Conditions: Colon Cancer Colorectal Cancer Colorectal Carcinoma Colon Disease
Keywords: colon rectum advanced refractory
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) (or the highest protocol-defined dose level in the absence of establishing an MTD) of ibrutinib in combination with pembrolizumab in participants with advanced, refractory colorectal cancers.

Detailed description:
On this study, one treatment cycle equals 21 days. On the first day of each study treatment cycle, 200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. In addition, participants will begin taking the ibrutinib capsules every day starting on cycle 1, day 1. Participants will have a follow-up visit every 3 weeks, on about the first day of each cycle with laboratories drawn to make sure that the study drugs are not causing any side effects. In addition, participants will have a computed tomography (CT) scan every 6 to 7 weeks to determine whether your cancer is getting better or worse.

Arms:
arm 1: Pembrolizumab intravenously (IV): 200 mg every 3 weeks (Q3W).

Ibrutinib by mouth (PO): Phase I Dose Escalation at doses of 420 mg daily (cohort 0) and 560 mg daily (cohort 1);. Phase II treatment at Recommended Phase II dose.

Interventions: intervention 1: Pembrolizumab intervention 2: Ibrutinib
Intervention descriptions: intervention 1: 200 milligrams of pembrolizumab will be given through an IV (intravenously) for about thirty minutes. Pembrolizumab is an anti-PD1 that functions by inhibiting checkpoint inhibition and reversing T cell suppression. intervention 2: Ibrutinib oral capsules every day starting on cycle 1, day 1. Ibrutinib is primarily a BTK inhibitor which has been approved for the treatment of several hematologic malignancies.

Protocol document:
Prot_SAP_000.pdf: 
 
A Phase I/II Study of Pembrolizumab in Combination with Ibrutinib for 
Advanced, Refractory Colorectal Cancers 
 
NCT03332498 
 
Version 8.0 
September 15, 2018 


 
1 
 
A Phase I/II Study of Pembrolizumab in Combination with Ibrutinib for 
Advanced, Refractory Colorectal Cancers 
 
 
MCC # 19091 
 
Sponsor and  
Principal Investigator:  
Richard Kim M.D. 
 
H. Lee Moffitt Cancer Center 
 
12902 Magnolia Drive, Tampa, Florida, 33612 
Telephone: 813-745-6898 
Fax: 813-745-7229 
E-mail: Richard.Kim@moffitt.org 
 
 
 
Co-Investigators:  
Dae Won Kim MD 
 
Rutica Mehta MD 
 
 
 
 
Statistician: 
Michael Schell, PhD 
 
Michael.Schell@moffitt.org 
 
 
Protocol Version Date: 
Sept 15rd, 2018 
Protocol Version Number: 8.0 
 
  
 
 
 
Funding provided by Janssen Scientific Affairs LLC 
Study drug (ibrutinib) provided by Janssen Scientific Affair LLC 
Study drug (pembrolizumab) provided by Merck Pharmaceuticals 
 
  
 
 
 
 
 
 
 
 
 
 


 
2 
 
 
Protocol Synopsis 
 
Title 
A Phase I/II Study of Pembrolizumab in Combination with Ibrutinib 
for Advanced, Refractory Colorectal Cancers 
Clinical study phase Phase I/II 
Study Agents 
Ibrutinib PO 
Pembrolizumab IV 
Background 
Colorectal cancer is one of the most common worldwide malignancies, 
with close to 50% of patients ultimately developing metastatic disease. 
There remains an urgent need for additional novel options for patients 
who have disease progression through standard therapies.  
 
Pembrolizumab is an anti-PD1 that functions by inhibiting checkpoint 
inhibition and reversing T cell suppression. It has activity in advanced, 
refractory colorectal cancer in patients with microsatellite instability but 
not tumors that are mismatch repair proficient. However, mismatch 
repair deficient tumors comprise a minority of metastatic colorectal 
cancers and work is underway to allow a wider application of 
immunotherapy in this common disease. 
 
Ibrutinib is primarily a BTK inhibitor which has been approved for the 
treatment of several hematologic malignancies. Recent pre-clinical data 
has shown that there might be a role for ibrutinib in the treatment of solid 
tumors through counteracting the immune tumor escape mechanism.  
 
Because of the immune modulatory function of ibrutinib, it has been 
suggested that the addition of checkpoint inhibitors could potentially 
produce a synergistic tumor response. This has been evaluated and 
confirmed in pre-clinical mouse models of microsatellite stable colorectal 
cancers.  
Rationale  
With this pre-clinical rationale, we hypothesize that ibrutinib added to 
pembrolizumab will be a safe and effective combination in microsatellite 
stable colorectal cancers.  


 
3 
 
Study objectives 
Primary Objective (Phase I Portion) 
To determine the safety and tolerability, describe the dose-limiting 
toxicities (DLTs), and determine the maximum tolerated dose (MTD) (or 
the highest protocol-defined dose level in the absence of establishing an 
MTD) of ibrutinib in combination with pembrolizumab in subjects with 
advanced, refractory colorectal cancers. 
 
Secondary Objectives (Phase I Portion)1. To determine the efficacy of 
ibrutinib in combination with pembrolizumab based on Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.12. To determine the efficacy of 
ibrutinib in combination with pembrolizumab based on the 
RECIST based immune-related response criteria (irRC) 
 
Primary Objective (Phase II Portion) 
To determine the efficacy of ibrutinib in combination with 
pembrolizumab based on Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1  
 
 
Exploratory Objectives 
1. To use the CancerPlex® panel to assess the neoantigen burden of 
the tumor. The resulting “immune signature” will be correlated 
with outcome in a descriptive analysis.  
2. To use the Luminex cytokine profiling system to analyze the 
effect of this combination on the immune system 
 


 
4 
 
Indication 
Patients with advanced, refractory colorectal cancer 
Diagnosis and main 
criteria for 
inclusion 
 Age ≥18 years of age. 
 Histologically confirmed diagnosis of colorectal adenocarcinoma 
 Measurable or non-measurable disease by Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1.  Stage IV or recurrent 
disease is required. 
 Patients must have received and progressed through or become 
intolerant to fluoropyrimidine, irinotecan, oxaliplatin, and 
bevacizumab, and if RAS wild type, cetuximab or panitumumab 
containing therapies. Prior therapy with regorafenib and/or TAS 
102 is allowed 
 ECOG Performance Score 0 or 1 
 Estimated life expectancy > 3 months 
 Adequate bone marrow, liver and renal function as assessed by 
the following: 
o Hemoglobin > 8.0 g/dl 
o Absolute neutrophil count (ANC) > 1,000/mm3 independent of 
growth factor support 
o Platelet count > 100,000/mm3  
o Total bilirubin < 1.5 times ULN unless bilirubin rise is due to 
Gilbert’s syndrome or of non-hepatic origin 
o AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x 
ULN for patients with liver involvement) 
o Creatinine clearance ≥ 30 ml/min 
 
Study design 
This is a phase I/II trial using the combination of ibrutinib and 
pembrolizumab in advanced, refractory colorectal cancer. This will be a 
3+3 design with 2 dose cohorts. 
 
Following the dose escalation phase, the phase II portion of the study 
will enroll 32 patients. 
 
Number of subjects 42 


 
5 
 
Plan for statistical 
analysis 
Sample Size 
The planned sample size is 6-12 patients in the dose-exploration portion 
(phase I) and 32 patients in the phase II portion.  
 
Phase I 
For the dose exploration phase, the number of subjects will depend upon 
the DLTs observed and the number of dose levels tested as the study 
progresses in accordance with a 3+3 design. 6-12 patients are expected to 
be enrolled. Additional subjects could be enrolled if dose de-escalations 
or expansion of dose exploration is needed. 
 
Phase II 
For the phase II portion of this study, the primary endpoint will be 
disease control rate (CR + PR + SD) at 4 months. Patients will be 
accrued to the protocol according to a two-stage Minimax design. At 
least 1 of 18 patients must have disease control at 4 months in the first 
stage to proceed to the second stage.  If the protocol proceeds to the 
second stage, at least 4 of 32 patients overall must have disease control at 
4 months for the therapy to be considered effective 
We anticipate an attrition rate of 10%, so around 49 patients will be 
recruited. Based on previous trials, we expect to enroll 42 patients in 12 
months.  
 
 
 
 
 


 
6 
 
Table of Contents 
  
1. 
Introduction 
............................................................................................................... 9 
1.1 
Background 
............................................................................................................... 9 
1.2 
Immunotherapy in colorectal cancer ........................................................................ 9 
1.3 
Ibrutinib 
.................................................................................................................... 9 
1.4 
Pembrolizumab 
....................................................................................................... 10
 
1.5 
Rationale 
................................................................................................................. 12 
2. 
Study Objectives 
..................................................................................................... 12
 
3. 
Study Design 
........................................................................................................... 13
 
4. 
Eligibility 
................................................................................................................ 14 
4.1 
Inclusion Criteria 
.................................................................................................... 14
 
4.2 
Exclusion Criteria 
................................................................................................... 15
 
4.3 
Withdrawal of Subjects from Study ....................................................................... 16 
4.3.1 Screen Failures/Dropouts/Replacements 
................................
................................ 17 
4.3.2 Removal of Patients from Protocol Therapy 
.......................................................... 18 
5. 
Treatment Plan 
........................................................................................................ 18
 
5.1 
Drug Administration 
............................................................................................... 18 
5.1.1 Rationale for Flat Dose Regimen of Pembrolizumab 
............................................. 20 
5.1.2 Definition of dose-limiting toxicity 
........................................................................ 21 
5.1.3 Definition of maximum tolerated dose 
................................................................... 21 
5.1.4 Definition of evaluable subject 
............................................................................... 22 
5.1.5 Dose Modifications for Treatment-Related Toxicity ............................................. 22 
5.1.6 Dose Delays for Treatment-Related Toxicity 
......................................................... 23 
5.2 
Concomitant therapy 
............................................................................................... 25 
5.2.1 Prohibited Concomitant Medications 
..................................................................... 26 
5.3 
Supportive Care Guidelines for Ibrutinib 
............................................................... 26 
5.5 
Management of Immune Related Adverse Events related to Pembrolizumab 
....... 28 
5.5.1 Pneumonitis: 
................................
........................................................................... 28 
5.5.2 Diarrhea/Colitis: ..................................................................................................... 28 
5.5.3 Type 1 diabetes mellitus 
......................................................................................... 29 
5.5.4 Hypophysitis: 
......................................................................................................... 29 
5.5.5 Hyperthyroidism or Hypothyroidism: 
.................................................................... 29 
5.5.6 Hepatic: 
................................................................................................................... 29 
5.5.7 Renal Failure or Nephritis: 
..................................................................................... 30 
5.5.8 Management of Pembrolizumab Infusion Reactions: 
............................................. 30 
5.6 
Blinding 
.................................................................................................................. 31 
5.7 
Drug Logistics and Accountability 
......................................................................... 31 
6. 
Visit schedule and Assessments 
............................................................................. 31 


 
7 
 
6.1 
Screening First Visit ............................................................................................... 31 
6.2 
Cycle 1 Day 1 
......................................................................................................... 32
 
6.3 
Cycle 2 day 1 and subsequent cycles (max of 32 cycles) 
....................................... 32 
6.4 
Start of every 3rd cycle (Cycle 3, Cycle 6, etc.) 
...................................................... 32 
6.5 
End of Treatment Visit and Follow up 
................................................................... 33 
6.6 
Calendar 
.................................................................................................................. 33 
7. 
Assessment types 
.................................................................................................... 35
 
7.1 
Pre-Treatment Assessments 
.................................................................................... 35 
7.2 
Efficacy 
................................................................................................................... 35 
7.3 
Safety 
...................................................................................................................... 35 
8. 
Safety monitoring and reporting ............................................................................. 36 
8.1 
Adverse Events 
....................................................................................................... 36
 
8.1.1 Definitions 
.............................................................................................................. 36 
8.1.2 Adverse Events of Special Interest (AESI) with Ibrutinib 
..................................... 37 
8.2 
Safety Monitoring 
................................................................................................... 38
 
8.2.1 Internal Monitoring Plan 
......................................................................................... 38 
8.3 
Reporting of Serious Adverse Events 
..................................................................... 38 
8.4 
Pregnancies 
............................................................................................................. 40 
9. 
Statistical Methods and Data Analysis 
.................................................................... 40 
9.1 
Definition of Study Endpoints 
................................................................................ 41 
9.2 
Determination of sample size ................................................................................. 41 
9.3 
Analysis Sets 
........................................................................................................... 41
 
9.4 
Statistical and analytical plans 
................................................................................ 42 
9.4.1 Demographic and other baseline characteristics 
..................................................... 42 
9.4.2 Adverse Events 
................................
....................................................................... 42 
9.5 
Calculation or derivation of safety variables 
.......................................................... 42 
9.6 
Calculation or derivation of tumor response variables 
........................................... 42 
9.7 
Methods of Statistical Analysis 
.............................................................................. 42 
10. 
Data Recording 
....................................................................................................... 44
 
10.1 
Institutional Review Board (IRB) Approval and Consent 
...................................... 44 
10.2 
Data Management and Monitoring/Auditing 
........... Error! Bookmark not defined. 
10.3 
Protocol Monitoring Committee 
.............................. Error! Bookmark not defined. 
10.4 
Adherence to the Protocol ...................................................................................... 44
 
10.5 
Emergency Modifications 
........................................ 
Error! Bookmark not defined. 
10.6 
Record Retention 
................................
.................................................................... 44 
10.7 
Obligations of Investigators 
.................................................................................... 45 


 
8 
 
11. 
Ethical and Legal Aspects ...................................................................................... 45 
11.1 
Ethical and Legal Conduct of the Study 
................................................................. 45 
11.2 
Subject Information and Consent 
........................................................................... 46 
11.3 
Confidentiality 
................................
........................................................................ 46 
12. 
 
 
 
 
 
 
 
12.4 
Flowcytometry 
....................................................................................................... 48 
13. 
Appendix ................................................................................................................. 50
 
APPENDIX A: CYP3A Inhibitors 
......................................................................................... 50
 
APPENDIX B: RECIST Criteria for Measuring Tumor Response Antitumor Effect ............. 51 
14. 
Appendix C: Janssen Safety Language 
................................................................... 54 
15. 
References 
............................................................................................................... 62 
 


 
9 
 
1. Introduction 
1.1 Background 
Colorectal cancer is one of the most common worldwide malignancies,1 and close to 50% of 
patients ultimately develop metastatic disease.2 Over the last few decades, there has been 
significant progress in the treatment of metastatic disease with the introduction of cytotoxic 
agents like oxaliplatin and irinotecan as well as biologic agents like bevacizumab and cetuximab. 
The median survival of those with metastatic disease at diagnosis is now over 2 years. Many 
patients maintain good performance status even after exhausting standard therapies and there 
remains an urgent need for additional novel options for these patients. 
 
In the refractory setting, the oral agent regorafenib has been approved based on the results of two 
phase III studies showing an overall survival (OS) benefit over best supportive care.3,4 However, 
drug toxicity is a significant concern, limiting the use of regorafenib. Recently TAS 102, an 
thymidine-based nucleic acid analogue, trifluridine, and a thymidine phosphorylase inhibitor, 
tipiracil hydrochloride, was approved based on a phase III study demonstrating modest overall 
survival (1.8 months) improvement against placebo. 
5  Once again toxicity (primarily 
neutropenia and diarrhea) is concerning. New approaches to the management of refractory 
disease with manageable toxicity represent a clinical unmet need for the majority of patients with 
advanced colorectal cancer.  
 
1.2 Immunotherapy in colorectal cancer 
Tumors contain unique genetic alterations that provide antigens by which they can be identified 
by the immune system. These antigens should be recognized and killed by T cell receptors.6 
Immune checkpoints are generally activated to allow for self-tolerance and prevent excess 
autoimmunity. The immune checkpoint inhibitors increase activation of the immune system and 
recognition of tumor cells for destruction.  
 
Colorectal cancer has long been known to have an immunologic component as tumors with 
immune infiltration have overall better prognosis.
7 However, immune checkpoint inhibitors and 
vaccine studies have generally not resulted in significant activity in colorectal tumors.8,9 Novel 
approaches using immunotherapy combinations are needed to better target these tumors. 
 
1.3 Ibrutinib 
 
Ibrutinib is primarily a BTK inhibitor which has been FDA approved for the treatment of several 
hematologic malignancies including CLL, previously treated mantle cell lymphoma, and 
Waldenstrom’s macroglobulinemia, Small lymphocytic lymphoma, Marginal Zone lymphoma 
and Graft versus host disease.  Recent pre-clinical data has shown that there might be a role for 
ibrutinib in the treatment of solid tumors, including lung and breast cancers.
10,11 Ibrutinib has 
been hypothesized to counteract the immune escape mechanism used by tumors wherein the Th2 
response is promoted and Th1 response (associated with cytotoxicity) is suppressed.
12 
 


 
10 
 
 
Pre-clinical Experience 
 
Ibrutinib was initially evaluated in hematologic malignancies but has recently been looked at in 
solid tumors. BTK inhibition by ibrutinib is hypothesized to modulate the tumor 
microenvironment (Ibrutinib investigator’s brochure). In breast cancer lines in vitro, ibrutinib 
was shown to have an inhibitory effect on tumor growth.13 In a pancreatic adenocarcinoma 
model, ibrutinib was found to inhibit tumor growth in vivo.14 There has also been activity shown 
in lung cancer cell lines and colon cancer mouse models.
11,15 
 
Clinical Experience 
 
Clinical Pharmacokinetics 
Ibrutinib has been evaluated in human subjects in multiple studies at doses ranging from 140 mg 
to 840 mg per day. Co-administration of ibrutinib with strong CYP3A inhibitors like 
ketoconazole has been found to increase exposure of ibrutinib. Based on data for the effects of 
food, ibrutinib could be taken with or without food at approximately the same time each day. 
 
Clinical Efficacy 
Ibrutinib has been FDA approved for the treatment of Chronic Lymphocytic Leukemia, including 
those tumors with a 17p deletion, previously treated Mantle Cell Lymphoma, and Waldenstrom’s 
Macroglobulinemia based on the results of clinical studies.16-19 
 
Clinical Safety 
According to the IMBRUVICA USPI (6/2016), the most common adverse reactions (>=20%) in 
patients with B-cell malignancies (MCL, CLL/SLL, WM) were thrombocytopenia, diarrhea, 
anemia, neutropenia, musculoskeletal pain, fatigue, bruising, nausea, rash, hemorrhage and 
pyrexia.The warnings and precautions for ibrutinib include: hemorrhage, infections, cytopenias, 
atrial fibrillation, hypertension, second primary malignancies, tumor lysis syndrome, embryo-
fetal toxicity. 
 
1.4 Pembrolizumab 
 
Human tumors have multiple genetic alterations leading to neoantigens which should be 
recognized by the immune system of the host. However, cancer can dysregulate immune 
checkpoint proteins as a way of evading the host immune system and ensuring tumor survival.20 
Immunotherapy in oncology has been evaluated as a means of upregulating the host immune 
system so that tumors can be recognized as foreign and endogenous anti-tumor immunity can 
attack tumor cells. Immune checkpoint pathway inhibitors such as anti-CTLA4 and anti-PD-1 
antibodies have been evaluated in the treatment of a variety of tumors. 
 
Programmed death 1 is a protein which limits T-cell activity in an effort to minimize 
autoimmunity.
21 When activated by ligands, PD-1 along with its costimulatory protein B7, 
decrease T cell activity which can allow tumors to escape immune recognition. Antibodies 
against PD-1 have been developed in an effort to increase T cell activity. 


 
11 
 
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity 
for PD-1.  
 
Pembrolizumab functions by inhibiting checkpoint inhibition and reversing T cell suppression.  
A recent study showed activity in advanced, refractory colorectal cancer in patients with 
microsatellite instability but not tumors that were mismatch repair proficient.22 The mechanism 
of action in these tumors is hypothesized to be that the increased immunogenicity of these highly 
mutated tumors provides multiple targets upon which the anti-PD1 agent can act. However, these 
tumors comprise only 2-4% of all metastatic colorectal cancers. 
 
 
Pre-Clinical Experience 
 
Pembrolizumab has been found to enhance T-cell activity in blood cells in vitro (Pembrolizumab 
Investigator’s Brochure). In addition, IL-2 and other cytokine production was enhanced. In 
addition, it was found to increase the antigen-specific recall response to tetanus toxoid in 
peripheral blood mononuclear cells from vaccinated individuals in vitro. In vivo, a 
pembrolizumab like antibody was tested as monotherapy in murine tumor models and found to 
inhibit tumor growth of a colon adenocarcinoma (Pembrolizumab Investigator’s Brochure). In 
toxicology studies of Cynomolgus monkeys, pembrolizumab at doses up to 200mg/kg weekly or 
every other week resulted in no treatment related adverse effects.  
 
Clinical Experience 
 
Clinical Pharmacokinetics 
Pembrolizumab has been tested in several thousand human subjects with doses ranging from 
1mg/kg to 10 mg/kg. Pembrolizumab has been found to have a low potential of eliciting anti-
drug antibodies.  
 
Clinical Efficacy 
Pembrolizumab has been FDA approved for the treatment of metastatic melanoma and metastatic 
non-small cell lung cancer based on clinical trial results.
23,24 The majority of responses have been 
durable and have exceeded 6 months. In melanoma, pembrolizumab has been approved in 
metastatic disease in the first line setting as well as after progression on ipilimumab or a BRAF 
inhibitor on patients with a BRAF mutation. In non-small cell lung cancer, it has been approved 
in advanced disease after progression on one prior treatment in patients whose tumor express PD-
L1. 
 
Clinical Safety 
The safety profile is similar across tumor types and there has been no pattern of adverse effects 
with regards to incidence or severity based on dose level. The incidence of drug related adverse 
effects was generally low and included nausea, fatigue, and diarrhea. Grade 3-5 drug related 


 
12 
 
adverse events have included anemia increased LFTs, and pulmonary toxicity. 
 
1.5 Rationale  
Because of the immune modulatory function of ibrutinib, it has been suggested that the addition 
of checkpoint inhibitors like pembrolizumab could potentially produce a synergistic tumor 
response. This was initially evaluated in a mouse model of lymphoma, which showed that anti-
PDL-1 therapy alone delayed tumor growth but was not curative. However, the combination of 
ibrutinib with anti-PDL1 resulted in about 50% of the mice being cured.25 This combination was 
then tested in colon and breast cancer mouse models and showed a similar synergistic effect. 
Interestingly, the colon mouse model (CT26) is not known to be associated with a microsatellite 
high phenotype.26 A similar study with the anti-CTLA4 agent ipilimumab showed synergy with 
ibrutinib, also in a colon mouse model.
27 
 
As there is known synergy between immunotherapy agents and ibrutinib in microsatellite stable 
colon mouse models, we hypothesize that ibrutinib added to pembrolizumab will lead to a 
disease response and improve survival in microsatellite stable colorectal cancers.  
 
The combination of pembrolizumab and ibrutinib is investigational as is for the treatment of 
colorectal cancer. On the basis of the data described above, we hypothesize that the combination 
of ibrutinib and pembrolizumab in refractory colorectal cancers will be safe and efficacious. 
 
2. Study Objectives 
 
 
Primary Objective (Phase I) 
 
To determine safety and tolerability, describe the dose-limiting toxicities (DLTs), and determine 
the maximum tolerated dose (MTD) (or the highest protocol-defined dose level in the absence of 
establishing an MTD) of ibrutinib in combination with pembrolizumab in subjects with 
advanced, refractory colorectal cancers. 
 
 
Secondary Objectives (Phase I) 
1. To determine the efficacy of ibrutinib in combination with pembrolizumab based on 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1  
2. To determine the efficacy of ibrutinib in combination with pembrolizumab based on the 
RECIST based immune-related response criteria (irRC).. 
3. To determine overall survival 
 
Primary Objective (Phase II) 
To determine the efficacy of ibrutinib in combination with pembrolizumab based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1  


 
13 
 
 
Exploratory Objective 
 
1.
     To use the immunohistochemical stains and HTG EdgeSeq ImmunoOncology Assay to 
assess the host immune response in tumor microenvironment. The resulting “immune 
gene expression profiles and immune cells profiles” will be correlated with clinical 
outcome in a descriptive analysis. 
2.   To use the Luminex Multiplex immunoassay and the flowcytometry, to analyze the effect 
of this combination on the immune system and immune cells in peripheral blood. 
 
3. Study Design 
This is a phase I/II open-label trial to assess the safety, tolerability, and preliminary anti-tumor 
activity of pembrolizumab and ibrutinib in subjects with advanced, refractory colorectal cancer. 
 
The study consists of two phases:  
 
Escalation phase (Phase I)  
 
The objective of this phase is to investigate the safety, tolerability and recommend the dose of 
the combination. Ibrutinib and pembrolizumab will be concurrently administered in sequential 
cohorts of 3- 6 subjects with each receiving pembrolizumab 200 mg every 3 weeks (Q3W) and 
ibrutinib at doses of 420 mg daily ( cohort 0)  and 560 mg daily (cohort 1) .  
 
The first cohort will enroll a minimum of 3 subjects, according to a standard 3+3 design. If 0 
out of the first 3 subjects in the first cohort experience a dose-limiting toxicity (DLT), then dose 
escalation will continue as planned. If 1 out of the first 3 subjects experience a DLT, then the 
cohort will be expanded to a total of 6 subjects, and if no more than 1 out of 6 subjects 
experiences a DLT in a given dose cohort, dose escalation will continue as planned. If ≥ 2 
DLTs are observed in the first dose cohort, the principle investigator will discuss with Janssen 
on how to proceed.  The DLT evaluation period will be defined as the time from the first dose 
of pembrolizumab and ibrutinib to 42 days after the first dose or if a subject experiences a DLT 
within this time period. A maximum of 2 cohorts is expected, making a total of approximately 
12 evaluable subjects during the dose escalation phase.  
 
Phase II (Phase II )  
 
The phase II portion of the study is to be conducted in patients with advanced, refractory 
colorectal cancer. The objective of this phase of study is to assess disease control rate (CR + 
PR+ SD) and further investigate the safety, tolerability and preliminary clinical activity of the 
combination at the recommended dose. 32 evaluable subjects with advanced, refractory 
colorectal cancer will be enrolled. Patients will be on treatment until unacceptable toxicity or 
disease progression for a maximum of 24 months.32 subjects with microsatellite stable 
colorectal cancer will receive concurrent ibrutinib PO qdaily and pembrolizumab 200 mg IV 
Q3W beginning on Day 1 using the recommended dose of ibrutinib from the escalation phase to 
evaluate disease control rate and further evaluate safety, tolerability and preliminary evaluation 


 
14 
 
of clinical efficacy. Initiation of expansion arms with the recommended dose of ibrutinib in 
combination with pembrolizumab at 200 mg IV will be based on an adequate safety and 
tolerability profile of the combination from the escalation phase. 
 
4. Eligibility 
4.1 Inclusion Criteria 
 
 Histologically confirmed diagnosis of colorectal adenocarcinoma 
 Measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1.  Stage IV or recurrent disease is required. 
 Patients must have received and progressed through or become intolerant to 
fluoropyrimidine, irinotecan, oxaliplatin, and bevacizumab. If RAS wild type, patients 
should have received and progressed or become intolerant to the above as well as 
cetuximab or panitumumab containing therapies. Prior therapy with Regorafenib and/or 
TAS 102 is allowed 
 ECOG Performance Score 0 or 1 
 Estimated life expectancy > 3 months 
 Adequate bone marrow, liver and renal function as assessed by the following: 
o Hemoglobin > 8.0 g/dl 
o Absolute neutrophil count (ANC) > 1,000/mm3 independent of growth factor support 
o Platelet count > 100,000/mm3  
o Total bilirubin < 1.5 times ULN unless bilirubin rise is due to Gilbert’s syndrome or of 
non-hepatic origin 
o AST, ALT and Alkaline Phosphatase ≤2.5 times the ULN ( ≤5 x ULN for patients with 
liver involvement) 
o Creatinine clearance ≥ 30 ml/min 
 Patients must not have had chemotherapy, major surgery, monoclonal antibody therapy 
or experimental therapy within the 21 days prior to the start of ibrutinib administration 
 Women of childbearing potential must have a negative serum orurine pregnancy test 
performed within 7 days prior to the start of study drug. Post-menopausal women 
(defined as no menses for at least 1 year) and surgically sterilized women are not required 
to undergo a pregnancy test. 
 Subjects (men and women) of childbearing potential must agree to use adequate 
contraception beginning at the signing of the ICF until at least 4 months for both females 
and males after the last dose of study drug. The definition of adequate contraception will 
be based on the judgment of the principal investigator or a designated associate. 
 Subjects (men and women) must agree to not donate sperm (males) or eggs (females) 
during and up to 120 days after the last dose of study treatment. 
 Subjects must be able to understand and be willing to sign the written informed consent 
form. A signed informed consent form must be appropriately obtained prior to the 
conduct of any trial-specific procedure. Subjects must be willing and able to comply with 
scheduled visits, treatment schedule, laboratory testing, and other study requirements. 
 


 
15 
 
4.2 Exclusion Criteria 
 Subjects with active CNS metastases are excluded. If CNS metastases are treated and 
subjects are at neurologic baseline for at least 2 weeks prior to enrollment, they will be 
eligible but will need a Brain MRI prior to enrollment. Subjects must be off 
corticosteroids or on a dose of less than 10mg per day. 
 Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only 
requiring hormone replacement, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll. 
 Subjects with a condition requiring systemic treatment with either corticosteroids (>10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days 
of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
  Prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab or any other antibody or drug specifically targeting T-
cell costimulation or checkpoint pathways). 
 Prior therapy with ibrutinib or other BTK inhibitors. 
 Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for 
curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder 
tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina 
propria)]. 
 Known history of human immunodeficiency virus (HIV) infection or acquired 
immunodeficiency syndrome (AIDS). 
 Serologic status reflecting active hepatitis B or C infection. Patients who are hepatitis B 
core antibody positive and who are antigen negative, will need to have a negative PCR 
result prior to enrollment. Those who are hepatitis B antigen positive or PCR positive, 
will be excluded.  
 Subjects with Child Pugh B or C cirrhosis.  
 History of severe hypersensitivity reactions to other monoclonal antibodies 
 Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the study or evaluation of the study results. 
 History or concurrent condition of interstitial lung disease of any grade or severely 
impaired pulmonary function.  
 Unresolved toxicity higher than CTCAE grade 1 attributed to any prior therapy or 
procedure, excluding alopecia. 
 Clinically significant cardiovascular disease such as uncontrolled or symptomatic 
arrhythmia, congestive heart failure, any Class 3 or 4 cardiac disease as defined by the 
New York Heart Association Functional Classification, or history of myocardial 
infarction within 6 months prior to first dose with study drug 


 
16 
 
 Unable to swallow capsules or disease significantly affecting gastrointestinal function 
and/or inhibiting small intestine absorption such as; malabsorption syndrome, resection 
of the small bowel, or poorly controlled inflammatory bowel disease affecting the small 
intestine. 
 Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. 
phenprocoumon). 
 Requires treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor. 
 History of stroke or intracranial hemorrhage within 6 months prior to enrollment. 
 Any illness or medical conditions that are unstable or could jeopardize the safety of the 
patient and his/her compliance in the study. 
 Major surgery or a wound that has not fully healed within 4 weeks of enrollment. 
 Vaccinated with live, attenuated vaccines within 4 weeks of enrollment 
 Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis within 6 months 
 
Excluded Therapies and Medications for Cancer 
 
 Anticancer chemotherapy during the study or within 4 weeks of study enrollment.  
Subjects must have recovered from the toxic effects of the previous anti-cancer 
chemotherapy (with the exception of alopecia). Anti-cancer therapy is defined as any 
agent or combination of agents with clinically proven anti-tumor activity administered 
by any route with the purpose of affecting the malignancy, either directly or indirectly, 
including palliative and therapeutic endpoints.  
 Hormonal therapy during the study or within 2 weeks of first study enrollment. 
 Radiotherapy to target lesions during study or within 2 weeks of enrollment. 
 An irradiated lesion is considered evaluable only if it has shown enlargement since the 
completion of last radiation. 
 Bone marrow transplant or stem cell rescue. 
 Investigational drug therapy outside of this trial during or within 4 weeks of first study 
treatment. 
 
4.3 Withdrawal of Subjects from Study 
 
Subjects must be withdrawn from the trial (treatment and procedures) for the following 
reasons:  
 Subject withdraws consent from study treatment and study procedures. A subject must be 
removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative. At any time during the trial and without giving reasons, a 


 
17 
 
subject may decline to participate further. The subject will not suffer any disadvantage as 
a result. 
 Pregnancy. Pregnancies will be reported to Janssen and Merck within 24 hours of having 
knowledge of the event. Pregnancy will not be reported as an SAE but the subject must 
be withdrawn from the trial immediately. (Note: subjects who have been withdrawn from 
treatment with study drug because of pregnancy should not undergo CT scans [with 
contrast]/MRI or bone scans while pregnant.) 
 If, in the investigator
's opinion, continuation of the trial would be harmful to the subject
's 
well-being. 
 Subject is lost to follow-up. 
 Death. 
 
All subjects who discontinue should comply with protocol specified follow-up and survival 
procedures. The ONLY exception to this requirement is when a subject withdraws consent for all 
study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject was 
withdrawn before completing the study, the reason for withdrawal must be entered on the 
appropriate case report form page. 
 
Subjects may be withdrawn from study treatment for the following reasons: 
 The subject is non-compliant with ibrutinib administration as measured by a dosing 
diary, pembrolizumab administration, or trial procedures; including the use of anti-
cancer therapy not prescribed by the study protocol. 
 Severe allergic reaction to ibrutinib or pembrolizumab. 
 The development of a second cancer. 
 Development of an illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
 Deterioration of ECOG performance status to 3 or 4. 
 Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial result. 
Any subject removed from the trial will remain under medical supervision until discharge or 
transfer is medically acceptable. 
Any subject with progression of disease will come off of treatment except for patients deriving 
clinical benefit as deemed by the principal investigator with a maximum of 24 months on 
therapy. In all cases, the reason for withdrawal must be recorded in the CRF and in the subject
's 
medical records. 
4.3.1 Screen Failures/Dropouts/Replacements 
A subject who discontinues study participation prematurely for any reasons except death, disease 
progression and severe toxicity is defined as a dropout. A subject who, for any reason (e.g., 
failure to satisfy the selection criteria), terminates the study before the time point used for the 
definition of “dropout” (see above) is regarded a “screening failure”. Subjects who withdraw 
from treatment (for any reason) during dose seeking phase may be replaced. Patients will be 


 
18 
 
considered inevaluable for the primary endpoint of disease control rate if they do not have at 
least one post-baseline disease response assessment.  Inevaluable patients may be replaced. 
 
4.3.2 Removal of Patients from Protocol Therapy 
Patients will be removed from study when any of the criteria listed  
 
 Disease progression  
 Intercurrent illness that prevents further administration of treatment  
 Unacceptable AE(s) 
  Patient decides to withdraw from the study OR  
  General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator  
Notify the Principal Investigator and document the reason for study removal and the date the patient 
was removed in the eCRF. The patient should be followed per protocol 
5. Treatment Plan 
 
5.1 Drug Administration 
 
Ibrutinib 
Ibrutinib should be administered orally once daily with a glass of water at approximately the 
same time each day. The capsules should be swallowed whole with water and should not be 
opened, broken, or chewed. Ibrutinib must not be taken with grapefruit juice or Seville orange 
juice 
Ibrutinib drug product is a white opaque, size 0, hard gelatin capsule marked with “ibr 140 mg” 
in black ink, containing 140 mg of ibrutinib. Ibrutinib capsules are supplied in a white HDPE 
bottle with a child-resistant closure containing 90 or 120 hard capsules.Keep ibrutinib out of the 
sight and reach of children. 
 
Ibrutinib Capsules, 140 mg should be stored according to the storage conditions indicated on 
the label. The recommended storage condition for ibrutinib capsules is 15°C to 25°C (59°F to 
77°F) with excursions permitted to 30°C (86°F). 
 
Pembrolizumab 
Pembrolizumab is provided as a white to off white lyophilized powder (50 mg/vial) or as a liquid 
solution (100 mg/vial) in Type I glass vials intended for single use only. 
 
Pembrolizumab Powder for Solution for Infusion, 50 mg/vial, is reconstituted with sterile water 
for injection prior to use. The drug product is stored as a stable lyophilized powder or liquid 
solution under refrigerated conditions (2 to 8°C). 
 


 
19 
 
The lyophilized drug product after reconstitution with sterile water for injection, and the liquid 
drug product are a clear to opalescent solutions, essentially free of visible particles. The 
reconstituted lyophilized product and the liquid product are intended for IV administration. The 
reconstituted drug product solution or 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 MK-
3475 solutions in the IV bags. 
 
Treatment 
Treatment will be administered on an outpatient basis. For ibrutinib a self-report pill diary will 
be utilized to report medication adherance. Reported AEs and potential risks are described in 
Section 8. Dose delays for ibrutinib and pembrolizumab are described in Section 5.1.6. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient
's malignancy. The starting dose of ibrutinib will 
be 420 mg daily, taken orally. The dose of pembrolizumab is fixed at 200 mg IV over 30 minutes 
every 3 weeks. Each cycle will last for 3 weeks. 
 
Subjects will be enrolled in 3 + 3 design with 3-6 subjects per cohort to ensure a minimum of 3 
and a maximum of 6 evaluable subjects per cohort. It is estimated that two cohorts will be 
needed during the dose escalation phase of the study as follows: 
 
Dose Escalation Schedule 
Cohort 
Dose 
Ibrutinib 
Pembrolizumab 
0 
420 mg PO qdaily 
200 mg IVover 60 min q3wk 
1 
560 mg PO qdaily 
200 mg IV over 60 min q3wk 
 
Based on current available data, the ibrutinib starting dose will be 420 mg (Cohort 0). Ibrutinib 
dose could be escalated to 560 mg (Cohort +1) based on the safety and tolerability profile of the 
combination in Cohort 0.  If DLT is seen with Cohort 0, the principal investigator will re-
evaluate and discuss with Janssen and Merck on how to proceed. 
 
Each subject will receive ibrutinib daily and pembrolizumab Q3W continuously and will 
undergo assessments for safety (DLTs, AEs, vital signs, clinical laboratory tests, ECOG 
performance status, and physical examinations) according to the schedule of assessments.  
 
The DLT evaluation period will be defined as the time from the first dose of ibrutinib or 
pembrolizumab to 42 days (2 cycles) after the first dose or if a subject experiences a DLT within 
this time period. The total duration of dose interruptions for ibrutinib will be up to 6 days 
(intermittent or continuously), during a period of 42 days without a subject being deemed 


 
20 
 
inevaluable.  
 
 
Rules for dose escalation and de-escalation are as follows: 
 
1. A minimum of 3 evaluable subjects will be enrolled in each dose cohort. The 
administration of ibrutinib and pembrolizumab to the first and second subjects of each 
cohort will be separated by at least 72 hours. Providing there are no serious or 
unexplained safety issues, dosing of the remainder of the cohort will continue as suitable 
subjects are identified. All safety data will be reviewed before proceeding with an 
escalation or de-escalation decision.  
 
2. A 3+3 dose-escalation design will be followed as summarized below: 
 
  If 0 out of the 3 evaluable subjects in a dose cohort experience a DLT during the DLT 
evaluation period, dose escalation may proceed to the next planned cohort. 
  If 1 of the 3 evaluable subjects in any dose cohort experiences a DLT during the DLT 
evaluation period, that dose cohort will be expanded to a total of 6 subjects. If no more than 1 
of 6 subjects in the dose cohort experiences a DLT, dose escalation may proceed to the next 
planned dose cohort. 
  If 2 or more subjects in a dose cohort experience a DLT during the DLT evaluation period, 
the MTD will have been exceeded and no further subjects will be enrolled into that dose 
cohort. 
 
There will be no intra-subject dose escalations. 
 
5.1.1 Rationale for Flat Dose Regimen of Pembrolizumab 
An open-label Phase I trial 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. No MTD has been identified to date. In pharmacokinetic studies, the relationship 
between clearance and body weight is within the range observed for other antibodies and would 
support both body weight normalized dosing or a fixed dose across all body weights.  
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe. A fixed dose regimen will simplify the dosing regimen to be more 
convenient for physicians and to reduce potential for dosing errors. A fixed dosing scheme will 
also reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
 


 
21 
 
5.1.2 Definition of dose-limiting toxicity  
A DLT is defined as any toxicity not attributable to the disease or disease-related processes 
under investigation, which occurs from the start of combination ( post dose Day 1 Cycle 1) up to 
42 days and is considered by the Investigator to be definitely, probably, or possibly related to the 
treatment. A DLT will be defined as any Grade 3 or higher treatment-related toxicity that occurs 
during the DLT evaluation period, including: 
 
1. Any Grade 4 immune-related AE (irAE) irrespective of duration  
 
 
2. Any Grade 3 or 4 non-infectious pneumonitis irrespective of duration  
 
3. Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade ≤ 2 
within 3 days after onset despite maximal supportive care including systemic corticosteroids or 
downgrade to Grade ≤ 1 within 14 days after onset of the event.  
 
4. Any ≥ Grade 2 pneumonitis or interstitial lung disease (ILD) that does not resolve to grade 1 
within 3 days of the initiation of maximal supportive care  
5. Liver transaminase elevation higher than 10 × upper limit of normal (ULN) or total bilirubin 
higher than 5 × ULN that lasts for longer than 7 days. Any grade 3-4 non hematologic toxicity 
which does not resolve within 4 days will be considered a DLT. 
 
 
A DLT excludes the following conditions: 
 
1. Vitiligo or alopecia of any grade.  
2. Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance.  
3. Grade 3 endocrinopathy that is managed with or without systemic corticosteroid therapy 
and/or hormone replacement therapy and the subject is asymptomatic  
4. Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) that resolves to ≤ 
Grade 1 within 30 days. Immune-related adverse events are defined as AEs of immune 
nature (i.e., inflammatory) in the absence of a clear alternative etiology. In the absence of 
clinical abnormality, repeat laboratory testing will be conducted to confirm significant 
laboratory findings prior to designation as a DLT. However isolated laboratory changes 
of any grade without clinical sequelae or clinical significance are not considered DLTs. 
 
5.1.3 Definition of maximum tolerated dose 
 
A dose will be considered non-tolerated and dose escalation will cease if 2 or more of up to 6 
evaluable subjects experience a DLT at a dose level. Once the non-tolerated dose is defined the 
MTD will be confirmed at the previous dose-level below the non-tolerated dose or a dose 
between the non-tolerated dose and the last tolerated dose may be investigated. Six evaluable 
subjects are required to determine the MTD.  


 
22 
 
 
5.1.4 Definition of evaluable subject 
For decisions on dose escalation, an evaluable subject is defined as a subject that meets all of the 
following criteria:  
 
 Has received ibrutinib at the protocol-specified dose for at least 36 out of first 42 days of 
combination therapy  
 Has received one infusion of pembrolizumab at the protocol-specified full dose during the first 
42 days of therapy 
 Has completed the minimum safety evaluation requirement which is defined as the time from 
consent to 42 days after the first dose.  
 
OR  
 
 Has experienced a DLT any time during the first 42 days of combination therapy.  
 
5.1.5 Dose Modifications for Treatment-Related Toxicity 
All toxicities will be graded according to National Cancer Institute’s (NCI’s) Common 
Terminology Criteria for Adverse Events (CTCAE) (NCI CTCAE v 4.03).  
 
Phase I: 
 
No dose modifications will be allowed in the escalation phase during the DLT evaluation period.  
 
If a subject experiences a clinically significant and/or unacceptable toxicity including a DLT not 
attributable to the disease or disease-related processes under investigation, dosing will be 
interrupted and supportive therapy administered as required. 
 
Phase II: 
 
Dose reductions for AEs related to ibrutinib will be performed as per Table 1 below. 
 
Dose modifications will not be required for AEs that are clearly not attributed to ibrutinib or 
pembrolizumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant.  
 
Dosing may continue despite concurrent vitiligo of any AE grade.  
 
If a subject experiences a clinically significant and/or unacceptable toxicity, dosing will be 
interrupted and supportive therapy administered as required.   
 






 
25 
 
5.2 Concomitant therapy  
 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 in the EMR 
 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 in the EMR 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 (see Appendix A) 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 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.  


 
26 
 
o Patients who need to be on anticoagulant therapy during treatment with ibrutinib 
should be treated with 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.  
 
 
5.2.1 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab or ibrutinib 
 Radiation therapy  
 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, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic 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. 
5.3 Supportive Care Guidelines for Ibrutinib 
The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, 
CLL/SLL, and WM) were neutropenia, thrombocytopenia, diarrhea, anemia, musculoskeletal 
pain, rash, nausea, bruising, fatigue, hemorrhage, and pyrexia. Listed below are guidelines on 
how to manage these common toxicities. 
 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 up to 6% of patients. Bleeding events of any grade, including bruising and 


 
27 
 
petechiae, occurred in approximately half 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 
serosanguineous 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 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 14% to 29% of patients. Cases of progressive multifocal 
leukoencephalopathy (PML) have occurred in patients treated with ibrutinib. Evaluate 
patients for fever and infections and treat appropriately per current guidelines.  
 Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 
19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) based on 
laboratory measurements occurred in patients treated with single agent ibrutinib. Monitor 
complete blood counts at least monthly.  
 Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in 
patients treated with ibrutinib, particularly in patients with cardiac risk factors, 
hypertension, acute infections, and a previous history of atrial fibrillation. Periodically 
monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic 
symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG 
performed. Atrial fibrillation should be managed appropriately, and if it persists, consider 
the risks and benefits of ibrutinib treatment and follow dose modification guidelines per 
the USPI for ibrutinib.  
 Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with 
ibrutinib with a median time to onset of 4.6 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 (range, 5 to 16%) including non-
skin carcinomas (range, 1 to 4%) have occurred in patients treated with ibrutinib. The 


 
28 
 
most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 
13%).  
 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 embryofetal 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.  
 
 
5.5 Management of Immune Related Adverse Events related to 
Pembrolizumab 
 
5.5.1 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. 
5.5.2 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. 


 
29 
 
5.5.3 Type 1 diabetes mellitus (T1DM) 
If new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated 
with ketosis (ketonuria) or metabolic acidosis (DKA). 
o 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. Evaluate 
patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
5.5.4 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. 
5.5.5 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. 
5.5.6 Hepatic: 
 For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o 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. 






 
32 
 
urea nitrogen (BUN), total protein and albumin 
 TSH, free T4 
 
 
 Carcinoembryonic antigen (CEA) 
 Serum/urine pregnancy test (if applicable) 
 Screening for Hepatitis B and C  
 Urinalysis including blood, glucose, protein, specific gravity 
 
 
 
6.2 Cycle 1 Day 1 
 History and assessment to include physical examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
 Baseline Toxicity/AE assessment  after first dose  
 ECOG Performance Status Assessment 
 Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
 Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, calcium, phosphate, magnesium, bicarbonate, sodium, 
potassium, chloride, creatinine, BUN, total protein and albumin 
6.3 Cycle 2 day 1 and subsequent cycles (max of 32 cycles) 
 History and assessment to include brief examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
 Toxicity/AE assessment 
 ECOG Performance Status Assessment 
 Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
 Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, calcium, phosphate, magnesium, bicarbonate, sodium, 
potassium, chloride, creatinine, BUN, total protein and albumin 
 Pregnancy test will be performed at baseline for WOCBP and then only as clinically 
indicated 
  
 
 
6.4 Start of every 3rd cycle (Cycle 3, Cycle 6, etc.) 
 
 Radiologic assessment: CT scan or MRI (chest, abdomen, pelvis) with tumor 
measurement and disease assessment of non-measurable diseaseaccording to 
RECIST 1.1 and irRC criteria (please see Appendix B) 
 TSH and free T4  
 Carcinoembryonic antigen (CEA) 


 
33 
 
 
 
 
 
6.5 End of Treatment Visit and Follow up 
End of Treatment Visit 
The end of treatment visit should be conducted when it is confirmed by the investigator 
that the patient will receive no further doses of drug on study. 
 
 History and assessment to include brief examination, vital signs (heart rate, 
respiration rate, temperature and BP) and review of systems 
 Toxicity/AE assessment 
 ECOG Performance Status Assessment 
 Hematology (hemoglobin, HCT, RBC, WBC with differential (neutrophils, 
bands, lymphocytes, monocytes, eosinophils and basophils) and platelet count 
 Chemistry (ALT, AST, AP, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase glucose, calcium, phosphate, magnesium, bicarbonate, sodium 
 Radiologic assessment: CT scan or MRI (chest, abdomen, pelvis) with tumor 
measurement and disease assessment of non-measurable diseaseaccording to 
RECIST 1.1 and irRC criteria (please see Appendix B) may be conducted if it 
has not been performed within the last 4 weeks. 
 
Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs 
that occur within 30 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded. 
 
 
Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase for 24 months and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
 
 
6.6 Calendar 
 
Screening 
within 28 
days of 
C1D1 
Cycl
e 1 
Day 
1    ± 
2 
days 
Cycle 2 
day 1  ± 2 
days and 
subsequent 
cycles 
Cycle 3 
day1 ± 5 
day and 
every 3
rd 
cycle 
thereafter 
EOTm 
Safety 
Follow-Up 
Visit ± 7 
daysn 
Post-
Progression 
Follow-up j  


 
34 
 
Complete 
History/Physicala 
X 
 
 
 
X 
 
 
History & 
Assessment b 
 
X 
X 
 
 
X 
 
Toxicity Notation 
 
X 
X 
 
X 
X 
 
ECOG 
X 
X 
X 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
Tumor 
Measurement/Dise
ase Assessmentc 
X 
 
 
X 
X 
 
 
Hematologyd 
X 
X 
X 
 
X 
 
 
Chemistrye 
X 
X 
X 
 
X 
 
 
Coagulationf 
X 
 
 
 
 
 
 
Urinalysisg 
X 
 
 
 
 
 
 
TSH, free T4 
X 
 
 
X 
 
 
 
CEA 
X 
 
 
X 
 
 
 
Hepatitis  
Screening h 
X 
 
 
 
 
 
 
Serum/urine 
Pregnancy, if 
applicable i 
X 
 
 
 
 
 
 
Survival f/u j 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. Complete medical history and physical examination including demographics, surgery, 
therapies, medications, smoking, alcohol history, co-existing diseases, allergy, NYHA 
classification, vital signs (heart rate, respiration rate, temperature and BP), height, weight 
and review of systems. A full physical exam should be performed during screening.  
b. History and assessment including brief examination, vital signs and review of systems. 
Note all toxicities and adverse events, using CTCAE version 4.03 and in accordance with 
section 9.1. The investigator or qualified designee will also perform a directed physical exam 
as clinically indicated prior to each treatment cycle administration.  
c. Tumor assessment using CT or MRI (chest, abdomen, pelvis) (at investigator’s 
discretion) will be collected at screening, after every 3 cycles, and as clinically indicated. 
Tumor response will be assessed using RECIST 1.1 and irRC criteria. Tumor 
measurement/disease assessment should be performed within 7 days at the beginning of 
every 3rd cycle. 
d. Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils and basophils) and platelet 
count. 
e. ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, creatine kinase, 
lipase, amylase, glucose, calcium, phosphate, magnesium, bicarbonate, sodium, 
potassium, chloride, creatinine, blood urea nitrogen (BUN), total protein and albumin. 


 
35 
 
f. PT-INR and aPTT. 
g. Urinalysis including blood, glucose, protein, specific gravity 
h. Hepatitis B surface antigen, surface antibody, and Hepatitis C antibody 
i. Pregnancy test will be performed at baseline for WOCBP and then only as clinically 
indicated 
j. After off treatment following disease progression survival f/u, can be performed over the 
phone every 3 months  
k. Archival tissues ( 10 unstained slides) if available 
l. The PBMC should be viably frozen (for flow cytometric analysis) and the plasma frozen 
separately .The actual analyses used will be based on response and determined by the 
investigator at a later date. Two green top (Sodium Heparin) tubes (about 20 ml) will be 
used each time. This will ONLY be collected at the screening and at the beginning of the 
3rd cycle.  
m. If a subject discontinues treatment due to confirmed PD, only the EOT disease 
assessment is required if it has been > 4 weeks since the last disease assessment 
n. The safety follow-up visit will be approximately 30 days after the last dose or prior to the 
start of a subsequent anti-cancer therapy. 
7. Assessment types 
 
7.1 Pre-Treatment Assessments 
The nature of the study and the associated potential risks will be explained to all study candidates 
and a signed informed consent must be obtained before any study-specific Pre-Treatment 
procedures are performed. Pre-Treatment assessments must be completed and reviewed within 
28 days prior to the start of study drug treatment to ensure eligibility for study entry 
 
Pre-Treatment evaluations will include inclusion/exclusion criteria evaluation, demographic data 
collection, ECOG performance status, NYHA classification, medical and surgical history 
collection, vital signs, complete physical examination (including height and weight), 12-lead 
ECG, biochemistry, hematology and urinalysis, pregnancy test (urine or serum β- hCG in women 
of childbearing potential only), and tumor assessments 
7.2 Efficacy 
Response and progression will be evaluated using the international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (see Appendix B). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria. 
7.3 Safety 
Safety assessments will consist of monitoring and recording all adverse events, including serious 
adverse events, the monitoring of hematology, blood chemistry, ECG and the regular monitoring 


 
36 
 
of vital signs, and physical condition as shown in corresponding tables. Safety and tolerability will 
be assessed according to the NIH/NCI CTC version 4.0. 
 
 
8. Safety monitoring and reporting 
8.1 Adverse Events 
8.1.1 Definitions 
An Adverse event (AE) is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. Medical conditions/diseases present 
before starting study drug are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, or require therapy. Clinically 
significant laboratory results are those requiring a change in the patient’s treatment, further 
diagnostic testing or specific clinical intervention (i.e., treatment delays or dose modifications, 
etc). The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, laboratory 
test, or other assessments. As far as possible, each adverse event should be evaluated by the 
investigator to determine: 
• the severity grade (mild, moderate, severe) or (grade 1-4) 
• its relationship to either or the study drugs (unrelated, unlikely, possible, probable, definite) 
• its duration (start and end dates or if continuing at final exam) 
• action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this adverse event; concomitant medication taken; non-drug 
therapy given; hospitalization/prolonged hospitalization) 
• whether it constitutes a serious adverse event (SAE) 
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows:  
• Definite: The AE is clearly related to the study treatment;  
• Probable: The AE is likely related to the study treatment;  
• Possible: The AE may be related to the study treatment;  
• Unlikely: The AE is doubtfully related to the study treatment;  
• Unrelated: The AE is clearly not related to the study treatment.  
 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
1. Is fatal or life-threatening. 
2. Requires or prolongs hospitalization. 
3. Results in persistent or significant disability/incapacity. 


 
37 
 
4. Constitutes a congenital anomaly or a birth defect. 
5. Is medically significant, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
For full adverse event reporting as per Janssen guidelines, see Appendix C. 
Events not considered to be serious adverse events are hospitalizations for the: 
 Routine  treatment  or  monitoring  of  the  studied  indication,  not  associated  with  any 
deterioration in condition. 
 Treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen. 
 Treatment  on  an  emergency,  outpatient  basis  for  an  event  not  fulfilling  any  of  the 
definitions of serious given above and not resulting in hospital admission. 
Pregnancy, although not itself a serious adverse event, should also be reported on a serious 
adverse event form or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects or congenital abnormalities. 
Serious adverse event reporting is initiated after the signs informed consent, and 
continues until 4 weeks after the patient’s last dose of study medication. The period 
after discontinuing study drug may be extended at investigators discretion. 
Progression of the cancer under study is not considered an adverse event. 
 
8.1.2 Adverse Events of Special Interest (AESI) with Ibrutinib 
 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities. These events (regardless of seriousness) will be reported to Janssen Drug 
Safety per the SAE reporting timelines.  
 
Major Hemorrhage  
Major hemorrhage is defined as any hemorrhagic event that is Grade 3 or greater in severity or 
which results in one of the following: 
(1) Intraocular bleeding causing loss of vision, 
(2) The need for a transfusion of 2 or more units of red cells, 
(3) Or an equivalent 
 
All hemorrhagic events requiring transfusion of red blood cells should be reported as grade 3 or 
higher AE per CTCAE v4.03. Events meeting the definition of major hemorrhage will be 
captured as an event of special interest. 
 
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. 
 


 
38 
 
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 
 
8.2 Safety Monitoring  
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 4.0 (CTCAE v4.03) that is available at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
The principal investigator will monitor the data and toxicities to identify trends and will be 
responsible for revising the protocol as needed to maintain safety. Serious adverse events will be 
reported to the IRB in accordance with IRB and Moffitt institutional policies and to the FDA as 
described below. 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 will provide to the PMC the following information for data and safety monitoring: 
statistical report of the study’s progress, summary of adverse events and deviations. Safety and 
monitoring reports are to be submitted to the PMC after completing each odd numbered dose 
level (i.e., 1,3,5, etc), or more frequently if requested by the PMC. A final safety and monitoring 
report must be submitted to the PMC within three months of defining the maximum tolerated 
dose (MTD). 
8.2.1 Internal Monitoring Plan 
The trial will be monitored per Moffitt Cancer Center policy MRI-P.PSO.03, Monitoring of 
Investigator Initiated Clinical Research. Data will be captured in Oncore, Moffitt’s Clinical Trials 
Management System, Regulatory documents and case report forms will be monitored internally 
according to Moffitt Cancer Center Monitoring Policies. Monitoring will be performed regularly to 
verify data is accurate, complete and verifiable from source documents; and the conduct of the trial is 
in compliance with the currently approved protocol/amendments, Good Clinical Practice, and 
applicable regulatory requirements.  
8.3 Reporting of Serious Adverse Events 
Moffitt Cancer Center will report SAEs within 24 hours of the study team becoming aware of 
the event by completing an SAE report in OnCore, the clinical trial management system.  
The definition of serious adverse events (SAEs) is given in Section 8.1.1. 
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 


 
39 
 
grade 4, according to CTCAE definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE.  CTCAE grade 4 baseline 
laboratory abnormalities that are part of the disease profile should not be reported as an SAE, 
specifically when they are allowed or not excluded by the protocol inclusion/exclusion criteria.   
 
Reporting Serious Adverse Events (SAEs) to the FDA  
Any event that is both serious and unexpected must be reported to the FDA as soon as possible 
and, in no event, later than 7 days (death or life-threatening event) or 15 days (all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. SAEs may be reportable 
to the FDA for both FDA-approved (post-market) drugs as well as investigational agents.  
For an event to be reportable to the FDA, it must meet both of the following requirements as 
determined by the principal investigator of the study:  
1. The event is possibly, probably or definitely related to the agent  
2. The event is unexpected (i.e., not listed in the protocol, investigational brochure, or informed 
consent)  
 
Expedited reporting to the FDA on a MEDWatch 3500A form will be used for all unexpected 
and related serious adverse events as defined in 21 CFR 312.32. 
The current MedWatch mandatory reporting form FDA 3500A can be found on the FDA 
website:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm  
Use: Form FDA 3500A - Mandatory Reporting  
Complete the MedWatch report and mail it to the appropriate address below (please also see 
FDA reporting fax number under section 7.4.2):  
For Drugs:  
Central Document Room Center for Drug Evaluation and Research Food and Drug 
Administration 5901-B Ammendale Road Beltsville, MD 20705-1266 
 
To report an event for an INVESTIGATIONAL AGENT under investigational new drug 
applications:  
Send a narrative of the event with circumstances, IND number, and why it is related and 
unexpected to the H. Lee Moffitt Cancer Center Regulatory Affairs IND Office. A MedWatch 
report for the event would suffice. The Regulatory Affairs IND Office at Moffitt Cancer Center 
will submit the reportable event as an IND safety report to the FDA on behalf of the principal 
investigator. 
If applicable, the site should also follow protocol guidelines for additional reporting to 
government agencies. 
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Merck and Janssen within 24 hours.  In the 
event of such an event, the investigator should refer to the Pharmacovigilance section of the 
contract for reporting procedures. The completed Medwatch/case report should be faxed 
immediately upon completion to the below: 
 


 
40 
 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
Janssen Drug Safety: (IIS-BIO-VIRO-GCO@its.jnj.com) or by fax if email is unavailable (866-
651-0219). 
 
The Investigator may report serious adverse events (SAEs) as described below. 
 
A MedWatch form available at http://www.fda.gov/medwatch/  
 
All reports shall be faxed to:  
 
PPD/PVG 
United States and Canada: Toll-Free Fax: 1-888-529-3580 
Rest of World: Toll-Free Fax: 93581-888-529-3580 (will automatically connect to 
PVGs toll-free safety fax number (1-888-529-3580) 
8.4 Pregnancies 
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) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of treatment, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform 
mole, blighted ovum, fetal death, intrauterine death, 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 to the Principal Investigator. Within 24 hours of 
the Investigator becoming aware, the pregnancy must be reported to: 
 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
Janssen Drug Safety: Janssen Secure Email (IIS-BIO-VIRO-GCO@its.jnj.com) or by fax if 
email is unavailable (866-651-0219). 
 
 
9.   Statistical Methods and Data Analysis 
 


 
41 
 
9.1 Definition of Study Endpoints 
To meet the objectives for this study, data for the following endpoints will be collected: 
 Safety and Tolerability (Phase I) 
 Disease control rate (CR + PR+ SD)   at 4 months (Phase II) 
 Tumor response by RECIST 1.1 and irRC (Secondary) 
 Exploratory biomarkers, including genetic sequencing and cytokine multiples assay 
(Exploratory) 
9.2 Determination of sample size 
The primary objective of the phase I portion of this study is to investigate the safety and 
tolerability and thereby identify the recommended dose of ibrutinib in combination with 
pembrolizumab for evaluation in future clinical studies. Hence the number of subjects has been 
based on the desire to obtain adequate tolerability, safety and pharmacodynamic data while 
exposing as few subjects as possible to the investigational product and procedures.  
For the dose escalation phase of the study, cohorts of 3-6 evaluable subjects (who have either 
failed to respond or relapsed following standard treatment, were unable to tolerate, or were not 
eligible for standard treatment) will be required. The total number of subjects will depend upon 
the number of dose escalations necessary.  
For the phase II portion of the study, 32 patients will be accrued. The primary endpoint of this 
portion is disease response (CR+ PR+ SD) at 4 months.  
Patients will be accrued to the protocol according to a two-stage Minimax 
design. 28 Based on patient disease control at 4 months (CR + PR + SD), we will either conclude 
that the therapy is effective or ineffective.  The two-stage design has the smallest maximum 
sample size with the following two properties: 
 
(1) if the true disease control rate is less than or equal to 5%, we will conclude that the therapy is 
ineffective with probability of  at least 0.90 (alpha = 0.10), and 
(2) if the true disease control rate is at least 20%, we will conclude that the therapy is effective 
with probability at least 0.90 (beta = 0.10). 
 
At least 1 of 18 patients must have disease control at 4 months in the first stage to proceed to the 
second stage.  If the protocol proceeds to the second stage, at least 4 of 32 patients overall must 
have disease control at 4 months for the therapy to be considered effective.Six patients treated at 
the MTD will be counted for disease control in the phase II portion of the study if the treatment 
plan or the eligibility criteria does not change.  
 
9.3 Analysis Sets 
All subjects who receive at least one dose of the study medication will be included in the safety 
evaluation.  
All subjects who undergo at least one staging reassessment will be used for efficacy evaluations.  


 
42 
 
9.4 Statistical and analytical plans  
9.4.1 Demographic and other baseline characteristics  
Demographics and baseline characteristics will be summarized by cohort and by treatment. 
Quantitative data will be summarized by descriptive statistics. Frequency tables will be provided 
for qualitative data.  
9.4.2 Adverse Events 
Individual listings of AEs will be provided. The incidence of treatment-emergent AEs and drug-
related AEs, respectively, will be summarized by cohort by treatment by worst NCI CTC grade. 
9.5 Calculation or derivation of safety variables 
Safety and tolerability will be assessed in terms of AEs, laboratory data, and vital signs. These 
will be collected for all subjects. Appropriate summaries of these data will be presented as 
described in Section 9.8. All subjects who received at least 1 dose of pembrolizumab or ibrutinib 
will be eligible. 
9.6 Calculation or derivation of tumor response variables  
At each visit subjects will be programmatically assigned a RECIST and irRC visit response of 
CR, PR, SD or PD depending on the status of their disease compared to baseline and previous 
assessments. See Appendix B. 
9.7 Methods of Statistical Analysis 
The statistical analyses will be performed by the Biostatistics Group at Moffitt Cancer Center. 
Data from the dose escalation phase (phase I ) and the dose expansion phase (phase II) ) will be 
presented separately.  
 
Demographic data  
Characteristics of the subjects, including medical history and disease characteristics at baseline 
will be listed for each subject and summarized by dose group and expansion phase arm. A 
medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. 
 
Reasons for discontinuation of investigational product will be listed including the study day of 
treatment discontinuation and will be summarized by dose group and expansion phase arm. 
 
Exposure  
Exposure to investigational product (i.e., total amount of study drug received) will be listed for 
all subjects.  
 
Total exposure and total time on study (date of last dose minus date of first dose) will be 
summarized with descriptive statistics. In addition, the number and percentage of subjects with at 
least one dose interruption/dose delay and at least one dose reduction will be presented 
separately for the initial period of evaluability defined as 28 days and for any time following this 


 
43 
 
initial period of the study.  
 
Safety  
Safety data will not be formally analyzed. All subjects who receive at least one dose of ibrutinib 
or pembrolizumab will be included in the assessment of the safety profile (safety analysis set). At 
the end of the study, appropriate summaries of all safety data will be produced, as defined below.  
 
Data from all cycles of initial treatment will be combined in the presentation of safety data. AEs 
will be listed individually by subject and dose group/expansion phase arm. For subjects who 
have a dose modification, all AEs (due to drug or otherwise) will be assigned to the initial dose 
group. The number of subjects experiencing each AE will be summarized by the Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class, MedDRA preferred term 
and CTCAE grade. The number and percentage of subjects with adverse events in different 
categories (e.g., causally related, CTCAE grade ≥3 etc.) will be summarized by dose 
group/expansion phase arm, and events in each category will be further summarized by 
MedDRA system organ class and preferred term, by dose group. SAEs will be summarized 
separately if a sufficient number occur.  
 
Any AE occurring before the first dose of investigational product (i.e., before study Day 1) will 
be included in the data listings but will not be included in the summary tables of adverse events.  
 
Any AE occurring within the defined 30 day follow-up period after discontinuation of 
investigational product will be included in the AE summaries. AEs occurring after the 90 day 
follow-up period after discontinuation of investigational product will be listed separately, but not 
included in the summaries. Hematology, clinical chemistry, vital signs, ECG data, urinalysis, 
demographic data, medical histories and concomitant medications will be listed individually by 
subject and suitably summarized. For all laboratory variables, which are included in the current 
version of CTCAE, the CTCAE grade will be calculated. Summary statistics of mean, median, 
standard deviation, minimum, maximum and number of observations will be used. Details of any 
deaths will be listed for all subjects. Any qualitative assessments will be summarized for all 
subjects using the number of subjects with results of negative, trace or positive. Graphical 
presentations of safety data will be presented as is deemed appropriate. This may include, but is 
not restricted to, presentation of parameters against time, concentration or shift plots. 
Appropriate scatter plots will also be considered to investigate trends in parameters compared to 
baseline. 
 
 
Tumor response  
Tumor response data will be summarized for dosed subjects with measurable disease at baseline.  
 
Objective response rate, disease control rate and PFS will be summarized in the expansion phase 
arm.  
 
Tumor response will be analyzed using RECIST 1.1 criteria (Appendix B) and the immune 
response criteria.
29 Confirmation of immune response will be done at the discretion of the 
investigator. 


 
44 
 
 
In this classification, the overall response is determined as follows:  
 
 Immune response CR (irCR) is a complete disappearance of all lesions (whether 
measurable or not, and no new lesions) with confirmation by a repeat, consecutive 
assessment no less than 4 weeks from the first documentation.  
 Immune response PR (irPR) is a decrease in tumor burden of greater than or equal to 50% 
relative to baseline. This must be confirmed by a consecutive assessment at least 4 weeks 
after the first documentation. 
 Immune response SD (irSD) is classified as those who do not meet criteria for irCR or 
irPR and who do not have irPD  
 Immune response PD (irPD) is an increase in tumor burden of greater than or equal to 
25%relative to  the minimum recorded tumor burden which must be confirmed by a 
repeat, consecutive assessment no less than 4 weeks from the first documentation. 
10. Data Recording 
10.1 Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of 
the study and will be given the opportunity to review the consent form. Each consent form must 
include all the relevant elements currently required by the FDA Regulations and local or state 
regulations.  Once this essential information has been provided to the patient and the investigator 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing an IRB-approved consent 
form. 
 
10.2 Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being 
of the study patient requires alternative treatment, the study shall be conducted exactly as 
described in the approved protocol. 
10.3 Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB correspondence and approval, signed 


 
45 
 
patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator. In all other cases, 
study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.4 Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients.  The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 
11.   Ethical and Legal Aspects 
11.1 Ethical and Legal Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the investigator abide by Good Clinical Practice (GCP) 
guidelines and under the guiding principles detailed in the Declaration of Helsinki. The study 
will also be carried out in keeping with applicable local law(s) and regulation(s). 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study 
conduct; the investigator may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by the investigator without 
discussion and agreement by Janssen Scientific Affairs, LLC. However, the investigator may 
implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to 
the trial subjects without prior IEC/IRB/Janssen approval/favorable opinion. As soon as possible, 
the implemented deviation or change, the reasons for it and, if appropriate, the proposed protocol 
amendment should be submitted to the IEC/IRB/head of medical institution. Any deviations 
from the protocol must be explained and documented by the investigator. 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki.  
The Principal Investigator is responsible for personally overseeing the treatment of all study 
patients. The Principal Investigator must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and properly documented. 


 
46 
 
11.2 Subject Information and Consent 
Each subject/legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without 
any disadvantage and without having to provide reasons for this decision. 
Only if the subject/legal representative or proxy consenter voluntarily agrees to sign the 
informed consent form and has done so, may he/she enter the study. Additionally, the 
investigator and other information provider (if any) will personally sign and date the form. The 
subject/legal representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject’s clinical record must clearly show that informed consent 
was obtained prior to these procedures. 
1. If the patient is not capable of providing a signature, a verbal statement of consent can also be 
given in the presence of an impartial witness (independent of Janssen/Merck, and the 
investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness. 
2. For adults under legal protection, consent shall be given by the legal guardian(s). The consent 
of an adult under legal protection shall also be requested where such a person is able to 
express his/her own will. His/her refusal or the withdrawal of his/her consent may not be 
disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of the 
patient’s legal representative(s) or proxy consenter, if present, should be requested.  The 
patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form and any other written information provided to subjects/legal 
representatives or proxy consenters will be revised whenever important new information 
becomes available that may be relevant to the subject’s consent, or there is an amendment to the 
protocol that necessitates a change to the content of the subject information and/or the written 
informed consent form. The investigator will inform the subject/legal representative or proxy 
consenter of changes in a timely manner and will ask the subject to confirm his/her participation 
in the study by signing the revised informed consent form. Any revised written informed consent 
form and written information must receive the IEC/IRB`s approval/favorable opinion in advance 
of use. 
11.3 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 


 
47 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
12.4 Flow cytometry 
The isolated peripheral blood mononuclear cells before, during and after treatment will be 
analyzed to measure the frequency of effector T cells and regulatory T cells (Treg)s using flow 
cytometry. Eight color flow cytometry analysis will be performed on the isolated mononuclear 
cells using the following antibodies: florescence conjugated anti-CD3, anti-CD4, anti-CD8, anti-
CD25, anti-CD127, anti-Foxp3, anti-granzyme B and anti-perforin (BD Bioscience or 
eBioscience). For extracellular staining, cells will be incubated for 30 minutes at 4°C with 
optimal dilution of each antibody. Intracellular staining for Foxp3, granzyme B and perforin will 
be preceded by fixation and permeabilization with intracellular staining kit (eBioscience). Flow 
cytometry will be performed on a FACS LSRFortessa (BD) and analyzed using CellQuest 
software (BD). The results of flowcytometry pre and post treatment will be correlated with the 
clinical efficacy to identify possible mechanisms of tumor response 
 
 
 


 
49 
 
 
 


 
50 
 
13. Appendix 
APPENDIX A: CYP3A Inhibitors 
Inhibitors of CYP3A are defined as follows. A comprehensive list of inhibitors can be 
found at the following website: http://medicine.iupui.edu/clinpharm/ddis/table.aspx. The 
general categorization into strong, moderate, and weak inhibitors according to the website 
is 
displayed below. Refer to Section 5.2 
on instructions for concomitant use of CYP3A 
inhibitors and inducers with ibrutinib. 
 
 
 
  
 
 


 
51 
 
APPENDIX B: RECIST Criteria for Measuring Tumor Response Antitumor Effect 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer et al., 2009). Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with ibrutinib or pembrolizumab. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥10 mm with CT scan, MRI or 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might be considered 
measurable if the lesion has increased in size since the radiation. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the 
case that, on occasion, the largest lesion does not lend itself to reproducible measurement in 


 
52 
 
which circumstance the next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow- 
up. 
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
 


 
53 
 
Response Criteria Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.) 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s). 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Principal Investigator. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient
's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 


 
54 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
Progression-Free Survival (PFS) 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first 
14. Appendix C: Janssen Safety Language 
 
As the sponsor of the Study, Moffitt Cancer Center shall be solely responsible for complying, 
within the required timelines, any safety reporting obligation to competent Health Authorities, 
IRB/ECs and any participating (co or sub) investigators, as defined in applicable laws and 
regulations.  Safety data includes adverse events, product quality complaints (PQCs), and special 
situations including pregnancies. 
 
Moffitt Cancer Center will provide safety information to Janssen Scientific Affairs, LLC on 
adverse events, special situations including pregnancies and product quality complaints as 


 
55 
 
defined below: 
 
1. Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events 
regardless of causality and special situations excluding those from subjects not exposed to a 
Janssen Medicinal Product and product quality complaints with or without an adverse event 
as described in this section will be reported from the time a subject has signed and dated an 
Informed Consent Form (ICF) until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety).  Serious adverse events will be reported 
for 30 days after the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: Ibrutinib (Imbruvica)  
  
2. Definitions 
2.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered 
a medicinal (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonisation [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
 
2.2. Adverse Events of Special Interest  
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. 
 


 
56 
 
 
2.3. 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 
 
2.4. Product Quality Complaint (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 
 Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, 
needle detaching from syringe 
 Suspected Contamination 
 Suspected Counterfeit 
 
2.5. Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
 
 Results in death 
 Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 


 
57 
 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 Is a congenital anomaly/birth defect 
 Is a suspected transmission of any infectious agent via a medicinal product 
 Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that 
may not be immediately life threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
2.5.1. Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during 
the study must be reported as a serious adverse event, except hospitalizations for the 
following: 
 Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
 Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 
considered serious adverse events. Any adverse event that results in a 
prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event.] 
 
 
2.5.2. Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious adverse event 
term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition. 
 
3. Unlisted (Unexpected) Adverse Event/Reference Safety Information 
 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For a medicinal product(s) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the applicable product information. 
  


 
58 
 
http://www.imbruvica.com/hcp/?utm_source=google&utm_medium=cpc&utm_campaign=Imbr
uvica&utm_term=imbruvica&utm_content=ibrutinib-
+Exact|mkwid|ssjPpM0Gh_dc|pcrid|39412243694 
 
 
4. 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. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded 
on a Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs, 
LLC within 24 hours of becoming aware of the event. 
 
 
Pregnancy  
 
 
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC within 24 
hours of their knowledge of the event using the Serious Adverse Event Form. Abnormal 
pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomaly, 
ectopic pregnancy) are considered serious adverse events and must be reported using the Serious 
Adverse Event Form.  
 
Any subject who becomes pregnant during the study must promptly discontinue further study 
treatment. 
 
 
 
 Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in 


 
59 
 
partners of male subjects exposed to a Janssen medicinal product will be reported 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. 
 
5. Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. Moffitt 
Cancer Center shall provide all adverse events, both serious and non-serious, in report 
format. However, in certain circumstances more frequent provision of safety data may be 
necessary, e.g. to fulfill a regulatory request, and as such the data shall be made available 
within a reasonable timeframe at Janssen Scientific Affairs, LLC request. 
 
6. Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to the COMPANY 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a Janssen medicinal product are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to a Janssen 
medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product should 
be followed-up in accordance with clinical practice. 
 
6.1. SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject
's participation in the study, must be followed 
until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
Moffitt Cancer Center will transmit all SAEs and special situations following exposure to 
a Janssen product under study in a form provided by Janssen Scientific Affairs, LLC in 
accordance with Section 10 ,Transmission Methods, in English within 24-hours of 
becoming aware of the event(s). 
 
All follow-up information for serious adverse events that are not resolved at the end of 
the study or by the time of patient withdrawal must be reported within 24 hours 
becoming aware, to Janssen Scientific Affairs, LLC using the Janssen Scientific Affairs, 


 
60 
 
LLC Serious Adverse Event Report  
 
All available clinical information relevant to the evaluation of a related SAE or special 
situation is required. 
 
 The principal investigator is responsible for ensuring that these cases are complete 
and if not are promptly followed-up. A safety report is not considered complete until 
all clinical details needed to interpret the case are received. Reporting of follow-up 
information should follow the same timeline as initial reports. 
 
 Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association 
with the Janssen Product under study, are to be provided to Janssen Scientific Affairs, 
LLC using a transmission method in Section 10 within 24 hours of such report or 
correspondence being sent to applicable health authorities. 
 
6.2. Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC 
according to the timeframe outlined in the Research Funding Agreement section entitled 
Reporting of Data. 
 
6.3. PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, 
and complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, LLC, and are 
mandated by regulatory agencies worldwide. Janssen Scientific Affairs, LLC has 
established procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be collected or any 
reports failure of expected pharmacological action (i.e., lack of effect). The product 
should be quarantined immediately and if possible, take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be reported to 
Janssen Scientific Affairs, LLC by Moffitt Cancer Center within 24 hours after being 
made aware of the event. The Janssen contact will provide additional information/form 
to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a 
serious adverse event or non-serious adverse event, Moffitt Cancer Center must report the 
PQC to Janssen Scientific Affairs, LLC according to the serious adverse event reporting 
timelines.  A sample of the suspected product should be maintained for further 
investigation if requested by Janssen Scientific Affairs, LLC. 
 
 
 
7. Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products  


 
61 
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, Moffitt Cancer Center should notify the appropriate 
regulatory/competent authority or the manufacturer of that medicinal product (in the absence 
of appropriate local legislation) as soon as possible. 
 
8. Transmission Methods 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs, LLC: 
 Electronically via Janssen SECURE Email service (preferred) 
 For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
 Telephone (if fax is non-functional). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
62 
 
15. References 
 
1.  
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