A Phase I Trial of Interleukin-2 (Aldesleukin) and Pembrolizumab Combination Therapy for Patients With Advanced Renal Cell Carcinoma
Phase: PHASE1
Conditions: Advanced Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer, Stage IV Renal Cell Cancer, Metastatic Clear Cell Renal Cell Carcinoma
Sponsor: University of Washington

COVER PAGE 
 
 
Title of Protocol 
A Phase I Trial of Interleukin-2 (Aldesleukin) and Pembrolizumab Combination Therapy 
for Patients with Advanced Renal Cell Carcinoma 
Principal Investigator 
Scott Tykodi, MD, PhD 
Institution  
University of Washington 
Supported by 
Merck 
Institutional Protocol Number 
CC 9611 
NCT Number 
NCT03260504 
 
 
 
 

 
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UNIVERSITY OF WASHINGTON 
 
Title of Protocol: 
A Phase I Trial of Interleukin-2 (Aldesleukin) and Pembrolizumab Combination Therapy for 
Patients with Advanced Renal Cell Carcinoma 
 
Investigators: 
Professional Title 
Phone Number 
Scott S. Tykodi, MD, PhD 
Principal Investigator 
Associate Professor, UW  
Associate Member, Fred Hutch 
(206) 606-7763 
John A. Thompson, MD 
Co-Investigator 
Professor, UW 
Member, Fred Hutch 
(206) 606-2044 
Shailender Bhatia, MD 
Co-Investigator 
Associate Professor, UW  
Associate Member, Fred Hutch 
(206) 606-6765 
Evan Hall, MD 
Co-Investigator 
Assistant Professor, UW 
Assistant Member, Fred Hutch 
(206) 606-2496 
Maria Tretiakova, MD, PhD 
Co-Investigator 
Associate Professor, UW 
(206) 897-4294 
Biostatistician: 
Mary Redman, PhD 
Associate Member, Fred Hutch 
(206) 667-4767 
Research Staff: 
Katie Viray 
 
Regulatory Coordinator 
(206) 606-7219 
Quynn Jacobs 
 
Clinical Coordinator 
(206) 606-7172 
 
Supported by: 
Merck 
 
 
 
IRO REC'D OCT 25 2022
FHCRC IRB Approval  
11/03/2022 
Document Released Date

 
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TABLE OF CONTENTS 
 
Section 
Page 
1.0 TRIAL SUMMARY 
11 
2.0 TRIAL DESIGN 
12 
2.1Trial Design  
12 
2.2 Dose Escalation 
12 
2.3 Cohort Expansion 
12 
2.4 Trial Diagram 
13 
3.0 OBJECTIVES 
13 
3.1 Primary Objective 
4 
3.2 Secondary Objective 
14 
3.3 Exploratory Objectives 
14 
4.0 BACKGROUND & RATIONALE 
14 
4.1 Background 
14 
4.2 Rationale 
19 
5.0 METHODOLOGY 
25 
5.1 Entry Criteria 
25 
5.2 Trial Treatments 
29 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
34 
5.4 Rescue Medications & Supportive Care 
35 
5.5 Diet/Activity/Other Considerations 
39 
5.6 Subject Withdrawal/Discontinuation Criteria 
39 
5.7 Treatment After Initial Evidence of Radiologic Disease Progression 
40 
5.8 Clinical Criteria for Early Trial Termination 
41 
6.0 TRIAL FLOW CHART 
42 
6.1 Study Flow Chart 
42 
7.0 TRIAL PROCEDURES 
46 
7.1 Subject Registration 
46 
7.2 Trial Procedures 
46 
7.3 Assessing and Recording Adverse Events 
52 
8.0 DATA AND SAFTY MONITORING 
58 
8.1 Safety Requirements 
58 
8.2 Records 
59 
8.3 Source Documents 
59 
8.4 Direct Access to Source Data and Documents 
59 

 
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9.0 STATISTICAL ANALYSIS PLAN 
59 
9.1 Statistical Analysis Plan 
59 
10.0 LABELING, PACKAGING, STORAGE AND DISPOSITION OF 
CLINICAL SUPPLIES 
60 
10.1 Investigational Product 
60 
10.2 Packaging and Labeling Information 
60 
10.3 Clinical Supplies Disclosure 
60 
10.4 Storage and Handling Requirements 
60 
10.5 Returns and Reconciliation 
61 
11.0 STUDY TERMINATION 
61 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
61 
12.1 Compliance with Trial Registration and Results Posting 
Requirements 
61 
13.0 APPENDICES 
62 
13.1 ECOG Performance Status 
62 
13.2 Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
63 
13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria 
for Evaluating Response in Solid Tumors 
64 
13.4 High-Dose Interleukin-2 (HDIL-2) Administration and Toxicity 
Management Guidelines 
65 
13.5 Contraceptive Guidance and Pregnancy Testing 
71 
14.0 LIST OF REFERENCES 
73 
 
 

 
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Table of In-Text Tables 
Table 1 
Drug Dose and Schedule 
13 
Table 2 
Adequate Organ Function Laboratory Values 
26 
Table 3 
Trial Treatment  
29 
Table 4 
Dose Modification Guidelines for Drug-Related Adverse Events 
31 
Table 5 
Infusion Reaction Treatment Guidelines 
38 
Table 6 
Laboratory Tests  
50 
Table 7 
Evaluating Adverse Events 
56 
Table 8 
Product Descriptions 
60 
Table 9 
ECOG Performance Status 
62 
Table 10 
Organ-by-Organ Toxicity Guidelines for Holding IL-2 Dosing 
67 
Table 11 
Standard Supportive Medications 
68 
Table 12 
As Needed Supportive Treatments 
69 
Table 13 
Additional Management Guidelines 
69 
Table 14 
Highly Effective Contraception Methods 
72 
 
 

 
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Table of In-Text Figures 
Figure 1 
Trial Diagram 
13 
Figure 2 
Study Flow Chart  
42 
 
 

 
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List of Abbreviations 
5HT3 
5-hydroxytryptamine3 receptor 
ADL 
Activities of daily living 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
attn 
attention 
B cell 
Bursa (or bone marrow)-derived lymphocyte 
BCG 
Bacillus Calmette–Guérin 
β-HCG 
Beta-Human chorionic gonadotropin 
BMP 
Basic metabolic panel 
BP 
Blood pressure 
CBC 
Complete blood count 
cc 
cubic centimeter 
CD 
Cluster of differentiation 
CDR 
Complementarity determining region 
CNA 
Copy number alteration 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRC 
Colorectal cancer 
CrCl 
Creatinine Clearance 
CRF 
Case report form 
CRS 
(Cancer Consortium) Clinical Research Support 
CSA 
Controlled Substance Act (Title II) 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte-associated Antigen-4 
D5LR 
5% Dextrose in Lactated Ringer`s solution 
DCR 
Disease control rate 
diff 
White blood cell differential 
DKA 
Diabetic ketoacidosis 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 

 
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DSMC 
Data Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
EC 
Ethics committee 
ECG/EKG 
Electrocardiogram 
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
ERC 
Ethics Review Committee 
EU 
European Union 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act  
FDAMA 
Food and Drug Administration Modernization Act  
FEV1 
Forced expiratory volume in 1 second 
FFPE 
Formalin fixed, paraffin embedded 
Fred Hutch 
Fred Hutchinson Cancer Center 
FT4 
Free T4 
FVC 
Forced vital capacity 
GI 
Gastrointestinal specialist (Gastroenterology) 
GFR 
Glomerular filtration rate 
Hct 
Hematocrit 
HCV 
Hepatitis C virus 
HD 
High-Dose 
HDIL-2 
High-Dose Interleukin-2  
HIF 
Hypoxia-inducible factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
hr 
hour 
HR 
Hazard ratio 
HSV 
Herpes simplex virus 
IB 
Investigator’s brochure 
ICU 
Intensive care unit 
IEC 
Independent ethics committee 
IFN-α 
interferon-alfa 
IFN-γ 
Interferon-gamma 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL-2 
Interleukin-2 

 
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IND 
Investigational New Drug 
INR 
International normalized ratio 
irAEs 
immune-related Adverse Events 
IRB 
Institutional Review Board 
IV 
Intravenous 
K 
potassium 
kg 
kilogram 
L 
Liter 
LD/LDH 
Lactate dehydrogenase 
LFT 
Liver function tests 
LVEF 
Left ventricular ejection fraction 
MAP 
Mean arterial pressure 
mAb 
monoclonal antibody 
mcg 
microgram 
mcL 
microliter 
MCV 
Mean corpuscular volume 
MD 
Medical doctor 
mg 
milligram 
Mg 
Magnesium 
min 
minute 
mL 
milliliter 
mmol 
millimole 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
mTOR 
mammalian Target of Rapamycin 
MUGA 
Multiple-Gated Acquisition Scan 
N 
Number 
NCI 
National Cancer Institute 
NK 
Natural killer cell 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OTC 
Over-the-counter 
PATS 
Protocol Accrual Tracking System 
PD 
Progressive disease 
PD1 
Programmed Cell Death 1 
PD-L1 
Programmed Cell Death 1 - Ligand 1 

 
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PD-L2 
Programmed Cell Death 1 - Ligand 2 
PFS 
Progression-free survival 
pH 
potential of Hydrogen 
PhD 
Doctor of Philosophy 
Phos 
Phosphate 
PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetic 
Plts 
Platelets 
PMDA 
Pharmaceutical and Medical Devices Agency 
PO 
Per os (by mouth) 
PR 
Partial response 
PT 
Protime 
Q1h 
Every hour 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
Q4h 
Every 4 hours 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors  
RN 
Registered nurse 
R/O 
Rule out 
RR 
Risk ratio 
SAE 
Serious adverse event 
SCCA 
Seattle Cancer Care Alliance 
SD 
Stable disease 
SDRB 
Safety Data Review Board 
SQ 
Subcutaneous 
SVT 
Supraventricular tachycardia 
T1DM 
Type 1 diabetes mellitus 
T cell 
Thymus-derived lymphocyte 
TCR 
T cell receptor 
TIL 
Tumor-infiltrating lymphocyte 
Teff 
Effector T Cell 
Treg 
Regulatory T cell 
TSH 
Thyroid-stimulating hormone 
U 
Unit 
ULN 
Upper limit of normal 
URI 
Upper respiratory infection 

 
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UTI 
Urinary tract infection 
UW 
University of Washington 
VEGF 
Vascular endothelial growth factor 
VHL 
Von Hippel-Lindau 
VT 
Ventricular tachycardia 
WBC 
White blood cell 
wk 
week 
 

 
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1.0 
TRIAL SUMMARY 
Abbreviated Title 
IL-2 and Pembrolizumab for Advanced RCC 
Trial Phase 
Phase I 
IND Number 
133532 
Clinical Indication 
Advanced or metastatic clear cell RCC 
Trial Type 
Therapeutic 
Type of control 
Historical control 
Route of administration 
SQ IL-2; IV IL-2   
IV pembrolizumab 
Trial Blinding 
None 
Treatment Groups  
Dose Level 1: SQ IL-2 plus IV pembrolizumab; 
Dose Levels 2 and 3: IV IL-2 plus IV pembrolizumab 
Number of trial subjects 
N=12 to 15 
Estimated Enrollment Period 
36 months 
Estimated duration of trial 
5 years 
Duration of Participation 
Maximum of 3 cycles of treatment (36 weeks) with follow-up. 
 
 
 

 
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2.0 
TRIAL DESIGN 
2.1 
Trial Design 
This is a phase I, open-label, dose escalation and conditional cohort expansion at the maximum 
tolerated dose (MTD) of Interleukin-2 (IL-2; aldesleukin), a soluble cytokine growth factor for T 
lymphocytes, in combination with pembrolizumab (MK-3475), a humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to target the Programmed Death 1 (PD1) 
membrane receptor on activated T lymphocytes.  Treatment is for patients with advanced or 
metastatic clear cell renal cell carcinoma (RCC). 
The study will consist of 3 periods: Screening (up to 28 days), Treatment (up to three 12-week 
courses), and Follow-Up (up to 1 year).  Each treatment course (“course” nomenclature is by the 
conventions of IL-2 treatment) is comprised of 4 doses (cycles) of pembrolizumab given by iv 
infusion every 3 weeks combined with 1 cycle of IL-2 given by SQ administration daily 5 
days/week for 6 weeks at Dose Level 1; or by IV bolus infusion (Dose Level 2 and 3) every 8 
hours to a maximum of 14 doses on weeks 1 (cycle 1) and 4 (cycle 2) of a treatment course.  
Investigator tumor response assessment (by RECIST v1.1) must be completed before the first 
dose of the next treatment course.  The maximum number of on-study treatment courses will be 
three. 
Following completion of treatment, patients with ongoing disease control (CR, PR, or SD) will 
enter Surveillance Follow-Up.  Disease status will be reassessed every 3 months for up to 1-year 
duration.  Patients with disease control completing one year of Surveillance Follow-Up or 
patients with disease progression will enter Survival Follow-Up to study completion. 
2.2 
Dose Escalation 
The study will use a 3 + 3 trial design for IL-2 dose escalation.  Rules for dose escalations are 
described in Section 5.2.1.2.  Definitions for dose-limiting toxicities (DLT’s) are described in 
Section 5.2.1.3.   
2.3 
Cohort Expansion 
On completion of Dose Escalation including data and safety analysis, the Principal Investigator 
and Merck will assess the feasibility to enroll additional patients at Dose Level 3 (or at the MTD 
Dose Level) to gain further preliminary insight into anti-tumor efficacy.  Commitment to open the 
Expansion Cohort and modification of the target enrollment will require protocol amendment. 
 
 

 
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Table 1  Drug Dose and Schedule 
Cohort 
Pembrolizumab 
IL-2 
1 
200 mg 
Q3W 
250,000 U/kg/dose 5 days/wk; wk 1; 
125,000 U/kg/dose 5 days/wk; wks 2-6 
SQ  
Dose Level 1 
2 
200 mg 
Q3W 
72,000 U/kg iv q 8 hrs x 14 doses;  
d2-6 and 23-27 of a 12 week course 
IV Bolus 
Dose Level 2 
3 
200 mg 
Q3W 
600,000 U/kg iv q 8 hrs x 14 doses;  
d2-6 and 23-27 of a 12 week course 
IV Bolus 
Dose Level 3 
 
Figure 1  Trial Diagram 
 
 
3.0 
OBJECTIVES 
The purpose of this study is to characterize the safety, tolerability, preliminary anti-tumor 
activity, and immunoregulatory (pharmacodynamic) activity of pembrolizumab in combination 
with IL-2 in patients with metastatic clear cell RCC.  The goal of this study is to demonstrate 
adequate safety and tolerability of the combination of pembrolizumab and IL-2 so as to permit 
further testing.  Information gathered will inform the dose and schedule of administration of 
pembrolizumab with IL-2 in future studies. 
3.1 
Primary Objective 
• To evaluate the safety and tolerability of IL-2 combined with pembrolizumab in patients with 
metastatic clear cell RCC. 
 

 
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3.2 
Secondary Objective 
• To assess preliminary antitumor activity of pembrolizumab in combination with IL-2. 
3.3 
Exploratory Objectives 
• To investigate the association of PD-L1 protein expression by pretreatment tumor with 
response to treatment. 
• To investigate the association of regulatory T cell (Treg) frequency and Treg to effector T 
cell (Teff) ratios in peripheral blood and tumor tissue with response to therapy. 
• To investigate the association of de novo serological and cellular responses against the 
ubiquitous RCC tumor antigen 5T4 with response to therapy. 
• To investigate the association of tumor infiltrating lymphocyte (TIL) repertoire clonality with 
response to therapy and to assess the detection of dominant TIL clones within peripheral 
blood over time in responding patients. 
• To investigate the association of whole genome copy number alterations measured on 
pretreatment archived, formalin fixed, paraffin embedded (FFPE) tumor with response to 
therapy. 
4.0 
BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Background on RCC and Standard Therapies 
RCC is the most common primary malignant tumor of the kidney in adults representing 
approximately 4% of all adult cancers [1].  RCC is rare in children and young adults, increasing 
in incidence with age and presenting with a median age at diagnosis of 64 [2].  RCC 
encompasses a heterogeneous group of tumors subdivided largely by their histologic appearance.  
The most common histologic types of RCC include clear cell (75% of tumors), papillary (10%), 
and chromophobe (5%) tumors.  Additional rare subtypes of RCC are recognized including 
medullary, collecting duct, and RCC associated with Xp11 translocation.  A pathologic diagnosis 
of unclassified RCC still accounts for 4-6% of all tumors [3].   
Clear cell RCC tumors in both hereditary and sporadic forms are associated with loss of function 
of the von Hippel-Lindau tumor suppressor gene on the short arm of chromosome 3 (3p25.3) as a 
result of deletion, mutation, or epigenetic silencing [4].  The loss of VHL expression results in 
the de-regulation of hypoxia-inducible factor (HIF)-1 and -2 transcription factors and 
constitutive expression of a number of hypoxia-responsive gene products that control 
angiogenesis, cell cycle, and energy homeostasis.  Insight into the abnormal molecular biology 
common to most clear cell RCC tumors has encouraged the clinical development of novel 
targeted therapies for this disease directed at signaling pathways affected by VHL inactivation.  
Since 2005, nine new anti-angiogenic drugs have been approved by the FDA for the treatment of 
advanced RCC.  These include oral tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, 

 
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axitinib, cabozantinib, and lenvatinib) that disrupt vascular endothelial growth factor (VEGF)-
receptor and other oncogenic pathway signaling mediated by receptor tyrosine kinases; the 
VEGF-specific monoclonal antibody (mAb) bevacizumab; and inhibitors of mammalian target of 
rapamycin (mTOR) (temsirolimus and everolimus).  Although these targeted therapies have been 
rapidly adopted as first and second line treatments for metastatic clear cell RCC, such therapies 
are fundamentally palliative as development of tumor resistance and disease progression has 
been a uniform observation.  The median time to tumor progression is < 12 months for patients 
treated with any of these single agents [5-13].   
Cumulative evidence suggests that cellular immune responses may play an important role in 
modulating tumor progression in cancer patients [14].  Specific examples include the 
documentation of rare spontaneous regressions of RCCs, melanomas, and other tumors [15], 
identification of naturally occurring T cells recognizing tumor-associated antigens in tumor 
patients [16, 17], and the positive association of T cell infiltration into tumors with favorable 
disease outcome  in various malignancies [14].  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. 
Such observations have encouraged the development and clinical testing of therapeutic strategies 
designed to augment tumor-specific T cell responses in cancer patients including vaccines, 
cytokines, cellular therapies, and most recently immune check point blocking antibodies.  
Identification and cloning of the genes for IL-2 and interferon-alfa (IFNα) led to the extensive 
clinical investigation of systemically delivered cytokines for RCC and other tumors beginning in 
the 1980’s.  IL-2 and IFNα were sufficiently active against advanced RCC to establish cytokine 
immunotherapy as standard front line treatment for RCC from the early 1990’s to the 
introduction of targeted agents beginning in 2005 [18].  
4.1.2 Interleukin-2 Therapy for Advanced RCC. 
Recombinant human IL-2 (aldesleukin), a potent growth and differentiation factor for T and NK 
cells was first explored as a cancer therapy in the mid 1980’s by investigators at the National 
Cancer Institute (NCI) Surgery Branch and subsequently other institutions.  Dose escalation 
studies identified the highest tolerable doses of IL-2 administered as an IV bolus on an every 8 
hour schedule.  Treatment with 720,000 U/kg or 600,000 U/kg by IV bolus every 8 hours to 
tolerance and a maximum of 14 doses on weeks 1 and 3 of a treatment course represented the 
high dose (HD) IL-2 regimen that received FDA approval for the treatment of metastatic RCC in 
1992.  Approval was based on pooled results of 255 patients treated as part of seven phase II 
clinical trials conducted at 21 institutions.  Patients received from 1 to 3 courses of therapy in 
total.  The overall objective response rate (ORR) was 14% with 5% complete responders (CRs) 
[19].  Most remarkable was the durability of CRs following IL-2 therapy.  For example, the long 
term follow-up of 259 RCC patients treated by HD IL-2 at the National Cancer Institute Surgery 
Branch noted recurrent disease in only 4 of 23 patients (17%) who achieved a CR with a median 
duration of ongoing CR > 11 years at the time of reporting [20].   
Despite acute and severe toxicities associated with administration of HD IL-2 necessitating 
inpatient and typically ICU-level care, the unique potential to achieve unmaintained CRs in RCC 
patients has sustained HD IL-2 as a viable first-line treatment option for highly selected RCC 

 
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patients even in the face of competition from the more recently available targeted therapies that 
are delivered in an outpatient setting. 
Alternate doses and schedules for IL-2 have also been investigated with the goal of avoiding 
severe toxicity and potentially the need for inpatient administration.  In a moderate size phase II 
study with 27 RCC patients, subcutaneous (SQ) IL-2 given once daily, 5 days per week for 6 
weeks in a fully outpatient setting observed an ORR of 23 % including 8% CR [21].  
Investigators at the NCI subsequently conducted a randomized, 3-arm trial to compare HD IL-2 
with low dose IL-2 regimens given as SQ dosing 5 days/week for 6 weeks, or 72,000 U/kg by IV 
bolus on a schedule of every 8 hours administration as for the standardized HD regimen.  
Although the low dose regimens demonstrated modest anti-tumor activity with ORR’s of 10% 
and 11% for SQ or low dose IV administration respectively, the investigators concluded the HD 
approach was superior for overall response rate (21%) depth of response (6% CR for HD vs 1-
2% for low-dose arms) and durability of response [22]. 
The Cytokine Working Group also studied standard HD IL-2 versus outpatient SQ IL-2 plus 
IFNα in a randomized phase III trial.  As seen in the NCI trial, HD IL-2 was also found to be 
superior to the SQ combination of IL-2 and IFNα by ORR (25% vs 12%), depth of response (8% 
vs 2% CR) and durability of response (median response duration 10 vs 7 months) [23]. 
The therapeutic index for HD IL-2 could be enhanced by improved selection of patients likely to 
respond.  Retrospective analyses of patient outcomes following HD IL-2 have empirically 
observed that clear cell RCC tumors are far more responsive than non-clear cell histologies to 
HD IL-2 [24, 25].  However, predictive markers for IL-2 response among clear cell RCC patients 
have remained elusive.  Selection of clear cell RCC patients suitable for treatment by HD IL-2 is 
based on clinical parameters that include a good performance status and intact cardiac, 
pulmonary, and renal function.   
4.1.3 PD-1/PD-L1 Pathway and Tumor Immunity  
Preclinical studies and results from early phase clinical trials now suggest that resistance 
mechanisms exploited by tumors may play a dominant role in limiting the effectiveness of T cell 
mediated cancer therapies [26].  Thus, an emerging and highly promising approach to cancer 
immunotherapy for advanced RCC and other cancers is antibody-mediated blockade of 
inhibitory co-receptors expressed on T lymphocytes; or so-called immune checkpoints. 
Programmed cell death-1 (programmed death-1; PD-1; CD279) is an immune checkpoint 
receptor emerging as a target for anti-tumor immunotherapy [26].  The PD-1 receptor-ligand 
interaction is a major pathway hijacked by tumors to suppress immune control.  
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, Tregs and Natural Killer cells.  The normal function of PD-1 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) [26].   

 
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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 [27].  
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. Tumor expression of PD-L1 has been associated with de-regulated oncogene signaling 
[28, 29], tumor hypoxia [30], and local inflammatory signals including IFN-gamma [31].  A 
model of tumor up-regulation of PD-L1 expression in response to TIL and local cytokine release 
as a mechanism to evade effector immune responses has been termed “adaptive resistance” and 
may represent the most common mechanism for PD-L1 expression in a wide variety of tumor 
histologies [31].  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. 
Regulatory T cells (Treg) inhibit cellular immune responses and help to maintain self-tolerance.  
Treg cells express constitutive high levels of several immune checkpoint receptors including 
CTLA4, PD-1 and others.  Rather than exerting inhibitory effects, these receptors appear to 
enhance Treg activity or proliferation.  Thus, separate from their influence on effector T cells, 
therapeutic antibodies blocking checkpoint receptors may also suppress the activity of Treg cells 
as an additional mechanism contributing to overall enhanced anti-tumor immunity [26]. 
The expression of PD-1 pathway proteins has been extensively studied in RCC tumors and 
shown to closely associate with RCC progression and poor disease specific outcomes.  In the 
largest reported series of 306 clear cell RCC tumors, Thompson and co-workers analyzed PD-L1 
expression by immunostaining formalin-fixed paraffin-embedded (FFPE) tissue samples.  Tumor 
cell membranous expression of PD-L1 (with a threshold of ≥ 5% of tumor cells stained with 
mAb 5H1) was seen in 24% of samples and strongly associated with cancer-specific death (risk 
ratio (RR) 3.92; P < 0.001).  This association also remained significant in multivariate modeling 
(RR 2.0, P=0.003) [32].  PD-1 expression by tumor-infiltrating lymphocytes has also been 
analyzed in both fresh-frozen or FFPE clear cell RCC tissue.  High PD-1 expression associated 
with distant metastatic relapse, and inferior relapse-free and overall survival versus the PD-1-
negative patient subset [33, 34]. 
The recognition of advanced RCC as a tumor responsive to immunotherapy together with 
evidence for a PD-1/PD-L1 mediated immune escape mechanism operating in RCC tumors has 
provided a compelling rationale for initial testing of blocking antibodies specific for PD-1 or PD-
L1 in patients with advanced RCC.  Nivolumab, a fully human IgG4 mAb specific for human 
PD-1 was tested in a dose escalation format in 296 patients that included 34 patients with 
advanced clear cell RCC treated at 1 or 10 mg/kg every 2 weeks [35].  In this heavily pre-treated 
cohort, significant anti-tumor activity was observed with an ORR of 27% and median duration of 
response 12.9 months.  Treatment was judged to be generally well tolerated and no MTD was 
reached.  Grade 3/4 treatment related adverse events were observed in 14% of patients and there 
were 3 drug-related deaths due to pneumonitis, however none in the RCC cohort [35].  In a phase 
II study, nivolumab was further studied in 168 RCC patients randomized to nivolumab at 0.3, 2 

 
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or 10 mg/kg every 3 weeks.  ORR by treatment group was 20%, 22% and 20% respectively and 
the overall rate of treatment related AE’s was 11%.  There were no high-grade pneumonitis 
events and no treatment related deaths.  There was no dose-response relationship detected for 
ORR, PFS, or incidence of treatment-related AE’s [36].  A phase III study of nivolumab 
(Checkmate 025) enrolled 821 RCC patients who had failed 1 to 3 lines of prior therapy 
including antiangiogenic treatment targeting the VEGF pathway.  Nivolumab given at 3 mg/kg 
every 2 weeks was compared to everolimus in 1:1 randomization.  Median overall survival 
favored nivolumab (HR 0.73, P=0.002) and the survival benefit for nivolumab treatment was 
seen independent of tumor expression of PD-L1.  The ORR determined by RECIST 1.1 was also 
superior for nivolumab (25% vs 5%).  There were no nivolumab associated deaths, and the 
incidence of grade 3/4 treatment-related AE’s was lower with nivolumab than everolimus (19% 
vs 37%). [37] 
Two blocking mAb’s targeting PD-L1 have also reported results from phase I clinical trials that 
included patients with advanced RCC.  Both BMS-936559 and MPDL3280A were judged to be 
well tolerated and demonstrated ORR’s of 12% and 14% respectively in heavily pre-treated RCC 
patients [38, 39].   
Taken together, the emerging data with blocking antibodies targeting PD1 or PD-L1 
demonstrating spontaneous and durable regressions for a subset of treatment-refractory RCC 
tumors suggests the PD-1 pathway represents a dominant control point for the regulation of 
tumor-reactive T cell responses.   
4.1.4 Preclinical and Clinical Trial Data for Pembrolizumab 
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.  Pembrolizumab has been studied in an open-label, single-arm, phase 2 trial 
(Keynote 427) as first-line, single-agent therapy for RCC patients with both clear cell (cohort A; 
N=110) and non–clear cell histology (cohort B; N=165) [40, 41].  With a median follow up of 
18.5 months, patients treated in Cohort A had a confirmed ORR of 36% and a median OS that 
has not been reached. The incidence of grade 3-5 treatment-related AE’s was 29% [40].Refer to 
the Investigator’s Brochure for additional pembrolizumab preclinical and clinical data.  
KeytrudaTM (pembrolizumab) is approved in the United Stated for the treatment of patients with 
advanced RCC (in combination with axitinib) and 14 additional cancer indications. 
4.1.5 Immune Checkpoint Antibody Combination Therapy for Advanced RCC 
The generally favorable safety profile for blocking antibodies targeting PD1 or PD-L1 has 
encouraged exploration of novel combinations incorporating these agents.  Nivolumab has been 
studied in combination with the anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) 
antibody, ipilimumab, versus sunitinib in the front-line setting in a randomized, phase 3 trial for 
patients with advanced, clear cell RCC (Checkmate 214).  In the primary analysis population of 
847 patients with intermediate or poor risk disease by International Metastatic Renal Cell 
Carcinoma Database Consortium (IMDC) criteria, ipilimumab plus nivolumab demonstrated a 
superior median OS that was not reached versus 26.0 months with sunitinib (hazard ratio for 
death, 0.63; P<0.001).  A superior ORR was observed with ipilimumab plus nivolumab versus 

 
Protocol/Amendment 3 v_16Sep2022 
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sunitinib (42% vs 27%; p<0.001) with a CR rate of 9% vs 1%, respectively.  Grade 3/4 
treatment-related adverse events occurred in 46% of nivolumab plus ipilimumab treated patients 
versus and 63% of sunitinib treated patients [42].  Based on these data, ipilimumab plus 
nivolumab received FDA-approval in April 2018 for treatment of intermediate and poor risk, 
previously untreated advanced RCC patients. 
 
Pembrolizumab has been studied in combination with axitinib, a VEGF-receptor selective TKI, 
in the front-line setting in a randomized phase 3 trial enrolling 861 patients with advanced clear 
cell RCC (Keynote 426).  After a median follow-up of 12.8 months, the estimated OS at 12 
months favored pembrolizumab–axitinib versus sunitnib (89.9% vs 78.3%; hazard ratio for 
death, 0.53; P<0.0001).  Median progression-free survival (PFS) also favored pembrolizumab-
axitinib (15.1 months vs 11.1 months; hazard ratio for disease progression or death, 0.69, 
P<0.001).  The ORR was 59% in the pembrolizumab–axitinib group and 36% in the sunitinib 
group (P<0.001).  The OS and PFS benefit of pembrolizumab plus axitinib was observed across 
all IMDC risk groups.  Grade 3/4 treatment-related adverse events occurred in 62.9% of 
pembrolizumab-axitinib treated patients versus and 58.1% of sunitinib treated patients [43].  
Based on these data, pembrolizumab plus axitinib received FDA-approval in April 2019 for the 
first-line treatment of patients with advanced RCC. 
 
The anti-PDL1 antibody avelumab has also been studied in combination with axitinib in the 
front-line setting in a randomized phase 3 trial enrolling 886 patients with advanced clear cell 
RCC (Javelin 101).  In the primary analysis population of 560 patients with PD-L1–positive 
tumors (63.2%), the median progression-free survival was 13.8 months with avelumab-axitinib 
versus 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61, P<0.001); 
and the ORR was 55.2% with avelumab plus axitinib versus 25.5% with sunitinib.  In the overall 
population, the median PFS for pembrolizumab-axitinib was 13.8 months, as compared with 8.4 
months for sunitinib (hazard ratio, 0.69, P<0.001) and PFS favored pembrolizumab-axitinib 
across all IMDC risk groups.  Grade ≥3 treatment-related adverse events occurred in 56.7% of 
avelumab-axitinib treated patients versus and 55.4% of sunitinib treated patients [44].  Based on 
these data, avelumab plus axitinib received FDA-approval in May 2019 for first-line treatment of 
patients with advanced RCC. 
 
In summary, treatment regimens containing blocking antibodies targeting PD1, CTLA-4 or 
PDL1 are now firmly established as front-line standard of care treatment options for most 
patients with advanced RCC. 
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Several preclinical and clinical observations support testing of the combination of IL-2 with 
pembrolizumab for patients with advanced clear cell RCC.  Recently, pretreatment tumor 
expression of PD-L1 was associated with response to HD IL-2 therapy [25].  In addition, high 
numbers of intratumoral Treg have been associated with poor survival for RCC patients treated 
with low- or intermediate-dose IL-2 [45].  These data suggest that PD-1 pathway blockade may 
disrupt counter-regulatory mechanism that limit the anti-tumor activity of IL-2 therapy in RCC 
patients. 

 
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The combination of IL-2 with PD-1 pathway blockade has been explored in a preclinical model 
of chronic viral infection and T cell exhaustion.  In the murine chronic lymphocytic 
choriomengitis virus infection model, IL-2 synergized with PD-1 pathway blockade enhancing 
virus-specific CD8+ T cell responses and deceasing viral load.  IL-2 proved more potent in this 
model than combining check point blocking antibodies targeting LAG-3 or TIM3 with anti-PD-
L1 or co-blockade of IL-10R and PD-L1 [46]. 
In a pilot study at the NCI, HD IL-2 was combined with the anti-CTLA4 mAb ipilimumab in 
melanoma patients.  Both drugs were able to be given at full doses without encountering dose 
limiting toxicity supporting the feasibility of developing combination therapy with immune 
checkpoint blockade and HD IL-2 [47].  Long-term follow-up of the patients in this study has 
suggested synergistic anti-tumor activity with 6/36 (17%) melanoma patients achieving CR [48].   
In a single-institution, single-arm study, patients with metastatic clear cell RCC were treated 
with pembrolizumab monotherapy x 3 cycles followed by pembrolizumab plus high dose bolus 
IL-2 delivered on a 5 dose per week schedule.  No treatment-limiting toxicity was encountered.  
Objective responses were observed in 20/26 patients (77%) including 3 CR (12%) [49]. 
4.2.2 Hypothesis for Combination Therapy 
The immune checkpoint receptor PD-1 and associated ligand PD-L1 may represent a dominant 
mechanism for RCC resistance and escape from immune surveillance and from anti-tumor 
effects mediated by IL-2.  Targeting PD-1 with the blocking mAb pembrolizumab in 
combination with IL-2 will result in a higher frequency and/or greater depth of anti-tumor effects 
in comparison to the historical experience with anti-PD1 or IL-2 monotherapy in untreated or in 
treatment-refractory patients. 
4.2.3 Rationale for Dose Selection/Regimen/Modification 
4.2.3.1  Rationale for Pembrolizumab Dose Selection 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W, representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2) 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 

 
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• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
 
4.2.3.2 Rationale for IL-2 Dose Selection 
IL-2 dosing will follow a 3+3 dose escalation scheme.  The starting Dose Level 1 will be 
250,000 U/kg/dose delivered SQ daily 5 days/week in the first week and then 125,000 
U/kg/dosed daily 5 days/week during the next 5 weeks as reported by investigators at the NCI 
[22].  The toxicity of low dose, SQ administered IL-2 is greatly reduced versus HD IV bolus 
dosing allowing a greater safety margin for assessing toxicity for IL-2 in combination with 
pembrolizumab.  This Dose Level also derives practical advantage for a fully outpatient 
treatment regimen.   
For dose escalation, IL-2 will convert to IV bolus dosing requiring inpatient administration.  At 
dose Level 2, patients will be treated by a low dose IV bolus regimen of 72,000 U/kg/dose IV 
every 8 hours to a maximum of 14 doses in 2 cycles per treatment course starting on day 2 and 
day 23 [22].  At Dose Level 3, patients will receive HD bolus dosing of 600,000 U/kg/dose IV 
every 8 hours to a maximum of 14 doses in 2 cycles per course starting on day 2 and day 23 
representing a conventional HD IL-2 treatment approach with cycle 2 dosing adjusted to follow 
pembrolizumab administered on day 22.  Recognizing there is practice heterogeneity in the 
delivery of HD IL-2, a two week (rather than 1 week) recovery period following cycle 1 
treatment is a standard approach at some treatment centers [50].  A 12 week treatment course for 
HD IL-2 is the standard convention of the Cytokine Working Group [25]. 
4.2.4 Rationale for Endpoints 
4.2.4.1 Primary Endpoint - Safety 
The primary objective of this trial is to characterize the safety and tolerability of pembrolizumab 
in combination with IL-2 in subjects with advanced clear cell RCC.  The safety analysis will be 
based on subjects who experience toxicities as defined by CTCAE v5.0 criteria.  Safety will be 
assessed by quantifying the toxicities and laboratory abnormalities by grades experienced, 
including any serious adverse events (SAEs).  Furthermore, potential immune-related adverse 
events (irAEs) will be collected and designated as immune-related events of clinical interest 
(ECIs) as described in Section 7.3.3.2.  The attribution to study drugs, time-of-onset, duration of 
the event, its resolution, and any concomitant medications administered will be recorded.  
 
4.2.4.2 Secondary Endpoint - Efficacy 
The efficacy objective of this trial is to evaluate the anti-tumor activity of pembrolizumab plus 
IL-2 in subjects with advanced RCC.  Responses will be evaluated by RECIST 1.1.  Best overall 
response rate (ORR) to include complete responders (CR) and partial responders (PR); disease 
control rate (DCR = CR+PR+stable disease, SD), and progression free survival (PFS) for 
patients treated with IL-2 combined with pembrolizumab will be collected and analyzed by 
cohort and for all treated patients.  Outcomes will be compared to historical data for RCC 
patients treated with IL-2 or anti-PD-1 as monotherapy. 

 
Protocol/Amendment 3 v_16Sep2022 
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Immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses which may be functionally anergic.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. In subjects who have initial evidence of radiological PD following a 
first course of treatment, it is at the discretion of the investigator whether to continue a subject on 
study treatment for a second treatment course. This decision should be based on the clinical 
judgment of the subject’s overall clinical condition, including performance status, clinical 
symptoms, laboratory data, and tolerance for study treatments.  
 
Subjects recommended to receive a second treatment course after PD should meet the following 
criteria: 
• Absence of signs and symptoms indicating disease progression 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
• Absence of rapid progression of disease 
• No decline in ECOG performance status 
This allowance takes into account the observation that some subjects can have a transient tumor 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response. 
 
4.2.4.3 Exploratory Endpoints - Biomarker Research 
4.2.4.3.1 Pretreatment Tumor PD-L1 Expression 
Responses to both IL-2 and to PD-1 pathway blocking mAb have been shown to be associated 
with PD-L1 expression on pretreatment RCC tumor cells [25, 36, 39] which may reflect the 
presence of a pre-treatment tumor-reactive adaptive immune response [51].  Thus, PD-L1 
represents a potential biomarker for tumor response to the combination of IL-2 and 
pembrolizumab.  FFPE archival or newly obtained tumor biopsy will be submitted to the central 
vendor for IHC analysis of PD-L1 expression. 
4.2.4.3.2 Regulatory T Cell Frequency in Peripheral Blood and the Tumor 
Microenvironment.  
As observed in other tumor histologies, increased numbers of Tregs (CD4+/CD25high/FOXP3+) 
are found in peripheral blood and TIL populations in RCC patients and are associated with 
adverse patient outcomes [52].  Tregs constitutively express IL-2 receptors and expand in 
response to IL-2 therapy representing a potential mechanism of tumor resistance to IL-2 
treatment.  Quantitatively higher numbers of intratumoral Treg have been associated with poor 
survival for RCC patients treated with low- or intermediate-dose IL-2 [45].  Tregs express high 
levels of several immune checkpoint receptors including CTLA4, PD-1 and others.  Rather than 
exerting inhibitory effects, these receptors appear to enhance Treg activity or proliferation.  
Thus, separate from their influence on effector T cells, therapeutic antibodies blocking 
checkpoint receptors may suppress the activity of Treg cells as an additional mechanism 
contributing to overall enhanced anti-tumor immunity [53].  Absolute numbers of Treg and the 

 
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Treg:Teff ratios in peripheral blood and TIL will be assessed at baseline and during therapy.  
Analyses of T cell subsets will be correlated with clinical outcomes. 
4.2.4.3.3 De Novo Immune Responses Targeting the Ubiquitous RCC Antigen 5T4. 
Detection of de novo serological and/or T cell responses specific for melanoma tumor antigens 
such as NY-ESO-1 likely represents on-target activity of immune check point blocking 
antibodies and is associated with favorable clinical outcomes in melanoma patients treated by 
ipilimumab [54, 55].  However, RCC does not commonly express CD8+ CTL-defined tumor 
antigens encoded by cancer-testis gene families (MAGE, BAGE, GAGE, or NY-ESO-1) 
frequently expressed in other tumor histologies [56].   
The 5T4 antigen is a cell surface glycoprotein expressed on many common epithelial tumors 
including 95% of primary RCC’s and is highly expressed on placental trophoblast cells, but is 
not detected on most other normal tissues.  A higher frequency of 5T4 expression has been 
associated with more advanced disease in patients with cervical, colorectal (CRC), ovarian, 
gastric, and non-small cell lung cancers (NSCLC) [57].  5T4 expression on NSCLC tumor-
initiating cells and by putative RCC tumor-initiating cells has also been recently described [58, 
59].   
The development of de novo 5T4 specific humoral and/or cellular immune responses during and 
following treatment of RCC patients with IL-2 plus pembrolizumab will be analyzed as a 
potential marker of “on target” effective anti-tumor immunity and correlated with clinical 
response.  
4.2.4.3.4 T Cell Receptor Repertoire Clonality in RCC TIL and Persistence of Dominant 
Clones in the Peripheral Blood of Responding Patients 
The array of potential tumor antigens including tumor mutation-specific neoantigens recognized 
by tumor-reactive T cells in RCC patients responding to immunotherapy with IL-2 or PD-1 
pathway specific agents is not well understood.  In addition, techniques to facilitate antigen 
identification in a clinically relevant time frame are also presently lacking.   
The application of high-throughput, quantitative sequencing applied to the T cell receptor (TCR) 
β chain CDR3 domains derived from complex T cell populations may yield a practical bioassay 
revealing T cell clonal expansions and thereby identifying an ongoing adaptive immune response 
within the tissue compartment that has been sampled.  Recently, such an approach was applied to 
analyze TIL within the tumor microenvironment of melanoma patients treated with 
pembrolizumab.  This study observed that a low TIL clonality phenotype was strongly associated 
with disease progression [51]. 
A similar sequencing analysis will be undertaken using pre-treatment archived RCC tumor.  The 
resulting TIL clonality score will then be correlated with clinical outcomes of RCC patients 
treated with IL-2 plus pembrolizumab.  Further, each unique TCRβ CDR3 sequence derived 
from an expanded TIL clone represents a screening tag that can be used to analyze other 
biological samples.  The presence/persistence of TIL-associated dominant clones detected within 
peripheral blood sampled over time on therapy will be associated with tumor response or 
progression. 

 
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4.2.4.3.5 The Association of Chromosomal Copy Number Alterations with Response to 
Therapy 
Gain-of-function oncogene mutations are rarely identified in whole-exome or whole-genome 
sequencing derived data sets for ccRCC tumors [60].  As a consequence, targeted gene-
sequencing based diagnostic panels have not made inroads into the clinical management of 
ccRCC patients.  In contrast, metastatic ccRCC tumors frequently contain large scale 
chromosomal abnormalities representing irreversible genetic derangements that can be readily 
identified by cytogenetic or array-based comparative genomic hybridization technologies [61, 
62].  Deletion of 3p is detected in the majority of ccRCC tumors and spans the Von Hippel 
Lindau (VHL) tumor suppressor gene at 3p21.  Additional common chromosomal abnormalities 
include gains (5q, 7) and losses (3p, 14q, 8p, 6q, 9p, 4p, and Y in males) occurring in > 10% of 
ccRCC tumors [61].  A subset of these chromosomal lesions (loss of 9p, 14q, and gain of 8q) 
represent independent poor prognostic markers for disease-specific survival [63-65].  
Hypothesis:  Subsets of ccRCC tumors defined by common chromosomal gains or losses will 
have different response rates to combination immunotherapy with IL-2 and pembrolizumab. 
Until recently, cytogenetic or array-based tumor genomic analyses required fresh tumor or frozen 
tissue specimens respectively, for analysis.  The OncoScan (Affymetrix, Santa Clara, CA) array 
platform is optimized for whole genome analysis of DNA isolated from formalin-fixed paraffin-
embedded (FFPE) tissue.  The ability to collect whole genome chromosomal CNA data 
retrospectively from FFPE tumor tissue now allows for directed analysis of patient cohorts 
receiving a common treatment to correlate genomic phenotypes with clinical outcomes.  
OncoScan chromosomal array analyses will be carried out on archived tumor for RCC patients 
treated with IL-2 and pembrolizumab and chromosomal CNAs correlated to objective response 
rate. 
 
 

 
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5.0 
METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 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. Be ≥ 18 years of age on day of signing informed consent. 
3. Have histologic confirmation of RCC with a clear cell component. 
4. Have advanced (not amenable to potentially curative surgery) or metastatic RCC. 
5. May have received previous systemic treatments or regimens for metastatic RCC.  Prior 
therapy can include checkpoint blocking antibodies targeting PD-1, PD-L1, or cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) and/or targeted agents including TKIs, mTOR 
inhibitors, or bevacizumab.  Patients may choose to receive study treatment as their initial 
therapy.   
6. Previously treated patients must have documented disease progression after their last line of 
therapy.   
7. Have measurable disease based on RECIST 1.1.   
8. Available tissue from an archival tissue sample or newly obtained core or excisional biopsy of 
a tumor lesion. 
9. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
10. Demonstrate adequate organ function as defined in Table 2.  All screening labs should be 
performed within 14 days of treatment initiation.   
 
 

 
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Table 2 Adequate Organ Function Laboratory Values 
System 
Laboratory or Study Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥40 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 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT)b 
 
Activated Partial Thromboplastin Time 
(aPTT)b 
≤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 
Pulmonary 
Pulmonary Function Testingc 
 
FEV1 and FVC ≥ 65% of predicted 
Cardiac 
 
LV functionc 
LVEF ≥ 50% measured by MUGA scan, echo, or stress test 
study with myocardial perfusion imaging 
Myocardial ischemia screeningc 
Normal/negative cardiac stress testing with myocardial 
perfusion imaging. OR 
Cardiac catheterization with non-significant angiogram 
findings reviewed by a Cardiology consultant 
aCreatinine clearance should be calculated by Cockcroft-Gault 
bDose Level 2 and 3 patients only.   
cTesting performed prior to study screening are allowable.  Pre-treatment testing must have been completed 
within 6 months of start of treatment. 
 
11. Female subject of childbearing potential should have a negative urine or serum pregnancy 
test 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.   
12. Female subjects of childbearing potential should be willing to use 2 methods of birth control 
or abstain from heterosexual activity for the course of the study through 140 days after the 
last dose of study medication (reference sections 5.5.2 and 13.5).  Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from menses 
for > 1 year.  
13. Male subjects who are not surgically sterile and have a female partner of childbearing 
potential should agree to use an adequate method of contraception or abstain from 

 
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heterosexual activity starting with the first dose of study therapy through 200 days after the 
last dose of study therapy (reference sections 5.5.2 and 13.5). 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has received prior therapy with IL-2 or other investigational systemic cytokine therapy 
signaling through a common γ-chain cytokine receptor including IL-7, IL-15 or IL-21. 
2. Is currently participating in or has participated in a study of an investigational agent or using 
an investigational device within 4 weeks of the first dose of treatment. 
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1.  Has had prior 
chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to 
study Day 1  
4. Adverse events due to prior treatment must be resolved to ≤ Grade 1. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. For patients previously treated with checkpoint blocking antibodies, no history of 
myocarditis, pneumonitis or nephritis of any grade associated with the prior treatment. 
6. Has had autoimmune toxicity associated with prior checkpoint blocking antibodies requiring 
more than one drug class of immune suppressive therapy to resolve (e.g. steroid-refractory 
toxicity requiring infliximab, mycophenolate mofetil, tacrolimus or other immune 
suppressive agent) or requiring continuous immune suppression > 12 weeks, or having a 
severity judged to be life threatening by the investigator. 
7. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include locally curable cancers such as basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the 
cervix or breast that has undergone potentially curative therapy.   
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
- 
(Dose Level 1) 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.   

 
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- 
(Dose Level 2 and 3) subjects may not have any history of or current CNS 
metastases.  Baseline imaging of the brain is required within 28 days prior to the 
start of study treatments. 
9. 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. 
 
10. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents.  Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule.  Subjects that require intermittent use of 
bronchodilators or local steroid injections would not be excluded from the study.  Subjects 
with hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be 
excluded from the study. 
11. Has history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or 
active, non-infectious pneumonitis/interstitial lung disease. 
12. Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation 
of the corrected QT interval defined as > 450 msec for males and > 470 msec for females. 
13. History of any of the following cardiovascular conditions within 6 months of enrollment: 
cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery 
bypass graft surgery, class III or IV congestive heart failure as defined by the New York 
Heart Association, symptomatic peripheral vascular disease, cerebrovascular accident, or 
transient ischemic attack. 
14. Has an active infection requiring systemic therapy. 
15. 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.   
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
17. 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. 
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
20. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of 
trial treatment.  Administration of killed vaccines are allowed. 

 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed. 
5.2 
Trial Treatments 
The treatments to be used in this trial are outlined below in Table 3 
Table 3 Trial Treatment 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Delivery 
Regimen/Treatment 
Period 
Use 
pembrolizumab 
200 mg 
Q3W 
IV infusion 
4 cycles per course 
Experimental 
Aldesleukin 
250,000 or 
125,000 U/kg 
Daily 
5days/7 
SQ 
1 six-week cycle per 
course 
Non-Standard 
Dose and 
Schedule 
Aldesleukin 
72,000 U/kg 
Q8 hrs x 14 
doses 
IV 
2 cycles per course 
Non-Standard 
Dose 
Aldesleukin 
600,000 U/kg 
Q8 hrs x 14 
doses 
IV 
2 cycles per course 
Standard 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 5.2.1.2. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
5.2.1.2 Rules for Dose Escalation 
Dose-limiting toxicities (DLT’s) observed in course 1 will be used to determine escalation to the 
next dose level.  A course is 12 weeks.  The study will use a 3 + 3 trial design for IL-2 dose 
escalation.  The first 3 patients will be enrolled at Dose Level 1.  If no dose-limiting toxicities 
(DLT’s) occur in the first 3 patients over treatment course 1, Dose Level 2 will then open for 
enrollment of the next 3 patients.  In the absence of DLT’s in three patients treated at Dose Level 
2, then Dose Level 3 will open for enrollment of the next 3 patients.   
If 1 of 3 subjects in a cohort experiences a DLT, the Cohort will expand to 6 pts.  If only 1 of 6 
patients experiences a DLT with all patients followed for safety endpoints to the end of course 1, 
then the next cohort dose level will open to enroll. 
If two or more patients in a cohort experience a DLT, that dose level exceeds the MTD. 
If two or more delayed DLT’s (i.e., DLT’s that occur after course 1) are noted within a dose-
escalation cohort, accrual will be held pending safety analysis by the Principal Investigator and 
Merck and restarted only with Principal Investigator and Sponsor approvals with IRB and FDA 
notification. 

 
Protocol/Amendment 3 v_16Sep2022 
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Dose escalations or de-escalations of pembrolizumab are not allowed.  Treatment delays for 
toxicity are allowable as described in Section 5.2.1.4.  Patients enrolled into Dose Level 3 who 
require treatment interruption and meet restarting criteria as described in Section 5.2.1.4 may 
have IL-2 dosing de-escalated to the IV IL-2 Dose Level 2 for the subsequent treatment cycle 
and/or course(s) 2 and/or 3.  Individual patient IL-2 dosing cannot be escalated. 
5.2.1.3 Definition of Dose-Limiting Toxicities 
All toxicities will be graded using the National Cancer Institute (NCI) CTCAE v5.0 (Appendix 
2; Section 13.2).  Dose-limiting toxicity (DLT) assessment will be based on events occurring 
during the DLT assessment period, which is defined as course 1.  Dose-limiting toxicities include 
all adverse experiences that are clearly not related to disease progression or intercurrent illness if 
judged by the investigator to be possibly, probably, or definitely related to study treatments that 
meet or exceed the following severity criteria: 
• Toxicities associated with pembrolizumab representing autoimmune phenomenon have 
been extensively characterized, and may be exacerbated by combination treatment with 
IL-2.  Treatment associated AE’s that represent immune mediated pathology are codified 
in Section 5.2.1.4, Table 4.  For patients at Dose Level 1, all AE’s resulting in Guideline 
recommendation for Treatment Discontinuation will also constitute a DLT. 
• A delay in the scheduled administration of either component of therapy of > 21 days for 
pembrolizumab or SQ or IV bolus IL-2. 
• Bolus IV dosing of IL-2 (Dose Level 2 and 3), especially at Dose Level 3, is known to be 
associated with acute severe toxicities.  Doses are administered to patient tolerance 
according to established treatment guidelines (Appendix 4, Section 13.4).  Toxicities 
associated with IL-2 administration will be initially managed according to the IL-2 
Toxicity Management Guidelines (Appendix 4, Section 13.4).  Toxicities that fail to 
stabilize within 48 hours of the last IL-2 dose or that fail to show improvement within 72 
hours of the last IL-2 dose will convert to management according to Section 5.2.1.4, 
Table 4 and resulting AE grade and Treatment Discontinuation assignment forming the 
basis for DLT determination. 
• Grade 5 toxicity 
5.2.1.4 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 drug-
related toxicities and severe or life-threatening AEs as per Table 4 below.  See Section 5.4.1 and 
Events of Clinical Interest Guidance Document for supportive care guidelines, including use of 
corticosteroids. 
Dose escalations or de-escalations of pembrolizumab are not allowed.   

 
Protocol/Amendment 3 v_16Sep2022 
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SQ IL-2 must be withheld for drug-related toxicities and severe or life-threatening AEs as per 
Table 4 below.  SQ IL-2 associated with AE’s requiring treatment interruption can be restarted at 
a reduced dose not lower than a 50% reduction of the recommended 125,000 U/kg dose. 
If possible, the Investigator may attribute each toxicity event to pembrolizumab or IL-2 alone 
with a resulting dose modification applied to a single study drug.  For example, local IL-2 
injection site reaction could result in a hold of SQ IL-2 dosing with pembrolizumab continued 
without interruption. 
Patients enrolled into Dose Level 3 who require treatment interruption and meet restarting 
criteria as described in Table 4 may have IL-2 dosing de-escalated to Dose Level 2 for the 
subsequent treatment cycle or course(s).  Individual patient IL-2 dosing cannot be escalated. 
Table 4 Dose Modification Guidelines for Drug-Related Adverse Events 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 
or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
4. 
Dependent on dose and duration of corticosteroid treatment, consider adding antacids for GI toxicity prophylaxis and 
antibiotics for opportunistic infection prophylaxis per clinic standard practice. 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs and 
symptoms of pneumonitis 
• Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
• Participants with 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. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 

 
Protocol/Amendment 3 v_16Sep2022 
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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable) 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-
hyperglycemic in participants 
with hyperglycemia  
 
• Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
• Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
• Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Asymptomatic 
Troponin 
Elevation 
Withhold 
• Consider corticosteroids 
• Repeat and monitor troponin 
• Consider Cardiology consultation 
for further diagnostic workup 
 
Grade 2 
Permanently 
discontinue 
• Administer corticosteroids 
(prednisone 2 mg/kg or 
equivalent) 
• Hospitalization 
• Urgent cardiology consultation for 
evaluation and management 
• Taper steroid over at least 1 month 
with close monitoring  
• Repeat cardiac MRI post 
treatment 
 
Grade 3 or 4 
Permanently 
discontinue 
• Immediate initiation of 
corticosteroids (prednisone 2 
mg/kg or equivalent or 1 g IV 
bolus) 
• Consider adding second 
immunosuppressive agent 
• Hospitalization to intensive 
cardiac care unit 
• Emergent cardiology consultation 
for evaluation and management 
• Taper steroid over at least 1 month 
with close monitoring  
• Repeat cardiac MRI post 
treatment 
 
 
 
 
 

 
Protocol/Amendment 3 v_16Sep2022 
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Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue  
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of 
AE administer corticosteroids  
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.   
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune 
related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; 
ULN=upper limit of normal. 
 
1NOTES:  
• 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab 
may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control 
(in case of T1DM).   
• 
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If 
control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
 
 
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 of the 
scheduled interruption, unless otherwise discussed with the Principal Investigator. The reason for 
interruption should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
Trial treatment should begin on Day 1 of each cycle after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).   
All pembrolizumab treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks (±2 days, 
see Section 6.0).  Every effort should be made to target infusion timing to be as close to 30 
minutes as possible.  However, given the variability of infusion pumps, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
IL-2 administration will follow pembrolizumab dosing for all cohorts.  Outpatient SQ IL-2 doing 
will begin on cycle day 1 after completion of the pembrolizumab infusion.  For day 1 cycle 1, 
patients should be observed ≥ 1 hour after completion of pembrolizumab before the first SQ IL-2 
dose. 
Patients will be admitted on cycle day 2 (or the next available ICU admission day) to begin IV 
IL-2 treatments for Cohorts 2 and 3. 

 
Protocol/Amendment 3 v_16Sep2022 
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5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
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 medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy 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 or 
the Principal Investigator.   
5.3.1 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 for the treatment of preexisting conditions in use immediately prior 
to the start of study treatment and/or up to 30 days after the last dose of trial treatment should 
also be recorded.  Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 7.3. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening, Treatment, 
and Follow-Up phases of this trial: 
• Anti-cancer 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 after consultation with Principal Investigator.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 

 
Protocol/Amendment 3 v_16Sep2022 
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vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed.  
• Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Principal Investigator.  
Subjects who, in the assessment by the investigator or Principal 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. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
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. 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.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
• Pneumonitis:  
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. 
• Myocarditis 

 
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o For Asymptomatic Troponin Elevation, repeat and monitor troponin.  Perform 
further diagnostic workup; ECG, cardiac MRI and consider Cardiology 
consultation.  Consider corticosteroids if troponin doesn’t normalize. 
o For Grade 2 events, hospitalize patients to expedite Cardiology consultation and 
evaluation.   
 Troponin and BNP; ECG and continuous cardiac monitoring; 
Echocardiogram and Cardiac MRI. 
 Administer prednisone or equivalent at 2 mg/kg.   
 Upon recovery, taper steroids over at least 1 month with close monitoring 
by lab testing and new symptoms.  Repeat cardiac MRI post treatment. 
o For Grade 3-4 events, hospitalize to intensive cardiac care unit with heart failure 
therapy as needed.  Emergent Cardiology evaluation 
 Troponin and BNP; ECG and continuous cardiac monitoring; 
Echocardiogram and Cardiac MRI. 
 Myocardial biopsy if feasible 
 Immediate initiation of immunosuppression with prednisone or equivalent 
at 2 mg/kg or 1 g IV bolus.  Consider adding a second immunosuppressive 
agent, such as ATG 
 Upon recovery, taper steroids over at least 1 month with close monitoring 
by lab testing and new symptoms.  Repeat cardiac MRI post treatment. 
• 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, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, 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 

 
Protocol/Amendment 3 v_16Sep2022 
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 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: 
o For Grade 2-4 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. 
• 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. 
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.  
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.  

 
Protocol/Amendment 3 v_16Sep2022 
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• 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 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
Table 5 Infusion Reaction Treatment Guidelines 
NCI CTCAE v5.0 Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
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. 
 
 

 
Protocol/Amendment 3 v_16Sep2022 
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5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
Pembrolizumab or IL-2 may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab or IL-2 have transient adverse effects on the composition of sperm.   
• Non-pregnant, non-breast-feeding women of childbearing potential (WOCBP) may be 
enrolled if they are abstinent from penile-vaginal intercourse or if they are willing to use 
2 methods of birth control (see section 13.5) for the duration of the study period up to 140 
days after the last dose of pembrolizumab.   
• Male participants with female partners of childbearing potential are eligible if they are 
abstinent from penile-vaginal intercourse or they and their partner(s) agree to use of 2 
methods of birth control (see section 13.5) for the duration of the study period up to 200 
days after the last dose of pembrolizumab. 
5.5.3 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 Principal Investigator and to Merck without 
delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a 
male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Principal Investigator and to Merck and followed 
as described above and in Section 7.3.2. 
5.5.4 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. 
5.6 
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 Principal Investigator if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  

 
Protocol/Amendment 3 v_16Sep2022 
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Specific details regarding discontinuation or withdrawal are provided in Section 7.2.4 – Other 
Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject withdraws consent. 
• Confirmed radiographic disease progression 
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 
5.7 
• Unacceptable adverse experiences as described in Section 5.2. 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s or Principal Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-Up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.2.5 (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 7.3.3.1).  Subjects who discontinue for 
reasons other than progressive disease will have post-treatment Surveillance 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 Survival Follow-Up until death, withdrawal of consent, or the end 
of the study, whichever occurs first. 
5.7 
Treatment After Initial Evidence of Radiologic Disease Progression 
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses which may be functionally anergic.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. In subjects who have initial evidence of radiological PD following a 
first course of treatment, it is at the discretion of the treating physician whether to continue a 
subject on study treatment for a second treatment course. This decision should be based on the 
clinical judgment of the subject’s overall clinical condition, including performance status, 
clinical symptoms, laboratory data, and tolerance for study treatments.  

 
Protocol/Amendment 3 v_16Sep2022 
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Subjects recommended to receive a second treatment course after PD should meet the following 
criteria: 
• Absence of signs and symptoms indicating disease progression 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
• Absence of rapid progression of disease 
• No decline in ECOG performance status 
 
This allowance takes into account the observation that some subjects can have a transient tumor 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response. 
 
5.8 
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. 
 
 

 
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Page 42 of 77 
6.0 
TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Study 
Screening 
Treatment Courses1 
Post-Treatment 
Treatment Cycle/Title: 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
Safety 
Follow-
Up 
Surveill-
ance 
Follow-
Up2 
Survival Follow-Up3 
Treatment Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
Scheduling Window (Days): 
-28 to -1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
±2 
 
±7 
30 ( ±7) 
days post 
EOT4 
Every 12 
(±1) week 
post EOT 
Every 12 (±1) week  
Administrative Procedures 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab Administration 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
SQ IL-2 Administration 
 
X5 
X5 
X5 
X5 
X5 
X5 
 
 
 
 
 
 
 
 
 
IV IL-2 Administration 
 
X6 
 
 
X6 
 
 
 
 
 
 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures / Assessments 
 
Review Adverse Events 
 
X 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
 
 
Physical Examination 
X 
X 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs9 and Weight 
X 
X 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
X 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
 
Pregnancy Test – Urine or Serum β-
HCG 10 
X 
X10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 

 
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Page 43 of 77 
Trial Period: 
Study 
Screening 
Treatment Courses1 
Post-Treatment 
Treatment Cycle/Title: 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
Safety 
Follow-
Up 
Surveill-
ance 
Follow-
Up2 
Survival Follow-Up3 
Treatment Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
Scheduling Window (Days): 
-28 to -1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
±2 
 
±7 
30 ( ±7) 
days post 
EOT4 
Every 12 
(±1) week 
post EOT 
Every 12 (±1) week  
HIV, Hepatitis-B and -C11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X12 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
Basic Metabolic Panel 
X 
X12 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
Hepatic Function Panel w/LD 
X 
X12 
X7,8 
X7 
X 
X7,8 
X7 
X 
 
 
X 
 
 
X 
X 
 
FT4 and TSH 
X 
X12 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Amylase and Lipase 
X 
X12 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Troponin-I 
X 
X 
 
 
X 
 
 
X13 
 
 
X13 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Function Testing14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Testing15 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Stress Testing16 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
Tumor Imaging17 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Achival Tissue Collection / Tumor Biopsy / Correlative Studies 
 
Archival or Newly Obtained Tissue 
Collection 
 
X18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for T cell subset 
quantitation by flow cytometry 
 
X18 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 

 
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Trial Period: 
Study 
Screening 
Treatment Courses1 
Post-Treatment 
Treatment Cycle/Title: 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
Safety 
Follow-
Up 
Surveill-
ance 
Follow-
Up2 
Survival Follow-Up3 
Treatment Week 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
Scheduling Window (Days): 
-28 to -1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
 
±2 
 
±7 
30 ( ±7) 
days post 
EOT4 
Every 12 
(±1) week 
post EOT 
Every 12 (±1) week  
Peripheral blood for future correlative 
studies 
 
X18 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
1Maximum duration of therapy is 3 courses. 
2Post-treatment surveillance for patients with SD, PR, or CR. 
3After PD, start of new cancer treatment, or completion of 1 year Surveillance Follow-Up 
4EOT = end of treatment 
5Dose Level 1 patients only.  For each cycle day 1, administer IL-2 after pembrolizumab.  Observe patients ≥ 1 hour after the first pembrolizumab dose (day 1, cycle1) before 
administering the first SQ IL-2 dose. 
6Dose Level 2 and 3 patients only.  Patients will admit to begin IV IL-2 treatment on cycle day 2, (or next available ICU admission day). 
7Evaluations for Dose Level 1 patients week 2,3,5,6 are only required during Course 1 
8Evaluations for Dose Level 2 and 3 patients on week 2 and 5 follow hospital discharge for IL-2 cycles 1 and 2 respectively. 
9Vital signs to include temperature, heart rate, respiratory rate, blood pressure, and pulse oximetry. 
10A negative pregnancy test must be documented < 72 hrs before each day 1 pembrolizumab dose for the start of each treatment course and at EOT.  Pregnancy testing should be 
repeated whenever an expected menstrual cycle is missed or when pregnancy is otherwise suspected. 
11Screening serologies within 28 days of day1 
12Don’t repeat labs cycle 1/day 1 if screening labs are < 14 days old. 
13Troponin-I testing prior to pembrolizumab cycle 3 and 4 required for course 1 only 
14LVEF ≥ 50% measured by MUGA scan, echo, or stress test study with myocardial perfusion imaging.  A cardiac study documenting LVEF  ≥ 50% (MUGA, echo, or stress 
testing) obtained prior to study enrollment and within 6 months of study day 1 is acceptable screening and does not need to be repeated. 
15Screening studies for Dose Level 2 and 3 patients only.  PFT testing completed prior to study enrollment and within 6 months of study day 1 is acceptable screening and does not 
need to be repeated 
16Myocardial ischemia screening by normal/negative cardiac stress testing with myocardial perfusion imaging. OR cardiac catheterization with non-significant angiogram findings 
reviewed by a Cardiology consultant.  Prior normal cardiac stress testing or negative cardiac angiogram findings obtained prior to study enrollment and within 6 months of study day 
1 is acceptable screening and does not need to be repeated. 
17Baseline imaging to include brain (MRI preferred; contrast CT acceptable) and chest, abdomen, and pelvis by CT or MRI.  Bone scan required for patients with known bone 
involvement on CT or MRI.  Restaging assessments to include chest, abdomen, pelvis body parts with brain imaging or bone scan required only for patients with tumor findings on 

 
Confidential  Limited Access 
 
 
 
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Page 45 of 77 
these studies at baseline.  Body imaging studies obtained prior to study enrollment and ≤ 6 weeks from the start of study treatment are acceptable as baseline studies and do not 
need to be repeated. 
18Collect blood samples for all eligible patients after screening is completed and before C1D1 treatment.  Blood samples can be collected before C1D1 or on C1D1 before 
treatment is given. Confirmation of available archival tissue samples prior to C1D1 treatment.  

 
Protocol/Amendment 3 v_16Sep2022 
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7.0 
TRIAL PROCEDURES 
7.1 
Subject Registration 
All subjects will be registered and entered into the University of Washington protocol accrual 
and patient tracking system.  Patients must be registered prior to starting protocol therapy.   
Documented informed consent, HIPAA authorization, and verification of subject eligibility must 
be completed prior to subject registration and assignment of a unique study number.  
If a patient is consented to the trial but is not registered or is withdrawn prior to initiation of 
protocol treatment, the reason for screen failure and/or withdrawal will be documented.  
However, no clinical trial data will be collected beyond the basic demographic data contained on 
the eligibility checklist.  The site (University of Washington) will use a registration log with 
entries for each patient registered. 
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 investigator and/or 
Merck for reasons related to subject safety.  
7.2.1 Administrative Procedures 
7.2.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature on a consent form along with the 
dated signature of the person conducting the consent discussion.  The investigator will obtain 
documented consent from each potential subject prior to conducting any study procedures in the 
clinical trial. 
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 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. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 

 
Protocol/Amendment 3 v_16Sep2022 
Page 47 of 77 
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 an 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 
7.2.1.4.1 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 immediately 
before starting trial therapies.  Treatment for the disease for which the subject has enrolled in this 
study will be recorded separately and not listed as a prior medication.  
7.2.1.4.2 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 7.3. 
7.2.1.5 Disease Details and Treatments 
7.2.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.2.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.2.1.5.3 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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7.2.2 Clinical Procedures/Assessments 
7.2.2.1 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 the NCI CTCAE v5.0 (see Section 13.2).  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).   
Please refer to section 7.3 for detailed information regarding the assessment and recording of 
AEs.   
7.2.2.2 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 complete physical exam should also be performed at monitoring visits performed during the 
Treatment and Follow-Up phases of the study.  
7.2.2.3 Vital Signs 
Vital signs will be collected 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, blood pressure and pulse 
oximetry. 
7.2.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 13.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart. 
7.2.2.5 Tumor Imaging and Assessment of Disease 
Tumor imaging by CT or MRI scans will be obtained at screening, at the end of each treatment 
course, and every 12 weeks following completion of therapy for patients who remain in 
Surveillance Follow-Up as specified in the Trial Flow Chart (Section 6.0).  Disease status will be 
assessed versus baseline imaging for response category by RECIST 1.1 criteria (see Section 
13.3). 

 
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7.2.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Blood and tissue collections for correlative studies will be obtained as specified in the Trial Flow 
Chart (Section 6.0). 
7.2.3 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 6.   

 
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Page 50 of 77 
Table 6 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
WBC (total and differential) 
Lactate dehydrogenase (LDH) 
Specific gravity  
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Amylase 
pH 
  (β-hCG)† 
Hematocrit 
Lipase 
Protein 
 
MCV 
Aspartate aminotransferase (AST) 
Glucose 
PT (INR) 
Platelet count 
Alanine aminotransferase (ALT) 
Ketones 
aPTT 
 
Alkaline phosphatase 
Bilirubin, Qual 
Free tyroxine (T4) 
 
Total Bilirubin 
Occult Blood 
Thyroid stimulating hormone (TSH) 
 
Direct Bilirubin 
Nitrite 
Troponin-I 
 
Total protein 
Leukocyte Esterase 
 
 
Albumin 
Urobilinogen 
Blood for correlative studies  
 
 
Microscopic exam (If abnormal)  
 
 
Sodium 
results are noted 
 
 
Potassium   
 
 
 
Chloride 
Urine pregnancy test † 
 
 
Carbon Dioxide  
 
 
 
Glucose  
 
  
 
Blood Urea Nitrogen  
 
  
 
Creatinine 
 
  
 
Calcium  
 
  
 
 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 
 
 

 
Protocol/Amendment 3 v_16Sep2022 
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Laboratory tests for screening or entry into the Second Course Phase should be performed within 
14 days prior to the first dose of treatment.  After pembrolizumab Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial treatment.  
7.2.4 Other Procedures 
7.2.4.1 Discontinuation 
When a subject discontinues study treatment 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 should be followed in accordance 
with the safety requirements outlined in Section 7.3 - Assessing and Recording Adverse Events.  
Subjects who attain a CR should return to the site for a Safety Follow-Up Visit (described in 
Section 7.2.5.2) and then proceed to the Surveillance Follow-Up Period of the study (described 
in Section 7.2.5.2.1). 
7.2.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.2 - Trial Procedures. 
7.2.5.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted 30 ( ±7) days after the last dose of 
trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first.  All 
treatment-related 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 should also be followed and recorded.   
7.2.5.2 Surveillance Follow-Up Visits 
Subjects who complete or discontinue trial treatment with a disease status of CR, PR or SD will 
move into the Surveillance Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 
days) by radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, or end of the study.  Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
7.2.5.2.1 Survival Follow-Up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the Survival Follow-Up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  Survival Follow ends for all patients when the last treated patient on 
study completes the Follow-Up Phase (end of study).  

 
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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 
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, 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. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as 
a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed 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 7.3.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., 
the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
7.3.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Principal Investigator and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose 
for pembrolizumab by 20% over the prescribed dose. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab should be 

 
Protocol/Amendment 3 v_16Sep2022 
Page 53 of 77 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
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 Principal Investigator and within 2 working days 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 Principal Investigator 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 the Principal Investigator and to Merck 
7.3.3.1 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 another important medical event  

 
Protocol/Amendment 3 v_16Sep2022 
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Refer to Table 7 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
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 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 Principal 
Investigator 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. 
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 Principal Investigator 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 7.3.1 - 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 

 
Protocol/Amendment 3 v_16Sep2022 
Page 55 of 77 
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. 
1. 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. 
7.3.4 Evaluating Adverse Events 
An investigator or qualified designee will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE) v5.0.  Any adverse event which changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

 
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Table 7 Evaluating Adverse Events 
An investigator or qualified designee will evaluate all adverse events as to: 
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 
 

 
Confidential  Limited Access 
 
 
 
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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 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

 
 
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7.3.5 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.  
8.0 
DATA AND SAFETY MONITORING 
8.1 
Safety Requirements 
At any time during the conduct of the trial, if it is the opinion of an investigator that the risks to 
the patient warrant early closure of the study, this recommendation should be made in writing to 
the Principal Investigator. 
 
8.1.1 Accrual and Study Progress Oversight 
The Principal Investigator will direct the formation of a Safety Data Review Board (SDRB) that 
will review study accrual and provide direction for dose escalations based on analysis of 
collected safety data including AE’s, SAE’s and DLT’s. The SDRB will consist of the Principal 
Investigator, designated sub-investigators, and study administrative staff.  Meetings will occur 
after completion of each dose-level cohort and on an as needed basis to address unanticipated 
adverse events.  Meeting minutes will be documented.  Any significant safety findings will be 
reported to Fred Hutch/University of Washington Cancer Consortium Institutional Review Board 
(IRB). 
 
8.1.2 Data Monitoring 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan (DSMP).  Under 
the provisions of this plan, Fred Hutch Clinical Research Support coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or Fred Hutch 
employees unaffiliated with the conduct of the study.  Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of previous 
visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) and the 
Fred Hutch/University of Washington Cancer Consortium Institutional Review Board (IRB).  
The review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating patients.  The 
IRB reviews the study progress and safety information to assess continued acceptability of the 
risk-benefit ratio for human subjects.  Approval of committees as applicable is necessary to 
continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 

 
 
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8.1.3 Auditing 
All trials conducted at UW/SCCA are subject to audit by the institution or any regulatory 
authority. 
8.2 
Records 
Case Report Forms (CRFs) for individual patients will be provided by the Principal Investigator.  
8.3 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site.  
 
All data entered in CRF’s that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained.  The investigator may need to request 
previous medical records or transfer records. 
 
8.4 
Direct Access to Source Data and Documents 
The investigator and institution will permit study-related monitoring, audits, EC review and 
regulatory inspection, providing direct access to all related source data / documents.  The study is 
monitored under the Cancer Consortium Data and Safety Monitoring Plan (DSMP) which details 
the full scope and extent of monitoring and provides for immediate action in the event of the 
discovery of major deviations. CRFs and all source documents, including progress notes and 
copies of laboratory and medical test results, must be available at all times for review by the 
clinical study monitor, auditor and inspection by health authorities (e.g. FDA). 
 
9.0 
STATISTICAL ANALYSIS PLAN 
9.1 
Statistical Analysis Plan 
The primary objective of this study is to evaluate the safety of IL-2 in combination with 
pembrolizumab.  Statistical analysis will be descriptive for observed toxicities.   
The secondary objective is to evaluate clinical outcomes (CR, PR, ORR, DCR, PFS) in 
comparison to historical data among advanced RCC patients treated with HD IL-2 or anti-PD1 
monotherapies.  The target enrollment for a conditional expansion cohort will be exploratory in 
nature, and no predictive statistical analysis has been applied. 
Progression-free survival will be defined from the time of registration to progression or death.  
Patients last known to be alive and progression-free will be censored at the date of their last 
disease assessment.  PFS will be evaluated using the method of Kaplan-Meier.  Median PFS 
times and associated 95% confidence interval will also be calculated.  
Exploratory objectives include the evaluation of the PD-1 pathway.  For this objective, PD-1 
pathway protein expression measures will be correlated with clinical outcomes.  Specifically, the 

 
 
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association between pre-treatment PD-L1 expression by IHC, TIL density and T cell subset 
identification for CD4+, CD8+ and Treg cells, and peripheral blood analysis to quantify 
lymphocyte subsets including CD4+/CD8+/Treg and overall response will be compared using 
logistic regression.  In addition, the association between end of cycle peripheral blood re-analysis 
to quantify lymphocyte subsets including CD4+/CD8+/Treg and PFS will be evaluated using a 
Cox proportional hazards model, among patients alive and progression-free at end of treatment.  
Similarly, the association between PD-L1 expression by IHC and TIL density and T cell subset 
identification for CD4+, CD8+ effector and Treg cells at the end of treatment and PFS will be 
evaluated among patients who do not achieve a CR but are also progression-free and the end of 
treatment.   
10.0 
LABELING, PACKAGING, STORAGE AND DISPOSITION OF CLINICAL 
SUPPLIES 
10.1 
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 8. 
Table 8 Product Description 
Product Name & Potency 
Dosage Form 
pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
10.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
10.3 
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. 
10.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 

 
 
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Clinical supplies may not be used for any purpose other than that stated in the protocol. 
10.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
11.0 
STUDY TERMINATION 
Discontinuation of individual study participant treatment may occur for reasons including patient 
decision to withdraw from study, unacceptable toxicity, disease progression, or investigator or 
Principal Investigator determination that it is not in the patient’s best interest to remain on trial. 
The study may be terminated prior to completion of planned enrollment and achievement of 
objectives if there is evidence that the study regimen is not tolerable.  
The IRB will be notified about the completion or early termination of the trial.  
 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 
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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13.0 
APPENDICES 
13.1 
ECOG Performance Status 
Table 9 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
 
 

 
 
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13.2 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
 
 
 

 
 
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13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 

 
 
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13.4 
High-Dose Interleukin-2 (HDIL-2) Administration and Toxicity Management 
Guidelines 
13.4.1 
Overview 
The toxicities of HDIL-2 result from a capillary leak syndrome that results in initial 
vasodilation/decreased systemic vascular resistance followed by leakage of fluid and albumin 
into interstitial spaces.  The initial manifestations are hypotension and tachycardia that may 
develop as early as 2 hours after the first dose, often after an initial rigor and fever.  Later 
manifestations include generalized body edema, total body rash, diarrhea, nausea, mild confusion 
and potentially acute renal failure. 
13.4.2 
Specific Toxicities and Corrective Intervention 
13.4.2.1 
Hemodynamics 
• Hypotension 
o IV Fluids 
Upon admission for HDIL-2 treatment, patients should be started on maintenance 
intravenous fluids in anticipation of ensuing capillary leak syndrome, vasodilation 
and decreased systemic vascular resistance.  Colloid has no advantage over 
crystalloid, even when the albumin falls, and D5LR at 100cc/hr is recommended. 
Bolus IV fluids and increase in the continuous IV rate may be of value for initial 
management of hypotension to keep MAP > 60, attempting to limit the cumulative 
positive fluid balance by the end of 5 days to no more than 10% of the patient’s dry 
weight by the end of each 5-day cycle of HDIL-2.  This is accomplished by the 
judicious balance of fluids and vasopressor agents, depending on the patient’s 
hemodynamic status, renal function, acid-base balance and pulmonary reserve.  
o Vasopressor agents 
If hypotension persists despite judicious fluid resuscitation, vasopressor support with 
an α-sympathomimetic agent (generally phenylephrine) is indicated.  Titration of 
phenylephrine should be between 0.5 and 2mcg/kg/min to keep the systolic blood 
pressure over 80-90 mm Hg (MAP > 60).  Since the BP nadir tends to occur 4-6 
hours after each dose of HDIL-2, a “reserve” should be available in the vasopressor 
dose, so that additional doses of HDIL-2 should be given only if the phenylephrine 
dose can be weaned to below about 1 mcg/kg/minute before the next IL-2 dose. 
 
13.4.2.2 
Renal 
• Oliguria 

 
 
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Oliguria is universal and is due to the combination of hypotension/hypoperfusion and 
decreased intravascular volume.  It may be amplified in uninephric patients and patients 
on vasopressors.  Oliguria per se is not an indication for fluids or diuresis; a bladder scan 
or urinary catheter may be useful to better assess the renal status if the patient is anuric, 
acidotic or has other reasons for urinary retention. 
13.4.2.3 
Pulmonary 
• Hypoxia 
The need for supplemental oxygen will vary among patients depending on their 
underlying lung function and disease.  Supplemental oxygen should be used to keep the 
patient’s oxygen saturation > 90-92%, and intravenous volume should be limited in 
patients whose oxygenation is difficult to maintain and in those with significant crackles 
and/or chest radiographic findings of pulmonary edema or significant pleural effusion. 
• Cardiogenic Pulmonary Edema 
Cardiogenic pulmonary edema is extremely rare in patients receiving HDIL-2 since 
patients are well-screened and HDIL-2 rarely causes global cardiomyopathy. Any patient 
with sudden pulmonary decompensation should be evaluated for causes of cardiac origin.  
13.4.2.4 
Cardiac 
• Ischemia 
Cardiac ischemia is also rare, but occasional focal myocarditis may occur, and 
arrhythmias or evidence of ischemia on EKG may mandate discontinuation of HDIL-2. 
• Cardiac Arrhythmias 
Atrial cardiac arrhythmias during HDIL-2 treatment are uncommon, but occasionally 
supraventricular tachycardia and atrial fibrillation may be seen.  Careful assessment 
should be performed for supervening causes such as ischemia, myocarditis, pericardial 
effusion or pulmonary events.  Treatment should include antiarrhythmic medications, and 
does not preclude continuation of HDIL-2.  Serious ventricular arrhythmias are rare and 
warrant discontinuation of HDIL-2 and resumption only if a minor, reversible/treatable 
cause was found. 
• Edema 
Although patients often experience moderate amounts of peripheral edema at the end of 
each cycle, it is rare that they will experience severe symptoms from this extravascular 
fluid accumulation.  Patients should be aggressively diuresed at the end of each cycle 
once they are hemodynamically stable. 

 
 
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13.4.3 
Dosing 
HDIL-2 is administered as cycles of a maximum of 14 doses given at 8-hour intervals.  Doses 
that are skipped for management of toxicities are not compensated by lengthening the cycle.  As 
a general rule, if a patient has severe enough toxicity to withhold 2 or more consecutive doses, 
IL-2 will probably need to be discontinued for the rest of that 5-day cycle.  
Organ-by-organ guidelines for IL-2 dosing must be individualized and considered in the context 
of the whole patient rather than in isolation.  Each dose should be given or withheld after an 
assessment of the patient by the RN and house officer, with consultation from the principal 
investigator or the SCCA HDIL-2 team, if needed. 
Table 10 Organ-by-Organ Toxicity Guidelines for Holding IL-2 Dosing 
System 
Generally Safe to Give 
HDIL-2 
(one or more present) 
Consider Holding  
HDIL-2 Dose 
(Especially if >1-2 criteria 
present) 
Unsafe to Give  
HDIL-2 
(any criterion present) 
Cardiac 
Sinus tach up to 130 
bpm, occasional 
ventricular ectopy 
Sustained sinus tach after 
correction of contributing 
factor such as fever, chills, 
hypotension or significant 
ectopy 
Ischemic ECG changes, 
atrial fibrillation, SVT, 
ongoing VT, elevated 
CPK/troponin 
Dermatologic 
Rash 
Urticaria 
Moist desquamation, 
bullae 
Gastrointestinal 
Mild diarrhea controlled 
with antimotility agents, 
isolated bilirubin 
elevation 
Severe nausea, emesis, 
marked elevation/rise of 
transaminases 
Ileus/abdominal 
distension, severe pain, 
intractable emesis 
Hemodynamic 
Phenylephrine support 
up to 1mcg/kg/min 
Phenylephrine support up 
to 1.5mcg/kg/min – must 
be stable or titrating down 
before next dose 
Phenylephrine support 
>1.5mcg/kg/min and or 
rising before next dose 
Hemorrhagic/ 
Thrombotic 
Thrombocytopenia 
Clinically significant 
bleeding requiring platelet 
transfusions 
Life threatening 
bleeding or clot 
Infection 
UTI, viral URI or 
localized HSV 
Bacterial infection 
contributing to 
hemodynamic compromise 
Infection requiring 
surgical intervention, or 
unresponsive to 
antibiotics 
Metabolic 
Asymptomatic and 
correctable: 
hypokalemia, 
hypocalcemia, 
hyperglycemia, 
hypophosphatemia, 
hypomagnesemia,  
Symptomatic electrolyte or 
metabolic disturbance  
Arrhythmia or other life 
threatening consequence 
or metabolic disturbance 

 
 
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Neurologic 
Mild somnolence, vivid 
dreams 
Mild confusion, 
hallucinations, patient 
aware 
Moderate – severe 
confusion, 
hallucinations, patient 
unaware or combative, 
seizures 
Pulmonary 
Mild dyspnea, hypoxia 
responsive to 4L or less 
of oxygen  
Moderate dyspnea, hypoxia 
requiring more than 40% 
oxygen, significant 
crackles, significant 
effusion not requiring 
treatment  
Severe dyspnea, 
hypoxia on oxygen, 
intubation, severe 
pulmonary edema, 
effusions requiring 
thoracentesis 
Renal 
Creatinine up to 3, 
oliguria, correctable 
acidosis 
Creatinine > 3, anuria or < 
100cc/8 hours, persistent 
acidosis 
Persistent anuria, 
dialysis for metabolic or 
renal indications 
 
Additional management recommendations are based on published treatment guideline 
monographs by Schwartzentruber, et al. J. Immunother. (2001) 24:287 and by Dutcher, J. P. et 
al. JITC (2014) 2:26. [66, 67] 
13.4.4 
Supportive Medications Used During HDIL-2 Therapy 
13.4.4.1 
Standard supportive care 
In order to minimize the toxicities of HDIL-2 treatment the following medications should be 
prescribed:    
Table 11 Standard Supportive Medications 
Medications 
Indications 
Acetaminophen 650 mg PO q4h 
Fever, 
myalgias 
NSAID (Example: Naproxen 500 or 750 mg PO BID)  
Fever, 
myalgias 
Proton pump inhibitor (Pantoprozole 40 mg PO/IV daily, or equivalent) 
Gastritis 
5HT3 blocker (Ex: Ondansetron 8 mg PO/IV daily, or prior to each dose of 
IL-2 as needed) 
Nausea, 
emesis 
Broad spectrum antibiotic, usually Levofloxacin 500 mg PO/IV daily 
Infection 
 
13.4.4.2 Symptom management 
For management of toxicity related symptoms, the following should be prescribed on an as 
needed basis:  

 
 
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Table 12 As Needed Supportive Treatments 
Medications 
Indications 
5HT3 blocker, as above, if not given prophylactically 
Nausea 
Benzodiazepine, usually Lorazepam 0.5 mg IV or 1 mg PO q4h 
Mild nausea, anxiety 
Butyrophenone, usually Haloperidol 1-5 mg IV q1h 
Agitation, hallucination 
Loperamide or Atropine-Diphenoxylate 1-2 tablets PO q4h, 
maximum 6 tablets/24h 
Diarrhea 
Meperidine 25 mg IV  or morphine sulfate 1-2 mg, repeat up to 
twice at 10 minute intervals 
Chills 
Tucks topically 
Perianal discomfort 
Diphenhydramine 12.5-25 mg IV or 25-50 mg PO q4h 
Pruritus 
Hydroxyzine 10-25 mg PO q4h 
Pruritus if paradoxical reaction to 
diphenhydramine 
Aveeno bath, lotion 
Severe pruritus 
Lubriderm-based lotion 
Pruritus, skin irritation 
“Magic” mouthwash (Diphenhydramine/Aluminum 
hydroxide/Lidocaine) 
Mouth irritation 
 
Pseudoephedrine 30 mg PO q4h 
Nasal congestion 
Zolpidem or temazepam 
Sleep 
Phenylephrine 25 mg/250 mL concentration,                                 
Titrate to BPs 80-90, range 0.1-2 mcg/kg/min 
Hypotension 
Magnesium sulfate  
Hypomagnesemia 
Potassium or sodium phosphate   
Hypophosphatemia 
Potassium chloride  
Hypokalemia 
 
13.4.5 
Additional Management Guidelines 
Table 13 Additional Management Guidelines 
Symptom/sign 
Intervention 
Anemia 
Transfuse to keep Hct 27-30 
Arrhythmia 
Correct other factors, R/O ischemia,effusions; arrhythmia specific 
treatment; Consider resuming IL-2 on or off anti-arrhythmic treatment 
Acidosis 
Keep bicarb level >20 
Edema, threatening 
compartment syndromes 
Elevation, attention to neuropathic symptoms 

 
 
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Fever pattern atypical (late 
spike) 
Culture, look for sources of bacterial infection 
Hypoalbuminemia 
No specific treatment 
Hypocalcemia 
Correct for low albumin, replace to normal values 
Infection documented 
 
Continuation of IL-2 depends on severity, interventions needed 
Other electrolyte disturbances Look for contributors, replace as needed   
 
 
13.4.6 
Monitoring  
13.4.6.1 
Monitoring guidelines:  ICU routine  
13.4.6.2 
Labs:  
• on admission (if not done on same day in clinic), CBC/plts/diff, PT/INR, chem. 
BMP/LFT/Mg/Phos, 
• Daily CBC/plts/LFT/Mg/Phos 
• Twice daily BMP 
• At least every other day PT/INR 
13.4.7 
Patient Management Following Completion of HDIL-2 
Since the hemodynamic effects of HDIL-2 begin to wane within hours of the last infusion, it is 
usually sufficient to wean the patient off pressors as rapidly as tolerated, followed by or 
accompanied by (depending on the patient’s particular hemodynamic needs and volume status) 
prompt discontinuation of parenteral fluids and then active diuresis.  Patients should have 
sufficient pulmonary reserve at the time of discharge to tolerate the possibility of mobilizing a 
few liters back into the vascular space (which can result in pulmonary edema) AND should be 
given at least 3-4 days of oral diuretics, with K as indicated, to return them to near dry weight 
(which is likely to be about 2-3 kg below their prior weight).  Patients can stop the diuretics on 
their own when their weight normalizes and/or edema resolves.  All patients experience 
desquamation and dry, pruritic skin, which is managed symptomatically with lubricants and anti-
pruritics (avoiding steroid). 
Patients should be discharged with their PICC line in place between cycles 1 and 2. 
 
 

 
 
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13.5. Contraceptive Guidance and Pregnancy Testing 
13.5.1. Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range 
is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
13.5.2. Contraception Requirements 
13.5.2.1. Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to one of the following during the protocol defined time frame in section 5.5.2:  
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Use of a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 14 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 

 
 
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13.5.2.2. Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to one of the 
following during the protocol defined time frame in section 5.5.2:   
• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
• Use a highly effective method of contraception consistently and correctly as described in 
Table 14 during the protocol-defined time frame in section 5.5.2 in combination with 
their male patterners use of a condom.  
Table 14  Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
Notes:  
a) Typical use failure rates may be higher than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) Hormonal contraception efficacy is possibly decreased due to interaction with study treatments; 
therefore condoms must be used in addition to the hormonal contraception during the treatment period 
and follow up after the last dose of study treatment as specified in section 5.5.2. 
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; and at the time points 
specified in the Trial Flow Chart (Section 6.0). 

 
 
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