Coordinated High Dose Interleukin-2 (Aldesleukin, Proleukin™) and Pembrolizumab (Anti-PD1, Keytruda™) for Therapy of Metastatic Kidney Cancer
Phase: PHASE2
Conditions: Kidney Cancer
Sponsor: H. Lee Moffitt Cancer Center and Research Institute

 
Coordinated High Dose Interleukin-2 (aldesleukin, Proleukin) and 
Pembrolizumab (anti-PD1, Keytruda) for Therapy of Metastatic Kidney Cancer 
 
NCT02964078 
 
Version 4 
March 16, 2020 

1 
 
 
 
 
Version date: 03/16/2020 
 
 
TITLE:  
Coordinated high dose interleukin-2 (aldesleukin, 
Proleukin™) and pembrolizumab (anti-PD1, Keytruda™) for 
therapy of metastatic kidney cancer 
 
 
MERCK study number: MISP# 52587 
Moffitt Cancer Center: MCC 18536 
Prometheus lab study ID: IIT15PLK02 
FDA IND #:  132688 
 
 
 
 
PI: 
Jad Chahoud MD, MPH 
 
Assistant  Member,  
Moffitt Cancer Center  
Department of  GU Oncology 
E-mail:  Jad.Chahoud@moffitt.org 
Office: 813-745-6926 
 
 
Moffitt Biostatistician: 
 
Michael Schell, PhD 

2 
 
 
 
 
PROTOCOL APPROVAL 
Coordinated high dose interleukin-2 (aldesleukin, Proleukin™) and pembrolizumab (anti- 
PD1, Keytruda™) for therapy of metastatic kidney cancer 
 
 
Protocol: IIT15PLK02 
 
Original Protocol Date: 9/30/15 
 
 
This protocol has been reviewed and approved by 
Prometheus: 
 
 
 
Date 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
Jad Chahoud MD 
Date 
 
Moffitt Cancer Center 

3 
 
 
Table of Contents 
Version date: 03/16/2020 .............................................................................................................. 1 
Jad Chahoud MD, MPH 
Moffitt Biostatistician: .................................................................................................................. 1 
Original Protocol Date: 9/30/15.................................................................................................... 2 
Narrative synopsis ........................................................................................................................ 7 
2.1 
TRIAL DESIGN ................................................................................................................ 8 
2.3 
Pembrolizumab dose plan .................................................................................................. 8 
2.4 
Trial Diagrams ................................................................................................................... 8 
2.4.2 
Infusion intervals .......................................................................................................... 10 
3.1 
OBJECTIVES & HYPOTHESES ................................................................................... 11 
3.3 
Secondary Objectives & Hypotheses ............................................................................... 11 
3.4 
Exploratory Objectives .................................................................................................... 12 
4.1 
BACKGROUND & RATIONALE ................................................................................. 12 
4.2.1 
Pharmaceutical and Therapeutic Background .............................................................. 13 
4.2.2 
Preclinical and Clinical Trial Data ............................................................................... 14 
4.2    Kidney cancer background ................................................................................................ 14 
4.3 
Aldesleukin IL-2 background .......................................................................................... 15 
4.4 
Rationale for the Trial and Selected Subject Population .................................................. 16 
4.4.2 
Rationale for the 5-in-a row IL-2 Schedule .................................................................. 17 
4.4.3 
Rationale for RCC subtypes ......................................................................................... 21 
4.4.4 
Rationale for Endpoints ................................................................................................ 22 
Rationale for assessment of the fraction of patients with at least half the doses ........................ 22 
4.4.4.2 Biomarker Research ..................................................................................................... 23 
4.5 
Combination rationale ...................................................................................................... 24 
5.1 
METHODOLOGY .......................................................................................................... 26 
5.2.2 
Subject Inclusion Criteria ............................................................................................. 26 
5.2.3 
Subject Exclusion Criteria ............................................................................................ 28 
5.2 
Trial Treatments ............................................................................................................... 30 
5.2.1 
Dose Selection/Modification ........................................................................................ 31 
5.2.1.2 Dose Modification ........................................................................................................ 31 
5.2.2 
Timing of Dose Administration ................................................................................... 33 
5.2.3 
No Trial Blinding ......................................................................................................... 35 
5.2.4 
IL-2 treatment checklist, before each IL-2 dose. ......................................................... 36 
5.3 
Response assessment and classification ........................................................................... 37 
5.3.1 
Measurable lesions ....................................................................................................... 37 
5.3.2 
Non-measurable lesions ............................................................................................... 37 
5.3.3 
Immune-related response criteria (irRC) ...................................................................... 37 
5.3.4 
Overall Response According to Immune-related response criteria (irRC) ................... 38 
5.4 
Randomization or Treatment Allocation .......................................................................... 38 
5.5 
Stratification ..................................................................................................................... 38 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................................... 39 
5.6.1 
Acceptable Concomitant Medications .......................................................................... 39 
5.6.2 
Prohibited Concomitant Medications ........................................................................... 40 
5.7 
Rescue Medications & Supportive Care .......................................................................... 41 

4 
 
 
• 
Pneumonitis: ........................................................................................................................ 41 
• 
Diarrhea/Colitis: .................................................................................................................. 42 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or .......... 42 
• 
Hypophysitis: ....................................................................................................................... 42 
• 
Hyperthyroidism or Hypothyroidism: ................................................................................. 43 
• 
Hepatic: ............................................................................................................................... 43 
• 
Renal Failure or Nephritis: .................................................................................................. 44 
5.8 
Diet/Activity/Other Considerations ................................................................................. 45 
5.8.2 
Contraception ............................................................................................................... 45 
5.8.3 
Use in Pregnancy ......................................................................................................... 46 
5.8.4 
Use in Nursing Women ................................................................................................ 46 
5.9 
Subject Withdrawal/Discontinuation Criteria .................................................................. 47 
5.9.1   Discontinuation of Study Therapy after CR .................................................................... 48 
5.10  Clinical Criteria for Early Trial Termination .................................................................... 48 
6.1 ............................................................................................................................................... 48 
6.2 
Additional retreatment will not be part of this protocol ................................................... 51 
7.1 
TRIAL PROCEDURES ................................................................................................... 52 
7.2.1 
Administrative Procedures ........................................................................................... 52 
General Informed Consent ...................................................................................................... 52 
7.2.1.2 Inclusion/Exclusion Criteria ......................................................................................... 53 
7.2.1.3 Medical History ............................................................................................................ 53 
7.2.1.4 Prior and Concomitant Medications Review ................................................................ 53 
7.1.1.4.2 
Concomitant Medications ......................................................................................... 53 
7.1.1.5 Disease Details and Treatments ................................................................................... 53 
7.1.1.5.2 
Prior Treatment Details ............................................................................................ 53 
7.1.1.5.3 
Subsequent Anti-Cancer Therapy Status .................................................................. 53 
7.1.1.6 Assignment of Screening Number ............................................................................... 54 
7.1.1.7 Assignment of Rando.mization Number ...................................................................... 54 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) .................................................... 54 
7.1.2 
Clinical Procedures/Assessments ................................................................................. 54 
7.1.2.2 Full Physical Exam ...................................................................................................... 55 
7.1.2.3 Directed Physical Exam ............................................................................................... 55 
7.1.2.4 Vital Signs .................................................................................................................... 55 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale ............................ 55 
7.1.2.6 Tumor Imaging and Assessment of Disease ................................................................ 55 
7.2 
Tumor Tissue Collection and Correlative Studies Blood Sampling ................................ 55 
7.2.1 
Laboratory Procedures/Assessments ............................................................................ 56 
7.2.1.1 Pharmacokinetic/Pharmacodynamic Evaluations ........................................................ 58 
7.2.2 
Other Procedures .......................................................................................................... 58 
7.2.3 
Visit Requirements ....................................................................................................... 58 
7.2.3.1 Screening period........................................................................................................... 58 
7.2.3.2 Treatment Period .......................................................................................................... 58 
7.2.3.3 Post-Treatment Visits ................................................................................................... 59 
Safety Follow-Up Visit ........................................................................................................... 59 
Follow-up Visits ..................................................................................................................... 59 
Survival Follow-up ................................................................................................................. 59 
Second Course Phase (Retreatment Period) ........................................................................... 59 

5 
 
 
7.3 
Assessing and Recording Adverse Events ....................................................................... 59 
7.3.1 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ................................................................................................................. 60 
7.3.2 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ........................... 61 
7.3.3 
Immediate Reporting of Adverse Events to Merck and to Prometheus ....................... 61 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number: +1-215-993-1220 ................................................................................ 62 
7.3.3.2 Events of Clinical Interest ............................................................................................ 63 
7.3.4 
Evaluating Adverse Events .......................................................................................... 64 
7.3.5 
Sponsor Responsibility for Reporting Adverse Events ................................................ 68 
8.1 
STATISTICAL ANALYSIS PLAN ................................................................................ 69 
8.3 
Statistical Analysis ........................................................................................................... 69 
8.4 
Planned primary reporting analyses ................................................................................. 70 
Secondary analysis of other populations that are defined above. ............................................... 70 
8.5 
Adverse Event tabulation and classification .................................................................... 71 
8.6 
Correlative studies on specimens of tumor and of blood specimens: .............................. 72 
9.1 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES . 74 
9.3 
Packaging and Labeling Information ............................................................................... 74 
9.4 
Clinical Supplies Disclosure ............................................................................................ 74 
9.5 
Storage and Handling Requirements ................................................................................ 74 
9.6 
Returns and Reconciliation .............................................................................................. 75 
10.1 ADMINISTRATIVE AND REGULATORY DETAILS ................................................ 75 
10.3 Compliance with Financial Disclosure Requirements ..................................................... 75 
10.4 Compliance with Law, Audit and Debarment ................................................................. 75 
10.5 Compliance with Trial Registration and Results Posting Requirements.......................... 75 
10.6 Quality Management System and the PMC ..................................................................... 76 
10.7 Data Management ............................................................................................................ 76 
11.1 APPENDICES ................................................................................................................. 77 
11.3 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) .............................. 77 
11.4 NOTE: Response Evaluation  are in section 5.3 .............................................................. 77 
12.0 LITERATURE CITED ....................................................................................................... 78 
 
 

6 
 
 
1.0  TRIAL SUMMARY 
FIGURE 1: BLOCK FORMAT TRIAL SUMMARY 
 
Abbreviated Title 
Kidney cancer treatment: 5-in-a-row IL2 w/ pembrolizumab 
Trial Phase 
Feasibility (phase II) 
Clinical Indication 
Metastatic kidney cancer 
Trial Type 
Treatment 
Type of control 
Historical 
Route of administration 
IV: pembrolizumab (Keytruda™) 
IV: IL-2 (aldesleukin; Proleukin™) 
Trial Blinding 
None—open label 
Treatment Groups 
Single dose level 
Number of trial subjects 
26 
Estimated 
enrollment 
period 
4/2017 to 3/2019 
Estimated duration of trial 3 years 
Duration of Participation 
9 months treatment. 1-year landmark evaluation. 
 
Funding supported by: Prometheus Labs, San Diego, CA. 
 
Drug supplied: Pembrolizumab [MK-3475] supplied by Merck. 
Aldesleukin IL-2: Commercial supply. 
Regulatory Sponsor: Moffitt Cancer Center 
Data management: Moffitt Cancer Center 

7 
 
 
 
Narrative synopsis 
 
Medication background: IL-2 is a cytokine drug and PD-1 antibodies are immunotherapy 
drugs with demonstrated activity in kidney cancer, including a few patients with complete 
responses. Whereas IL-2 binds to an activating receptor (CD25/CD122/CD132; IL-2Rαβγ) 
on lymphocytes, and has decades of experience in clinical application, PD-1 antibodies such 
as pembrolizumab bind to and block the function of PD-1 receptors (CD 279) that decrease 
activation that would be prevented by ligation of PD-L1 (CD274; B7-H1), and are relative 
new entrants in oncologic therapeutics. The downstream physiologic events for either 
medication are well-studied, but complex, with changes of behavior of multiple, and varying, 
subsets of lymphocytes that may ultimately mediate the therapeutic effect. There is not a 
particular specific pathway that can be claimed to be a simple mechanism of action, for 
either. Similarly prediction of for whom there will be a major therapeutic response remains 
an inexact process, despite significant efforts in the separate experiences. While IL-2 therapy 
(referring to Proleukin™ prescribing information) requires a controlled, experienced setting 
for safe administration, pembrolizumab is a relatively simpler infusion process (as described 
on the Keytruda™ prescribing information), with outpatient infusions typically with no 
immediate complications. Immune-related or cytokine-related side effects of the two 
medicines also differ as far as kinetics. Typically (even when severe), IL-2 side effect 
subside within days of cessation of administration; immune activation events of PD-1 
directed immunotherapy may require active therapy with corticosteroids or other 
immunosuppressants, for weeks or more. 
 
Outcome goals background: As a fundamental goal of anticancer therapy, the durable, 
complete response remains a gold standard. In this prospective protocol concurrent, 
coordinated use of these two immunotherapies will be administered to patients in a 
prospective series, in the setting of an experienced IL-2 center. The use of a single-arm trial 
format will accommodate the key scientific developmental question of feasibility. An 
estimate of response completeness and durablility will also be calculated. Response and side 
effect experiences can be tabulated, but without the scale of a trial with a randomized 
treatment assignment, cross trial comparisons remain mathematically limited. 
 
Treatment plan: Patients with clear cell kidney cancer will be included; the extent of recent 
prior pretreatment will be restricted, consistent with the usual use of IL-2 (initial therapy) or 
with the indication of a related medication (nivolumab: after anti-angiogenic therapy). There 
are four blocks of 9 weeks (3 pembrolizumab infusions each, and interval radiologic and 
clinical disease assesment); the second and third blocks have concurrent administration of 
IL-2, with 20 planned doses divided into four courses of 5 doses each; and then the protocol 
treatment is discontinued which will address unmaintained durability for responses.This IL-2 
schedule differs from the Proleukin™ prescribing information in which two courses of 14 
doses each are used, by having more planned breaks, but the cumulative planned dose (20 IL- 
2 doses/block) is comparable to the typical delivered dose of the 14-dose plan. In the prior 
institutional experience with the 5-in-a-row IL-2 treatment as monotherapy, the 5 year OS 
was 65% among 20 kidney cancer subjects. 

8 
 
 
 
 
2.1 TRIAL DESIGN 
 
2.2 
Trial Design 
 
Overall schedule plan: The treatment is organized into blocks of 9 weeks, with 
pembrolizumab treatment planned for weeks 1, 4 and 7. On the second and third blocks, 
interleukin-2 is added, for 5 doses at a time, one dose every 8 hours, on a weekly schedule on 
the two weeks after the week 1 and the week 4 pembrolizumab doses. This works out to a 
plan of 20 doses per 9 week block. The fourth block is again pembrolizumab monotherapy, 
as was the first. If delays occur prior to the 2nd or 3rd block, up to one additional 3 week (one 
dose) pembrolizumab dose may be added, to keep the overall pattern, within the second and 
third blocks. If a complete response is identified (including after block 1), then 
pembrolizumab can be continued as specified to the end of block 4, or stopped sooner after at 
least 2 interval scans showing complete response, at the discretion of the treating physician 
or the study PI. The protocol specified treatment finishes after the end of the 4th block. This 
will typically be 36 weeks after start, but extra 3-week cycles of pembrolizumab are allowed, 
if needed to maintain the overall schedule, so duration of treatment may turn out to be a 
month or two longer. 
 
There is no dose escalation portion: The dose and schedule of IL-2 is fixed, 600,000 
IU/kg/dose, with a cap of 66 mIU/dose. Doses may be omitted for safety. The dose of 
pembrolizumab is fixed, flat dose 200 mg/dose. 
 
Safety monitoring: Sequential boundaries will be used to monitor dose-limiting toxicity rate. 
There is a detailed plan in section 8.5 
 
2.3 
Pembrolizumab dose plan 
 
Note: The definitions of immune related adverse events (irAE)  are 7.1.2.1. 
 
The dose of pembrolizumab is 200 mg/dose. This is an immunotherapy for which a sharp 
dose-response relationship of the irAEs to the pembrolizumab is not anticipated. 
 
The pembrolizumab dose of subjects already on treatment may be delayed or omitted for 
safety reasons. 
 
 
2.4 
Trial Diagrams 
 
2.4.1 Treatment intervals 
 
Key features: In the absence of schedule adjustments, all treatment starts (pembrolizumab or 
IL-2 admission) could be the same day of the week. 

9 
 
 
 
At least 5 days between the end of IL-2 admission and next pembrolizumab infusion gives 
time for resolution of IL-2 side effects before the irAE assessment before the next 
pembrolizumab dose. 
 
FIGURE 2: DOSE DAYS INTERVAL DIAGRAM 
 
 
 
 
 
 

10 
 
 
 
2.4.2 Infusion intervals 
 
FIGURE 3: INFUSION TIMES AND INTERVALS SUMMARY 
 
 
 
 

11 
 
 
 
3.1 OBJECTIVES & HYPOTHESES 
 
3.2 
Primary Objective & Hypothesis 
 
(1) Objective-Efficacy portion: Estimate the frequencies of disease response so as to be 
a basis to commit to more development of this schedule. Note that this is framed 
broadly, with the understanding that the decision to commit to further development of 
the schedule includes a variety of feasibility endpoints. 
 
The ORR will be defined as the CR + PR patients, with confirmation of the response 
status (numerator), among those ever treated (denominator). Hypothesis: For the 
efficacy portion H0: ORR is <20% and HA: ORR is>45%. Thus, a 45% ORR (CR + 
PR) would be considered of definite interest for further development, contingent on 
the feasibility assessment as well, as part of the decision. With a Simon 2-stage 
design, 24 evaluable patients are needed. 
 
Objective –Safety portion: The co-primary endpoint of adverse event and serious 
adverse event tabulation comprises a critical portion of the ultimate assessment of 
feasibility for moving forward with additional and directly comparative trials using 
this regimen. There are known frequencies of these (referencing the respective 
monotherapy prescribing information documents) for which this tabulation can be 
compared. The relatively small sample size of this series versus those series typically 
would prevent specific hypothesis testing. 
 
 
3.3 
Secondary Objectives & Hypotheses 
 
(1) Objective:  ORR for patients getting at least 4 doses of pembrolizumab and one dose of 
IL-2: 
 
 
(2) 
Objective: ORR for, and for patients completing at least 6 doses of pembrolizumab 
and at least 20 doses of IL-2 (designated as “completing at least half of the treatment 
per-protocol”.) 
 
 
(3) Objective: This is an exploratory safety objective: OS will be not demonstrably 
inferior to contemporary subjects with matched clinical risk features from 
PROCLAIM database observed OS (using p > .05) 
 
Hypothesis: H0: OS[1-year] is more than 20% lower than matched controls 
HA: ORR is same or better (using p > .05) 

12 
 
 
 
 
 
3.4 
Exploratory Objectives 
 
These objectives are expected to be developed as part of testing in parallel with testing of 
patients on other trials. While the specific conceptual goals are outlined here, the specific 
tests are not prespecified. 
 
(1) Objective: Exploratory analyses dividing retrospectively designated best 
responders versus remaining patients with respect to a variety of cell subsets, 
for example: DC:MDSC ratio; CD4+ : CD4: FoxP3+ ratio. CD8+ : NK cell ratio. 
 
Hypothesis: Pretreatment leukocyte characteristics will predict response 
 
(2) Objective: Exploratory analyses dividing retrospectively designated best 
responders versus remaining patients with respect to sets of immune related 
proteins assayed by Nanostring™ testing of tumor specimens for gene sets that 
have been proposed to be related to the chance of anticancer immune response. 
 
Hypothesis: The good-responder patients will have an overall  pattern 
consistent with those seen patients with other diagnoses who had had good 
response after other PD-1 treatment. For example, better responses if there is 
tissue PD-L1 expression > 5%, or interferon-gamma related gene expression. 
 
(3) Objective: Exploratory analyses of selected serum proteins to analyze for 
markers of immune response. 
 
Hypothesis: The good-responder patients will have an overall  pattern 
consistent with those seen patients with other diagnoses who had had good 
response after other PD-1 treatment. 
 
 
4.1 BACKGROUND & RATIONALE 
 
4.2 
Background –pembrolizumab (MK-3475) 
 
Refer  to  the  Investigator’s  Brochure  (IB)/approved  labeling  for  detailed  background 
information on MK-3475. 

13 
 
 
 
4.2.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. 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). 
The structure of murine PD-1 has been resolved. 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. 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. 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. Expression has also been shown during thymic development on CD4- 
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. 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 . 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. 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). 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 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. KeytrudaTM (pembrolizumab) has been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
4.2.2 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure of Pembrolizumab for Preclinical and Clinical data. 
 
4.2    Kidney cancer background 
 
4.2.1   Clear cell renal carcinoma 
 
In 2015 in the US, an estimated 61,560 new cases of renal cell cancer and 14,080 deaths 
were predicted (National Cancer Institute website 2015. Approximately 85% of renal cancers 
are adenocarcinomas, which may be classified as clear cell, with a subset of granular cell. 
The majority of patients are diagnosed when the tumor is still relatively localized. Renal cell 
carcinoma can be cured if it is diagnosed and treated at this early stage, and overall 
approximately 40% of patients survive for 5 years. However, for those patients with 
advanced, recurrent or metastatic disease prognosis is much poorer, and almost all Stage IV 
tumors are incurable. Of interest, renal cell carcinoma is one of the few tumors in which 
rare, but well-documented cases of spontaneous regression occur without treatment. 
 
Treatment for Stage IV renal cell carcinoma may include surgical resection of the primary 
tumor, or of localized metastatic disease, or other localized therapies in selected patients. 
Cytotoxic chemotherapy shows little benefit but cytokine therapy with interferon alpha or 
interleukin-2 (IL-2) induces an overall response rate of approximately 15%. High dose IL-2 
alone produces durable complete remissions in approximately 5% of patients (Rosenberg 
1987, Fisher 1988, Weiss 1992, Rosenberg 1994, Fyfe 1995, McDermott 2005). 
 
Advances in the understanding of the biology of cancer have led to the development and 
regulatory approval of 6 new drugs since 2005 which target specific growth pathways. Most 
clear cell renal cell carcinomas carry the Von–Hippel Lindau (VHL) mutation which results 
in the constitutive production of angiogenesis factors (Schraml 2002), and several recently 
approved anti-angiogenic targeted drugs have been shown to delay progression in renal cell 
carcinoma.  Axitinib, a highly selective and potent inhibitor of VEGF receptors 1, 2 and 3, is 
 
16 

 
 
the most recently approved drug specifically for the treatment of advanced renal cell 
carcinoma after the failure of one prior systemic therapy. 
 
In addition to primary effects on tumor angiogenesis through the VEGF-signaling axis, there 
is increasing evidence that these targeted drugs may also elicit anti-tumor effects via complex 
interactions with the immune system. For example, sunitinib has been shown to reduce 
recruitment of myeloid-derived suppressor cells (MDSC) and tumor infiltrating Tregs to the 
tumor site, resulting in augmentation of the anti-tumor response. Renal carcinoma patients 
treated with sunitinib have improved peripheral blood Type 1 T cell responses (increased 
gamma interferon and decreased IL-4 production) and also a decrease in circulating Tregs. 
Increased peritumoral Tregs are a factor associated with poorer overall survival (Finke 2008, 
Xin 2009). If used in combination with a strong immune-enhancer such as IL-2, the anti- 
immunosuppression effects of targeted therapies may therefore have a synergistic anti-tumor 
growth effect. 
 
4.3 
Aldesleukin IL-2 background 
 
Use of IL-2 to treat kidney cancer has been an on-label standard of care for over 20 years, 
with the particular distinction that there is a consistent observation of a core of durable 
complete responders. That core has been a low percentage; while the durability has been 
excellent among the responders, and even those who do not have complete response appear 
to have survival better than the overall population of kidney cancer patients, the key 
challenge is to get complete responses for more patients. 
 
Another challenge with IL-2 treatment is drug delivery schedule. At least a dozen schedules 
have ranged from the high dose bolus (600,000 or 720,000) IU/kg/dose for a series of 14 
doses (current product label), 600,000 IU/kg/dose on a 5-in-a-row schedule (the one this trial 
is based on; Yang 2003; McDermott 2005), decrescendo high dose schedule (Lewis 2008), 
18 mIU/m2/24 hours x 120 hours continuous infusion (Negrier 1998), 5 mIU/m2/24 hours 
(Koulova 2005) bolus dosing at 72,000 IU/kg/dose (Yang 1994), and many subcutaneous 
regimens, such as 250,000 IU/kg/dose for 5 doses and then 125,000 IU/kg/dose for 25 doses 
at 5 doses per week (Sleijfer, 1992), some integrating interferon alpha (e.g. Atzpodien 1990) 
and GM-CSF, and other complementary immunomodulatory modalities (e.g. Antonia 2002; 
Nefedova 2007). 
 
What is missing to make the frequency of complete response higher? The issue of an 
unmaintained durable complete response has largely eluded the experience of VEGF and 
mTOR targeted pathway drugs, although they are the main treatments that most of the 
patients with kidney cancer are getting. That is not to say that the benefit of the targeted 
drugs is not real; objective tumor regression and impacts on survival are real, just mostly 
different from the experience of durable, complete response. 
 
17 

 
 
Checkpoint inhibitor therapies are inducing some instances of complete response in an 
unprecedented range of cancers of different histologic types, a big contrast with the prior 
experience of IL2 that was largely limited to clear cell kidney cancer and melanoma. 
Observed major responses of checkpoint inhibitor after prior cytokine therapy was observed 
in early nivolumab experiences, and also in later kidney cancer specific trials, and in a case 
report the converse sequence showed that IL-2 induced complete response after no regression 
on nivolumab. PDL1 expression in RCC has been suggested as a possible predictor of better 
response to IL-2 (Bailey 2103). 
 
The tumor attributes that are permissive for an effective complete response to occur remain 
to be studied and decoded. Ultimately, this project and others will be a part of this scientific 
discovery process; the answers will be complex, not simple single protein or cell type 
classifications. 
 
 
4.4 
Rationale for the Trial and Selected Subject Population 
 
4.4.1 Rationale for Pembrolizumab Dose Selection 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475. 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 MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity. Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
Pharmacokinetic data analysis of MK-3475 administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer to IB). 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q2W and Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475  were found to  be dependent  on body weight.  The relationship 
 
18 

 
 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights. MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). 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 indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
 
4.4.2 Rationale for the 5-in-a row IL-2 Schedule 
 
A variety of IL-2 schedules have been tested in the clinical development. An incomplete list 
demonstrating the spectrum of these include the on-label dose, 14 consecutive doses, at 15 
minute infusion, of 600,000 or 720,000 IU/kg/dose for the first course, and then a second 
course 9-16 days later, with each series of 14 being ended by a composite ending criterion 
 
19 

20 
 
 
 
rule including creatinine elevation, transaminitis, hyperbilirubinemia, peripheral edema, 
dyspnea, oliguria, tachycardia, hypotension, fatigue, or other clinical defined stopping issue. 
Others which have been formally tested include low doses given intravenously (72,000 
IU/kg/dose) on about the same schedule; continuous intravenous infusion (18 million 
IU/kg/24 hours x 120hours); subcutaneous schedules such as 250,000 IU/kg/dose, daily for 5 
days in week 1 then 125,000 IU/kg/dose for 5 daily doses in weeks 2-6; concurrent with TIL 
(tumor infiltrating lymphocyte) administration on a high dose schedule, and decrescendo 
schedule, and with concurrent chemotherapy (biochemotherapy) and with concurrent 
interferon. 
 
Of note, the on-label dose was the superior arm in two separate phase III randomized studies 
that compared that dose to either low-dose subcutaneous interferon and interleukin-2, or to 
low-dose interleukin-2 monotherapy. 
 
On a biological basis, two main populations of IL-2 receptors are present: The low-affinity 
receptor, with IL-2Rβ and IL-2Rγ (CD 122 and CD132) only, and the high affinity receptor 
with IL2-Rα (CD25) IL-2Rβ and IL-2Rγ. While either are ligated during the high dose 
administration, only the latter have high activation during low dose administration. It is the 
former, low affinity receptors, that may be the drivers of the functional anticancer 
lymphocyte effectors of kidney cancer clearance. Whether the NK cells, or CD8 T cells are 
either exclusively the relevant effector subset is not demonstrably established, despite 
decades of study. 
 
The 5-in-a-row schedule to be developed further here was the subject of a single-arm trial at 
Moffitt Cancer Center. The maintenance of the high dose, bolus format was selected to 
maintain the same biologic level of receptor ligation as on a standard schedule. A typical 
dose-delivery on the on-label 14-in-a-row schedule is 8-10 doses, or for two courses, about 
20 doses. The nominal total of 28/28 doses has been seldom attained. By splitting the total 
IL-2 of the IL-2 doses into four parts, of 5 planned doses each, a few favorable features are 
obtained: Each run of IL-2 is usually completed, or if not, the severity of the course-limiting 
event is less extreme. Most practically, the need to transfer patient to intensive care unit 
monitoring could be less frequent, and that will contribute substantially to perception of 
feasibility of the treatment. The total overall dose delivery is maintained. There are 3 natural 
breaks between the four courses, instead of just one, and this accommodates adjustment of 
intervals between doses as needed for side effects management. Additionally, since each 
hospitalization is for 3 days, the start and finish can be defined with more certainty, helpful 
for planning admissions, and helpful for the patient’s psychological outlook on the duration 
of each inpatient block 
 
In that pilot study, among 20 kidney cancer patients, 5 had major responses (two complete), 
and median overall survival was not reached at 5 years. (Finkelstein 2010) 16 melanoma 

21 
 
 
 
patients were also treated on that study. While a single arm study of the that protocol’s size 
cannot typically be mathematically definitive as comparative basis for the relative efficacy of 
the standard schedule, it does at least appear not worse than the 7%-8% CR rate and 21-23% 
ORR and ~17-24 months median survival described in the phase III clinical trials that used 
high dose IL-2 bolus (14-in-a-row) therapy as one arm (Yang 2003; McDermott 2005), or the 
phase III trial with continuous infusion (18 months; Negrier 1998). Those trials were in the 
pre-VEGFR-TKI era; contemporary risk stratification additionally makes a direct comparison 
prohibitive. Prior IL-2 therapy and then progression and then axitinib was described to show 
median overall survival of 30 months (Rixe 2007); the contemporary experience of IL-2 then 
targeted therapy is the subject of pending analysis through the PROCLAIM registry. Finally, 
the total cumulative dose administration, per course, is maintained, with most of the subjects 
in the pilot study getting 18-20 doses, out of the 20 planned. 
 
The aspect of the 14-in-a-row IL-2 schedule which is concurrently a subjective barrier for 
patient and physician acceptance and more frequent application, and also a barrier for IL-2 
combination therapy development is the use of runs of IL-2 treatment courses that 
consistently end with a limiting problem within the composite endpoint as described: 
hypotension, oliguria, malaise and others. These present an almost guaranteed high-grade 
side effect exposure, and this can be anticipated to obfuscate the relative contribution to acute 
side effects of a putative partner drug. This defines another theoretical advantage that is a 
rationale for selection of the 5-in-a-row IL-2 schedule for use in this trial. 
 
4.4.3 Rationale for RCC subtypes 
 
Most kidney cancer drug development has been either on an open histology basis – using the 
anatomic site of origin to restrict patients, mostly in older studies, or limited to clear cell type 
kidney cancer, in most newer studies. With retrospectively observed IL-2 complete responses 
mainly in clear cell RCC subtypes, and recognizing that the reference group for response 
assessments will be clear cell RCC patients treated with IL-2, at a practical level most of the 
patients should be clear cell RCC. 
 
Since part of the study hypothesis is that the anticancer activity of these drugs together will 
be better than either alone, and the feasibility of the regimen is a primary endpoint, a few 
patients that are not clear cell type could be allowed in the cohort. Initially, however, to 
maintain a study population that is comparable to prior experiences, only clear cell type will 
be included. Future development need not continue that restriction. 

22 
 
 
 
4.4.4 Rationale for Endpoints 
 
4.4.4.1 Efficacy & Dose Delivery Endpoints 
 
This is primarily a feasibility study. There is a formal safety format, because this is the initial 
human clinical experience with the two drugs together on this schedule. Feasibility for 
further development encompasses two issues: 
 
The first is the response rate of the disease. The trial design is a small, single arm design and 
would not be definitive for a registration or practice changing decision. Thus, the response 
rate will not be determined with high precision. Since differentiation of CR and very-good 
PR, by radiologic criteria, can be an issue for which determinations are ambiguous, and since 
the CR+PR (major response rate) is the typical metric for a new combination evaluation, the 
CR will be assessed, but the CR+ PR will be used as the primary outcome measure. Another 
key metric is overall survival or progression free survival; these have been shown to be 
typically better among patients who have been treated with IL-2 than those (non-randomly 
assigned) to not get IL-2, but require much longer time frame for follow up, and again do not 
lend themselves to definitive analysis in the present single arm trial. 
 
The second is the dose delivery. The proposition of this trial is that each of the drugs will 
contribute, and that this schedule is relevant. That can only be part of the logical conclusion 
if patients actually get the treatments as planned. If a very low dose delivery is achieved, and 
a high response rate is observed – that is generally good, but favors planning to use a 
different schedule in further testing. If a high dose delivery is achieved, but the response rate 
is unfavorable, that technically meets feasibility, but does not favor planning to continue to 
use this schedule. If the overall response rate (primary endpoint) of the trial is met and the 
dose delivery is relatively good, that would favor continued development of this dose and 
schedule for these drugs, for these type of patients. 
 
Rationale for assessment of the fraction of patients with at least half the doses 
In the randomized study of nivolumab versus everolimus, the median progression free 
survival was 4.6 months, corresponding to what would be about 6.5 blocks of 21 days. Thus, 
6 pembrolizumab doses is of interest, because it corresponds to a duration of PD-1 inhibition 
for which an overall survival benefit was demonstrated in patients with metastatic clear cell 
renal cancer. The total number of pembrolizumab doses planned in this study is 12. Six 
doses, whether all in a row, or in the unusual circumstance of interruption and then later 
administration, would be a cumulative dose of interest for that reason. (Motzer 2015) 
 
The total number of doses needed to have an IL-2 response is not firmly defined, despite 
decades of study. In the randomized study of high dose IL-2 vs low dose IL-2 and interferon, 
for which a statistically superior overall survival difference was observed in the former arm, 

23 
 
 
 
the dose delivery of 68% of 28 doses, that is 19 doses was used, for cycle #1. Later cycles 
were not summarized, the majority of patients did not get later cycles. (McDermott 2015) In 
the 2016 ASCO meeting, a threshold of at least 18 high dose IL-2 doses was identified as a 
marker of better response outcomes (Chow et al. 2016) 
 
Thus 6 doses of pembrolizumab covers about the same dose duration of nivolumab, and 20 
doses of IL-2 define threshold levels of drug delivery for which survival impact has been 
demonstrated in phase III randomized immunotherapy trials in patients with metastatic clear 
cell kidney cancer. The patients in those trials are not anticipated to be a group of patients 
which can be directly compared to the patients in this trial, because of the shifting availability 
other drugs, and contemporary patient selection. (Motzer 2015) 
 
 
For this purpose, a prospective definition of a achieving a minimal dose delivery will be set 
as at least 6 pembrolizumab doses and at least 20 IL-2 doses. Each patient will be assessed 
for this, not the overall averages. Other definitions can be considered; this feasibility concept 
is one that is used in conjunction with the efficacy part of the primary objective, the ORR 
estimate. 
 
 
4.4.4.2 Biomarker Research 
 
Biomarkers of the capacity for anticancer response are an important objective across the field 
of immunotherapy. 
 
Specimen collection at 4 time points will accommodate testing in coordination with other 
data sets. The plan will include: 
 
FIGURE 4: TYPES AND TIMES OF CORRELATIVE SPECIMENS 
 
 
 
Baseline 
(pretreatment or B1D1) 
Archival tumor 
Leukocytes 
Serum 
After 4 doses pembrolizumab/before IL-2 
(B2W2) 
Leukocytes 
Serum 
After 10x IL-2 
Leukocytes 

24 
 
 
 
(B2W4) 
Serum 
After all IL-2 
(B4W1) 
Leukocytes 
Serum 
 
 
4.5 
Combination rationale 
 
IL-2 and kidney cancer: The susceptibility of kidney cancer to IL-2 treatment has been a 
cornerstone of the cancer immunotherapy, but with limitations that define a ceiling on its 
overall the kidney cancer and generalizable oncologic impacts. Dimensions of this are 
limitations on how frequently complete responses are observed, and how many patients can 
tolerate a standard schedule, and how to build on (the current label) standard schedule, and 
how to have more centers available to patients. On the other hand, the achievement of 
unmaintained durable responses at 10-20+ years is not a limitation, but an opportunity and a 
standard for other anticancer therapies to aspire. The standard high-dose IL-2 inpatient 
treatment has associated high frequency side effects that must be managed in an experienced 
setting; not necessarily severe or debilitating, but requiring a base of experience for hospital 
staff and physician. Building on over 20 years’ experience, many functional IL-2 
administration centers with a steady (narrow) stream of patients having IL-2 administration 
and responses. These are tabulated in the Prometheus sponsored PROCLAIM registry (Wong 
et al. J Immunother Cancer. 2014; 2: 20). As practical issues of immunotherapy response 
determinants are developed, driven by responses and durable responses, a wider use of 
immunotherapy – cell therapies, checkpoints, or cytokines – can be anticipated. 
 
Checkpoint inhibition and kidney cancer: Cancer immunotherapy with checkpoint inhibitors 
has demonstrated potential for clinical impact in many cancers, including in kidney cancer. 
With regard to clinical experiences in PD-1 inhibition, trials with nivolumab monotherapy 
(Choueiri ASCO 2014 #5012), and with ipilimumab + nivolumab (Hammers ASCO 2014 
#4504) are examples of patients with kidney cancer with observed major regression after 
treatment including PD-1 checkpoint inhibition without other therapies. VEGF + checkpoint 
inhibition. Our case report observation of RCC regression on IL-2 after prior nonresponse to 
nivolumab (Brayer 2014) is a pointed example that immunotherapy responses to different 
drugs do not all represent responses within the same small subset of patients. Use of more, 
different immunotherapies may be a way to on a bigger fraction of the incident patient 
population. Registrational size phase III studies of nivolumab after VEGFR-TKI progression 
and of iplimumab + nivolumab as initial therapy are ongoing, with trial hypotheses to impact 
on median (50th percentile) survival. The relative potential of pembroluzimab vs other PD-1 
pathway  antibody  drugs  such  as  nivolumab,  MEDI-4376,  MPLD3280a,  particularly  in 

25 
 
 
 
patients with tumors that bear markers of immune susceptibility (such as lymphocytic 
infiltrates, or 12-chemokine signature, or PD-L1 expression) remains to be developed for 
kidney cancer therapy. Combination therapies overlapping checkpoint inhibition with VEGF 
treatments, just in kidney cancer, include axitinib and pembrolizumab (open at Moffitt), as 
well as nivolumab, and ipilmimab. Many other disease states are under study, including with 
approved VEGF pathway drugs. 
 
Checkpoints and cytokines, together: Every lymphocyte that is an effector of checkpoint 
inhibition response has IL-2 receptor on it (NK cells, T cells, B-cells all have IL-2 receptors). 
Conversely, every IL-2 activated lymphocyte, whether bearing low & intermediate affinity 
receptor (CD25 [IL2Rα] or CD 122 & 132 [IL2Rβ & IL2RƔ]) or high affinity receptor 
(CD25, CD122, CD132) has potential to have been modulated by PD-1 pathway, or to be 
later affected either directly through its own PD-1 receptors, or indirectly through the 
changed behavior of other lymphocytes bearing PD-1 receptor. As described by in our recent 
AACR poster (Choueiri et al 2014) PD-1 inhibition in kidney cancer patients induces two 
changes that are encouraging for synergy – more intratumoral lymphocytes, and more IL-2 
receptor (βchain). 
 
The core common feature of these immune therapies is that the lymphocytes bear receptors 
of both of these drugs and the intratumoral resistance mechanisms remain to be completely 
defined. One common feature, for example, may be that tumors with no discernable 
penetration by leukocytes are resistant. Another may be that patients with a high burden of 
tolerance promoting myeloid derived suppressor cells will not reach a response. How will 
NK and T cells respond to IL-2 in the context of PD-1 inhibition? That is the central 
biological question. That biological question is fundamental to the key clinical questions: 
Will more tumors regress? Will immunologic side effects be amplified in the short term? 
Will immunologic side effects be amplified in the long term? Both drugs have limitations— 
IL-2 with short term toxicity, pembrolizumab with unestablished durability of responses, 
potential for late autoimmune toxicity, and both with limited overall response frequency and 
incomplete algorithms for patient selection. However, this study will work towards finding a 
regimen that is feasible, and ultimately raising rates of durable, unmaintained remissions the 
central goal of oncolytic therapeutics. 
 
The rationale for the pembroluzimab and IL-2 combination in this study is to achieve safely a 
cooperative anticancer effect of both drugs. This is to use high dose, bolus IL-2 (so as to still 
have ligation of low affinity IL-2R), on a schedule that we had developed to accommodate 
having a relatively more stable overall dose delivery (5-in-a-row doses x four 3-day 
admissions instead of 14-in-a-row with two 6 day admissions; Finkelstein 2010), on a 
schedule that is reliable, and usually ends each course without a critical IL-2 dosing 
limitation. This now will be done in a context of inhibition of PD-1.  This development will 

26 
 
 
 
have to be done in a measured way, using experienced centers because of the unknowns as 
far as possible exacerbations of immune-related side effects. If response frequency and dose 
delivery appear promising, multicenter development will be appealing. In a small series such 
as this, the potential of each drug to induce a completer response in some patients is 
acknowledged – this is totally consistent with the rationale of combining these two for the 
central oncologic goal of increasing the fraction of complete responses. The scope of this 
study is limited to establishing this a as feasible schedule. Efficacy can be measured as 
progression free survival, major response rate, complete response rate, landmark 1-year 
survival, or median overall survival, any of which could be fundamental and reasonable 
components for the rational further development of oncologic therapeutics. 
 
Pharmacodynamic testing of lymphocytes should recapitulate the experiences of the 
nivolumab RCC treatment trial, as far as altered expression of lymphocytes proteins, and 
may define a way to understand the processes underlying clinical resistance, to be tested in 
further future trials. 
 
 
5.1 METHODOLOGY 
 
5.2 
Entry Criteria 
 
5.2.1 Diagnosis/Condition for Entry into the Trial 
 
Metastatic kidney cancer. Clear cell histology component from primary or metastatic lesion. 
 
5.2.2 Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1. Be willing and able to provide written informed consent for the trial. 
 
2. Age over 18 on day of signing informed consent. 
 
3. Have measurable disease based on RECIST 1.1.  
http://ctep.cancer.gov/protocolDevelopment/docs/Recist_Guideline.pdf 
4. Be willing to provide tissue from a newly obtained or archival tissue, if available. 
 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
6. Demonstrate adequate organ function as defined in Table 1. 
 
Table 1  Adequate Organ Function Laboratory Values 

27 
 
 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
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 
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  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
7. Female subjects of childbearing potential must 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. 
 
8. Female subjects of childbearing potential must agree 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 
5.8.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
 
9. Male subjects must 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. 
 
10. Cardiac testing with either exercise stress test or thallium stress test, within 3 months 
of start of the first treatment day. Atrial fibrillation that is rate controlled is allowed. 
Note – the first treatment day is about 9 weeks before the first IL-2 treatment day. If a 
cardiologist’s evaluation determines that this is superfluous based on other 
assessments, then this may be omitted. 
 
11. Pulmonary function test is required, within 3 months of start. The treating physician 
will assess suitability by usual clinical criteria  used for IL-2 treatment generally 

28 
 
 
 
consistent  with  the  Proleukin™  prescribing  information.  There  is  no  specific 
minimum result specified by the procotol 
 
5.2.3 Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has a known history of active TB  (Bacillus Tuberculosis) 
 
4. Has hypersensitivity to pembrolizumab or any of its excipients. 
 
 
5. The number of prior therapies is restricted as follows: 
 
Zero or one prior therapies during the preceding one year. This serves to limit the treatment 
cohort to patients with either only slowly progressive disease, or up to one prior therapy. 
 
No prior PD-1 or PD-L1 antibody therapies are allowed, as in #16 
Prior IL-2 is allowed, if it finished more than 1 year prior. 
The following are not counted as medical therapies:  nephrectomy, radiation therapy, other 
energy-ablative techniques, or metastasectomy. 
 
 
6. Has had a prior anti-cancer monoclonal antibody (mAb) 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. 
 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
 
- 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
 
- 
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy. 

29 
 
 
 
. 
 
8. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability. 
 
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (e.g.. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment that would be exclusionary. 
 
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
 
12. Has an active infection requiring systemic therapy. 
 
13. 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. 
 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
15. 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. 
 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
19. Has received a live vaccine within 30 days of planned start of study therapy. 

30 
 
 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed 
 
20. Myocardial  infarction,  stroke,  coronary artery  bypass  surgery,  coronary  stent,  or 
unstable angina within one year are excluded. 
 
Note: A subject may enroll in the study and have a start date set in the near future in a way 
that meets the timelines for exclusion items by the treatment start date 
 
 
5.2 
Trial Treatments 
 
The treatment to be used in this trial is outlined below in 
Table 2 
 
 
Table 2 Trial Treatment 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
outpatient 
Every 21d ± 3d 
Experimental 
Interleukin-2 
15 minute 
infusion of 
600,000 
IU/kg/dose* 
q8h x5 
IV infusion 
over 15 
minutes, 
inpatient 
Two courses set after 
corresponding 
pembrolizumab that 
defines day 1 of the 
cycle with intervals 
of: 
P W1: 2-9 days, 
usually 7 days 
W1 W2: 6-9 days 
usually 7 days 
Standard 
*actual body weight; capped at 66 million IU/dose for subjects > 110 kg. 
P = date of pembrolizumab dose 
W1 = date of first IL-2 dose of the course 
W2 = date of first IL-2 dose of the next course 
 
 
Trial treatment should begin as close as practical to the date on which eligibility is 
established and treatment level is allocated (for those patients on the part of the trial where 
the pembrolizumab dose is still not fixed). 

31 
 
 
 
5.2.1 Dose Selection/Modification 
 
5.2.1.1 Dose Selection 
 
The rationale for selection of the 200 mg/dose flat dose to be used in this trial is provided in 
Section 4.0 – Background and Rationale. 
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual. 
 
5.2.1.2 Dose Modification 
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
pembrolizumab-related toxicities and severe or life-threatening AEs as per Table 3 below. 
See Section 5.6.1 and Events of Clinical Interest Guidance Document for supportive care 
guidelines, including use of corticosteroids. 
 
In general, dose modifications of pembrolizumab are not required for events that appear to be 
directly related to interleukin-2 treatment and have resolved to a grade that is assessed as safe 
by the principle investigator, at the time of the next planned pembrolizumab treatment. 

32 
 
 
 
Table 3 
 
Dose Modification Guidelines for Drug-Related Adverse Events 
 
 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new onset Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure. 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug- 
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 

33 
 
 
 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
Note: These evaluations should be done in relation to each pembrolizumab dose. Adverse 
events that occur or are noted in between scheduled pembrolizumab infusions, but are within 
2 weeks after IL-2 administration and appear to meet Table 3 criteria, and have resolved at 
the point of the next pembrolizumab dose, and are attributed to the IL-2 treatment’s acute 
side effects do not count as events that are required to be managed as indicated in Table 3. 
For example, grade 3 creatinine elevation that resolved after the IL-2 was finished but before 
the next pembrolizumab infusion would not count as an AE that requires interruption of the 
pembrolizumab treatment schedule. 
 
5.2.2 Timing of Dose Administration 
 
Trial pembrolizumab treatment should be administered on Day 1 of each 3 week 
pembrolizumab cycle after all procedures or assessments have been completed as detailed on 
the Trial Flow Chart (Section 6.0), within the specified window. Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative or other practical reasons. 
 
Pembrolizumab 200 mg target infusion time is to be 30 minutes 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, which is 25 to 40 minutes). 
 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
 
Terminology notes: 
 
To keep with most of the pembrolizumab development, one “cycle” is designated as a 3 week 
span of time with one dose of pembrolizumab on the first day. To avoid confusion, for this 
document, the term “cycle” will be avoided for the IL-2 treatment courses, or for the time in 
between CT scans. 
 
One “block” for protocol purposes is a group of three (or four) pembrolizumab cycles. The 
pembrolizumab cycles are numbered a #1, #2, and #3.  A fourth cycle will be designated as 
#4e”, where “e” means extra, for an extra pembrolizumab-only 3-week cycle added to 
accommodate any scheduling issues. 
 
There are eight hospital admissions for IL-2 treatment, which are in the second and third 
weeks on the first and second cycles of the second and third blocks. These will be designated 
by the approximate week within the block, using B2 for the second block and B3 for the third 
block, and thus, for B2: B2W2, B2W3, B2W5, B2W6, and correspondingly for B3W2, 
B3W3, B3W5 & B3W6. 

34 
 
 
 
Since the “week” designation can be affected by intervals that are permissible (such as 6 
days, that would technically be during the same (conventional definition) calendar week, the 
protocol document will avoid designating the IL2 doses a being scheduled within a particular 
“week”, but instead will use the abbreviations defined above. (B2W2, etc.) where possible. 
 
 
This is the whole schedule: 
 
Start of block B1: 
 
Cycle 1 pembrolizumab dose 1. Interval to next dose 21 ± 3 days. 
 
Cycle 2  pembrolizumab dose 2. Interval to next dose 21 ±3 days. 
 
Cycle 3 pembrolizumab dose 3. Interval to next dose 21 ±3 days. 
 
End of block 1: 21 days after third pembrolizumab dose, or first pembrolizumab dose of next 
cycle, or 87 days after start. (This accommodates possible insertion of a “#4e” extra cycle of 
pembrolizumab, if needed). 
 
 
Start of block B2: 
 
Cycle 1 pembrolizumab dose 1. Interval to next dose 21 ±3 days. 
 
IL2 admission designated as “B2W2”: Usually 7 days, but target 2-9  days after block 2 cycle 
1 pembrolizumab. 
 
IL2 admission designated as “B2W3”: Usually 7 days, but target 6-9 days after B2W2. 
 
Cycle 2  pembrolizumab dose 2. At least 3 days but usually 7 days, or up to 10 days after 
B2W3.  Interval to next pembrolizumab dose 21 ±3 days. 
 
IL2 admission designated as  “B2W5”: Usually 7 days, but target  2-9  days after block 2 
cycle 2 pembrolizumab. 
 
IL2 admission designated as “B2W6”: Usually 7 days, but target 6-9 days after B2W5. 
Cycle 3 pembrolizumab dose 3. Interval to next dose 21 ± 3 days. 
End of block B2: 21 days after third pembrolizumab dose, or first pembrolizumab dose of 
next cycle, or 87 days after start of the first pembrolizumab dose of the block (If “#4e” used.) 

35 
 
 
 
Start of block B3: 
 
Cycle 1 pembrolizumab dose 1. Interval to next dose 21 ±3 days. 
 
IL2 admission designated as“B3W2”: Usually 7 days, but target  2-9  days after block 2 cycle 
1 pembrolizumab. 
 
IL2 admission designated as “B3W3”: Usually 7 days, but target 6-9 days after B3W2. 
 
Cycle 2  pembrolizumab dose 2. At least 3 days but usually 7 days, or up to 10 days after 
B2W3.  Interval to next pembrolizumab dose 21 ±3 days. 
 
IL2 admission designated as “B3W5”: Usually 7 days, but target   2-9   days after block 2 
cycle 2 pembrolizumab. 
 
IL2 admission designated as “B3W6”: Usually 7 days, but target 6-9 days after B3W5. 
Cycle 3 pembrolizumab dose 3. Interval to next dose 21 ±3 days. 
End of cycle 3: 21 days after third pembrolizumab dose, or first pembrolizumab dose of next 
cycle, or 87 days after start of the first pembrolizumab dose of the block. (If cycle #4e is 
used.) 
 
 
Start of block B4: 
 
Cycle 1 pembrolizumab dose 1. Interval to next dose 21 ±3 days. 
 
Cycle 2  pembrolizumab dose 2. Interval to next dose 21 ±3 days. 
 
Cycle 3 pembrolizumab dose 3. Interval to next dose 21 ±3 days. 
 
End of block 4: 21 days after third pembrolizumab dose. A cycle #4e may be used if a scan 
delay is anticipated. The end of block 4 is the end of the treatment phase of the study. 
 
5.2.3 No Trial Blinding 
 
This is an open-label trial; therefore, the Sponsor, investigator, staff, and subject will know 
the treatment administered. 

36 
 
 
 
 
5.2.4 IL-2 treatment checklist, before each IL-2 dose. 
 
 
Note: This list does not supersede the treating physician judgment on whether to withhold a 
dose or not.  
 
Lab results – refer to most recent results, generally fewer than 28 hours old.  
 
a. 
No current use of steroids or other anti-immune treatments prescribed for 
management of autoimmune problems. (Use of glucocorticoids for patients 
who are hypoadrenal is allowed). 
b. 
No Grade 2 or worse ongoing pembrolizumab-attributed events (Table 6b). 
c. 
Patient willingness to take another IL-2 dose – query nausea, motivation. 
d. 
Not requiring oxygen supplement 2L/min or less for oxygen saturation of 90% 
or more. 
e. 
Most recent creatinine level should be:  
a. under 150% of baseline value to start a course 
b. under 250% of baseline at most recent evaluation for later doses in the 
same course. (see note on physician judgment) 
f. 
 Systolic blood pressure above target level:  
a. i. Target = 80 mmHg if baseline was <100  
b. ii. Target = 85 mmHg if baseline was 100-120  
c. iii. Target =90 mmHg if baseline was 120+ mmHg systolic 
g. 
If atrial fibrillation is present—treating physician evaluation on per-case basis.  
h. 
Heart rate not documented as continuously 120 for more than 1 hour (during 
prior 8 hours). 
i. 
Dopamine off, or less than or equal to 2 mcg/kg/min. 
j. 
Urine output > 150 ml over last 8 hours. 
k. 
Two or fewer 500 ml NS bolus had been required in last 8 hours for treating 
blood pressure or urine output. 
l. 
Electrolytes and liver function tests should be reviewed by treating physician. 

37 
 
 
 
5.3 
Response assessment and classification 
 
Only patients with measurable disease at baseline should be included because objective 
tumor response is a part of the primary endpoint. Tumor assessments will be taken at 
baseline and during a defined window at the end of each Block and at 1 year. 
 
 
5.3.1 Measurable lesions 
 
Measurable Lesions are lesions that can be accurately measured in two perpendicular 
diameters, with at least one diameter ≥ 20 mm and the other dimension ≥ 10 mm (10 mm x 
10 mm for spiral CT). The area will be defined as the product of the largest diameter with its 
perpendicular 
 
5.3.2 Non-measurable lesions 
 
All other lesions, including unidimensionally measurable disease and small lesions (lesions 
without at least one diameter ≥ 20 mm), and any of the following: 
• Lesions occurring in a previously irradiated area (unless they are documented as new 
lesions since the completion of radiation therapy), bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonis, 
abdominal masses that are not pathologically/cytologically confirmed and followed 
by imaging techniques and cystic lesions. 
All measurable and non-measurable lesions should be measured at screening and at the 
defined tumor assessment time points. Extra assessments may be performed, as clinically 
indicated, if there is a suspicion of progression 
 
5.3.3 Immune-related response criteria (irRC) 
 
The irRC are the measurement of overall tumor burden as a metric of disease progression, as 
compared to the limitation to baseline lesion measurements taken with WHO and RECIST. 
According to irRC, new lesions do not constitute disease progression if net tumor burden 
(including new lesions) is stable or decreases. The irRC also permit disease progression 
prior to response and introduce the concept of confirmation of progression at a subsequent 
time point after first detection. This accounts for the period required for activated T-cells to 
infiltrate the tumor, which may cause initial tumor volume increase but can subsequently 
translate into tumor shrinkage. The irRC also classify durable stable disease as clinical 
activity. (Wolchok et al., 2009) 
 
Note: irRECIST will be used for the primary response tabulations. 

38 
 
 
 
5.3.4 
Overall Response According to Immune-related response criteria (irRC) 
 
FIGURE 5: irRC SUMMARY 
 
irRC 
New, measurable lesions (i.e. 
≥5 x 5 mm) 
Incorporated into tumor burden 
New, nonmeasurable lesions 
(i.e., <5 x 5 mm) 
Do not define progression 
(but preclude irCR) 
Non-index lesions 
Contribute to defining irCR (complete disappearance required) 
Complete Response (CR) 
Disappearance of all lesions in two consecutive observation not less 
than 4 weeks apart 
Partial Response (PR) 
≥50% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart 
Stable Disease (SD) 
50% decrease in tumor burden compared with baseline cannot be 
established nor 25% increase compared with nadir 
Progressive Disease (PD) 
At least 25% increase in tumor burden compared with nadir (at any 
single time point) in two consecutive observations at least 4 weeks 
apart 
Near Complete Response 
(Near CR) 
Reduction in tumor by > 90% and no new lesions in two 
consecutive observations not less than 4 weeks apart. 
Unknown (UN): 
Assessment of target lesions cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given. 
 
Note: If tumor response data is missing for target lesions, the overall assessment must be UN 
(unknown) unless there is new disease that would result in an overall assessment of PD. 
However, if there is missing or unevaluable data for non-target lesions, but data is available 
for all target lesions, the overall response for that time point will be assigned based on the 
sum LD of all target lesions. Additionally, the assessment of CR cannot be made if there is 
missing or unevaluable data for non-target lesions. In this case, the overall assessment would 
be PR. 
 
Definition of New Lesion: Previously unseen lesions >5x5 mm in size will be incorporated 
into tumor burden. 
 
 
5.4 
Randomization or Treatment Allocation 
 
There is no randomization on this trial. 
 
5.5 
Stratification 
 
There is no stratification on this trial, as there is only one arm.. 
 
Risk features are tabulated for accommodation of retrospective comparisons of outcomes. 

39 
 
 
 
These may include: 
 
1. Age 
 
2. Time from diagnosis to treatment 
 
3. Sites of metastatic disease 
 
4. Absolute neutrophil count 
 
5. Hemoglobin 
 
6. Platelet count 
 
7. LDH 
 
8. Calcium 
 
9. Albumin 
 
10. Nephrectomy status 
 
11. Prior therapy 
 
 
5.6 
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 
vaccination may be required. The investigator should discuss any questions regarding this 
with the Merck Clinical team. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. 
 
5.6.1 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 

40 
 
 
 
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. 
 
5.6.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Treatment Phase of 
this trial: 
 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy 
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
Note: A supportive medication or vaccination that has been prospectively approved by the 
principal investigator, or administered for a medically urgent reason and then later approved 
by the principal investigator, at a point in time after the patient has met inclusion criteria and 
before administration of the medication nor vaccination in question, and the patient has 
started on the first pembrolizumab dose cannot count as a protocol violation for reason of a 
prohibited concomitant medication violation. 

41 
 
 
 
5.7 
Rescue Medications & Supportive Care 
 
5.7.1 Supportive Care Guidelines for events attributed to pembrolizumab 
 
Note: Each adverse event will be attributed by the treating physician or the PI as follows: 
 
(1) Likely from pembrolizumab, but not to particularly to  IL-2 
 
(2) Likely from IL-2, but not particularly to pembrolizumab 
 
(3) Likely from the combination of IL-2 and pembrolizumab 
 
(4) Not apparently related to either IL-2  nor pembrolizumab. 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. 
 
The treatment guidelines are intended to be applied when the investigator determines the 
events to be related to pembrolizumab. The treatment of events that the investigator 
determines to be related to interleukin-2 may be managed in the usual manner, with no 
specific restrictions related to the participation in the protocol. 
 
Note: If after the evaluation the event is determined to be not related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification. For this trial, this particularly pertains to adverse events that are assessed to be 
usual events as described on the Proleukin™ prescribing information. (www.proleukin.com) 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 
 
• Pneumonitis: 

42 
 
 
 
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 
 
• Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
• Hypophysitis: 

43 
 
 
 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation), and for clinical signs and symptoms of 
thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
 Note: hyper- and hypothyroidism may occur in relation to IL-2 as well. 
The discontinuation or continuation of pembrolizumab is at the 
discretion of the treating physician. 
 
o Grade 3-4 hyperthyroidism 
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 

44 
 
 
 
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o Note: Isolated elevation of creatinine occurring in relation to IL-2 administration 
should be evaluated over several days to assess if there is actually a nephritis or not, 
before committing to use of systemic corticosteroids. 
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
 
 
 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
 
Table 4 Infusion Reaction Treatment Guidelines 
 
Note: Every event, such as isolated hypotension or oliguria or elevation of creatinine should 
be critically evaluated for attribution to IL-2 or to pembrolizumab. Those occurring after IL- 
2 treatment should be expected to have resolved before the next pembrolizumab infusion, 
which is at least 6 days later. 
 
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 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 

45 
 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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. 
 
 
 
5.8 
Diet/Activity/Other Considerations 
 
5.8.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.8.2 Contraception 
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has 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. 

46 
 
 
 
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 
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 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. 
 
5.8.3 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 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 and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck 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. 
 
5.8.4 Use in Nursing Women 
 
It is unknown whether pembrolizumab is 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. 

47 
 
 
 
5.9 
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 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. 
 
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. 
 
• Confirmed radiographic disease progression 
 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
 
• 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 
 
• Completed 
24 
months 
of 
uninterrupted 
treatment 
with 
pembrolizumab. 
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 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 end of treatment as described in Section 7.2.3.1). Subjects 
who discontinue 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. 

48 
 
 
 
Note: The treatment plan is for approximately 12 pembrolizumab infusions (36 weeks) 
treatment. 
 
5.9.1   Discontinuation of Study Therapy after CR 
 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declaredThere is no 
retreatment phase on this protocol. 
 
Subject Replacement Strategy 
 
Subjects with an apparent CR after B1, 9 weeks of pembrolizumab, may be treated with up to 
12 doses pembrolizumab, but no IL-2, at the investigator discretion. These will be replaced 
(up to the total enrollment target of 26). 
 
Subjects with clinical events after initial B1 dose of pembrolizumab, but then later not 
meeting usual criteria for treatment with IL-2 at the point in time of the B2W2 IL-2 start, 
despite having previously met them before start – for example new onset rapid atrial 
fibrillation – may continue on pembrolizumab at treating physician discretion, up to 12 
doses. These will be replaced (up to the total enrollment target of 26). 
 
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 
 
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. 

Product:  Pembrolizumab 
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6.0  TRIAL FLOW CHART FIGURE 6: STUDY FLOW CHART 
 
6.1 
 
 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Monotherapy 
(B1, B4, cE) 
IL2 combination (B2, B3) 
Treatment Cycle/Title: 
Pre- 
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
w1 
w4 
w7 
eval 
w9 
w1 
w4 
W7 
Eval 
w9 
Discontin- 
uation 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow- 
Up 
IL2 weekly: 
W2 or W5  = 2-9 days after pembro. 
W3 or W6 = 6-9 days after W2 or W5 
Pembrolizumab Scheduling Window 
(Days): 
-28 to 0 
B1 
<d1> 
* 
± 3 
± 3 
± 5 
W2 
W3 
± 3 
W5 
W6 
± 3 
± 3 
± 5 
At time of 
Discon- 
uation 
± 10 
30 days 
post 
discon- 
uation 
visit. 
± 10 
Every 2 
months 
post 
discon- 
uation. 
± 10 
Every 3 
months 
(by 
phone 
okay) 
± 30 
B4 
± 3 
Administrative Procedures 
Pre-screening 
x 
Informed Consent 
x 
Inclusion/Exclusion Criteria 
x 
Demographics and Medical History 
x 
Prior and Concomitant Medication Review 
x 
Pembrol Treatment Administration 
x 
x 
x 
x 
x 
x 
IL-2 treatment  called “W2” or “W5” 
x 
x 
IL-2 treatment  called “W3” or “W6” 
x 
x 
Post-study anticancer therapy status 
x 
Survival Status 
x 
x 
x 
x 

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Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Monotherapy 
(B1, B4, cE) 
IL2 combination (B2, B3) 
Treatment Cycle/Title: 
Pre- 
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
w1 
w4 
w7 
eval 
w9 
w1 
w4 
W7 
Eval 
w9 
Discontin- 
uation 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow- 
Up 
IL2 weekly: 
W2 or W5  = 2-9 days after pembro. 
W3 or W6 = 6-9 days after W2 or W5 
Pembrolizumab Scheduling Window 
(Days): 
-28 to 0 
B1 
<d1> 
* 
± 3 
± 3 
± 5 
W2 
W3 
± 3 
W5 
W6 
± 3 
± 3 
± 5 
At time of 
Discon- 
uation 
± 10 
30 days 
post 
discon- 
uation 
visit. 
± 10 
Every 2 
months 
post 
discon- 
uation. 
± 10 
Every 3 
months 
(by 
phone 
okay) 
± 30 
B4 
± 3 
Clinical Procedures/Assessments 
Review Adverse Events 
x 
x 
x 
x 
x 
x 
x 
Full Physical Examination 
x 
x 
W2 
W3 
W5 
W6 
x 
x 
x 
none 
Directed Physical Examination 
x 
x 
x 
x 
W1 
W4 
x 
x 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
x 
x 
x 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG 
(only for women of child bearing potential; 
must be <72 hours before first dose.) 
x 
x 
x 
x 
x 
x 
x 
PT/INR and aPTT 
x 
CBC with Differential & 
Comprehensive Serum Chemistry Panel 
x 
W1 
W2 
W4 
W5 
x 
x 
x 

Product:  Pembrolizumab 
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Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Monotherapy 
(B1, B4, cE) 
IL2 combination (B2, B3) 
Treatment Cycle/Title: 
Pre- 
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
w1 
w4 
w7 
eval 
w9 
w1 
w4 
W7 
Eval 
w9 
Discontin- 
uation 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow- 
Up 
IL2 weekly: 
W2 or W5  = 2-9 days after pembro. 
W3 or W6 = 6-9 days after W2 or W5 
Pembrolizumab Scheduling Window 
(Days): 
-28 to 0 
B1 
<d1> 
* 
± 3 
± 3 
± 5 
W2 
W3 
± 3 
W5 
W6 
± 3 
± 3 
± 5 
At time of 
Discon- 
uation 
± 10 
30 days 
post 
discon- 
uation 
visit. 
± 10 
Every 2 
months 
post 
discon- 
uation. 
± 10 
Every 3 
months 
(by 
phone 
okay) 
± 30 
B4 
± 3 
W3 
W6 
Urinalysis 
x 
x 
W2 
W3 
W5 
W6 
x 
x 
x 
T3, FreeT4 and TSH 
x 
x 
x 
x 
Efficacy Measurements 
Tumor Imaging 
x 
x 
x 
x 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
TissueCollection ** 
x 
Correlative Studies Blood Collection** 
(30 ml per time point) 
Pre- 
treatment 
(or 
B1W1) 
B4 
W1 
Pre 
B2 
W2 
At 
B2 
W4 
* B1W1 = this is by definition the first treatment day, so +/- 3 does not apply. B4: the +/-3 does apply. 

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** Correlative blood specimen collection procedure: 
 
Vaccutainer type or CPT tubes will be used for collection of 30 ml peripheral blood specimens. The tubes should be filled and inverted 8-10 
times after collection and prior to separation. The samples should be processed within 8 hours of collection and should not be refrigerated or 
frozen. 
 
Peripheral blood mononuclear cells (PBMC) will be isolated by density centrifugation using Ficoll™ and the cells will be frozen in 10% 
DMSO, 90% fetal calf serum and stored in vapor phase liquid nitrogen until ready for testing. 
 
Serum will be isolated by centrifugation and frozen similarly. 
Specimens will be stored in the Tissue Core repository. 
The PI will designate which specimens will be analyzed, based on factors including disease response and dose delivery. 
 
 
 
 
 
 
 
6.2 
Additional retreatment will not be part of this protocol 

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52 
 
 
 
 
7.1 TRIAL PROCEDURES 
 
7.2 
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 and/or 
Merck 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. 
 
7.2.1 Administrative Procedures 
 
7.2.1.1 Informed Consent 
 
The Investigator or designee must obtain documented consent from each potential subject 
prior to participating in a clinical trial. 
 
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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53 
 
 
 
 
7.2.1.2 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. 
 
7.2.1.3 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 the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
 
7.2.1.4 Prior and Concomitant Medications Review 
 
7.1.1.4.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
 
7.1.1.4.2 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. 
 
7.1.1.5 Disease Details and Treatments 
 
7.1.1.5.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
7.1.1.5.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
7.1.1.5.3 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. 

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7.1.1.6 Assignment of Screening Number 
 
This will be through the Oncore computer program. 
 
7.1.1.7 Assignment of Rando.mization Number 
 
Not applicable to this protocol 
 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
 
Medication compliance documentation: same as infusion schedule. 
 
Concomitant medication compliance: At least once per treatment block (9 weeks). 
Activity compliance: No restrictions; no data collected. 
Diet compliance: No restrictions; no data collected. 
Other compliance: At review of other treatments. 
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 11.2). Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an 
event of clinical interest (ECI) of a potentially immunologic etiology (termed immune- 
related adverse events, or irAEs); see the separate ECI guidance document regarding the 
identification, evaluation and management of potential irAEs. 
 
Note: Events that are consistent with the expected adverse events of IL-2 therapy, as 
annotated on the Proleukin ™ prescribing information, and which resolve along the expected 
time course (generally within a few days) are to be distinguished from pembrolizumab irAEs. 
 
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs. 

55 
Product:   Pembrolizumab 
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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, 
 
7.1.2.3 Directed Physical Exam 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration. 
 
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 need be measured at screening only. 
 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Section 11.1) 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 
 
About every 9-12 weeks, during the treatment cycles, and about every 2-3 months , through 1 
year, then as clinically indicated after that, using CT or MRI, at the discretion of the treating 
physician. Generally, the same modality will be used throughout, and should cover all known 
sites of disease. 
 
Several days interval should be used between administration of IV contrast and 
administration of high dose IL-2. The protocol schedule typically puts these at least a week 
apart. 
 
7.2 
Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
The following tissue and blood markers will be considered for correlative testing. 
 
(1) Quantitation of circulating cells with flow cytometry counts for  cells with lymphocyte 
phenotypes of CD3+, CD4+, T-regulatory, CD8+, NK+, MDSC, or DC, and conventional 
differential for granulocytes, platelets or other subtypes. 
 
(2) On the pretreatment tumor specimen, quantitation of infiltrating leukocytes that are positive 
for CD3, CD4 or CD8, by immunohistochemistry. 

56 
Product:   Pembrolizumab 
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56 
 
 
 
 
 
 
(3) On the pretreatment tumor specimen, quantiation of PD-L1. 
 
(4) Quantitation of serum cytokines and other proteins, including but not limited to: CXCL9, 
CXCL10 
 
(5) CD8+ lymphocyte analyses of gene expression; using the NanoString product, Multiplexed 
Cancer Immune Response Analysis nCounter® PanCancer Immune Profiling Panel for Gene 
Expression. A similar assay on other leukocyte subsets may be performed. 
 
The analysis plan for these secondary correlative endpoints is given in Section 8.5. 
 
7.2.1 Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below: Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. 

 
Product:   Pembrolizumab 
57 
Protocol/Amendment No.: 
Table 5  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 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
Uric Acid 
PK [not on this protocol] 
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) 
Total protein 
Blood Urea Nitrogen 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
‡ If considered standard of care in your region. 
 
 
 
 
 
57 

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58 
 
 
 
 
Laboratory tests timing and evaluation are described in section 6.1 . 
 
7.2.1.1 Pharmacokinetic/Pharmacodynamic Evaluations 
 
7.2.1.1.1 Blood Collection for Serum Pembrolizumab 
 
There is no pembrolizumab pharmacokinetics evaluation. 
 
7.2.1.1.2 Blood Collection for Anti-Pembrolizumab Antibodies 
The serum from the B1W1 and B4W1 will be used for this assay. 
Missing data will not be considered a deviation for this assay. 
Specimens  will  be  under  standard  Tissue  Core  program  procedures  for  collection  and 
storage. 
 
 
7.2.2 Other Procedures 
 
7.2.2.1 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. Subjects who a) attain a CR or b) complete all of the on-protocol 
treatment with pembrolizumab may discontinue treatment. After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit  and then the Follow-Up Period of the study. 
 
7.2.3 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. 
 
7.2.3.1 Screening period 
 
Evaluation of eligibility for inclusion and absence of exclusion. Target less than 30 days 
from consent to start of treatment. Tests as specified in the inclusion and exclusion criteria 
should be scheduled and evaluated. 
 
7.2.3.2 Treatment Period 
 
Approximately 36 weeks overall, divided into 4 blocks of 9 weeks each. 

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7.2.3.3 Post-Treatment Visits 
 
 
Every 2-3 months after the end of the treatment, through 24 months. These are necessary to 
accommodate screening for the occurrence of late adverse events. 
 
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. Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
 
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 as clinically indicated by radiologic 
imaging to monitor disease status, usually about every 2-3 months during the first year. 
After 1 year, usually every 3 months. Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, end of the study. Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
 
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 or other conventional communication method every 3 months to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
Second Course Phase (Retreatment Period) 
 
There is no retreatment course within this protocol. 
 
 
7.3 
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 

Product:   Pembrolizumab 
Protocol/Amendment No.: 
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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 Merck’s product 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. 
 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
 
All adverse events will be recorded from the time of Cycle 1 Day 1  through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. For purposes of this trial only lab findings that are deemed 
clinically significant and related to Pembrolizumab by the Investigator will be recorded.  
Only Adverse events or ESI’s related to Pembrolizumb will be recorded. Any Expected 
Adverse Event related to the administration of IL-2 will not be recorded in the CRF’s. 
 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (over 5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
 
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Product:   Pembrolizumab 
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any cause other than progression of the cancer under study that occurs to any subject from 
61 
 
 
 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical 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 and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
7.3.2 Reporting of Pregnancy and Lactation to the Sponsor 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 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 and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
7.3.3 Immediate Reporting of Adverse Events to Merck and to Prometheus 
 
7.3.3.1 Merck Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product 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 an other important medical event 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to 

Product:   Pembrolizumab 
Protocol/Amendment No.: 
62 
62 
 
 
 
 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 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 Merck product 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 the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number: +1-215-993-1220 
 
 
 
 
 
 
 
 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission. 
Additionally 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. 
  
Drug Safety Fax: (858) 754-3046  
 
A copy of any SAE report submitted to the IRB must be sent to Prometheus 
Laboratories. 
If Proleukin® (Aldesleukin, IL-2) is a suspect or co-suspect drug reported on the 
FDA Form 3500A MedWatch report, Prometheus Laboratories also requests a 
courtesy copy of the FDA Form 3500A MedWatch report that was submitted to the 
US Food and Drug Administration, via email or fax, to Drug Safety and 
Pharmacovigilance at Prometheus Laboratories, Inc.   
The report should include the  site contact information. 
Drug Safety Email: drugsafety@prometheuslabs.com 
Reporting to Prometheus 
7ADDITIONALLY: 

63 
Product:   Pembrolizumab 
Protocol/Amendment No.: 
63 
 
 
 
 
7.3.3.2 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 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 Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results. 
 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
 
*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. Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously 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. 
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to study 
treatment, consistent with standard SAE reporting guidelines. 
 
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. 

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65 
Product:   Pembrolizumab 
Protocol/Amendment No.: 
65 
 
 
 
 
• and respite care. 

Product:  MK-3475 
Protocol/Amendment No.: 
66 
 
 
 
Table 6b Evaluating Adverse Events with respect to pembrolizumab 
 
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 at any dose or during any use of Merck product 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 and units 
Action taken 
Did the adverse event cause the Merck product to be discontinued? 
Relationship  to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product 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 test drug and the adverse event 
based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
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 

Product:  MK-3475 
Protocol/Amendment No.: 
67 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
be present to be indicative of a Merck product relationship). 
 
ence of the AE onset relative to the administration of the Merck product 
n by another cause. 
 
 
the AE onset relative to administration of the Merck product is not 
or a subject with overdose without an associated AE.) 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued) 
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency 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 the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
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: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT 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 
Is the clinical/pathological presentation of the AE consistent with previo 
with Trial 
or toxicology? 
Treatment 
Profile 
us knowledge regarding the Merck product or drug class pharmacology 
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 
Yes, there is a reasonable 
There is evidence of exposure to the Merck product.  The temporal sequ 
possibility of Merck product 
is reasonable.  The AE is more likely explained by the Merck product tha 
relationship. 
No, there is not a reasonable 
Subject did not receive the Merck product OR temporal sequence of
possibility Merck product 
reasonable OR there is another obvious cause of the AE. (Also entered f
relationship 

Product:  MK-3475 
Protocol/Amendment No.: 
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7.3.5 Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 

Product:  MK-3475 
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8.1 STATISTICAL ANALYSIS PLAN 
 
8.2 
Statistical Analysis Plan Summary 
 
Overall response rate (ORR) and the 95% confidence interval of that estimate will  be 
obtained through binomial distribution theory, using the ITT population, with a one-sided 
endpoint, for the primary endpoint. Progression free survival, overall survival, landmark one- 
year progression free survival, landmark one-year overall survival will be obtained by 
Kaplan-Meier method. 
 
The adverse events will be tabulated descriptively, by grade. All AEs will be summarized by 
system organ class and preferred term. Listings and summary tables will be provided. 
Separate data listings and summaries will be presented for all serious adverse events (SAEs) 
and deaths. 
 
The correlative study tests will be analyzed as an exploratory assessment, or as part of a 
separate correlative protocol. 
 
8.3 
Statistical Analysis 
 
Study population definitions 
 
The primary endpoint, ORR, will be estimated, along with a with one-sided 95% confidence 
interval, counting evaluable patients (the “combination treatment population”) getting at least 
one per-protocol dose of IL-2, using binomial distribution theory. 
 
The response assessment and safety assessment populations are defined for the analyses as 
follows: 
 
FIGURE 7: Population definitions 
 
 
 
name 
description 
Intent to treat (ITT) population 
(ITT efficacy analysis) 
Eligible and registered 
Ever-treated population 
(Safety evaluation population) 
At least one dose of pembrolizumab 
Combination treatment population 
At least one dose of pembrolizumab (start of 
block  B1)  and  at  least  one  dose  of  IL-2 

Product:  MK-3475 
Protocol/Amendment No.: 
70 
 
 
 
(usually indicating a start of block B2, and 
usually at least 4 doses of pembrolizumab). 
Combination threshold population 
At least 6 doses of pembrolizumab and at 
least 10 doses of IL-2 (In any block). 
 
 
 
 
8.4 
Planned primary reporting analyses 
 
Analysis: Overall response rate ORR is defined with confirmation of the response status CR 
or PR among the combination treatment population patients; the binomial estimate and its 
one-sided 95% confidence interval will be reported. 
 
Analysis: Overall survival (OS) of ITT patients counting from the eligible date to death from 
any cause, or censored on end of known follow up, either within this study or in the 
PROCLAIM registry. 
 
Analysis: Progression-free survival (PFS) of ITT patients from the confirmed eligible date to 
the first occurrence of disease progression or death, from any cause, or lost to follow up, 
whichever is earliest; or censored at last follow-up during study. 
 
Kaplan-Meier method will be used for OS as well as PFS analysis. 
 
The Simon minimax two-stage design (Simon, 1989) with a 10% type I error and 90% 
power will be used to test the null hypothesis that overall response rate (CR+PR) ≤ 0.20 
versus the alternative hypothesis of overall response rate >0.45. In the 1st stage, 15 
patients will be treated. If 3 or fewer respond, the trial will be terminated. If 4 or more 
respond, an additional 9 evaluable patients (the “combination treatment population”) will 
be studied in the 2nd stage (a total of n=24 evaluable patients). If the total number 
responding is less than or equal to 7, the drug is rejected. This design has an expected 
sample size of 18 patients with a probability of early termination of 0.65. 
 
The overall total number of patients, counting patients with at least one dose of IL-2 
administered, will be up to n =26. This will accommodate replacement of subjects who 
are in the intent-to-treat(ITT) population, but not part of the main developmental 
objective of the study, which is the combination treatment population. 
 
 
Secondary analysis of other populations that are defined above. 
 
These include “ever treated”, “combination treatment” and “combination  threshold 
treatment” as described above. 

Product:  MK-3475 
Protocol/Amendment No.: 
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8.5 
Adverse Event tabulation and classification 
 
FIGURE 8: AE classification by population 
 
AEs will be classified in each of these categories: 
 
Population 
name 
AE 
category 
ITT population 
Ever-treated 
population 
Combination 
ever-treated 
population 
Combination 
Threshold 
population 
After enrollment 
but before any 
study drug 
administration 
After 
administration of 
at least one dose 
of 
pembrolizumab 
Among those 
with at least one 
dose of 
pembrolizumab 
and at least one 
dose of IL-2 
Among those 
with at least 6 
doses of 
pembrolizumab 
and at least 10 
doses of IL-2 
Unrelated 
Possibly related 
Probably 
related 
Definitely 
related 
 
 
AEs possibly, probably or definitely related to the study treatment (shaded area) will be 
summarized by system organ class and preferred term. 
 
Listings and summary tables will be provided. 
 
Separate data listings and summaries will be presented for all serious adverse events (SAEs) 
and deaths. 
 
1. Safety monitoring: Sequential boundaries will be used to monitor dose-limiting toxicity 
rate. The method is developed by Ivanova, Qaqish, and Schell (Biometrics, 2005) 
Briefly, the accrual of new patients to the trial will be suspended to accommodate re- 
evaluation of safety issues if the number of patients with dose-limiting toxicities is equal 
to or exceeds bn out of n patients who are part of the combination treatment population 
(see table). This is a Pocock-type stopping boundary that yields the probability of 
crossing the boundary at most 0.05 when the rate of dose-limiting toxicity is equal to the 
acceptable rate 0.15. 

Product:  MK-3475 
Protocol/Amendment No.: 
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Patients who have already enrolled, but not yet started on treatment with any 
pembrolizumab, at a point in time at which the accrual was suspended may be treated at 
the discretion of the investigator based on the safety evaluation. 
 
FIGURE 9: Table of Pocock boundary evaluation 
 
Table for number of patients k and Pocock boundary bk. 
Number 
of 
Patients, k 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
Boundary, 
bn 
- 
- 
3 
3 
4 
4 
4 
5 
5 
5 
5 
6 
6 
6 
6 
7 
7 
7 
7 
8 
8 
8 
8 
8 
 
 
If the number of patients k who have DLT events that are possibly, probably or 
definitely related equals or exceeds the boundary bk, the accrual to the trial will be suspended 
pending reevaluating toxicity by study PI and the Protocol Monitor Committee (PMC). This 
may include recommendations on patients who have already started on treatment. 
 
The DLT events for this safety purpose will exclude events that are judged by the PI to be 
typical for IL-2 treatment, referencing the experience as described in the package insert for 
Proleukin™ and have resolved by the point in time that the next dose of pembrolizumab is 
due. The DLT events to be counted here will include at least those defined as in section 7.3.4 
as these: 
 
• AEs leading to permanent dosing discontinuation of either pembrolizumab or HD IL- 
2 
 
• AEs ≥ Severity Grade 3 occurring after the HD IL-2 administration dates 
 
• Unexpected (according to medical judgment) AEs 
 
• Additionally, other events that the PI may designate. 
 
8.6 
Correlative studies on specimens of tumor and of blood specimens: 
 
These are all secondary endpoints, 
 
Responders versus remaining patients will be compared. 
 
The following tissue markers will be considered for correlative testing. 
 
(1) Quantitation of circulating cells with flow cytometry counts for  cells with lymphocyte 
phenotypes of CD3+, CD4+, T-regulatory, CD8+, NK+, MDSC, or DC, and conventional 

Product:  MK-3475 
Protocol/Amendment No.: 
73 
 
 
 
differential for granulocytes, platelets or other subtypes. The relevant ratios, such as DC: 
MDSC ratio; CD4+ : CD4/FoxP3+ ratio; CD8+ : NK cell ratio will be computed. 
 
(2) On the pretreatment tumor specimen, quantitation of infiltrating leukocytes that are positive 
for CD3, CD4 or CD8, by immunohistochemistry. 
 
(3) On the pretreatment tumor specimen, quantiation of PD-L1. 
 
(4) Quantitation of serum cytokines including but not limited to: CXCL9, CXCL10 
 
If the data follow a normal distribution, t test will be used for biomarker level comparison. If the data 
do not follow normal distribution then a power transformation (e.g. square-root, log) or non- 
parametric Wilcoxon rank-sum test approach will be adopted. The Bonferroni-Holm approach will be 
used to account for multiple testing to control type I error at 5%. Some tests may be dropped from 
the multiple testing group prior to analysis after the overall distribution of the biomarker is examined, 
but before it is divided by response group. Tests outside the multiple testing group will be studied at 
alpha = .05 individually, and considered as exploratory analyses. 
 
 
 
(5) CD8+ lymphocyte subset analyses of gene expression; using the NanoString product, 
Multiplexed Cancer Immune Response Analysis nCounter® PanCancer Immune Profiling 
Panel for Gene Expression. A similar assay on other leukocyte subsets may be performed. 
 
The 760 genes expressed will be compared for the responders versus the nonresponders, for 
the baseline specimens. 
 
The 
760 
genes 
expressed 
will 
be 
compared for the specimens after the 3 on 
treatment 
specimens 
versus 
baseline 
specimens. 
 
These analyses will identify genes for 
which there is a statistically significant 
difference 
of 
expression 
level. 
The 
description of these genes’ expression 
difference will be the endpoint, to address 
the hypothesis that differences of CD8+ 
gene expression are a consequence of the 
treatment with these medications that have 
targets on lymphocytes. 
 
 
The validation of the included genes are relevant to immune assessment is not a point of discussion to 
be repeated in the text of this protocol. The reader must refer to the white paper. These are the links: 

Product:  MK-3475 
Protocol/Amendment No.: 
74 
 
 
 
http://nanostring.yipkos.com/service/documents/ASCO2016/White%20Papers/NanoString_IO_White  
paper_Final%20(005).pdf 
 
http://nanostring.yipkos.com/service/documents/ASCO2016/White%20Papers/LBL-10117-  
02_WP_PanCancer_Immune_Profiling.pdf 
 
 
 
 
9.1 LABELING, PACKAGING, STORAGE AND 
RETURN 
OF CLINICAL 
SUPPLIES 
 
9.2 
Investigational Product 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
9.3 
Packaging and Labeling Information 
 
Clinical  supplies  will  be  affixed  with  a  clinical  label  in  accordance  with  regulatory 
requirements. 
 
9.4 
Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 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. 
 
9.5 
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 the 
trial site. 

Product:  MK-3475 
Protocol/Amendment No.: 
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Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.6 
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 
 
. 
 
10.1 ADMINISTRATIVE AND REGULATORY DETAILS 
 
10.2 Confidentiality 
 
The data will be maintained on the ONCORE program at the Moffitt Cancer Center. No 
personally identifiable data will be published. 
 
Outcome data will be available to Merck and to Prometheus. 
 
10.3 Compliance with Financial Disclosure Requirements 
 
All Financial disclosures, relationship to sponsors, will be organized as required by law. 
 
10.4 Compliance with Law, Audit and Debarment 
 
All applicable laws will be complied. 
 
No debarred physicians will be study investigators. 
 
10.5 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), the Sponsor of the trial 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. 

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10.6 Quality Management System and the PMC 
 
The principal investigator has the authority to stop the study, including stopping accrual, or stopping 
protocol-treatment. 
 
The principal Investigator is ultimately responsible for the study. 
The principal Investigator will review the Serious Adverse Events 
The principal investigator has the authority to stop the study, including stopping accrual, or stopping 
protocol-treatment. 
 
The adverse event data will be reviewed by the principal investigator in conjunction with the study 
biostatisticians. 
This is an investigator initiated trial, that will be monitored according to the Moffitt Cancer Center 
Policy for Monitoring of Investigator Initiated Clinical Research. Data will be captured in the Oncore 
computer database program. 
 
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 are accurate, complete and verifiable from 
source documents. 
 
Monitoring will be performed to ensure that the conduct of the trial is in compliance with currently 
approved protocol, and with Good Clinical Practice guidelines, and with applicable regulatory 
requirements. 
 
The study will be reviewed by the PMC for data and safety monitoring. This is the standard Moffitt 
Cancer Center Data Safety Monitoring Plan for investigator initiated studies. The PMC monitors for 
adverse event reporting, for data and safety monitoring, and internal audit findings. The PMC, upon 
review of an agenda item, may approve the study for continuation, recommend revisions, or 
suspend or close a protocol. 
 
10.7 Data Management 
 
Data  will  be  tabulated  from  source  documents  and  placed  into  custom  forms  on  the 
ONCORE program at Moffitt Cancer Center. 

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11.1 APPENDICES 
 
11.2 ECOG Performance Status 
 
FIGURE 10: ECOG PS table 
 
Grade 
Description 
0 
Normal  activity.  Fully  active,  able  to  carry  on  all  pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self- 
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
 
11.3 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) 
 
11.4 NOTE: Response Evaluation  are in section 5.3 
 
11.5 NOTE: Events of Clinical Interest Guidance Document is a separate document 

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12.0 LITERATURE CITED 
 
 
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