Clinical trial NCT03149822
Conditions: Metastatic Renal Cell Carcinoma
Sponsor: University of Colorado, Denver
Start date: 2017-09-28; Completion date: 2024-02-16
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in the phase I dose escalation part of the study to determine the recommended phase 2 dose (RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with pembrolizumab in the phase II dose expansion part of the study.

Detailed description:
Primary Objectives

* To determine the efficacy based on objective response rate \[ORR = complete response (CR) + partial response (PR)\] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma..

Secondary Objectives

* To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination.
* To assess other measures of anti-tumor activity of the combination of pembrolizumab and cabozantinib in subjects with locally advanced or metastatic renal cell carcinoma.

Arms: arm 1: Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 40 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. arm 2: Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. arm 3: Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib at the RP2D orally once daily for up to 35 cycles, until disease progression, unacceptable toxicity, or consent withdrawal. All participants who stop pembrolizumab after 35 cycles with SD or better may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping pembrolizumab from the initial treatment phase.
Interventions: intervention 1: Cabozantinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Pharmaceutical form: tablets Route of administration: oral intervention 2: Pharmaceutical form: solution Route of administration: injection

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Phase I/II Study of Pembrolizumab and Cabozantinib in Patients with Metastatic Renal Cell 
Carcinoma 
Elaine Lam, MD 
 
NCT03149822 
 
Protocol Version 16, dated June 17, 2021 


Product:   Pembrolizumab 
COMIRB 16-2300 
Version Date: 6/17/2021  
PI:  Elaine Lam, MD 
 
1 
 
 
 
 
 
PROTOCOL (COMIRB) #:   
16-2300 
 
PROTOCOL TITLE: 
 
Phase I/II Study of Pembrolizumab and Cabozantinib in 
Patients with Metastatic Renal Cell Carcinoma 
 
VERSION DATE: 
 
 
Version 16, 6/17/2021  
 
SPONSOR/ 
PRINCIPAL INVESTIGATOR: 
Elaine Lam, MD 
University of Colorado, Anschutz Medical Campus 
 
 
IND NUMBER: 
135065 
 
FUNDING SUPPORT: 
Merck & Co, Inc. 


Product:   Pembrolizumab 
COMIRB 16-2300 
Version Date: 6/17/2021  
PI:  Elaine Lam, MD 
 
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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................... 14 
1.0  PROTOCOL/TRIAL SUMMARY ................................................................................. 15 
2.0 
TRIAL DESIGN .......................................................................................................... 17 
2.1 Description of Study ..................................................................................................... 17 
2.1.1 Phase I Dose Escalation ........................................................................................ 18 
2.1.2 
Definition of Dose Limiting Toxicity .................................................................... 19 
2.1.3 
Dose Escalation Rules ........................................................................................... 19 
2.1.4 
Definition of Maximum Tolerated Dose (MTD) ................................................... 21 
2.1.5 
Definition of Recommended Phase 2 Dose (RP2D) .............................................. 21 
2.1.6 
Intra-Subject Dose Escalation ............................................................................... 21 
2.1.7 Phase II Dose Expansion ...................................................................................... 22 
2.1.8 Archival Tumor and Optional Fresh Tissue Biopsies ........................................... 22 
2.2 
Trial Diagram .......................................................................................................... 22 
3.0 
OBJECTIVES ............................................................................................................. 23 
3.1 
Primary Objectives ................................................................................................. 23 
3.2 
Secondary Objectives .............................................................................................. 23 
3.3 
Exploratory Objectives ........................................................................................... 23 
4.0 
BACKGROUND & RATIONALE ............................................................................ 24 
4.1 
Background ............................................................................................................. 24 
4.1.1 Pharmaceutical and Therapeutic Background ....................................................... 25 


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4.1.2 
Preclinical and Clinical Trial Data ........................................................................ 27 
4.2 
Rationale .................................................................................................................. 27 
4.2.1 
Rationale for the Trial and Selected Subject Population ....................................... 27 
4.2.2 
Rationale for Dose Selection/Regimen/Modification ............................................ 28 
4.2.3 
Rationale for Endpoints ......................................................................................... 30 
5.0 
METHODOLOGY ...................................................................................................... 31 
5.1 
Trial Participation Criteria .................................................................................... 31 
5.1.1 Subject Inclusion Criteria...................................................................................... 31 
Table 1: Adequate Organ Function Laboratory Values ................................................... 32 
5.1.2 Subject Exclusion Criteria .................................................................................... 33 
5.2 
Trial Treatments—Study Agents ........................................................................... 36 
Table 2a: Trial Treatment Overview ................................................................................. 37 
Table 2b: Phase I Dose Escalation .................................................................................... 37 
Table 2c: Phase II Dose Expansion................................................................................... 37 
5.2.1 
Dose Selection/Modification ................................................................................. 37 
Table 3: Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab ................................................................... 39 
5.2.1.3.2 
Pembrolizumab Second Course .................................................................... 43 
Table 4: Dose Modification Guidelines for Cabozantinib Drug-Related Adverse Events45 
Table  5:  Dose  Modification  Guidelines  for  Toxicities  of  Unclear  Attribution  or 
Deemed to be Related to Both Pembrolizumab and Cabozantinib ....................... 46 
5.2.2 Timing of Dose Administration ............................................................................ 47 
5.2.3 Trial Blinding/Masking and Treatment Allocation..................................................... 48 


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5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ........................ 48 
5.3.1      Acceptable Concomitant Medications ................................................................. 48 
5.3.2 
Prohibited Concomitant Medications and Therapies ............................................. 49 
5.4 
Rescue Medications & Supportive Care ............................................................... 49 
5.4.1 
Supportive Care Guidelines for Pembrolizumab-Related Toxicities ..................... 49 
Table 6: Infusion Reaction Treatment Guidelines ............................................................. 52 
5.4.2 
Supportive Care Guidelines for Cabozantinib-Related Toxicities ......................... 53 
Table 7: Management of Cabozantinib-Related Palmar-Plantar Erythrodysesthesia (PPE) 
Syndrome .............................................................................................................. 56 
Table 8: Management of Cabozantinib-Related Hypertension .......................................... 57 
Table 9: Management of Cabozantinib-Related Proteinuria ............................................. 58 
5.5 
Diet/Activity/Other Considerations ....................................................................... 59 
5.5.1 
Diet ........................................................................................................................ 59 
5.5.2 
Contraception ........................................................................................................ 60 
5.5.3 Use in Pregnancy .................................................................................................. 62 
5.5.4 Use in Nursing Women ......................................................................................... 62 
5.6 
Subject Withdrawal/Discontinuation Criteria ..................................................... 62 
5.6.1 Subject Withdrawal ............................................................................................... 62 
5.6.2 Subject Discontinuation ........................................................................................ 62 
5.6.3 Clinical Criteria for Early Trial Termination ........................................................ 63 
5.7 
Treatment Beyond Disease Progression ............................................................... 64 
5.8 
Subject Replacement Strategy ............................................................................... 64 


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5.9 
Known Potential Benefits ....................................................................................... 65 
6.0  TRIAL SCHEDULE OF EVENTS CHART ................................................................. 66 
7.0 
TRIAL PROCEDURES .............................................................................................. 68 
7.1 
Trial Procedures ..................................................................................................... 68 
7.1.1 Administrative Procedures .................................................................................... 68 
7.1.2 Clinical Procedures/Assessments .......................................................................... 70 
7.1.3 Laboratory Procedures/Assessments .................................................................... 72 
Table 10: Laboratory Tests ............................................................................................... 73 
7.1.4 Other Procedures—Withdrawal/Discontinuation ................................................. 74 
7.1.5 Visit Requirements ................................................................................................ 74 
7.2 
Assessing and Recording Adverse Events ............................................................ 75 
7.2.1 Definition of AEs .................................................................................................. 75 
7.2.2 Assessment of AEs ............................................................................................... 75 
7.2.3 Reporting of AEs .................................................................................................. 76 
7.3 
Serious Adverse Events (SAE) ............................................................................... 76 
7.3.1 Definition and Assessment of SAEs ..................................................................... 76 
7.3.2 Immediate Reporting of SAEs .............................................................................. 77 
7.4 
Events of Clinical Interest (ECI) ........................................................................... 79 
7.4.1 Definition and Assessment of ECI ........................................................................ 79 
7.4.2 Reporting ECIs ...................................................................................................... 79 
7.5 
An Overdose for this Protocol ............................................................................... 80 
7.5.1 Definition and Assessment of an Overdose for this Protocol ............................... 80 


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7.5.2 Reporting of an Overdose for This Protocol ......................................................... 80 
7.6 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ............... 80 
7.7 
Definition of Unanticipated Problems (UAP) ....................................................... 81 
7.8 
Evaluating Adverse Events .................................................................................... 81 
7.9 
Sponsor-Investigator Responsibility for Reporting Adverse Events ................. 81 
Table 11: Evaluating Adverse Events ................................................................................... 82 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................... 85 
8.1 
Statistical Analysis Plan Summary ....................................................................... 85 
8.2 
Statistical Analysis Plan ......................................................................................... 85 
8.2.1 Analysis of Overall Conduct of Study .................................................................. 85 
8.2.2 Analysis of Safety ................................................................................................. 85 
8.2.3 Analysis of Anti-Tumor Activity .......................................................................... 86 
8.2.4 Analysis of Exploratory Endpoints ....................................................................... 87 
8.2.5 Sample Size ........................................................................................................... 87 
Table 12: Probability of Observing DLTs for Different Underlying DLT Rates .............. 87 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES.................................................................................................................... 88 
9.1 
Investigational Product- Pembrolizumab ............................................................. 88 
Table 13: Product Descriptions ............................................................................................. 88 
9.2 
Cabozantinib ........................................................................................................... 88 
9.3 
Packaging and Labeling Information ................................................................... 89 
9.4 
Clinical Supplies Disclosure ................................................................................... 89 


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9.5 
Storage and Handling Requirements .................................................................... 89 
9.6 
Returns and Reconciliation .................................................................................... 89 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ......................................... 89 
10.1 
Confidentiality ......................................................................................................... 89 
10.2 
Conflict of Interest Policy and Compliance with Financial Disclosure 
Requirements .......................................................................................................... 90 
10.3 
Compliance with Law, Audit and Debarment ..................................................... 90 
10.4 
Compliance with Trial Registration and Results Posting Requirements .......... 91 
10.5 
Quality Management System ................................................................................. 91 
10.6 
Data Management ................................................................................................... 91 
10.6.1 Monitoring and Oversight ..................................................................................... 91 
10.6.2 Quality Control and Quality Assurance ................................................................ 92 
10.7 
Institutional Review Board .................................................................................... 93 
11.0 REFERENCES ................................................................................................................ 94 
12.0 
APPENDICES ............................................................................................................. 96 
12.1 
ECOG Performance Status .................................................................................... 96 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ................. 96 
12.3 
Response  Evaluation  Criteria  in  Solid  Tumors  (RECIST)  1.1  Criteria  
for Evaluating Response in Solid Tumors ............................................................ 97 
12.4 
Immune Response modification to Response Evaluation Criteria in Solid 
Tumors (irRECIST) for Evaluating Response in Solid Tumors ....................... 98 
12.4.1 Baseline Assessment Using irRECIST ................................................................. 98 
12.4.2 Post-Baseline Assessments Using irRECIST ....................................................... 98 
 


 
 
 
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STATEMENT OF COMPLIANCE 
This is an investigator-initiated study. The Principal Investigator (PI), Elaine Lam, MD, is 
conducting the study and acting as the sponsor. As the sponsor-investigator, both the 
legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
applicable United States (US) laws and applications, including but not limited to United States 
(US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
 
The PI will assure that no changes to the protocol will take place without documented approval 
from the Institutional Review Board (IRB). All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
 
Sponsor-Principal Investigator: 
Elaine Lam, MD 
 
 
 
 
  
 
 
Print/Type Name  
 
 
Date:    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Signature  
 
Site Principal Investigator:   
 
Steven R. Schuster, MD 
 
 
 
  
 
 
 
Print/Type Name  
 
 
Date:    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Signature  
 
Site Principal Investigator:   
 
Geetika Srivastava, MD 
 
 
 
  
 
 
 
Print/Type Name  
 
 
Date:    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Signature  
 


 
 
 
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1.0  PROTOCOL/TRIAL SUMMARY 
 
Protocol Title 
Phase  I/II Study of Pembrolizumab and Cabozantinib for 
Metastatic Renal Cell Carcinoma 
Protocol Number 
16-2300 
Trial Phase 
I/II 
Objectives 
Primary Objective: 
• To determine the efficacy based on objective response 
rate [ORR = complete response (CR) + partial 
response (PR)] of pembrolizumab and cabozantinib 
when administered in combination in subjects with 
locally advanced or metastatic renal cell carcinoma. 
Secondary Objectives: 
• To characterize dose-limiting toxicities (DLTs), 
maximum tolerated dose (MTD), and recommended 
phase 2 dose (RP2D) for the combination. 
• To assess other measures of anti-tumor activity of the 
combination of pembrolizumab and cabozantinib in 
subjects with locally advanced or metastatic renal cell 
carcinoma. 
o irRECIST (Immune-related response criteria) 
response 
o Progression-free survival 
o Overall survival 
o Time to progression of overall disease 
o Time to progression of bone metastasis or skeletal- 
related event 
o Clinical benefit rate [complete response (CR) + 
partial response (PR) + stable disease (SD)] 
o Duration of response or disease stability 
o Duration on treatment in subjects treated beyond 
progression 
Exploratory Objectives, may include: 
• Bone turnover markers, such as β C-terminal 
telopeptide     (β-CTX),   bone     specific     alkaline 


 
 
 
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phosphatase, and procollagen type 1 amino-terminal 
propeptide (P1NP). 
• Bone scan responses 
• PD-L1 IHC testing on archival samples. 
• PD-L1 IHC testing on fresh tumor baseline and/or 
post-treatment samples. 
• Evaluation of immuno-oncology markers 
Endpoints 
Primary Endpoint: 
To determine the efficacy (defined as objective response 
rate, ORR) of the combination of pembrolizumab and 
cabozantinib. 
Secondary Endpoints: 
To 
characterize 
dose 
limiting 
toxicities (DLTs), 
maximum tolerated dose (MTD), and recommended 
phase 2 dose (RP2D) for the combination of 
pembrolizumab and cabozantinib, as well as, other 
measures of efficacy including response by immune- 
mediated response criteria (irRECIST), progression-free 
survival, overall survival, time to progression of overall 
disease, time to progression of bone metastasis or 
skeletal-related events, clinical benefit rate [complete 
response (CR) + partial response (PR) + stable disease 
(SD)], duration of response or disease stability, and 
duration on treatment in subjects 
treated beyond 
progression. 
Exploratory Endpoint: 
We will include mandatory archival tumor collection and 
optional pre- and post-treatment tumor biopsies for PD- 
L1 (QualTek Molecular Laboratories) and other immune- 
oncology testing which may include evaluation of other 
immune checkpoint markers, immune cell markers, and 
Subject Population 
Clinical Indication:  Renal Cell Carcinoma (RCC) 
Gender: Male and Female 
Age Range: 18-100 years 
Trial Type 
Interventional 


 
 
 
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Type of control 
Non-randomized 
Description of Study 
Agents 
1. Pembrolizumab (Keytruda®) will be administered 
intravenously (IV). The manufacturer (Merck) is 
providing this product. 
2. Cabozantinib 
(CABOMETYX™) 
will 
be 
administered orally. This is standard therapy for RCC. 
Trial Blinding 
Open-label 
Treatment Groups 
Single arm combination study 
Number of trial subjects 25-55 
Estimated enrollment 
period 
3 years 
Estimated duration of 
trial 
5 years 
Duration of 
Participation 
5 years 
Estimated average 
length of treatment per 
subject 
8 months 
 
 
2.0 TRIAL DESIGN 
 
  2.1 Description of Study 
 
This is a Phase I/II open-label study designed to evaluate the combination of pembrolizumab 
and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell 
carcinoma. 
 
Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in 
the phase I dose escalation part of the study to determine the recommended phase 2 dose 
(RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with 
pembrolizumab in the phase II dose expansion part of the study. A standard 3+3 design will 
be used in Phase I to determine RP2D and a Simon two-stage design will be used in Phase II 
to determine efficacy of the combination. The planned enrollment for this study is 
approximately 25-55 total subjects, to account for screen failures, in order to achieve 
6-9 evaluable subjects in Phase I dose escalation and 20-38 evaluable subjects in Phase II 
dose expansion.   


 
 
 
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Pembrolizumab will be administered by IV infusion on Day 1 of 21-day cycles. Cabozantinib 
will be taken orally once daily on a continuous basis. Subjects may continue treatment in the 
absence of unacceptable toxicity or clinically compelling disease progression. Treatment 
beyond progression per standard RECIST v1.1 criteria may be allowed if certain criteria are 
met and with the approval of the Principal Investigator. 
 
2.1.1 Phase I Dose Escalation 
 
Approximately 6-9 subjects will be enrolled using a standard 3+3 design. Three to six subjects 
will be enrolled in each dose cohort and receive cabozantinib and pembrolizumab in 
accordance with the dose escalation rules described below to determine the maximum tolerated 
dose (MTD) and RP2D (Section 2.1.3). The dose limiting toxicity (DLT) assessment window 
will be 21 days (Days 1−21 of Cycle 1).  If a delayed DLT is observed, the DLT assessment 
window may be extended after the first administration of pembrolizumab and cabozantinib for 
all subjects in that cohort and any subsequent dose-escalation cohorts. 
 
Any dose-escalation stage subject who does not complete the DLT assessment window for a 
reason other than a DLT will be considered non-evaluable for dose escalation decisions, as 
well as, the MTD assessment and may be replaced by an additional subject at that same dose 
level. 
 
A subject who has any component of study treatment held during the DLT assessment window 
for a reason other than a DLT such that administration of the next planned pembrolizumab 
dose is delayed by more than 7 days and/or ≥25% of the planned cabozantinib doses are missed, 
will be considered non-evaluable for dose-escalation decisions and the MTD assessment and 
may be replaced by an additional subject at that same dose level. 
 
 
Cohort 
Pembrolizumab Dose 
Cabozantinib Dose 
-1 
200 mg IV every 3 weeks 
20 mg PO daily 
1* 
200 mg IV every 3 weeks 
40 mg PO daily 
2 
200 mg IV every 3 weeks 
60 mg PO daily 
* Starting dose level. 


 
 
 
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2.1.2 Definition of Dose Limiting Toxicity 
 
Any one of the following events will be considered a DLT if it occurs during the DLT 
assessment window and is assessed by the investigator to be likely related to study treatment 
(pembrolizumab and/or cabozantinib). 
 
o Grade ≥ 3 non-hematologic, non-hepatic adverse event, with the following exceptions: 
• Grade 3 hypertension that resolves to Grade ≤ 2 with addition or adjustment of anti- 
hypertensive therapy in ≤ 7 days 
• Grade 3 fatigue that resolves to Grade ≤ 2 in ≤ 5 days 
• Grade 3 laboratory abnormalities that are asymptomatic, considered by the 
investigator not to be clinically significant, and that resolve to Grade ≤ 2 in ≤ 48 hours 
• Grade 3 rash that resolves to Grade ≤ 2 in ≤ 5 days with or without therapy equivalent 
to prednisone 10 mg/day or less 
• Grade 3 hand-foot syndrome that resolves to baseline within 3 weeks 
• Grade 3 arthralgia and/or myalgia that resolves to baseline within 3 weeks 
• Grade 3 autoimmune thyroiditis or other endocrine abnormality that resolves to Grade 
≤ 2 within 3 weeks 
 
o Grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite maximal medical 
therapy. 
o Grade ≥ 4 neutropenia (ANC < 500 cells/μL) lasting > 7 days 
o Grade ≥ 3 febrile neutropenia 
o Grade ≥ 4 anemia 
o Grade ≥ 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with clinically 
significant bleeding 
o Grade ≥ 3 elevation of serum hepatic transaminase (ALT or AST). 
o Grade ≥ 3 elevation of serum total bilirubin. 
o ALT or AST > 3 × upper limit of normal (ULN) AND total bilirubin >2 × ULN will 
require permanent treatment discontinuation. 
 
2.1.3 Dose Escalation Rules 
 
Pembrolizumab will be administered at a fixed dose of 200 mg IV every 21 days on Day 1 of 
each cycle. 


 
 
 
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The starting dose of cabozantinib for subjects in the first cohort will be 40 mg PO once daily 
for 21 consecutive days of each cycle (Days 1−21). For the second cohort, the dose of 
cabozantinib will be 60 mg PO once daily. If the starting dose of 40mg is not tolerated (2 or 
more out of 6 subjects experiencing DLT), then a lower dose of 20 mg will be evaluated. 
 
Once the DLT assessment period has passed, pembrolizumab and/or cabozantinib may be held 
or dose modified independent of the other agent for adverse events attributed to one but not 
both drugs.  The Principal Investigator should be notified when this occurs. 
In addition to any DLTs, other available relevant demographic, adverse event, laboratory, and 
dose administration data will be reviewed prior to all dose-escalation decisions. 
 
Dose escalation will occur in accordance with the rules: 
o A minimum of 3 subjects will be enrolled in each cohort. 
o If none of the first 3 DLT-evaluable subjects experiences a DLT, enrollment of the next 
cohort may proceed. 
o If 1 of the first 3 DLT-evaluable subjects experiences a DLT, the cohort will be expanded 
to a minimum of 6 subjects. If there are no further DLTs in the first 6 DLT-evaluable 
subjects, enrollment of the next cohort may proceed. 
o If 2 or more of the first 6 DLT-evaluable subjects in a cohort experience a DLT, the MTD 
will have been exceeded and dose escalation will stop. The preceding cohort will also be 
expanded to a minimum of 6 subjects, unless 6 subjects have already been evaluated at that 
dose level. 
o If the MTD is exceeded at any dose level, the highest dose at which fewer than 2 of 6 DLT- 
evaluable subjects experience a DLT will be declared the MTD. 
o If the MTD is not exceeded at any dose level, the highest dose administered in this study 
will be declared the maximum administered dose. 
o Any dose level may be expanded in the absence of a DLT if warranted based on investigator 
evaluation of non-DLT adverse events, including events occurring after Cycle 1 and events 
observed in the expansion cohorts. 
o To be considered evaluable for dose escalation, subjects must have received at least 1 dose 
of pembrolizumab and ≥75% of planned dosing of cabozantinib prior to completing the 
DLT assessment window of 21 days. 


 
 
 
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2.1.4 Definition of Maximum Tolerated Dose (MTD) 
 
The Maximum Tolerated Dose (MTD) is defined as the highest dose level with no more than 
1 DLT reported in 6 DLT-evaluable subjects. 
 
2.1.5 Definition of Recommended Phase 2 Dose (RP2D) 
 
The Recommended Phase 2 Dose (RP2D) of cabozantinib will be selected based on the clinical 
data and will not exceed the MTD. If < 2/6 subjects experience a DLT at 60 mg daily during 
dose escalation, then 60 mg daily will be considered the RP2D. If ≥ 2/6 subjects experience 
DLTs at 60 mg daily, and ≤ 1/6 subjects experience a DLT at 40 mg daily, then 40 mg daily 
will be considered the RP2D. The Principal Investigator, in consultation with other 
investigators, will continue to evaluate the safety data accumulated during the phase II dose 
expansion part of the study and may amend the RP2D with further experience. 
 
2.1.6 Intra-Subject Dose Escalation 
 
There will be no dose reduction or escalation of pembrolizumab, which is to be administered 
at a fixed dose of 200 mg IV every 21 days. 
 
Intra-subject dose escalation of cabozantinib to a higher dose level will be allowed if all of the 
following conditions are met: 
o One or fewer of the first 3 DLT-evaluable subjects, or fewer than 2 of the first 6 DLT- 
evaluable subjects experience a DLT at the higher dose level cohort. 
o The subject has completed at least 3 cycles at their originally assigned dose level. 
o The subject has not experienced a DLT or an adverse event occurring outside the DLT 
window that would otherwise meet the definition of a DLT. 
o The subject is clinically stable with no decrement in performance status. 
o The Principal Investigator has approved the dose escalation. 
o The overall  benefit/risk  balance  favors  continued  treatment,  in  the  opinion  of  the 
investigator. 


 
 
 
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2.1.7 Phase II Dose Expansion 
 
A Simon two-stage design will be used. Based on the primary endpoint of objective response 
rate, twenty evaluable subjects will be enrolled in Stage I portion of Phase II. If there are at 
least 2 responses among the 20 evaluable subjects, an additional 18 evaluable subjects will be 
entered. If there are fewer than 2 responses among the first twenty evaluable subjects, then 
this trial will be stopped early for futility. If at least 12 are observed among the 38 evaluable 
subjects, then the treatment will be considered effective. 
 
Subjects from the Phase I part of the study who are treated at the RP2D may be included in the 
efficacy assessments in Stage I of the Phase II part of the study. 
 
2.1.8 Archival Tumor and Optional Fresh Tissue Biopsies 
 
Archival tumor tissue is mandatory for enrollment in both the Phase I dose escalation and 
Phase II dose expansion parts of the study. 
 
In addition, subjects may consent for optional fresh tissue biopsies at baseline (during 
screening period) and/or post-treatment at approximately 3-6 weeks (during cycle 2) after 
initiation of study treatment. 
 
2.2 Trial Diagram 
 
 
Phase I Dose 
Escalation 
6-9 patients 
Determination of 
MTD and RP2D 
Phase II Dose 
Expansion 
20-38 patients 
 
 
 
 
 
 
 
 
 
 


 
 
 
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3.0 OBJECTIVES 
 
3.1 Primary Objectives 
 
The primary objective for this study is to determine the efficacy based on objective 
response rate [ORR = complete response (CR) + partial response (PR)] of 
pembrolizumab and cabozantinib when administered in combination in subjects with 
locally advanced or metastatic renal cell carcinoma. 
 
3.2 Secondary Objectives 
 
The secondary objectives for this study are: 
 
o To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), 
and recommended phase 2 dose (RP2D) for the combination. 
 
o To assess other measures of anti-tumor activity of the combination of 
pembrolizumab and cabozantinib in subjects with locally advanced or metastatic 
renal cell carcinoma. 
 
 irRECIST (Immune-related response criteria) response 
 
 Progression-free survival 
 
 Overall survival 
 
 Time to progression of overall disease 
 
 Time to progression of bone metastasis or skeletal-related event 
 
 Clinical benefit rate [complete response (CR) + partial response (PR) + stable 
disease (SD)] 
 
 Duration of response or disease stability 
 
 Duration on treatment in subjects treated beyond progression 
 
3.3 Exploratory Objectives 
 
The exploratory objectives for this study may include: 
 
o Bone turnover markers, such as β C-terminal telopeptide (β-CTX), bone specific 
alkaline phosphatase, and procollagen type 1 amino-terminal propeptide (P1NP). 
 


 
 
 
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o Bone scan responses 
o PD-L1 IHC testing on archival samples. 
o PD-L1 IHC testing on fresh tumor baseline and/or post-treatment samples. 
o Evaluation of immuno-oncology markers 
 
 
4.0 BACKGROUND & RATIONALE 
 
4.1 Background 
 
Over the past decade, multiple vascular endothelial growth factor (VEGF) and molecular target 
of rapamycin (mTOR) pathway targeted therapies have been approved and have significantly 
improved the morbidity and mortality among subjects with advanced or metastatic renal cell 
carcinoma (mRCC).   Nevertheless, mRCC remains a largely incurable disease.   Tyrosine 
kinase inhibitors (TKI) and VEGF-directed antibodies are widely used as standard first- and 
second-line treatments for metastatic RCC. Despite the improvements seen with the currently 
available VEGF-directed therapies, treatment resistance and disease progression occur in the 
majority of subjects with continued treatment and these agents do not produce durable 
responses.[1] Acquired resistance to vascular endothelial growth factor (VEGF) pathway 
inhibitors is frequently mediated through the activation of alternative signaling pathways that 
restore tumor perfusion, including upregulation of the expression of angiopoietins, c-MET, 
activin receptor-like kinase-1 (ALK-1) receptor and interleukin 8 (IL-8), and loss of p53 
function.[2] In addition, VEGF also acts as an immunosuppressive molecule and can inhibit 
maturation of dendritic cells, promote immune suppressive cell infiltration and enhance 
immune checkpoint molecules expression.[3] 
 
Renal cell carcinoma is an immunogenic tumor with a dysfunction immune cell infiltrate that 
allows malignant progression through evasion of immune surveillance. Novel immune- 
modulating agents that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and 
programmed death receptor-1 (PD-1) significantly enhances antitumor immunity.[4] The 
benefit of anti-PD-1 antibodies in the treatment of mRCC was confirmed in the CheckMate 
025 study, which was a phase III study of nivolumab (an anti-PD-1 antibody) vs. everolimus 
in the second-line treatment of mRCC. Compared to everolimus, nivolumab showed 
significant improvements in overall survival (25.0 vs. 19.6 months; HR 0.73; P=0.002) and 
objective response rate (25% vs. 5%).[5] 
 
Recent major discoveries in tumor immunology and agents that can trigger immune responses, 
along with better understanding of the mechanisms of VEGF inhibitor therapy provide 
rationale for combination therapies in the treatment of mRCC. There are multiple proposed 
mechanisms of synergy between inhibiting both VEGF- and PD-1. In addition to angiogenic  


 
 
 
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activity, VEGF may promote immunosuppression by inhibiting dendritic cell maturation and 
VEGF inhibitors reverse this immunosuppression by reducing numbers of circulating 
regulatory T cells and myeloid-derived suppressor cells and allowing for better maturation of 
dendritic cells.[1, 6, 7] VEGF inhibitors such as sunitinib may also enhance CD4+ T and 
CD8+ T cell intratumoral infiltration.[8] In mouse models, VEGF-A has been shown to 
modulate the expression of inhibitory checkpoints such as PD-1 on CD8+ T cell in tumors.[9] 
These data provide rationale for clinical investigations of combined angiogenesis inhibition 
and immunotherapy/immune checkpoint inhibition. 
 
4.1.1 Pharmaceutical and Therapeutic Background 
 
4.1.1.1 PD-1/PD-L1 Blockade 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.   Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T- 
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of 
murine PD-1 has been resolved. PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding  
and a cytoplasmic tail which is responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins. PD-1 was expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, T regs and Natural Killer cells. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively 
expressed or can be induced in a variety of cell types, including non-hematopoietic tissues 
as well as in various tumors. Both ligands are type I transmembrane receptors containing 


 
 
 
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both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-
L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell 
activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL). This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) is currently approved in the United States 
for the treatment of melanoma, non-small cell lung cancer, small cell lung cancer, , head and 
neck squamous cell carcinoma, classical Hodgkin Lymphoma, primary mediastinal large B-cell 
lymphoma, ulcerative colitis, microsatellite instability-high tumors, gastric or gastroesophageal 
junction adenocarcinoma, esophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel 
cell carcinoma, RCC, endometrial carcinoma, tumor mutational burden – high cancer, 
cutaneous Squamous Cell Carcinoma, Microsatellite instability-high cancer or mismatch repair 
deficient Colorectal Cancer. 
 
4.1.1.2 MET and VEGFR2 in Renal Cell Carcinoma 
 
Hepatocyte growth factor receptor protein (MET) and the VEGF receptor 2 (VEGFR2) are 
receptor tyrosine kinases that play a role in the promotion of tumor cell growth, invasiveness, 
metastasis, and/or angiogenesis in multiple tumor types including RCC.[10] Clear cell renal 
carcinomas commonly arise due to mutations in the tumor suppressor von Hippel-Lindau 
(VHL) gene which trigger an accumulation of hypoxia inducing factor (HIF) protein, which 
leads to an increase in expression of VEGF and of the receptor tyrosine kinase MET, resulting 
in angiogenesis, tumor cell proliferation, and invasive growth.[11] High MET expression has 
been observed in bone and brain metastases in subjects with mRCC and is associated with poor 
pathologic features and poor prognosis in RCC.[12-14] 
 
Cabozantinib is an oral, small molecule tyrosine kinase inhibitor that targets MET, 
VEGFR2/KDR, RET, KIT, FLT3, and AXL. In a phase III clinical trial comparing 
cabozantinib vs. everolimus in subjects with mRCC who have progressed after a VEGFR- 
targeted therapy, cabozantinib demonstrated improved median progression-free survival (7.4 
vs. 3.8 months), objective response rate (21% vs. 5%), and overall survival (HR 0.67, 
P<0.005).[15]  In the phase II CABOSUN study comparing cabozantinib versus sunitinib in the  


 
 
 
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first-line setting for patients with intermediate- and poor-risk mRCC, cabozantinib was 
associated with statistically increased median progression-free survival (8.2 months vs 5.6 
months), lower rate of progression or death (HR 0.66), and improved overall response rate (46% 
vs 18%) compared to sunitinib. [16] Based on these two studies, cabozantinib is currently 
approved for first-line, as well as, second-/subsequent-line treatment for metastatic renal cell 
carcinoma. 
 
4.1.2 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 Rationale 
 
4.2.1 Rationale for the Trial and Selected Subject Population 
 
PD-1-targeted and VEGF-targeted therapies have separately shown survival benefit in subjects 
with advanced or metastatic renal cell carcinoma (mRCC). Mechanisms of synergy between 
VEGF and PD-1 inhibition have been proposed in the current literature. In this study, we will 
evaluate the efficacy of combining the PD-1 (pembrolizumab) and VEGF-targeted 
(cabozantinib) therapies in subjects with locally advanced, recurrent, or metastatic renal cell 
carcinoma. 
 
The phase I dose escalation part will determine the maximum tolerated dose (MTD) and 
recommended phase 2 dose (RP2D) of the combination of pembrolizumab and cabozantinib. 
 
The phase II dose expansion part will evaluate efficacy (as defined by objective response rate) 
of the combination given at the RP2D in mRCC subjects who are immunotherapy-naïve and 
also those who have previously received immunotherapy. 
 
With the approval of nivolumab, we anticipate that many subjects will have received 
immunotherapy prior to study entry. Given the preclinical data for synergy with the 
combination of PD-1 and VEGF inhibition, we hypothesize that there will be subjects who did 
not previously respond to either PD-1 or VEGF-directed therapies alone, but who may respond 
to the combination. 
 
The treatment of bone metastases and prevention of skeletal related events for mRCC is 
particularly challenging, and represents an unmet need for this cancer. There is preclinical 
evidence of a direct link between loss of von Hippel-Lindau and up-regulation of c-Met, as 
well as, evidence for high MET expression in bone metastases specimens.[17] High MET 
expression has been demonstrated both in RCC bone metastases and brain metastases.[13, 14] 
In addition to anti-angiogenic effects, cabozantinib has activity against MET. In this study, 
we will also explore the preliminary efficacy of targeting PD-1, VEGFR, and MET  
simultaneously with the combination of pembrolizumab and cabozantinib, in terms of time to 


 
 
 
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progression of bone metastasis or skeletal-related events. 
 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
 
4.2.2.1 Rationale for Dose Selection of Pembrolizumab 
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475 (pembrolizumab). The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and 
no dose-limiting toxicities were observed. This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD was identified. 10.0 mg/kg Q2W, the 
highest dose tested in PN001, was the dose and schedule utilized in Cohorts A, B, C and D 
of this protocol to test for initial tumor activity.  Recent data from other clinical studies within 
the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL- 
2 release assay) suggested that peripheral target engagement is durable (>21 days). This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 2,993 subjects. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights. MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 


 
 
 
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2 mg/kg or 10 mg/kg Q3W in melanoma subjects, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual subject 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual subjects exposure in the exposure range established 
in melanoma that are well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
 
The currently approved dose of pembrolizumab across multiple cancers is 200 mg IV every 3 
weeks and this is the fixed dose used for this study. 
 
4.2.2.2 Rationale for Dose Selection of Cabozantinib 
 
Cabozantinib at a dose of 140 mg/day has been studied in 25 subjects with advanced RCC 
enrolled in a Phase 1 study (XL184-008).[18] Adverse events were the primary reason for 
treatment discontinuation in 24% of subjects and dose reduction was required in 80% (20/25) 
subjects. The median average daily dose was approximately 75.5 mg/day. Despite the dose 
reductions, 7 subjects (28%) had partial response and 13 subjects (52%) had stable disease, 
with a disease control rate of 80%. The median PFS was 12.9 months with a median follow- 
up of 14.7 months. In some subjects, there was evidence of clinical activity against bone 
metastatic lesions. Based on the long-term tolerability and clinical activity associated with 
doses of cabozantinib <140 mg in this and other trials, 60 mg daily was selected as the 
recommended starting dose in the phase III METEOR study of cabozantinib versus everolimus 
in advanced renal cell carcinoma.[15] This study showed a significant PFS benefit of 
cabozantinib over everolimus (median PFS 7.4 months vs. 3.8 months). Dose reductions 
occurred in 60% (197 of 331) subjects treated with cabozantinib and the median average daily 
dose was 44mg of cabozantinib. The rate of treatment discontinuation due to adverse events 
was 9%. 
 
In addition, results from a National Cancer Institute phase 1 trial of cabozantinib in 
combination with nivolumab in subjects with previously treated genitourinary tumors were 
presented during a poster discussion session (Abstract #774PD) at the European Society for  


 
 
 
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Medical Oncology (ESMO) 2016 Congress. Between July 2015 and September 2016, 24 
subjects were accrued with metastatic urothelial carcinoma (n=7), urachal adenocarcinoma 
(n=4), squamous cell carcinoma of the bladder or urethra (n=3), germ cell tumor (n=4), 
castration-resistant prostate cancer (n=4), renal cell carcinoma (n=1), or trophoblastic tumor 
(n=1) and were treated in Part I of the study, which evaluated the combination of cabozantinib 
and nivolumab at four dose levels. The median number of prior systemic therapies was 3, and 
10 subjects had received 4 or more prior therapies. The objective response rate was 43 percent 
among the 23 subjects who were evaluable for response, with one complete response and nine 
partial responses. Four of six subjects (67 percent) with urothelial cancer achieved a response. 
The recommended doses for the ongoing expansion cohorts were determined to be 
cabozantinib at 40 mg daily and nivolumab at 3 mg/kg once every 2 weeks. 
 
Given the phase I and phase III cabozantinib dosing and toxicity data, and the recent results of 
the phase I cabozantinib plus nivolumab study identifying a RP2D of 40 mg/day for 
cabozantinib, we have chosen a starting dose of cabozantinib 40mg/day for this combination 
study of cabozantinib and pembrolizumab with standard 3+3 design.  If none of the first 3, or 
if 1 or fewer of the first 6, DLT-evaluable subjects experiences a DLT, subjects will enroll in 
the next cohort with cabozantinib 60 mg/day. If 2 or more of the first 6 DLT-evaluable subjects 
in the 40 mg/day cohort experience a DLT, then subjects will enroll at one dose reduction with 
cabozantinib 20 mg/day. 
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
 
The primary endpoint of this study is to determine the efficacy (defined as objective response 
rate, ORR) of the combination of pembrolizumab and cabozantinib. 
 
The secondary endpoints of this study are to characterize dose limiting toxicities (DLTs), 
maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination 
of pembrolizumab and cabozantinib, as well as, other measures of efficacy including response 
by immune-mediated response criteria (irRECIST), progression-free survival, overall 
survival, time to progression of overall disease, time to progression of bone metastasis or 
skeletal-related events, clinical benefit rate [complete response (CR) + partial response (PR) 
+ stable disease (SD), duration of response or disease stability, and duration on treatment in 
subjects treated beyond progression. 
 
4.2.3.2 Biomarker Research 
 
It is unclear whether PD-L1 expression is a predictive biomarker for response and survival 
with anti-PD-1 and PD-L1 agents in metastatic renal cell carcinoma. In the phase III  
nivolumab versus everolimus clinical trial in mRCC subjects (CheckMate 025) which 


 
 
 
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demonstrated overall survival advantage with nivolumab, PD-L1 expression did not correlate 
with probability of overall survival.[5] Therefore, evaluation of other potential immune 
biomarkers is necessary. 
 
In this study, we will include mandatory archival tumor collection and optional pre- and post- 
treatment tumor biopsies for PD-L1 (QualTek Molecular Laboratories) and other immune- 
oncology testing which may include evaluation of other immune checkpoint markers, immune 
cell markers, and immune function markers. Biospecimens collected under this study will 
only be used for this research and will be destroyed upon completion of this study. 
 
5.0 METHODOLOGY 
 
5.1 Trial Participation Criteria 
 
5.1.1 Subject Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1. Subjects must have histological or cytological documentation of renal cell carcinoma.  
 
2. Subjects must have locally advanced, recurrent, or metastatic disease.  
 
3. Be willing and able to provide written informed consent/assent for the trial. 
 
4. Stated willingness to comply with all study procedures and be available for the duration 
of the trial. 
5. Be ≥ 18 years of age on day of signing informed consent. 
 
6. Have measurable or evaluable disease based on RECIST 1.1. 
 
7. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior 
treatments, unless AE(s) are clinically non-significant and/or stable on supportive 
therapy. 
 
8. Confirmed availability of representative archival tumor specimens in paraffin blocks 
(preferred) or ≥ 10 unstained slides, with an associated pathology report. 
 
Acceptable samples include core needle biopsies for deep tumor tissue or 
excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
 
Tumor tissue from bone metastases is not evaluable for PD-L1 expression and 


 
 
 
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is therefore not acceptable. 
 
A subject with insufficient or unavailable archival tissue may be eligible, upon 
discussion with the Principal Investigator, if the subject is willing to consent 
to undergo a pretreatment core, punch, or excisional/incisional biopsy sample 
collection of the tumor. 
 
9. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
10. Demonstrate adequate organ function as defined in Table 1.   
 
Table 1: Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤ 1.5 X upper limit of normal (ULN) OR 
≥ 60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Urine protein 
≤ 1+ or ≤ 30 mg/dL OR urine protein/creatinine ratio ≤ 1 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN.  For subjects with Gilbert’s disease ≤ 3 mg/dL. 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
 
11. Female participants of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication and 
should not be breastfeeding. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. 
 


 
 
 
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12. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.5.2 – Contraception, for the course of the study 
through 120 days after the last dose of study medication. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the participant. 
 
13. Male participants of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.5.2 – Contraception, starting with the first dose 
of study therapy through 120 days after the last dose of study therapy and refrain from 
donating sperm during this period. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
 
5.1.2 Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
equivalent to ≥ 10 mg/day of prednisone, or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment. 
 
3. Has a known history of active TB (Bacillus Tuberculosis). 
 
4. Has had prior treatment with pembrolizumab. 
 
5. Has had prior treatment with cabozantinib. 
 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.  
 
- 
Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may 
qualify for the study. 
 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 at 
baseline) from adverse events due to a previously administered agent. 
 


 
 
 
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- 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
 
- 
Note: Subjects with hypertension managed with medication are an exception 
to this criterion and may qualify for the study. 
 
- 
Note: Subjects with ≤ Grade 2 endocrinopathy (e.g. hypothyroidism or adrenal 
insufficiency managed with medication) are an exception to this criterion and 
may qualify for the study. 
 
8. Has had major surgery within 4 weeks or minor surgery within 2 weeks prior to study 
Day 1.  Subjects must have recovered adequately from the toxicity and/or 
complications from the intervention prior to starting therapy. 
 
9. Prior treatment with immune checkpoint inhibitors is allowed, provided that no 
treatment-related Grade ≥ 3 adverse events (other than Grade 3 endocrinopathy 
managed with replacement therapy) were observed and at least a minimum of 28 days 
have elapsed between the last dose of prior treatment and the proposed Cycle 1 Day 1. 
 
10. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer, 
carcinoma in situ or superficial bladder cancer, low-grade prostate cancer, intraductal 
papillary mucinous neoplasm (IPMN), and other low-grade cancers that is suitable for 
active surveillance in the opinion of the investigator. 
 
11. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Active CNS metastases will be defined as brain lesions that 1) require 
intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy 
(WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal 
therapy. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
after completion of focal therapy for brain metastases and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment. This exception 
does not include carcinomatous meningitis, which is excluded regardless of clinical 
stability. 
 
12. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed. 
 


 
 
 
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13. Has history of solid organ transplantation. 
 
14. Has history of osteonecrosis of the jaw. 
 
15. Has history of reversible posterior leukoencephalopathy syndrome. 
 
16. Has history of wound dehiscence or complications requiring medical intervention 
within 6 months of study entry. 
 
17. Has history of (non-infectious) pneumonitis that required steroids or active, non- 
infectious pneumonitis. 
 
18. Has an active infection requiring systemic therapy with IV antibiotics. 
 
19. Has uncontrolled, significant intercurrent or recent illness including, but not limited to, 
the following conditions: 
 
a. Cardiovascular disorders: 
 
i. Symptomatic congestive heart failure, unstable angina pectoris, serious 
cardiac arrhythmias. 
 
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or 
> 100 mm Hg diastolic despite optimal antihypertensive treatment. 
 
iii. Stroke (including TIA), myocardial infarction, or other ischemic event, or 
thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) 
within 3 months before randomization. 
 
b. Gastrointestinal  (GI) disorders  including  those  associated  with  a  high  risk  of  
 
perforation or fistula formation: 
 
i. Tumors invading the GI-tract, active peptic ulcer disease, inflammatory 
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary 
duct, or gastric outlet obstruction. 
 
ii. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or 
intra-abdominal abscess within 6 months before randomization. Complete 
healing of an intra-abdominal abscess must be confirmed before study 
initiation. 
 
c. Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon 
within 3 months before randomization. 


 
 
 
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d. Known endobronchial disease manifestation.  Patients with suspected endobronchial 
disease on imaging who have no evidence of endobronchial disease on bronchoscopy 
are allowed.  Patients with treated endobronchial disease are also allowed provided 
they are stable.   
 
e. Lesions invading major pulmonary blood vessels. 
 
20. 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. 
 
21. Has known  psychiatric  or  substance  abuse  disorders  that  would  interfere  with 
cooperation with the requirements of the trial. 
 
22. 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. 
 
23. Has an inability to swallow tablets or capsules. 
 
24. Has a previously identified allergy or hypersensitivity to components of the study 
treatment formulations. 
 
25. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
26. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 
27. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start 
of study therapy. Administration of killed vaccines is allowed. 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
 
5.2 Trial Treatments—Study Agents 
 
The treatment to be used in this trial is outlined below in Tables 2a-c   


 
 
 
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Table 2a: Trial Treatment Overview 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 
3-week cycle 
Experimental 
Cabozantinib 
20-60 mg 
Daily 
Oral 
Continuous 
Experimental 
 
 
Table 2b: Phase I Dose Escalation 
 
Cohort 
Pembrolizumab Dose 
Cabozantinib Dose 
-1 
200 mg IV every 3 weeks 
20 mg PO daily 
1* 
200 mg IV every 3 weeks 
40 mg PO daily 
2 
200 mg IV every 3 weeks 
60 mg PO daily 
* Starting dose level. 
 
Table 2c: Phase II Dose Expansion 
 
Cohort 
Pembrolizumab Dose 
Cabozantinib Dose 
Expansion 
200 mg IV every 3 weeks 
RP2D PO daily 
 
 
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 4.2.2 
–Rationale for Dose Selection/Regimen/Modification. 
 
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual. 
 
Cabozantinib (Cabometyx®) will be obtained commercially. CABOMETYX (cabozantinib) 
tablets are supplied as film-coated tablets containing 20 mg, 40 mg, or 60 mg of cabozantinib, 
which is equivalent to 25 mg, 51 mg, or 76 mg of cabozantinib (S)-malate, respectively. 
CABOMETYX also contains the following inactive ingredients: microcrystalline cellulose, lactose 
anhydrous, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and 
magnesium stearate. The film coating contains hypromellose, titanium dioxide, triacetin, and iron 
oxide yellow. 
 


 
 
 
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5.2.1.2 Dose Modification (Escalation/Titration/Other) 
 
Subjects will be monitored for AEs from the time of signing informed consent through 30 days 
after the date of the decision to permanently discontinue pembrolizumab and/or cabozantinib 
treatment. 
 
Once the DLT assessment period has passed, pembrolizumab and/or cabozantinib may be held 
or dose modified independent of the other agent for adverse events attributed to one but not 
both drugs.  The Principal Investigator should be notified when this occurs. 
 
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, subject 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 subject's study record. 
 
Interruption of pembrolizumab and/or cabozantinib treatment for AEs may occur at any time 
per investigator discretion, if the investigator feels it is in the interest of the subject’s safety 
and/or will optimize drug tolerability. If treatment is interrupted due to AEs for more than 6 
weeks, discussion and approval from the Principal Investigator is required prior to resuming 
therapy. 
 
5.2.1.3 Pembrolizumab 
 
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. 
 
There will be no dose modification of pembrolizumab, which is to be administered at a fixed 
dose of 200 mg IV every 21 days. A window of +/- 3 days is allowed for administrative/ 
scheduling reasons.   
 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-threatening AEs 
as per Table 3 below. See S e c t i o n  5 . 4  for supportive care guidelines, including 
use of corticosteroids. 
 
 


 
 
 
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Table 3: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive 
treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 
12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
Immune-related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4.0) 
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 
• Add prophylactic antibiotics for 
opportunistic infections 
 
• 
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 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 


 
 
 
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clear fluids.  If sufficient oral fluid intake 
is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2a 
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 3b or 4c 
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 
Withholdd 
• Initiate insulin 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 to 
treat adrenal insufficiency and 
other hormonal replacements as 
clinically indicated 
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency). 
Grade 3 or 4  
Withhold or 
permanently 
discontinued  
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 
discontinued 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of 
care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
 


 
 
 
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Nephritis: grading 
according to 
increased 
creatinine or acute 
kidney injury 
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 
Grade 1  
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 2-4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
Stevens-
Johnson 
Syndrome 
(SJS), toxic 
epidermal 
necrolysis 
(TEN), or 
Drug Rash 
with 
Eosinophilia 
and Systemic 
Symptom 
(DRESS) 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 


 
 
 
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All other immune-
related AEs 
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 
evente 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 
10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d 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. 
e Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, pancreatitis, encephalitis, sarcoidosis,myasthenic syndrome-
myasthenia gravis (including exacerbation), myelitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 


 
 
 
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5.2.1.3.2 Pembrolizumab Second Course  
The participant’s initial course of treatment with pembrolizumab will be the First Course, and 
in the absence of disease progression may be administered for up to 35 cycles. After the First 
Course, all participants who stop pembrolizumab after 35 cycles with SD or better may be 
eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if 
they progress after stopping pembrolizumab from the initial treatment phase.   
This retreatment is termed the Second Course phase and is only available if the participant 
continues on cabozantinib monotherapy and remains on study after completing the First Course 
of pembrolizumab and meets the following conditions:  
Either 
• Stopped initial study intervention after attaining an investigator-determined confirmed 
CR based on RECIST 1.1, and 
o Was treated with at least 8 cycles of pembrolizumab before discontinuing treatment, 
and 
o Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared 
OR 
 
• Had SD, PR, or CR and stopped pembrolizumab after completion of 35 administrations 
(approximately 2 years) of study intervention for reasons other than disease progression 
or intolerability 
 
AND 
 
• Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after stopping initial treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and 
o The patient remained on study while still continuing to dose with cabozantinib 
monotherapy after stopping initial pembrolizumab treatment (First Course). 
 
Additionally, the treating physician must determine at the time of progression after stopping 
initial treatment that continuing cabozantinib and resuming pembrolizumab is the best 
treatment course for the patient.   


 
 
 
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An objective response or disease progression that occurs during the Second Course Phase for a 
participant will not be counted as an event for the primary analysis of either endpoint in this 
study. 
 
Participants who have experienced an initial disease progression by RECIST 1.1 and have an 
iSD, iPR,or iCR per iRECIST after completion of 35 administrations of study intervention for 
reasons other than disease progression or intolerability may be considered for the Second 
Course Phase after consultation with the Sponsor-Investigator. 
 
For patients who have already treated beyond 35 cycles of pembrolizumab at the time of the 
protocol version 20-OCT-2020, and have SD or better, the patient should discontinue 
pembrolizumab after their next scheduled cycle. If the patient progresses after discontinuing 
pembrolizumab, they may be eligible for up to 17 additional cycles of pembrolizumab.  
For patients who have already signed consent to treat beyond progression at the time of the 
protocol version 20-OCT-2020, the patients should discontinue pembrolizumab at cycle 35 or 
after the next scheduled treatment cycle (if they have already completed 35 cycles or more). If 
the patient subsequently progresses, they may be eligible for up to 17 additional cycles of 
pembrolizumab.  


 
 
 
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5.2.1.4 Cabozantinib 
 
 
See Sections 2.1.1 to 2.1.6 for dosing of cabozantinib during the DLT assessment window in 
Phase I dose escalation. 
 
Dose modification criteria for cabozantinib outside the DLT assessment window and in the 
dose expansion stage are shown in Table 4. Dose reductions and/or interruptions should be 
implemented for unacceptable toxicity. Dose modifications or interruptions may also occur in 
the setting of lower grade toxicity than defined in Table 4, if the investigator feels it is in the 
interest of the subject’s safety and will optimize drug tolerability. 
 
Table 4: Dose Modification Guidelines for Cabozantinib Drug-Related Adverse Events 
 
CTCAE v4.0 Grade 
Recommended Guidelines for Management 
Grade 1 AEs 
Add supportive care as indicated. 
Continue cabozantinib treatment at current dose level if AE is manageable and 
tolerable. 
Grade 2 AEs which are tolerable and 
are easily managed 
Continue cabozantinib treatment at current dose level with supportive care. 
Grade 2 AEs which are intolerable and 
cannot be adequately managed 
At the discretion of the investigator, cabozantinib should be dose reduced or 
interrupted until symptoms become more tolerable or are better managed. 
Grade  3  AEs  (except  clinically  non- 
relevant laboratory abnormalities) 
Hold cabozantinib treatment and optimize supportive care. 
Once AE improves to ≤ Grade 2 and is tolerable and manageable, resume 
cabozantinib: 
• 
At same dose if first occurrence of Grade 3 AE despite optimal 
supportive care. 
• 
At one dose reduction (decrease by 20mg/day) if second occurrence 
of Grade 3 AE despite optimal supportive care. 
Permanently discontinue cabozantinib if third occurrence of Grade 3 AE despite 
optimal supportive care. 
Grade  4  AEs  (except  clinically  non- 
relevant laboratory abnormalities) 
Hold cabozantinib treatment immediately. 
Discontinue cabozantinib permanently UNLESS the following criteria are met: 
• 
Subject  is  deriving  clear  clinical  benefit  as  determined  by  the 
investigator and agreed by the Principal Investigator. 
• 
Toxicity can be managed with a dose reduction following recovery to 
Grade 1 (or baseline) and optimal medical care. 


 
 
 
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Cabozantinib should be permanently discontinued for any of the following: 
 
o Development of visceral perforation or fistula formation 
o Severe hemorrhage 
o Serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction) 
o Nephrotic syndrome (e.g. proteinuria > 2 grams/day on 24 hour urine or urine protein 
creatinine ratio >3.5 AND serum albumin < 2 mg/dL AND edema) 
 
o Malignant  hypertension,  hypertensive  crisis,  persistent  uncontrolled  hypertension 
despite optimal medical management. 
 
o Osteonecrosis of the jaw 
o Reversible posterior leukoencephalopathy syndrome 
 
5.2.1.4.2 Pembrolizumab AND Cabozantinib 
 
In situations where the attribution of toxicities in unclear, of if the toxicity is deemed to be 
related to both pembrolizumab and cabozantinib, follow dose modification guidelines 
presented in Table 5. 
 
Table  5:  Dose  Modification  Guidelines  for  Toxicities  of  Unclear  Attribution  or Deemed 
to be Related to Both Pembrolizumab and Cabozantinib 
 
Toxicity 
Grade 
Modification 
Diarrhea/Colitis 
2-3 
Hold both pembrolizumab and cabozantinib. 
Institute maximal anti-diarrheal therapy. 
Consider corticosteroids if no improvement on anti-diarrheal 
therapy within 24-48 hours. 


 
 
 
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Consider colonoscopy. 
4 
Permanently discontinue 
Hypothyroidism 
2-3 
Therapy with pembrolizumab and cabozantinib can be 
continued while thyroid replacement therapy is instituted. 
4 
Hold pembrolizumab and cabozantinib until Grade ≤ 2. 
AST, ALT or Increased Bilirubin 
2 
Hold pembrolizumab and cabozantinib until Grade ≤ 1. 
Dose reduce cabozantinib by 1 dose level for Grade ≤ 2 ALT, 
AST, or bilirubin lasting longer than 1 week. 
3-4 
Permanently discontinue 
AST, ALT AND Increased Bilirubin 
2-4 
ALT/AST elevations > 3 × ULN in combination with a 
bilirubin elevation > 2 × ULN require permanent treatment 
discontinuation. 
All Other Drug-Related Toxicity 
3 or Severe 
Hold pembrolizumab and cabozantinib until Grade ≤ 1. 
Permanently discontinue if G3 or severe toxicity recurs. 
4 
Permanently discontinue 
 
These treatment guidelines are intended to be applied when the investigator determines the 
events to be related to both pembrolizumab and cabozantinib, or if the attribution is unclear. 
If the investigator determines the events to be related to both study drugs, these dose 
modifications are required. Any questions about interpretation of the dose modifications or 
special circumstances should be discussed with the PI. 
 
Note: if after instituting these guidelines and after further evaluation, the event is 
determined to be more likely related to pembrolizumab or cabozantinib, and not both, then 
dose modification guidelines for either pembrolizumab (Table 3) or cabozantinib (Table 4) 
should be followed. 
 
5.2.2 Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Schedule of Events 
Chart (Section 6.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 


 
 
 
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Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. 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 from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
Cabozantinib will be obtained commercially. Subjects will be given oral and/or written 
instructions on dose to be taken by the investigator or by properly trained staff designee. 
Subjects will receive a medication diary with written dosing instructions and be asked to record 
the time and date they take each dose. Subjects will be instructed to bring their medication 
diary to each study visit for assessment of compliance. 
 
5.2.3 Trial Blinding/Masking and Treatment Allocation 
 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. This is a single arm, open-label study. All subjects will receive the combination 
of pembrolizumab and cabozantinib. 
 
5.3 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. One exception is the use of corticosteroids during the study 
to treat an immune-mediated adverse event, as noted in Section 5.2.1.3, Table 3, 
and Section 5.4.1. If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician. 
 
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 should be recorded in the subject research chart 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and Events of Clinical Interest (ECIs) as defined in Section 7.4. 
 


 
 
 
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5.3.2 
Prohibited Concomitant Medications and Therapies 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
• Antineoplastic systemic chemotherapy or biological therapy 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and cabozantinib 
• Radiation therapy to a target lesion 
o Note:  Palliative radiation therapy to a symptomatic non-target lesion, 
including the brain, may be allowed at the investigator’s discretion. 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
 
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology should be first discussed 
with and approved by the Principal Investigator.  
 
• 
Additionally, the use of physiologic 
doses of corticosteroids may be 
approved after consultation with the Principal Investigator. 
 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
 
 
5.4 Rescue Medications & Supportive Care 
 
5.4.1 
Supportive Care Guidelines for Pembrolizumab-Related Toxicities 
 
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 


 
 
 
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the investigator determines the events to be related to pembrolizumab. 
 
Note: if after the evaluation, the event is determined not to be related to pembrolizumab, 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, skin 
biopsy, 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. 
 
• 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. 
 
 
 
 
 
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≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
• Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 
• Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor subjects 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. 
 
 


 
 
 
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• 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. 
• 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 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 6: Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for 
< =24 hrs 
Stop Infusion and monitor symptoms. Additional appropriate 
medical therapy may include but is not limited to: 
IV fluids Antihistamines 
NSAIDS 
Acetaminophen Narcotics 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further trial treatment administration. 
Subject 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 


 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids Antihistamines 
NSAIDS 
Acetaminophen Narcotics Oxygen 
Pressors Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically indicated until the 
subject is deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
5.4.2 Supportive Care Guidelines for Cabozantinib-Related Toxicities 
 
The side effect profile of cabozantinib includes GI symptoms (such as nausea, vomiting, and 
diarrhea, mucositis/stomatitis), fatigue/asthenia, anorexia, weight loss, skin disorders 
including PPE syndrome, elevated liver function tests (including ALT and AST), increased 
pancreatic enzymes with rare cases of overt pancreatitis, thyroid function disorders, as well as 
side effects associated with inhibition of VEGF signaling. The latter of these include arterial 
and venous thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism 
(PE), transient ischemic attack, and myocardial infarction, hypertension, hemorrhagic events, 
proteinuria, wound complications, and rare cases of GI perforation, fistulae formation and 
rectal/perirectal abscess, osteonecrosis, and reversible posterior leukoencephalopathy (RPLS). 
 
• 
Gastrointestinal Disorders: 
o Diarrhea 
• Subjects should be instructed to notify their physician immediately at 
the first signs of poorly formed or loose stool or an increased frequency 
of bowel movements. 
• Administration of anti-diarrheal/ anti-motility agents is recommended 
at the first sign of diarrhea as initial management. Some subjects may 
require more than one antidiarrheal agent. 
• When therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, cabozantinib treatment should be temporarily 
interrupted or dose reduced. Treatment may resume when acceptable 
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• In addition, general supportive measures should be implemented 
including continuous oral hydration, correction of fluid and electrolyte 
abnormalities, small frequent meals, and stopping lactose-containing 
products, high fat meals, and alcohol. 
• If diarrhea is high grade or persistent, treat as per diarrhea/colitis related 
to pembrolizumab. 
o Nausea and vomiting 
• Antiemetic agents are recommended as clinically appropriate at the first 
sign of nausea and vomiting or as prophylaxis to prevent emesis, along 
with supportive care according to clinical practice guidelines. 
• The 5-HT3 receptor antagonists are recommended over chronic use of 
NK-1 receptor antagonists and dexamethasone (NK-1 receptor 
antagonists can induce or inhibit CYP3A4, and glucocorticoids induce 
CYP3A4 and thus could lower cabozantinib exposure. 
o Stomatitis and Mucositis 
• Removal of local factors should be instituted as indicated, such as 
modification of ill-fitting dentures and appropriate care of gingivitis. 
• During treatment with cabozantinib, good oral hygiene and standard 
local treatments such as non-traumatic cleansing and oral rinses (e.g. 
with a weak solution of salt and baking soda) should be maintained. 
• Local treatment should be instituted at the earliest onset of symptoms. 
• Obtain bacterial/viral culture if oral infection is suspected and treat 
infection as indicated by local guidelines. When stomatitis interferes 
with adequate nutrition and local therapy is not adequately effective, 
dose reduction or temporary withholding of cabozantinib should be 
considered. 
 
• Hepatobiliary Disorders: 
o Elevations of ALT, AST, and bilirubin have been observed during treatment 
with cabozantinib. 
o Subjects with elevation of ALT, AST, and/or bilirubin should have more 
frequent laboratory monitoring of these parameters. 
o Whenever possible, concomitant hepatotoxic medications should be avoided or 
discontinued in subjects who develop increased values of ALT, AST, or 
bilirubin. 
 


 
 
 
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o Dose reductions of study treatment should be considered in any subject who 
develops drug-related 
• Grade 2 elevated ALT, AST, or bilirubin lasting longer than 1 week. 
• Grade ≥ 3 elevated ALT, AST, or bilirubin. 
• ALT/AST  elevations  >  3  ×  ULN  in  combination  with  a  bilirubin 
elevation > 2 × ULN require permanent treatment discontinuation. 
 
• Hematologic Disorders: 
o Complete blood counts with differentials and platelets should be performed 
regularly. 
o Subjects with hematologic toxicities may require additional or more frequent 
laboratory monitoring of these parameters. 
o Febrile neutropenia or evidence of infection associated with neutropenia must 
be assessed immediately and treated appropriately and in a timely manner 
according to institutional guidelines. 
o Use of granulocyte colony-stimulating factor support for neutrophil recovery is 
allowed per investigator discretion and in accordance with accepted guidelines 
after the first incidence of clinically relevant cytopenia. 
o Dose reductions or dose interruptions for anemia are not mandated but can be 
applied as clinically indicated. 
o Supportive care such as red blood cell or platelet transfusions may be managed 
according to institutional guidelines. 
 
● Fatigue, Anorexia, and Weight Loss: 
o Common causes of fatigue such as anemia, deconditioning, emotional distress 
(depression and/or anxiety), nutrition, sleep disturbance, and hypothyroidism 
should be ruled out and/or these causes treated according to standard of care. 
o Dose reduction of cabozantinib should be considered when general or 
pharmacological measures have not been successful in reducing symptoms. 
Dose interruption may be considered for Grade ≥ 3 fatigue despite optimal 
management, at the investigator’s discretion. 
o Anorexia and weight loss should be managed according to local standard of 
care including nutritional support. 
 
 
 


 
 
 
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• Skin Disorders: 
o Palmar-plantar erythrodysesthesia syndrome (also known as hand-foot 
syndrome), skin rash (including blisters, erythematous rash, macular rash, skin 
exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, and 
erythema have been reported in cabozantinib-treated subjects. 
o All subjects on study should be advised on prophylactic skin care. 
o Subjects with skin disorders should be carefully monitored for signs of 
infection. 
o Early signs of hand-foot syndrome could be tingling, numbness, and slight 
redness or mild hyperkeratosis. Early manifestations include painful, 
symmetrical red and swollen areas on the palms and soles. 
o Aggressive management of symptoms is recommended, including early 
dermatology or podiatry referral. 
 
Table 7: 
Management of 
Cabozantinib-Related Palmar-Plantar 
Erythrodysesthesia (PPE) Syndrome 
 
CTCAE v4.0 Grade 
Action To Be Taken 
1 
Cabozantinib treatment may be continued at the 
current dose if PPE is clinically insignificant and 
tolerable. 
If clinically significant or intolerable, cabozantinib 
should be interrupted and/or reduced to the next lower 
dose level. 
Start urea 20% cream twice daily and clobetasol 
0.05% cream once daily.  Reassess weekly. 
Reassess at least weekly; if PPE worsens at any 
time or does not improve after 2 weeks, 
proceed to the intervention guidelines for Grade 
2. 
2 
Cabozantinib treatment may be continued if PPE is 
tolerated. 
Cabozantinib should be dose reduced or interrupted if 
PPE is intolerable. 
Continue urea 20% cream twice daily and clobetasol 
0.05% cream once daily and add analgesics (e.g., 
NSAIDs/GABA agonists) for pain control if needed. 
Reassess at least weekly; if PPE does not improve 
within 2 weeks or worsens or affects self-care, proceed 
to the intervention guidelines for Grade 3. 


 
 
 
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3 
Interrupt 
cabozantinib 
treatment 
until 
severity 
decreases to Grade 1 or Grade 0. 
Continue treatment of skin reaction with clobetasol 
0.05% cream twice daily and analgesics. 
Resume cabozantinib at reduced dose if PPE recovers 
to Grade 0 or 1. 
Discontinue cabozantinib treatment if intolerable PPE 
recurs after dose reduction or does not improve within 
6 weeks. 
• Hypertension: 
o Blood pressure should be monitored at each visit. 
 
Table 8: Management of Cabozantinib-Related Hypertension 
 
Blood pressure or Condition 
Action to be Taken 
SBP 150-160 or DBP 100-110 mmHg 
Optimize antihypertensive treatment by adding new or 
additional 
antihypertensive 
medications 
and/or 
increase dose of existing medications. 
Reduce cabozantinib treatment by one dose level if 
optimal antihypertensive therapy (usually to include 3 
agents) does not result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic. 
If subject is symptomatic, interrupt study treatment. 
SBP > 160 or DBP > 110 mmHg 
If optimized antihypertensive therapy (usually to 
include 3 agents) does not result in BP < 150 mm Hg 
systolic or < 100 mm Hg diastolic, cabozantinib 
treatment should be dose reduced further or 
interrupted. 
Interrupt cabozantinib treatment if upper limits of BP 
(≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic) are 
sustained and not adequately manageable or if BP is > 
180 mm Hg systolic or > 120 mm Hg diastolic or if 
subject is symptomatic. 
Restart cabozantinib treatment at the most tolerable 
dose and re-escalate cabozantinib dose only if BP falls 
to and is sustained at < 140 mm Hg systolic and < 90 
mm Hg diastolic. 
Hypertensive crisis or hypertensive encephalopathy 
Discontinue cabozantinib treatment. 
 
• Thromboembolic Events: 
o Subjects who develop a PE or DVT should have cabozantinib treatment held 
until therapeutic anticoagulation with heparins (e.g., LMWH) is established. 
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uncomplicated PE or DVT and are deriving clinical benefit from cabozantinib 
treatment. 
o Subjects with life-threatening PE or DVT should have study treatment 
discontinued unless toxicity can be managed and subject is deriving clear 
clinical benefit as determined by the treating physician and agreed by the 
Principal Investigator. 
o Cabozantinib treatment should be discontinued in subjects who develop an 
acute myocardial infarction or any other clinically relevant arterial 
thromboembolic complication. 
 
● 
Proteinuria: 
o If urinalysis shows proteinuria ≥ 3+, obtain spot urine protein creatinine ratio. 
 
Table 9: Management of Cabozantinib-Related Proteinuria 
 
Severity of Proteinuria (UPC Ratio) 
Action to be Taken 
UPC Ratio ≤ 1 
No change in cabozantinib treatment or monitoring. 
UPC Ratio > 1 to < 3.5 
No change in cabozantinib treatment required. 
 
Consider 
confirming 
with 
a 
24-hour 
protein 
assessment within 7 days. 
Repeat UPCR within 7 days and once per week. If 
UPCR < 1 on 2 consecutive readings, UPCR 
monitoring can revert to protocol-specific times. 
UPC Ratio ≥ 3.5 
Hold cabozantinib treatment pending repeat UPCR 
within 7 days and/or 24-hour urine protein. 
If ≥ 3.5 on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR 
decreases to < 2, restart cabozantinib treatment at a 
reduced 
dose 
and 
monitoring 
of 
urine 
protein/creatinine should continue weekly until the 
UPCR decreases to < 1. 
Nephrotic syndrome (e.g. proteinuria > 2 grams/day on 
24 hour urine or urine protein creatinine ratio >3.5 
AND serum albumin < 2 mg/dL AND edema) 
Discontinue cabozantinib treatment. 
 
 
 
 
 


 
 
 
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• Hypophosphatemia: 
o Serum phosphorus should be monitored frequently while receiving 
cabozantinib. 
o Mild to moderate hypophosphatemia should be managed by oral replacement 
including food that are high in phosphate (diary items, meats, beans) and/or oral 
phosphate supplements according to standard clinical practice guidelines. 
 
• Thyroid Function Disorders: 
o Changes in thyroid function tests (TFTs) and hypothyroidism have been 
reported with cabozantinib and other tyrosine kinase inhibitor treatment as a 
result of altered thyroid hormone regulation. 
o Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) 
should follow accepted clinical practice guidelines. 
 
• Hemorrhagic Events: 
o Discontinue cabozantinib treatment in subjects who have been diagnosed with 
a severe bleeding complication. 
 
• GI Perforation/Fistula and Non-GI Fistula Formation: 
o Carefully monitor for episodes of abdominal pain, especially in subjects with 
known risk factors for developing GI perforation/fistula or non-GI fistula, to 
allow for early diagnosis. 
o Discontinue cabozantinib treatment in subjects who have been diagnosed with 
GI or non-GI perforation/fistula. 
 
• Osteonecrosis of the Jaw: 
o Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic 
drugs and bisphosphonates and denosumab in cancer subjects. 
o Subjects with any documented case of osteonecrosis should have study 
treatment discontinued, and appropriate clinical management should be 
initiated. 
 
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. 


 
 
 
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5.5.2 Contraception 
 
Pembrolizumab and/or cabozantinib may have adverse effects on a fetus in utero. Animal 
reproduction studies have not been conducted with pembrolizumab; however, 
blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt 
tolerance to the fetus and to result in an increase in fetal loss. These results indicate a potential 
risk, based on its mechanism of action, that administration of pembrolizumab during pregnancy 
could cause fetal harm, including increased rates of abortion or stillbirth. Human IgG4 is known 
to cross the placental barrier and pembrolizumab is an IgG4; therefore, pembrolizumab has the 
potential to be transmitted from the mother to the developing fetus. Pembrolizumab is not 
recommended during pregnancy unless the clinical benefit outweighs the potential risk to the fetus. 
 
Furthermore, it is not known if pembrolizumab and/or cabozantinib have transient adverse 
effects on the composition of sperm.  
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
 
Female subjects will be considered of non-reproductive potential if they are either: 
 
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
 
OR 
 
(2) Have  had  a  hysterectomy and/or  bilateral  oophorectomy,  bilateral  salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
 
OR 
 
(3) Have a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following: 
 
(1) Practice abstinence† from heterosexual activity; 
OR 


 
 
 
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(2) Use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
 
Single method (one of the following is acceptable): 
 
• 
Intrauterine device (IUD) 
 
• 
Vasectomy of a female subject’s male partner 
 
• 
Contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
 
• 
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
 
• 
Cervical cap with spermicide (nulliparous women only) 
 
• 
Contraceptive sponge (nulliparous women only) 
 
• 
Male condom or female condom (cannot be used together) 
 
• 
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin- 
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. 
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy. If there is any question that a subject of childbearing potential 


 
 
 
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will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
5.5.3 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
cabozantinib, the subject will immediately be removed from the study. The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor- 
Investigator without delay and within 24 hours and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). 
 
The 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-Investigator. If a 
male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor-Investigator and to Merck and 
followed as described above and in Section 7.7. 
 
5.5.4 Use in Nursing Women 
 
It is unknown whether pembrolizumab or cabozantinib are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
5.6 Subject Withdrawal/Discontinuation Criteria 
 
5.6.1 Subject Withdrawal 
Subjects may withdraw consent at any time for any reason or be taken off study 
treatment at the discretion of the investigator should any untoward effect occur. In 
addition, a subject may be withdrawn by the investigator or the Sponsor if enrollment 
into the trial is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons. 
 
5.6.2 Subject Discontinuation 
A subject must be discontinued from the taken off study treatment for any of the 
following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 


 
 
 
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• 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, 
provided they meet all criteria for treatment beyond progression and have 
approval of the Principal Investigator (Section 5.7) 
 
• Unacceptable adverse experiences as described in Section 5.2.1.2, 5.2.1.3, 5.2.1.3.1, 
and 5.2.1.3.2. 
 
• Intercurrent illness that prevents further administration of treatment 
 
• Investigator’s decision to withdraw the subject 
 
• The subject has a confirmed positive serum pregnancy test 
 
• Noncompliance with trial treatment or procedure requirements 
 
• The subject is lost to follow-up 
 
• Administrative reasons 
 
5.6.3 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
 
• Quality or quantity of data recording is inaccurate or incomplete. 
• Poor adherence to protocol and regulatory requirements. 
• Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects. 
• Plans to modify or discontinue the development of the study drug. 
 
In the event of Merck’s decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
Specific details regarding the procedures to be followed due to subject discontinuation or 
withdrawal from the study are provided in Section 7.1.4 – Other Procedures – 
Withdrawal/Discontinuation. 
 
The End of Treatment/ Follow-up visit procedures are listed in Section 6 (Trial Schedule of 
Events) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 


 
 
 
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for 90 days after the end of treatment as described in Section 7.2.5.3). Subjects who 
discontinue treatment for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up. 
 
5.7 Treatment Beyond Disease Progression 
 
Subjects may continue study treatment after standard RECIST v1.1 criteria for progressive 
disease are met provided they meet all the following criteria: 
 
o Absence of symptoms and signs (including worsening of laboratory values, e.g., new or 
worsening hypercalcemia) indicating unequivocal progression of disease. 
 
o Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
o Absence of tumor progression at critical anatomical sites such as the central nervous 
system,  central  airway,  the  great  vessels,  and  other  organs  or  tissues  where  tumor 
progression would be expected to result acutely in severe and/or irreversible disability or 
death. 
 
o Subjects must provide written consent to acknowledge discussion with the treating 
investigator of the benefit-risk balance of continuing study treatment beyond radiographic 
progression. 
 
o If radiographic disease progression is confirmed at a subsequent tumor assessment, 
subjects may be considered for continued study treatment at the investigator’s discretion 
after discussion with the Principal Investigator, if they continue to meet the criteria above 
and have evidence of clinical benefit, as evidenced by improvement in one or more 
symptoms or signs attributable to the underlying cancer. 
 
5.8 Subject Replacement Strategy 
 
Any dose-escalation subject who does not complete the DLT assessment window for a reason 
other than a DLT will be considered non-evaluable for dose escalation decisions, as well as, 
the MTD and RP2D assessment and may be replaced by an additional subject at that same dose 
level. 
 
A subject who has any component of study treatment held during the DLT assessment window 
for a reason other than a DLT such that administration of the next planned pembrolizumab 
dose is delayed by more than 7 days and/or ≥25% of the planned cabozantinib doses are missed, 
will be considered non-evaluable for dose-escalation decisions and the MTD assessment and 
may be replaced by an additional subject at that same dose level. 
 


 
 
 
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5.9 Known Potential Benefits 
 
The risks to subjects are reasonable in relation to the anticipated benefits to subjects and/or 
society, and in relation to the importance of the knowledge that may reasonably be expected 
to result, thereby falling in favor of performing the study: 
 
• To Participant: Potential benefit of improved efficacy of the combination of 
cabozantinib and pembrolizumab. 
• To Society: Potential benefit of establishing benefit of this combination as a 
treatment option to future patients with metastatic renal cell carcinoma. 
Justify the importance of the knowledge gained: While there are survival 
benefits of cabozantinib monotherapy and nivolumab (an anti-PD-1 antibody 
similar to pembrolizumab currently approved for metastatic renal cell 
carcinoma) monotherapy, these treatments are not curative and resistance 
develops.  The hope is that the combination would provide lead to more 
response rates and slower resistance to treatment, compared to each agent 
alone. 
 


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6.0  TRIAL SCHEDULE OF EVENTS CHART 
Trial Period: 
Screening 
Treatment Cyclesa 
End of Treatment/ Follow 
Up Visit 
Survival 
Follow-Upm 
 
 
Treatment Cycle/Title: 
Main 
Study 
Screening  
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
To be repeated 
beyond 7 cycles 
Safety Follow-up 
Overall Survival 
 
5 
6 
7 
Every 6 months 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Within 30 days post treatment 
discontinuation 
±1 month 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
Demographics and Medical History 
X 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pembrolizumab Treatment Administrationl 
X 
X 
X 
X 
X 
X 
X 
Cabozantinib Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
Post-study Anticancer Therapy Status 
X 
 
Survival Statusm 
X 
Xm 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead EKG 
X 
X 
Xk 
X 
 
Pregnancy Test – Urineb 
X 
Xj 
X 
X 
X 
X 
X 
X 
PT/INR, aPTT, LDH 
X 
CBC with Differential 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel, including 
Phosphorus 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
 
Total T3, Free T4, and TSHi 
X 
X 
X 
X 
 


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a Each treatment cycle = 3 weeks. 
b Urine pregnancy test is required only in women of childbearing potential. 
c CT or MRI CAP +/- bone scan and RECIST 1.1 assessments will be obtained at baseline and after every 3 cycles. irRECIST = immune-related response criteria.  PET/CT is an acceptable alternative imaging 
modality. All scans can be performed ± 7 days from the scheduled date. 
d Whole Body Bone Scan is required for subjects with known or suspected bone metastases. All scans can be performed ± 7 days from the scheduled date. 
e The baseline optional fresh tumor biopsy should be obtained during the screening period, prior to C1D1 treatment. The post-treatment optional fresh tumor biopsy should be obtained approximately 3-6 weeks (during 
cycle 2). Subjects may consent for separately for either baseline and/or post-treatment biopsies. 
g Bone turnover markers may include β C-terminal telopeptide (β-CTX), bone specific alkaline phosphatase, and procollagen type 1 amino-terminal propeptide (P1NP). †Bone turnover markers will be collected through 
cycle 7 but not beyond.  Bone tumor markers are not required during the second course of treatment. 
i Total T3 = Total thriiodothyronine, Free T4= T4 (thyroxine) Free 
j Screening labs and pregnancy tests do not need to be repeated at C1D1 if done within 7 days of C1D1.  
k EKG tests will be performed through cycle 7, and then only as clinically indicated. 
l  In the absence of disease progression, pembrolizumab may be administered for up to 35 cycles (first course). If the patient progresses after discontinuing pembrolizumab, they may resume dosing for up to 17 additional 
cycles (second course), providing they meet criteria for retreatment. See protocol section 5.2.1 for additional information. 
m Survival status:  patients will be followed for survival every 6 months (±1 month) for 3 years after completion of study treatment or until study discontinuation, whichever occurs first. 
Trial Period: 
Screening 
Treatment Cyclesa 
End of Treatment/ Follow Up 
Visit 
Survival 
Follow-Upm 
 
 
 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 2) 
1 
2 
3 
4 
To be repeated 
beyond 7 cycles 
 
Safety Follow-up 
Overall Survival 
5 
6 
7 
Every 6 months 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Within 30 days post treatment 
discontinuation 
±1 month 
Tumor Imagingc 
(CT or MRI C/A/P +/- Whole Body Bone Scan d) 
 
X 
 
 
 
 
X 
 
 
 
X 
RECIST 1.1 and irRECIST radiology readc 
X 
X 
X 
Archival Tumor Collection 
X 
Optional Fresh Tumor Biopsies (baseline and post-
treatment) 
Xe 
Xe 
• 
PD-L1 Testing 
X 
X 
• 
Immuno-Oncology Marker Testing 
X 
X 
Correlative Studies 
• 
Bone Turnover Markersg (in subjects with 
bone metastases only) 
 
X 
X 
 
X 
 
 
X† 


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7.0 
TRIAL PROCEDURES 
 
7.1 Trial Procedures 
 
The Trial Schedule of Events 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 for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
7.1.1 Administrative Procedures 
 
7.1.1.1 Informed Consent Process 
 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
subject and the Investigator must obtain a documented informed consent form (ICF) from 
each potential subject prior to participating in this clinical trial (i.e., starting intervention/ 
administration of study product). The Informed Consent Process will continue throughout the 
subject’s participation in this clinical trial. 
 
The study allows the inclusion of non-English speaking and non-reading subjects. Witnesses to 
these consent processes will be individuals not associated with the trial and will not have a 
conflict of interest. 
 
7.1.1.1.1 Informed Consent Form (ICF) and Documentation 
 
ICFs will be IRB-approved and the subject will be asked to read and review the document. 
A designated study staff member will explain the research study to the subject and answer 
any questions that may arise. All subjects will receive a verbal explanation in terms suited 
to their comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. Subjects will have the opportunity to carefully review 
the written ICF and ask questions prior to signing. Subjects will have the opportunity to 
discuss the trial with their surrogates or think about it prior to agreeing to participate. 
 
Consent will be documented on the ICF by the subject’s dated signature along with the dated 
signature of the person conducting the consent discussion. 
 
 


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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 (ICF), any subsequent revised ICF and any written 
information provided to the subject will receive the IRB’s approval 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 and IRB 
approved ICF or addendum to the original ICF that captures the subject’s dated signature. 
 
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 
 
Subjects will sign the ICF prior to any procedures being done specifically for this trial. 
 
Subjects may withdraw consent at any time throughout the course of the trial. A copy of the 
ICF will be given to the subjects for their records. The rights and welfare of the subjects will be 
protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this trial. 
 
7.1.1.1.2 Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
 
7.1.1.2 Medical History 
 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history. 
 
7.1.1.3 Prior and Concomitant Medications Review 
 
7.1.1.3.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication. 
 
 
 


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7.1.1.3.2    Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
 
7.1.1.4 Disease Details and Treatments 
 
7.1.1.4.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status including stage, histologic subtype (e.g. clear cell, non-clear cell, mixed, sarcomatoid, 
etc.), prior nephrectomy status, and site(s) of metastatic disease (e.g. bone, lung, brain, lymph 
node, etc.). Whenever possible, Memorial Sloan Kettering Cancer Center (MSKCC) renal cell 
carcinoma risk stratification will be documented. 
 
7.1.1.4.2    Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. When available, data on response to and duration 
on prior treatments will be recorded. 
 
7.1.1.4.3    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 within the 30 day follow up period. 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. 
 
7.1.2 Clinical Procedures/Assessments 
 
7.1.2.1 Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Schedule of Events Chart (Section 6) and more 
frequently if clinically indicated. Adverse experiences will be graded and recorded throughout 
the study and during the follow-up period according to NCI CTCAE Version 4.0 (see Section 
12.3). Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment. 
 
Please refer to section 7.3 for detailed information regarding the assessment and recording of 
AEs. 
 
 
 


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7.1.2.2 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 
physical exam should be performed during screening and during each study visit. 
 
7.1.2.3 Vital Signs 
 
The investigator or qualified designee will review vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Schedule of Events Chart (Section 6.0). Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure. Height will be measured at screening only. 
 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Section 12.2) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Schedule of Events Chart. 
 
7.1.2.5 Tumor Imaging and Assessment of Disease 
 
Radiographic tumor assessments will include a CT or MRI of the chest, abdomen, and pelvis 
(CAP). In subjects with known bone metastases, a technetium bone scan should also be 
obtained. If MRI is performed of the abdomen and pelvis at screening, then at least a non- 
contrast CT of the chest should be performed as well. 
 
CT or MRI CAP +/- bone scan and RECIST 1.1 assessments will be obtained at baseline and 
after every 3 cycles. All scans can be performed ± 7 days from the scheduled date.  The same 
imaging modalities should be used at screening and for subsequent tumor assessments. 
Radiographic response and disease progression will be determined using RECIST version 1.1 
and immune-related response criteria (irRECIST). 
 
PET/CT is an acceptable alternative imaging modality. 
 
7.1.2.6 Tumor Tissue Collection 
 
Archival tumor tissue is mandatory for enrollment in both the dose escalation and dose 
expansion cohorts. A subject with insufficient or unavailable archival tissue may be eligible, 
upon discussion with the Principal Investigator, if the subject is willing to consent to undergo 
a pretreatment core, punch, or excisional/incisional biopsy sample collection of the tumor. 
 
In addition, subjects may consent for optional fresh tissue biopsies at baseline (during 
screening period) and/or post-treatment at approximately 3-6 weeks (during cycle 2) after 
initiation of study treatment. 
 


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These archival and fresh tumor specimens will be used for PD-L1 and/or other immune- 
oncology marker testing. 
 
7.1.3 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 10. 


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Table 10: Laboratory Tests 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin (β-
hCG)2 
 
Hemoglobin 
Alkaline phosphatase 
Glucose 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
aPTT 
Red Blood Cell Count 
Carbon Dioxide 
Microscopic exam (If abnormal 
results are noted) 
 
Total triiodothyronine (T3) 
Absolute Neutrophil Count 
 Lactate dehydrogenase (LDH)1 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
Calcium 
Urine pregnancy test 2 
Thyroid stimulating hormone (TSH) 
Chloride 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total Bilirubin 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
Total protein 
Blood Urea Nitrogen 
1 LDH only required at screening 
2 Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
 
 


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After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment.  
 
7.1.4 
Other Procedures—Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events. 
 
7.1.5 
Visit Requirements 
 
Visit requirements are outlined in Section 6.0 - Trial Schedule of Events Chart. Specific 
procedure-related details are provided above in Section 7.1 - Trial Procedures. 
 
7.1.5.1 Screening Period 
 
All screening evaluations must be completed and reviewed to confirm that 
subjects meet all eligibility criteria before initiating study treatment. Written 
informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent 
Forms for subjects who are not subsequently enrolled will be maintained at the 
study site. 
 
Screening and pre-treatment tests and evaluations will be performed within 28 
days preceding Cycle 1 Day 1 (defined as the day of first dose of study 
treatment), unless otherwise specified. Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within 28 days 
prior to study entry may be used; such tests do not need to be repeated for 
screening. 
 
See the study Schedule of Events (Section 6.0) for schedule of screening 
assessments. 
 
7.1.5.2 Treatment Period 
 
All visits must occur within ± 3 days from the scheduled date, unless otherwise 
noted. All assessments will be performed on the day of the specified visit unless 
a time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed prior to study drug 
infusion, unless otherwise noted. C1D1 laboratory assessments do not need to be 
repeated if screening labs were done within 7 days of C1D1.  


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See the study Schedule of Events (Section 6.0) for schedule of treatment period 
assessments. 
 
7.1.5.3 End of Treatment/Safety Follow-Up Visit 
 
The End of Treatment/Safety Follow-Up Visit should be conducted 
approximately 30 days after the last dose of trial treatment, or before the initiation 
of a new anti-cancer treatment, whichever comes first. 
 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. 
Subjects with an AE of Grade > 1 will be followed until the resolution of the 
AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy 
(including single agent cabozantinib SOC) whichever occurs first. SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-
cancer treatment (including single agent cabozantinib SOC) should also be 
followed and recorded. 
 
7.1.5.4 Survival Follow-Up 
 
Patients will be followed for survival every 6 months (±1 month) for 3 years 
after completion of study treatment or until study discontinuation, whichever 
occurs first. 
 
7.2 
Assessing and Recording Adverse Events 
 
7.2.1 Definition of AEs 
 
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. 
 
7.2.2 Assessment of AEs 
 
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. 
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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 as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
 
Progression of the cancer under study is not considered an adverse event. 
 
7.2.3 Reporting of AEs 
 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject 
to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
 
From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such 
events will be recorded 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 7.4.1- Definition and Assessment of SAEs. The 
investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome. 
 
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 
Serious Adverse Events (SAE) 
 
7.3.1 Definition and Assessment of SAEs 
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; 


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• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event. 
 
• Note: In addition to the above criteria, adverse events meeting either of the 
below criteria, although not serious per ICH definition, are reportable to the 
Merck in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection 
purposes. 
o Is a new cancer (that is not a condition of the study); 
o Is associated with an overdose. 
 
Refer to Table 11 for additional details regarding each of the above criteria. 
 
7.3.2 Immediate Reporting of SAEs 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, 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 
(reference Section 7.4.2.1-Protocol Specific Exceptions to Serious Adverse Event 
Reporting for additional details) that occurs to any subject must be reported within 24 
hours to the Sponsor-Investigator and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, 
or follow up to a serious adverse event, including death due to any cause other than 
progression of the cancer under study (reference Section 7.4.2.1-Protocol Specific 
Exceptions to Serious Adverse Event Reporting for additional details), whether or not 
related to the Merck product, must be reported within 24 hours to the Sponsor- 
Investigator and within 2 working days to Merck Global Safety. The SAE should also 
be submitted within 7 (for fatal or life-threatening events) or 15 (non-life-threatening 
events) calendar days of the sponsor investigator receiving notification of the 
occurrence to the Data and Safety Monitoring Committee (DSMC) at the University of 
Colorado Cancer Center. 
 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention of the 
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follow-up period specified in the paragraph above, or at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the 
Sponsor and to Merck Global Safety. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number: +1-215-661-6229 Merck will include a copy 
of all 15 Day Reports and Annual Progress Reports for their submissions as required 
by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) 
or other local regulators. The Sponsor-Investigator of this study will cross reference the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission 
to the FDA, the IND application for this study. Additionally, investigators will submit 
a copy of these safety and annual progress reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 661-6229) at the time of submissions to the FDA. 
 
7.3.2.1 
Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as 
described in Section 7.3.2 - Immediate Reporting of AEs, unless there is evidence 
suggesting a causal relationship between the drug and the event. Any such event 
will be submitted to the Sponsor-Investigator within 24 hours and to Merck Global 
Safety within 2 working days either by electronic or paper media. The SAE should 
be submitted within 7 (for fatal or life-threatening events) or 15 (non-life-
threatening events) calendar days of the sponsor investigator receiving notification 
of the occurrence to the DSMC at the University of Colorado Cancer Center. 
 
Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study. 
 
The Sponsor-Investigator will monitor unblinded aggregated efficacy endpoint 
events and safety data to ensure the safety of the subjects in the trial. Any suspected 
endpoint which upon review is not progression of the cancer under study will be 
forwarded to Merck Global Safety as a SAE within 2 working days of determination 
that the event is not progression of the cancer under study. The SAE should be 
submitted within 7 (for fatal or life-threatening events) or 15 (non-life-threatening 
events) calendar days of the sponsor investigator receiving notification of the 
occurrence  to the DSMC at the University of Colorado Cancer Center. 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be 
considered a SAE. 
 
 
 
 


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7.4 Events of Clinical Interest (ECI) 
 
7.4.1 Definition and Assessment of ECI 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and for this trial include: 
 
1. An overdose of Merck product, as defined in Sections 7.5.1 - Definition of an 
Overdose for This Protocol and 7.5.2 - Reporting of Overdose for this Protocol 
that is not associated with clinical symptoms or abnormal laboratory results. 
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing*. 
 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
7.4.2 Reporting ECIs 
ECIs and must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215- 
661-6229).  
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject 
must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.  
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to Merck product, must be reported within 24 hours to 
the Sponsor-Investigator and within 24 hours to Merck Global Safety.  
 
 
 
 


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7.5 An Overdose for this Protocol 
 
7.5.1 Definition and Assessment of an Overdose for this Protocol 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose 
of 1,000 mg or greater (≥5 times the indicated dose). 
 
No specific information is available on the treatment of overdose of pembrolizumab. 
Appropriate supportive treatment should be provided if clinically indicated. In the 
event of overdose, the subject should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. 
 
7.5.2 Reporting of an Overdose for This Protocol 
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 Sponsor-Investigator and within 2 working days hours to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
 
7.6 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) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator. All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 


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Such events must be reported within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229). 
 
7.7 Definition of Unanticipated Problems (UAP) 
 
The Office of Human Research Protection (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• Suggests that the research places participants or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
This study will use the OHRP definition of UAP. 
 
7.8 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
7.9 Sponsor-Investigator 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. 


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Table 11: Evaluating Adverse Events 
 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring 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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event. A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
subject’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days. 


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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 Merck product to be discontinued? 
Relationship to 
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator who 
Merck Product 
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 Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to 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 
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 


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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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to 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) 
Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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. 
 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship) 
Yes, there is a reasonable 
possibility of Merck product 
relationship 
There is evidence of exposure to Merck product. The temporal sequence of the AE is more likely explained by Merck product than another cause.  
The AE onset relative to administration of Merck product is reasonable.  
No, there is not a reasonable 
possibility of Merck product 
relationship 
 
 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR is 
more likely explained by another cause than the Merck product.(also entered for a subject with overdose without an associated AE.) 
 
 
 
 
 


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8.0 STATISTICAL ANALYSIS PLAN 
 
8.1 
Statistical Analysis Plan Summary 
 
The final study analysis will be based on subject data collected through study discontinuation. 
Analyses will be based on the safety-evaluable population, defined as all subjects who receive 
any amount of study treatment. In general, data will be summarized as warranted, and listings 
will be provided in place of tables when sample sizes are small. Summaries will be presented 
by the assigned dose regimen and designated treatment arm. 
 
8.2 
Statistical Analysis Plan 
 
8.2.1 Analysis of Overall Conduct of Study 
 
Enrollment and major protocol violations, study treatment administration, and reasons 
for 
subject discontinuations from the study treatment will be described and listed or 
summarized. 
 
Demographic and baseline characteristics, such as age, sex, histology, prior 
nephrectomy status, site(s) of metastatic disease, prior treatments including response and 
duration, MSKCC renal cell carcinoma risk stratification, and baseline ECOG performance 
status will be summarized. 
 
8.2.2 Analysis of Safety 
 
Safety will be assessed through summaries of DLTs, adverse events, clinically 
significant changes in laboratory test results, clinically significant changes in vital signs 
and ECGs, and exposure to components of study treatment. All subjects who receive 
any amount of study treatment will be included in the safety analyses. 
 
Adverse event data will be listed by dose cohort. Events occurring on or after treatment 
on Cycle 1, Day 1 will be summarized by AE term, NCI CTCAE v4.0 grade, and 
relationship to either pembrolizumab and/or cabozantinib. 
 
Serious adverse events, including deaths, will be listed separately and summarized. 
Adverse events leading to treatment discontinuation will be listed. 
Adverse events meeting the criteria for DLT will be listed. Subjects who withdraw from 
the study prior to completing the DLT assessment window for reasons other than a DLT 
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8.2.3 Analysis of Anti-Tumor Activity 
 
Descriptive statistics will be used to summarize all demographic and analytic data. 
Continuous 
data will be summarized using means, standard deviation, range, etc. 
Categorical data will be summarized using frequency tables. 
 
Tumor response analyses will be based on definitions of responses according to both 
RECIST v1.1 and immune-related response criteria (irRECIST). 
 
Objective response is defined as a complete or partial response, as determined by 
investigator assessment using RECIST and irRECIST. Subjects with missing or no 
response assessments will be classified as non-responders. For the primary objective, a 
one-sided exact binomial test will be used to assess whether the ORR is significantly 
greater than 20% in subjects taking a combination of pembrolizumab and cabozantinib. 
 
Clinical benefit rate (CR + PR +SD) and duration will also be recorded. 
 
Among subjects with an objective response, duration of response will be defined as the 
time from first occurrence of a documented objective response until the time of documented 
disease progression or death from any cause during the study, whichever occurs first. 
For all other subjects, duration of objective response will be censored at the day of the 
last tumor assessment. 
 
Progression-free survival (PFS) will be defined as the time from study treatment 
initiation (Cycle 1, Day 1) to the first occurrence of documented disease progression or 
death from any cause during the study, whichever occurs first. For subjects who do not 
have documented progressive disease or death during the study, PFS will be censored at 
the day of the last tumor assessment. 
 
Overall survival (OS) will be defined as the time from study treatment initiation (Cycle 
1, Day 1) to death from any cause. For subjects who do not have documented death 
during or after the study, OS will be censored at the day of known survival status. 
 
In subjects with bone metastases, time to progression of bone metastases or skeletal 
related event (SRE, defined as pathologic fracture, spinal cord compression, and radiation 
to bone or surgery to bone related to cancer) will also be recorded from Cycle 1 Day 1 
to the time of progression or SRE. 
 
Progression-free survival, overall survival, duration of response/duration on treatment, and 
time to skeletal related event or bone progression will be assessed using Kaplan-
Meier curves and hazard ratios. The clinical benefit rate and duration of clinical benefit 
will be summarized using descriptive statistics. 
 


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Among subjects who receive treatment beyond progression, duration on treatment will 
be recorded. 
 
Response data may be listed, summarized in tables, and/or presented as a swimmer plot. 
 
8.2.4 Analysis of Exploratory Endpoints 
 
Bone biomarkers that are correlated with objective response will be identified using a 
Wilcoxon rank sum test comparing biomarker levels in those with and without objective 
response to treatment. The expression of PD-L1 and other immunologic biomarkers will 
be compared in biopsies before therapy, on-treatment, and at progression using a 
Wilcoxon signed-rank test on each pair of observations. As appropriate, expression 
levels will be dichotomized to meaningfully present versus not present. 
 
8.2.5 Sample Size 
 
The proposed study is a single-arm, phase I/II study of pembrolizumab in combination 
with cabozantinib in subjects with metastatic RCC. We will use a Simon two-stage design 
for the phase II portion this study based on the primary endpoint of objective response 
rate. The planned enrollment for this study is approximately 25-55 total subjects, to 
account for screen failures, in order to achieve 6-9 evaluable subjects in Phase I 
dose escalation and 20-38 evaluable subjects in Phase II dose expansion.  Subjects from 
the Phase I part of the study who are treated at the RP2D may be included in the efficacy 
assessments in Stage I of the Phase II part of the study.  
 
Phase I: 
Any subject who does not complete the DLT assessment window for any reason other than 
a DLT will be considered non-evaluable for dose-escalation decisions and MTD and 
RP2D assessment and will be replaced by an additional subject at that same dose level. 
 
Table 12 describes the probability of not observing any DLTs in 3 subjects, and the 
probability of observing fewer than two DLTs in 6 subjects for different underlying DLT 
rates. 
 
Table 12: Probability of Observing DLTs for Different Underlying DLT Rates 
 
Underlying DLT Rate 
Probability of Observing No DLTs 
in 3 Subjects 
Probability of Observing Fewer 
Than Two DLTs in 6 Subjects 
0.10 
0.73 
0.89 
0.20 
0.51 
0.66 
0.33 
0.30 
0.36 
0.40 
0.22 
0.23 
0.50 
0.13 
0.11 
0.60 
0.06 
0.04 
 


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For a given adverse event with a true rate of 10%, 5%, or 1%, the probability of observing 
at least one such adverse event in a given cohort of 6 subjects is 47%, 26.5%, and 
5.8%, respectively. 
 
Phase II: 
The Simon’s two-stage design will be implemented to test the null hypothesis that ORR ≤ 
0.20 versus the alternative that ORR ≥ 0.50. After the enrollment of 20 evaluable patients 
in the first stage, the trial will be terminated if 2 or fewer respond. If the trial goes on to the 
second stage, a total of 38 patients will be studied. If the total number responding is greater 
than 12, the treatment is considered effective. 
 
This two-stage design has an expected sample size of 34.29 and a probability of early 
termination of 0.206. If the drug is actually not effective, there is a 0.029 (satisfied the 0.05 
type I error rate constraint) probability of concluding that it is. If the drug is actually 
effective, there is a 0.017 probability of concluding that it is not, which corresponding to a 
98% power (satisfied the 90% power constraint).  
 
 
9.0 LABELING, PACKAGING, 
STORAGE 
AND RETURN 
OF CLINICAL 
SUPPLIES 
 
9.1 Investigational Product- Pembrolizumab 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol, Investigator’s Brochure, and any 
applicable laws and regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 13. 
 
Table 13: Product Descriptions 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
 
9.2 Cabozantinib 
 
Cabozantinib (Cabometyx®) will be prescribed and obtained commercially as tablets through 
a specialty pharmacy, per standard of care. 
 
Refer to the package insert for additional information. 


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9.3 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
9.4 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
9.5 Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.6 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
10.1 Confidentiality 
 
To maintain subject privacy, study drug accountability records, study reports, and 
communications will identify the subject by initials where permitted and/or by the assigned 
subject number. The subject’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
 


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Qualified representatives from the relevant regulatory agencies, the drug manufacturer 
(Merck), or its agents may inspect the subject/study records. Subject data obtained during the 
study may be presented in scientific publications, but at no time will subject names be used. 
 
10.2 Conflict of Interest Policy and Compliance with Financial Disclosure Requirements 
 
Independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Any actual conflict of interest of persons who have a role 
in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed.by the University of Colorado Denver’s (UCD) Office of Regulatory Compliance 
Conflict of Interest and Commitment Management (COIC) program. Persons with a perceived 
conflict of interest will have such conflicts managed in a way that is appropriate to their 
participation in the trial. Conflict of Interest management plans are project-specific and are 
reviewed at least annually. UCD has integrated the institutional conflict of interest 
management program with its existing program. 
 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). All investigators 
participating in this trial will also be required to complete a Financial Disclosure Form (FDF) 
to provide his/her financial interests in and/or arrangements with the Sponsor-Investigator, 
and/or a manufacturer of the investigational agent(s) being studied in this clinical trial. The 
submission of an FDF must be a complete and accurate certification and disclosure of financial 
interests held by the investigators. 
 
10.3 Compliance with Law, Audit and Debarment 
 
The Sponsor-Investigator will ensure that this study is conducted in full conformity with 
regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56. International Conference on Harmonisation (ICH) Guidance on 
Good Clinical Practice ([GCP] CPMP/ICH/135/95) may also be followed to the extent it has 
been adopted by and is in accordance with FDA regulations. 
 
Clinical monitoring of all study site locations will be allowed periodically, in accordance with 
the CMP, to assess data quality and study integrity. On site, they will review study records and 
directly compare them with the original source documents, discuss the conduct of the study 
with the investigator, and verify that the facilities remain acceptable. 
 
In addition, the study may be evaluated by auditors designated by the Sponsor-Investigator and 
by government inspectors who must be allowed access to CRFs, source documents, and all 
other study files. Sponsor-Investigator audit reports will be kept confidential. 


 
Page 1 of 10 
COMIRB #10-1028 
Version Date: 4/8/2019 
 
PI: Jennifer Raybin RN, CPNP 
w
COMIRB Protocol 
 
 
 
PROTOCOL #: 
10-1028 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055   
Fax:  303-724-0990 
 
 
 
Project Title: 
Creative Arts Therapy (CAT) in the Center for Cancer and Blood 
Disorders 
 
 
 
Principal Investigator:  Jennifer Raybin, RN, MSN, CPNP 
 
Co-Investigators:  
Molly Hemenway, RN, CPNP 
 
 
Version Date:  
5/10/2019 
 
 
 
 
 
 
I. Hypotheses and Specific Aims   
The purpose of the study is to evaluate the effectiveness of Creative Arts Therapy (CAT) on 
pediatric patients undergoing chemotherapy in the Infusion Center at Children’s Hospital 
Colorado Center for Cancer and Blood Disorders. Findings from a previous pilot study support 
the hypothesis that CAT may improve quality of life (QOL), resiliency, physical posture, and 
emotional response to pain of pediatric oncology patients undergoing chemotherapy.  
 
Specific aims include: 
 
a. Does CAT improve the child’s reported QOL? 
 
b. Is the child’s resiliency enhanced by CAT? 
c. Does CAT influence the physical posture of the child?  
d. Does CAT impact the child’s emotional response to pain? 
e. Are patients, families, and staff satisfied with the CAT program? 
 
II. Background and Significance 
Although survival rates of children with cancer are improving, their QOL is known to be 
poorer than their healthy peers.  As survival rates of pediatric cancer now approach 85%, the 
need for quality psychosocial care including creative arts has increased (Askins & Moore, 
2008).   Oncology patients are known to have significant morbidity during treatment as a result 
of the surgery, radiation and chemotherapy, but little is published on the day to day effects of 
treatment on the quality of life of pediatric oncology patients (Banks, 2008). Tremolada et al 
looked at parental perception of QOL in newly diagnosed children with leukemia and found 
that increasing the knowledge of QOL may improve communication and psychosocial care 
during initial treatment for leukemia (2010).  In addition, quality of life among adolescents 
with cancer may be worse during treatment than for those not currently on therapy (Ward-
Smith et al., 2007).  Another study has shown that interventions to promote happiness may be a 
good predictor of QOL in adolescent cancer survivors (Bitsko et al., 2008).   
 
It has been acknowledged that even the act of coming to the clinic weekly for chemotherapy 
infusions impacts on the patient’s life.  In addition, vincristine, a commonly used 
chemotherapy, is also well-known to cause significant morbidity (leg pain, numbness, tingling, 
and constipation) requiring dose-limiting regimes.  Steroids are another common medication 


 
Page 2 of 10 
COMIRB #10-1028 
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PI: Jennifer Raybin RN, CPNP 
with toxicities affecting QOL.  Toxicities of steroids include weakness, sleep and mood 
disturbance, and pain with dose reduction (Sanford et al., 2008; Hinds et al., 2007).   
 
Resilience is a subset of QOL that has been studied in pediatric chronic illness including cancer 
(Haase et al., 2004).  Resilience has been defined as a characteristic that moderates stress and 
the ability to cope with change or misfortune (Wagnild & Young, 1993).  Resilient individuals 
have positive outcomes in spite of adversity (Rew & Horner, 2003).  Therefore nurses who 
understand resilience can promote those characteristics during times of illness or stress (Ahern 
et al., 2006).  There is a paucity of literature directly studying resilience in pediatric oncology 
patients and further work is warranted. 
 
Emotional response to pain is another subset of QOL that has been measured in this population.  
It is well known that pediatric oncology patients experience pain (Lervat, 2009).  Experts 
recommend rigorous research using established measures to evaluate childrens’ response to 
pain (McGrath et al., 2008).  The Faces scale has been studied with children as young as 5 
years to evaluate their emotional response to pain compared with their parents’ perceptions 
(Breau et al., 2001).  Pilot data on emotional response on the Faces scale has been shown to 
improve after group CAT (Madden et al., 2010). 
 
Physical functioning and muscle strength are aspects of QOL that have been shown to be worse 
than healthy peers in children with cancer (Hartman et al., 2008).  This aspect may also be 
affected by the central venous access lines placed in almost all pediatric cancer patients.  Long-
term central venous access is critical in pediatric cancer patients and the evolution of these 
devices has improved QOL in terms of pain and distress of venipuncture (Spagrud, 2008).  The 
literature is rich with discussion of complications and risk of infection, but little is published 
about the effects on body image and QOL (Albanese, 1993; Nam, 2010).  Anecdotally, patients 
have improved body awareness and posture (less kyphosis) after CAT.  In addition, it has been 
postulated that increased kyphosis may correspond with psychosocial factors including anxiety, 
depression, and insecurity. Body awareness is a type of physical functioning that may be 
measured by kyphosis.  Measuring posture with an inclinometer has been shown to be reliable, 
but further work is needed to establish validity (Lewis & Valentine, 2010).  Piloting this tool 
may establish a way to physically measure an individual’s sense of self by the way that he or 
she stands.   
 
The use of complementary and alternative medicine (CAM) is one intervention that has been 
shown to improve QOL in this population.  Current trends show increasing popularity of the 
use of CAM in even among children with cancer.  Martel et al (2005) looked at prevalence of 
use of CAM in children.  In their survey, almost 50% of the children used at least one type of 
CAM.  Specifically to cancer, in 2009, Post-White et al used a survey of 281 patients to show 
that CAM was used in 59% of pediatric cancer patients versus 36% of general pediatric 
patients.  The authors confirmed that children with cancer and other chronic illnesses use more 
CAM therapies than children seen in primary care clinics.  Roth et al (2009) examined 
pediatric oncologists’ perceptions of CAM and found that although they place importance in 
CAM, they lack time and knowledge to ask about patients’ use of CAM.  These authors 
recommend CAM research in pediatric oncology on modalities that could improve QOL. 
 
CAT is a subset of CAM that may improve QOL.  CAT is a broad term encompassing the 
modalities of dance/movement, music, art. Bringing creativity into health care is a current trend 
in oncology nursing and throughout the medical professions (Garland et al., 2007; Lane, 2006; 
Petterson, 2001; Strickland, 2008).  There is a growing body of literature establishing the use 


 
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PI: Jennifer Raybin RN, CPNP 
of CAT, but the studies use non-standardized tools, small sample sizes, adult populations, and 
non-rigorous designs.  Much of the work on CAT in cancer patients studies adult populations 
using qualitative measures (Forzoni et al, 2010; Jones et al., 2009; Visser, et al, 2008; Bar-Sela, 
et al., 2007; Nainis et al., 2006).  Other work looked at the family caregivers of patients with 
cancer and showed significantly reduced stress, anxiety, and increased positive emotions after a 
creative arts intervention (Walsh et al., 2004).  Randomized controlled studies are in the 
literature and have shown improvement in QOL, but only for the population of women with 
breast cancer (Oster et al, 2006; Monti et al, 2006; Svensk et al, 2009; Thyme et al, 2009).  
Music was shown to decrease heart rate in children with leukemia, but the therapeutic aspects 
were not studied (Kemper et al., 2008).  The literature is rich with other examples of types of 
music, art, movement therapies that may improve QOL in adult and pediatric oncology 
patients, but there are few rigorous studies to document the importance of CAT during the 
cancer treatment (Sencer et al, 2007; Dibell-Hope, 2000; O’Callaghan et al, 2007; Robb et al, 
2003; Barrera, 2002; Hilliard, 2006).  
 
Therefore, a pilot study of CAT on the QOL of pediatric brain tumor patients used a mixed-
model approach with a randomized, controlled phase comparing CAT to a control.  Pre- and 
post- measurements using the PedsQL showed statistically significant improvement on Parent 
report of child’s hurt (problems with having a lot of pain), p=0.03 and Parent report of child’s 
nausea (becoming nauseated while thinking about medical treatment), p=0.0061.  The second 
non-randomized phase pre- and post- tested any child in group session of CAT.  The subjects 
showed improved mood with statistical significance on the Faces Scale (p < 0.01), and patients 
were more excited (p < 0.05), happier (p < 0.02), and less nervous (p < 0.02) on the Emotional 
Responses Checklist (Madden et al, 2010).   
 
Rationale 
The pilot study was limited by the small sample size; therefore we propose a study with a 
larger sample size and broader inclusion criteria.  We would also like to explore outcomes of 
resilience and body awareness measured by physical posture based on our observations during 
the pilot study.   
 
 
Significance 
Nurses have been shown to provide valuable information on QOL for this population (Klaassen 
et al, 2010).  In addition, the pediatric oncology nurse is in a key position to incorporate the art 
and science of nursing to improve psychosocial treatment outcomes (Cantrell, 2007).  
Therefore this nursing research study will provide valuable insight to contribute to the body of 
knowledge of CAM for pediatric oncology patients. The use of CAM for pediatric oncology 
patients may improve QOL, resiliency, emotional response, and body awareness. 
 
III. Preliminary Studies/Progress Report  
See above regarding the previous pilot study.  Small sample size limited the statistical 
significance. 
 
IV. Research Methods 
A. Outcome Measure(s)   
1. Peds QL—Cancer module 
The PedsQL 4.0 Cancer Module is evolved from the PedsQL 4.0 Generic Core Scale 
(Varni, 1998). The system employs a Parent-Proxy Report for ages 2-18 years and a 
companion Child Self-Report for children aged five years and older.  Validity and 
reliability testing for both the Core Scale and Cancer Module has been extensive.   


 
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Reliability, assessed by internal consistency, yielded coefficient alphas ranging from 
.80-.90 across total and individual scales and are, thus, appropriate for the group 
comparisons planned in this study.  The Cancer Module is a 27-item instrument that 
assesses eight subscales (Pain and hurt, nausea, procedural anxiety, treatment anxiety, 
worry, cognitive problems, perceived physical appearance, and communication).  It is 
easily completed by parents in less than 10 minutes and reverse-scored and linearly-
transformed in five minutes or less.  Validity for both the Core Scale and the Cancer 
Module was established by expert panel review; similarly, construct validity for both 
measures was performed by comparing the responses of children with cancer across 
both measures to a group of healthy matched controls.  In all cases, the Peds QL 4.0 
Cancer Module was able to distinguish the responses of children with cancer from 
those of healthy children at a statistically significant level.   
 
The instruments have been successfully employed in several small studies of children 
with cancer (Bhat, 2005; Meeske et al, 2004).  The PedsQL has been shown to be the 
most responsive to change when compared with other measures of QOL used with 
children undergoing chemotherapy (Banks et al, 2008; Klaassen et al, 2010). 
 
2. The Resilience Scale (RS) 
The RS-14 is a 14-item scale using a 7-point rating (1-7).  The construct of resilience is 
measured by two factors: personal competence and acceptance of self and life.  
Wagnild and Young have completed psychometric testing that established internal 
consistency reliability and concurrent validity (Wagnild & Young, 1993).  Many 
studies have validated that the scale may be used with samples of any age or ethnic 
background (Ahern et al, 2006), but it is written at a 6th grade level.  The authors who 
developed the tool are currently using it in adolescents (personal communication, 
5/25/10).  Given that it is expected that half the population of this study will be 
teenagers, this tool will be used with subjects ages 12 and over to obtain initial data on 
CAT’s effect on resilience.  
 
3. Faces Scale 
The Faces Scale has been used for evaluating emotional responses to pain on children 
3-17 years old.  It is a one page form with nine faces in order of happy to upset.  
Numerical values are given to each face as determined by childrens’ perspectives for 
an affective value by asking 200 children to directly scale the feelings depicted by the 
faces.  Consistent rating was measured by children over 5 years regardless of age, 
gender, or health status (McGrath, 1990).  The scale is a facial affective scale and has 
been integrated as a routine measure for management of acute, recurrent, and chronic 
pain (McGrath, 1990; McGrath et al., 1996).  For children less than 3 years old, parents 
will be asked to complete the Faces Scale.  Although this scale has been used for 
emotional response to pain, it is felt to be an appropriate measure for the emotional 
response to the discomfort and anxiety in the infusion room. 
4. Postural Measurement  
Thoracic kyphosis will be measured using two gravity dependent inclinometers 
(Isomed Inc.).  Spinal processes will be determined by palpation by a registered nurse 
or pediatric nurse practitioner.  The feet of the inclinometers will be placed over the 
spinal processes thought to be at T1, T2 and T12, L1.  The measurements will be taken 
in relaxed standing and measured 3 times in succession.  Clinical assessment of the 
thoracic kyphosis angle is considered essential in postural examination, but can be time 


 
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PI: Jennifer Raybin RN, CPNP 
consuming when measured radiographically (Lewis, 2010).  Lewis and Valentine 
studied intra-rater reliability in subjects with and without symptoms and found 
measurements of less than 1.7 degrees should be considered measurement error.  The 
test-re-test reliability established excellent intra-rater reliability.  Although validity of 
this measure is less studied, the measurement is thought to provide guidance of how 
much change of the kyphoscoliosis angle is a real consequence of intervention over 
time (Lewis, 2010).  
 
5. Patient/Family Surveys 
A brief ten minute written survey will be administered to subjects to ascertain level of 
satisfaction with the program.  
 
B. Description of Population to be Enrolled:  Study Design and Research Methods 
1. Population 
The Center for Cancer and Blood Disorders (CCBD) at Children’s Hospital Colorado 
sees approximately 240 new Oncology patients each year.  Approximately 45% of 
these patients receive vincristine, a chemotherapy agent that is known to affect 
physical functioning. In addition, about 25% of these patients receive steroids, another 
medication known to affect physical functioning and quality of life.  About half of the 
new patients each year are anticipated to fit the inclusion criteria.  Therefore, we 
expect approximately 100 eligible subjects per year, with a 50% attrition rate, for a 
total sample size of 100 subjects over a two year period. 
 
Enrollment for this study was reached in 2019.  At this time, an additional 10 patients 
will be allowed to enroll on study to help supplement the data.  
 
2. Eligibility Criteria  
Inclusion 
• 
Center for Cancer and Blood Disorders (CCBD) patient with Oncology or 
Neuro-oncology diagnosis 
• 
No more than 2 previous sessions of CAT as an outpatient in the CCBD 
• 
English speaking 
• 
Receiving outpatient chemotherapy, biotherapy, or transfusions in the infusion 
center approximately weekly for at least 3 months. 
• 
Ages 3 to 18 years  
       Exclusion 
• 
Hematology or other patients in the infusion center 
• 
Patients who have previously received more than 2 sessions of CAT in the 
infusion center 
• 
Non-English speaking patients 
 
3. Study Design  
A repeated measures design will be used with each patient serving as his/her own 
control. 
 
Any Oncology patient in the CCBD who has not previously received more than two 
sessions of CAT in the outpatient unit and who will be receiving approximately weekly 
infusions of at least one hour in the infusion center will be identified by a research 
assistant.  The study will be explained to the patient/family and informed consent will 


 
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PI: Jennifer Raybin RN, CPNP 
be obtained by the principal investigator or the research assistant.  A demographic 
form will be completed including the information of diagnosis, age, treatment, 
educational level of parents, zip code, prior experience with art, music, movement.   
 
The intervention will consist of approximately weekly CAT in the infusion center 
during cancer therapy.  The interventionist is a Master’s prepared, licensed 
dance/movement therapist who is experienced in music and art therapies as well.  The 
CAT includes dance/movement such as playing with a parachute, simple yoga 
breathing and postures, and work with physioballs.  The music includes singing, 
listening to music, and playing instruments.  The art consists of drawing, finger 
painting, working with clay.  The CAT may occur in individual sessions in private 
infusion rooms, or in groups in the middle of the infusion center.  The CAT is not only 
a distraction, but also a therapeutic process addressing the stressors of cancer and its 
treatment.  The “dose” of CAT will be recorded (number and type of sessions) and will 
be factored into the analysis.   
 
The subjects and/or parents will be tested with all instruments before the intervention, 
and approximately every 30 days for no less than 3 months and a maximum 
participation of 6 months.  Treatment time points will be at least 30 days apart.  
Because some subjects are not scheduled to come into the clinic every 30 days for SOC 
appointments, they are unable to complete 3 sessions of CAT in a 3 month time period.  
For those subjects who are scheduled to come into clinic every 1-2 months for SOC 
appointments, study participation may take up to 6 months.  This 6 month time period 
would allow for the completion of 4 different time points of CAT.  
 
The testing will take place in an exam room after vital signs have been completed upon 
intake to the clinic.  The trained research assistant, trained RN, or PI will administer 
the questionnaires.  The PedsQL includes a subject report (ages 5 and over) and a 
parent report.  The Resilience Scale is a self-report and will be used for ages 12 and 
over.  The Faces Scale will use parent report for ages less than 5 and self-report for 
ages 5 and over.  In order to confirm consistency, the posture measure will be 
completed by the PI (nurse practitioner) or registered nurse on the study after training 
with the manual included with the inclinometer tool. 
 
Off Study Criteria 
1. Subject discontinues CAT 
2. Unable to complete 4 time points in 6 months 
 
C. Description, Risks and Justification of Procedures and Data Collection Tools 
The anticipated risks include psychological distress incurred by completing the outcome 
measure questionnaires as well as the therapeutic process.  This risk will be minimized by 
the presence of the Master’s prepared, experienced dance/movement therapist.  The 
patients’ social workers through the clinic will be available during the intervention as well. 
    
D. Potential Scientific Problems 
Based on the pilot data, the anticipated scientific problem is slow accrual due to unforeseen 
events during the traumatic time of a new diagnosis in pediatric oncology.  We are unable 
to randomize because CAT is standard of care for any patient in the infusion center and 
therefore we feel it is unethical to deny CAT to a control arm.  Therefore, we will compare 
the subjects to themselves over time to look at longitudinal changes of CAT.   


 
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PI: Jennifer Raybin RN, CPNP 
 
E. Data Analysis Plan  
The primary outcome is Peds QL at approximately 3 months; secondary outcomes will be 
the Resilience Scale, Faces Scale, and postural measurement at approximately 3 months.  
A repeated measures analysis of variance will be used to analyze the primary and 
secondary outcomes. We will also use the repeated measures analysis of covariance with 
the addition of covariates, depending on their statistical significance, such as gender, age, 
cancer diagnosis, and previous exposure to arts/music/dance. All of the analysis will be 
adjusted for baseline measures.   
We expect to recruit 100 patients, we also expect patients will be equally distributed in the 
following 3 categories: receiving low (0-3), intermediate (4-6) and high (7+) CAT sessions 
due to the nature of each patient’s random visits. Power analysis was done based on pair-
wised T-Test with these assumptions for simplicity.  With 33 patients in each group, 
assuming 80% power and 0.017 significance level of alpha after Bonferroni ad justification 
of multiple comparisons, we will observe a minimum effect size of 0.813. This is to say 
that 80% of the Peds QL scores in the lower session CAT group will be below the average 
of scores in the higher session CAT group.  Thus, what we would expect to see in the 
positive dose-response relationship. 
We will also conduct subgroup analysis by age group if the sample size is large enough 
since Peds QL is designed by age group. 
F. Summarize Knowledge to be Gained 
Integrative and holistic therapies are being used throughout healthcare.  We know that 
families are using alternative therapies without rigorous evidence documenting their worth.  
We therefore strive to build a body of literature showing evidence that CAT helps children 
with cancer feel better. 
 
G. Appendices 
1. PedsQL 
2. Resilience Scale 
3. Faces Scale 
4. Inclinometer information 
5. Patient/Family Survey 
 
H. References:  
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resilience. Issues Compr Pediatr Nurs, 29, 103-25. 
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Surg Oncol, 9, 467-77. 
Askins MA, Moore BD. (2008) Psychosocial support of the pediatric cancer patient: lessons 
learned over the past 50 years. Curr Oncol Rep, 10,469-76. 
Banks BA, Barrowman NJ, Klaassen R. (2008) Health-related quality of life: changes in children 
undergoing chemotherapy. J Pediatri Hematol Oncol,30, 292-7. 
Bar-Seal G, Atid L, Danos S, Gabay N, Epelbaum R. (2007) Art therapy improved depression and 
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Barrera ME, Rykov MH, Doyle SL. (2002) The effects of interactive music therapy on hospitalized 
children with cancer: a pilot study. Psychooncology, 11, 379-388. 
Bhat SR, et al. (2005) Profile of daily life in children with brain tumors: an assessment of health-
related quality of life.[see comment]. J Clin Oncol, 23, 5493-5500. 


 
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Cantrell MA. (2007) The art of pediatric oncology nursing practice. J Pediatr Oncol Nurs, 24, 132-
8. 
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chemotherapy sessions: an analysis of the patients' perception of helpfulness. Palliat Support 
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Garland SN, Carlson LE, Cook S, Lansdell L, Speca M. (2007) A non-randomized comparison of 
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Haase, JE. (2004) The Adolescent Resilience Model as a guide to interventions. JPediatr Onc 
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Oncol, 4, 75-8. 
Hinds PS, et al. (2004) Quality of life as conveyed by pediatric patients with cancer. Qual Life Res, 
13, 761-772. 
Hinds PS, Hockenberry M, Rai SN, Zhang L, Razzouk BI, Cremer L, McCarthy K, Rodriguea-
Galindo C. (2007) Clinical field testing of an enhanced-activity intervention in hospitalized 
children with cancer. J Pain Symptom Manage, 33, 686-97.  
Jones G, Browning M. (2009) Supporting cancer patients and their carers: the contribution of art 
therapy and clinical psychology. In J Palliat Nurs, 15, 609-14. 
Kemper KJ, Hamilton CA, McLean TW, Lovato J. (2008) Impact of music on pediatric oncology 
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Klaassen RJ, Krahn M, Gaboury I, Hughes J, Anderson R, Grundy P, Ali SK, Jardine L, Abla O, 
Silva M, Barnard D, Cappelli M. (2010) Evaluating the ability to detect change of health-
related quality of life in children with Hodgkin disease. Cancer, 116, 1608-14. 
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24, 70-75. 
Lervat C. (2009) [Current management of pain in pediatric oncology.] Bull Cancer, 96, 5-14. 
Lewis JS, Valentine RE. (2010) Clinical measurement of the thoracic kyphosis. A study  of the 
intra-rater reliability in subjects with and without shoulder pain. BMC Musculoskeletal 
Disorders, 11, 39. 
Madden JR, Mowry P, Gao D, McGuire Cullen P, Foreman NK. (2010) Creative arts therapy 
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Pediatr Oncol Nurs, 27,133-45. 
Martel D, et al. (2005) Use of alternative and complementary therapies in children with cancer. 
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McGrath PA. Pain in children: Nature, assessment, and treatment. New York: The Guilford Press; 
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McGrath PA, et al. (2008) Core outcome domains and measures for pediatric acute and 
chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain, 9, 771-83. 
Meeske K, Katz ER, Palmer SN, Burwinkle T, Varni JW. (2004) Parent proxy-reported health-
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Monti DA, Peterson C, Kunkel EJ, Hauck WW, Pequignot E, Rhodes L, Brainard GC. (2006) A 
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Consent and Authorization Form Approval
 COMIRB #10-1028
Page 1 of 6
Version Date:  5/10/2019
Study Title:
Creative Arts Therapy (CAT) in the Center for Cancer and Blood 
Disorders
Principal Investigator:
Jennifer Raybin, RN, MSN, CPNP
COMIRB No:
10-1028
Version Date:
5/10/2019
In this form, we use the words “you” and “your.”  If you are reading this form and deciding for 
someone else, the words ‘you’ and ‘your’ refer to that other person, not to you.
You are being asked to be in a research study.  This form provides you with information about 
the study. A member of the research team will describe this study to you and answer all of your 
questions. Please read the information below and ask questions about anything you don’t 
understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about how creative arts therapy will affect your quality of life 
during your treatment for cancer.  
You are being asked to be in this research study because you will be receiving outpatient 
therapy in the Center for Cancer and Blood Disorders for the next few months.  
Other people in this study
Up to 110 people from Children’s Hospital Colorado will participate in the study.   
What happens if I join this study?
If you decide to join this study:

Before the study starts, you will be asked to complete a demographic form with a 
member of the study team.  This will help us find out more about you, your therapy, 
and what kind of experience you have had with art, music, and movement.   

You will be asked to complete the following measurements before the study starts 
and then 3 more times over a three to six month period (depending on how often you 
come to the clinic for your regularly scheduled visits).  You will complete these with 
a member of the study team to assess the effect of creative arts therapy on your 
quality of life during your treatment for cancer:
o
PedsQL – This is a survey that asks questions about your level of pain and 
hurt, anxiety, worry, problems with thinking, your physical appearance, and 
communication.  This survey has 27 questions and should take less than 10 
COMIRB
APPROVED
15-May-2019


Consent and Authorization Form Approval
 COMIRB #10-1028
Page 2 of 6
Version Date:  5/10/2019
minutes each time to complete.  Your parent may be asked to complete a 
portion of this survey.  
o
Resilience Scale – This is a scale that measures how well you are able to cope 
with the changes in your life that have come with your cancer diagnosis and 
treatment.  This scale has 25 items and should take less than 10 minutes to 
complete.
o
Faces Scale – This is a scale that measures your emotional response to your 
treatment for cancer.  This scale has 9 items and should take less than 5 
minutes to complete.
o
Posture Measurement – A member of the study staff will measure the angle 
of your back three times during each of these visits.  This should take less than 
10 minutes to complete.  
o
Patient/Family Survey – This is a survey that asks questions about your 
parent’s satisfaction with the creative arts therapy program.  This survey has 
13 questions and should take less than 10 minutes to complete.

Once you have completed these four visits over three to six months, you will be 
finished with this study.  
You will be allowed to do creative arts therapy during your clinic visits as many times as it is 
offered and as much as you would like to participate.  This study will not limit the number of 
times you can do creative arts therapy, and it will not require you to do more creative arts 
therapy visits than you want to do.  We will track how many times you receive creative arts 
therapy over a three-month period in the clinic.  
What are the possible discomforts or risks?
Discomforts you may experience while in this study include some stress you may feel while 
completing the measurements.  If you feel this stress, please let the study staff know.  
Other possible risks include the risk of the loss of confidentiality of your protected health 
information; however, the chance of such a loss is small. Children’s Hospital Colorado has 
procedures in place to keep your information private. No identifiable information about you 
will be published or presented at scientific meetings.
What are the possible benefits of the study?
This study is designed for the researcher to learn more about how creative arts therapy affects 
children who are receiving treatment for cancer.  
This study is not designed to treat any illness or improve your health. 


Consent and Authorization Form Approval
 COMIRB #10-1028
Page 3 of 6
Version Date:  5/10/2019
Who is paying for this study?
This study is being paid for by a grant from The Daisy Foundation.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
It will not cost you anything to be in the study.
Is my participation voluntary?
Taking part in this study is voluntary.  You have the right to choose not to take part in this 
study.  If you choose to take part, you have the right to stop at any time.  If you refuse or 
decide to withdraw later, you will not lose any benefits or rights to which you are entitled. 
If you leave this study, you will still receive your normal medical care. 
 
If there are any new findings during the study that may affect whether you want to continue 
to take part, you will be told about them.
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the 
primary investigator thinks that being in the study may cause you harm, or for any other 
reason. 
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should call Jennifer Raybin, RN, CPNP 
immediately.  Her phone number is 720-777-3407.
We will arrange to get you medical care if you have an injury that is caused by this research.  
However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The researcher carrying out this study is Jennifer Raybin, RN, CPNP.  You may ask any 
questions you have now. If you have questions, concerns, or complaints later, you may call 
Jennifer Raybin at 720-777-3407.  You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Jennifer 
Raybin with questions.  You can also call the Colorado Multiple Institutional Review Board 
(COMIRB) at 303-724-1055. 


Consent and Authorization Form Approval
 COMIRB #10-1028
Page 4 of 6
Version Date:  5/10/2019
Who will see my research information?
Children’s Hospital Colorado has rules to protect information about you.  Federal and state 
laws including the Health Insurance Portability and Accountability Act (HIPAA) also protect 
your privacy.   This part of the consent form tells you what information about you may be 
collected in this study and who might see or use it.  
The institution involved in this study is Children’s Hospital Colorado.
CHCO shares a medical record system with the Barbara Davis Center and PedsConnect; 
therefore it is also possible that your information could be viewed by healthcare professionals 
at these organizations.
We cannot do this study without your permission to see, use, and give out your information.  
You do not have to give us this permission.  If you do not, then you may not join this study.  
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside Children’s Hospital Colorado and its 
affiliate hospitals may not be covered by this promise.
We will do everything we can to keep your records a secret.  It cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s Primary 
Investigator at the name and address listed below.  If you do cancel your permission to use 
and disclose your information, your part in this study will end and no further information 
about you will be collected.  Your cancellation would not affect information already 
collected in this study.  
Primary Investigator Name:
Jennifer Raybin RN, CPNP
Primary Investigator Address:
Children’s Hospital Colorado
13123 E. 16th Ave. B115
Aurora, CO 80045
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information.  

Federal offices such as the Food and Drug Administration (FDA) that protect research 
subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

Jennifer Raybin, RN, CPNP and her team of researchers.

The Daisy Foundation, who is the organization paying for this research study.

Officials at Children’s Hospital Colorado who are in charge of making sure that we 
follow all of the rules for research

The Clinical Investigations Shared Resources at the University of Colorado Cancer 
Center who also make sure that we follow all of the rules for research


Consent and Authorization Form Approval
 COMIRB #10-1028
Page 5 of 6
Version Date:  5/10/2019
We might talk about this research study at meetings.  We might also print the results of this 
research study in relevant journals.  But we will always keep the names of the research 
subjects, like you, private.  
You have the right to request access to your personal health information from the 
Investigator. 
The investigator (or staff acting on behalf of the investigator) will also make all or some of 
the following health information about me available to:  

The Cancer Clinical Trials Office at the University of Colorado Cancer Center
Information about me that will be seen, collected, used and disclosed in this study:

Name and Demographic Information (age, sex, ethnicity, address, phone number, 
etc.)

Name and demographic portions of my previous and current medical records that 
are relevant to this study, including but not limited to Diagnosis(es), History and 
Physical, Laboratory or tissue studies, radiology studies, procedure results

Research visit and research test records

The results of your Peds QL, Resilience Scale, Faces Scale, postural 
measurements, and Patient/Family Survey.
What happens to Data that is collected in this study? 
Scientists at Children’s Hospital Colorado involved in this study work to find the causes and 
cures of disease.  The data collected from you during this study is important to this study and 
to future research.  If you join this study:

The data is given by you to the investigators for this research and so no longer 
belongs to you.  

Both the investigators and any sponsor of this research may study your data 
collected from you.

If data is in a form that identifies you, Children’s Hospital Colorado may use it for 
future research only with your consent or IRB approval.

Any product or idea created by the researchers working on this study will not 
belong to you.

There is no plan for you to receive any financial benefit from the creation, use or 
sale of such a product or idea. 


Consent and Authorization Form Approval
 COMIRB #10-1028
Page 6 of 6
Version Date:  5/10/2019
Agreement to be in this study
I have read this paper about the study or it was read to me.  I understand the possible risks 
and benefits of this study.  I know that being in this study is voluntary.  I choose to be in this 
study: I will get a copy of this consent form.
Signature:
Date:
Subject (if 18 years old); OR Parent/Guardian
Print Name:
Signature:
________________________________________________
Date:
Subject (Ages 13-17, in addition to Parent Signature)
Consent form explained by:
Date:
Print Name:


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10.4 Compliance with Trial Registration and Results Posting Requirements 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act of 2007 (FDAAA), as the Sponsor of this 
trial, this trial and its results are subject to the requirements for submission to the Clinical Trials 
Data Bank, and will be properly registered at http://www.clinicaltrials.gov. Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information. 
 
10.5 Quality Management System 
 
By signing this protocol, the Sponsor-Investigator agrees to be responsible for implementing 
and maintaining a quality management system with written development procedures and to 
ensure that trials are conducted and data are generated, documented, and reported in 
compliance with the protocol, accepted standards of Good Clinical Practice, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical trial. 
 
The investigational site will provide direct access to all trial-related sites, source data/ 
documents, and reports for the purpose of monitoring and auditing by the DSMC audit team, 
and inspection by local and regulatory authorities. 
 
10.6 Data Management 
 
10.6.1 Monitoring and Oversight 
 
The sponsor investigator will be responsible for monitoring the trial per the trial monitoring 
plan, in addition to overseeing the safety and efficacy of the trial including any specimens 
collected, executing the data and safety monitoring (DSM) plan, and complying with all 
reporting requirements to local and federal authorities. This oversight will be accomplished 
through additional oversight from the Data and Safety Monitoring Committee (DSMC) at the 
University of Colorado Cancer Center (CU Cancer Center). The DSMC is responsible for 
ensuring data quality and study participant safety for all clinical studies at the CU Cancer 
Center, which is the coordinating institution of this trial. A summary of the DSMC’s activities 
is as follows:  
 
• 
Conduct of internal audits  
• 
Ongoing review of all serious adverse events (SAEs) and unanticipated 
problems (UAPs)  
• 
May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to the DSMC, 


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IRB and the sponsor investigator per protocol. All SAEs and UAPs are to be reported to the 
DSMC within 7 (for fatal or life-threatening events) or 15 (non-life-threatening events) 
calendar days of the sponsor investigator receiving notification of the occurrence. 
 
Each subject’s treatment outcomes will be discussed by the site PI and appropriate staff at 
regularly scheduled meetings. Data regarding number of subjects, significant toxicities, dose 
modifications, and treatment responses will be discussed. 
 
The sponsor investigator will provide a DSM progress report to the CU Cancer Center DSMC 
on a recurring basis (either every six or twelve months based on DSMC vote). The DSM 
report will include a protocol summary, current enrollment numbers, summary of toxicity data 
to include specific SAEs, UAPs and AEs, any dose modifications, all protocol deviations, and 
protocol amendments. The DSM report submitted to the DSMC will also include, if 
applicable, the results of any efficacy data analysis conducted. Results and recommendations 
from the review of this progress report by the DSMC will then be provided to the sponsor 
investigator in a DSMC review letter. The sponsor investigator is then responsible for ensuring 
this letter is submitted to the site’s IRB of record at the time of IRB continuing review.  
 
10.6.2 Quality Control and Quality Assurance 
 
Clinical site monitoring will be conducted to ensure that the rights and well-being of human 
participants are protected, that the reported trial data are accurate, complete, and verifiable, 
and that the conduct of the trial is in compliance with the currently approved protocol/ 
amendment(s), with GCP, and with applicable regulatory requirement(s). 
 
Site monitoring visits will be performed by the CU Cancer Center Clinical Monitor on a 
regular basis, pursuant to the Clinical Monitoring Plan (CMP), incorporated herein by 
reference. The CMP describes in detail who will conduct the monitoring, at what frequency 
monitoring will be done, at what level of detail monitoring will be performed, and the 
distribution of the monitoring reports. During these visits, information recorded on the 
CRFs will be verified against source documents. Additional computer programs that 
identify selected protocol deviations, out-of-range data, and other data errors within the 
electronic data entry may also be used to help monitor the study. As necessary, requests 
for data clarification or correction will be sent to the PI. 


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Independent audits will be conducted by the CU Cancer Center DSMC to ensure 
monitoring practices are performed consistently across all participating sites, if applicable, 
and that monitors are following the CMP. In addition, audits may be conducted at any time 
by appropriate regulatory authorities and/or the IRB. 
 
 
10.7 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the Colorado Multiple Institutional Review Board (COMIRB) for review 
and approval. Approval of both the protocol and the consent form must be obtained before 
any subject is enrolled. Any amendment to the protocol will require review and approval 
by COMIRB before the changes are implemented to the study. All changes to the consent 
form will COMIRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
 
 


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11.0 REFERENCES 
 
1. 
Gunturi A, McDermott DF. Potential of new therapies like anti-PD1 in kidney cancer.  
 
Curr Treat Options Oncol 2014; 15: 137-146. 
2. 
Philips GK, Atkins MB. New agents and new targets for renal cell carcinoma. Am Soc  
 
Clin Oncol Educ Book 2014; e222-227. 
3. 
Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint  
 
inhibitors in hepatocellular carcinoma. Immunotherapy 2016; 8: 299-313. 
4. 
Massari F, Santoni M, Ciccarese C et al. PD-1 blockade therapy in renal cell carcinoma:  
 
current studies and future promises. Cancer Treat Rev 2015; 41: 114-121. 
5. 
Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus Everolimus in  
 
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1803-1813. 
6. 
Ko JS, Zea AH, Rini BI et al. Sunitinib mediates reversal of myeloid-derived  
 
suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 2009; 15:  
 
2148- 2157. 
7. 
Tartour E, Pere H, Maillere B et al. Angiogenesis and immunity: a bidirectional link  
 
potentially relevant for the monitoring of antiangiogenic therapy and the development of  
novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 2011; 30: 
83-95. 
8. 
Terme M, Colussi O, Marcheteau E et al. Modulation of immunity by antiangiogenic  
 
molecules in cancer. Clin Dev Immunol 2012; 2012: 492920. 
9. 
Voron T, Colussi O, Marcheteau E et al. VEGF-A modulates expression of inhibitory  
 
checkpoints on CD8+ T cells in tumors. The Journal of experimental medicine 2015;  
 
212: 139- 148. 
10. 
Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer  
 
and other angiogenic diseases. Nat Rev Drug Discov 2011; 10: 417-427. 
11. 
Nickerson ML, Jaeger E, Shi Y et al. Improved identification of von Hippel-Lindau  
 
gene alterations in clear cell renal tumors. Clin Cancer Res 2008; 14: 4726-4734. 
12. 
Gibney GT, Aziz SA, Camp RL et al. c-Met is a prognostic marker and potential  
 
therapeutic target in clear cell renal cell carcinoma. Ann Oncol 2013; 24: 343-349. 
13. 
Mukai S, Yorita K, Kawagoe Y et al. Matriptase and MET are prominently expressed  
 
at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis.  
 
Hum Cell 2015; 28: 44-50. 
14. 
Schiefer AI, Mesteri I, Berghoff AS et al. Evaluation of tyrosine kinase receptors in  
 
brain metastases of clear cell renal cell carcinoma reveals cMet as a negative prognostic  
 
factor. Histopathology 2015; 67: 799-805. 
15. 
Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus Everolimus in Advanced  
 
Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1814-1823. 
16. 
Choueiri TK, Halabi S, Sanford BL, et al.  Cabozantinib Versus Sunitinib As Initial  
 
Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or  
Intermediate Risk: The Alliance A031203 CABOSUN Trial.  J Clin Oncol. 2017 Feb 
20;35(6):591-597. doi: 10.1200/JCO.2016.70.7398. Epub 2016 Nov 14. 


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17. 
Harshman LC, Choueiri TK. Targeting the hepatocyte growth factor/c-Met signaling  
 
pathway in renal cell carcinoma. Cancer J 2013; 19: 316-323. 
18. 
Choueiri TK, Pal SK, McDermott DF et al. A phase I study of cabozantinib (XL184)  
 
in patients with renal cell cancer. Ann Oncol 2014; 25: 1603-1608. 


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12.0 APPENDICES 
 
12.1 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. 
 
 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 


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12.3 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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12.4 Immune Response modification to Response Evaluation Criteria in Solid Tumors 
(irRECIST) for Evaluating Response in Solid Tumors 
 
irRECIST* will also be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per irRECIST, CT is the preferred imaging technique in this study. 
 
* As published in Clinical Cancer Research: 
 
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Can Res 
2009;15:7412−20. 
 
• Unidimensional measurements (longest diameter) have been shown to have less variability. 
 
• PD thresholds for irRECIST and RECIST are aligned, allowing for comparisons to be made 
between trials and to historical data 
 
 
12.4.1 Baseline Assessment Using irRECIST 
 
Step 1. Identify the index target lesions (unidimensional, >/= 10mm, five lesions total, 
two lesions per organ). 
 
Step 2. Add the sum of all target lesions. 
 
12.4.2 Post-Baseline Assessments Using irRECIST 
 
Step 1. Identify the index target lesions. 
 
Step 2. Add the sum of all target lesions.  New lesions are incorporated in the total tumor 
burden measurement.   
 
Step 3. Assess response per criteria in table below. 
Step 4. Wait up to 12  weeks to confirm PD to account for flare. 


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Response Criterion 
Immune-mediated complete response (irCR) 
Complete disappearance of all lesions (whether 
measurable or not, and no new lesions). 
Immune-mediated partial response (irPR) 
Decrease in tumor burden ≥ 30% relative to 
baseline.  
Immune-mediated stable disease (irSD) 
Criteria for irCR, irPR, and irPD are not met; does 
not require confirmation. 
Immune-mediated progressive disease (irPD) 
Increase in tumor burden ≥ 20% relative to nadir 
(minimum 5mm)confirmed by a consecutive 
assessment ≥ 12 weeks from the date first 
documented. 
 


Consent and Authorization Form
Phase II
Page 1 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Principal Investigator:
Elaine Lam, MD
COMIRB No:
16-2300
Version Date:
July 17, 2019
Study Title:
Phase I/II Study of Pembrolizumab and Cabozantinib in 
Patients with Metastatic Renal Cell Carcinoma
You are being asked to be in a research study.  This form provides you with information 
about the study. A member of the research team will describe this study to you and 
answer all of your questions. Please read the information below and ask questions 
about anything you don’t understand before deciding whether or not to take part. 
Why is this study being done?
This study plans to learn more about a combination of drugs called pembrolizumab and 
cabozantinib, and how they work together to treat your type of cancer. Pembrolizumab 
works by stimulating the immune system to target the cancer cells. Cabozantinib blocks 
some of the ways that tumor cells grow and spread. Pembrolizumab is approved by the 
U.S. Food and Drug Administration (FDA) to treat other types of cancers. Cabozantinib 
is approved by the FDA to treat your type of cancer. This is considered an 
“investigational” study, which means that this combination of drugs has not been 
approved by the FDA. 
You are being asked to be in this research study because you have been diagnosed 
with locally advanced, recurrent, or metastatic renal cell carcinoma. 
Pembrolizumab and cabozantinib will be called “study drugs” when referenced together 
throughout the rest of this consent form.
Other people in this study
This study has two parts. The first part is a dose escalation, also called Phase I. The 
second part is an expansion, also called Phase II. The part of the study you are being 
asked to participate in will be described in the next section of this consent form.
Up to 46 people from your area will participate in the Phase II part of this study. Up to 55 
people will participate in both parts of this study. 
COMIRB
APPROVED
For Use
09-Nov-2019
09-Jul-2020


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 2 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
What happens if I join this study?
If you join the study, you will be asked to sign this consent form. You will be given a 
copy to keep and the original form will be kept at the clinic. You can withdraw from the 
study at any time and without giving a reason. This will not affect the standard medical 
care you receive. 
There are 2 parts to this study. If you decide to participate in this study, you will be in 
Part II:
Part II – Phase II
Expansion group (cohort) – In this part of the study, we are looking at how safe 
combination of study drugs is and how well they work together to treat your type 
of cancer. 
By signing this consent form you will be taking part in Part II of this study, which has 3 
sections:

Before starting the study (Screening)

During the study (Treatment)

End of study (After treatment follow-up)
There are also optional parts of this study. These optional procedures are voluntary and 
are not required. You can still take part in the main study if you choose not to take part 
in the optional study procedures. You will be given the choice later in this consent form 
to decide if you would like to take part in these optional procedures.
This next section is an overview of what will be expected of you, and what you can 
expect if you take part in this study.
Study Procedures:
Below are the study procedures and schedule of events (when each procedure will take 
place) for Part II of this study.  Some procedures are the same as you would receive as 
standard of care treatment of your disease even if you did not take part in this trial. If 
you have had some of these procedures recently, they may not need to be repeated. 
Some procedures are required only for this research study and will be called “research” 
procedures. 
The time points when these study procedures will take place are specified in the next 
section called “Study Visits”.


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 3 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)

Informed Consent  
This informed consent form will be discussed with you and you will be given a 
copy of this document. If you join the study, you will be asked to sign this consent 
form before you receive any study related tests or procedures.

Medical and Cancer History 
Before you start the study we will record your date of birth, race, ethnicity, and 
complete medical history. This history will look at the background and progress of 
your cancer and any treatments you have received for your disease. 

Physical Examination
A physical examination will be completed as part of your standard of care. We 
will also assess if the study drug is affecting your body functions including lungs, 
heart, abdomen, extremities, skin, head (eyes, ears, nose, hair, etc.) and 
neurologically.

Electrocardiogram (ECG or EKG)
This is a simple, noninvasive procedure that records the electrical activity of the 
heart. Electrodes are placed on the skin of the chest and connected in a specific 
order to a machine. Output usually appears on a long scroll of paper that displays 
a printed graph.  

Positron Emission Tomography (PET)/Computed Tomography (CT)
Computed tomography scans use x-rays to make detailed pictures of parts of the 
body and the structures inside the body. Positron emission tomography creates 
computerized pictures of organs and tissues in the body.

MRI
Magnetic resonance imaging is a test that uses a magnetic field and pulses of 
radio wave energy to make pictures of organs and structures inside the body.

Whole body bone scan
A bone scan is a nuclear imaging procedure. In nuclear imaging, tiny amounts of 
radioactive materials (tracers) are injected into a vein and are taken up in varying 
amounts at different sites in the body. Areas of the body where cells and tissues 
are repairing themselves most actively take up the largest amounts of tracer. 
Nuclear images highlight these areas, suggesting the presence of abnormalities 
associated with disease or injury. A bone scan includes both an injection and the 
actual scan.


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 4 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)

Vital Signs 
We will take your blood pressure, heart rate, respiratory rate, body temperature 
and weight.  Height will be measured only during screening.

Performance Status  
We will assess how well you are performing your daily activities.

Other Medications
Your study doctor will let you know which other medications you can and cannot 
take while taking part in this study.  From the time you first receive the study 
drugs through 30 days after the last dose, we will record other medications you 
may be taking. 

Review Adverse Events
Some risks have been identified because of the disease process or through use 
of the study drugs themselves and these will be followed very closely by the 
Principal Investigator and study staff. More information will be provided in the 
Risk area of this consent. 

Tumor Biopsy – Optional
You will have the option later in this consent form to participate in two tumor 
biopsies. If you agree to participate in the optional biopsies, either a core biopsy 
or a punch biopsy will be taken from your tumor. A numbing medication will be 
applied to the area of the biopsy before the procedure. In a core biopsy, a hollow 
needle is inserted through the skin into the tumor. A small “core” of tissue is 
removed using the needle. Your doctor may use ultrasound or x-ray equipment to 
guide the needle to the correct position. In a punch biopsy, a small circular blade 
is rotated through the skin into the tumor. A small sample of tissue is removed 
using the blade. This procedure leaves a small wound that is closed with sutures.
Study Visits:
1.  SCREENING
After you sign this consent form you will have the following done to see if you can be in 
this study:

Review your medical and cancer history

Physical exam

Vital signs including height and weight

ECOG performance status


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Blood tests:
o
Complete blood count (CBC) including types – white cells, red cells and 
platelets (differential)
o
Comprehensive serum chemistry panel
o
Thyroid tests (T3, FT4 and TSH)
o
Blood clotting (PT/INR and aPTT)

Review of medications

EKG – research

Urine pregnancy test (women of childbearing potential only)

Urinalysis

Tumor imaging by PET/CT or MRI. This may include a whole-body bone scan.

Archival tumor collection – research 

Tumor biopsy – optional research procedure
2. TREATMENT
During the Treatment portion of this study, you will receive the study drugs. The study 
drugs are given in “cycles”. You will have a study visit at the beginning of each cycle. 
One cycle is 3 weeks long. 
The following procedures will be done at every Treatment visit:

Review of medications

Review of adverse events

Physical exam

Vital signs including weight

Performance status

Urine pregnancy test (women of childbearing potential only)

Blood draw, including:
o
CBC and differential
o
Comprehensive serum chemistry panel

Urinalysis

Receive study drugs – research
Cycle 1

All the procedures in the group above

Blood draw, including the tests above and:
o
Bone turnover markers (subjects with bone metastases only) - research


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Cycle 2

All the procedures in the group above

Tumor biopsy – optional research procedure

Blood draw, including the tests above and:
o
Bone turnover markers (subjects with bone metastases only) – research
Cycle 3

All the procedures in the group above
Cycle 4

All the procedures in the group above

EKG – research

Blood draw, including all the tests above and:
o
Thyroid tests (T3, FT4 and TSH)
o
Bone turnover markers (subjects with bone metastases only) – research

Tumor imaging by PET/CT or MRI. This may include a whole-body bone scan.
Cycle 5

All the procedures in the group above
Cycle 6

All the procedures in the group above
Cycle 7

All the procedures in the group above

EKG – research

Blood draw, including all the tests above and:
o
Thyroid tests (T3, FT4 and TSH)
o
Bone turnover markers (subjects with bone metastases only) – research

Tumor imaging by CT or MRI. This may include a whole-body bone scan.
If you continue to receive study treatment beyond 7 cycles, Cycles 5-7 will be repeated.


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Version Date:  7/17/2019
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3. AFTER TREATMENT FOLLOW-UP
After you stop receiving the study treatment, you will have a safety follow-up visit within 
30 days. The following procedures will be done at this end-of-study visit:

Review of medications

Review of adverse events

Review of any anticancer therapies you have taken or are taking after the study.

Physical exam

Vital signs including weight

Performance and survival status

EKG – research

Blood draw, including:
o
CBC and differential
o
Comprehensive serum chemistry panel
o
Thyroid tests (T3, FT4 and TSH)

Urinalysis
How long will I be on the study?
You may take part in this study for as long as you tolerate the study treatment and your 
disease is stable or improving. You may continue to receive treatment with the study 
drugs until your disease progresses or you have an unacceptable drug-related side 
effect.
If your study doctor feels that you are still receiving a clinical benefit from the study 
drugs when your disease progresses, you may be able to continue treatment with the 
study drugs. If this is an option for you, you will be given a separate consent form and 
an opportunity to ask questions. 
What are the possible discomforts or risks?
As with any study drug, side effects may occur when taking these study drugs. While 
taking part in this study, and being treated with the study drugs, you will be watched 
carefully for any side effects. Some side effects may go away after you stop taking the 
study drug. Some side effects can be long lasting and may never go away or may even 
lead to death.
You should talk to your study doctor about any side effects or discomfort you may have. 


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The study doctor may give you some medicine that will help with some side effects. The 
study doctor may also interrupt or discontinue the study drug.
You will be notified by your study doctor of any new side effects seen in other patients 
that occur during the time you are on the study. This may affect you wanting to continue 
in this research study.
Based on animal studies and/or other studies with similar types of drugs, side effects or
discomforts you may experience while in this study include:
Risks of the Study Drugs
Pembrolizumab, which is approved in the USA and some other countries, is available by 
prescription to treat several different cancers, but may not be approved to treat your 
type of cancer. 
Pembrolizumab works by helping your immune system to fight your cancer. 
However, pembrolizumab can also cause your immune system to attack normal organs 
and tissues in your body and can affect the way they work, which can result in side 
effects. These side effects may be serious (i.e. causing hospitalization or be life-
threatening), may result in death, and/or may occur after you stop taking 
pembrolizumab. These side effects can affect more than one of your normal organs and 
tissues at the same time. 
VERY COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-
threatening or where noted, may cause death) – occurring in more than 20 people out 
of 100 people:
Itching of the skin
Loose or watery stools
Cough
COMMON, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or 
where noted, may cause death) occurring in at least 5 but less than 20 people out of 
100 people: 
Joint pain
Rash
Fever
Back pain
Pain in your belly
Loss of skin color


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Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have 
infrequent or hard stools
Low level of salt in the blood that may cause you to feel tired, confused, have a 
headache, muscle cramps, or an upset stomach
UNCOMMON, SOME MAY BE SERIOUS - i.e. causing hospitalization, life-
threatening, or where noted, may cause death)– occurring in at least 1 to less than 5 
people out of 100 people 
Inflammation of the lungs so you may feel short of breath and cough. Rarely 
this might lead to death.
Too much thyroid hormone so you may feel anxious, angry, have trouble 
sleeping, feel weak, tremble, sweat, feel tired, have loose and watery stools
Infusion reaction, where you may feel dizzy or faint, flushed, get a rash, have a 
fever, feel short of breath, experience a decrease in your blood pressure at the 
time of receiving your infusion (IV) or just after, or pain at the site of infusion
Inflammation of the bowels/gut that can cause severe stomach pain with loose 
or watery stools, or stools that are black, tarry, sticky or stools with blood or 
mucus
A condition called Stevens Johnson Syndrome (SJS) or Toxic Epidermal 
Necrosis (TEN). This condition involves inflammation of the skin, which may 
cause peeling of the skin, itchiness, and/or skin redness. The skin inflammation 
(i.e. peeling, itching and redness) could also be widespread throughout your 
body. More severe skin reactions may involve the inside of your mouth, the 
surface of your eye and genital areas, and/or may cause the top layer of your 
skin to peel from all over your body, which can cause severe infection. These 
severe conditions can rarely lead to death.
RARE, SOME MAY BE SERIOUS (i.e. causing hospitalization, life-threatening, or 
where noted, may cause death)  – in less than 1 out of 100 people:  

Inflammation of the nerves that may cause 
o
Pain
o
Weakness or tingling in the hands and feet, and may spread to the 
legs, arms and upper body leading to severe muscle weakness and 
possible temporary paralysis

Inflammation of the muscles so you may feel weak or have pain in the 
muscles, sometimes referred to as myasthenic syndrome

Inflammation of the pancreas (a gland in your abdomen that controls sugar 
levels) so you may:
o
Have severe upper belly pain that may move to the back 
o
Feel sick to your stomach 
o
Have vomiting that gets worse when you eat


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
Inflammation of the eye so you may have:
o
Redness 
o
Blurred vision
o
Sensitivity to light
o
Eye pain
o
See floaters
o
Headaches
   Inflammation of the liver that may make you:
o
  Feel sick to your stomach and vomit 
o
  Feel like not eating
o
  Feel tired 
o
  Have a mild fever 
o
  Have pain in the right side of your belly
o
  Have yellow eyes and skin
o
  Have dark urine
  Inflammation of the pituitary gland (a gland in the head) which may cause you  
  to:
o
Feel sick to your stomach or have headaches 
o
Have changes in your behavior
o
Have Double vision 
o
Have few to no menstrual cycles
o
Have Weakness 
o
Vomit
o
Have Dizziness or fainting 

Adrenal glands (glands on top of the kidneys) that may not produce enough 
hormone which could cause:
o
  Tiredness
o
  Weight loss
o
  Muscle weakness
o
  Feeling faint
o
  Joint, muscle, and belly aches
o
  Nausea
o
  Vomiting
o
  Loose or watery stools
o
  Fever
o
  Salt craving
o
  Darkening of the skin like a suntan

Type 1 Diabetes, a condition that can cause too much sugar in the blood, 
which may make you: 
o
Feel thirstier than usual
o
Frequently urinate


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o
Lose weight
o
Need regular insulin shots

Inflammation of the kidney, so you may:
o
Pass less urine 
o
Have cloudy or bloody urine 
o
Have swelling 
o
Have low back pain

Inflammation of the middle layer of your heart (myocarditis), that may cause 
your heart to have difficulty pumping blood throughout your body, which can 
cause:
o
Chest pain
o
Shortness of breath
o
Swelling of the legs
o
Fast or irregular heartbeat (that may cause dizziness or fainting)
o
Death

Inflammation of the thyroid gland, an organ that makes and stores thyroid 
hormones. This condition may lead to change in your:
o
Heart rate
o
Blood pressure
o
Body temperature
o
Metabolism (the rate at which food is converted into energy)  

A condition that may make you feel weak and tired and might have drooping 
of the eyelids, blurred or double vision, difficulty swallowing, slurred speech, 
weakness in your arms and legs, or difficulty breathing.

The formation of small clusters of immune cells (called granulomas) in parts 
of your body such as your lymph nodes, eyes, skin, or lungs.

Inflammation of the brain with confusion and fever, which may also include: 
o
Disorientation
o
Memory problems 
o
Seizures (fits) 
o
Changes in personality and behavior 
o
Difficulty speaking
o
Weakness or loss of movement in some parts of your body
o
Loss of consciousness
Additionally, since pembrolizumab was approved in September 2014, the following side 
effects have been reported by people receiving pembrolizumab. These side effects 
were voluntarily reported from a group of people of unknown size. It is not possible to 
estimate the frequency of this side effect:

Inflammation of the joints which may include joint pain, stiffness and/or
swelling.


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
Severe responses of the immune system that cause the body to attack its 
own blood cells, spleen, liver, lymph nodes, skin and brain. This may include 
fever, rash, inflammation of the liver, yellowing of the skin, an enlarged liver 
and spleen, low blood counts, and enlarged lymph nodes. The nervous 
system may also be affected and cause confusion, seizures, and even coma.
If you have had an allogeneic stem cell transplant (a procedure in which a person
receives blood-forming stem cells from a donor), you may experience graft versus host
disease (GvHD), which may include diarrhea, skin rashes, and liver damage, after
receiving pembrolizumab. Sometimes this condition can lead to death.
Cabozantinib
Common side effects (in more than 20 out of 100 people)

Diarrhea

Nausea

Vomiting

Stomach pain and inflammation

Constipation

Abdominal pain

Fatigue

Decreased appetite

Hand-foot syndrome (redness, swelling, and pain on the palms and soles 
of the feet)

Rash – you should report any unusual rash to your study doctor 
immediately

High blood pressure

Weight loss

Changes in taste

Hypothyroidism
Less common side effects (in 5 to 20 out of 100 people)

Upset stomach

Inflammation of the mouth and esophagus, which may make it painful or 
difficult to eat and drink

Loss of energy 

Dry skin

Headache

Dizziness

Difficulty breathing


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
Cough

Low red blood cell count (anemia), which may make you feel tired, weak, 
or short of breath

Changes in hearing

Pain in your hands, feet, arms, or legs

Muscle spasms

Joint pain

High levels of protein in your urine
Rare, but serious side effects (in fewer than 5 out of 100 people)

Severe bleeding (hemorrhage), which can be life-threatening

Development of holes in the stomach or intestines, which can be life-
threatening

Blood clots

Severe high blood pressure, which can lead to stroke

A syndrome called Reversible Posterior Leukoencephalopathy Syndrome, 
which includes symptoms of headache, confusion, seizures, and loss of 
vision.
Hypoglycemia (low blood sugar) has been reported in drugs similar to cabozantinib 
occurring in 5-20 out of 100 people. This side effect is more commonly seen in 
patients with diabetes who are on insulin therapy. This side effect has occurred in one 
participant at our site and could possibly be related to cabozantinib.
These drugs are being studied in combination, which means there is potential for 
increased frequency or higher severity of certain side effects. 
Risks of the Study Procedures
Risks of Having an IV Inserted in Your Vein
In this study we will insert a needle, connected to a plastic tube, into a vein in 
your arm. We will use the tube to take blood samples and to give you the study 
drugs and fluids. You will feel some pain when we first insert the tube into your 
vein. You may have some redness, swelling, or bruising where the tube goes 
under your skin. In some cases, this type of tube can cause an infection where it 
goes under the skin. In rare cases, it can cause a blood clot in the vein. You will 
have this tube inserted for about 24 hours.
Risks of Having Blood Taken


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In this study, depending on the study visit, we will need to get about 4-10 
tablespoons of blood from you at each study visit. We will get blood by putting a 
needle into one of your veins and letting the blood flow into a vacuum tube.  You 
may feel some pain when the needle goes into your vein.  A day or two later, you 
may have a small bruise where the needle went under the skin. 
Risks of Biopsy
In this study, if you agree to participate in the optional biopsy procedures, we will 
take 1 or 2 biopsies from you. There are some risks to taking a biopsy. There is a 
small chance that you could get an infection where the needle goes in. You may 
also experience redness, swelling, minor bleeding or bruising at the site where 
the cut was made or the needle inserted. You may experience mild to moderate 
pain at the site of the needle puncture. There is also a small chance that you 
could have an allergic reaction to the numbing medicine. After your skin heals up, 
you may have a small scar where we take the samples. If an X-ray is used to 
help place the needle, you will be exposed to additional radiation. The amount of 
radiation you receive during each biopsy procedure is approximately equal to the 
radiation you would receive in about 4 years in your normal environment.
The core biopsy procedure has some additional risks, depending on where your 
tumor is located. If you have a biopsy of a solid organ, like your liver or a kidney, 
or of a lymph node, there is a risk of pain, bleeding, and infection. There is a risk 
of damage to nearby structures or organs, and a small risk of tract seeding 
(spreading cancer along the tract that is created by the needle during the biopsy). 
There is a risk of injury due to positioning of the needle, and a small risk of heart 
or lung problems. If you have a lung biopsy, there is a risk of air getting into the 
space around your lung that would require a tube to be placed in between your 
ribs to draw the air out. If this tube is placed, some additional risks include 
damage to other nearby structures, including the lung, a prolonged air leak, and 
a possible need for additional tubes or procedures. There is a small risk of death 
from complications of a biopsy.
Risks of having an EKG
An electrocardiogram (EKG) is a test that records the electrical activity of the 
heart.  Skin irritation is rare but could occur during an EKG from the electrodes or 
gel that is used.
Risks of Magnetic Resonance Imaging (MRI)
In this study we may take an MRI of your chest, abdomen, and pelvis, The MRI 
machine uses powerful magnetic waves to take pictures inside the body. The 


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waves themselves are not harmful, but they can cause metal to heat up and 
electronics to stop working.
You should NOT have an MRI if you have metal or electronic devices inside 
your body. Heart pacemakers and insulin pumps are examples of electronic 
devices.
The MRI machine is a small round tube. It might make you uncomfortable if you 
do not like tight spaces.
The most common side effect of having an MRI is flashing lights in the eyes. This 
is caused by the magnetic waves and is not harmful. Some people also 
experience warmth and reddening of the skin. This usually goes away after a few 
minutes.
Risks of Positron Emission Tomography (PET)/Computed Tomography (CT)
As part of this study we may perform a PET/CT scan of your chest, abdomen, 
and pelvis (CAP). PET is a way of taking pictures of your body using tracers that 
are radioactive. The actual scanning done by PET is a form of radiation. CT is 
also a way of taking detailed pictures inside your body by using X-rays. X-rays 
are a type of radiation.
You get some radiation from your environment. You get radiation from bricks and 
concrete, from some foods, and from radon gas, which is an invisible gas that 
seeps out of the ground.  The amount of radiation that PET/CT scans will deliver 
to your body (give you) is about the same as you would get from living in your 
environment for 5 years.
This is an estimate. The amount of radiation you get could be higher or lower, 
depending on the machine, the power setting, and your body weight. Exposure to 
radiation at high levels increases a risk of developing cancer. There is no 
evidence of such risks for diagnostic procedures. 
The risk of this procedure is not equal for everyone.  The risk is much higher for 
unborn babies if the mother has this procedure.  The risk is also much higher for 
young children and teenagers.  The risk is much lower for people over the age of 
30. 
Risks of Bone Scan


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If your cancer has spread to your bones, we will perform a bone scan of your 
whole body.  A bone scan is a way of seeing if there are any problems with the 
way your bones are growing.  
To do the bone scan we will need to inject a radioactive tracer into your blood 
stream.  You will get some radiation from this tracer.
Your natural environment has some radiation in it. It comes from the outer space, 
from soil, rocks, bricks and concrete, from some foods, and from radon gas, 
which is an invisible gas that seeps out of the ground.  The amount of radiation 
that this procedure will give you is about the same as you would get from your 
environment in 1 year.  
The risk of this procedure is not equal for everyone.  The risk is much higher for 
unborn babies if the mother has this procedure.  The risk is also significantly 
higher for young children and teenagers who have this procedure.  The risk is 
much lower for people over the age of 30.  
Risks Associated with Pregnancy
The use of the study drugs in pregnant females and nursing mothers has not been 
studied. The effects of the study drugs on human eggs and sperm has not been studied. 
The risks to a human fetus are unknown. However, based on the way the drugs work, it 
cannot be ruled out that there is potential for the study drugs to cause birth defects in 
humans. If the study drugs are taken during pregnancy, they may cause birth defects or 
death to an unborn baby. Females must not become pregnant while taking the study 
drugs.
Women who are able to get pregnant must use effective birth control while taking 
pembrolizumab and for at least 4 months after the last dose of pembrolizumab. 
Before you begin study treatment, your doctor will discuss acceptable forms of birth 
control with you. 
Risk of Loss of Confidentiality
There is a risk that people outside of the research team will see your research 
information.  We will do all that we can to protect your information, but it cannot be 
guaranteed.
The study may include risks that are unknown at this time.


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What are the possible benefits of the study?
This study is designed for the researcher to learn more about the effects of the study 
drugs on your disease.  However, there is no guarantee that your health will improve if 
you join this study.  Also, there could be risks to being in this study.  If there are risks, 
these are described in the section describing the discomforts or risks.
Are there alternative treatments? 
There may be other ways of treating your cancer. Instead of taking part in this study:

You may choose to receive treatment with another experimental therapy.

You may choose to receive treatment with another approved therapy.

You may choose to receive comfort/palliative care.

You could also choose to get no treatment at all.
You should talk to your doctor about your choices.  Make sure you understand all of 
your choices before you decide to take part in this study.  You may leave this study and 
still have these other choices available to you. 
Who is paying for this study? 
Merck & Co, Inc. is providing a grant of funding support for this study. Merck 
manufactures the study drug Pembrolizumab and will provide this drug for the study.  
This research is being conducted by Dr. Elaine Lam. The research study will only pay 
for procedures not considered standard of care.
Will I be paid for being in the study?  
You will not be paid to be in the study. 
Will I have to pay for anything?
The drug manufacturer, Merck, will pay for the cost of the study drug Pembrolizumab. 
The funding for this study will also pay for any tests or procedures that are related to the 
research study, including the optional tumor biopsies. 
The drug Cabozantinib is considered standard treatment for your type of cancer. This 
drug will be obtained through your insurance, and you will be responsible for any 
applicable copays required by your insurance policy. 


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There are some medical procedures that you would get for your condition whether you 
were in this study or not, such as blood draws and tumor imaging. These are 
considered standard of care. You and/or your health insurance may be billed for the 
costs of medical care during this study, if these expenses are related to standard of care 
procedures. If you have health insurance, the cost of these services will be billed to your 
insurance company. If your insurance does not cover these costs, or you do not have 
insurance, these costs will be your responsibility. 
Ask your study doctor to discuss the costs that will or will not be covered by this 
research study. This discussion should include the costs of treating possible side effect. 
Otherwise, you might have unexpected expenses from being in this study.
Is my participation voluntary?
Taking part in this study is voluntary. You have the right to choose not to take part in 
this study.  If you choose to take part, you have the right to stop at any time. If you 
refuse or decide to withdraw later, you will not lose any benefits or rights to which you 
are entitled. 
If you leave this study, you will still receive your normal medical care. The only medical 
care that you will lose is the medical care you are getting as part of this study. You 
might be able to get that same kind of medical care outside of the study. Ask your study 
doctor. 
If there are any new findings during the study that may affect whether you want to 
continue to take part, you will be told about them.
Can I be removed from this study? 
The study doctor may decide to stop your participation without your permission if the 
study doctor thinks that being in the study may cause you harm, or for any other reason. 
Also, the sponsor may stop the study at any time.
What happens if I am injured or hurt during the study? 
If you have an injury while you are in this study, you should immediately call the study 
doctor at your hospital:

University of Colorado Hospital, Dr. Elaine Lam. Her phone number is (720) 848-
0170.


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
Poudre Valley Health System (UCHealth North), Dr. Steven Schuster. His 
number is (970) 493-6337. This number is answered 24 hours a day.

UCHealth Memorial Hospital (UCHealth South), Dr. Geetika Srivastava. Her 
phone number is (719) 365-6568. This number is answered 24 hours a day.
We will arrange to get you medical care if you have an injury that is caused by this 
research.  However, you or your insurance company will have to pay for that care. 
Who do I call if I have questions?
The primary researcher carrying out this study is Dr. Lam. However, Dr. Schuster is the 
lead site researcher carrying out this study at Poudre Valley Health System (UCHealth 
North), and Dr. Srivastava is the lead site researcher carrying out the study at Memorial 
Hospital (UCHealth South). You may ask any questions you have now. 
If you have questions, concerns, or complaints later, you may call Dr. Lam at 720-848-
0170, Dr. Schuster at (970) 493-6337, or Dr. Srivastava at (719) 365-6568. 
You will be given a copy of this form to keep.  
You may have questions about your rights as someone in this study. You can call Dr. 
Lam or Dr. Schuster or speak with your treating physician with questions.  You can also 
call the responsible Institutional Review Board (COMIRB). You can call them at 303-
724-1055. 
A description of this clinical trial will be available on http://www.Clinical Trials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.
Optional Study Procedures
These are the optional parts of this study. Remember, no matter what you decide to 
do about these optional parts of the study, you may still take part in the main 
study. If you decide to withdraw your consent for the optional parts, you can continue to 
take part in the main study, unless you withdraw your consent for the main study as 
well. 
Following each optional procedure is a statement asking if you want to participate in the 
optional procedure. Please read the statement and think about your choice. After 
reading the sentence, please check “Yes” or “No” and initial next to your choice. If you 
have any questions, please talk to your doctor or nurse.


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 20 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
1. Optional Consent for Baseline Tumor Biopsy
As part of this study, you are being asked if you would like to participate in 
optional tumor biopsies. If you have a tumor from which a core or punch biopsy 
can be obtained and you agree to this procedure, a small sample of your tumor 
tissue will be taken before you begin study treatment. This tumor tissue will be 
used for research on the study drugs and how they impact tumor cells. If you 
agree to this procedure, you will be given a separate hospital consent form to 
review and sign before having the biopsy.
I give my permission for a biopsy of my tumor to be taken before I begin study 
treatment.
   Yes
   No
   N/A (re-consenting – my previous
   selection has not changed)
_________Initials
2. Optional Consent for Treatment Tumor Biopsy
As part of this study, you are being asked if you would like to participate in 
optional tumor biopsies. If you have a tumor from which a core or punch biopsy 
can be obtained and you agree to this procedure, a small sample of your tumor 
tissue will be taken approximately 3-6 weeks after you begin study treatment, 
during Cycle 2. This tumor tissue will be used for research on the study drugs 
and how they impact tumor cells. If you agree to this procedure, you will be given 
a separate hospital consent form to review and sign before having the biopsy.
I give my permission for a biopsy of my tumor to be taken during Cycle 2 of the 
study treatment.
   Yes
   No
   N/A (re-consenting – my previous
   selection has not changed)
_________Initials
Who will see my research information?
The University of Colorado Denver (UCD) and its affiliated hospital(s) have rules to 
protect information about you.  Federal and state laws including the Health Insurance 
Portability and Accountability Act (HIPAA) also protect your privacy.   This part of the 


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 21 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
consent form tells you what information about you may be collected in this study and 
who might see or use it.  
The institutions involved in this study include:
University of Colorado Denver
University of Colorado Hospital
Poudre Valley Health System (UCHealth North)
UCHealth Memorial Hospital (UCHealth South)
We cannot do this study without your permission to see, use and give out your 
information.  You do not have to give us this permission.  If you do not, then you may 
not join this study.  
We will see, use and disclose your information only as described in this form and in our 
Notice of Privacy Practices; however, people outside the UCD and its affiliate hospitals 
may not be covered by this obligation.
We will do everything we can to maintain the confidentiality of your personal information 
but confidentiality cannot be guaranteed. 
The use and disclosure of your information has no time limit.  You can cancel your 
permission to use and disclose your information at any time by writing to the study’s 
Principal Investigator (PI), at the name and address listed below.  If you do cancel your 
permission to use and disclose your information, your part in this study will end and no 
further information about you will be collected.  Your cancellation would not affect 
information already collected in this study.  
Elaine Lam, MD
University of Colorado Denver
Anschutz Medical Campus
12801 East 17th Avenue
Mail Stop 8117
Aurora, CO 80045
Steven Schuster, MD
Poudre Valley Hospital
2121 E. Harmony Road
Suite 170
Fort Collins, CO 80528
Geetika Srivastava, MD


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 22 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
UCHealth Memorial Hospital 
525 Bob Peters Grove
Colorado Springs, CO  80909
Both the research records that identify you and the consent form signed by you may be 
looked at by others who have a legal right to see that information, such as:
  

Federal offices such as the Food and Drug Administration (FDA) and the Office 
of Human Research Protections (OHRP) that protect research subjects like you.

People at the Colorado Multiple Institutional Review Board (COMIRB)

The study doctor and the rest of the study team.

Merck & Co., Inc, the company funding this research study.

Officials at the institution where the research is conducted and officials at other 
institutions involved in this study who are in charge of making sure that we follow 
all of the rules for research
We might talk about this research study at meetings.  We might also print the results of 
this research study in relevant journals. But we will always keep the names of the 
research subjects, like you, private. 
You have the right to request access to your personal health information from the 
Investigator.
The investigator (or staff acting on behalf of the investigator) will use your information 
for the research outlined in this consent form. They will also make some of the following 
health information about you collected in this study available to: QualTek Molecular 
Laboratories, a lab company performing some of the tumor testing.
Information about you that will be seen, collected, used and disclosed in this 
study: 

Name and demographic information (age, sex, ethnicity, address, phone number, 
etc.

Portions of your previous and current medical records that are relevant to this 
study, including but not limited to diagnoses, history and physical, laboratory or 
tissue studies, radiology studies, procedure results.

Research visit and research test records.

Tissue samples and the data with the samples. 


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 23 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
What happens to data, tissue, blood and specimens that are collected in this 
study? 
Scientists at the University of Colorado Denver and the hospitals involved in this study 
work to find the causes and cures of disease.  The data, tissue, blood and specimens 
collected from you during this study are important to this study and to future research.  If 
you join this study:

The data, tissue, blood, or other specimens given by you to the investigators 
for this research no longer belong to you.  

Both the investigators and any sponsor of this research may study your data, 
tissue, blood, or other specimens collected from you.

If data, tissue, blood, or other specimens are in a form that identifies you, 
UCD or the hospitals involved in this study may use them for future research 
only with your consent or Institutional Review Board (IRB) approval.

Any product or idea created by the researchers working on this study will not 
belong to you.

There is no plan for you to receive any financial benefit from the creation, use 
or sale of such a product or idea. 
HIPAA Authorization for Optional Additional Study Procedures 
In this form, you were given the option to agree to additional, optional research 
procedures.  You must also give us your permission, under HIPAA rules, to use and 
disclose the information collected from these optional procedures, as described above.  
  
If you decline to give us permission to use and disclose your information, you cannot 
take part in these optional procedures, but you can still participate in the main study.  
Please initial next to your choice:
_____ I give permission for my information, from the optional procedures I have 
agreed to above, to be used and disclosed as described in this section.
_____ I do not give permission for my information for any optional procedures to be 
used and disclosed; I understand that I will not participate in any optional 
procedures.
[SIGNATURES ON NEXT PAGE]


Consent and Authorization Form
Phase II
COMIRB 16-2300
PI:  Elaine Lam, MD
Version Date:  7/17/2019
Page 24 of 24
Combined Biomed ICF and Compound HIPAA (CF-151.C, Effective 9-29-15)
Agreement to be in this study and use my data
I have read this paper about the study or it was read to me.  I understand the possible 
risks and benefits of this study.  I understand and authorize the access, use and 
disclosure of my information as stated in this form.  I know that being in this study is 
voluntary.  I choose to be in this study: I will get a signed and dated copy of this consent 
form.
Signature: 
Date: 
Print Name: 
Consent form explained by: 
Date: 
Print Name: 
A signature line for a witness is required for consent of 
non-reading subjects and consent using a short form.
Witness Signature: 
  Date: 
Witness Print Name:  
Witness of Signature

Witness of consent process