Clinical trial NCT02313272
Conditions: Malignant Glioma
Keywords: neoplasms high-grade glioma recurrent glioma glioma Hypofractionated Stereotactic Irradiation (HFSRT) Bevacizumab Pembrolizumab recurrent high-grade glioma Grade III malignant glioma Grade IV malignant glioma brain and nervous system
Sponsor: H. Lee Moffitt Cancer Center and Research Institute
Start date: 2015-07-28; Completion date: 2021-08-09
Enrollment: 32 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see if the addition of the investigation drug called pembrolizumab (Keytruda®) to radiation therapy and bevacizumab (Avastin®) is safe and can help with controlling the growth of tumors, in participants with recurrent high grade glioma.

Detailed description:

Arms: arm 1: Hypofractionated Stereotactic Irradiation (HFSRT). Pembrolizumab intravenous (IV) infusion every 3 weeks. Bevacizumab administered intravenously every 2 weeks.
Interventions: intervention 1: Hypofractionated Stereotactic Irradiation (HFSRT) intervention 2: Pembrolizumab intervention 3: Bevacizumab
Intervention descriptions: intervention 1: Radiation therapy treatment (FSRT) which will be given to participants over 5 days. intervention 2: Dose Escalation: The dose of pembrolizumab will be escalated per schema in a 3+3 fashion. The starting dose (i.e., dose level 1) will be 100 mg.

Dose Expansion: The pembrolizumab dose used in the dose expansion cohort will be maximum tolerated dose (MTD) determined from the dose escalation phase. intervention 3: Initial cycle of bevacizumab must start within 10 days of registering to the trial. It will be given concurrent with radiation therapy. Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks. Doses will be adjusted if there is a \> 10% change in weight.

Protocol documents:
Prot_SAP_000.pdf: 
A Phase I Trial of Hypofractionated Stereotactic Irradiation (HFSRT) with MK-
3475 and Bevacizumab in Patients with Recurrent High Grade Gliomas 
NCT02313272 
Version 7.0 
December 6, 2015 


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SPONSOR: Moffitt Cancer Center 
 
TITLE: A Phase I Trial of Hypofractionated Stereotactic Irradiation (HFSRT) with  
              Pembrolizumab and Bevacizumab in Patients with Recurrent High Grade Gliomas. 
 
IND NUMBER: 124861 
 
EudraCT NUMBER: 
 
PRINCIPAL INVESTIGATOR: Solmaz Sahebjam MD 
                                                         Department of Neuro-Oncology, Moffitt Cancer Center 
 
 
 
 
         12902 Magnolia Drive 
 
 
 
 
         Tampa, FL 33612 
 
 
 
 
         Telephone: 1-813-481-8523 
 
 
 
 
         Fax: 1-813-745-3068 
 
 
 
 
         Email: Solmaz.Sahebjam@Moffitt.org  
 
 
CO-INVESTIGATORS: John A. Arrington MD 
                                           Heiko Enderling  PhD                                            
                                           Peter Forsyth MD 
                                           Peter A. Johnston MD                                            
                                           Sungjune Kim MD, PhD 
                                           Anthony M. Neuger MS 
                                           Natarajan Raghunand, PhD 
                                           Nam D. Tran MD, PhD       
                                           H. Michael Yu MD 
 
                                
                                            
 
 
Statistician:  
 
Dung-Tsa Chen, PhD 
 
Original Protocol: 
 
Version 7.0, Dec 6, 2015 
 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase I trial of HFSRT with pembrolizumab and bevacizumab for 
recurrent high grade gliomas 
Trial Phase 
Ib 
Clinical Indication 
Recurrent high grade gliomas  
Trial Type 
Open label 
Route of administration 
Intravenous 
Trial Blinding 
Not applicable 
Treatment Groups  
1 Group 
Number of trial subjects 
32 
Estimated duration of trial 
36 months 
Duration of Participation 
24 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a standard 3+3 design and will include 2 cohorts: 1) dose escalation cohort, and 2) 
dose expansion cohort. 
2.2 
Trial Diagram 
 
 
 
 
                                                     Dose Escalation Phase 
                                              Dose Escalation Schedule 
Dose Level 
Dose 
Pembrolizumab 
IV 
every       3 weeks 
Bevacizumab IV every 
2 weeks 
Level 1 
100 mg 
10 mg/kg 
Level 2 
200 mg 
10 mg/kg 
 
 
 
                                                   Dose Expansion Phase 
 
 
 
Two groups of patients (bevacizumab naïve and bevacizumab failure) 
will be treated with pembrolizumab at MTD 
 (from dose escalation phase) and bevacizumab concurrent and after 
HFSRT 
 
Patients with recurrent 
high grade glioma 
Bevacizumab 10 mg/kg and 
Pembrolizumab concurrent 
with HFSRT (6 Gy x 5) on 
day 1 
Bevacizumab 10 mg/kg IV            
every 2 weeks and Pembrolizumab IV   
every 3 weeks  


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3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To evaluate the safety, tolerability, and to determine the maximum 
tolerated dose (MTD) of pembrolizumab given in combination with bevacizumab and 
hypofractionated stereotactic re-irradiation of recurrent high grade gliomas. 
Hypothesis:  Intravenous administration of pembrolizumab in combination with 
bevacizumab and hypofractionated stereotactic re-irradiation will have acceptable safety 
and tolerability. 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To evaluate the response rate of pembrolizumab given in combination with 
bevacizumab and hypofractionated stereotactic re-irradiation of recurrent high grade 
gliomas. 
Hypothesis:  Addition of pembrolizumab to bevacizumab and hypofractionated 
stereotactic re-irradiation will augment the response to treatment. 
3.3 
Exploratory Objective 
(1) Objective: To explore tissue and blood biomarkers that may predict tumor 
response to pembrolizumab in combination with bevacizumab and 
hypofractionated stereotactic re-irradiation in patients with recurrent high 
grade gliomas. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 


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8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [15; 16].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17].  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [18; 19; 20; 13].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) 
[21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale and Biomarker Research 
4.2.1 Rationale for the Trial and Selected Subject Population 
High grade gliomas remain one of the most fatal tumors with a median survival of about 15 
months for glioblastoma (GBM), despite aggressive combination therapy.  


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Malignant gliomas are highly vascular and characterized by overexpression of VEGF-A 
which plays a key role in tumor-associated angiogenesis [22]. Bevacizumab, an anti-VEGF-
A molecule, has shown clinical benefit in patients with recurrent GBM for which no effective 
treatment existed [23; 24]. However, the response to bevacizumab usually is short-lived and 
the overall survival for patients with recurrent GBM treated with bevacizumab monotherapy 
is about 9 months [23]. Thus, recurrent high grade gliomas remain a largely unmet medical 
need requiring novel and effective treatment strategies. 
Pre-clinical studies have shown significant increase in expression of PD-1 on peripheral 
blood CD4+ and CD8+ T cells in patients with high grade gliomas. In a study by Wei et al., 
PD-1+CD4+ T cells were clearly increased in peripheral blood of patients with anaplastic 
astrocytoma (12.3±0.9 %) and GBM (16.3±0.6 %) [25]. 
Rational for combining bevacizumab with pembrolizumab 
A growing body of evidence indicates that abnormal tumor vasculature, partly caused by 
proangiogenic 
factors 
such 
as 
VEGF, 
creates 
an 
immunosuppressive 
tumor 
microenvironment by increasing immunosuppressive cells (tumor associated macrophages 
and regulatory T cells) and decreasing antitumor lymphocytes [26; 27]. Furthermore, 
circulating VEGF exerts a systemic influence on the host immune system by affecting 
proliferation, differentiation, and function of immune cells [27]. Elevated levels of VEGF 
have been associated with inhibition of T-cell immune response by suppressing the 
maturation of Dendritic cell precursors and by enhancing the proliferation and peripheral 
blood proportion of regulatory T cells (Tregs) [28]. 
The benefit of combined anti-VEGF agents with immunotherapy has been studied in several 
cancer models including breast carcinoma, colon carcinoma, melanoma, and sarcoma [29; 
30; 31; 32; 33]. In these models, combination therapy has resulted in increased tumoral 
infiltration of CD4+ and CD8+ T cells, decreased Tregs, significant decrease in negative co-
stimulatory molecules PD-1 and CTLA4, and increased tumor growth delay.  
Rational for combining re-irradiation therapy with bevacizumab and pembrolizumab 
Concomitant administration of bevacizumab with hypofractionated stereotactic radiotherapy 
(HFSRT) in previously irradiated gliomas has shown promising anti-tumor activity in both 
preclinical and clinical studies [34]. VEGF has been shown to abrogate the killing of 
endothelial cells by radiation, whereas blockade of VEGF sensitizes the tumor endothelium 
to radiation and leads to a synergistic effect [35]. Safety and efficacy of this treatment 
strategy has been investigated in a prospective study carried out by Gutin et al. where 25 
patients with recurrent high grade gliomas were treated with HFSRT (30 Gy; 6 Gy delivered 
in 5 fractions) combined with bevacizumab (10 mg/kg) every 2 weeks of 28-day cycles. The 
combination therapy was safe and well tolerated without any cases of radiation necrosis. The 
reported clinical outcome was more favorable than other trials using bevacizumab in 
recurrent high grade gliomas. For the GBM cohort, overall response rate was 50% with 
median survival of 12.5 months and 1 year survival of 54%. Five out of 25 patients enrolled 


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in this study achieved complete response. Partial response was observed in 8 out of 25 
patients [34].   
Moreover, there is emerging evidence that hypofractionated radiotherapy acts synergistically 
with immunotherapy to enhance the immune response against tumor cells. Several preclinical 
studies have shown that radiotherapy synergizes with CTLA-4 and anti-PD 1/PD-L1 
blockade and produces tumor regression and long-term survival in a variety of cancer models 
[36; 37; 38; 39; 40]. In a study by Zeng et al., combination of anti-PD-1 antibody with 
stereotactic radiosurgery (10 Gy) in a mouse orthotopic GBM model generated robust and 
durable responses and doubled the survival when compared with either modality alone [40]. 
In this study, analysis of the brain and spinal cord of animals treated with combination 
therapy showed an increase in the cytotoxic to regulatory T cell ratio with increased tumor 
infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) [40].  
The optimum human dose of radiation therapy in combination with immunotherapy is not 
known. However pre-clinical experiments have demonstrated the highest tumor-specific T 
cell response, lowest regulatory T cells and best tumor control with the use of a higher dose 
per fraction [41; 42]. For example, Schaue et al. investigated the optimal radiotherapy dose-
fractionation that maximizes anti-tumor immunity in a murine melanoma model. They 
compared the following single fraction doses: 5 Gy; 7.5 Gy; 10 Gy; and 15 Gy. 
Radiotherapy-induced tumor growth delay after 7.5 Gy and 10 Gy were associated with an 
increase in tumor-specific T cell response and a decrease in the proportion of regulatory T 
cells (Tregs) in the spleen [42]. A single fraction of 5 Gy had little effect on tumor growth, 
whereas a single fraction of 15 Gy increased both the tumor-specific T cell response and 
Tregs. They also compared fractionated treatment: 3 Gy x 5; 5 Gy x 3; 7.5 Gy x 2 and 15 Gy 
x 1. Two fractions of 7.5 Gy resulted in the best tumor control, highest tumor-specific T cell 
response and lowest Tregs. Schaue et al. concluded that fractionated treatment with medium-
size radiotherapy doses of 7.5 Gy per fraction gave the best tumor control and anti-tumor 
immunity [42].  Dewan et al. examined 3 dose-fractionation regimens for their ability to 
synergize with CTLA-4 blockade using poorly immunogenic murine mammary and colon 
carcinoma: 20 Gy x 1; 8Gy x 3; and 6 Gy x 5.10 Anti-CTLA-4 Ab by itself or in combination 
with a single fraction of 20 Gy was ineffective. Fractionated treatment with 8 Gy x 3 was 
more effective than 6 Gy x 5 at synergizing with anti-CTLA-4 Ab: 80% versus 60% of the 
tumors outside the radiation field regressed completely, respectively [41].  
Collectively, these studies suggest that fractionated radiotherapy with medium-sized 
radiotherapy dose of 7.5 – 10 Gy per fraction is the optimal regimen for synergizing 
with immunotherapy. Therefore, although the entire tumor will be treated with the 6 Gy x 5 
hypofractionated regimen described above, a small volume within the tumor will be treated 
using a dose-painting technique to a dose of 8 Gy x 5 as a strategy to enhance immune 
response. 
In summary, there is strong pre-clinical evidence that combining PD-1/PDL-1 blockade with 
antiangiogenic agents and hypofractionated radiotherapy independently enhance anti-tumor 
immune responses and tumor regression. In addition, HFSRT with bevacizumab represents a 
standard approach in the treatment of recurrent high grade gliomas. An additional benefit of 


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including bevacizumab in this regimen is its ability to decrease peritumoral edema, thereby 
obviating the need of steroids in this patient population, which would negatively influence 
the activity of pembrolizumab.  Hence, it is of great interest to study the combination of all 
these three treatment modalities in high grade glioma patients with recurrent disease and with 
very limited treatment options. 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
The dose regimen of 200 mg Q3W of pembrolizumab is planned for solid tumor trials 
including current study. Available PK results in subjects with melanoma, NSCLC, and other 
solid tumor types support a lack of meaningful difference in PK exposures obtained at a 
given dose among tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is 
being conducted to evaluate the safety and clinical activity of single agent pembrolizumab.  
The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 
mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors.  All three 
dose levels were well tolerated and no dose-limiting toxicities were observed.  This first in 
human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  
No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.  For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 
26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set 
(FAS)).  The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types.  Population PK analysis has been performed and has 
confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab to a 
clinically meaningful extent.  Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being 
evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated 
in head and neck cancer in PN012, which are expected to provide additional data supporting 
the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.  A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using available 


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data from 476 subjects from PN001.   The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some 
tendency for individual values to range slightly higher with the 200 mg fixed dose.   The 
slight increase in PK variability predicted for the fixed dose relative to weight-based dosing 
is not expected to be clinically important given that the range of individual exposures is well 
contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to 
provide similar efficacy and safety.  The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different tumor types and indication settings. However, due to lack of 
information on combination therapy with radiation and bevacizumab, starting dose of 
pembrolizumab for this study will be 100 mg Q3W. 
 
 
4.2.3 Biomarker Research 
• 
Archival tissue (mandatory for dose expansion cohort) will be assessed by 
immunohistochemistry (IHC) or immunofluorescence (IFC) staining for the following 
biomarkers for direct evaluation of the intratumoral immune compartment. If biopsy or 
surgical tumor specimens become available following stereotactic radiation therapy and 
pembrolizumab treatment, these tissues will be included in the analysis. First, PD-L1 
expression by the tumor will be evaluated utilizing anti-PD-L1 antibody developed by 
Merck. Second, tumor infiltrating lymphocytes (TILs) will be identified and their PD1 
expression level will be assessed by IFC. Third, intratumoral recruitment of the tolerogenic 
immune cells, Tregs and MDSCs, will be assessed.  
• 
Phenotypic characterization of peripheral blood immune cell compartments including 
dendritic cells (DCs), myeloid derived suppressor cells (MDSCs), regulatory T lymphocytes 
(Tregs), CD4 and CD8 T lymphocytes will be also performed via flow cytometry prior to and 
after HFSRT + bevacizumab and pembrolizumab administration. The expression levels of 
CD86 expression on DCs or CD3z and PD1 expression on T lymphocytes will be analyzed to 
evaluate the overall immune activation/exhaustion status. These tests will be performed only 
in dose expansion cohort. 
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Recurrent WHO Grade III (except anaplastic oligodendroglioma) or grade IV 
gliomas. 


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5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the below criteria must be met: 
1. Histologically confirmed diagnosis of World Health Organization Grade III (except 
anaplastic oligodendroglioma) or IV malignant glioma. 
2. Documented recurrence by diagnostic biopsy or contrast enhanced magnetic 
resonance imaging (MRI) performed within 28 days of entry in to the trial as per 
RANO criteria.  
3. Patients with recurrent WHO Grade III gliomas should have received one prior 
treatment for recurrent high grade disease. 
4.  Maximum diameter of enhancing tumor (target lesion) should be ≤ 3.5 cm.  
5. An interval of at least 6 months after the end of prior radiation therapy is required 
unless there is a new recurrence outside of the previous radiotherapy treatment field. 
6. Previous first line treatment with at least standard dose of radiotherapy (total dose ≥ 
54 Gy) and temozolomide 
7.  An interval of ≥ 4 weeks since surgical resection prior to entry in to the trial 
8. An interval of ≥ 4 weeks after the last administration of any investigational agent or 
prior cytotoxic therapy (except bevacizumab). There should be 14 days interval 
between the last dose of bevacizumab and first day of treatment on study. 
9. Be  18 years of age on day of signing informed consent. 
10. Karnofsky performance status of 70 or higher 
11. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 14 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Urine protein/ creatinine (UPC) ratio 
 
< 1.0 within 14 days prior to registration  


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If the UPC ratio is ≥ 1.0 then the patients should undergo a 24-
hour urine collection and must demonstrate ≤ 1g of protein in 24 
hours to be eligible).  
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   
 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
12. Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest. 
13. Patients must have recovered from the toxic effects of prior therapies. 
14. Be willing and able to provide written informed consent/assent for the trial. 
15. Life expectancy ≥ 12 weeks 
16. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
17. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
18. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has more than three recurrences of high grade glioma. 
2. Has anaplastic oligodendroglioma. 
3. Has received reradiation to recurrent disease (other than standard frontline adjuvant 
radiation therapy). 


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4. Recurrent tumors near the brainstem and optic chiasm must not have received prior 
radiation therapy. 
5. Has infratentorial, or leptomeningeal evidence of recurrent disease. 
6. Has recurrent or persistent tumor (enhancing area) greater than 3.5 cm in maximum 
diameter. 
7. Has prior treatment with Gliadel unless it was administered as first line treatment and 
at least 3 months prior to study treatment. 
8. Is unable (due to existent medical condition) or unwilling to have a contrast enhanced 
MRI of brain. 
9. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment. 
10. Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment. Physiologic doses of 
steroid therapy (≤ 10 mg/day prednisone equivalents) is allowed.  
11. Has had a prior chemotherapy, targeted small molecule therapy, or monoclonal 
antibody (except bevacizumab) within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. Wash out period for bevacizumab is 14 days. 
12. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
13. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects 
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
14. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
15. Has an active infection requiring systemic therapy. 
16. Has prior allergic reaction to Bevacizumab. 
17. Has prior history of uncontrolled hypertension, hypertensive crisis or hypertensive 
encephalopathy. 


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18. Has history of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) 
prior to entry in to the trial. 
19. Has history of gastrointestinal bleeding or any other hemorrhage/bleeding event ≥ 
grade 3 (CTCAE, v. 4) within 30 days prior to entry in to the trial. 
20. Had major surgical procedure, open biopsy, or significant traumatic injury within 28 
days prior to day 1 of treatment on study. 
21. Requires escalating or chronic supraphysiologic doses of corticosteroids (> 10 
mg/day prednisone equivalents). 
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
24. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
27. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
28. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
5.2 
Radiation therapy 
5.2.1 Dose Specifications 
Treatment will be performed using a dose-painting technique.  The planning treatment 
volume (PTV), which is defined as the contrast enhancing lesion (or post-operative cavity if 
no residual disease is present) or gross tumor volume (GTV) + a 5 mm expansion, will be 
treated to a peripheral dose of 6 Gy/fraction x 5 fractions.  If residual disease is present, a 
small volume within the GTV (≤0.5 cc), termed boost tumor volume (BTV), will be treated 
to 8 Gy/fraction x 5 fractions as a strategy to enhance immune response.  


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5.2.2 Critical Structures 
Normal Structures to be contoured will include the brainstem, optic nerves, and chiasm.  
Normal tissue maximal dose limits are 25 Gy (0.03 cc).   
5.2.3 Localization, Simulation, and Immobilization 
MRI of ≤1.5mm slices will be obtained within 1 week of a treatment planning CT (≤3mm 
slices). MRI will be fused with the treatment planning CT. At the time of the treatment 
planning CT, a rigid immobilization device will be created.   Image guided localization will 
be performed daily prior to treatment.  Reduction in the PTV may be made at the discretion 
of the treating physician if the volume is adjacent to normal critical structures. 
5.2.4 Radiation Therapy Adverse Events 
5.2.4.1 Acute 
Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or 
soreness of the scalp. Potential acute toxicities include nausea and vomiting as well as 
temporary aggravation of brain tumor symptoms such as headaches, seizures, and weakness. 
Reactions in the ear canals and on the ear should be observed and treated symptomatically; 
these reactions could result in short-term hearing impairment. Dry mouth or altered taste 
have been occasionally reported. 
5.2.4.2 Early Delayed 
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1-3 months after radiotherapy treatment. 
5.2.4.3  Late Delayed 
Possible late delayed effects of radiotherapy include risk of radiation necrosis, and endocrine 
dysfunction. In addition, neurocognitive deficits, which could lead to mental slowing and 
behavioral change, are possible. Permanent hearing impairment and visual damage are rare. 
Cataracts can be encountered. 
 
5.3 
Trial Treatments 
Treatment must begin within 14 days of registering to the trial. Each cycle will consist of    6 
weeks.  
The drug treatment to be used in this trial is outlined below in Table 2. 


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Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
100 mg or 200 
mg based on 
dose level 
Every 3 
weeks 
IV infusion 
Until progression or 
up to 24 months, 
whichever occurs 
first 
Experimental 
Bevacizumab 
10 mg/kg 
Every 2 
weeks 
IV infusion 
Until progression 
 
Standard 
 
   Bevacizumab: 
Bevacizumab will be administered intravenously at a dose of 10 mg/kg every 2 weeks. Doses 
will be adjusted if there is a > 10% change in weight. 
Initial cycle of bevacizumab must start within 14 days of registering to the trial. It will be 
given concurrent with radiation therapy. Concurrent bevacizumab cycle may be given either 
on the day prior to start of radiation or on day 1 of radiation. Subsequent bevacizumab doses 
may be given every 14+/-3 days apart. In all patients, treatment with study drugs will 
continue until confirmed disease progression, patient refusal, patient lost to follow up, 
unacceptable toxicity, whichever occurs first, or the study is terminated by the Sponsor 
(Moffitt Cancer Center). 
   Pembrolizumab: 
Pembrolizumab will be administered intravenously. Initial cycle of pembrolizumab must start 
within 14 days of entry in to the trial. It will be given concurrent with radiation therapy. 
Concurrent pembrolizumab may be given either on the day prior to start of radiation or on 
day 1 of radiation. 
Dose Escalation Phase: 
 
 
The dose of pembrolizumab will be escalated per schema in a 3+3 fashion. The starting dose 
(i.e., dose level 1) will be 100 mg. Provided that maximal tolerated dose (MTD) has not been 
reached, pembrolizumab dose will be increased to 200 mg as below: 
                                              Dose Escalation Schedule 
Dose Level 
Dose 
Pembrolizumab IV every 3 weeks 
Bevacizumab IV every 2 weeks 
Level 1 
100 mg 
10 mg/kg 
Level 2 
200 mg 
10 mg/kg 


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Pembrolizumab will be given as 30-minute intravenous infusion every 3-week (+/-3 days). In 
all patients, treatment with study drugs will continue up to 24 months, until confirmed 
disease progression, patient refusal, patient lost to follow up, unacceptable toxicity, 
whichever occurs first, or the study is terminated by the Sponsor (Moffitt Cancer Center). 
Dose Expansion Phase: 
 
The pembrolizumab dose used in the dose expansion cohort will be MTD determined from 
the dose escalation phase.  
Definition of Maximum Tolerated Dose: 
 
The maximum tolerated dose (MTD) is the highest dose of pembrolizumab in combination 
with bevacizumab after radiation therapy that does not cause unacceptable toxicity in more 
than one of six patients at that dose level. The MTD is defined as one dose level below the 
highest toxic dose (i.e., the DLT dose). 
 
5.3.1 Definition of Dose-Limiting Toxicity 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE 
version 4.0. Dose limiting CNS and non-CNS toxicities will be defined differently and will 
be based on events that occur during the study period. In order to be declared as dose-
limiting toxicity, an adverse event must be related to study treatment. 
A dose-limiting toxicity (DLT) will be defined as any one of the following adverse events 
occurring within 6 weeks from last dose of radiation therapy: 
     CNS toxicities: 
      Acute CNS toxicities (occurring ≤ 30 days after completing radiation therapy):  
 Any grade 3 or higher central nervous adverse events including but not limited 
to headache, dizziness, vertigo, new onset seizures, cerebral edema, cerebral 
hemorrhage, and new onset neurologic deficit. 
      Delayed onset CNS toxicities (occurring >30 days after completing radiation therapy): 
 Any grade 3 or 4 adverse event arising within the irradiated volume including 
but not limited to radiation necrosis or focal neurological deficits. 
      Non-CNS toxicities:       
 Any grade 3 or higher non-hematologic adverse event with the exception of 
alopecia, and fatigue. 
  Grade ≥3 nausea, vomiting or diarrhea despite maximal medical therapy. 


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 Grade ≥ 3 hypertension despite maximal medical therapy. 
 Grade ≥3 laboratory value if: 1) Medical intervention is required to treat the 
patient, or 2) The abnormality leads to hospitalization 
 Dose escalation will be determined based on the occurrence of DLTs. For the purposes of 
determining whether to advance the dose levels, DLTs will be counted by patient. In the 
event of the development of any grade 3 or 4 toxicity felt to be at least possibly related to 
study treatment, both drugs will be held until resolution to grade 1 or baseline assuming that 
occurs within 6 weeks window. Treatment with pembrolizumab can be resumed after 
resolution of DLT to grade 1 or baseline except for following adverse events: ≥ Grade 3 
infusion reactions, ≥ Grade 3 pneumonitis, ≥ Grade 3 nephritis, ≥ Grade 3 colitis, increased  
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 5 times 
upper limit of normal or total bilirubin greater than 3 times upper limit of normal.   
 
 
Dose escalation will follow the standard 3+3 design. The enrollment to second dose level 
will be delayed for 6 weeks after the completion of radiation therapy by the last patient 
enrolled at the first dose level. This period of 6 weeks will allow monitoring potential 
delayed toxicities. Dose escalation will proceed according to the following scheme.   
 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
or 
≥ 2 grade 2 CNS toxicities 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the dose to be used in the expanded cohort and will 
be considered recommended phase 2 dose. At least 6 
patients must be entered at this dose. 
 


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5.3.2 Dose Selection/Modification 
5.3.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
 Details on the dose calculation, preparation and administration are provided in the Pharmacy 
Manual. 
5.3.2.2 Dose Modification  
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, Grade 2 
pneumonitis, Grade 2 colitis, Grade 2 hypophysitis, Grade 2 nephritis, increased alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times upper limit 
of normal and up to 5 times upper limit of normal or a total bilirubin greater than 1.5 and up 
to 3 times upper limit of normal, and other severe or life-threatening AEs as per Table 3 
below. 
Investigators should also refer to Section 5.6.1 and the “Pembrolizumab Event of Clinical 
Interest Guidance Document”, available as an appendix, for additional instructions and 
information regarding the management of pembrolizumab toxicities. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopenia 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
 Grade 2 alopecia 
 Grade 2 fatigue 
 
For 
additional 
information 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendations 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 


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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
regarding 
Adverse 
Events 
with a potential Immune-
Etiology 
reference 
Section 
5.6.1.1. 
regarding 
pneumonitis) 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Specific 
toxicities 
mentioned in 
the text. 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, 
pembrolizumab should be discontinued after consultation with principal investigator.  With 
investigator and Sponsor agreement, subjects with a laboratory adverse event still at Grade 2 
after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.  For 
information on the management of adverse events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from 
pembrolizumab. 
Pembrolizumab should permanently discontinued for any of the following adverse events: ≥ 
Grade 3 infusion reactions, ≥ Grade 3 pneumonitis, ≥ Grade 3 nephritis, ≥ Grade 3 colitis, 
inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 12 weeks, increased alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) greater than 5 times upper limit of normal or total bilirubin greater than 3 times upper 
limit of normal.   


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5.3.3 Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 
3 days before or after the scheduled day due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered every 3 weeks (+/- 3 days) starting on C1 Day 1. 
Bevacizumab will be administered every 2 weeks (+/- 3 days) starting on C1 D1. 
Pembrolizumab will be administered as a 30 minute IV infusion.  Every effort will be made 
to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration. 
Bevacizumab should be administered as a continuous intravenous infusion using a rate–
regulating device. The initial dose will be administered over a minimum of 90 (-5 min/+10 
min) minutes. If no adverse reactions occur, the second dose will be administered over a 
minimum of 60 (-5 min/+10 min) minutes. If no adverse reactions occur after the second 
dose, subsequent doses will be administered over a minimum of 30 (-5 min/+10 min) 
minutes. If infusion-related adverse reactions occur, all subsequent infusions should be 
administered over the shortest period that was well tolerated. 
5.3.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.4 
Treatment Allocation 
Dose level allocation will be performed by the Sponsor after patients have given their written 
informed consent and have completed the necessary baseline assessments. 
After review of patient’s eligibility and concomitant medications, the Sponsor (Moffitt 
Cancer Center) will approve patient’s enrollment, if appropriate, and assign a patient 
identification number, which will be used on all Case Report Form (CRF) pages and other 
trial-related documentation or correspondence referencing that patient. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 


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vaccination may be required.  The investigator should discuss any questions regarding this 
with principal investigator of study. Prophylactic use of hematopoietic growth factors is not 
permitted. The final decision on any other supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor (Moffitt Cancer Center), and the subject.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy other than bevacizumab 
 Immunotherapy other than pembrolizumab 
 Investigational agents other than pembrolizumab 
 Prophylactic hematopoietic growth factors 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
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. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines for Pembrolizumab Toxicities 
Investigator should consult Immune-Related Adverse Event Guidance (Appendix 12.2) for 
management of pembrolizumab toxicities. Subjects should receive appropriate supportive 
care measures as deemed necessary by the treating investigator including but not limited to 
the items outlined below: 
 Diarrhea: 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).  In 
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are 
persistent and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should 
be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started 
and continued over at least 1 month. Bevacizumab should be withheld until 
symptoms improve to grade 1 or less. 
o In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started.  If symptoms are 
persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  When symptoms improve 
to Grade 1 or less, corticosteroid taper should be started and continued over at 
least 1 month.  Regarding guidelines for continuing treatment with 
pembrolizumab see Section 5.3. 
o All subjects who experience diarrhea 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. 
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
 Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 


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 Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   
 Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or 
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting. 
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 4 Infusion Reaction (Pembrolizumab) Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of Pembrolizumab 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be 
suggestive of potential irAEs.  An irAE can occur shortly after the first dose or several 
months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of 
Clinical Interest and Immune-Related Adverse Event Guidance Document (Appendix 12.2) 
located in the Administrative Binder.  Subjects who develop a Grade 2 or higher irAE should 
be discussed immediately with principal investigator of the study.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 5. 
Table 5 General Approach to Handling irAEs 
 


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irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold Pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold Pembrolizumab 
Discontinue 
if 
unable 
to 
reduce corticosteroid dose to < 
10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab 
and have an evaluation.  The evaluation may include bronchoscopy and pulmonary function 
tests to rule out other causes such as infection.  If the subject is determined to have study 
drug associated pneumonitis, the suggested treatment plan is detailed in Table 6 and 
Appendix 12.2. 
Table 6 Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab, 
may return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue pembrolizumab 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
 Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis  Grade 2 
 


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5.6.2 Supportive Care Guidelines for Bevacizumab Toxicities 
Treatment should be interrupted or discontinued for certain adverse events, as described 
below. If bevacizumab is interrupted for > 8 weeks, the patient should discontinue 
bevacizumab therapy on protocol. 
Event 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Allergic reactions  
or  
Acute infusional 
reactions/ cytokine 
release syndrome  
 
Grade 1-2 
 
 
 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
 
 
 
 
Stop Infusion and monitor 
symptoms.  
Do not restarted on the same 
day. Bevacizumab may be 
permanently discontinued or re-
instituted with premedications. 
and administered no faster than 
60 minutes. If bevacizumab is 
re-instituted, it should not been 
administered faster than 60 
minutes and the patient should 
be closely monitored for a 
duration comparable to or longer 
than the duration of the previous 
reactions.  
 
Discontinue bevacizumab 
permanently. 
 
Subjects may be 
premedicated 
 
 
 
 
 
Subjects should  be 
premedicated 
Arterial Thrombosis 
  - Cardiac ischemia/    
     infraction 
  - CNS ischemia (TIA,    
     CVA) 
  - any peripheral or   
     visceral arterial    
    ischemia/thrombosis 
Grade 2 ( if new or 
worsened since 
bevacizumab therapy) 
 
Grade 3-4 
Discontinue bevacizumab 
permanently. 
 
 
Discontinue bevacizumab 
permanently. 
 
 
 
Venous Thrombosis  
 
Grade 3 OR 
asymptomatic Grade 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bevacizumab may be resumed 
during the period of full-dose 
anticoagulation IF all of the criteria 
below are met: 
- The subject must have an in-range 
INR (usually 2-3) on a stable dose 
of warfarin or be on a stable dose of 
heparin prior to restarting 
bevacizumab 
- The subject must not have 
pathological conditions that carry 
high risk of bleeding (eg, tumor 
involving major vessels or other 
conditions) 
- The subject must not have had 
hemorrhagic events while on study 
 
 
 


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Event 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
 
 
 
 
Grade 4 (symptomatic) 
 
If thromboemboli worsen/recur 
upon resumption of study therapy, 
discontinue bevacizumab 
 
Discontinue bevacizumab 
permanently. 
Congestive 
Heart 
Failure  
 ≥ Grade 3 
Discontinue bevacizumab 
permanently. 
 
 
Hypertension  
 
Grade 1 
 
Grade 2 asymptomatic but 
diastolic BP < 100 mmHg 
 
Grade 2-3 Symptomatic OR 
Diastolic BP > 100 mmHg 
 
 
Grade 4 
Monitor BP frequently. 
 
Begin anti-hypertensive therapy 
and continue bevacizumab. 
 
Hold bevacizumab until symptoms 
resolve AND BP < 160/90mmHg. 
 
 
Discontinue bevacizumab 
permanently. 
 
 
RPLS 
(reversible 
posterior 
leukoencephalopathy 
syndrome or PRES 
(posterior reversible 
encephalopathy 
syndrome)  
 
Discontinue bevacizumab 
permanently. 
 
Proteinuria  
 
Urine protein creatinine 
(UPC) < 3.5 
 
UPC ratio > 3.5 
 
 
Grade 4 or nephrotic 
syndrome 
Continue bevacizumab. 
 
 
Hold bevacizumab until UPC 
recovers to < 3.5 
 
Discontinue bevacizumab 
permanently. 
 
 
Hemorrhage 
(CNS 
or pulmonary)  
 
Hemorrhage 
(non-CNS; 
non-
pulmonary)  
 
 
 
 
≥ Grade 2 
 
 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discontinue bevacizumab 
permanently. 
 
 
 
If patient requires full-dose 
anticoagulation, discontinue 
bevacizumab permanently. 
 
If patient is  not receiving full-dose 
anticoagulation, hold bevacizumab 
until ALL of the following criteria 
are met: 
- the bleeding has resolved and Hb 
is stable 
- there is no bleeding diathesis that 
would increase the risk of therapy 
- there is no anatomic or pathologic 
condition that could increase the 
risk of hemorrhage recurrence. 
 


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Event 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
 
 
 
Grade 4 or recurrence of 
Grade 3 
 
 
Discontinue bevacizumab 
permanently. 
 
Gastrointestinal 
perforation, 
leak 
or 
fistula 
 
Discontinue bevacizumab 
permanently. 
 
 
Bowel obstruction  
 
Grade 2 requiring medical 
intervention 
 
 
 
≥ Grade 3 
Hold bevacizumab until complete 
resolution, with a minimum of 4 
weeks after surgery. 
 
 
-Hold bevacizumab until complete 
resolution 
-If surgery is required, patient may 
restart bevacizumab after full 
recovery from surgery, and at 
investigator‘s discretion 
 
Wound 
dehiscence 
requiring medical or 
surgical intervention  
 
Discontinue bevacizumab 
permanently. 
 
 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab and bevacizumab may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if pembrolizumab or bevacizumab have transient adverse effects on the 
composition of sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are 
willing to use 2 methods of birth control or are considered highly unlikely to conceive.  
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 1 year will be 
considered postmenopausal), or 3) not heterosexually active for the duration of the study.  
The two birth control methods can be either two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects should start using birth control from study 
Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 


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estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor (Moffitt Cancer Center) and to Merck.  If there is 
any question that a subject will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with study treatments, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor (Moffitt Cancer 
Center) and to Merck without delay and within 24 hours if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).  The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor.  If a male subject impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and to Merck and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether study drugs are excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor (Moffitt Cancer Center) if enrollment into the 
trial is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Specific details regarding discontinuation or withdrawal are provided in Section 
7.1.4 – Other Procedures. 
 


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A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Unacceptable adverse experiences as described in Section 5.3.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After discontinuation of treatment, each 
subject will be followed for 30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment as described in Section 7.2.3.1).  
Subjects who discontinue treatment for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up.  After documented disease 
progression each subject will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
5.9 
Subject Replacement Strategy 
In dose escalation phase, subject will be replaced if they are considered inevaluable. A 
subjects will be considered DLT-evaluable if they have incurred a DLT within a DLT 
evaluation period or meet all of the following criteria: a) have received at least 85% of the 
prescribed doses of bevacizumab, b) have received at least 85% of the prescribed doses of 
pembrolizumab, and c) have received the full dose of HFSRT.  
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 


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4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
5.11 STOPPING RULES 
The reported rate for grade 3 CNS toxicity with HFSRT and bevacizumab is 4% [34]. A 
higher rate of treatment related grade 3 CNS toxicity (> 10%) in this study would imply that 
the combination of HFSRT with bevacizumab and pembrolizumab is excessively toxic and 
not suitable for further clinical development. In addition grade ≥ 3 delayed-onset toxicity in 
this study would imply that the combination of HFSRT with pembrolizumab and 
bevacizumab is excessively toxic. In such condition, the results will be discussed with 
Merck, Protocol Monitoring Committee and IRB to determine whether discontinuation of 
trial is subsequently warranted. 
 


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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles  
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) a 
Cycle 1 (6 weeks) 
Cycles 2 and beyond (6 
weeks) 
Discon 
Safety 
Follow-up 
Follow Up 
Visits b 
Survival 
Follow-Up 
Scheduling Window (Days): 
 
-13 to -1 
D1 
D2 
D3 
D4 
D5 
D15 
± 3 
D22 
± 3 
 
D29 
± 3 
D1  
± 3 
D15 
± 3 
D22 
± 3 
D29 
± 3 
At time of 
Discon 
30 days 
post discon 
Every 8 
weeks post 
discon 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Radiation therapy 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Bevacizumab 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
Pembrolizumab 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events c 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Symptom Directed Physical Examination 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EORTC QLQ-C30, BNS20, EQ-5D 
Questionnaire 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
Karnofsky Performance Status 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 


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Trial Period: 
Screening Phase 
Treatment Cycles  
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main Study 
Screening 
(Visit 2) a 
Cycle 1 (6 weeks) 
Cycles 2 and beyond (6 
weeks) 
Discon 
Safety 
Follow-up 
Follow Up 
Visits b 
Survival 
Follow-Up 
Scheduling Window (Days): 
 
-13 to -1 
D1 
D2 
D3 
D4 
D5 
D15 
± 3 
D22 
± 3 
 
D29 
± 3 
D1  
± 3 
D15 
± 3 
D22 
± 3 
D29 
± 3 
At time of 
Discon 
30 days 
post discon 
Every 8 
weeks post 
discon 
Every 12 
weeks  
Pregnancy Test – Urine or Serum -HCG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
CBC with Differential 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
X 
 
T3, FT4 and TSH 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Efficacy Measurements 
Brain MRI  with/without contrast 
 
X 
 
 
 
 
 
 
 
 
Q6wk (C1-3),Q12wk then 
X 
 
X 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection  
 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
a Visit 1 assessment (physical examination and laboratories) can be used for main study screening (visit 2) if visit 2 occurs within 3 days from visit 1. 
b There will be two follow up visits which include full physical examination, laboratories, and brain MRI. 
c After the end of treatment, each subject will be followed for 30 days for adverse event monitoring. Serious adverse events will be collected for 90 days after the treatment. 
 
 
 
 


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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 


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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent. 
7.1.1.4 Medical History 
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.  Details regarding brain tumor 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.5 Prior and Concomitant Medications Review 
7.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
washout requirement, and record prior medication taken by the subject within 28 days before 
starting the trial.  Treatment for the brain cancer for which the subject has enrolled in this 
study will be recorded separately and not listed as a prior medication.  
7.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.6 Disease Details and Treatments 
7.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding status of 
brain cancer.  
7.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 


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7.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
All AEs of unknown etiology associated with study treatment should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the 
administrative binder regarding the identification, evaluation and management of AEs of a 
potential immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, and study visits as per 
the Trial Flow Chart. 
7.1.2.3 Directed Physical Exam 
For visits that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 


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7.1.2.5 Karnofsky Performance Scale (KPS) 
The investigator or qualified designee will assess KPS status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
All subjects will receive efficacy assessments with brain MRI at time points specified in Trial 
Flow Chart.  All MRIs (except the initial screening MRI) should occur at +/- 7 days per 
scheduled visits. Investigators may obtain more frequent follow-up MRI scans as medically 
indicated. Cases of suspected radiologic disease progression will be confirmed by an MRI 
performed approximately 8 weeks after the initial radiological assessment of progression. 
Response Assessment Criteria for High-Grade Gliomas (RANO Criteria) will be used for 
assessing the response to study treatment. 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Peripheral blood and archival tumor tissue will be collected prior to therapy. Peripheral blood 
samples will also be collected at selected time points specified in Trial Flow Chart. If a 
biopsy or surgical resection is performed at the time of progression, tumor sample (block or 
slides) should be submitted for analysis. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood volume collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood volumes drawn by visit and 
by sample type per subject can be found in the Procedures Manual.  
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.  
The total amount of blood to be drawn over the course of the trial (from pre-trial to post-trial 
visits), including approximate blood volumes drawn by visit and by sample type per subject 
can be found in the Procedures Manual.  
 


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Table 7 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Blood Urea Nitrogen 
results are noted 
Free tyroxine (T4) 
 
Uric Acid 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Serum creatinine 
 
 
 
Total protein 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  
 
 
 


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After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.  
7.1.3.2 Pharmacodynamic Evaluations 
7.1.3.2.1 Blood Collection for Correlative Studies 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures Manual. 
The time points for blood sampling are described in Section 6 – Trial Flow Chart.  
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  After discontinuing treatment, these subjects should return to the 
site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the 
Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
Screening period begins by establishing the subject’s initial eligibility and signing of the 
informed consent form (ICF). Study treatment should be given within 14 days of signing 
ICF. 
7.1.5.2 Treatment Period 
Treatment period should start within 14 days of signing ICF. Treatment period will start with 
5 days of radiation therapy (6 Gy x5) and one dose of bevacizumab 10 mg/kg IV and 
pembrolizumab IV on C1 D1. 
Bevacizumab 10 mg/kg IV will be continued every two weeks. Pembrolizumab IV will start 
on C1 D1 and will be continued every three weeks. 


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All of the laboratories and vital signs will be collected prior to study drug dosing at the time 
points specified in Trial Flow Chart. 
Adverse event assessments will be documented at each visit throughout the study. 
Quality of Life assessments using EORTC QLQ-C30 and BNS20 and EQ-5D to be 
completed as described in Trial Flow Chart. 
Correlative biomarker blood samples will be collected according to the schedule in Trial 
Flow Chart.  
Response to treatment will be assessed by the investigator and according to the RANO 
criteria. Brain MRI will be performed every 6 weeks beginning at the end of Week 6 (± 1 
week) for 3 cycles and then every 12 weeks (± 1 week) until disease progression or treatment 
discontinuation, whichever occurs later. Brain MRIs can be obtained in shorter intervals as 
per physician discretion. 
7.1.5.3 Post-Treatment Visits 
Post-Treatment period begins when the decision to discontinue a subject from study therapy 
is made (no further study treatment). 
There will be two follow-up visits which include full physical examination, laboratories, and 
brain MRI. 
Quality of Life questionnaires will be completed in post-treatment visits. 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  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 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
7.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (± 1 week) by 
radiologic imaging to monitor disease status.  All radiologically determined disease 
progression must be confirmed by an additional confirmatory MRI scan approximately 8 
weeks following the initial assessment of radiological progression. 


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Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death or end of the study. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
7.1.5.4.1 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 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.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the pembrolizumab, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Adverse events may occur during the course of the use of study treatment in clinical trial or 
within the follow-up period, from overdose (whether accidental or intentional), and from 
withdrawal. 
All adverse events will be recorded day 1 of study treatment (D1 C1) through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. Relation of adverse event to study treatment will be defined as definitely, 
probably, possibly, unlikely, or unrelated. The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab or bevacizumab by 20% over the prescribed dose. No specific 
information is available on the treatment of overdose of pembrolizumab or bevacizumab. In 
the event of overdose, pembrolizumab and bevacizumab should be discontinued and the 
subject should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated. 


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If an adverse event(s) is associated with (“results from”) the overdose of study treatment, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria 
are met. 
If a dose of study treatment meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor (Moffitt Cancer Center) and within 2 working days hours to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to Moffitt Cancer Center and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  
All subjects and female partners of male subjects who become pregnant 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 Sponsor (Moffitt Cancer Center) and 
within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor (Moffitt Cancer Center) 
and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring during study treatment that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is another important medical event  


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Refer to Table 8 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time of starting study treatment through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to study 
treatment, must be reported within 24 hours to the Sponsor (Moffitt Cancer Center) and 
within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Moffitt Cancer Center and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to study treatment that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to Moffitt Cancer Center and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to Moffitt 
Cancer Center. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA 
and other local regulators.  Investigators will submit a copy of these reports to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of submission to 
FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor (Moffitt Cancer Center) and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
Events of clinical interest for this trial include: 
1.  an overdose of pembrolizumab, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor (Moffitt Cancer Center), that is not 
associated with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal.* 


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*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the Sponsor (Moffitt Cancer Center) within 24 hours and to 
Merck Global Safety within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to the Sponsor (Moffitt 
Cancer Center) within 24 hours and to Merck Global Safety within 2 working days of the 
event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the study treatment, must be reported within 24 hours to the Sponsor (Moffitt 
Cancer Center) and to Merck Global Safety within 2 working days. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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Table 8 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring during study treatment that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time.  
Action taken  
Did the adverse event cause the study treatment to be discontinued? 
Relationship to 
study 
treatment  
Did the study treatment cause the adverse event? The determination of the likelihood that the study treatment caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the study treatment and the adverse 
event based upon the available information.  
The following components are to be used to assess the relationship between the pembrolizumab  and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the study treatment caused the adverse event (AE): 
 
Exposure 
Did the subject receive the study treatment? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the study treatment?  
Is the time of onset of the AE compatible with a drug-induced effect? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 


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Relationship 
The following components are to be used to assess the relationship between the study treatment and the AE: (continued) 
to study 
treatment  
Dechallenge 
Was the study treatment discontinued reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of study treatment.) 
 
Rechallenge 
Was the subject re-exposed to the study treatment? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if the initial AE resulted in death or permanent disability). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE STUDY TREATMENT, OR IF REEXPOSURE TO THE STUDY TREATMENT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the study treatment? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of study treatment relationship). 
Yes, there is a reasonable 
possibility of study treatment 
relationship. 
Subject has received the study treatment.  The temporal sequence of the AE onset relative to the administration of study treatment is reasonable.  
The AE is more likely explained by the study treatment than by another cause. 
No, there is not a reasonable 
possibility study treatment 
relationship 
Subject did not receive the study treatment OR temporal sequence of the AE onset relative to administration of the study treatment is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events except grade 1 and 2 toxicities which are  unrelated to study treatment, 
will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all 
applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The number of patients for the dose escalation cohort will depend on the number of dose 
levels reached. There are two dose escalation cohorts and therefore the maximum sample size 
for the dose escalation cohorts will be 12 patients. In the dose expansion cohort, a total of 20 
(10 bevacizumab naïve and 10 bevacizumab failure) evaluable patients will be enrolled to 
confirm the safety at this dose and assess response to treatment. The sample size of 26 
patients in the MTD dose (20 patients from dose expansion cohort and 6 patients from the 
dose escalation) will give a two-sided 95% confidence interval (95%CI) of 39% to 79% for a 
response rate of 60%. If the response rate increases to 80%, the corresponding 95%CI will be 
60% to 93%. Therefore, the maximum sample size of the study is 32 patients. 
8.2 
Statistical Analysis Plan 
Data will be summarized overall using descriptive statistics. Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, standard 
deviation, coefficient of variation, and geometric mean (where applicable). Categorical data 
will be summarized using frequency counts and percentages. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Products  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational products in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
Table 9 Product Description 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 


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Bevacizumab should be stored, prepared, and administered in accordance to the package 
insert, summary of product characteristics (SmPC) or similar document. 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor (Moffitt 
Cancer Center) and/or designee are not blinded to treatment. Drug identity (name, strength) 
is included in the label text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at 
Moffitt Cancer Center. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  Patient medical 
information obtained for the purposes of this study is confidential, and disclosure to third 
parties, other than those noted below, is prohibited.  Patients should be identified only by 
their initials and protocol-assigned patient ID number. For those patients whose surgical 
specimen is processed and read by the central pathology laboratory, the patient’s billing 


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information will be requested by this laboratory and will not be shared with the sponsor or 
any of its affiliates or representatives.  
Study personnel should follow the requirements of the Health Insurance Portability and 
Accountability Act (HIPAA). 
All clinical information is confidential, but data generated for this study must be available for 
inspection on request to representatives of the U.S. FDA, other national or local regulatory or 
health authorities, Endo Pharmaceuticals representatives, and the associated IRB. 
All records must be kept in a secured area. 
10.2 Compliance with Financial Disclosure Requirements 
Documentation of each Investigator’s proprietary or financial interest is required by the U.S. 
Code of Federal Regulations (21 CFR 54).  A financial disclosure form provided by Moffitt 
Cancer Center must be completed, signed, and dated by the Principal Investigator and each 
Sub-investigator listed on the Form FDA 1572.  This form must be executed prior to the 
personnel’s participation in the study.  The original form will be retained by Moffitt Cancer 
Center.  Each Investigator must inform Moffitt Cancer Center of any change in his/her 
financial interest for up to one year after the end of the study. 
10.3 Compliance with Law, Audit, Debarment and Quality Management System 
The Investigator must conduct the study according to this protocol. 
The study must be conducted by all Investigators in compliance with Good Clinical Practices 
(GCP) as defined as described in the U.S. FDA Code of Federal Regulations 21 CFR 312 
(Investigational New Drug Application), 21 CFR 50 (Protection of Human Subjects), 21 CFR 
54 (Financial Disclosure by Clinical Investigators), 21 CFR 56 (Institutional Review Boards) 
and ICH guidelines (Guideline to Good Clinical Practice). 
The PI of this study is ultimately responsible for every aspect of the design, conduct and 
actions of all members of the research team. This includes the final analysis of the protocol. 
All protocols include a Data Safety Monitoring Plan (DSMP) and procedures for its 
implementation commensurate with the risk and complexity of the study. The DSMP must 
include a structured adverse event determination, monitoring and reporting system, including 
standardized forms and procedures for referring and/or treating subjects experiencing adverse 
events. The plan must include data and safety-monitoring procedures for subjects enrolled 
who may be receiving a part of their protocol-required treatment at community sites. 
The PI of this study will have primary responsibility for ensuring that the protocol is 
conducted as approved by the SRC and IRB. The PI will ensure that the monitoring plan is 
followed, that all data required for oversight of monitoring are accurately reported to a 
DSMP and/or to the Protocol Monitoring Committee (PMC) and IRB as required, that all 


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adverse events are reported according to protocol guidelines, and that any adverse actions 
reflecting patient safety concerns are appropriately reported. 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. 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 (GCP), and 
applicable regulatory requirements. 
The PMC monitors its assigned ongoing research protocols monthly for: adverse event 
reporting, data and safety monitoring, and internal audit findings. The PMC upon review of 
any agenda item may approve the study for continuation, require revisions, suspend or close 
a protocol. 
Investigators of studies which are designed to be reviewed by the PMC for data and safety 
monitoring, shall provide a statistical report of the study’s progress and summary of adverse 
events and deviations based on the phase of the study and the associated risk of the study or 
more often if applicable. The external DSMP (if applicable) shall forward its report for high-
risk studies designated for external review at least annually or more often if applicable. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), Moffitt Cancer Center is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
10.5 Data Management 
Data will be maintained by the Moffitt Cancer Center. 
 
 
 
 
 


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associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.   
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
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5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
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Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.   
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Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7. 
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
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12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.   
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.   


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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.   
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.   
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.   
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.   
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.   
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.   
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.   
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regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
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irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40. 
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25.  Wei B, Wang L, Zhao X, Du C, Guo Y, Sun Z. The upregulation of programmed death  
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safety of Pembrolizumab in patients with advanced melanoma.  Pigment Cell 
Melanoma Res 2012;25:836-903. 
51. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 
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12.0 APPENDICES 
12.1 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
12.2 Immune-Related Adverse Event Guidance 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
1 
Version 5.0                             
                         
 
 
 
 
 
 
 
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
 
 
 
EVENT OF CLINICAL INTEREST  
 
GUIDANCE DOCUMENT 
 
 
Version 5.0 
 
 
 
 
 
 
 
 
 
 
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
2 
Version 5.0                             
                         
 
 
 
REVISION HISTORY LOG 
 
Version 
Effective 
Date* 
Revision 
Author 
Action 
1 
08-Aug-2012 
Kevin Gergich 
Initial Release of guidance document for MK-3475 
 
2 
07-June-2013 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Revised title, formerly was “MK-3475 Immune-Related 
Adverse Event Identification, Evaluation and Management 
Guidance Document for Investigators” 
 
Revised the format of irAE Guidance document, including 
layout, font, sectioning, etc. for consistency with Sponsor 
Events of Clinical Interest guidance documents. 
 
Modified Categories for irAEs: 
– 
Replaced GI with Colitis category. 
– 
Removed Neurologic category. 
– 
Added Renal category. 
 
Removed detail in the irAE Guidance document that can 
be located in the Investigator’s Brochure for MK-3475. 
 
Removed details regarding non-MK-3475 compounds. 
 
Added ECI reporting guidelines. 
 
Included a Table Events of Clinical Interest: Immune-
Related Adverse Events that includes the key terms. 
– 
Also placed a pull-out quick-review sheet in the 
Appendix. 
 
Updated background, diagnosis and course of treatment 
details for irAEs. 
 
3 
10-Sep-2014 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Renamed the document: “Pembrolizumab Program (MK-
3475) - Events of Clinical Interest Guidance Document”. 
 
Introduced generic name: pembrolizumab (MK-3475) and 
inserted throughout the document. 
 
Updated Overview – Section 1  
- Clarified the scope of the document and the reporting 
window for ECIs 
 
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria. 
 
- Updated the dose modification/discontinuation section to 
clarify discontinuation and hold terminology. 
 
Updated Section 2 – ECI Reporting Guidelines  


Pembrolizumab Event of Clinical Interest Guidance Document 
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Version 5.0                             
                         
 
 
 
– Clarified that ECIs must be reported to Merck within 24 
hours regardless of attribution to study treatment or 
etiology. 
 
Updated Section 3  
– For All Sections, removed the Course of Action for 
Grade 1 events. 
 
- Section 3.1 Pneumonitis 
– 
Moved Pneumonitis to beginning of ECI Section 
– 
Updated management guidelines for Grade 2 and 
Grade 3-4 events 
 
- 
Section 3.2 Colitis:   
- 
Updated AE terms and ECI criteria, updated 
course of action language for clarity  
 
- Section 3.3 Endocrine:   
- 
Updated ECI criteria and updated course of action 
language for clarity.   
- 
Added subsections for hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines. 
 
- Section 3.4 Hematologic:   
- 
New section added. 
 
- Section 3.5:  Hepatic:   
- 
Updated terms and added additional guidance for 
reporting of DILI ECI; updated course of action 
for clarity 
 
- Section 3.6 Neurologic:  
- 
New section added. 
 
- Section 3.7 Ocular:   
- 
Changed the name of this section from Eye to 
Ocular 
- 
Added the term “iritis”, updated ECI guidance, 
and updated course of action language for clarity 
 
- Section 3.8 Renal:  
- 
Updated section for clarity. 
 
- Section 3.9 Skin:   
- 
Updated list of terms and added terms for 
reporting of other skin ECIs; added section 3.9.1: 
Immediate Evaluation for Potential Skin ECIs 
 
- Section 3.10 Other:  
- 
Updated list of terms for clarity; revised course of 
action for clarity.   
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
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Version 5.0                             
                         
 
 
 
- Section 3.11 Infusion Reactions:   
- 
New section added. 
 
- Section 3.12:  Follow-up to Resolution:  
- 
New section added. 
 
- Section 4:  
- 
References updated. 
 
- Section 5:  
- 
ECI table updated for consistency with Table 1.  
 
- Section 6: Appendix 2 – Past Medical History Related to 
Dermatologic Event:  New section added. 
 
- Section 7: Appendix 3 – Presentation of the 
Dermatologic Event:  New section added. 
 
- Section 8: Appendix 4 – Focused Skin Examination:  
New section added. 
4 
04-Dec-2014  Scot Ebbinghaus, 
Oswaldo Bracco, 
Holly Brown, 
Kevin Gergich 
- Table 1 
- 
Updated Endocrine (reported as ECI if  ≥ Grade 3 
or ≥ Grade 2 and resulting in dose modification or 
use of systemic steroids to treat the AE) Section 
to include: 
- 
Hyperglycemia, if ≥Grade 3 and associated 
with ketosis or metabolic acidosis (DKA) 
- 
Created new section in Table 1 – Endocrine 
(reported as ECI) and added: 
- 
Type 1 diabetes mellitus (if new onset) 
- 
Hepatic: Clarified Transaminase elevations as: 
- 
Transaminase elevations (ALT and/or AST) 
- Section 3.2 Colitis 
- Updated the duration of diarrhea requirments  
under the Course of Action for Grade 2 and Grade 
3 
- Section 3.3 Endocrine 
- 
Clarified Course of Action for hyperthyroidism 
and hypothyroidism 
- 
Added Course of Action section for Type 1 
diabetes mellitus (if new onset) and ≥ Grade 3 
hyperglycemia 
- Section 5 
- 
Updated Reference Table in Appendix 1 
5 
18-Dec-2014 
Holly Brown 
Kevin Gergich 
- Section 3.3 Endocrine 
- 
Updated the Course of Action for Hypophysitis 
- 
Merged Grades 2-4 into one course of action 
*Ensure that you are using the most current version of this document.  


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
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Version 5.0                             
                         
 
 
 
TABLE OF CONTENTS 
 
 
 
1. OVERVIEW ............................................................................................................................... 6 
2. ECI REPORTING GUIDELINES .............................................................................................. 8 
3. ECI CATEGORIES AND TERMS ............................................................................................ 8 
3.1 Pneumonitis .......................................................................................................................... 9 
3.2 Colitis .................................................................................................................................. 10 
3.3 Endocrine ............................................................................................................................ 12 
3.4 Hematologic ........................................................................................................................ 15 
3.5 Hepatic ................................................................................................................................ 16 
3.6 Neurologic ........................................................................................................................... 18 
3.7 Ocular .................................................................................................................................. 19 
3.8 Renal ................................................................................................................................... 20 
3.9 Skin ..................................................................................................................................... 21 
3.9.1. Immediate Evaluation for Potential Skin ECIs ........................................................... 22 
3.10 Other ................................................................................................................................. 23 
3.11 Infusion Reactions ............................................................................................................ 24 
3.12 Follow-up to Resolution ................................................................................................... 26 
4. REFERENCES ......................................................................................................................... 27 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ...................................... 28 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event ................................... 29 
7. APPENDIX 3 – Presentation of the Dermatologic Event ........................................................ 30 
8. APPENDIX 4 – Focused Skin Examination ............................................................................. 32 
 
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
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Version 5.0                             
                         
 
 
 
1. OVERVIEW 
 
The purpose of this document is to provide study sites with guidance on the identification and management of 
Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program.   
 
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, potential 
immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). Immune-related AEs 
are adverse events associated with the treatment of patients with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. Based on these potential irAEs, the sponsor has 
defined a list of specific adverse event terms (ECIs) that are selected adverse experiences that must be 
reported to Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence, 
regardless of whether or not the investigator/physician considers the event to be related to study drug(s). In 
addition, these ECIs require additional detailed information to be collected and entered in the study database.  
ECIs may be identified through spontaneous patient report and / or upon review of subject data. Table 1 
provides the list of terms and reporting requirements for AEs that must be reported as ECIs for MK-3475 
protocols.  Of note, the requirement for reporting of ECIs applies to all arms, including comparators, of MK-
3475 clinical trials  
 
Given that our current list of events of clinical interest is not comprehensive for all potential immune-related 
events, it is possible that AEs other than those listed in this document may be observed in patients receiving 
pembrolizumab. Therefore any Grade 3 or higher event that the investigator/physician considers to be 
immune-related should be reported as an ECI regardless of whether the specific event term is in Table 1 and 
reported to Merck within 24 hours from the time the Investigator/physician is aware of such an occurrence.  
Adverse events that are both an SAE and an ECI should be reported one time as an SAE only, however the 
event must be appropriately identified as an ECI as well in in the database.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
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Version 5.0                             
                         
 
 
 
Table 1: Events of Clinical Interest 
Pneumonitis (reported as ECI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Autoimmune hemolytic anemia  
Aplastic anemia  
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation 
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if  ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
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Version 5.0                             
                         
 
 
 
Each of the events above is described within this guidance document, along with site requirements for 
reporting these events to the Sponsor.  The information collected should be entered into the narrative field(s) 
of the Adverse Event module in the database (please note, if narrative entry into the database is not available, 
please use the narrative text box on the 1727/AER Form).  If additional Medical History or Concomitant 
Medications are reported, the Medical History and Concomitant Medication modules in the database must be 
updated.   
 
In addition, the guidelines include recommendations on the management of these ECIs. These guidelines are 
intended to be applied when the physician determines the events to be related to pembrolizumab. Note: if after 
the evaluation the event is determined not to be related, the physician is instructed to follow the ECI reporting 
guidance but does not need to follow the treatment guidance (below). Therefore, these recommendations 
should be seen as guidelines and the treating physician should exercise individual clinical judgment based on 
the patient.  For any question of dose modification or other treatment options, the specific language in the 
protocol should be followed.  Any questions pertaining to the collection of this information or management of 
ECIs should be directed to your local Sponsor contact.  
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab for each 
immune related adverse event.  Of note, when the guidance states to “discontinue” pembrolizumab this is the 
permanent discontinuation of treatment with pembrolizumab. “Hold” means to stop treating with 
pembrolizumab but resumption of treatment may be considered assuming the patient meets the criteria for 
resumption of treatment.   
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck within 24 hours 
regardless of attribution to study treatment.  The AEs listed in this document and any event that meets the ECI 
criteria (as noted) in Table 1 or in the respective protocol (event term and Grade) must be reported regardless 
of physician-determined causality with study medication and whether or not considered immune-related by the 
physician (unless otherwise specified).   Physicians/study coordinators/designated site personnel are required 
to record these experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or on 
paper) and to provide supplemental information (such as medical history, concomitant medications, 
investigations, etc.) about the event.   
 
– 
Please refer to the Data Entry Guidelines (DEGs) for your protocol.  
– 
Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug Induced 
Liver Injury (DILI).   
3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guidelines when an ECI is 
reported.      
 
 


Pembrolizumab Event of Clinical Interest Guidance Document 
Final 18-Dec-2014 
 
9 
Version 5.0                             
                         
 
 
 
3.1 Pneumonitis 
 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Pneumonitis 
– 
Interstitial lung disease 
– 
Acute interstitial pneumonitis  
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a cardiology 
consultation should be considered.  
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral infection.  It 
is important that patients with a suspected diagnosis of pneumonitis be managed as per the guidance 
below until treatment-related pneumonitis is excluded.  Treatment of both a potential infectious etiology 
and pneumonitis in parallel may be warranted.  Management of the treatment of suspected pneumonitis 
with steroid treatment should not be delayed for a therapeutic trial of antibiotics.  If an alternative 
diagnosis is established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– 
Consider ID consult 
– 
Conduct an in person evaluation approximately twice per week 
– 
Consider frequent Chest X-ray as part of monitoring 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.   
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks.    
– 
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient develops 
a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab. 
– 
Hospitalize patient 
– 
Bronchoscopy with biopsy and/or BAL is recommended. 
– 
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When symptoms 
improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks. 
– 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 
hours, treat with additional anti-inflammatory measures. Discontinue additional anti-inflammatory 
measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms 
worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 
mg followed by a more prolonged taper and administer additional anti-inflammatory measures, as 
needed 
– 
Add prophylactic antibiotics for opportunistic infections. 


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3.2 Colitis 
 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic steroids 
to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:  
 
– 
Colitis  
– 
Colitis microscopic 
– 
Enterocolitis 
– 
Enterocolitis hemorrhagic  
– 
Gastrointestinal perforation 
– 
Intestinal obstruction  
– 
Necrotizing colitis 
– 
Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic infection, 
viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by examination for stool 
leukocytes, stool cultures, a Clostridium difficile titer and endoscopy.   However the AE should be reported 
regardless of etiology. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, abdominal 
pain, mucus or blood in stool):   
– 
Report as ECI 
– 
Hold pembrolizumab.  
– 
Symptomatic Treatment 
– 
For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or mucus,  
o Consider GI consultation and endoscopy to confirm or rule out colitis  
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks.    
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– 
If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– 
Report as ECI 
– 
Hold pembrolizumab.  
– 
Rule out bowel perforation.  Imaging with plain films or CT can be useful. 
– 
Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
– 
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral steroids 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours)  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 
hours, consider treatment with additional anti-inflammatory measures as described in the literature [5]. 
Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer 
additional anti-inflammatory measures as needed.  
 


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Grade 4 events:  
– 
Report as ECI 
– 
Permanently discontinue pembrolizumab. 
– 
Manage as per Grade 3. 


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3.3 Endocrine 
 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/ 
modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor within 24 
hours of the event:   
 
– 
Adrenal insufficiency 
– 
Hyperthyroidism 
– 
Hypophysitis 
– 
Hypopituitarism  
– 
Hypothyroidism 
– 
Thyroid disorder  
– 
Thyroiditis  
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or infection.  
However the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-4 events: 
– 
Report as ECI if appropriate 
– 
Hold pembrolizumab 
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 
returned to baseline values. 
– 
Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of the 
pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– 
Treat with prednisone 40 mg p.o. or equivalent per day.  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.  
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks.  
– 
Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis. 
– 
Consultation with an endocrinologist may be considered. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Hyperthyroidism and 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, Grade 2-4 hypothyroidism events: 
– 
Report as ECI if appropriate (see Table 1) 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 
returned to baseline values. 
– 
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– 
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is instituted.  
– 
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.  
– 
Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– 
Report as ECI 
– 
Hold pembrolizumab.  
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day.  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.  
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab.  
– 
Manage as per Grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours of the 
event: 
 
– 
Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)  
– 
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA). 
 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of pre-
existing diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made to rule 
out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, 
physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but 
events meeting the above criteria should be reported as ECIs regardless of etiology. The patients may present 
with hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or 
laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic acidosis, or low 
or undetected c-peptide. 
 
 
Course of Action 
 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
- 
Report as ECI if appropriate (see Table 1) 
- 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia associated 
with evidence of beta cell failure, and resume pembrolizumab when patients are clinically and 
metabolically stable.  
- 
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.  
- 
Consultation with an Endocrinologist is recommended. 
- 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin may be 
obtained.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4 Hematologic 
 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic steroids to 
treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
 
– 
Autoimmune hemolytic anemia 
– 
Aplastic anemia 
– 
Disseminated Intravascular Coagulation (DIC) 
– 
Haemolytic Uraemic Syndrome (HUS) 
– 
Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– 
Thrombotic Thrombocytopenic Purpura (TTP) 
– 
Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.   Relevant 
diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy 
or Coomb’s test, etc., should be considered to confirm the diagnosis. However the AE should be reported 
regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab 
– 
Prednisone 1-2 mg/kg daily may be indicated 
– 
Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Hematology consultation.  
– 
Hold pembrolizumab   Discontinuation should be considered as per specific protocol guidance. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Hematology consultation 
– 
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic 
malignancies. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate 
 


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3.5 Hepatic 
 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or use of 
systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours 
of the event:   
 
– 
Autoimmune hepatitis  
– 
Hepatitis  
– 
Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic 
diseases. However the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the 
laboratory criteria for potential DILI defined as:  
 
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than 
or equal to three times (3X) the upper limit of normal (ULN) and  
 
An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
 
At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,  
 
As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI event.   
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times 
ULN. 
– 
Monitor liver function tests more frequently until returned to baseline values (consider weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to 
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume pembrolizumab per protocol  
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– 
Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with 
Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative to baseline and lasts ≥1 
week. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times 
ULN.   
– 
Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary 
– 
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours.  When symptoms improve to 
Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg 
should be started and continued over no less than 4 weeks.  
– 
If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to 
its potential for hepatotoxicity. 


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– 
Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events:  
– 
Report as ECI 
– 
Permanently discontinue pembrolizumab 
– 
Manage patient as per Grade 3 above 
 


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3.6 Neurologic 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Autoimmune neuropathy 
– 
Demyelinating polyneuropathy 
– 
Guillain-Barre syndrome 
– Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other medications or infectious 
causes. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Moderate (Grade 2) – consider withholding pembrolizumab.  
– 
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– 
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab 
– 
Obtain neurology consultation.  Consider biopsy for confirmation of diagnosis 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. If 
condition worsens consider IVIG or other immunosuppressive therapies as per local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 


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3.7 Ocular 
 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to 
treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
 
– 
Uveitis 
– 
Iritis  
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular 
disease (e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events:  
– 
Evaluation by an ophthalmologist is strongly recommended. 
– 
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– 
Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical 
immunosuppressive therapy. 
 
Grade 3 events: 
– 
Evaluation by an ophthalmologist is strongly recommended  
– 
Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. 
– 
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
 
Grade 4 events:  
– 
Evaluation by an ophthalmologist is strongly recommended  
– 
Permanently discontinue pembrolizumab. 
– 
Treat with corticosteroids as per Grade 3 above 
 
 
 
 
 


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3.8 Renal 
 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event: 
 
– 
Nephritis 
– 
Nephritis autoimmune 
– 
Renal failure 
– 
Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to treat the 
AE. 
 
 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of disease, or 
injury due to other chemotherapy agents.  A renal consultation is recommended. However the AE should be 
reported regardless of etiology. 
 
 
Course of Action 
 
 
Grade 2 events: 
– 
Hold pembrolizumab 
– 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3-4 events:  
– 
Discontinue pembrolizumab 
– 
Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once per 
day.   
 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.   
 
 
 
 


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3.9 Skin 
 
Rash and Pruritus 
 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor within 
24 hours of the event:  
 
– 
Pruritus 
– 
Rash 
– 
Rash generalized 
– 
Rash maculo-papular 
– 
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's 
judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and 
could possibly include rashes such as the following:  
o rash with a duration >2 weeks; OR  
o rash that is >10% body surface area; OR  
o rash that causes significant discomfort not relieved by topical medication or temporary cessation 
of study drug. 
 
Other Skin ECIs 
 
The following AEs should always be reported as ECIs, regardless of grade, and should be reported to the 
Sponsor within 24 hours of the event:  
 
– 
Dermatitis exfoliative 
– 
Erythema multiforme 
– 
Steven’s Johnson syndrome 
– 
Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– 
Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 
0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-pruritics 
(e.g., diphenhydramine HCl or hydroxyzine HCl).  
– 
Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– 
Hold pembrolizumab. 
– 
Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– 
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per 
day or dexamethasone 4 mg four times orally daily.  When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Permanently discontinue pembrolizumab. 
– 
Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
– 
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 


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3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
A. Photographs:  
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as possible. 
Obtain appropriate consent for subject photographs if a consent form addendum is required by your 
IRB/ERC.  
– 
Take digital photographs of:  
o the head (to assess mucosal or eye involvement),  
o the trunk and extremities, and  
o a close-up of the skin lesion/rash.  
 
– 
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of 
distance.  
– 
The time/date stamp should be set in the 'ON' position for documentation purposes.  
– 
Photographs should be stored with the subject’s study records.  
– 
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will provide 
guidance to the site, if needed.  
 
B. Past Medical History:  
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical History 
Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported (e.g., drug 
allergy) should be entered into the Medical History eCRF.  
 
C. Presentation of the Event:  
Collect information on clinical presentation and potential contributing factors using the questions in Appendix 
3 (Presentation of the Dermatologic Event) as a guide. This information should be summarized and entered in 
narrative format in the AE eCRF. Please use the available free-text fields, such as Signs and Symptoms. Note 
pertinent negatives where applicable to reflect that the information was collected. Any treatments administered 
should be entered on the Concomitant Medication eCRF.  
 
D. Vitals Signs and Standard Laboratory Tests:  
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital Signs 
eCRF.  Perform standard laboratory tests (CBC with manual differential and serum chemistry panel, including 
LFTs).  
 
E. Focused Skin Examination:  
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) as a 
guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the 
narrative.  
 
F. Dermatology Consult  
Refer the subject to a dermatologist as soon as possible.  
– 
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event.  
– 
For clinically significant rash, the subject should be seen within 3-5 days.  
 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a 
pathologist experienced in reviewing skin specimens.  
 
The site should provide the dermatologist with all relevant case history, including copies of clinical 
photographs and laboratory test results.  
 


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3.10 Other 
 
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
 
– 
Myocarditis 
– 
Pericarditis 
– 
Pancreatitis 
– 
Any additional Grade 3 or higher event which the physician considers to be immune related 
 
All attempts should be made to rule out other causes.  Therapeutic specialists should be consulted as 
appropriate. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– 
Withhold pembrolizumab.   
– 
Systemic corticosteroids may be indicated.  
– 
Consider biopsy for confirmation of diagnosis. 
– 
If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– 
Hold pembrolizumab 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day.   
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks.   
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may be restarted and the 
dose modified as specified in the protocol 
 
Grade 4 events: 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day.   
– 
Discontinue pembrolizumab  
 
 
 


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3.11 Infusion Reactions 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
– 
Allergic reaction 
– 
Anaphylaxis 
– 
Cytokine release syndrome 
– 
Serum sickness 
– 
Infusion reactions 
– 
Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Refer to infusion reaction table in the protocol and below. 


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Infusion Reactions  
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
p.o. (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration.
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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3.12 Follow-up to Resolution  
 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with information 
regarding duration and clinical course of the event. Information obtained from the consulting specialist, 
including diagnosis, should be recorded in the appropriate AE fields. Free-text fields should be used to record 
narrative information:  
 
– 
Clinical course of the event  
– 
Course of treatment  
– 
Evidence supporting recovery  
– 
Follow-up to the clinical course  
 
Any treatments administered for the event should also be entered in the Concomitant Medication eCRF.  


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4. REFERENCES 
 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature Reviews Cancer 
2012; 12:252-264. 
 
2. Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein 
Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-9118/10/1-10. 
 
3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and Kinetics 
of 
Response 
With 
Ipilimumab. 
J 
Clin 
Oncol 
30. 
2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
 
4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with Ipilimumab in 
Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
 
5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, Activity, and 
Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454. 
 
6. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 Antibody in 
Patients with Advanced Cancer.  N Engl J Med 2012; 366:2455-2465. 
 
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase II study 
comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic 
budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591-5598, 2009. 
 
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the Management 
of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
 
9. Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal Antibodies in Patients with 
Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–3021. 
 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse reactions—
YERVOY Risk Evaluation and Mitigation Strategy (REMS). http://www.yervoy.com/hcp/rems.aspx 
 
11. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 


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5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
Pneumonitis (reported as ECI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Autoimmune hemolytic anemia  
Aplastic anemia  
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation 
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if  ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 


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6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
 
Past Medical History:  
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical 
History eCRF.  
 
1. Does the subject have any allergies? □ Yes □ No  
 
If yes, please obtain the following information:  
 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No  
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
______________________________________________  
_____________________________________________________________  
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? □ Yes □ 
No  
 
Describe the agent and type of allergic response: _____________________  
_____________________________________________________________  
 
c. Any allergy to food? □ Yes □ No  
 
Describe the food and type of allergic response: _____________________  
____________________________________________________________  
 
d. Any allergy to animals, insects? □ Yes □ No  
 
Describe the allergen and type of allergic response: ___________________  
____________________________________________________________  
 
e. Any other allergy? □ Yes □ No  
 
Describe the allergen and type of allergic response: _________________  
___________________________________________________________  
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
4. Is the current finding similar to a past experience? □ Yes □ No  
 


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7. APPENDIX 3 – Presentation of the Dermatologic Event 
 
Presentation of the event:  
Collect information on clinical presentation and potential contributing factors. Key information should be 
summarized and entered on the Adverse Experience eCRF. Any treatments administered should be entered on 
the Concomitant Medication eCRF.  
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
___________________________________________  
2. Has the subject contacted any known allergens? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, personal 
care product, poison ivy, etc.)? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)?           
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No  
 
If so what kind? __________________________________________________  
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No  
 
If so who and what? _____________________________________________  
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. Molluscum 
Contagiosum)?  □ Yes □ No  
 


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9. Has the subject had recent sun exposure? □ Yes □ No  
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
i. Anaphylaxis? □ Yes □ No  
ii. Signs of hypotension? □ Yes □ No  
iii. Signs of dyspnea? □ Yes □ No  
iv. Fever, night sweats, chills? □ Yes □ No  
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No  
 
List medication(s) and dose(s): _________________________________________  
___________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? □ Yes □ No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. APPENDIX 4 – Focused Skin Examination 
 
Focused Skin Examination:  
Key information should be summarized and entered on the Adverse Experience eCRF.  
 
Primary Skin Lesions Description  
Color: _______________________________________________________  
 
General description:  
______________________________________________________________  
______________________________________________________________  
 
Describe the distribution of skin reaction, skin eruption, or rash on the body:  
______________________________________________________________  
______________________________________________________________  
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
______________________________________________________________  
______________________________________________________________  
 
Any associated signs on physical examination? 
______________________________________________________________