1   Event of Clinical Interest for Pembrolizumab 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be recorded as such on the Adverse Event case report form and reported within 24 hours to Merck 
Global Safety (See Section 8.1.2). 
 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, (as defined in Section 8.1.1.1 - Definition of an Overdose)   
     that is not associated with clinical symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and 
an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing. 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event should be 
reported as an ECI within 24 hours to Merck Global Safety (See Section 8.1.2) 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and Immune-
Related Adverse Event Guidance Document.”  This document provides guidance regarding 
identification, evaluation and management of ECIs and irAEs.  Additional ECIs are identified in this 
guidance document and also need to be reported within 24 hours to Merck Global Safety.   
 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 
8.4.4 
EVENTS OF SPECIAL INTEREST 


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Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and 
subjects should be asked for signs and symptoms suggestive of an immune-related event.  Subjects who 
develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then additional testing 
should be performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to 
be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to the 
Merck’s product, must be reported within 24 hours to Merck Global Safety (See Section 8.1.2). 
 
 
 
8.4.4.2   Janssen Special Reporting Situations 
Safety events of interest for a Janssen medicinal product that require expediting reporting and/or safety 
evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen medicinal product 
• 
Medication error involving a Janssen medicinal product (with or without patient exposure to the 
Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, from Janssen Scientific Affairs, 
LLC perspective, they are treated in the same manner as adverse events. Special situations should be recorded 
on the Adverse Event page of the CRF. 
 
 
 
 
Safety assessments will consist of monitoring and recording all adverse events and serious adverse 
events, the regular monitoring of hematology and blood chemistry parameters and regular physical 
examinations. Adverse events will be evaluated continuously throughout the study. Safety and 
tolerability will be assessed according to the NIH/NCI Common Terminology Criteria for Adverse 
Events version 5.0  (CTCAE v5.0) that is available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The Protocol Monitoring Committee (PMC) at Moffitt monitors its assigned ongoing research protocols 
for: adverse event reporting, data and safety monitoring, and internal audit findings. The PMC, upon 
review of any agenda item, may approve the study for continuation, require revisions, suspend or close a 
protocol. 
Investigators of studies which are designated to be reviewed by the PMC for data and safety monitoring,  
shall provide a statistical report of the study’s progress and summary of adverse events and deviations 
based on the phase of the study and the associated risk of the study or more often if applicable. The PI 
will be notified for recommendations or notifications after the PMC review in regards of continuation or 
stopping the clinical trial 
 
 
8.5 
STUDY HALTING RULES 


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Serious Adverse Events: Serious Adverse Events (SAEs) from this protocol will be reported 
concurrently to the IRB and the study sponsor within 24 hours of staff awareness of the event. The 
Protocol Monitoring Committee (PMC) will review these SAEs in accordance with their policy. The 
data and safety plan will define dose limiting toxicities, rules for escalation of dose, and criteria for 
stopping the trial according to rules set forth by this protocol. This trial will be continuously monitored 
by the PI and the research team. A final safety and monitoring report will be submitted to the PMC. This 
protocol will be subject to periodic internal audits based on risk or as recommended by the PMC. 
 
 
 
Data will be captured in OnCore, Moffitt’s electronic Clinical Trials Database. For each participant 
enrolled, the electronic CRF must be completed by the assigned data manager or other authorized study 
staff. Any paper forms should be typed or filled out indelible ink and must be legible. Errors should be 
crossed out but not obliterated, the correction inserted, and the change initialed and dated by the 
investigator or his/her authorized delegate. This also applies to records for those patients who fail to 
complete the study. If a patient stops dosing or terminates from the study, the dates and reasons must be 
noted on the CRF. If a patient terminates from the study because of a DLT, thorough efforts should be 
made to clearly document the outcome. Regulatory documents and case reports forms will be monitored 
internally according to the Moffitt Cancer Center monitoring policies. Monitoring will be performed 
regularly by the MCC Clinical Monitoring Core for accuracy, completeness, and source 
verification on data entry, validation of appropriate consent process, reporting on SAEs, and 
adherence of the protocol, GCP guidelines and applicable regulatory requirements. 
 
 
 
 
 
 
Enrolled patients will be evaluable for response assessment if receiving at least 4 weeks into ibrutinib therapy 
and at least 2 cycles of pembrolizumab. It will be used for efficacy and safety analysis.  The primary endpoint 
of this trial is the complete response (CR) with the hypothesis of obtaining CR in 30% of patients and the 
secondary end point is the overall response rate (ORR, the immune response to the vaccine measured as T cell 
subset alterations, B-cell immune response potency to the vaccine and the cytokine patterns in treated 
patients.  Exact binomial 95% confidence intervals for the true ORR will be calculated.   
 
 
 
 
 
 
 
The Simon’s minmax two-stage design will be used to test the null hypothesis that complete response (CR) ≤ 
10% versus the alternative that CR ≥ 30% with 90% power and a type I error rate of 10%.  This will result in 
an expected sample size of 20.37 and a probability of early termination of 0.52. After testing the drug 
combination on 16 patients in the first stage, the trial will be terminated if 1 or fewer respond. If the trial goes 
on to the second stage, a total of 25 patients will be studied. If the total number responding is less than or 
equal to 4, the drug combination will be rejected. Statistical analyses will be descriptive in nature. Patients’ 
demographics, AEs and serious AEs, disease status, and CR will summarized by descriptive statistics. 
8.6 
SAFETY OVERSIGHT 
9 
CLINICAL MONITORING 
10 
STATISTICAL CONSIDERATIONS 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
10.2 
DESCRIPTION OF STATISTICAL METHODS 
10.2.1 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 


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Clinical response rates will be calculated with 95% CIs.  
 
 
 
 
1. Change in T cell exhaustion and/or inhibition following treatment 
2. Change in serum immunoglobulin levels following treatment 
3. Progression free survival (PFS) and association with immune biomarkers 
 
To determine if T cell exhaustion or inhibition have change due to treatment with the combination therapy at 
baseline immune testing to immune testing following completion of pembrolizumab and ibruntinib treatments 
(week 52) using paired t-tests with the null hypothesis being that there is no change in immune measurements 
following treatment  (i.e., 𝐻𝐻𝐻𝐻: 𝜇𝜇𝑑𝑑= 0). If the assumptions of normality do not hold upon assessment, we will 
instead use nonparametric t-tests (i.e., Wilcoxon Sign Rank Test).  Similar tests will be used to determine if 
changes in serum immunoglobulin levels also resulted following treatment. Tests will be one-sided as based 
on biology expect the change in immune response to be in one direction following treatment. Tests will be 
considered statistically significant if the p-value is less than 0.05.  Assuming the study go on to stage II and 
enroll 25 patients, we will be able to detect a modest effect size of 0.60.  To determine the association of 
progression free survival (PFS) with immune biomarkers (T cell exhaustion and/or inhibition, serum 
immunoglobulin levels), Cox proportional hazards models will be fit with assumption of proportional hazards 
(PH) assumption check via Schoenfeld residuals. If the PH assumption does not hold, we will rely on use of 
non-parametric methods (Kaplan-Meier curve with log-rank tests) where the biomarkers will be dichotomized 
for analysis based on an optimal cut-point determination based on an outcome-oriented approach outlined by 
Contral and O’Quigley (Contal C, O'Quigley J. An application of changepoint methods in studying the effect 
of age on survival in breast cancer. Computational Statistics & Data Analysis. 1999;30:253-70.). A Cox 
regression of the log hazard ratio on the continuous biomarker (assuming a standard deviation of 1 and an 
anticipated event rate of 0.50) will have 80% power at a 0.05 significance level to detect a regression 
coefficient equal to 0.79 (i.e., hazard ratio of 2.20).  
 
 
 
 
 
Evaluation is based on strict stopping criteria for unacceptable toxicities. Specifically, in the 1st stage, we 
continuously evaluate toxicity for the 1st 16 patients (e.g., patients in first stage of Phase II study). Toxicity 
will be also evaluated at end of the 2nd stage for the total 25 patients. We consider 20% as the maximum 
allowable unacceptable toxicity rate (failure to engraft included) with a 0.05 probability of stopping early.  
Sequential boundaries will be used to monitor dose-limiting toxicity rate as outlined by Ivanova et al. [59]. 
The accrual will be halted if excessive numbers of dose-limiting toxicities are seen, that is, if the number of 
dose-limiting toxicities is equal to or exceeds bn out of n patients (see table below).  
 
 
Number of Patients, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Boundary, bn 
- 
- 
3 
4 
4 
4 
5 
5 
5 
6 
6 
6 
7 
7 
7 
7 
 
 
 
 
 
 
 
 
. 
10.2.2 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
10.2.3SAFETY REVIEW 


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Biological samples for each of the 25 patients enrolled in the trial will be collected at 4 time-points.  As the 
correlative experiments are not the primary focus of the study and are more exploratory in nature, no sample 
size / power calculations were completed.  Summary statistics will be used to summarize the quantitative 
measures (e.g., cytokine levels, expression levels) for the patients at the 4 time-points with two-sample t-test 
use to determine if quantitative measurements differ between patients that response and patients that do not 
response at each time point. When assessing changes in quantitative measurements between time-points (e.g., 
pre and post treatment measurements) paired t-tests will be used. Longitudinal analysis with linear mixed 
models will also be used to look for statistical differences between the responders and non-responders using 
quantitative measurements at all 4 time-points. Correlation between quantitative measurements will be 
assessed with Spearman correlation.  
 
 
 
 
 
The PI and other appropriate study staff are responsible for maintaining appropriate medical and research 
records for this trial, in compliance with ICH E6 and regulatory and institutional requirements for the 
protection of confidentiality of participants. Representatives of Merck, Janssen, and federal regulatory 
agencies may examine records for the purpose of quality assurance reviews, evaluation of the study safety, 
progress of the trial, and data validity.  
 
Source documentation in both electronic and paper form shall be retained for at least two years after the 
final closure of the trial. These include hospital records, clinical research subject charts (with paper AE 
logs), research laboratory notes, electronic CRFs, and pharmacy dispensing records.  
 
 
  
 
Quality control procedures will be implemented beginning with the OnCore data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the staff for clarification/resolution. 
 
Following written SOPs, the Moffitt internal monitors will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements (e.g., good laboratory practices (GLP), good manufacturing 
practices (GMP)). 
 
The investigational site will provide direct access to source data/documents, and reports for the purpose 
of monitoring and auditing, and inspection by local and regulatory authorities. 
 
All staff will be trained by the PI through a site initiation presentation, power point training for training 
on the initial protocol for those staff unable to attend the initiation presentation, and ongoing self-study 
as protocol amendments are approved. Training will be documented on a signature log that will be filed 
in the electronic regulatory binder.  
 
 
 
 
10.2.4 
EXPLORATORY ANALYSES 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
13 
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The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
 
 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the 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. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
 
 
 
 
 
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS  
 
Consent forms describing in detail the study agent, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be required prior to starting 
intervention/administering study product. 
Other documents to be submitted for review: 
• 
Oral study drug Patient Compliance Diary 
 
 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential 
risks of the study and of their rights as research participants.  Participants will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. The participants may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. 
 
 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
13.1 
ETHICAL STANDARD 
13.2 
INSTITUTIONAL REVIEW BOARD 
13.3 
INFORMED CONSENT PROCESS 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY 


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sponsor and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
 
The Moffitt study monitor, other authorized representatives of Moffitt, representatives of the IRB or 
pharmaceutical companies supplying study products may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Moffitt. This will not include the participants’ contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
Moffitt research staff will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the Moffitt. 
 
 
 
 
 
Data collected for this study will be analyzed and stored at Moffitt Cancer Center. After the study is 
completed, the de-identified, archived data will be stored at Moffitt Cancer Center, under the supervision of 
Eva Sahakian, PhD, for use by other researchers including those outside of the study. Software tracking 
programs include FileMaker Pro and Excel.  
With the participant’s approval and as approved by local IRBs, de-identified biological samples will be 
stored at Dr. Sahakian’s lab at Moffitt Cancer Center. These samples could be used for research into the 
causes of CLL, its complications, and other conditions for which individuals with CLL are at increased 
risk, and to improve treatment. After completion of the study, samples to be stored will be identified by 
using only the subject initials and date of collection.  
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage will not be possible after the study is completed. 
When the study is completed, access to study data and/or samples will be provided through Eva Sahakian, 
PhD or her successor.  
 
 
 
 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. 
 
13.5 
FUTURE USE OF STORED SPECIMENS 
14 
DATA HANDLING AND RECORD KEEPING 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 


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All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change.  All paper source 
documents will be scanned into the electronic medical record of each subject for storage. DO NOT 
ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained and 
captured in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into OnCore, a 21 CFR Part 11-compliant data capture system provided 
by Moffitt. The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
 
 
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development 
of the drug combination studied in this protocol. No records will be destroyed without the written 
consent of the sponsor, if applicable.  
 
 
 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site staff. As 
a result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations as defined by 
the Moffitt Clinical Trials Office standard. All deviations must be addressed in study source documents. 
Protocol deviations must be sent to the local IRB per their guidelines. The site PI/study staff is responsible 
for knowing and adhering to their IRB requirements.  
 
 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
14.2 
STUDY RECORDS RETENTION 
14.3 
PROTOCOL DEVIATIONS 
14.4 
PUBLICATION AND DATA SHARING POLICY 


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patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine.  
 
The PI will provide to the Protocol Information Specialist at Moffitt Cancer Center, details as 
requested for registering and reporting results for this clinical trial on ClinicalTrials.gov. At the 
conclusion of the trial, the PI will make study results available to the research community and the 
public-at-large.  
Authorship in publications will be determined by the PI depending on participation, enrollment, 
and significant contribution during trial process and manuscript elaboration. 
 
 
 
 
 
Not Applicable 
 
 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the trial.  The study leadership and the Moffitt Cancer 
Center have established policies and procedures for all study group members to disclose all conflicts of 
interest and will establish a mechanism for the management of all reported dualities of interest. 
 
 
 
 
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15 
STUDY ADMINISTRATION 
15.1 
STUDY LEADERSHIP 
16 
CONFLICT OF INTEREST POLICY 
17 
LITERATURE REFERENCES 


Ibrutinib and PD-1 Blockade to Improve Immune Dysfunction in 
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microenvironment is driven by CD8(+) T cells. Sci Transl Med, 2013. 5(200): p. 200ra116. 
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6580-7. 
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39(1): p. 1-10. 
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immunotherapy. Nat Rev Cancer, 2014. 14(2): p. 135-46. 
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Cancer Immunotherapies in the Era of Checkpoint Inhibition. Clin Cancer Res, 2016. 22(8): p. 1865-74. 
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74(24): p. 7168-74. 
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neoantigens. Proc Natl Acad Sci U S A, 2005. 102(44): p. 16013-8. 
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Defective antigen presentation in tumor-bearing hosts. Cell Immunol, 1996. 170(1): p. 101-10. 
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Engl J Med, 2012. 366(26): p. 2455-65. 
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melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med, 
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pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. in ASCO Annual 
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Appendix A  
iwCLL Criteria to Initiate Treatment of CLL (Reference #14) 
c. Evidence of progressive marrow failure manifested as worsening anemia and/or 
thrombocytopenia (Rai stages III or IV) 
d. Massive or progressive or symptomatic splenomegaly. 
e. Massive lymphadenopathy (at least 10 cm in the longest diameter) or progressive or 
symptomatic lymphadenopathy 
f. Progressive lymphocytosis with an increase of more than 50% over a 2 month period or 
lymphocyte doubling time (LDT) of less than 6 months. LDT can also be obtained as liner 
regression at 2 weeks intervals over an observation period of 2 to 3 months. 
g. Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids or other 
standard therapy 
h. Constitutional symptoms defines as: unintentional weight loss of 10% or more within the 
previous 6 months, significant fatigue (i.e, ECOG PS 2 or worse, inability to work or perform 
usual activities), fever higher than 100.5 oF (38.0 oC for 2 or more weeks without evidence of 
infection, night sweats. 
 
Appendix B 
APPENDIX 


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ECOG Performance Status  
Grade 
Description 
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. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
 
Appendix C 
Response Criteria per International CLL Working Group  
The International Workshop on Chronic Lymphocytic Leukemia (IWCLL) included updated response criteria 
in their 2008 publication [14].  
The response categories are: 
• 
Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by 
immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, 
absence of constitutional symptoms and satisfactory blood counts  
• 
Complete remission with incomplete marrow recovery (CRi), defined as CR above, but without 
normal blood counts  
• 
Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in 
lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral 
blood counts  
• 
Progressive disease (PD), defined as ≥ 50% rise in lymphocyte count to > 5 x109/L, ≥ 50% increase in 
lymphadenopathy, ≥ 50% increase in liver or spleen size, Richter’s transformation, or new cytopenias 
due to CLL  
• 
Stable disease, defined as not meeting criteria for CR, CRi, PR or PD  


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ICF_001.pdf: 
MCC # 19199 
 
 
Version 2 version date 1/31/2019 
Advarra IRB Approved Version 31 Jan 2019  
               Page 1 of 16 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY  
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
 
Study Title: 
Phase II Trial of Ibrutinib and PD-1 Blockade in High Risk 
Chronic Lymphocytic Leukemia to Improve Immune 
Function  
Protocol Number: 
Sponsor: 
MCC# 19199 
Moffitt Cancer Center 
Principal Investigator: 
(Study Doctor) 
Julio C. Chavez, MD 
Telephone: 
(24 hour number) 
813-745-8986 
Address: 
Moffitt Cancer Center 
12902 Magnolia Drive 
Tampa, FL 
33612 
 
WHAT IS THIS STUDY ABOUT? 
You are being asked to take part in a research study. Before you decide it is important for you to 
understand why the research is being done and what it will involve. Please take time to read the 
following information carefully and discuss it with family, friends and your general practitioner if 
you wish. Ask if there is anything that is not clear or if you would like more information. Take 
time to decide whether or not you wish to take part. 
You are being asked to take part in this research study because you have untreated Chronic 
Lymphocytic Leukemia (CLL). This study involves pembrolizumab, a drug that works by helping 
your immune system to fight your cancer and ibrutinib, an approved treatment for patients with 
CLL. The purpose of this study is to see how pembrolizumab and ibrutinib affects your CLL.  
If you agree to participate and qualify for this study, you will be given the following study 
treatments: 
• 
200mg of pembrolizumab by intravenous infusion every 3 weeks for one year and up to 
2 years 
• 
420mg of ibrutinib daily by mouth starting at week 6 for one year. If there is clinical 
benefit, an additional year may be prescribed.  
 


MCC # 19199 
 
 
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Advarra IRB Approved Version 31 Jan 2019  
               Page 2 of 16 
 
After you are done taking the study treatments, you will be asked to return for the follow up visits 
listed below to see how you are doing after taking the study treatments: 
• 
end of treatment visit within 3 days of taking your last dose of ibrutinib 
• 
safety follow up visit within 35 days of your last dose of ibrutinib  
• 
follow up visit about every 12 weeks for 12 months and up to 24 months 
More information about what will be done at each study visit will be discussed in a later section 
of this informed consent form. 
This study is only going to be done at Moffitt Cancer Center and there will be a total of 25 
participants.  
STUDY SCREENING PROCEDURES:  
In order to determine if you are eligible to participate in the study you will complete the 
screening procedures (activities, tests, and evaluations) described in this form. 
● 
Informed consent  
● 
Demographic Questions – We will ask you to give personal information, such as 
your name, date of birth, race, and gender 
● 
Health and Medication Questions – We will ask you to answer questions about your 
health, your medical history, and the medications you take. 
● 
Childbearing potential – You will be asked about your sterility status and contraceptive 
methods, if applicable to you. 
● 
Pregnancy Test (only for females who are able to become pregnant) 
● 
Physical Exam – Vital Signs (blood pressure, heart rate, respiratory rate, and 
temperature), Weight, and Height 
● 
Performance status – Your study doctor will assess and assign a score based on your 
ability to perform daily tasks by asking questions. 
● 
Blood Testing – Whole blood samples will be taken from your arm for laboratory tests. 
● 
Urine Testing – Take a urine sample to do laboratory tests. 
● 
Blood and urine tests to monitor your health. It will check your blood counts 
(number of each type of blood cell), chemistries (elements and minerals in your 
blood), blood clotting and how well your organs are functioning. 
● 
ECG – A test which records the electrical activity of your heart 
● 
Disease Assessment – You study doctor will evaluate your disease status using bone 
marrow biopsy, imaging tests (like CT scans) and lab results. 
STUDY PROCEDURES: 
If you are eligible to participate in this study, you will undergo one or more of the study 
procedures described in this form at each study visit. The study doctor and study team will 
be able to answer any questions you have about these procedures. 
● Physical Exam – See how tall you are and see how much you weigh. You should ask 
the study doctor or study staff about what else will happen during this exam. 
● Health and Medication Questions – Ask you to answer questions about your 
health, your medical history, and the medications you take. 
● Vital Signs – Check your blood pressure by putting a band around your arm (this will 
squeeze your arm for about a minute), count the number of heartbeats over time, 
count the number of times you breathe in and out over a period of time, and take your 
temperature. 
● Blood tests to monitor your health. It will check your blood counts (number of each 


MCC # 19199 
 
 
Version 2 version date 1/31/2019 
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               Page 3 of 16 
 
type of blood cell), chemistries (elements and minerals in your blood), and how well 
your organs are functioning. You will be checked for hepatitis and HIV viruses. 
● Prevnar 13 Vaccination – If you have not had this vaccination in the last 8 weeks, 
you will be given this vaccine. By giving you this vaccine, the investigators will be 
able to measure how well your immune system is working while you are in this 
study.   
● Research blood samples- will be drawn to check your immune system on day 1, of 
week 1, week 6, week 21, and at the end of ibrutinib treatment.  
● Bone marrow biopsy/aspirate – To collect a bone marrow biopsy/aspirate, an area 
around the hip or pelvis typically or other site is numbed, and a small amount of 
bone marrow and bone is sucked out through a needle. 
● Pregnancy Testing – Test your blood or urine to see if you are pregnant. You will 
only have pregnancy testing if you are a woman and can have children. 
- The study doctor or study staff will tell you if the pregnancy test results are positive. 
- The results of the pregnancy testing must be negative in order for you to be in the 
study. 
● Performance status – Your study doctor will assess and assign a score based on 
your ability to perform daily tasks by asking questions. 
● Study Treatment – As described in an earlier section, you will be given 
pembrolizumab by IV. You will also be given a supply of ibrutinib oral medication 
and the study team will tell you how to take it. You will be asked to bring back all 
unused oral study drug, including empty bottles, to each visit. 
● Disease Assessment - During the course of your study treatment, your study 
doctor will evaluate your response to study treatment using bone marrow, CT 
scans, and lab results. 
● Study Diary - Give you a study diary and tell you how to use it. Ask you to bring the 
completed diary back to the study center at each visit. 
● Post-study treatment visits – You may be asked to return to the study center for 
limited tests or you may receive a phone call to provide information, such as new 
therapies you may have started. 
PARTICIPANT RESPONSIBILITIES: 
● 
In order for this study to provide good information about how the study drugs work in 
participants with your condition, you will be expected to do the following: starting with 
the pre-screening or screening visit through 90 days after the last dose of study 
treatment. 
● 
Attend all study visits. 
● 
Tell the study doctor if you are feeling bad or worse than before. 
● 
Tell the study doctor if you have any changes in medications during the study. 
● 
Follow the directions of the study doctor and research team, including requirements 
to use an appropriate birth control method. 
● 
Refrain from participation in other research studies while you are a participant in this 
study. 
● 
Do not change any of your medications or start any new medications without checking 
with your study doctor. 
● 
Take and store your study drug as instructed and return the unused study drug 
and/or empty containers to the study doctor's office at each visit. 
● 
Do not share your study drug with anyone.  You are the only person allowed to take 
the study drug. 
● 
Keep the study drug and study supplies out of the reach of children and persons of 


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limited ability to read or understand. 
● 
Tell the study staff about any health problems you are having even if you don't think 
they are important. 
● 
Tell the study staff if you wish to stop being in the study. 
● 
Do not eat grapefruit, grapefruit products, Seville oranges (including marmalade 
containing Seville oranges) while taking Ibrutinib 
STUDY DRUG RISKS: 
Potential Risks Associated with Pembrolizumab 
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but is not approved to treat your type of cancer. 
Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs and 
tissues in your body and can affect the way they work, which can result in side effects that may 
become serious or life-threatening, and in some cases, may lead to death. 
VERY COMMON, SOME MAY BE SERIOUS (for example, causing hospitalization, life- 
threatening or where noted, may cause death). Out of 100 people who receive pembrolizumab, 
20 or more people may have the following: 
• 
Itching of the skin 
• 
Loose or watery stools 
• 
Cough 
COMMON, SOME MAY BE SERIOUS (for example, causing hospitalization, life-threatening, or 
where noted, may cause death). Out of 100 people who receive pembrolizumab, at least 5 but 
less than 20 people may have the following: 
• 
Joint pain 
• 
Rash 
• 
Fever 
• 
Back pain 
• 
Pain in your belly 
• 
Loss of skin color 
• 
Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have 
infrequent or hard stools 
• 
Low levels of salt in the blood that may cause you to feel tired, confused, have a 
headache, muscle cramps and/or feel sick to your stomach 
UNCOMMON, SOME MAY BE SERIOUS (for example, causing hospitalization, life- 
threatening, or where noted, may cause death). Out of 100 people who receive pembrolizumab, 
at least 1 but less than 5 people may have the following: 
• 
Inflammation of the lungs so you may feel short of breath and cough. Sometimes this 
might lead to death 
• 
Too much thyroid hormone so you may feel anxious, angry, have trouble sleeping, feel 
weak, tremble, sweat, feel tired, have loose and watery stools 


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• 
Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a fever, 
feel short of breath at the time of receiving your infusion (IV) or just after, or pain at the 
site of infusion 
• 
Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus 
• 
Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (for example, peeling, itching and redness) could also 
be widespread throughout your body. More severe skin reactions may involve the 
inside of your mouth, the surface of your eye and genital areas, and/or may cause the 
top layer of your skin to peel from all over your body which can cause severe infection. 
These severe conditions can sometimes lead to death. 
RARE, SOME MAY BE SERIOUS (for example, causing hospitalization, life- threatening, or 
where noted, may cause death). Out of 100 people who receive pembrolizumab, less than 1 
person may have the following: 
• 
Inflammation of the nerves that may cause pain, weakness or tingling in your hands 
and feet, and may spread to your legs, arms and upper body leading to severe muscle 
weakness and possible temporary paralysis 
• 
Inflammation of the muscles so you may feel weak or have pain in your muscles 
• 
Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so 
you may have severe pain in the top part of your belly that may move to your back, feel 
sick to your stomach, and vomiting that gets worse when you eat 
• 
Inflammation of the eye so you may have eye redness, blurred vision, sensitivity to 
light, eye pain, see floaters or have headaches 
• 
Inflammation of the liver that may make you feel sick to your stomach and vomit, feel 
like not eating, feel tired, have a mild fever, have a pain in the right side of your belly, 
yellow eyes and skin, and dark urine 
• 
Inflammation of the pituitary gland (a gland in the head), which may cause you to feel 
sick to your stomach or have headaches, changes in your behavior, double vision, few 
to no menstrual cycles, weakness, vomiting and dizziness or fainting 
• 
Adrenal glands (glands on top of the kidneys) that may not make enough hormone, 
which could cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle 
and belly aches, nausea, vomiting, loose or watery stools, fever, salt craving, and 
sometimes darkening of the skin like a suntan 
• 
Type 1 Diabetes, a condition that can cause too much sugar in your blood, feeling 
thirstier than usual, frequent urination and weight loss. You are likely to need regular 
insulin shots. 
• 
Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, 
swelling and low back pain 
• 
Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness 
of breath and swelling of the legs. You may experience a fast or irregular heartbeat that 
may cause dizziness or fainting. Sometimes this condition can lead to death 
• 
Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. 
This condition may lead to change in your heart rate, blood pressure, body 
temperature, and the rate at which food is converted into energy. 
• 
A condition that may make you feel weak and tired and might have drooping of the 
eyelids, blurred or double vision, difficulty swallowing, slurred speech, weakness in your 
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• 
The formation of small clusters of immune cells (called granulomas) in parts of your 
body such as your lymph nodes, eyes, skin, or lungs 
• 
Inflammation of the brain with confusion and fever. This may also include: 
disorientation, memory problems, seizures (fits), changes in personality and behavior, 
difficulty speaking, weakness or loss of movement in some parts of your body, and loss 
of consciousness 
Patients treated with pembrolizumab who then go on to allogeneic stem cell transplant (a 
procedure in which a person receives blood-forming stem cells from a donor), should inform 
their transplant physicians that they have received pembrolizumab in the past. 
In patients with any hematologic malignancy (cancers of the blood like Hodgkin lymphoma, 
multiple myeloma): there is a potential for an increased risk of severe complications following 
allogeneic stem cell transplant in patients who previously received pembrolizumab. 
Reports of clotting of blood within the liver and severe graft versus host disease (which can 
include skin, liver and gastrointestinal symptoms), including death, have been received for 
patients who received allogeneic stem cell transplant after pembrolizumab therapy. 
Potential Risks Associated with Ibrutinib 
You may develop side effects while participating in this study. You should tell the study doctor 
about any side effects that you develop. 
 
The side effects listed below have been reported by patients who have received ibrutinib in 
clinical trials. 
 
The most common side effects, occurring in at least 1 of every 5 (20%), patients have been: 
Occurrence or increase in frequency of loose or watery stools (Diarrhea) 
• 
Muscle and bone pain (Musculoskeletal pain) 
• 
Nausea 
• 
Low white blood cell count (cells that help fight infection) (Neutropenia) 
• 
Bleeding (Hemorrhage) 
• 
Rash 
• 
Fever (Pyrexia) 
• 
Side effects that have been seen in at least 1 of every 10 (10%) patients include: 
• 
Low platelet count (cells that help blood to clot) (Thrombocytopenia) 
• 
Common cold (Upper Respiratory Tract Infection) 
• 
Pneumonia 
• 
Constipation 
• 
Swelling of the hands or feet (Oedema peripheral) 
• 
Muscle spasms 
• 
Vomiting 
• 
Joint aches (Arthralgia) 
• 
Sores in mouth (Stomatitis) 
• 
Headache 
• 
High Blood pressure (Hypertension) 
• 
Skin infection 
• 
Weakness, tingling, numbness, and pain from nerve damage, usually in the hands and 
feet 
• 
(Peripheral neuropathy) 
 


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Side effects that have been seen in at least 1 of every 100 (1%) patients include: 
• 
Dizziness 
• 
Urinary tract infection 
• 
Sinus infection (Sinusitis) 
• 
Increased level of uric acid in the blood (Hyperuricemia) 
• 
Abnormal heart rhythm (Atrial fibrillation) 
• 
Non-melanoma skin cancer 
• 
Blurry vision (Vision blurred) 
• 
Low white blood cell counts with fever (Febrile neutropenia) 
• 
Severe infection throughout the body (Sepsis) 
• 
Redness of the skin (Erythema) 
• 
Increase in white blood cell counts (Leukocytosis) 
• 
Breaking of the nails (Onychoclasis) 
• 
Inflammation within the lungs that may lead to permanent damage (Interstitial lung 
disease) 
 
Side effects that have been seen in less than 1 of every 100 (less than 1%) patients include: 
• 
Increase in white blood cell count (Lymphocytosis) 
• 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells, 
which may lead to changes in kidney function, abnormal heartbeat, or seizures. (Tumor 
lysis syndrome) 
• 
Itchy rash (Urticaria) 
• 
Inflammation of the fatty tissue underneath the skin (Panniculitis) 
• 
Swollen face, lip, mouth, tongue, or throat (Angioedema) 
• 
High WBC count with abnormal clumping that can lead to bleeding (Leukostasis 
syndrome) 
• 
Severe rash with blisters and peeling skin, particularly around the mouth, nose, eyes, 
and genitals 
• 
(Stevens-Johnson syndrome) 
• 
Liver failure (Hepatic failure) 
• 
Abnormal rapid and/or irregular heart rhythm that starts from the lower chambers 
(ventricles) of the heart (Ventricular tachyarrhythmias). 
 
Most of these side effects listed above have been mild to moderate in severity; however severe 
side effects have occurred. Some side effects have been severe enough to lead to study drug 
discontinuation, dose modification or reduction, hospitalization, disability, and sometimes death. 
 
You should tell your study doctor or medical team about any side-effects you are having. Your 
study doctor may be able to give you medications to help treat the side effects and prevent them 
from becoming worse. Your study doctor may also choose to stop ibrutinib for a short time or 
reduce its dose to allow you to recover from any side effects. 
 
Bleeding 
You may experience bruising or nosebleeds during treatment with ibrutinib. Rarely, serious 
internal bleeding, such as bleeding in your stomach, intestine, or brain may occur, sometimes 
resulting in death. If you take other medicines or supplements that increase your risk of 
bleeding, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) or medicines used to 
prevent or treat blood clots or stroke, ibrutinib may increase this risk. Blood thinners such as 
warfarin or other vitamin K antagonists should not be taken together with ibrutinib. Supplements 


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such as fish oil and vitamin E preparations should be avoided while taking ibrutinib. Call your 
study doctor if you have signs or symptoms of serious bleeding, such as blood in your stools or 
urine or bleeding that lasts for a long time or that you cannot control. 
 
Effects on the heart 
Abnormal rapid and/or irregular heart rhythm (atrial fibrillation, atrial flutter, and/or ventricular 
tachyarrhythmia) have been reported in patients treated with ibrutinib, especially when they also 
have heart conditions, increased blood pressure, infections, or had abnormal heartbeat in the 
past. 
The heartbeat may be fast or irregular causing symptoms such as a pounding or racing heart, 
dizziness, weakness, feeling light-headed, shortness of breath, chest discomfort or fainting. If 
you develop any of these symptoms while on the study drug, you should tell your study doctor 
immediately. 
 
Infections 
You may experience viral, bacterial, or fungal infections during treatment with ibrutinib. Some of 
these infections have led to hospitalization and death. Contact your study doctor immediately if 
you have fever, chills, weakness, confusion, body aches, cold or flu symptoms, vomiting, 
jaundice, feel tired or feel short of breath - these could be signs of an infection. Your study 
doctor may start or continue medication to help prevent or treat an infection. 
A rare and usually fatal viral disease in the brain, Progressive Multifocal Leukoencephalopathy 
(PML), has been reported in patients treated with ibrutinib in combination with rituximab and in 
patients who were previously treated with rituximab. If you experience symptoms such as 
weakness, paralysis, vision loss and/or impaired speech, you should tell your study doctor 
immediately. 
 
Lymphocytosis and leukostasis 
You may experience an increase in the number of lymphocytes, which is a type of white blood 
cell, in your blood (lymphocytosis). This may occur in the first few weeks of treatment and you 
should not assume that this increase in white blood cells means that your disease is worsening. 
This increase may last for several weeks to months. Increased number of white blood cells in 
your bloodstream may change the blood flow, resulting in bleeding or clotting (leukostasis). 
Isolated cases of these events have been reported in patients treated with ibrutinib. Your study 
doctor will monitor your blood counts and may administer additional therapy as needed. Talk to 
your study doctor about what your test results mean. 
 
Decreased blood counts 
Severe decreases in white blood cells, red blood cells, and platelets (neutropenia, anemia, and 
thrombocytopenia) were reported in subjects treated with ibrutinib. If you experience symptoms 
such as fever, weakness, or easy bruising and/or bleeding, you should tell your study doctor 
immediately. 
 
Allergic reactions 
Sometimes people have allergic reactions to drugs. Serious allergic reactions can be 
life-threatening. If you have an allergic reaction to ibrutinib, you might develop a rash, difficulty 
breathing, wheezing when you breathe, sudden low blood pressure with light-headedness, 
swelling around the mouth, throat or eyes, a racing heartbeat, and/or sweating. 
Before starting the study drug, you must tell your study doctor about any drug allergies. You 
should tell the study doctor right away if you have any allergy symptoms listed above. 
 
Rash 


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A maculopapular rash (flat, red areas on the skin with small bumps) has been commonly 
reported 
in patients treated with ibrutinib alone or in combination with other drugs. Most rashes are mild 
to moderate in severity and begin 2 to 3 weeks or longer after starting ibrutinib. 
 
There have been rare reports of severe skin reactions (known as severe cutaneous adverse 
reaction or “SCAR”, involving more than 50% of the body) or rash with blisters and peeling skin, 
which may include open ulcers or sores in the mouth and other areas of the body (Stevens-
Johnson syndrome). These skin rashes could be life-threatening. You should notify your study 
doctor immediately if you develop a rash that spreads quickly, or if you notice peeling of your 
skin, with or without ulcers or sores in your mouth. 
 
Non-Melanoma Skin Cancer and Other Cancers 
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma of the skin) 
have 
been reported with more frequency and may be related to the use of ibrutinib. Other cancers 
have 
been reported such as solid tumors and blood cancers, the relationship to the use of ibrutinib is 
unknown. You should tell your study doctor if you develop a new cancer while in the study. 
 
Tumor Lysis Syndrome (TLS) 
Unusual levels of chemicals in the blood caused by the fast breakdown of cancer cells have 
happened during treatment of cancer and sometimes even without treatment. This may lead to 
changes in kidney function, abnormal heartbeat, or seizures. Your study doctor may do blood 
tests to check for TLS. 
 
Hypertension 
Hypertension is also called high blood pressure, and has been commonly reported in subjects 
treated with ibrutinib. Sometimes, people with high blood pressure may have headaches, 
dizziness, nervousness, sweating, difficulty in sleeping, facial flushing, or nosebleeds, but in 
some cases, there may be no symptoms and it may go undetected. After starting ibrutinib, your 
doctor may measure your blood pressure regularly. You should let your study doctor know if you 
have any of the symptoms of high blood pressure which may mean that you have developed 
hypertension or that your hypertension is getting worse. Your study doctor may adjust existing 
anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. 
 
Liver Failure 
Rare cases of liver failure have been reported in patients treated with ibrutinib. Symptoms of 
liver failure include yellowing of the eyes and skin (jaundice), itching of the skin, dark colored 
urine, gray or clay-colored stools, confusion, nausea, loss of appetite, and fatigue or diarrhea. 
You should tell your study doctor immediately if you have any of these symptoms which may 
suggest liver disease. Your study doctor may be able to diagnose and provide you required 
medical care. 
 
Interstitial lung disease 
Interstitial lung disease is a group of lung disorders in which the tissues become inflamed and 
may become damaged. Interstitial lung disease is not associated with infections (for example, 
bacteria, viruses, fungi) and has been reported in patients treated with ibrutinib. You should 
report to your physician if you have cough, any signs of new or worsening respiratory symptoms 
such as shortness of breath or difficulty breathing. 
 


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Interference with other drugs 
Some foods like grapefruit juice and Seville oranges, as well as some medications, may 
interfere with the way your body processes ibrutinib. This interference could cause the amount 
of Ibrutinib in your body to be higher or lower than expected. It is also possible that taking the 
study drug with your regular medications or supplements, including fish oil, Vitamin E, or other 
vitamins, may change how your regular medications, or your regular supplements, work. It is 
very important that you avoid grapefruit juice and Seville oranges and tell the study doctor about 
all medications, supplements, or herbal medicine like St. John’s wort that you are taking during 
the study. You should notify your study doctor immediately about any side effects to avoid 
possible harm. 
 
Drug interruption for any surgical procedures 
Ibrutinib may increase the risk of bleeding with any surgical procedure. Ibrutinib should be held 
at least 3 to 7 days before and after surgery depending upon the type of surgery and the risk of 
bleeding. Please contact your study doctor if you have any planned surgical procedures. For 
emergency surgical procedures, ibrutinib should be discontinued (stopped) after the procedure 
until the surgical site is reasonably healed (not oozing fluid). 
 
Please contact your study doctor as soon as possible and your study doctor will tell you when to 
stop ibrutinib and when to restart it following a surgical procedure. 
 
In addition to the risks listed above, there could be unknown or unexpected side effects 
associated with the use of ibrutinib. You will be told in a timely manner, verbally and in writing, 
of any new information, findings, or changes to the way the research will be done that might 
influence your willingness to continue your participation in this study. 
 
You may have all, some, or none of the listed side effects of ibrutinib. Your study doctors and 
nurses will check you closely for side effects. You may receive medicines or other treatments to 
prevent or reduce some of these effects. Please tell the study doctor or study staff right away if 
you have any side effects. Please tell them if you have any other problems with your health or 
the way you feel during the study, whether or not you think they are related to the study drug. 
 
You should get medical help and contact the study doctor or study staff if you have any of these 
or any other side effects during the study. 
 
Reproductive effects 
The effects of ibrutinib on a developing baby are unknown; therefore, women who are pregnant 
or nursing are not allowed to be in this study. Nobody knows what these risks are right now. 
Some drugs cause women to have their babies prematurely (early) or to have babies with birth 
defects. 
 
Women: If you are able to have children, you must use a highly effective method of birth control 
and a barrier method, or sexual abstinence (which is defined as refraining from all aspects of 
sexual activity), while taking study treatment, as well as for 1 month after you stop taking study 
treatment, to prevent pregnancy, unless your partner is sterilized. A “highly effective method of 
birth control” is defined as a method that has a low failure rate (for example, less than 1% per 
year) when used consistently and correctly and includes implants, injectables, birth control pills 
with 2 hormones, some intrauterine devices (IUDs). If you are using hormonal contraceptives 
such as birth control pills or devices, a second barrier method of contraception (for example, 
condoms) must be used. 
 


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Men: You must use a barrier method while on treatment with ibrutinib and for 3 months after the 
last dose of treatment to prevent pregnancy of your partner. You should not donate sperm while 
you are taking the study drug and for 3 months after you stop taking the study drug. 
 
Note: Some birth control pills may not work when you are taking certain drugs. If you have any 
questions about this, please discuss this with the study doctor. 
 
Be aware that you can still become pregnant even if you use a highly effective method of birth 
control. 
 
Women: If you become pregnant while you are on study treatment or within 1 month of your last 
dose of ibrutinib you must notify the study staff. If you become pregnant on the study, you must 
immediately stop taking the study treatment. The Sponsor will continue to collect information 
about your pregnancy and the birth of your baby even after study treatment is stopped. 
 
Men: If your partner becomes pregnant while you are on study treatment, or within 3 months of 
your last dose of ibrutinib, you must notify the study staff. The study staff will discuss this with 
you further. 
 
Breast-feeding 
It is not known whether ibrutinib or its metabolites are excreted in human milk. Because many 
drugs are excreted in human milk and because of the potential for serious adverse reactions in 
nursing infants from ibrutinib, breast-feeding should be discontinued during ibrutinib treatment. 
PREGNANCY AND BREASTFEEDING RISKS: 
The study drugs, pembrolizumab and ibrutinib, can cause harm to a pregnant woman, embryo, 
developing fetus, or nursing infants.  
If you are female, you cannot participate in this study if you are pregnant, plan to become 
pregnant or are nursing a child. If you are able to have children you will need to use an 
appropriate form of birth control as directed by your doctor starting with the pre-screening or 
screening visit through 90 days after the last dose of study treatment. 
If you are male and you have a sexual partner(s) who is able to get pregnant, you must agree 
that you and your partner(s) will use an appropriate form of birth control as directed by your 
doctor starting with the pre-screening or screening visit through 90 days after the last dose of 
study treatment. 
RISKS RELATED TO STUDY PROCEDURES: 
● 
Blood Testing/Research Blood Samples - Blood draws may cause pain, bleeding, 
and/or bruising. You may faint and/or develop an infection with redness and irritation 
of the vein at the site where blood is drawn. Frequent blood collection may cause 
anemia (low red blood cell count), which may create a need for blood transfusions. 
● 
Bone marrow biopsy/aspirate - pain for a few days that requires some pain medication 
or rarely infection at the site can be risks. 
● 
CT scans - involve radiation exposure. Scientists disagree on whether radiation doses 
at the low levels used in these scans are harmful. A possible effect that could occur at 
doses associated with this study is a slight increase in the risk of developing cancer 
later in life. You may have an allergic reaction to the contrast material that may cause 
rash, hives, shortness of breath, wheezing, and itching and, rarely, may cause your 
heart to stop beating (in other words, “cardiac arrest”). The use of contrast material 


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during these tests would be a normal part of measuring your response to therapy even 
if you were not taking part in this research study. 
 
BENEFITS 
You may or may not benefit from being in this study but your participation in this research study 
may benefit future patients with your disease or condition.  Your condition may get better, it may 
get worse, or it may stay the same. 
ALTERNATIVES TO PARTICIPATION 
You do not have to participate in this study to get help for your condition. An alternative to the 
study is observation which is usually indicated in patients with asymptomatic CLL.  Alternatives to 
this study for the treatment of your condition may include drugs already approved or being used 
for treatment of your condition, or other experimental drugs. Your study doctor can discuss the 
risks and advantages of these alternative treatment methods with you.  In addition, you may 
discuss your options with your regular health care provider. 
WILL IT COST ANYTHING TO BE IN THIS STUDY? 
You and/or your insurance company will be financially responsible for hospital inpatient, 
outpatient and follow-up visits that would normally or routinely occur in the management of your 
disease.  Inpatient and outpatient visits could include charges for treatments, medications, 
physician visits, laboratory tests and procedures.   You and /or your insurance company will be 
responsible for paying for the charges which are considered routine, since you would have 
received these services even if you were not participating in this study.   You will be responsible 
for any costs not covered by your insurance company, including deductibles, co-payments and 
all out-of-pocket expenses. Before you agree to be in this study, you should contact your health 
insurer to see if your plan will cover the costs required as part of your participation.   
You and/or your insurance company will not be responsible for paying for study related items 
and services that are specifically required for this research study and are not considered part of 
the routine management of your disease, if these procedures are performed at Moffitt Cancer 
Center.   
During your participation in this study, pembrolizumab will be provided Merck & Co., Inc. at no 
additional charge to you for up to 24 months. Ibrutinib will be provided by Janssen Scientific 
Affairs, LLC., at no additional charge for up to 12 months. If, per your treating physician, there is 
benefit with continuing ibrutinib, your insurance will be contacted about coverage for this drug. 
You and/or your insurance company will be responsible for the charges related to the 
administration of the study drugs. 
If you would like more information on the costs of being on this study or have other insurance 
related questions then please let your clinical trial coordinator know or contact our Business 
Office at 813-745-8422. 
REIMBURSEMENT AND PAYMENTS 
You will not be paid for being in this study. 


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WHAT IF I GET HURT OR SICK WHILE I AM IN THIS STUDY? 
If you need emergency care: 
• 
Call 911 or go to your nearest emergency room right away. Moffitt Cancer Center does 
not have an emergency room or the facilities to provide emergency care. 
If you do NOT need emergency care: 
• 
Call or go to your regular doctor. It is important that you tell your regular doctor that 
you are participating in a research study. If possible, take a copy of this consent 
form with you when you go. 
If you experience a side effect or a change in the way that you feel, call the study doctor at the 
telephone number listed on the first page of this form. 
By signing and dating this informed consent and research authorization form, you have not given 
up any legal rights to seek compensation for injuries from the sponsor. 
MOFFITT CANCER CENTER INJURY STATEMENT 
If you believe you have been injured as a result of your participation in this study or if you have 
questions about your rights as a person who is taking part in a research study, you may call the 
Moffitt Cancer Center Risk Manager at 813-745-4219. Moffitt Cancer Center and its 
investigators have made no provision for monetary compensation in the event of physical illness 
or injury resulting from this study. Likewise, Moffitt Cancer Center and its investigators have 
made no provision for payment of lost wages, disability, or discomfort in the event of physical 
illness or injury resulting from this study. Florida law (Statute 768.28) limits the liability of Moffitt 
Cancer Center. This statute provides that damages are available only to the extent that 
negligent conduct of a Moffitt Cancer Center employee caused your injuries, and are limited by 
law. A copy of this statute is available upon request at 813-745-1869. 
HOW WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
We understand that information about you and your health is personal, and we are committed to 
protecting the privacy of that information.  Because of this commitment and because of federal 
law, we must obtain your written authorization before we use or disclose your information for this 
study. 
By signing this form, you are permitting researchers at Moffitt Cancer Center to use personal 
health information for research purposes within its organized health care arrangements. You 
are also allowing the Moffitt Cancer Center to disclose your personal health information to 
outside organizations or individuals that participate in this study. We may publish what we find 
out from this study.  If we do, we will not let anyone know your name. We will not publish 
anything that would directly let people know who you are. 
Your research samples collected during the trial, will be coded with a number and will not 
contain any of your personal information.  
WHO WILL DISCLOSE, RECEIVE, AND/OR USE YOUR INFORMATION? 
Your records and research blood sample results are confidential and they will be kept in a 
secure environment and protected to the full extent of the law. 
To do this research, the following people and/or organization(s) will be allowed to disclose, 
use, and receive your information, but they may only use and disclose the information to the 
other parties on this list, to you or your personal representative, or as permitted by law: 


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• 
Every research site for this study, including the Moffitt Cancer Center, and each 
site’s study team, research staff and medical staff. 
• 
Any person who provides services or oversight responsibilities in connection with this 
study. 
• 
Every member of the Moffitt Cancer Center workforce who provides services in 
connection with this study. 
• 
Any laboratories, individuals, and organizations that use your health information in 
connection with this study. 
• 
Any sponsor of the study, including the following sponsors: Merck & Co, Inc. and 
Janssen Pharmaceuticals, Inc. 
• 
Any federal, state, or local governmental agency that regulates the study (such as 
the U.S. Food and Drug Administration (FDA) and Florida Department of Health 
(FDH). The U.S. Department of Health & Human Services (DHHS), Office for 
Human Research Protections (OHRP). 
• 
Other government agencies in this or other countries. 
• 
The designated Protocol Review and Monitoring Committees, Institutional Review 
Boards such as Advarra IRB, Privacy Boards, Data and Safety Monitoring Board and 
their related staff that have oversight responsibilities for this study. 
• 
The National Cancer Institute in evaluating the ongoing research of the Moffitt Cancer 
Center as a Comprehensive Cancer Center. 
The organizations and people listed above may employ or pay various consultants and 
companies to help them understand, analyze and conduct this study.  All of these people may 
not be known now, but if you would like to have more specific information about this at any time 
during the study, you may ask the study doctor and your questions will be answered. 
Moffitt Cancer Center cannot guarantee the privacy of your information, or block further use or 
distribution, after the information has left the Moffitt Cancer Center. Others listed above may 
further disclose your information, and it may no longer be covered by federal privacy 
regulations. If all information that does or can identify you is removed from your records, the 
remaining information will no longer be subject to this authorization and may be used or shared 
for other purposes. You might have the right to see and copy your health records related to this 
research.  Any results from testing on your research blood samples will not be disclosed to you. 
You might not be able to see or copy some of your records until after all participants finish the 
study.  If it is necessary for your care, your records will be provided to you or your regular 
doctor. 
WHAT INFORMATION WILL BE USED OR DISCLOSED? 
By signing and dating below, you authorize the use and disclosure of your entire study record 
and any medical or other records held by Moffitt Cancer Center, including, but not limited to, 
HIV/AIDS, mental health, substance abuse or genetic information. The purpose for the uses 
and disclosures you are authorizing is to conduct the study explained to you during the informed 
consent and research authorization process and to ensure that the information relating to that 
study is available to all parties who may need it for research purposes. 
Your authorization to use your health information will never expire unless and until you expressly 
revoke it in writing to the study doctor listed on the first page of this form.  
Any data collected before your letter will continue to be used as necessary to preserve the 
integrity of the study, however no additional information will be collected after you withdraw your 
authorization. 


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You will receive a signed and dated copy of this form. 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
telephone number listed on the first page of this consent document.  If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.   
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants.  If you have any questions about your rights as a research 
participant, and/or concerns or complaints regarding this research study, contact: 
• 
By mail: 
Study Participant Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• 
or call toll free:        877-992-4724 
• 
or by email:              adviser@advarra.com 
Please reference the following number when contacting the Study Participant 
Adviser: Pro00027749. 
WHERE CAN I GET MORE INFORMATION? 
You may call the National Cancer Institute’s (NCI) Information Service at:  
1-800-4-CANCER (1-800-422-6237). 
Visit the NCI’s Websites at: 
• 
CancerTrials: comprehensive clinical trial information at: http://cancertrials.nci.nih.gov 
• 
CancerNet:  accurate cancer information including PDQ at: http://cancernet.nci.nih.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
Use of Your Research Samples 
As part of this study, there will be tests performed in a Moffitt laboratory using your blood 
samples. The tests are to learn how the study treatment affects your immune system. If you 
agree below, you can change your mind at any time.  If you want to withdraw your consent for 
the use of your samples during the study, tell your study doctor that you no longer want your 
samples stored or used for research.  If you want to withdraw your consent after the close of the 
study, follow the instructions provided to you by the study doctor.  Then, any samples that 
remain will be destroyed.  If you change your mind and your samples have already been tested, 
those results will still remain as part of the overall research data.  In the event of your death or 
loss of competence, your specimens and data will continue to be used as part of the study 
doctor’s sample storage. If you withdraw or discontinue from the study, your samples will 
continue to be stored and used for research unless you specifically ask that they be destroyed. 
My remaining blood samples from the study may be used by Moffitt researchers this study and 
for future research on CLL and CLL-related diseases. 


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Please indicate your preference below: 
YES _____ (initials)  I agree to participate in the sub-study described above. 
 
NO   _____ (initials)  I do not agree to participate in the sub-study described above. 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
Your decision to participate in this study is voluntary.  You may choose to not participate or you 
may withdraw from the study for any reason without penalty or loss of benefits to which you are 
otherwise entitled and without any effect on your future medical care.  However, please note 
that the FDA requires that any information collected up to the point of your withdrawal cannot be 
removed from the study. 
The Investigator or the sponsor can stop your participation at any time without your consent for 
the following reasons: 
• 
If it appears to be medically harmful to you; 
• 
If you fail to follow directions for participating in the study; 
• 
If it is discovered that you do not meet the study requirements; 
• 
If the study is canceled; or  
• 
For administrative reasons. 
If you leave the study for any reason, the Investigator may ask you to have some end-of-study 
tests for your safety.   
 
STATEMENT OF CONSENT 
 
I have read this form and its contents were explained to me.  I agree to be in this research 
study for the purposes listed above. All of my questions were answered to my satisfaction.  I 
will receive a signed and dated copy of this form for my records. 
 
 
  _________________________________________________________ 
Printed Name of Participant 
 
 
 
 
Signature of Participant 
Date 
 
STATEMENT OF PERSON OBTAINING INFORMED CONSENT/RESEARCH 
AUTHORIZATION 
 
I attest that the participant named above had enough time to consider this information, had 
an opportunity to ask questions, and voluntarily agreed to be in this study. 
 
 
 
Printed Name of Person Explaining Consent 
 
 
 
 
Signature of Person Explaining Consent 
Date