A Phase II Trial of Pembrolizumab and Cabozantinib in Patients With RM SCCHN
Phase: PHASE2
Conditions: Metastatic Head and Neck Carcinoma, Paranasal Sinus Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Oral Cavity Squamous Cell Carcinoma, Recurrent Oropharyngeal Squamous Cell Carcinoma, Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7, Stage IV Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IV Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Hypopharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVA Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Hypopharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVB Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVC Hypopharyngeal Squamous Cell Carcinoma AJCC v7, Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7, Stage IVC Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7, Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7, Unresectable Head and Neck Squamous Cell Carcinoma
Sponsor: Emory University

EMORY UNIVERSITY INVESTIGATOR-SPONSORED 
CLINICAL STUDY PROTOCOL  
A phase II trial of pembrolizumab and cabozantinib in patients with RM 
SCCHN 
PROTOCOL NUMBER:
Winship 4234-17
STUDY DRUG:
Cabozantinib (XL184)
IND NUMBER:
137,920
SPONSOR INVESTIGATOR:
STUDY PI:    
STUDY C0-PI:
STUDY CO-INVESTIGATORS: 
MULTI-SITE COORDINATOR:  
Nabil Saba, MD
Winship Cancer Institute 
Emory University
1365-C Clifton Rd NE
Atlanta, GA 30322
Nabil F Saba, MD (Emory)
Christine Chung, MD (Moffitt)
Department of Head and Neck-Endocrine Oncology
H. Lee Moffitt Cancer Center and Research Institute
12902 Magnolia Drive
Tampa, FL 33612
Dong M Shin, MD (Emory)
Conor Steuer, MD (Emory)
Quin Boynes
Emory University, Winship Cancer Institute
Phone 404-778-1319
Fax: 404-778-0417

DATE FINAL:
                                       
E-mail: quin.l.boynes@emory.edu
 
28 February 2024

SYNOPSIS 
TITLE
A phase II trial of pembrolizumab and cabozantinib in patients with RM SCCHN 
PROTOCOL NUMBER:  Winship4234-17
CLINICAL PHASE
Phase II
RATIONALE
Recent studies suggest that mechanisms of resistance to EGFR inhibition include escape signaling 
through other HER receptor members (HER3 through its ligand or through its heterodimerization 
with HER2) as well as MET expression. MET amplification may lead to resistance to EGFR 
through upregulation of other HER members such as HER3. In SCCHN, elevated VEGF levels 
have been implicated as a poor prognostic indicator of increased risk of recurrent disease in 
addition to radio-resistance. Activated MET signaling can lead to cell motility and scattering, 
angiogenesis, proliferation, branching morphogenesis, invasion, and metastasis. 
Pembrolizumab is a checkpoint inhibitor that has recently been approved by the FDA for treating 
patients with recurrent/metastatic (RM) SCCHN who have failed platinum based therapy. In light 
of the fact that pembrolizumb seems to be effective in a patient population that has failed EGFR 
based therapy, it would make sense to combine pembrolizumab with targeted agents possibly 
helpful in overcoming the resistance mechanisms to EGFR, such as MET and VEGF inhibitors. 
The current approval for pembrolizumab in advanced SCCHN requires failure from platinum 
based therapy and does not require failure from EGFR based therapy such as cetuximab; 
Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has 
been shown to reduce tumor growth, metastasis, and angiogenesis. Its role has been clearly 
established in well differentiated thyroid cancer however it has not been evaluated in SCCHN. 
Given the recent approval of pembrolizumab for platinum failing patients with RM disease, a 
combination trial of cabozantinib with pembrolizumab is a rational approach in this patient 
population. 
OBJECTIVES
The objectives of this study are:
Primary Objectives:
Run in phase: To determine the safety and tolerability of pembrolizumab and cabozantanib in 
patients with recurrent and/or metastatic SCCHN 
Phase II: To estimate the overall response rate (ORR) of patients with RM SCCHN who receive 
the combination of pembrolizumab and cabozantanib 
Secondary Objectives:

To estimate the progression free survival of patients treated with the combination of 
pembrolizumab and cabozantanib 


To further define the toxicities associated with these regimens in patients with SCCHN. 
Exploratory Objectives:

To identify potential biomarkers related to response to combination of pembrolizumab 
and cabozantanib in patients with recurrent and/or metastatic HNSCC. 
o
Evaluate whether markers of angiogenesis, hypoxia, Met or pMet expression, or 
inflammatory activation can predict response to the combination or PFS.
o
Evaluate circulating cell free DNA (cfDNA) in plasma and its association with 
response to the combination or PFS.
o
Evaluate potential neoantigens in the tumor DNA, their expression, and their 
association with response to the combination or PFS.
o
Evaluate peripheral blood mononuclear cells (PBMC) for immune monitoring 
and their association with  response to the combination or PFS.

To determine a quantitative radiomics based on CT and/or PET images as a prognostic 
biomarker in recurrent or metastatic HNSCC. 

To determine a computational pathology (or pathomics) based prognostic marker from 
standard digitized H&E images of the tumor in recurrent or metastatic HNSCC.
STUDY DESIGN
Run in phase: 
Pembrolizumab will be initiated in Cycle 1 at the standard dose of 200 mg Q 3 weeks. 
A run in phase of cabozantinib at 40 mg/day will be performed for the first 6 patients, beginning in 
Cycle 1. If the combination is well tolerated the trial will complete accrual at this dose level. If the 
combination is not well tolerated, with 2 DLTs observed in the first 6 patients, the dose of 
cabozantinib will be decreased to 20 mg/day which will be the dose used for the rest of the study.
Phase II:
Pembrolizumab will be administered at the standard dose of 200 mg Q 3 weeks. Cabozantinib will 
be given at the dose determined in the run in phase. Both agents will be initiated on Day 1 of 
Cycle 1 and will continue in combination. 
NUMBER OF SUBJECTS
The sample size will be up to 34 subjects in which the first 6-9 patients will be in the safety run-in 
phase with an interim futility assessment after 20 patients were treated.
TARGET POPULATION
Cancer patients will be eligible for enrollment as defined by the inclusion and exclusion criteria as 
follows:

Inclusion Criteria
1.
The subject has a histologic or cytologic diagnosis of squamous cell carcinoma of the oral cavity, 
oropharynx, paranasal sinuses, hypopharynx, nasopharynx or larynx. Squamous cell carcinoma of 
unknown primary in cervical lymph node can be included only if HPV status is positive.
2.
Patients must have refractory, recurrent or metastatic disease, which is deemed to be inoperable. 
3.
In case patients received prior systemic therapy within the definitive or metastatic setting, disease 
progression must be documented following prior therapy; this can be in the recurrent or metastatic 
setting or in the concurrent setting. 
4.
Measurable disease per RECIST 1.1 as determined by the investigator;
5.
A maximum of one prior radiotherapy regimen, curative or palliative, to the head and neck is 
allowed. If the radiation is combined with chemotherapy, a minimum of 4 months must elapse 
between the end of radiotherapy and registration. If the radiation is given alone, a minimum of 8 
weeks must elapse between the end of radiotherapy and registration. A minimum of 3 weeks must 
elapse between prior radiation to other areas and registration. Treatment areas should be healed 
with no sequelae from RT that would predispose to fistula formation
6.
The subject has had an assessment of all known disease sites eg, by computerized tomography 
(CT) scan, magnetic resonance imaging (MRI), bone scan or PET/CT scan as appropriate, within 
28 days before the first dose of cabozantinib;
7.
The subject is ≥ 18 years old on the day of consent;
8.
Life expectancy of greater than 3 months.
9.
The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
10. 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;
11. The subject has organ and marrow function and laboratory values as follows within 7 days before 
the first dose of cabozantinib:
a.
The ANC ≥ 1000/mm3 without colony stimulating factor support;
b.
Platelets ≥ 100,000/mm3;
c.
Hemoglobin ≥ 9 g/dL;
d.
Bilirubin ≤ 1.5  the ULN. For subjects with known Gilbert’s disease, bilirubin ≤ 3.0 
mg/dL;
e.
Serum albumin ≥ 2.8 g/dl;
f.
Serum creatinine ≤ 1.5  ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For creatinine 
clearance estimation, the Cockcroft and Gault equation should be used:
i.
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72);
ii.
Female: Multiply above result by 0.85;
g.
ALT and AST ≤ 2.0  ULN;
h.
Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of 
pancreatitis;
i.
UPCR ≤ 1;
j.
Serum phosphorus, calcium, magnesium and potassium ≥ LLN.
12. The subject is capable of understanding and complying with the protocol requirements and has 
signed the informed consent document;

13. Sexually active subjects (men and women) must agree to use medically accepted barrier methods 
of contraception (eg, male or female condom) during the course of the study and for 4 months 
after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of 
reproductive potential must agree to use both a barrier method and a second method of birth 
control during the course of the study and for 4 months after the last dose of study drug(s);
14. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming pregnant 
(ie, females who have had any evidence of menses in the past 12 months, with the exception of 
those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more 
months are still considered to be of childbearing potential if the amenorrhea is possibly due to 
prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons.
15. A male participant must agree to use a contraception as detailed in this protocol during the 
treatment period and for at least during the active treatment plus an additional 90 days (a 
spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose] after the 
last dose of study treatment and refrain from donating sperm during this period.
Exclusion Criteria
1.
Patients who have HPV negative squamous cell carcinoma of unknown primary in cervical lymph 
node.
2.
The subject has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 4 weeks, or 
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment;
3.
Prior treatment with cabozantinib or pembrolizumab; or any prior immunotherapy for treating 
squamous cell carcinoma of the head and neck; 
4.
Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 
4 weeks before the first dose of study treatment. Systemic treatment with radionuclides within 6 
weeks before the first dose of study treatment. Subjects with clinically relevant ongoing 
complications from prior radiation therapy are not eligible;
5.
Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) 
– such as VEGF inhibitors (examples, but not restricted to, sorafenib, sunitinib) within 14 days 
before the first dose of study treatment;
6.
The subject has received any other type of investigational agent within 28 days or 5 half-lives, 
whichever is shorter, before the first dose of study treatment;
7.
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy 
and/or surgery (including radiosurgery) and stable for at least 4 weeks before the first dose of 
study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid 
treatment at the time of the start of study treatment;
8.
The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3  the 
laboratory ULN within 7 days before the first dose of study treatment;
9.
Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel); 
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin 
(< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are 
permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without 
radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 6 weeks 

before first dose of study treatment, and who have had no clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor ;
10. The subject has experienced any of the following:
a.
clinically-significant GI bleeding within 6 months before the first dose of study 
treatment;
b.
hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first dose 
of study treatment;
c.
any other signs indicative of pulmonary hemorrhage within 3 months before the first dose 
of study treatment.
11. The subject has radiographic evidence of cavitating pulmonary lesion(s);
12. The subject has tumor invading or encasing any major blood vessels;
13. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large 
bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days 
before the first dose of cabozantinib;
14. The subject has uncontrolled, significant inter-current or recent illness including, but not limited 
to, the following conditions:
a.
Cardiovascular disorders including:
i.
Congestive heart failure (CHF): New York Heart Association (NYHA) Class III 
(moderate) or Class IV (severe) at the time of screening;
ii.
Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) 
> 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days of the first dose of study treatment;
iii.
Any history of congenital long QT syndrome;
iv.
Any of the following within 6 months before the first dose of study treatment:

unstable angina pectoris;

clinically-significant cardiac arrhythmias;

stroke (including transient ischemic attack (TIA), or other ischemic 
event);

myocardial infarction;
b.
GI disorders particularly those associated with a high risk of perforation or fistula 
formation including:
i.
Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel 
disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis or appendicitis, acute pancreatitis or acute obstruction of the 
pancreatic duct or common bile duct, or gastric outlet obstruction
ii.
Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess 
within 6 months before  randomization, 
Note: Complete healing of an intra-abdominal abscess must be confirmed prior 
to randomization. Also no pre-existing fistula of head and neck area. No pre-
existing ONJ  
c.
Other clinically significant disorders that would preclude safe study participation;
15. Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing 
from major surgery must have occurred 1 month before the first dose of study treatment. Minor 
surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study 
treatment with complete wound healing at least 10 days before the first dose of study treatment. 
Subjects with clinically relevant ongoing complications from prior surgery are not eligible;

16. QTcF > 500 msec within 1 month before the first dose of study treatment:
a.
Three ECGs must be performed for eligibility determination. If the average of these three 
consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
17. Pregnant or lactating females;
18. Inability to swallow intact tablets or inability to take pembrolizumab or cabozantinib 
19. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations;
20. Patients with a history of other prior malignancy must have been treated with curative intent and 
must have remained disease-free for 1 year post diagnosis. Patients with a prior history of 
squamous cell or basal carcinoma of the skin or in situ cervical cancer must have been curatively 
treated.
21. Patients with known history of interstitial lung disease or idiopathic pneumonitis. 
ESTIMATED LENGTH OF SUBJECT PARTICIPATION
Subjects may continue to receive study treatment until they experience unacceptable drug-related 
toxicity or disease progression.
ESTIMATED STUDY DATES
December 2017 (first study screening visit) to December 2019 (last study follow-up visit)
INVESTIGATIONAL REGIMEN DOSE/ROUTE/DURATION
Cabozantinib is supplied as 20-mg tablets. 
COMBINATION DRUG(S)
Pembrolizumab.
SAFETY ASSESSMENTS
Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, hematology tests) 
will be performed every 3 weeks for the first 9 weeks followed by assessments every 6 weeks. 
Other safety evaluations including EKGs and urinalysis will be performed at regular intervals.
Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by 
the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.
TUMOR ASSESSMENTS
Tumors will be assessed by RECIST v1.1 response criteria by CT/MRI or PET CT scan at a 
frequency of every 9 weeks.
BIOMARKER ASSESSMENTS
Tumor samples will be collected from all patients through archival tissue or biopsies performed 
from at least one site of disease prior to the first dose administration of therapy. Tumor samples 
collected through these biopsies will be compared with the historical samples and will also be 
analyzed to explore the biomarkers that could predict response to cabozantinib. Optional end of 

treatment tumor biopsy (or at the time of progression) is allowed at both Emory Winship Cancer 
Institute and Moffitt Cancer Center.  Patients will need to be off cabozantinib for at least 2 weeks 
before the biopsy
Baseline biopsies or surgical specimens from trial participants will be analyzed for the following:

Tumor pVEGFR2/VEGFR2, pMet/Met, pSTAT3/STAT3, and PD-L1 protein expression 
as well as markers of hypoxia, antigen presenting cells, T cells, and B cells among the 
tumor infiltrating immune cells using multiplex immunohistochemistry (IHC). 

Tumor DNA whole exome sequencing and RNA sequencing to determine potential 
neoantigens and their expression. 
Blood samples will be collected at screening, at 9 weeks on treatment, at 6 months on treatment, 
and end of treatment (or disease progression whichever is sooner).  

Plasma biomarkers will include HGF, IL-6, IL-8, VEGF, and IFN-γ determined by 
ELISA analyses. 

Circulating cell free DNA (cfDNA) in plasma will be determined by DNA sequencing.

Peripheral blood mononuclear cells (PBMC) will be evaluated by flow cytometry for 
immune monitoring.
For a quantitative radiomics, CT and/or PET images will also be collected.  For quantitative 
pathomics, digitized H&E images will also be collected.
STATISTICAL METHODS
The sample size will be up to 34 subjects in which the first 6 patients will be in the safety run-in 
phase with an interim futility assessment after 20 patients were treated.
The ORR for this patient population is reported as 18% with pembrolizumab as a single agent. We 
estimate that the ORR will improve to about 35% with the combined treatment. We expect to 
accrue patients for 2 years and follow up for additional 12 months. The sample size will be 34 by a 
one-arm design with null hypothesis as ORR <=0.15 vs. its one-sided alternative. If the number of 
responses is <= 9 out of 34, the trial will be claimed as not promising.  The design yields a type 1 
error of 0.05 and a power of 80% when the true response rate is 35%. An interim look after 20 
patients will take place, and if <= 4 responses are observed, the trial will stop earlier and claim a 
futility.
Statistical analysis for biomarker studies: The ORR will be calculated with 95% confidence 
interval by Binomial distribution. The median PFS will be estimated by Kaplan-Meier method 
along with 95% confidence interval. The ability of biomarkers to predict ORR will be estimated 
by Chi-square test and/or logistic regression model, and association with PFS will be assessed by 
the Kaplan Meier method, Log-rank test, and Cox model, and the frequency of adverse events and 
serious adverse events will be summarized accordingly.

TABLE OF CONTENTS
TABLE OF CONTENTS...................................................................................................10
1
BACKGROUND AND RATIONALE.....................................................................16
1.1
Background:.....................................................................................................16
1.2
Cabozantinib (XL184) .....................................................................................22
1.2.1
Pharmacology ......................................................................................22
1.2.2
Cabozantinib Nonclinical Toxicology.................................................24
1.2.3
Clinical Experience..............................................................................24
1.2.3.1
Clinical Summary .......................................................................24
1.2.3.2
Clinical Safety Profile.................................................................24
1.2.3.3
Clinical Pharmacokinetics ..........................................................26
1.2.3.4
Clinical Activity..........................................................................26
1.3
Rationale ..........................................................................................................29
2
STUDY OBJECTIVES AND DESIGN ...................................................................30
2.1
Study Objectives..............................................................................................30
2.2
Study Design....................................................................................................31
2.2.1
Overview of Study Design...................................................................31
2.3
Treatment Assignment.....................................................................................33
2.4
Blinding and randomization.............................................................................33
2.5
Study Sites .......................................................................................................33
2.6
Withdrawals.....................................................................................................33
3
TREATMENTS........................................................................................................35
3.1
Composition, Formulation, and Storage..........................................................35
3.1.1
Investigational Treatment ....................................................................35
3.1.2
Cabozantinib Tablets ...........................................................................35
3.2
Dose, Schedule and Route ...............................................................................36
3.3
Cabozantinib Dose Modifications, Interruptions, and Discontinuation...........36
3.3.1.1
Cabozantinib Dose Reinstitution and Reescalation....................39
3.3.2
Warnings and Precautions and Guidelines for the Management of 
Adverse Events ....................................................................................39
3.3.2.1
Guidelines for Management of Potential Adverse Events..........40
3.3.2.2
Gastrointestinal Disorders...........................................................41
3.3.2.3
Hepatobiliary Disorders..............................................................43
3.3.2.4
Hematological Disorders ............................................................43
3.3.2.5
Fatigue, Anorexia, and Weight Loss...........................................44
3.3.2.6
Skin Disorders.............................................................................44
3.3.2.7
Wound Healing and Surgery.......................................................45

3.3.2.8
Hypertension...............................................................................46
3.3.2.9
Thromboembolic Events.............................................................47
3.3.2.10
Proteinuria...................................................................................48
3.3.2.11
Corrected QTc Prolongation.......................................................49
3.3.2.12
Hypophosphatemia .....................................................................51
3.3.2.13
Thyroid Function Disorders........................................................51
3.3.2.14
Hemorrhagic Events....................................................................52
3.3.2.15
GI Perforation/Fistula and Non-GI Fistula Formation................53
3.3.2.16
Osteonecrosis of the Jaw.............................................................54
3.3.2.17
Angioedema................................................................................54
3.3.2.18
Musculoskeletal and Connective Tissue Disorders ....................54
3.3.2.19
Respiratory, Thoracic and Mediastinal Disorders ......................55
3.4
Concomitant Medications and Therapies.........................................................55
3.4.1
Anticancer Therapy..............................................................................55
3.4.2
Other Medications................................................................................63
3.4.3
Allowed Therapies...............................................................................63
3.4.4
Prohibited or Restricted Therapies.......................................................65
3.4.5
Potential Drug Interactions ..................................................................66
3.5
Compliance ......................................................................................................68
3.6
Study Drug Accountability ..............................................................................68
4
STUDY POPULATION...........................................................................................68
4.1
Inclusion Criteria .............................................................................................68
4.2
Exclusion Criteria ............................................................................................71
5
STUDY ASSESSMENTS AND PROCEDURES....................................................74
5.1
Pre-Treatment Period.......................................................................................74
5.2
Treatment Period..............................................................................................75
5.3
Post-Treatment Period .....................................................................................79
5.4
Laboratory Assessments ..................................................................................80
5.5
Tumor Assessment...........................................................................................81
6
SAFETY ...................................................................................................................82
6.1
Adverse Events and Laboratory Abnormalities...............................................82
6.1.1
Adverse Events ....................................................................................82
6.1.2
Serious Adverse Events .......................................................................83
6.1.3
Serious Adverse Event Reporting........................................................84
6.1.4
Regulatory Reporting...........................................................................85
6.2
Other Safety Considerations ............................................................................85
6.2.1
Laboratory Data ...................................................................................85
6.2.2
Pregnancy.............................................................................................86

6.2.3
Medication Errors/Overdose................................................................86
6.2.4
Follow-Up of Adverse Events .............................................................86
7
STATISTICAL CONSIDERATIONS......................................................................86
7.1
Analysis Population .........................................................................................86
7.1.1
Safety Population.................................................................................86
7.2
Safety Analysis ................................................................................................86
7.2.1
Adverse Events ....................................................................................86
7.3
Sample Size......................................................................................................87
8
OTHER ANALYSES ...............................................................................................87
9
DATA QUALITY ASSURANCE............................................................................88
10
STUDY COMMITTEES ..........................................................................................88
11
ETHICAL ASPECTS ...............................................................................................90
11.1
Local Regulations ............................................................................................90
11.2
Informed Consent.............................................................................................90
11.3
Institutional Review Board/Ethics Committee ................................................90
11.4
Future Use of Patient Samples.........................................................................91
12
CONDITIONS FOR MODIFYING THE PROTOCOL ..........................................91
13
CONDITIONS FOR TERMINATING THE STUDY .............................................91
14
STUDY DOCUMENTATION AND RECORDKEEPING.....................................91
14.1
Investigator’s Files and Retention of Documents............................................91
14.2
Source Documents and Background Data .......................................................92
14.3
Audits and Inspections.....................................................................................92
14.4
Case Report Forms...........................................................................................92
15
MONITORING THE STUDY..................................................................................93
16
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS...94
17
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ...........95
18
REFERENCES .........................................................................................................96
LIST OF TABLES
Table 3-1:
Cabozantinib Tablet Components and Composition .................................36
Table 3-2:
Dose Reductions of Cabozantinib .............................................................37

Table 3-3:
Dose Modifications of Cabozantinib for Treatment-Related AEs ............38
Table 3-4:
Management of Treatment-Emergent Hand-Foot Syndrome (PPES) .......45
Table 3-5:
Management of Hypertension Related to Cabozantinib............................47
Table 3-6:
Management of Treatment-emergent Proteinuria......................................49
Table 5-1:
Study Assessments.....................................................................................77
LIST OF APPENDICES
Appendix A:
Performance Status Criteria.....................................................................101

LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the plasma drug concentration time curve
BP
blood pressure
BUN
blood urea nitrogen
CHF
congestive heart failure
CrCl
creatinine clearance
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DBP
diastolic blood pressure
DLT
dose-limiting toxicity
DVT
deep vein thrombosis
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ESC
Exelixis Safety Committee
ESMO
European Society of Medical Oncology
ESR
erythrocyte sedimentation rate
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GABA
γ-aminobutyric acid
GCP
Good Clinical Practice
GI
gastrointestinal
GGT
γ-glutamyl transferase
GnRH
gonadotropin-releasing hormone
ICH
International Conference on Harmonisation
IME
important medical event
INR
International Normalized Ratio
IRB
Institutional Review Board
LFT
liver function test
LHRH
luteinizing hormone-releasing hormone
LMWH
low molecular weight heparin
LLN
lower limit of normal

MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTC
medullary thyroid cancer
NCI
National Cancer Institute
NSAID
non-steroidal anti-inflammatory drug
NYHA
New York Heart Association
PD
progressive disease
PE
pulmonary embolism
PI
principal investigator
PPE
palmar-plantar erythrodysesthesia
PT
prothrombin time
PTT
partial thromboplastin time
qd
once daily
ONJ
osteonecrosis of the jaw
QTc
corrected QT interval
QTcF
QTc calculated by the Friderica formula
RBC
red blood cell
RPLS
reversible posterior leukoencephalopathy syndrome
SAE
serious adverse event
SBP
systolic blood pressure
TFT
thyroid function test
TIA
transient ischemic attack
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein/urine creatinine ratio
VEGF(R)
vascular endothelial growth factor (receptor)

1
BACKGROUND AND RATIONALE
1.1
Background: 
SCCHN:
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common malignancy 
worldwide, representing a major international health problem. In the United States, close to 
59,000 new cases of oral cavity, pharyngeal, and laryngeal cancers were estimated in 2015 
accounting for 3.3% of new cancers and close to 12,000 deaths (1). Despite advances in 
multimodal therapy, the survival rates and functional outcomes of patients remain limited with 
an overall 5-year survival rate that is still close to 50% (1). Novel strategies are urgently needed 
particularly in patients with recurrent or metastatic disease. The majority of patients with 
SCCHN are diagnosed with locally advanced regional disease, and in more than 50 percent of 
cases, the disease is incurable and relapses locally or at distant sites (2-4). Patients with relapsed 
or metastatic SCCHN have a poor prognosis and limited therapeutic options. Therapeutic 
advances, such as the use of multi-modality therapies, have significantly improved survival of 
advanced stage SCCHN patients over the past 10-15 years (5-7). However, still 30-40% of 
patients have recurrences or distant metastases (8, 9). There has been very little improvement in 
survival in this group of patients. Chemotherapeutic agents employed in the management of 
recurrent and/or metastatic SCCHN include methotrexate, taxanes and platinum-based regimens 
with response rates in the range of 10-40% (10-12). Unfortunately, the duration of response is 
limited (2-4 months) and a survival advantage has not been shown beyond the median survival of 
6-10 months (13, 14). 
EGFR in SCCHN:
The human epidermal growth factor receptor (EGFR) family consists of four types of trans-
membrane tyrosine kinase receptors, HER1 (EGFR, ErbB1), HER2 (ErbB2), HER3 (ErbB3), and 
HER4 (ErbB4). The general structure of ErbB members includes an extracellular ligand-binding 
region, an α-helical trans-membrane segment, a cytoplasmic tyrosine-kinase-containing domain, 
and a C-terminal phosphorylation tail (15, 16). ErbB members are widely expressed in epithelial, 
mesenchymal, and neuronal tissues and regulate cell division, proliferation, differentiation, and 
other normal cellular processes (17, 18). The ErbB network is key to important signaling 
pathways and has been preserved throughout evolution.
The epidermal growth factor receptor (EGFR) is a 170 kDa membrane-anchored protein tyrosine 
kinase that has been implicated in tumorigenesis. Ligands such as transforming growth factor 
alpha or EGF activate the EGFR, resulting in its dimerization or heterodimerization with other 

receptors that are closely related such as Her2/neu. Phosphorylation of these receptors through 
their tyrosine kinase domains leads to the recruitment of downstream effectors and activation of 
proliferation and cell-survival signals (19). This process appears to be overactive in malignancy 
(20).
Although expressed in non-malignant cells, the EGFR is highly expressed in a variety of tumors, 
and its expression is correlated with poor response to treatment and poor survival (21). EGFR 
activation has been shown to promote tumor proliferation, angiogenesis, metastases and invasion 
(22). Abnormal EGFR signaling is reportedly correlated with advanced disease, poor response to 
chemotherapy and poor prognosis (23, 24). Human malignancies use several mechanisms that 
activate the EGF pathway, including overproduction of ligands, overproduction of receptors or 
constitutive activation of receptors (25, 26). EGFR is expressed in many normal epithelial 
tissues, and overexpression occurs in many types of tumors including esophageal (92%), head 
and neck (90%) and colorectal (72%) cancer (27, 28).
The EGFR is expressed in more than 80% of SCCHN (29). Ligand binding, resulting in 
homodimerization or heterodimerization with other HER family members, causes 
phosphorylation of the tyrosine kinase domain and cell proliferation. The EGFR-specific 
monoclonal antibody drug cetuximab decreases tumor cell line growth, and increases apoptosis 
of SCCHN cells (30). In vitro and xenograft studies have shown that cetuximab decreases tumor 
cell proliferation (31-34). 
The combination of cetuximab with radiation therapy for the treatment of locally advanced 
SCCHN disease significantly improved loco-regional control and median overall survival 
compared to radiation therapy alone (35). In addition, for patients with recurrent metastatic 
disease, cetuximab plus platinum-based chemotherapy doublet (cisplatin or carboplatin) 
improved survival as well as response rate when compared to platinum based chemotherapy 
alone (36). These results led to the approval of cetuximab for SCCHN both in the concurrent and 
metastatic settings. Since the approval of cetuximab, efforts have focused on combining EGFR 
inhibitors with systemic cytotoxic therapies with the goal of improving outcome for patients with 
locally advanced as well as metastatic SCCHN. None of these efforts have led yet to the 
adoption of a novel standard of care in first line recurrent or metastatic SCCHN. Despite the 
success, the overall response rate to cetuximab as a single agent does not exceed 13% with a 
response duration less than 70 days (37). In addition, a number of patients frequently display 
primary resistance to EGFR monoclonal antibodies; acquired resistance may also emerge over 
time (38, 39). Possible mechanisms for de novo and acquired resistance to cetuximab include 
mutations in the KRAS, BRAF and NRAS genes (38), a secondary mutation (S492R) in the 

extracellular domain of EGFR receptor (38, 39), overexpression of the MET proto-oncogene (c-
Met) (40), and in SCCHN, the expression of the in-frame deletion mutation of EGFR variant III 
(41). 
Despite the fact that cetuximab is the only approved targeted agent in SCCHN, the clinical 
response to cetuximab therapy in this disease is fairly meager (42). Possible mechanisms of 
resistance to EGFR based therapy may include up-regulation of EGFR (43), resistance through 
dimerization with other HER members such as HER2 and HER3 and its ligand neuregulin 
(NRG), as well as nuclear translocation of EGFR (42, 44). In addition, mutations in the 
extracellular EGFR domain such as EGFRvIII (45) have been reported in SCCHN. 
Intracellularly, downstream signaling pathways may be constitutively activated as a mechanism 
to overcome EGFR inhibition; such pathways include the Ras/Raf/ MEK/MAPK and the 
PI3K/AKT/mTOR pathways (46-49). 
Recently, an increasing body of literature has suggested that resistance to anti-EGFR therapy 
arises frequently through activation of alternative signaling pathways that bypass the original 
target (50, 51). Compensatory HER3 signaling and sustained PI3K/AKT activation are 
associated with sensitivity and resistance to anti-EGFR targeted therapies, especially in SCCHN 
(50-53). Unlike other HER receptors, HER3 has diminished intracellular kinase activity but has 
known ligands. These characteristics make HER3 an obligate heterodimerization partner for 
HER2 (53).
MM-121 (SAR256212) is a fully human IgG2 antibody that directly binds to the extracellular 
domain of HER3 (54, 55) and induces receptor downregulation. We have explored the activity of 
MM-121 as a single agent and in combination with cetuximab in preclinical models of SCCHN. 
Our findings indicate that HER3 is active in the majority of SCCHN cell lines, and that a 
combination of EGFR and HER3 inhibition with cetuximab and MM-121 provides improved 
antitumor activity relative to either inhibitor alone. Of note is that the combination inhibited 
signaling in vitro and in vivo through both ERK and PI3K/AKT pathways (56). These findings 
provide a rationale to target HER3, HER2 and HER1 in order to overcome resistance to 
cetuximab. 

Recent data reported at the American Society of Clinical Oncology (ASCO 2014) have 
suggested that the use of HER3 inhibitors in different tumor types such as ovarian, breast and 
lung carcinoma has clinical activity based on a certain biomarker profile mostly centered around 
heregulin (HRG) expression in primary tumor samples. In general, a high NRG expression has 
correlated with improved outcome when HER3 inhibition was added to the standard systemic 
therapy in these tumor types. We also reported in the same meeting that HRG is associated with 
worse overall survival in a retrospective database of patients with SCCHN treated at our 
institution (Figure 1) (57, 58). It has however not been possible to further develop HER3 
inhibition in SCCHN in light of the negative clinical trials in other disease sites and lack of 
interest from sponsors to develop such a concept; we 
therefore have chosen to use a pan HER inhibitor 
instead of a specific HER3 inhibitor in combination 
with cetuximab in patients who have failed cetuximab 
based therapy. Our focus on MET stems from the fact 
that there is a clear correlation between failure from 
EGFR-based therapy and upregulation of other HER 
pathways as well as MET. NRG is the ligand for HER3 
signaling and has been implicated in the resistance to a 
number of cytotoxic therapies including taxanes and 
other anti-cancer agents in preclinical models (59, 60). 
The HER3 ligand HRG was shown to be over-expressed to a greater degree in SCCHN cell 
lines compared to other cell lines (61). When we compared the expression of HER3 and HRG in 
different types of tumors including squamous cell and non-squamous cell cancers using data 
from TCGA, heregulin expression was higher in SCCHN compared to other tumor types (Figure 
2) (57). We have also explored the levels of EGFR, HER2, HER3, and HRG and their clinical 
associations in a retrospective tissue repository of 96 patients with a diagnosis of oropharyngeal 
HPV positive and negative SCCHN. EGFR, HER2, and HER3 levels were measured by qIHC 
and HRG mRNA was measured by RNA ISH. p16 status was determined by IHC and HPV 
status was confirmed by HPV DNA ISH. The correlations between each protein level and 
clinical characteristics and their effects on disease-free survival (DFS) or overall survival (OS) 
were also assessed, and our data were presented at ASCO 2014 (62).  Strikingly, a high HRG 
level was correlated with a worse overall survival in both HPV positive and negative SCCHN 
(57). 
Figure 1: Association between HRG expression 
and OS in a retrospective database of patients 
with SCCHN treated at Emory

MET and its role in resistance to 
HER inhibition in SCCHN:
Activation of c-Met signaling can 
lead to angiogenesis, proliferation, 
enhanced cell motility, invasion, and 
eventual metastasis. c-Met is a 
disulfide linked a-b heterodimeric 
membrane RTK that has been 
previously identified as a 
protooncogene and is expressed in 
both normal and malignant cells (63-
65). c-Met has high affinity to scatter-factor/ hepatocyte growth factor (HGF), which is its only 
known ligand (for review see references (66-69)). Mature c-Met is composed of disulfide bound 
α- and β-subunits. The extracellular α-subunit contains the ligand binding domain and the β-
subunit holds the juxtamembrane and tyrosine kinase domains. Binding of HGF triggers 
dimerization and transphosphorylation at the C-terminus of the receptor. In addition, c-Met is 
able to interact with EGFR, HER2, and HER3 through dimerization (70-72). The human Met 
(HGF receptor) gene is located on chromosome 7 band 7q21–q31 and spans more than 120 kb in 
length (73, 74).  HGF is a member of the plasminogen-related growth factor (PRGFs) family, 
thus is sometimes also referred to as PRGF-1. The gene encoding HGF spans 70 kb on 
chromosome 7q21.1 and is initially produced as pro-HGF, which is subsequently cleaved by a 
protease to HGF (75, 76). 
MET receptor tyrosine kinase and its ligand HGF regulate a variety of cellular functions, many 
of which can be dysregulated in human cancers. Activated MET signaling can lead to cell 
motility and scattering, angiogenesis, proliferation, branching morphogenesis, invasion, as well 
as metastasis (77). Activation of HGFR can occur through binding to its ligand, HGF, 
overexpression/amplification, mutation, and/or decreased degradation. Amplification of HGFR 
can occur de novo or in resistance to therapy (78). In pre-clinical studies of SCCHN cell lines 
and tissue analysis, 84% of SCCHN samples showed MET overexpression, whereas 18 of 20 
SCCHN cell lines (90%) expressed MET. HGF overexpression was present in 45% of SCCHN. 
In addition, MET inhibition abrogated MET signaling, cell viability, motility/ migration in vitro, 
and tumor angiogenesis in vivo (79). There does not seem to be a clear pattern of MET 
expression as a function of HPV status; Met expression and gene amplification were not 
associated with survival outcomes in oropharyngeal SCC patients, whereas HGF may be a 
Figure 2: HER3 and HRG expression in different tumor types (TCGA data).

potential prognostic marker in HPV-negative disease (80). HER family members have increased 
activity in cetuximab-resistant SCCHN and NSCLC cells and MET expression seems to be 
increased in these cells as well (44). MET amplification leads to resistance to EGFR inhibition 
by activating ERBB3 signaling; In addition, concurrent inhibition of MET and EGFR suppresses 
growth of HCC827 GR cells and leads to down-regulation of ERBB3/PI3K/AKT signaling, 
further supporting the rationale for combining EGFR inhibition with MET inhibition (81). 
Compensatory c-Met signaling and sustained RAS/RAF/MEK/ERK and PI3K/AKT activation 
have been associated with sensitivity and resistance to anti-EGFR agents in different tumor types 
(40, 82, 83).  Increasing c-Met copy numbers and mutations in the kinase domain have been 
reported in SCCHN (69, 84, 85). These mutations were significantly correlated with lymph node 
and distant metastasis (86).  Examining SCCHN tissues by immunohistochemistry (IHC) 
revealed overexpression and activation of c-Met in 85% and 66% of cases, respectively (84).  
Nisa et al., has summarized c-Met expression and its correlation with clinico-pathological 
features of SCCHN from 14 publications in a review article (67). Furthermore, activated c-Met 
signaling was detected in cancer stem-like cells in SCCHN and shown to contribute to resistance 
to chemoradiation therapies (87, 88). Taken together, c-Met plays an important role in the 
development and progression of cancers, including SCCHN.
Similar to resistance to EGFR targeted therapy, accumulated evidence demonstrates that 
activation of EGFR/HER3 pathways is responsible for resistance to c-Met targeted therapy (71, 
72, 89-91). 
Immune checkpoint inhibitors in SCCHN:
Targeted immunotherapy has resulted in improved survival and durable objective responses in 
different solid tumors and offers a rationale for use in SCCHN (92); PD-L1 expression is  
observed in close to 68% of SCCHN patients regardless of HPV status (93, 94).  Furthermore 
immune checkpoint inhibitors (CPIs) such as the PD-1 inhibitors nivolumab and pembrolizumab 
were recently noted to have a significant clinical activity in heavily pre-treated patients with 
SCCHN regardless of HPV status (95)(96). 
The FDA granted accelerated approval for pembrolizumab based on results from the Keynote-
012 trial in 174 patients with recurrent/metastatic SCCHN who had disease progression on or 
after platinum-containing chemotherapy. In the first arm, patients with PD-L1-postive HNSCC 
received pembrolizumab at 10-mg/kg (n = 60). In the second group, patients received 
pembrolizumab at 200 mg every 3 weeks regardless of PD-L1 status (n = 132). The objective 

response rate (ORR) was 16%, complete response rate of 5%, and responses lasting for 6 months 
or longer observed in 82% (23/28) of the responding patients. The ORR and duration of response 
were similar regardless of human papillomavirus (HPV) status (96).  Safety data were evaluated 
in 192 patients with SCCHN receiving at least one dose of pembrolizumab 10 mg/kg every 2 
weeks or 200 mg every 3 weeks. The most common (greater than or equal to 20%) adverse 
reactions were fatigue, decreased appetite, and dyspnea. A more recent analysis reported ORR of 
18% and 6-month PFS and OS rates of 23% and 59%, respectively (97).
Full FDA approval for pembrolizumab is contingent upon confirmatory results from a larger 
study. Currently, the phase III KEYNOTE-040 study is comparing pembrolizumab with 
methotrexate, docetaxel, or cetuximab in 466 patients with recurrent or metastatic head and neck 
cancer. The primary completion date for this study is January 2017, and the study has fully 
accrued. (NCT02252042). In a second phase III study, pembrolizumab is being explored as a 
frontline treatment for patients with recurrent or metastatic HNSCC. The PD-1 inhibitor is being 
compared with platinum-based chemotherapy plus 5-FU and cetuximab or in combination with 
platinum-based therapy and 5-FU. This study plans to enroll 780 patients, with an estimated 
primary completion date of November 2017 (NCT02358031).  
These studies support the use of PD-1 inhibitors in a heavily pre-treated patient population who 
are at high risk of recurrence and disease related mortality such as patients with recurrent 
platinum and cetuximab refractory disease who cannot be cured with local therapies. 
More recent results from the KN048 revealed that response to Pembrolizumab in the first line 
setting is close to 18%; Pembrolizumab in combination with chemotherapy resulted in superior 
overall survival to platinum based regimen for patients with recurrent or metastatic disease 
regardless of PD-L1 status and was superior to chemotherapy for patients with PD-L1 positive 
disease (CPS score >1) (Burtness B et al, ESMO 2018)
1.2
Cabozantinib (XL184)
1.2.1
Pharmacology
Cabozantinib is a multi-targeted inhibitor of RTKs. Cabozantinib inhibits several RTKs known 
to play important roles in tumor cell proliferation and/or tumor neovascularization, namely MET, 
VEGFR2 (also known as KDR), AXL, and RET. Other recognized targets include ROS1, 
TRKA, TRKB, TIE2, TYRO3, MER, VEGFR1, VEGFR3, KIT and FLT-3. Similar to other 
drugs targeting RTKs, cabozantinib binds in a fully reversible manner to a region of the kinase 

domain (including the ATP-binding site) which forces the kinase activation loop into a pseudo-
inactive conformation, thereby inhibiting subsequent catalytic activity.
Data from pharmacodynamic experiments have shown that cabozantinib inhibits MET and 
VEGFR2 in vivo. Treatment with cabozantinib results in anti-angiogenic effects in xenograft 
tumors and is associated with pro-apoptotic effects. These effects translate into significant tumor 
growth inhibition or tumor regression after cabozantinib treatment in multiple tumor models 
including MTC, breast cancer, lung carcinoma, and GB (Yakes et al. 2011). Data from the RIP-
Tag2 mouse model of neuroendocrine pancreatic cancer suggest that dual inhibition of MET and 
VEGFR2 with cabozantinib leads to potent antitumor efficacy, including protection from 
metastatic tumor escape, which translates into survival advantages.
Cabozantinib showed no adverse effects on neurobehavioral or respiratory-system function in 
rats, and no significant changes in cardiovascular or electrocardiographic parameters (including 
QTc) in telemeterized dogs at plasma exposures (AUC values) ≥ 10-fold higher clinically-
relevant plasma exposures. No direct inhibition of hERG channel activity (IC50 > 30 μM) was 
observed for cabozantinib and four metabolites. Of 74 pharmacologic targets (including 
receptors, transporters, and enzymes) exposed to cabozantinib at 1 μM in an in vitro study of its 
inhibitory specificity, only the adenosine A3 receptor was inhibited > 50% (cabozantinib IC50 = 
0.9 μM).
Nonclinical PK of cabozantinib was studied in mice, rats, dogs, and monkeys. Oral 
bioavailability was comparably high in rats (80-86%), dogs (87%) and monkeys (73%) and 
moderately high in mice (42-51%) when cabozantinib was formulated with an aqueous vehicle. 
In rats, systemic drug exposure parameters (Cmax and AUC0-t) increased less than dose-
proportionally in association with single cabozantinib oral doses, and generally dose-
proportionally with moderate accumulation (≤ 4-fold) following repeat daily oral dosing. In 
dogs, systemic drug exposure parameters increased less than dose-proportionally with increasing 
single cabozantinib oral doses, and generally dose-proportionally with little or no accumulation 
(≤ 2-fold increase) following repeat daily dosing.
Further details can be found in the Investigator’s Brochure.
1.2.2
Cabozantinib Nonclinical Toxicology
Toxicity associated with oral administration of cabozantinib was characterized in definitive 
(GLP-compliant) single-dose and repeat-dose studies in mice, rats, and dogs; a fertility study in 
rats; embryotoxicity/teratogenicity studies in rats and rabbits; juvenile toxicity studies in rats; in 

vitro and in vivo genotoxicity bioassays; and an in vitro phototoxicity study. Target tissues for 
cabozantinib-related toxicity identified in these studies include GI tract, bone marrow, lymphoid 
tissues, reproductive tract tissues, endocrine tissues, kidney and skin. Histopathologic changes 
were also present in bone, central nervous system (CNS) tissues and liver/gall bladder. Adverse 
findings associated with cabozantinib administration were: (1) generally dose-related; (2) often 
correlative with clinical signs and/or clinical pathology parameter changes reflective of 
associated target tissue histopathologic findings; (3) generally reversible upon discontinuation of 
treatment; and (4) often observed in both rodent and non-rodent species. In definitive 
reproductive and developmental toxicity studies, cabozantinib reduced fertility in male and 
female rats, was embryotoxic in rats, produced a fetal soft-tissue malformation (small spleen) in 
rabbits and produced fetal external malformations (cleft palate/lip, dermal aplasia and kinked or 
rudimentary tail) in rats. Cabozantinib was negative in in vitro bacterial and mammalian 
genotoxicity, clastogenicity, and phototoxicity bioassays. The metabolite present at highest 
plasma concentrations in humans administered cabozantinib, EXEL-1644, was negative in an in 
vitro bacterial genotoxicity bioassay and caused no systemic tissue toxicity in rats dosed 
subcutaneously with EXEL-1644 for two weeks. 
The carcinogenic potential of cabozantinib is being evaluated in an ongoing two-year bioassay in 
rats. No carcinogenic signal was observed in the rasH2 transgenic mouse model following 
cabozantinib dosing for 26 weeks.
Further details can be found in the Investigator’s Brochure.
1.2.3
Clinical Experience
1.2.3.1
Clinical Summary
Details of all studies may be found in the Investigator’s Brochure.
1.2.3.2
Clinical Safety Profile
A pooled analysis through 29 February 2016 included 2410 subjects with cancer who had been 
treated with single-agent cabozantinib in company-sponsored clinical trials. The subjects in that 
dataset were predominately White (83.4%) and male (77.5%) with a median age of 64.0 years; 
the gender distribution reflects the inclusion of CRPC studies in the pooled analysis. Summaries 
of safety data were also captured for several individual studies including phase 3 studies.
The severity of AEs was assessed using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 3.0 or version 4.0, and AE and SAE PTs were coded with the Medical 
Dictionary for Regulatory Activities (MedDRA) version 17.0 for all studies. For AEs and SAEs, 

multiple occurrences of the same event in any individual subject are counted once at the highest 
grade reported. Events that were assessed as possibly related or probably related to cabozantinib 
are reported as “related,” and events that were assessed as not related or unlikely related to 
cabozantinib are reported as “not related.”
1.2.3.2.1
Adverse Events
In the pooled analysis of 2410 patients treated with single-agent cabozantinib, the most common 
AEs (≥ 5% incidence) reported at severity of Grade 3 and above were fatigue (15.3%), 
hypertension (13.7%), diarrhea (10.4%), anemia (8.3%), PPES (7.7%), asthenia (6.8%), 
pulmonary embolism (6.1%), and decreased appetite (5.6%). 
The most frequently (≥ 20% incidence) observed AEs reported as related to cabozantinib were 
diarrhea (53.9%), fatigue (53.2%), decreased appetite (44.8%), nausea (44.1%), PPES (34.0%), 
weight decreased (27.8%), vomiting (25.4%), dysgeusia (25.1%), hypertension (25.0%), and 
dysphonia (21.6%).
Based on AE data available as of the data cutoff dates, 533 subjects (22.1%) in the pooled single-
agent cabozantinib studies discontinued cabozantinib due to an AE (including events related to 
disease progression). The most frequently reported AEs (≥ 1% of subjects) that led to treatment 
discontinuation were fatigue (2.9%), general physical health deterioration (1.8%), asthenia 
(1.3%), decreased appetite (1.2%), nausea (1.0%), and diarrhea (1.0%).
Further details can be found in the Investigator’s Brochure.
1.2.3.2.2
Serious Adverse Events
The most commonly reported SAEs (≥ 1% incidence), excluding events of disease progression, 
were pulmonary embolism (5%), vomiting (3.4%), nausea (3%), general physical health 
deterioration (2.9%), dehydration (2.9%), and pneumonia (2.9%). 
Further details can be found in the Investigator’s Brochure.
1.2.3.2.3
Deaths
As of 29 February 2016, the incidence of Grade 5 AEs from the pooled single-agent studies was 
10.5% (254 subjects). The Grade 5 events that occurred at the highest frequency (≥ 1% 
incidence) were prostate cancer (2.9%) and general physical health deterioration (1.0%). Since 
prostate cancer was the progression of cancer in CRPC studies, only general physical health 
deterioration was assessed as related to study treatment. Thirty-three (33) of the 254 subjects 
with Grade 5 AEs had events assessed as related to the study treatment. The only related Grade 5 

AEs that occurred more than once were pulmonary embolism (n=4), death (unspecified; n=3), 
hemorrhage (n=2), respiratory failure (n=2), and sudden death (n=2).
Further details can be found in the Investigator’s Brochure,
1.2.3.3
Clinical Pharmacokinetics
The clinical pharmacology of cabozantinib (XL184) has been characterized in studies in healthy 
subjects and cancer subjects evaluating in vivo drug-drug interaction potential, effect of food 
intake on cabozantinib plasma PK, intrinsic and extrinsic factors as covariates in a PopPK 
analysis, and routes of elimination and metabolite identification.
Details can be found in the Investigator’s Brochure.
1.2.3.4
Clinical Activity
Cabozantinib has been evaluated in three Phase 3 clinical trials, in renal cell carcinoma (Study 
XL184-308 (METEOR; N=658)), medullary thyroid cancer (Study XL184-301 (EXAM; 
N=330)), and castration-resistant prostate cancer (Study XL184-307 (COMET-1; N=1023)). 
Study XL184-308 enrolled patients with histologically or cytologically confirmed advanced 
RCC with a clear cell component, measurable disease by CT/MRI per Response Evaluation 
Criteria in Solid Tumors (RECIST), and who had received treatment with at least one prior 
VEGFR-TKI. Eligible subjects were randomized 1:1 to receive either cabozantinib (60 mg, tablet 
formulation) or everolimus (10 mg) which was the standard of care for the second-line setting at 
the time of the initiation of the study. The primary PFS analysis in the Primary Endpoint Intent-
to-Treat [PITT] population (N=375) demonstrated a statistically significant improvement in PFS 
per IRC for subjects in the cabozantinib arm (n=187) compared with the everolimus arm 
(n=188): the HR adjusted for stratification factors was 0.58 (95% CI: 0.45, 0.74; stratified log-
rank p-value < 0.0001). The Kaplan-Meier estimates for median duration of PFS were 7.4 
months in the cabozantinib arm vs 3.8 months in the everolimus arm. The second interim OS 
analysis with 13 months of follow-up demonstrated a highly statistically significant prolongation 
of OS for subjects in the cabozantinib arm compared with the everolimus arm: the HR, adjusted 
for stratification factors was 0.66 (95% CI: 0.53, 0.83; stratified log-rank p-value 0.0003). 
Kaplan-Meier estimates for median duration of OS were 21.4 months in the cabozantinib arm 
and 16.5 months in the everolimus arm.
Study XL184-301 enrolled 330 patients with medullary thyroid cancer with radiographically 
documented disease progression by modified RECIST (mRECIST) compared with a radiologic 
assessment performed within the previous 14 months. The estimated median PFS was 11.2 

months for cabozantinib versus 4.0 months for placebo (HR 0.28; 95% CI, 0.19 to 0.40; p < 
.001). The estimated median OS for the cabozantinib arm was 26.6 months versus 21.1 months 
for the placebo arm (HR = 0.85; 95% CI 0.64, 1.12; p = 0.2409). The subgroup analysis of 
subjects with a RET M918T mutation revealed a larger improvement in OS for the cabozantinib 
arm: the median OS was 44.3 months for the cabozantinib arm versus 18.9 months for the 
placebo arm (HR = 0.60; 95% CI 0.38, 0.94; p = 0.0255 not adjusted for multiple subgroup 
analyses.
Study XL184-307 enrolled 1023 subjects with advanced CRPC with bone metastases. The 
prespecified primary analysis of the primary endpoint (OS) was based on an ITT analysis of all 
randomized subjects. The analysis included 614 events (578 were required) and did not 
demonstrate a statistically significant improvement in OS for subjects in the cabozantinib arm 
compared with the prednisone arm: the adjusted HR was 0.90 (95% CI: 0.76, 1.06; stratified 
logrank p-value 0.213). The Kaplan-Meier estimates for median duration of OS were 11.0 
months in the cabozantinib arm and 9.8 months in the prednisone arm, an estimated 1.2 month 
difference in the medians. The secondary efficacy endpoint was the proportion of subjects with a 
BSR per IRC at Week 12. BSR was defined as a ≥ 30% decrease in total bone-scan lesion area 
compared with baseline without soft-tissue disease progression. The analysis demonstrated a 
statistically significant improvement in the cabozantinib arm compared with the prednisone arm 
(42% vs 3%; stratified Cochran-Mantel-Haenszel [CMH] p-value < 0.001). The median duration 
of BSR was 5.8 vs 1.8 months. Median PFS per Investigator was 5.6 months in the cabozantinib 
arm and 2.8 months in the prednisone arm. The HR adjusted for randomization stratification 
factors was 0.48 (95% CI 0.40, 0.57; stratified logrank p-value < 0.0001).
Further details can be found in the Investigator’s Brochure. 
1.2.3.5
Translational Medicine
In RCC, tumor MET status was assessed as a biomarker. Subgroup analyses demonstrated 
benefits for treatment with cabozantinib over everolimus for subjects irrespective of baseline 
MET status.
In MTC, exposure to cabozantinib resulted in significant changes in levels of the circulating 
biomarkers placental growth factor (PlGF), VEGF, soluble VEGFR2 (sVEGFR2), and 
erythropoietin (EPO). Calcitonin (CTN) and carcinoembryonic antigen (CEA) levels and 
doubling times in subjects with MTC have been found to correlate with tumor burden and risk of 
progressive disease (PD), respectively (Giraudet et al. 2007). There were clear treatment-related 
reductions in both markers in the majority of subjects with MTC in Study XL184-001 treated 

with cabozantinib. In the placebo-controlled Phase 3 Study XL184-301, from baseline to Week 
12, the cabozantinib arm displayed significant decreases in CTN (mean of -45.2%) compared 
with increases in the placebo arm (mean of +57.3%; P < 0.001). Changes in CEA levels from 
baseline to Week 12 showed a similar trend (-23.7% in the cabozantinib arm compared with 
+88.7% in the placebo arm; P < 0.001). A generally linear relationship was observed when 
changes in CTN and CEA from baseline to Week 12 (up to approximately 200% increases) were 
compared with changes in target lesion size. In the Phase 3 Study XL184-301, archival tumor 
samples to determine RET mutational status in tumors and a whole blood sample to determine 
hereditary RET status were collected. The subgroup analysis of subjects with a RET M918T 
mutation revealed a larger improvement in OS for the cabozantinib arm: the median OS was 44.3 
months for the cabozantinib arm versus 18.9 months for the placebo arm.
In CPRC, circulating biomarker analyses have focused on markers of bone turnover, including 
the C-terminal cross-linked telopeptides of type I collagen (CTx) and N-terminal cross-linked 
telopeptides of type I collagen (NTx), which are markers of osteoclast activity and bone 
resorption, and bone-specific alkaline phosphatase (BSAP), a marker of osteoblast activity and 
bone formation. In a Phase 3 comparator-controlled study (XL184-307), treatment with 
cabozantinib (60 mg qd) decreased these biomarkers to a greater extent than in the prednisone 
arm based on best change from baseline at Week 6 or Week 12 (BSAP: -10% cabozantinib, 11% 
prednisone; NTx: -24%, 0%; CTx: -12%, 0%). When assessing circulating tumor cells (CTCs) in 
the same study, a higher percentage of subjects in the cabozantinib arm with ≥ 5 CTCs/7.5 mL 
blood at baseline converted to < 5 cells post-baseline (cabozantinib 33%, prednisone 6%). 
Conversely, a lower percentage of subjects in the cabozantinib arm with < 5 CTCs/7.5 mL blood 
at baseline converted to ≥ 5 cells as best post-baseline result (cabozantinib 5%, prednisone 19%).
Further details can be found in the Investigator’s Brochure.
1.3
Rationale 
Rationale for targeted therapy in SCCHN focusing on checkpoint inhibitors and MET 
inhibition:
Based on the aforementioned studies, it is clear that mechanisms of resistance to EGFR 
inhibition include escape signaling through other HER receptor members (namely HER3 through 
its ligand or through its heterodimerization with HER2) as well as MET expression. It is clear 
that MET amplification may lead to resistance to EGFR through upregulation of other HER 
members such as HER3 (81). In SCCHN, elevated VEGF levels have been implicated as a poor 
prognostic indicator of increased risk of recurrent disease in addition to radio-resistance (98, 99). 

Activated MET signaling can lead to cell motility and scattering, angiogenesis, proliferation, 
branching morphogenesis, invasion, as well as metastasis (77). 
Pembrolizumab is a checkpoint inhibitor that has recently been approved by the FDA for treating 
patients with RM SCCHN who have failed platinum based therapy. In light of the fact that 
pembrolizumb seems to be effective in a patient population that has failed EGFR based therapy, 
failed platinum based therapy as well as patients who have not had systemic therapy, it would 
make sense to offer this agent in all of these clinical scenarios; it would also make sense to 
combine pembrolizumab with targeted agents that are possibly helpful in overcoming the 
resistance mechanisms to EGFR, such as MET and VEGF inhibitors and be good therapeutic 
partners with Pembrolizumab. 
Cabozantinib is a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has 
been shown to reduce tumor growth, metastasis, and angiogenesis. Its role has been clearly 
established in medullary thyroid cancer however it has not been evaluated in SCCHN. Given the 
recent approval of pembrolizumab for platinum failing patients with RM disease, as well as its 
approval in the first line setting, a combination trial of cabozantinib with pembrolizumab is a 
rational approach in this patient population. 
There may be possible cooperative effects between pembrolizumab and cabozantinib based on 
cabozantinib’s role in supporting a more immune permissive environment. It was recently shown 
that a suppressive tumor microenvironment plays a major role in the immunosuppression 
observed in patients with SCCHN; this is now better corroborated through biomarker studies 
suggesting that an inflamed T cell phenotype in the microenvironment contributed to a higher 
response to single agent pembrolizumab (Abstract #6009, ASCO 2017). Since cabozantinib 
produces a more immune permissive environment (Cabozantinib IB version 13, section 4.2.2), its 
combination with a checkpoint inhibitor such as pembrolizumab is welcomed.  
In this protocol we will be starting with a cabozantinib dose of 40 mg daily instead of 60 mg 
daily, which is the dose approved for renal cell carcinoma. The rationale is based on unpublished 
information obtained from investigators indicating a poor tolerance to the combination of high 
dose cabozantinib at 60 mg with PD-1 inhibitors. 

2
STUDY OBJECTIVES AND DESIGN
2.1
Study Objectives
The objectives of this study are as follows:
Primary Objectives:
To estimate the overall response rate (ORR) of patients with RM SCCHN who receive the 
combination of pembrolizumab and cabozantinib. 
Secondary Objectives:

To estimate the progression-free survival (PFS) of patients treated with the combination of 
pembrolizumab and cabozantinib.

To further define the toxicities associated with these regimens in patients with SCCHN. 
Exploratory Objectives:

To identify potential biomarkers related to response to the combination of pembrolizumab 
and cabozantinib in patients with RM SCCHN. Specifically, to evaluate whether markers 
of angiogenesis, hypoxia, Met or pMet expression, or inflammatory activation can predict 
response to the combination or PFS.

To gather exploratory clinical data on a potentially predictive set of biomarkers (potential 
biomarkers include MET expression by FISH, NGS and IHC/IHF of cMET, pMET, HGF, 
HER2, HER3 and heregulin mRNA level).

To evaluate circulating cell free DNA (cfDNA) in plasma and its association with response 
to the combination or PFS.

To evaluate potential neoantigens in the tumor DNA, their expression, and their association 
with response to the combination or PFS. 

Evaluate peripheral blood mononuclear cells (PBMC) for immune monitoring and their 
association with  response to the combination or PFS.

To determine a quantitative radiomics based on CT and/or PET images as a prognostic 
biomarker in recurrent or metastatic HNSCC. 

To determine a computational pathology (or pathomics) based prognostic marker from standard 
digitized H&E images of the tumor in recurrent or metastatic HNSCC.

Endpoints
Primary Endpoint 
ORR: The proportion of subjects with partial response (PR) or complete response 

(CR) as defined by RECIST v1.1 response criteria.
Secondary Endpoints
PFS: The duration from date of treatment start to the date of objectively 
documented progression or death due to any cause, whichever status is recorded 
first.
2.2
Study Design
2.2.1
Overview of Study Design
All patients will require measurable disease by RECIST 1.1 and will need documentation of 
disease progression after platinum based therapy; archival tissue will need to be submitted; if 
archival tissue is not possible a fresh biopsy is mandated. 
Run-in phase: 
Pembrolizumab will be initiated in Cycle 1 at the standard dose of 200 mg Q 3 weeks for one 
cycle.  
A run in phase of cabozantinib at 40 mg/day will be performed for the first 6 patients, beginning 
in Cycle 1. If the combination is well tolerated (<2 DLTs in the first cycle), the trial will 
complete accrual at this dose level. If the combination is not well tolerated, with 2 DLTs in the 
first treatment cycle observed in the first 6 patients, the dose of cabozantinib will be decreased to 
20 mg/day which will be the dose used for the rest of the study.
DLT Criteria 
Adverse events (AEs) will be graded in accordance to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) (v4.0). Dose-limiting toxicity (DLT) is 
defined as any of the following treatment-related AEs occurring during the DLT Evaluation 
Period, which will be during the first cycle of combined pembrolizumab and cabozantinib.

Treatment-Related Non-Hematologic AEs:
1. Any related ≥ Grade 3 AE which is unexpected in severity and/or duration 
compared to the known safety profiles of cabozantinib and pembrolizumab when 
used as single agents, and that cannot be managed by dose modification 
(reduction or interruption) and adequate supportive care, and requires permanent 
discontinuation of cabozantinib and/or pembrolizumab. 

2. Inability to take ≥ 75% of the total planned cabozantinib dose for the DLT 
Evaluation Period because of a treatment-related AE leading to dose reductions 
and/or interruptions
For the AEs described in Section 3.3.2 - 3.3.2.19,  the specific AE management guidelines in this 
section should be followed to determine the need for dose reductions and dose interruption.

Treatment-Related Hematologic AEs:
1. Grade 3 neutropenia of  ≥ 7 days duration or any Grade 4 neutropenia 
2. ≥ Grade 3 febrile neutropenia;
3. All other hematologic toxicities of Grade 4 (except anemia as described in Section 
3.3.2.4)
A subject will be replaced if the subject does not have a DLT but is not fully evaluable for DLT 
due missing more than 25% in total of the dosing days due to progressive disease or for reasons 
other than cabozantinib-related toxicity.
Each subject’s course will consist of three periods:

A Pre-Treatment Period in which subjects are consented and undergo screening 
assessments to be qualified for the study (Section 16.o);

A Treatment Period in which subjects receive study treatment and undergo study 
assessments (Section 16.o);

A Post-Treatment Period in which subjects no longer receive study treatment but undergo 
follow-up study assessments and contacts (Section 16.o).
Phase II:
Pembrolizumab will be administered at the standard dose of 200 mg Q 3 weeks. Cabozantinib 
will be given at the dose determined in the run in phase. Both agents will be initiated on Day 1 of 
Cycle 1 and will continue in combination for the rest of the study. 
Patients will be evaluated every 3 weeks on the study with a physical exam, clinic visit. CT scans 
MRIs or PET/CT will be required for staging every 9 weeks.

2.3
Treatment Assignment 
It is the responsibility of the investigator to assign a subject number before treating each subject 
with cabozantinib.
2.4
Blinding and randomization
Not applicable.
2.5
Study Sites
This study will be conducted at up to 2 sites: Emory Winship Cancer Institute and Moffitt Cancer 
Center.
2.6
Registration
Pre-registration: Emory: Pre-registration must be completed and sent to the Central Subject 
Registrar and to the Office of Clinical Research.  After receipt of the pre-registration form and 
confirmation of a valid, signed informed consent form/HIPAA authorization form, the Winship 
Clinical Trials office will assign a patient study number.
Participating site(s): After each subject signs consent, the Central Subject Registration form is to 
be completed and sent to Winship Clinical Trial Office within 48 hours of consent. This form, 
along with the valid, signed informed consent form/HIPAA authorization form, is to be faxed or 
emailed to Winship’s Central Subject Registrar per instructions on the form. The Winship 
Clinical Trials office will assign a patient study number to these patients.
Patient study number assignment/confidentiality: Subjects will be assigned a coded designation 
according to the site at which the subject signs consent. Actual names, contact information and 
relationship to this code will be kept secure in the Winship Clinical Research Office.  
Registration: Participating site(s): The Eligibility checklist is to be printed from OnCore and 
verified by 2 people, of which one must be a clinical investigator or co-investigator. The 
completed and signed eligibility checklist along with all redacted supporting source 
documentation must be submitted to the Winship Multi-site Coordinator or designee (fax 404-
778-5033) within 14 days after pre-registration but no later than 2 business days from scheduled 
treatment visit.  Eligibility will be confirmed by a clinical principal or co-investigator and the 
Multi-site Coordinator or designee within 2 business days of receipt of all eligibility 
documentation and confirmation will be sent to the participating site along with cohort 
assignment, if subject meets criteria. Once eligibility is confirmed, then patient will be registered 
and scheduled for appropriate appointments.

2.7
Withdrawals
Subjects may discontinue study treatment or withdraw their consent to participate in the study at 
any time without prejudice. The investigator may withdraw a subject from study treatment or 
from the study if, in his or her clinical judgment, it is in the best interest of the subject or if the 
subject cannot comply with the protocol. 
In addition, any of the following conditions require discontinuation of the subject from study 
treatment:

An AE or intercurrent illness that in the opinion of the investigator warrants the subject’s 
withdrawal from study treatment;

The investigator believes it  is not in the best interest of the subject to continue on study

Specific conditions described in the Management of Adverse Events Sections 3.3.2 and 
3.3.2.1;

Necessity for treatment with other anticancer treatment prohibited by protocol;

Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, male condom, female condom) during the course of the study and for 
4 months after discontinuation of study treatment;

Women who become pregnant or are breastfeeding;

If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 
weeks, the subject will have study treatment discontinued unless there is unequivocal 
evidence that the subject is benefitting. In this situation, a subject may be able to restart 
therapy with a dose reduction upon resolution of the toxicity and with agreement of the 
principal investigator / Sponsor;

Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol;

Significant noncompliance with the protocol schedule in the opinion of the investigator;

The minimum dose of study treatment will be 20 mg once daily (qd). Subjects who 
cannot tolerate 20 mg qd will have study treatment discontinued;


Progressive disease (PD) or the subject no longer experiences clinical benefit as 
determined by the investigator
3
TREATMENTS
3.1
Composition, Formulation, and Storage
At study sites, all study medication will be stored as described in the pharmacy manual and 
inventoried in accordance with applicable state and federal regulations.
3.1.1
Investigational Treatment 
Chemical Name: 
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-
hydroxybutanedioate
3.1.2
Cabozantinib Tablets 
Exelixis internal number: XL184
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, 
hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate 
and Opadry® yellow. All tablet strengths are prepared from a common blend and are 
distinguished by shape. The 20 mg tablets are round. The components of the tablets are listed in 
Table 3-1.

Table 3-1:
Cabozantinib Tablet Components and Composition
Ingredient 
Function
% w/w
Cabozantinib malate (25% drug load as cabozantinib)
Active Ingredient
31.7
Microcrystalline Cellulose (Avicel PH-102)
Filler
38.9
Lactose Anhydrous (60M)
Filler
19.4
Hydroxypropyl Cellulose (EXF)
Binder
3.0
Croscarmellose Sodium (Ac-Di-Sol)
Disenegrant
6.0
Colloidal Silicon Dioxide,
Glidant
0.3
Magnesium Stearate
Lubricant
0.75
Opadry Yellow Film Coating which includes:
-
HPMC 2910/Hypromellose 6 cp 
-
Titanium dioxide 
-
Triacetin 
-
Iron Oxide Yellow
Film Coating
4.00
3.2
Dose, Schedule and Route
Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily. 
Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to eat for at 
least 2 hours before and at least 1 hour after taking cabozantinib.  Subjects should be instructed 
to take their cabozantinib dose at approximately the same time every day.  If a subject misses a 
dose, the dose may be taken later only if it is within 12 hours of when the missed dose should 
have been taken.  The missed dose should not be made up if it is within 12 hours of the next 
scheduled dose.  
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The tablets 
should not be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be 
avoided by subjects taking cabozantinib.
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 3.3 below.
3.3
Cabozantinib Dose Modifications, Interruptions, and Discontinuation
Subjects will be monitored for AEs from the time of signing informed consent through their last 
follow-up visit (30 days after the date of the last dose of cabozantinib treatment.) Subjects will 
be instructed to notify their physician immediately at the onset of any AE. Causality assessment 
of AEs will be determined by the investigator. AE severity will be graded by the investigator in 
accordance with CTCAE v.4.0. 

The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruption):

As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity considered related to the study treatment. Should this be ineffective, dose 
interruptions and/or reductions should be considered to prevent worsening of toxicity. 

Dose modification criteria for cabozantinib are shown in Table 3-3. Dose interruptions and/or 
reductions should be implemented for unacceptable toxicity. Doses may be modified at any 
time while a subject is on treatment.
The assigned starting dose for cabozantinib is 40 mg/day. 1 dose reduction level of 
cabozantinib is permitted to 20 mg/day (seeTable 3-2).

Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined in Table 3-3, if the investigator feels it is in the interest of a subject’s safety and will 
optimize drug tolerability.

Interruption of cabozantinib treatment for cabozantinib-related AEs may occur at any time 
per investigator discretion. If treatment is interrupted due to related AEs for more than 
6 weeks, cabozantinib should be discontinued unless there is unequivocal evidence that the 
subject is benefitting. In this situation, a subject may be able to restart therapy with a dose 
reduction upon resolution of the toxicity per the discretion of the investigator.

Dose interruptions for reason(s) other than related AEs (eg, surgical procedures) can be 
longer than 6 weeks per the discretion of the investigator.
Table 3-2:
Dose Reductions of Cabozantinib
Guidelines for the management of specific AEs are provided in Section 3.3.2. 
When cabozantanib or 
pembrolizumab are 
discontinued for reasons 
deemed to be related to one or 
the other agent, the protocol calls for the discontinuation of both agents until and when the 
toxicities have reached a tolerable level (as specified in the dose modification sections) at which 
time both agents will be re-initiated. Patients who have interruption of both agents for more than 
6 consequential weeks will be removed from the study; response assessment for these patients 
will still be assessed if available; in addition to assessment of OS and PFS based on the intent to 
treat analysis principle. 
Assigned dose
First Dose Level 
Reduction
40-mg cabozantinib oral 
qd
20-mg cabozantinib oral qd

Table 3-3:
Dose Modifications of Cabozantinib for Treatment-Related AEs
CTCAE v.4.0 Grade
Recommended Guidelines for Managementa
Grade 1 AEs
Add supportive care as indicated. Continue cabozantinib 
treatment at the current dose level if AE is manageable and 
tolerable.
Grade 2 AEs which are tolerable 
and are easily managed
Grade 2 AEs which are intolerable 
and cannot be adequately 
managed 
Continue cabozantinib treatment at the current dose level with 
supportive care.
At the discretion of the investigator, cabozantinib should be 
dose reduced or interrupted.
Note: It is recommended that dose holds be as brief as possible. 
Grade 3 AEs (except clinically 
non-relevant laboratory 
abnormalities)
Cabozantinib should be interrupted unless the toxicity 
can be easily managed with a dose reduction and optimal 
medical care. 
Note: It is recommended that dose holds be as brief as 
possible.
Grade 4 AEs (except clinically 
non-relevant laboratory 
abnormalities)
Subjects should have cabozantinib interrupted 
immediately. 
Discontinue cabozantinib unless the following criteria are 
met: 

Subject is deriving clear clinical benefit as 
determined by the investigator and agreed by the 
Sponsor

Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care 
AE, adverse event.
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 
3.3.2. For re-treatment criteria of study treatment after a dose hold see Section 3.3.1.1.
a Study treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib 
treatment or had an unclear relationship to cabozantinib treatment.
Please refer to Sections 3.3.2.2 – 3.3.2.19 for the expected adverse events and 
management guidelines for cabozantinib. 

3.3.1.1
Cabozantinib Dose Reinstitution and Reescalation
If the subject recovers from his or her toxicities to CTCAE v.4.0 Grade  1 or to the baseline 
value (or lower) and the toxicity was unrelated to study treatment, then study treatment may be 
restarted with no change in dose. 
If the subject recovers from his or her toxicities to Grade  1 or to the baseline value (or lower) 
the toxicity was deemed possibly related to study treatment, then study treatment may be 
restarted at a reduced dose (see Table 3-2 for the schedule of dose reductions). 
Subjects receiving a daily dose of 20 mg may be restarted at the same dose if deemed safe at the 
discretion of the investigator. Subjects unable to tolerate a daily dose of 20 mg should 
discontinue study treatment.
Re-escalation to the previous dose, (but not higher than 40 mg/day) may be allowed at the 
discretion of the investigator and agreement of the Sponsor for AEs which have resolved or 
recovered to Grade 1 (or baseline value) and deemed tolerable and easily managed by optimized 
supportive treatment. Dose re-escalation is not allowed for a drug-related dose reduction 
triggered by Grade 4 hematologic toxicities or by Grade 4 AEs affecting major organs (eg, 
central nervous system, cardiac, hepatic, renal).
3.3.2
Warnings and Precautions and Guidelines for the Management of Adverse 
Events
The most frequent adverse events experienced by ≥ 20% of subjects treated with cabozantinib 
were diarrhea, fatigue, nausea, decreased appetite, vomiting, weight decreased, PPES, 
constipation, hypertension, dysgeusia, dysphonia, and asthenia.
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects treated 
with cabozantinib include anemia, AST increased, ALT increased, hypothyroidism, 
hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, lipase 
increased, lactate dehydrogenase (LDH) increased, neutropenia, ALP increased, hyponatremia, 
and leukopenia. Mild to moderate QTc interval prolongation (10-15ms) has also been observed 
with a QT interval calculated by the Fridericia formula (QTcF) not exceeding 500 ms.
Subjects may also experience medically important but less frequent adverse events including 
arterial and venous thrombotic AEs (eg, DVT, pulmonary embolism [PE], transient ischemic 
attack [TIA], and myocardial infarction [MI]), severe hemorrhagic events, proteinuria, wound 
healing complications, GI perforation, abscesses including intra-abdominal and pelvic abscess, 

GI and non-GI fistulae formation, osteonecrosis, and reversible  posterior leukoencephalopathy 
syndrome (RPLS).
Cabozantinib treatment should be permanently discontinued for the following adverse events: 
visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic 
events, nephrotic syndrome, malignant hypertension, hypertensive emergency, persistent 
uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw (ONJ), 
and RPLS.
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are presented 
in the next sections. Each dose reduction of cabozantinib should be to one dose level lower that 
the current dose. Dose reductions of more than one dose level are acceptable per Investigator 
judgment. All AEs should also be managed with supportive care at the earliest signs of toxicity.   
Adverse reactions are presumed to be attributable to study drug. Adverse events classified as 
“not related” are defined as AEs that are, without question, not associated with the study 
treatment and definitely attributable to another cause.
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating 
therapy with cabozantinib, it will take most subjects 2 to 3 weeks to reach steady state. If AEs 
attributable to cabozantinib occur within the initial 3-week period of dosing, early intervention 
with dose modifications may be justified for AEs that, if worsened, could potentially be 
dangerous or debilitating, because without a dose adjustment, systemic exposure of cabozantinib 
might be expected to increase after the onset of the AE.  
Events that generally have an early onset include hypocalcemia, hypokalemia, 
thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, constipation, 
diarrhea and vomiting. In addition, earlier onset for events of dehydration was observed in 
subjects with CRPC when compared with subjects with other tumor types.
3.3.2.1
Guidelines for Management of Potential Adverse Events
Sections 3.3.2.2 – 3.3.2.19 present management guidelines or warnings/precautions for the 
following cabozantinib treatment-emergent adverse events/serious adverse events of particular 
interest.

Gastrointestinal disorders (diarrhea, nausea and vomiting, dehydration [prostate cancer 
studies], stomatitis and mucositis)

Hepatobiliary disorders (elevated ALT and AST) 


Hematological disorders

Fatigue, anorexia, and weight loss

Skin disorders (palmar-plantar erythrodysesthesia syndrome [PPES] and rash)

Wound healing and surgery

Hypertension

Thromboembolic events (venous and arterial)

Proteinuria

QTc prolongation

Hypophosphatemia

Thyroid function disorders 

Hemorrhagic events

Osteonecrosis of the jaw (ONJ)

Angioedema

Musculoskeletal and connective tissue disorders

Respiratory, thoracic, and mediastinal disorders
Please refer to the Investigator’s Brochure for additional practice guidelines and management 
recommendations for these and other AEs potentially related to cabozantinib treatment (e.g. 
intra-abdominal and pelvic abscess; nervous system disorders; infections and infestations; and 
respiratory thoracic and mediastinal disorders) use in specific populations, and overdose and first 
aid measures for accidental cabozantinib exposure.
As with all investigational products, unknown AEs may occur. Subjects should be monitored 
closely for all AEs. As with other agents in development, additional AEs are unknown. 
3.3.2.2
Gastrointestinal Disorders 
The most common non-hepatobiliary GI AEs reported in clinical studies with cabozantinib 
regardless of causality are diarrhea, nausea, decreased appetite, vomiting, constipation, stomatitis 
and abdominal pain. 
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 
antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one antidiarrheal 

agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, 
study treatment should be temporarily interrupted or dose reduced per Table 3-3.
In addition, general supportive measures should be implemented including hydration, correction 
of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-containing 
products, high fat meals, and alcohol. 
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 in accordance to 
clinical practice guidelines. The 5-HT3 receptor antagonists are recommended over chronic use 
of NK-1 receptor antagonists. When therapy with antiemetic agents does not control the nausea 
or vomiting to tolerable levels, study treatment should be temporarily interrupted or dose reduced 
per Table 3-3.
Dehydration may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented.
Stomatitis and Mucositis
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before study treatment is initiated. Appropriate correction 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 
nontraumatic cleansing and oral rinses (eg, with a weak solution of salt and baking soda) should 
be maintained. The oral cavity should be rinsed after meals, and dentures should be cleaned and 
brushed often to remove plaque. 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 per Table 3-2 and Table 3-3.
3.3.2.3
Hepatobiliary Disorders
Elevations of ALT, AST, and bilirubin have been observed during treatment with cabozantinib. 
It is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more 

frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant 
medications should be discontinued in subjects who develop increased values of ALT, AST, or 
bilirubin. 
Subjects on this study may enter with increased ALT/AST serum levels up to 2  ULN. 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. A subject who develops 
Grade ≥ 3 elevated ALT, AST, or bilirubin should have study treatment held and restarted at a 
reduced dose (see Table 3-2) after ALT, AST, and bilirubin levels resolve to at least Grade ≤ 1 or 
baseline. In subjects with recurrence of drug-related Grade ≥ 3 elevated ALT, AST, or bilirubin 
at the lowest dose level, study treatment should be discontinued. In subjects who develop 
ALT/AST elevations > 3  ULN in combination with a bilirubin elevation > 2  ULN without 
reasonable other explanation, drug-induced liver injury should be suspected and cabozantinib 
treatment interrupted. Reinstitution of study treatment after recovery of ALT, AST, and bilirubin 
to Grade 1 or baseline level is at the discretion of the investigator.
3.3.2.4
Hematological Disorders
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. 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.
Complete blood counts with differentials and platelets should be performed regularly. Subjects 
with hematologic toxicities may require additional or more frequent laboratory tests according to 
institutional guidelines. Results of such tests are to be forwarded to the local laboratory data 
management vendor.
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.
Dose reductions or dose interruptions for anemia are not mandated but can be applied as 
clinically indicated. Supportive care such as red blood cell transfusions may be managed 
according to institutional guidelines.

3.3.2.5
Fatigue, Anorexia, and Weight Loss
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as 
anemia, deconditioning, emotional distress (depression and/or anxiety), poor nutrition, sleep 
disturbance, and hypothyroidism should be ruled out and/or these causes treated in accordance to 
standard of care. Individual non-pharmacological and/or pharmacologic interventions directed to 
the contributing and treatable factors should be given. Refer to Table 3-3 for general 
management guidelines.
Anorexia and weight loss should be managed in accordance to local standard of care including 
nutritional support. If fatigue, anorexia, or weight loss cannot be adequately managed, study 
treatment should be temporarily interrupted or dose reduced per Table 3-2 and Table 3-3.
3.3.2.6
Skin Disorders
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot syndrome), skin 
rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported in cabozantinib-treated subjects. All subjects on study should be advised on 
prophylactic skin care. This includes the use of hypoallergenic moisturizing creams, ointment for 
dry skin, and sunscreen with sun protection factor ≥ 30, avoidance of exposure of hands and feet 
to hot water, removal of calluses, protection of pressure-sensitive areas of hands and feet, and 
use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. 
Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo).
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. The lateral sides of the fingers or peri-ungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms 
is recommended, including early dermatology referral. Treatment guidelines for PPE related to 
study treatment are presented in Table 3-4.
In the case of study treatment-related skin changes (eg, rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent. 
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve. 

Table 3-4:
Management of Treatment-Emergent Hand-Foot Syndrome (PPES)
CTCAE v.4.0 Grade 
Action To Be Taken 
Grade 1
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced to the 
next lower dose level.a Start urea 20% cream twice daily AND clobetasol 0.05% 
cream once daily. Reassess at least weekly; if PPES worsens at any time or does 
not improve after 2 weeks, proceed to the intervention guidelines for Grade 2.
Grade 2 
Study treatment may be continued if PPES is tolerated. Study treatment should be 
dose reduced or interrupted if PPES is intolerable. Continue urea 20% cream 
twice daily AND clobetasol 0.05% cream once daily and add analgesics 
(eg, NSAIDs/gamma-aminobutyric acid agonists) for pain control if needed. 
Reassess at least weekly; if PPES worsens or affects self-care, proceed to the 
intervention guidelines for Grade 3.
Grade 3
Interrupt study treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with clobetasol 0.05% cream twice daily AND 
analgesics. Resume study drug at a reduced dose if PPES recovers to Grade ≤ 1. 
Discontinue subject from study treatment if PPES does not improve within 
6 weeks.
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPES, palmar 
plantar erythrodysesthesia syndrome.
a Permitted dose levels are defined by individual protocols.
3.3.2.7
Wound Healing and Surgery 
VEGFR inhibitors can cause wound healing complications and wound dehiscence which may 
occur even long after a wound has been considered healed. Therefore, surgical and traumatic 
wounds must have completely healed before starting cabozantinib treatment and be monitored 
for wound dehiscence or wound infection while the subject is being treated with cabozantinib. If 
possible, cabozantinib treatment should be stopped for at least 28 days prior to major surgery.
3.3.2.8
Hypertension
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been 
reported among subjects treated with cabozantinib.
Treatment guidelines for hypertension deemed related to cabozantinib are presented in Table 3-5. 
Blood pressure should be monitored in a constant position at each visit (either sitting or supine). 
In general, subjects with known hypertension should be optimally managed before study entry. 
Decisions to decrease or hold the dose of study treatment must be based on blood pressure 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes after the first measurement.  Other than for hypertension requiring immediate 

therapy, the presence of new or worsened hypertension should be confirmed at a second visit 
before taking therapeutic action. It is recommended that this second visit occurs within 1 week.
Cabozantinib should be discontinued in subjects with hypertensive crises or hypertensive 
encephalopathy.
Table 3-5:
Management of Hypertension Related to Cabozantinib
Criteria for Dose Modifications
Treatment/Cabozantinib Dose Modification
Subjects NOT receiving optimized anti-hypertensive therapy
> 150 mm Hg (systolic)a and < 160 mm Hg
OR
> 100 mm Hg (diastolic) and < 110 mm Hg

Optimize antihypertensive medications by adding new or 
additional antihypertensive medications and/or increase 
dose of existing medications.

Reduce study 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
≥ 160 mm Hg (systolic)
OR
≥ 110 mm Hg (diastolic)

Reduce cabozantinib by one dose levelb or interrupt study 
treatment per investigator discretion

Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP 
< 150 mm Hg systolic or < 100 mm Hg diastolic, study 
treatment should be dose reduced further or interrupted

Study treatment should be dose interrupted if upper limits of 
systolic BP (≥ 160 mm Hg) are sustained and not adequately 
manageable or if systolic BP is > 180 mm Hg or diastolic 
BP > 110 mm Hg, or if subject is symptomatic

Re-start study treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at 
< 150 mm Hg systolic and < 100 mm Hg diastolic
Hypertensive emergencyc

Discontinue study treatment
BP, blood pressure.
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 or 
diastolic BP >100 based on their clinical judgment and assessment of the individual subject.
b Permitted dose levels are defined by individual protocols.
c Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of progressive or 
impending end-organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary 
edema, encephalopathy, kidney damage).

3.3.2.9
Thromboembolic Events
Thromboembolic complications are frequent in cancer patients due to procoagulant changes 
induced by the malignancy or anticancer therapy including inhibitors of VEGF pathways. Deep 
vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal 
events (please refer to the Investigator’s Brochure). Subjects who develop a PE or DVT should 
have cabozantinib treatment held until therapeutic anticoagulation with heparins (eg, low 
molecular weight heparin [LMWH]) is established. LMWH are the preferred management for 
thrombotic events, warfarin is not recommended. Cabozantinib treatment may be resumed in 
subjects who are stable and have uncomplicated PE or DVT and are deriving clinical benefit 
from cabozantinib treatment and that anticoagulation does not place them at a significant risk that 
outweighs the benefit of resuming treatment per discretion of the investigator/Sponsor. During 
anticoagulation treatment, subjects need to be monitored on an ongoing basis for bleeding risk 
and signs of bleeding which may require additional or more frequent laboratory tests in 
accordance to institutional guidelines. If there are any signs of clinically significant bleedings, 
cabozantinib treatment should be permanently discontinued.
Arterial thrombotic events (eg, transient ischemic attack, myocardial infarction) have been 
observed in studies with cabozantinib. Subjects should be evaluated for preexisting risk factors 
for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, hypertension, coronary 
artery disease, history of tobacco use, and cardiac or thromboembolic events that occurred before 
initiation of study treatment. Cabozantinib treatment should be discontinued in subjects who 
develop an acute myocardial infarction, cerebral infarction or any other clinically relevant 
arterial thromboembolic complication.
3.3.2.10
Proteinuria
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and 
other inhibitors of VEGF pathways. Management guidelines are provided in Table 3-6.  
Cabozantinib should be permanently discontinued in subjects who develop nephrotic syndrome 
(proteinuria > 3.5 grams per day in combination with hypoalbuminemia and peripheral edema 
[hyperlipidemia and thrombotic disease may also be present]) or any other relevant renal disease.

Table 3-6:
Management of Treatment-emergent Proteinuria
Severity of Proteinuria 
(UPCR)
Management of Proteinuria
≤ 1 mg/mg
(≤ 113.1 mg/mmol)

No change in cabozantinib treatment or monitoring
> 1 and < 3.5 mg/mg
(> 113.1 and < 395.9 
mg/mmol)

Consider confirming with a 24-hour protein assessment within 7 days

No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 hours on 24-hour urine collection.

Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 hours on 24-hour urine 
collection. Continue cabozantinib on a reduced dose if UPCR decreases to 
< 2 mg/mg. Consider holding cabozantinib treatment if UPCR remains > 2 
mg/mg despite a dose reduction until UPCR decreases to < 2 mg/mg. 
Restart cabozantinib treatment at a reduced dose after a dose hold unless 
otherwise approved by sponsor.

Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 
consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of 
first reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or 
is determined to be stable (< 20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated.
≥ 3.5 mg/mg
(≥ 395.9 mg/mmol)

Hold cabozantinib treatment pending repeat UPCR within 7 days and/or 
24-hour urine protein. 

If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib treatment 
and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg, restart 
cabozantinib treatment at a reduced dose and monitoring of urine 
protein/creatinine should continue weekly until the UPCR decreases to < 1 
mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is 
determined to be stable (< 20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated.
Nephrotic syndrome

Discontinue all study treatment
UPCR, urine protein/creatinine ratio.
3.3.2.11
Corrected QTc Prolongation
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a 
placebo-controlled study in subjects with MTC. A mean increase in QTcF of 10-15 ms was 
observed after 4 weeks after initiating cabozantinib treatment. A concentration-QTc relationship 
could not be definitively established. Changes in cardiac wave form morphology or new rhythms 
were not observed. No cabozantinib-treated subjects in this study had a QTcF > 500 ms.

Unless otherwise specified in certain protocols, only subjects with a baseline QTcF ≤ 500 msec 
are eligible for cabozantinib research studies. Cabozantinib should be used with caution in 
subjects with QT prolongation risk, a history of QT interval prolongation, or who are taking 
antiarrhythmics or drugs known to prolong the QT interval. Concomitant treatment with strong 
CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be avoided. 
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an increase 
of > 60 ms above baseline, two additional ECGs must be performed with intervals not less than 
3 min apart within 30 min after the initial ECG.
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above baseline, 
the following actions must be taken:

Withhold study treatment

Immediately notify the Sponsor

Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management

Consider cardiology consultation for asymptomatic subjects for evaluation and management

Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as 
clinically indicated

Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org)

Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert.
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced dose level 
if all of the following conditions are met:

Symptoms are determined to be unrelated to the QT interval prolongation

The QTcF value > 500 ms or increase of > 60 ms above baseline is not confirmed according 
to protocol procedures

Study treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline.

QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved 

Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment

Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points.
All study treatment must be permanently discontinued if either of the following applies:

Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation

Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of study 
treatment at a reduced dose
3.3.2.12
Hypophosphatemia
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus 
should be monitored frequently while receiving cabozantinib. Other causes of hypophosphatemia 
should be ruled out and/or these causes treated in accordance to standard of care. Mild to 
moderate hypophosphatemia should be managed by oral replacement including food that are 
high in phosphate (dairy items, meats, beans) and/or oral phosphate supplements in accordance 
to standard clinical practice guidelines. 
Clinically relevant hypophosphatemia should be managed in accordance to the dose modification 
guidelines as outlined in Table 3-2 and Table 3-3 or as clinically indicated.
3.3.2.13
Thyroid Function Disorders
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib therapy and other tyrosine kinase inhibitors as a result of altered thyroid hormone 
regulation by mechanisms that seem to be specific for each agent (100). Currently available data 
are insufficient to determine the mechanism of TFT alterations and its clinical relevance. Routine 
monitoring of thyroid function and assessments for signs and symptoms associated with thyroid 
dysfunction is recommended before initiation and during treatment with cabozantinib. 
Management of thyroid dysfunction (eg, symptomatic hypothyroidism) should follow accepted 
clinical practice guidelines and dose modification guidelines as outlined in Table 3-2 and Table 
3-3. 
3.3.2.14
Hemorrhagic Events
Hemorrhagic events have been reported with cabozantinib. In order to mitigate risk of severe 
hemorrhage, subjects should be evaluated for potential bleeding risk factors before initiating 
cabozantinib treatment and monitored for bleeding events with serial complete blood counts and 
physical examination while on study. Risk factors for hemorrhagic events may include (but may 
not be limited to) the following:


Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, major blood 
vessels. The anatomic location and characteristics of tumor as well as the medical history 
must be carefully reviewed in the selection of subjects for treatment with cabozantinib;

Recent or concurrent radiation to the thoracic cavity;

Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease and 
ulcerative colitis;

Underlying medical conditions which affect normal hemostasis (eg, deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia);

Concomitant medication with anticoagulants or other drugs which affect normal hemostasis;

History of clinically significant hemoptysis.
The risk of hemorrhage in cabozantinib-treated subjects with brain metastases has not been 
thoroughly analyzed. Though the incidence of CNS hemorrhage events in a study of subjects 
with GB was higher than observed in general population of subjects with cancer treated with 
cabozantinib, it is not clear how the risk of hemorrhage in GB translates to a risk of hemorrhage 
for subjects with brain metastases. Currently, brain metastases of carcinomas are not 
contraindications to the use of cabozantinib, but subjects with brain metastases should be 
monitored with a high index of suspicion if symptoms that could be due to a CNS hemorrhage 
occur.
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 2.5 mL of red blood).
3.3.2.15
GI Perforation/Fistula and Non-GI Fistula Formation
Gastrointestinal perforation/GI fistula: Prior to initiation of treatment with cabozantinib, subjects 
should be carefully evaluated for potential risk factors including (but not limited to) the 
following:

Tumors invading GI or respiratory tracts

Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s 
disease), diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis 

History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess

Ongoing visceral complications from prior radiation therapy

Prior GI surgery (particularly when associated with delayed or incomplete healing)

Complete healing following abdominal surgery and/or resolution of intra-abdominal abscess 
must be confirmed prior to initiating treatment with cabozantinib. 
After starting cabozantinib, subjects should be monitored for early signs of GI perforation such 
as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for 
developing GI perforation or fistula are present. 
Discontinue cabozantinib treatment in subjects who have been diagnosed with GI 
perforation/fistula.
Non-GI fistula formation: Complications from radiation therapy has been identified as a possible 
predisposing risk factor for fistula formation in subjects undergoing treatment with cabozantinib.
Subjects with any clinically relevant ongoing complications from prior radiation therapy (ie, 
radiation esophagitis or other inflammation of the viscera) should not be treated with 
cabozantinib.
Radiation therapy to the thoracic cavity (including mediastinum) should be avoided within 
3 months of starting treatment with cabozantinib (excluding local radiation for bone metastases). 
Fistula should be ruled out as appropriate in cases of onset of severe mucositis or difficulty 
swallowing after start of therapy. Discontinue cabozantinib and initiate appropriate management 
in subjects who have been diagnosed with a non-GI fistula.
Discontinue cabozantinib treatment in subjects who have been diagnosed with non-GI fistula.
3.3.2.16
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in subjects treated with cabozantinib. 
Additional risk factors for ONJ have been identified including the use of bisphosphonates and 
denosumab, chemotherapy, corticosteroids, local radiotherapy, and dental or orofacial surgery 
procedures.  
Osteonecrosis of the jaw can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or 
periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow 
healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.
Perform an oral examination prior to initiation of cabozantinib and periodically during 
cabozantinib therapy. Advise subjects regarding oral hygiene practice and to quickly report 
symptoms to investigator. Caution should be used in subjects receiving bisphosphonates.

Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be held for at least 4 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a 
protracted time.
3.3.2.17
Angioedema
Angioedema should be managed according to standard practice. The subject should be observed 
until symptoms resolve, with particular attention to maintaining an open airway. 
3.3.2.18
Musculoskeletal and Connective Tissue Disorders
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on 
nonclinical GLP-compliant toxicology studies. The development of new or progressive, 
unexplained musculoskeletal symptoms such as pain or weakness should be assessed for 
underlying causes.
Rhabdomyolysis has been reported. Cabozantinib should be discontinued in subjects with serious 
and life-threatening rhabdomyolysis and interrupted if less severe forms occur when there are no 
other clear causes. Reinitiation of cabozantinib treatment must be discussed with and approved 
by the sponsor. Therapy of rhabdomyolysis should include supportive care and standard medical 
intervention.
A diagnosis of reversible posterior leukoencephalopathy syndrome requires  permanent 
discontinuation of cabozantinib.
3.3.2.19
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea has been reported in clinical studies with cabozantinib. Symptoms should be managed 
according to locally accepted clinical practice including an assessment for underlying causes. 
Pulmonary embolism should be considered as possible causes for new onset dyspnea given the 
risk of thrombosis associated with inhibition of VEGF signaling. Furthermore, fistula formation 
(Section 0) and pneumonia have been reported in subjects treated with cabozantinib and should 
be considered as clinically indicated in subjects presenting with pulmonary symptoms.
3.4
Concomitant Medications and Therapies
3.4.1
Anticancer Therapy
Local intervention is discouraged unless medically unavoidable. Subjects receiving local 
intervention (eg, palliative radiation) are allowed to continue to receive study treatment at the 
investigator’s discretion.

Pembrolizumab Drug information: 
Brand Names: US 
Keytruda
Dosing: Adult
Head and neck cancer, squamous cell, recurrent or metastatic: 
IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients 
without disease progression) for up to 24 months.
Dosing: Geriatric 
Refer to adult dosing.
Dosing: Renal Impairment 
No dosage adjustment necessary. In a pharmacokinetic study, no difference in clearance was noted 
for patients with eGFR ≥15 mL/minute/1.73 m2.
Dosing: Hepatic Impairment
Hepatic impairment prior to treatment initiation:
Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN 
and any AST): No dosage adjustment necessary.
Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 
times ULN and any AST) impairment: There are no dosage adjustments provided in the 
manufacturer’s labeling (has not been studied).
Hepatotoxicity during treatment: 
Note: For patients with baseline grade 2 ALT or AST abnormalities due to liver metastases, 
permanently discontinue if AST or ALT increases by ≥50% (relative to baseline) and 
persists at least 1 week.
AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment; 
may resume therapy upon recovery to grade 0 or 1 toxicity. Also administer 
corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] followed by a taper).
AST or ALT >5 times ULN or total bilirubin >3 times ULN: Permanently discontinue. Also 
administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed a 
taper).

Ocular toxicity: Optic neuritis which could manifest as a sudden onset of vision loss, loss of 
color vision, pain when moving eyes, and/or loss of peripheral vision. It may affect one or both 
eyes at the same time (optic neuritis).
Dosing: Adjustment for Toxicity
Withhold treatment for any of the following (may resume upon recovery to grade 0 or 1 toxicity):
Colitis, moderate (grade 2) or severe (grade 3); also administer corticosteroids (prednisone 1 
to 2 mg/kg/day [or equivalent] followed by a taper).
Endocrinopathies:
Hyperglycemia, severe (Grade 3); also administer antihyperglycemics.
Hyperthyroidism, severe (grade 3) or life threatening (grade 4); manage with 
thionamides and beta-blockers as appropriate.
Hypophysitis, grade 2 (symptomatic); also administer corticosteroids (followed by a 
taper) and hormone replacement therapy if appropriate.
Hypoparathyroidism (Low levels of parathyroid hormone) (may occur rarely (<1%) 
which may result in low blood calcium and cause muscle cramps or spasms; fatigue 
or weakness; numbness, tingling or burning in fingertips, toes or lips 
Nephritis, grade 2; also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or 
equivalent] followed by a taper).
Pneumonitis, moderate (grade 2); also administer corticosteroids (prednisone 1 to 2 
mg/kg/day [or equivalent] followed by a taper).
Other treatment-related toxicity, severe or grade 3; may require corticosteroids (based on 
severity). Upon improvement to grade 0 or 1, initiate corticosteroid taper and continue 
to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at 
grade 0 or 1 following corticosteroid taper. May consider other systemic 
immunosuppressants if not controlled by corticosteroids (based on limited data).
Withhold (may resume upon recovery to grade 0 or 1 toxicity) or discontinue for:
Hyperthyroidism, severe (grade 3) or life-threatening (grade 4); manage with thionamides 
and beta-blockers as appropriate.
Hypophysitis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids 
and hormone replacement as appropriate.

Permanently discontinue for:
Adverse reactions that are life-threatening, persistent grade 2 or 3 adverse reaction (excluding 
endocrinopathies controlled with hormone replacement therapy) that does not recover to 
grade 0 or 1 within 12 weeks after the last pembrolizumab dose, or any recurrent severe 
or grade 3 treatment-related adverse reaction. Also administer corticosteroids (may 
consider other systemic immunosuppressants if not controlled by corticosteroids [based 
on limited data]).
Colitis, life-threatening (grade 4); also administer corticosteroids (prednisone 1 to 2 
mg/kg/day [or equivalent] followed by a taper).
Immune mediated adverse reactions: Discontinue permanently if unable to reduce 
corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks.
Infusion-related reaction, grade 3 or 4.
Nephritis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids 
(prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).
Pneumonitis, severe (grade 3), life-threatening (grade 4), or moderate (grade 2) that recurs; 
also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed 
by a taper).
Dosage Forms: US 
Excipient information presented when available (limited, particularly for generics); consult 
specific product labeling.
Solution, Intravenous [preservative free]:
Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]
Solution Reconstituted, Intravenous [preservative free]:
Keytruda: 50 mg (1 ea) [contains polysorbate 80]
Medication Guide and/or Vaccine Information Statement (VIS) 
An FDA-approved patient medication guide, which is available with the product information and 
at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM417493.pdf, must be dispensed with 
this medication.
Administration 

IV: Infuse over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding 
inline or add-on filter. Do not infuse other medications through the same infusion line. Would 
allow a 10 minutes window of infusion duration. 
Use
Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma.
Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in 
patients with PD-L1-expressing tumors (as determined by an approved test) who have disease 
progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK 
genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-
directed therapy) prior to receiving pembrolizumab.
Head and neck cancer, squamous cell, recurrent or metastatic: Treatment of recurrent or 
metastatic squamous cell carcinoma of the head and neck in patients with disease progression 
on or after platinum-containing chemotherapy.
Adverse Reactions Significant 
Incidence of adverse reactions include unapproved dosing regimens.
>10%:
Cardiovascular: Peripheral edema (10%)
Central nervous system: Fatigue (43% to ≤44%)
Dermatologic: Pruritus (12% to 28%), skin rash (18% to 24%; immune-mediated <1%)
Endocrine & metabolic: Hyperglycemia (48% to 49%; grades 3/4: 3% to 6%), hyponatremia 
(37% to 38%), hypoalbuminemia (32% to 37%), hypertriglyceridemia (23% to 33%), 
decreased serum bicarbonate (22%), hypocalcemia (21%), hypercholesterolemia (20%)
Gastrointestinal: Decreased appetite (20% to 25%), nausea (18% to 22%), constipation (15% 
to 22%), diarrhea (15% to 20%), abdominal pain (13%), vomiting (12% to 13%)
Hematologic & oncologic: Anemia (12% to 44%; grades 3/4: ≤10%), lymphocytopenia (40%; 
grades 3/4: 9%)
Hepatic: Increased serum alkaline phosphatase (26%), increased serum AST (20% to 24%; 
grades 3/4: 1% to 2%), increased serum ALT (21%; grades 3/4: 2%)
Neuromuscular & skeletal: Weakness (10% to ≤44%), arthralgia (14% to 15%)
Respiratory: Cough (18% to 29%), dyspnea (23%)

Miscellaneous: Fever (12% to 14%)
1% to 10%:
Cardiovascular: Pulmonary embolism (≥2%)
Central nervous system: Peripheral neuropathy (2%)
Endocrine & metabolic: Hypothyroidism (immune-mediated; 7% to 8%), hyperthyroidism 
(immune-mediated; 2% to 3%; grade 2: <1%; grade 3: <1%)
Gastrointestinal: Colitis (immune-mediated; ≤2%; grade 2: <1%, grade 3: <1%)
Neuromuscular & skeletal: Back pain (10%)
Respiratory: Pneumonitis (2% to 4%; grade 2: ≤1%; grade 3: ≤1%; grade 4: <1%), pleural 
effusion (≥2%), pneumonia (≥2%)
<1% (Limited to important or life-threatening): Adrenocortical insufficiency (immune-mediated), 
antibody development, arthritis (immune-mediated), bullous pemphigoid (immune-
mediated), 
chronic 
inflammatory 
demyelinating 
polyradiculoneuropathy, 
diabetic 
ketoacidosis, exfoliative dermatitis (immune-mediated), Guillain-Barré syndrome (immune-
mediated), hemolytic anemia (immune-mediated), hepatitis (including autoimmune 
hepatitis), hypophysitis, infusion-related reaction, interstitial nephritis (with renal failure), 
Lambert-Eaton syndrome (immune-mediated), myasthenia gravis (immune-mediated), 
myositis (immune-mediated), nephritis (autoimmune), optic neuritis (immune-mediated), 
pancreatitis (immune-mediated), partial epilepsy (immune-mediated; in a patient with 
inflammatory foci in brain parenchyma), rhabdomyolysis (immune-mediated), serum 
sickness (immune-mediated), severe dermatitis, type 1 diabetes mellitus, uveitis (immune-
mediated), vasculitis (immune-mediated)
New identified risk of myelitis has been added to the safety profile of Pembrolizumab 
Contraindications
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to pembrolizumab or any component of the formulation.
Warnings/Precautions
Concerns related to adverse effects:
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs (irAEs) may 

occur 
shortly 
after 
the 
first 
dose 
or 
several 
months 
after 
the 
last 
dose 
of 
pembrolizumab/combination treatment and may affect more than onone body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation.

Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). 
Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin therapy 
may be required; if severe hyperglycemia is observed (Grade 3), administer 
antihyperglycemics and withhold pembrolizumab treatment until glucose control has been 
accomplished.

Gastrointestinal toxicity: Immune-mediated colitis has occurred, including cases of grade 2 
to 4 colitis. The median time to onset of colitis was 3.4 months (range: 10 days to ~10 
months) and the median duration was 1.4 months (range: 1 day to ~7 months) in patients 
with melanoma. In patients with NSCLC, the median time to onset was 1.6 months (range: 
~1 to ~2 months) and the median duration was 16 days (range: 1 to ~6 weeks). In some 
melanoma patients, colitis was managed with high-dose systemic corticosteroids for a 
median duration of 6 days (range: 1 day to 5.3 months), followed by a corticosteroid taper. 
Most patients with colitis experienced complete resolution. May require treatment 
interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for 
signs and symptoms of colitis; administer systemic corticosteroids for grade 2 or higher 
colitis.

Hepatotoxicity: Immune-mediated hepatitis occurred (grades 2 to 4 hepatitis). The median 
onset for hepatitis was 26 days (range: 8 days to 21.4 months); the median duration was 1.2 
months (range: 8 days to 4.7 months). Hepatitis resolved in most patients. Administer 
corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] for grade 2 hepatitis, and 
prednisone 1 to 2 mg/kg/day [or equivalent] for grade 3 or higher, each followed by a taper), 
and withhold or discontinue therapy based on the severity of liver enzyme elevations. The 
median duration of high-dose corticosteroid therapy was 5 days (range: 1 to 14 days) 
followed by a taper. Monitor for liver function changes. May require treatment interruption, 
systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.


Hypophysitis: Immune-mediated hypophysitis occurred (grades 2, 3, and 4). In patients with 
melanoma, the median time to onset was 3.3 months (range: 1 days to 7.2 months) and the 
median duration was 2.7 months (range 12 days to 12.7 months). The time to onset in 
NSCLC (1 patient) was 3.7 months. Monitor for signs/symptoms of hypophysitis (eg, 
hypopituitarism, adrenal insufficiency). May require treatment interruption, systemic 
corticosteroids and hormone replacement therapy (as clinically indicated), and/or permanent 
discontinuation.

Infusion-related reactions: Infusion-related reactions (including severe and life-threatening 
cases) have occurred. Monitor for signs/symptoms of a reaction (eg, rigors, chills, wheezing, 
pruritus, flushing, rash, hypotension, hypoxemia, and fever). Interrupt infusion and 
permanently discontinue for severe (grade 3) or life-threatening (grade 4) infusion-related 
reactions.

Nephrotoxicity: Immune-mediated nephritis has occurred. The onset for autoimmune 
nephritis in melanoma patients was 5.1 months (range: 12 days to 12.8 months) and the 
median duration was 1.1 months (range: 3 days to 3.3 months). Grade 2 or higher nephritis 
should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day 
[or equivalent], followed by a taper). The median duration of corticosteroid use was 15 days 
(range: 3 days to 1.6 months), followed by a taper. Nephritis resolved in some patients. 
Monitor for renal function changes. May require treatment interruption, systemic 
corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including fatal 
cases. For patients with melanoma, the median time to development was 4.3 months (range: 
~2 days to ~19 months) and the median duration was 2.6 months (range: 2 days to ~15 
months). Some patients required initial management with high-dose systemic 
corticosteroids, the median duration of initial corticosteroid therapy was 8 days (range: 1 to 
34 days) followed by a corticosteroid taper. Pneumonitis completely resolved in nearly two-
thirds of melanoma patients. For patients with NSCLC, the median time to development was 
1.7 months (range: 4 days to ~13 months) and the median duration was 1.2 months (range: 
5 days to ~12 months). Some NSCLC patients had complete resolution of pneumonitis. May 
require treatment interruption, corticosteroid therapy (prednisone 1 to 2 mg/kg /day [or 
equivalent] followed by a taper, for grade 2 or higher pneumonitis), and/or permanent 
discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is 
suspected, evaluate with radiographic imaging and administer systemic corticosteroids for 
grade 2 or higher pneumonitis. For NSCLC, pneumonitis occurred more frequently in 
patients with a history of asthma, COPD, or prior thoracic radiation.


Thyroid disorders: Immune-mediated hyperthyroidism and hypothyroidism have occurred. 
The median onset for hyperthyroidism was 1.4 to 1.8 months (range: 1 day to ~22 months), 
and the median duration was 1.7 to 4.5 months (range: 1 day to ~13 months). 
Hyperthyroidism resolved in over two-thirds of melanoma patients. Hypothyroidism 
occurred with a median onset of 3.3 to 4.2 months (range: 5 days to 19 months) and median 
duration of 5.4 to 5.84 months (range: 6 days to 24.3 months), and occurred in some patients 
with no prior history of thyroid disorders. Hypothyroidism was generally managed with 
long-term thyroid hormone replacement therapy, although some patients only required short-
term replacement therapy. Hypothyroidism did not require systemic corticosteroid therapy 
or discontinuation. Thyroid disorders may occur at any point in pembrolizumab therapy. 
Monitor for changes in thyroid function (at baseline, periodically during treatment and as 
clinically indicated) and for signs/symptoms of thyroid disorders. Administer thionamides 
and beta-blockers for hyperthyroidism as appropriate; may require treatment interruption 
and/or permanent discontinuation. Isolated hypothyroidism may be managed with 
replacement therapy (without corticosteroids and treatment interruption).

Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders 
have been observed, including rash, exfoliative dermatitis, bullous pemphigoid, uveitis, 
arthritis, vasculitis, myositis, Guillain-Barré syndrome, pancreatitis, hemolytic anemia, 
serum sickness, myasthenia gravis, and partial seizures (in a patient with inflammatory foci 
in brain parenchyma). If an immune-mediated adverse event is suspected, evaluate 
appropriately to confirm or exclude other causes; withhold treatment and administer 
systemic corticosteroids based on severity of reaction. Upon resolution to grade 0 or 1, 
initiate corticosteroid taper (continue tapering over at least 1 month). When reaction remains 
at grade 1 or less during taper may reinitiate pembrolizumab. Immune-mediated adverse 
reactions that do not resolve with systemic corticosteroids may be managed with other 
systemic immunosuppressants (based on limited data). Discontinue permanently for severe 
or grade 3 immune-mediated adverse event that is recurrent or life-threatening.
Pregnancy Implications 
Animal reproduction studies have not been conducted. Immunoglobulins are known to cross the 
placenta; therefore fetal exposure to pembrolizumab is expected. Based on the mechanism of 
action, pembrolizumab may cause fetal harm if administered during pregnancy; an alteration in 
the immune response or immune mediated disorders may develop following in utero exposure. 

Women of reproductive potential should use highly effective contraception during therapy and for 
at least 4 months after treatment is complete.
Breast-Feeding Considerations 
It is not known if pembrolizumab is excreted into breast milk. The manufacturer recommends that 
breast-feeding be discontinued during therapy and for 4 months following the final dose. 
Immunoglobulins are excreted in breast milk; therefore pembrolizumab may be expected to appear 
in breast milk.
Monitoring Parameters 
PD-L1 expression status in patients with NSCLC; liver function tests (AST, ALT, and total 
bilirubin); renal function; thyroid function (at baseline, periodically during treatment and as 
clinically indicated); glucose; signs/symptoms of colitis, hypophysitis, thyroid disorders, 
pneumonitis, infusion reactions.
3.4.2
Other Medications
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before the first dose of study treatment through 30 days after the date of the 
last dose of study treatment are to be recorded in the case report forms.
3.4.3
Allowed Therapies 

Antiemetics and antidiarrheal medications are allowed prophylactically in accordance to 
standard clinical practice if clinically indicated; 

Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, American Society of Clinical Oncology [ASCO] or [European Society for 
Medical Oncology] ESMO guidelines); 

Drugs used to control bone loss (eg, bisphosphonates and denosumab) are allowed if started 
before screening activities but may not be initiated or exchanged during the course of the 
study and require Sponsor approval;

Transfusions, hormone replacement, and short term higher doses of corticosteroids should be 
utilized as indicated by standard clinical practice;


Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances: 
o Low dose heparins for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion. 
o Therapeutic doses of low molecular weight heparins (LMWH) at the time of first dose 
are allowed if the subject has no evidence of brain metastasis, has been on a stable 
dose of LMWH for at least 6 weeks, and has had no complications from a 
thromboembolic event or the anticoagulation regimen. 
o Therapeutic doses of low molecular weight heparins (LMWH) after first dose are 
allowed if clinically indicated (eg, for the treatment of deep venous thrombosis), and 
the benefit outweighs the risk per the investigator’s discretion. For management of 
thromboembolic complications while on study, refer to Section 3.3.2.9. 
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (eg, due to kidney dysfunction); 
o For restrictions on oral anticoagulants see Section 3.4.4.

Administration of the PPI esomeprazole resulted in no clinically-relevant effect on 
cabozantinib plasma PK in healthy volunteers (Study XL184-018). Therefore, concomitant 
use of gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib.  Cimetidine should be avoided due to 
potential CYP interactions.
Potential drug interactions with cabozantinib are summarized in Section 3.4.5.
3.4.4
Prohibited or Restricted Therapies 
The following therapies are prohibited while the subject is on study:

Any investigational agent or investigational medical device;

Any drug or herbal product used specifically for the treatment of SCCHN;


Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related agents, 
direct thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or chronic 
use of aspirin above low dose levels for cardioprotection per local applicable guidelines);

Any other systemic anticancer treatment (eg, chemotherapy, immunotherapy, radionuclides) 
and local anticancer treatment such as surgery, ablation, or embolization. 
The following therapies should be avoided if possible, while the subject is on study:

Palliative external radiation to bone metastasis for bone pain should not be performed while 
on study. Subjects who have such an intervention may be considered not evaluable (and may 
be assigned a censoring or progression date) for certain efficacy endpoints;

Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence and/or progression associated with 
erythropoietin(101);

Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg,  phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended;

Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, because this could 
significantly increase the exposure to cabozantinib;

Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations and should be avoided. Grapefruit and 
Seville oranges may also increase plasma concentrations of cabozantinib and should be 
avoided.
Additional information on potential drug interactions with cabozantinib is provided in Section 
3.4.5.
3.4.5
Potential Drug Interactions
Cytochrome P450 (CYP): Data from a clinical drug interaction study (Study XL184-008) show 
that clinically relevant steady-state concentrations of cabozantinib appear to have no marked 

effect on the area under the plasma drug concentration time curve (AUC) of co-administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit 
CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 
isozymes that have lower [I]/Ki values compared with CYP2C8 (ie, CYP2C9, CYP2C19, 
CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib 
concentrations (30 μM). 
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with 
caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended. 
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) 
may increase cabozantinib concentrations. Grapefruit and Seville oranges may also increase 
plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should 
be avoided and other drugs that inhibit CYP3A4 should be used with caution because these drugs 
have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended. 
In addition, cimetidine should be avoided because of its potential to interfere with CYP3A4 
mediated metabolism of cabozantinib.

Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways:
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm  
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib and/or 
a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic 
effect).
Other Interactions: 
Food may increase exposure levels of cabozantinib by 57%, fasting recommendations should be 
followed. Subjects should fast (with the exception of water) for at least 2 hours before taking 
their dose of cabozantinib. After the 2-hour fast, subjects are to take cabozantinib with a full 
glass of water (minimum of 8 oz or 240 mL) with no more food intake for one hour post-dose.
In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein, but it does 
appear to have the potential to inhibit the P-glycoprotein transport activity. Therefore, 
cabozantinib may have the potential to increase plasma concentrations of co-administered 
substrates of P-glycoprotein. 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations.
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure.
3.5
Compliance
Drug accountability and subject compliance will be assessed with drug dispensing and return 
records. 

3.6
Study Drug Accountability
The investigator will maintain accurate records of receipt of all cabozantinib, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study treatment 
is dispensed and used by each subject in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all unused cabozantinib will be reconciled and 
destroyed in accordance with applicable state and federal regulations.
4
STUDY POPULATION
4.1
Inclusion Criteria
A subject must fully meet all of the following criteria to be eligible for the study:
1. The subject has a histologic or cytologic diagnosis of squamous cell carcinoma of the oral 
cavity, oropharynx, paranasal sinuses, hypopharynx, nasopharynx or larynx. Squamous 
cell carcinoma of unknown primary in cervical lymph node can be included only if HPV 
status is positive.
2. Patients must have refractory, recurrent or metastatic disease, which is deemed to be 
inoperable. 
3. In case patients received prior systemic therapy within the definitive or metastatic setting, 
disease progression must be documented following prior therapy; this can be in the 
recurrent or metastatic setting or in the concurrent setting. 
4. Measurable disease per RECIST 1.1 as determined by the investigator; 
5. A maximum of one prior radiotherapy regimen, curative or palliative, to the head and 
neck is allowed. If the radiation is combined with chemotherapy, a minimum of 4 months 
must elapse between the end of radiotherapy and registration. If the radiation is given 
alone, a minimum of 8 weeks must elapse between the end of radiotherapy and 
registration. A minimum of 3 weeks must elapse between prior radiation to other areas 
and registration. Treatment areas should be healed with no sequelae from RT that would 
predispose to fistula formation.
6. The subject has had an assessment of all known disease sites eg, by computerized 
tomography (CT) scan, magnetic resonance imaging (MRI), bone scan or PET/CT as 
appropriate, within 28 days before the first dose of cabozantinib;
7. The subject is ≥ 18 years old on the day of consent;

8. Life expectancy of greater than 3 months.
9. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1;
10. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior 
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy;
11. The subject has organ and marrow function and laboratory values as follows within 
7 days before the first dose of cabozantinib:
a.
The ANC ≥ 1000/mm3 without colony stimulating factor support;
b. Platelets ≥ 100,000/mm3;
c.
Hemoglobin ≥ 9 g/dL;
d. Bilirubin ≤ 1.5  the ULN. For subjects with known Gilbert’s disease, bilirubin 
≤ 3.0 mg/dL;
e.
Serum albumin ≥ 2.8 g/dl;
f.
Serum creatinine ≤ 1.5  ULN or creatinine clearance (CrCl) ≥ 40 mL/min. For 
creatinine clearance estimation, the Cockcroft and Gault equation should be used:
i.
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72);
ii.
Female: Multiply above result by 0.85;
g. ALT and AST ≤ 2.0  ULN;
h. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical evidence of 
pancreatitis;
i.
UPCR ≤ 1;
j.
Serum phosphorus, calcium, magnesium and potassium ≥ LLN.
12. The subject is capable of understanding and complying with the protocol requirements 
and has signed the informed consent document;

13. Sexually active subjects (men and women) must agree to use medically accepted barrier 
methods of contraception (eg, male or female condom) during the course of the study and 
for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. 
All subjects of reproductive potential must agree to use both a barrier method and a 
second method of birth control during the course of the study and for 4 months after the 
last dose of study drug(s);
14. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming 
pregnant (ie, females who have had any evidence of menses in the past 12 months, with 
the exception of those who had prior hysterectomy). However, women who have been 
amenorrheic for 12 or more months are still considered to be of childbearing potential if 
the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, 
ovarian suppression or other reasons.
15. A male participant must agree to use a contraception as detailed in this protocol during the treatment period 
and for at least during the active treatment plus an additional 90 days (a spermatogenesis cycle) for study 
treatments with evidence of genotoxicity at any dose] after the last dose of study treatment and refrain from 
donating sperm during this period.
o Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study:
1. Patients who have HPV negative squamous cell carcinoma of unknown primary in 
cervical lymph node.
2. The subject has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 4 weeks, or 
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment;
3. Prior treatment with cabozantinib or pembrolizumab; or any prior immunotherapy for 
treating squamous cell carcinoma of the head and neck;
4. Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Systemic treatment with 
radionuclides within 6 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not eligible;

5. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 14 days before the first dose of study treatment;
6. The subject has received any other type of investigational agent within 28 days or 5 half-
lives, whichever is shorter, before the first dose of study treatment;
7. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks 
before the first dose of study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time of the start of study 
treatment;
8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test 
≥ 1.3  the laboratory ULN within 7 days before the first dose of study treatment;
9. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, 
direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel); 
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose 
warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are 
permitted.  Anticoagulation with therapeutic doses of LMWH is allowed in subjects who 
are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, 
and who have had no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor. 
10. The subject has experienced any of the following:
a.
clinically-significant GI bleeding within 6 months before the first dose of study 
treatment;
b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first 
dose of study treatment;
c.
any other signs indicative of pulmonary hemorrhage within 3 months before the 
first dose of study treatment.
11. The subject has radiographic evidence of cavitating pulmonary lesion(s);
12. The subject has tumor invading or encasing any major blood vessels;

13. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib;
14. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions:
a.
Cardiovascular disorders including:
i.
Congestive heart failure (CHF): New York Heart Association (NYHA) 
Class III (moderate) or Class IV (severe) at the time of screening;
ii.
Concurrent uncontrolled hypertension defined as sustained blood pressure 
(BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days of the first dose of study 
treatment;
iii.
Any history of congenital long QT syndrome;
iv.
Any of the following within 6 months before the first dose of study 
treatment:

unstable angina pectoris;

clinically-significant cardiac arrhythmias;

stroke (including transient ischemic attack (TIA), or other ischemic 
event);

myocardial infarction;
b. GI disorders particularly those associated with a high risk of perforation or fistula 
formation including:
i.
Tumors invading the GI tract, active peptic ulcer disease, inflammatory 
bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis or acute 
obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction

ii.
Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal 
abscess within 6 months before randomization, 
Note: Complete healing of an intra-abdominal abscess must be confirmed 
prior to randomization. Also no pre-existing fistula of head and neck area. 
No pre-existing ONJ.
c.
Other clinically significant disorders that would preclude safe study participation;
15. Major surgery within 12 weeks before the first dose of study treatment. Complete wound 
healing from major surgery must have occurred 1 month before the first dose of study 
treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days 
before the first dose of study treatment with complete wound healing at least 10 days 
before the first dose of study treatment. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible;
16. QTcF > 500 msec within 1 month before the first dose of study treatment:
a.
Three ECGs must be performed for eligibility determination. If the average of 
these three consecutive results for QTcF is ≤ 500 msec, the subject meets 
eligibility in this regard.
17. Pregnant or lactating females;
18. Inability to swallow intact tablets or inability to take pembrolizumab or cabozantinib 
19. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations;
20. Patients with a history of other prior malignancy must have been treated with curative 
intent and must have remained disease-free for 1 year post diagnosis. Patients with a prior 
history of squamous cell or basal carcinoma of the skin or in situ cervical cancer must have 
been curatively treated. 
21. Patients with known history of interstitial lung disease or idiopathic pneumonitis. 
16. STUDY ASSESSMENTS AND PROCEDURES
o Pre-Treatment Period
During the Pre-Treatment Period, subjects are consented and qualified (screened) for the study. 
Informed consent must be obtained before initiation of any clinical screening procedure that is 

performed solely for the purpose of determining eligibility for this study. Evaluations performed 
as part of routine care before informed consent can be considered as screening evaluations if 
done within the defined screening period, and if permitted by the site’s institutional review board 
(IRB)/ethics committee (EC) policies. 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening and on Study Day 1 before study treatment administration. The following 
assessments will be conducted before subjects receiving their first dose of cabozantinib on this 
protocol:

History and physical

ECOG performance status

Tumor measurement

Blood analysis: CBC and differential, blood chemistries, blood or urine pregnancy test if 
appropriate

Urine analysis, liver function tests

Tumor biopsy (fresh biopsy if paraffin blocks are not available); If tumor blocks cannot be 
provided 20 unstained slides are requested; if 20 slides cannot be provided due to tumor 
sample size a minimum of 10 unstained slides are required; 

Blood sample for research purposes

Radiology: CT scan of neck, chest, abdomen, pelvis
For each subject, the Pre-Treatment Period ends upon receipt of the first dose of study treatment 
or final determination that the subject is ineligible for the study.
o Treatment Period 
During the Treatment Period subjects will receive cabozantinib with pembrolizumab until either 
disease progression, the occurrence of unacceptable drug-related toxicity or for other reason(s) 
for subject withdrawal as described in Section 2.6. Subjects should be instructed to immediately 
inform the principal investigator (PI) of any AEs. Subjects experiencing dizziness, sleepiness, or 
other symptoms that could influence alertness or coordination should be advised not to drive or 
operate other heavy machinery.

The following schedule of assessments applies to all subjects 

Table 5-1). More frequent assessments should be obtained if clinically indicated.

Table 16-1:
Study Assessments
Study Treatment Period
Post-Treatment Period
Testa
Pre-therapy
(Day -14
to 0)
Day 1 of each cycle 
(21 days) while on 
study drugsn
30 - 37 Days 
after last dose
At one year b
End of 
follow up at 
2 years b
History and Physical
X
X
X (and every 3 
months)b
X
X
Weight and ECOG PS
X
X
X (and every 3 
months)b
X
X
Tumor Measurement
Xa
X (every 9 weeks)
X m
CBC and diff d
X
Xc
X (and after 3 
months)
X
X
Chemistries (Na, CL, CO2, K, BUN, blood glucosee  
Creatinine, Ca, Mg, Phos), Urine analysis
X
Xc,e
X (and after 3 
months)
X
X
Liver function panelf
X
Xc
X (and every 3 
months)
X
X
PT, PTT, INR
X
Xc
X
X
TSH
X
Xc
X (and every 3 
months)
X
X
12-lead ECG
XL
XL
Tissue for Research Purposes (paraffin embedded)g
X
Blood for Research Purposes
Xk
Toxicity Assessmenth
X
X
Radiology: CT-neck, chest, abdomen, and pelvis for 
tumor measurementsi
X
X (every 9 weeks)
X
Blood or Urine B-HCGj
X
a.a range of 4 days before or after the scheduled scans and screening tests is allowed – for scans , a 28 days period is allowed to obtain scans before initiation of therapy) 
b. Once the patient has fully recovered from the study drug-related toxicities or the patient enrolls in a hospice, the follow up can be done by a phone call if the patient is off the study 
drugs.
c Laboratory testing will be performed every 3 weeks for the first 9 weeks followed by assessments every 6 weeks. CBC with diff, liver function panel and blood chemistries 
(excluding T3, T4, TSH, GGT, LDH, Amylase, Lipase; PT, PTT/INR)  will continue to be done every 3 weeks with each new cycle following the first 9 weeks of therapy. 
d. CBC and diff includes: WBC, ANC, HCT, HGB, PLT, % lymphocytes, % monocytes, % neutrophils, other Differential (labs need to be done within 7 days of start of therapy)
sea
e. GGT, Amylase, Lipase, LDH can be performed every 3 cycles 
f. Liver function panel includes: Alk Phos, Total Bilirubin, SGOT (AST), SGPT (ALT), Total Protein.(Labs need to done within 7 days of start of therapy) 
g. If tumor paraffin blocks are not available, fresh biopsy will be obtained before the first treatment. If fresh biopsy is indicated, one core (or punch) will be collected in formalin and the 
second core (or punch) will be collected in liquid nitrogen. Optional end of treatment tumor biopsy (or at the time of progression) is allowed at Emory University and Moffitt Cancer 
Center. If fresh biopsy is indicated, one core (or punch) will be collected in formalin and the second core (or punch) will be collected in liquid nitrogen.
       
       

h. Toxicity assessment: Common Toxicity Criteria (CTC) version 4.0 will be used. All toxicity grades (including grade 1) should be captured on the case report forms.  All toxicities that 
occurred during treatment should be followed until resolution.    
    
i Tumor measurement: The same type of scan should be used for repeat measurements. (CT, MRI or PET/CT are acceptable) ; A PET CT can be exchangeable with a CT scan for the 
purpose of tumor measurements ; A CT of the pelvis at screening can be omitted if a prior PET CT scan does not show pelvic involvement within 3 months from enrollment; CT scans 
(tumor measurements)  during treatment (i.e. after baseline) should be obtained every 9 weeks from C1D1
j. Pregnancy test should be done in woman of child bearing age who are sexually active and may potentially be pregnant. Prior to study enrollment, women of childbearing potential 
(WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy.  In addition, men enrolled on 
this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. All WOCBP MUST have a negative 
pregnancy test within 7 days prior to first receiving investigational product.  If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled 
in the study. In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any 
time during study participation. 
k Blood for research before therapy, 9 weeks into therapy, at 6 months, and end of treatment (or at the time of progression whichever is sooner). 
LScreening EKG in triplicate at eligibility. On treatment routine EKGs at each cycle for 3 cycles, and then every 9 weeks thereafter
M Only for select patients who have lack of prior progression at one year 
N- A 2 days window for infusion of Pembrolizumab is allowed for logistic reasons- Every effort should be made to avoid interruption in Cabozantinib administration as a result of changes 
in Pembrolizumab schedule.  A 2 day window for clinical labs and history & physical is also allowed for logistical reasons.

If the subject is unable to have a study assessment taken within the defined time window due to 
an event outside of his or her control (eg, clinic closure, personal emergency, inclement weather, 
vacation), the assessment should be performed as close as possible to the required schedule. 
Regular tumor assessments should be performed in accordance to the guidelines in Section o to 
determine if PD is present. 
The Treatment Period ends when a subject receives his or her last dose of study treatment; the 
subject then enters the Post-Treatment Period.
o Post-Treatment and End on Treatment Period
Subjects will return to the study site 30 to 37 days after their last dose of cabozantinib, 
pembrolizumab or both to complete end-of-study assessments.
At the end of 24 months of treatment on the combination of pembrolizumab and cabozantinib, 
patients who are in continued response and who in the opinion of the investigators can continue 
to benefit from therapy will be given the options of either terminating therapy, or continuing on 
the combination with the use of the EASE program overlooked by Exelixis ; This program will 
provide commercial cabozantinib to patients who wish to continue therapy for an additional 12 
months of treatment; patients who continue on the EASE program will be followed as per 
standard of care at the respective institutions. 
Laboratory and physical examinations will be performed. Remaining study treatment will be 
returned by the subject, and treatment compliance will be documented. Additional follow-up will 
occur for subjects with AEs related to study treatment that are ongoing at the time of this visit, 
and for subjects with SAEs related to study treatment that occur after the time of this visit.

o Laboratory Assessments
Laboratory panels are composed of the following: 
Hematology

WBC count with 
differential (including at 
minimum: neutrophils, 
basophils, eosinophils, 
lymphocytes, 
monocytes)

hematocrit

platelet count

RBC count

hemoglobin

ESR

reticulocytes
Serum chemistry

albumin

ALP

amylase

ALT

AST

bicarbonate

BUN

chloride

creatinine

GGT

Glucose 

ionized calcium or
total and corrected 
calcium

lactate dehydrogenase 

lipase

magnesium

phosphorus

potassium

sodium

total bilirubin

total protein
Urinalysis

appearance

color

pH

specific gravity

ketones

protein

UPCR

Glucose

bilirubin

nitrite

creatinine

urobilinogen

occult blood 
(microscopic 
examination of 
sediment will be 
performed only if the 
results of the urinalysis 
dipstick evaluation are 
positive)
Other

TSH, Free T3 and T4

Pregnancy text (urine or 
serum) for women of 
child-bearing potential

Blood for research 
studies

PT/INR or PTT

24 hour urine collection 
for protein
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; ESR, 
erythrocyte sedimentation rate ; GGT, -glutamyltransferase; INR, International Normalized Ratio; PT, prothrombin time; PTT 
partial thromboplastin time; RBC, red blood cell; TSH, thyroid stimulating hormone; UPCR, urine protein/creatinine ratio; WBC, 
white blood cell.
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, dose 
delayed [withheld] or reduced, requirement for additional medication, treatment or monitoring) 

are considered clinically significant for the purposes of this study, and will be recorded on the 
Adverse Events Case Report Form (CRF). If laboratory values constitute part of an event that 
meets criteria defining it as serious, the event (and associated laboratory values) must be reported 
as an SAE.
o Tumor Assessment
Response Criteria (RECIST 1.1)
For subjects who have measurable disease at baseline, this is a summary of overall response 
status calculation. 
Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target 
lesions, taking as reference the baseline sum LD
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum of the LD recorded since the treatment started or the appearance of 
one or more new lesions
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator).

17. SAFETY
o
Adverse Events and Laboratory Abnormalities

Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been enrolled in a clinical study and who may have been given an investigational product, 
regardless of whether or not the event is assessed as related to the study treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, regardless 
of whether or not the event is assessed as related to the investigational product. Pre-existing 
medical conditions that worsen during a study should be recorded as AEs. Abnormal laboratory 
values, ECG findings, or vital signs are to be recorded as AEs if they meet the criteria described 
in Section 3.3.
All untoward events that occur after informed consent through 30 days after the decision to 
discontinue study treatment (or the date the subject is deemed to be a screen failure) are to be 
recorded by the investigational site. This requirement includes AEs from unscheduled as well as 
scheduled visits.
Assessment of the relationship of the AE to the study treatment by the investigator is based on 
the following two definitions:

Not Related: A not-related AE is defined as an AE that is not associated with the study 
treatment and is attributable to another cause or there is no evidence to support a causal 
relationship;

Related: A related AE is defined as an AE where a causal relationship between the event 
and the study treatment is a reasonable possibility. A reasonable causal relationship is 
meant to convey that there are facts (eg, evidence such as dechallenge/rechallenge) or 
other clinical arguments to suggest a causal relationship between the AE and study 
treatment.

Serious Adverse Events 
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Topic E2A.
An SAE is defined as any untoward medical occurrence that at any dose: 


Result in death;

Is immediately life-threatening (ie, in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death);

Requires inpatient hospitalization or results in prolongation of an existing hospitalization;

Results in persistent or significant disability or incapacity:
o
Note: The term “disability” refers to events that result in a substantial disruption 
of a subject’s ability to conduct normal life function.

Is a congenital anomaly or birth defect;

Is an important medical event (IME): 
o
Note: The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, may not be immediately life-threatening or result 
in death or hospitalization, but may jeopardize the subject or require intervention 
to prevent one of the other serious outcomes listed under the definition of SAE. 
Examples of IMEs include intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of product dependency or product abuse.

Serious Adverse Event Reporting
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
should be documented to the extent that information is available.

Investigator shall notify sponsor within twenty-four (24) hours of making such discovery 
by submitting a completed SAE report form and any other pertinent SAE information as 
indicated on the SAE reporting form;

Written IND safety reports will be submitted to the FDA by the IND sponsor, for serious, 
unexpected suspected adverse reactions within 15 calendar days of learning of its 
occurrence. If the event is fatal or is deemed to be life threatening, the report will be 
made within 7 calendar days.  The IND sponsor will also make an assessment of whether 
the event constitutes an unanticipated problem posing risks to subjects or others (UP). 
This assessment will be provided to the Emory University IRB, which, in turn will make 

a final determination.  If the Emory IRB determines an event is a UP it will notify the 
appropriate regulatory agencies and institutional officials.

For multicenter studies the Investigator must notify the IND/CTA Sponsor by submitting 
a completed SAE report form and any other pertinent SAE information as indicated on 
the SAE reporting form within 24 hours to allow the IND/CTA Sponsor to submit the 
SAE report form to Exelixis no later than 2 business days.

This report must be submitted by sponsor to Exelixis at e-mail: drugsafety@exelixis.com 
or fax 650-837-7392, even if it is not felt to be drug related;

Pregnancy (for a subject or for the partner of a subject), although not itself an SAE, 
should also be reported on a pregnancy form and be followed up to determine outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities;

SAEs that must be recorded on an SAE Reporting form include the following:
o
all SAEs that occur after informed consent and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen 
failure);
o
any SAEs assessed as related to study treatment or study procedures, even if the 
SAE occurs more than 30 days after the decision to discontinue study treatment;
o
although most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or previously 
scheduled surgeries or procedures for pre-existing conditions that have not 
worsened after initiation of treatment (eg, a previously scheduled ventral hernia 
repair); pre-specified study hospitalizations for observation; or events that result 
in hospital stays of fewer than 24 hours and that do not require admission (eg, an 
emergency room visit for hematuria that results in a diagnosis of cystitis and 
discharge to home on oral antibiotics). SAEs must, however, be reported for any 
surgical or procedural complication resulting in prolongation of the 
hospitalization.


Regulatory Reporting
All serious unexpected adverse drug reactions (unexpected related SAEs) must be reported to all 
appropriate regulatory authorities, Emory IRB, and Ethics Committees by the investigator as 
required by 21 CFR 312.32 or by Directive 2011/20/EC:

These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) or a 
CIOMS-1 form;

The final MedWatch Form or CIOMS-1 form must be submitted by the sponsor to 
Exelixis within one to two business days of submission to the FDA or applicable 
regulatory agency (including confirmation of date that the report was submitted) to allow 
Exelixis time to cross-report to Exelixis’ IND. E-mail: drugsafety@exelixis.com; Fax 
650-837-7392.

Exelixis reserves the right to upgrade the Investigator assessment of an SAE based on 
Sponsor reporting responsibilities.
o Other Safety Considerations

Laboratory Data
All laboratory data required by this protocol and any other clinical investigations should be 
reviewed. Any abnormal value that leads to a change in subject management (eg, dose reduction 
or delay or requirement for additional medication or monitoring) or that is considered to be of 
clinical significance by the investigator should be reported as an AE or SAE as appropriate.

Pregnancy
If a subject becomes pregnant during the study, she will be taken off study treatment and will be 
followed through the end of her pregnancy. The investigator must inform the Sponsor of the 
pregnancy. Forms for reporting pregnancies will be provided to the study sites upon request. The 
outcome of a pregnancy (for a subject or for the partner of a subject) and the medical condition 
of any resultant offspring must be reported to Exelixis or designee. Any birth defect or 
congenital anomaly must be reported as an SAE, and any other untoward events occurring during 
the pregnancy must be reported as AEs or SAEs, as appropriate.

Medication Errors/Overdose
Any study drug administration error or overdose that results in an AE, even if it does not meet 
the definition of serious, requires reporting within 24 hours to Exelixis or designee.


Follow-Up of Adverse Events
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after 
the decision to discontinue study treatment must be followed until either resolution of the event 
or determination by the investigator that the event has become stable or irreversible. This follow-
up guidance also applies to related SAEs that occur > 30 days after the decision to discontinue 
study treatment. The status of all other continuing AEs will be documented as of 30 days after 
the decision to discontinue study treatment.
18. STATISTICAL CONSIDERATIONS
o Analysis Population

Safety Population
The safety population will consist of all subjects who receive any amount of study treatment.
o Safety Analysis
Safety will be assessed by evaluation of AEs. All safety analyses will be performed using the 
safety population.

Adverse Events
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and relationship to 
study treatment will be assessed by the investigator. Severity grade will be defined by the 
National Cancer Institute (NCI) CTCAE v4.0. Listings of AEs will be provided. 
o Sample Size
The sample size will be up to 34 evaluable subjects in which the first 6 patients will be in the 
safety run-in phase with an interim futility assessment after 20 patients were treated. 
(Evaluable subjects based on the primary endpoint are defined as subjects who received therapy 
on study and had at least one follow up scan after initiation of study treatment)
The ORR for this patient population is reported as 18% with pembrolizumab as a single agent. 
We estimate that the ORR will improve to about 35% with the combined treatment. We expect to 
accrue patients for 2 years and follow up for additional 12 months. The sample size will be 34 by 
a one-arm design with null hypothesis as ORR <=0.15 vs. its one-sided alternative. If the number 
of responses is <= 9 out of 34, the trial will be claimed as not promising.  The design yields a 
type 1 error of 0.05 and a power of 80% when the true response rate is 35%. An interim look 
after 20 patients will take place, and if <= 4 responses are observed, the trial will stop earlier and 
claim a futility.

Statistical analysis for biomarker studies: The ORR will be calculated with 95% confidence 
interval by Binomial distribution. The median PFS will be estimated by Kaplan-Meier method 
along with 95% confidence interval. The ability of biomarkers to predict ORR will be estimated 
by Chi-square test and/or logistic regression model, and association with PFS will be assessed by 
the Kaplan Meier method, Log-rank test, and Cox model, and the frequency of adverse events 
and serious adverse events will be summarized accordingly. The performance of predictability of 
biomarker for clinical outcomes will be described by AUC for binary outcome ORR and Uno’s 
C-statistics for PFS with 95% CI and ranked accordingly.
19. OTHER ANALYSES
Tumor samples will be collected from all patients through archival tissue or biopsies performed 
from at least one site of disease prior to the first dose administration of therapy. Tumor samples 
collected through these biopsies will be compared with the historical samples and will also be 
analyzed to explore the biomarkers that could predict response to cabozantinib. Optional end of 
treatment tumor biopsy (or at the time of progression) is allowed at both Emory Winship Cancer 
Institute and Moffitt Cancer Center.
Baseline biopsies or surgical specimens from trial participants will be analyzed for the following:

Tumor pVEGFR2/VEGFR2, pMet/Met, pSTAT3/STAT3, and PD-L1 protein expression 
as well as markers of hypoxia, antigen presenting cells, T cells, and B cells among the 
Tumor infiltrating immune cells using multiplex immunohistochemistry (IHC). 

Tumor DNA whole exome sequencing and RNA sequencing to determine potential 
neoantigens and their expression. 
Blood samples will be collected at screening, at 9 weeks on treatment, at 6 months on treatment, 
and end of treatment (or disease progression whichever is sooner).  

Plasma biomarkers will include HGF, IL-6, IL-8, VEGF, and IFN-γ determined by 
ELISA analyses. 

Circulating cell free DNA (cfDNA) in plasma will be determined by DNA sequencing.

Peripheral blood mononuclear cells (PBMC) will be evaluated by flow cytometry for 
immune monitoring.
For detailed tissue collection and processing information, please see LAB MANUAL. 
 
20. DATA QUALITY ASSURANCE
Accurate and reliable data collection will be ensured by verification and crosscheck of the CRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug–dispensing log by the investigator.

OnCore: The clinical management system being used for this study is The Online Collaborative 
Research Environment (OnCore). OnCore will be used to record all study related information for 
all registered subjects, including their assigned patient ID and assigned dose cohort. All data 
must be entered no later than 30 days following registration and each visit completion. All 
queries are to be resolved within 4 weeks of issue. The Multi Site Coordinator (MSC) will 
provide OnCore training and request access to the appropriate staff at the participating site.
21. STUDY COMMITTEES
This study will be under the purview of the Winship Data and Safety Monitoring Committee 
(DSMC). The committee monitors the research charts of patients enrolled to all investigator-
initiated studies at the Winship Cancer Institute (Winship DSMC will only monitor Emory 
patients). Approximately 10% of charts are reviewed on these studies. The monitoring report will 
be reviewed by the DSMC and will be forwarded to the sponsor. Audits/inspections may also be 
conducted by the FDA in the case of studies using drugs covered by an IND or devices covered 
by an IDE. 
The DSMC reports, and recommends corrective action if needed, to the PI. The Monitoring 
Committee may initiate an external audit of any trial at any time if it determines such action to be 
necessary. The Monitoring Committee will review all internally audited trials annually. The 
Monitoring Committee is responsible for oversight. If deficiencies are discovered during the 
annual review, the Monitoring Committee will first inform the PI. If the deficiencies cannot be 
corrected, the Monitoring Committee will involve the PI’s direct supervisor and may refer the 
protocol to the Medical Director for corrective action including possible termination of the trial. 
The Medical Director has the authority to terminate trials for cause.
The Data and Safety Monitoring Committee (DSMC) of the Winship Cancer Institute will 
provide oversight for the conduct of this study.  The DSMC functions independently within 
Winship Cancer Institute to conduct internal monitoring functions to ensure that research being 
conducted by Winship Cancer Institute Investigators produces high-quality scientific data in a 
manner consistent with good clinical practice (GCP) and appropriate regulations that govern 
clinical research.    Depending on the risk level of the protocol, the DSMC review may occur 
every 6 months or annually.  For studies deemed High Risk, initial study monitoring will occur 
within 6 months from the date of the first subject accrued, with 2 of the first 5 subjects being 
reviewed.  For studies deemed Moderate Risk, initial study monitoring will occur within 1 year 
from the date of the first subject accrued, with 2 of the first 5 subjects being reviewed.  

Subsequent monitoring will occur in routine intervals per the Winship Data and Safety 
Monitoring Plan (DSMP). 
The DSMC will review pertinent aspects of the study to assess subject safety, compliance with 
the protocol, data collection, and risk-benefit ratio. Specifically, the Winship Cancer Institute 
Internal Monitors assigned to the DSMC may verify informed consent, eligibility, data entry, 
accuracy and availability of source documents, AEs/SAEs, and essential regulatory documents.  
Following the monitoring review, monitors will provide a preliminary report of monitoring 
findings to the PI and other pertinent individuals involved in the conduct of the study.  The PI is 
required to address and respond to all the deficiencies noted in the preliminary report.  Prior to 
the completion of the final summary report, monitors will discuss the preliminary report 
responses with the PI and other team members (when appropriate).  A final monitoring summary 
report will then be prepared by the monitor.  Final DSMC review will include the final 
monitoring summary report with corresponding PI response, submitted CAPA (when applicable), 
PI Summary statement, and available aggregate toxicity and safety data.  
The DSMC will render a recommendation and rating based on the overall trial conduct.  The PI 
is responsible for ensuring that instances of egregious data insufficiencies are reported to the 
IRB.  Continuing Review submissions will include the DSMC recommendation letter.  Should 
any revisions be made to the protocol-specific monitoring plan after initial DSMC approval, the 
PI will be responsible for notifying the DSMC of such changes.  The Committee reserves the 
right to conduct additional audits if necessary.
22. ETHICAL ASPECTS
o Local Regulations
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct 
of the study complies with the basic principles of GCP as outlined in the current version of 
21 Code of Federal Regulations, subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators” Part 50, “Protection of Human Subjects” and Part 56, “Institutional Review 
Boards.”
o Informed Consent
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject participating in this study after adequate explanation 
of the aims, methods, anticipated benefits, and potential hazards of the study. In the case where 
the subject is unable to read, an impartial witness should be present during the entire informed 

consent discussion. After the subject has orally consented to participation in the trial, the 
witness’s signature on the form will attest that the information in the consent form was 
accurately explained and understood.
The CRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated as necessary. All 
subjects (including those already being treated) should be informed of the new information, 
should be given a copy of the revised form, and should give their consent to continue in the 
study.
o Institutional Review Board/Ethics Committee 
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The investigator will 
send a letter or certificate of IRB/EC approval to Exelixis (or designee) before subject enrollment 
and whenever subsequent modifications to the protocol are made.
o Future Use of Patient Samples
Tumor and blood samples will be collected from all patients and used for biomarker studies. 
Unused samples will be stored in the Winship tissue bank with consent from participants.
23. CONDITIONS FOR MODIFYING THE PROTOCOL
Protocol modifications may be made and will be prepared, reviewed, and approved by 
representatives of the sponsor.
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (eg, change in monitor or change of telephone number).
24. CONDITIONS FOR TERMINATING THE STUDY
Exelixis reserves the right to terminate the study, and investigators reserve the right to terminate 
their participation in the study, at any time. Should this be necessary, Exelixis and the 
investigator will arrange the procedures on an individual study basis after review and 

consultation. In terminating the study, Exelixis and the investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interests.
25. STUDY DOCUMENTATION AND RECORDKEEPING
o Investigator’s Files and Retention of Documents
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) the investigator’s study file, and 
(2) subjects’ clinical source documents.
The investigator’s study file will contain the protocol and protocol amendments, CRFs, query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence.
Subjects’ clinical source documents include the subjects’ hospital/clinic records; physicians’ and 
nurses’ notes; original laboratory, ECG, electroencephalogram, X-ray, pathology and special 
assessment reports; signed informed consent forms; consultant letters; and subject screening and 
enrollment logs. 
The investigator must keep these two categories of documents on file for at least the latest of 
2 years following the marketing application approval date for the study treatment in the 
indication being investigated, 2 years after the investigation is completed or discontinued, or for 
a time consistent with local regulatory requirements. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Exelixis. If the 
investigator wants to assign the study records to another party or move them to another location, 
Exelixis must be notified in advance.
If the investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Exelixis to store 
these in a sealed container outside of the study site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site.
o Source Documents and Background Data
Upon request, the investigator will supply its licensees and collaborators with any required 
background data from the study documentation or clinic records. This is particularly important 

when CRFs are illegible or when errors in data transcription are suspected. In case of special 
problems or governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that subject confidentiality is protected.
o Audits and Inspections
The investigator should understand that source documents for this study should be made 
available, after appropriate notification, to qualified personnel from the Exelixis Quality 
Assurance Unit (or designee) or to health authority inspectors. The verification of the CRF data 
must be by direct inspection of source documents.
o Case Report Forms 
For enrolled subjects, all and only data from the procedures and assessments specified in this 
protocol and required by the CRFs should be entered on the appropriate CRF. Data from some 
procedures required by the protocol, such as physical examinations and laboratory results, will 
be recorded only on the source documents and will not be transcribed to CRFs. Additional 
procedures and assessments may be performed as part of the investigator’s institution or medical 
practice standard of care and may not be required for CRF entry. 
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI 
or authorized delegate from the study staff.
All paper forms should be typed or filled out using indelible ink and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed and 
dated by the investigator or his or her authorized delegate. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
in the CRFs and in all required reports.
26. MONITORING THE STUDY
Winship internal monitors will monitor the Emory sites and the Multi-site coordinator will 
monitor all other non-Emory sites. 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
study, according to the DSMP, to verify both adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them. The monitor should have access to 
laboratory test reports and other subject records needed to verify the entries on the CRF. The 
investigator (or designee) must agree to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved.

The Emory Winship Cancer Institute (Winship) clinical trial office will serve as the coordinating 
center for this study. The sponsor will review responses and toxicity and report these to the 
regularly scheduled meetings of the DSMC of the Emory Winship Cancer Institute. Each 
participating site is expected to have its own data monitoring and safety plan (DMSP) with 
regard to forwarding information to their IRBs. If the data reveals a change in the risk/benefit 
ratio, the investigator will notify the IRB and the PI.
The PI and co-investigators will review the data and forward any changes or protocol 
amendments to the IRBs. All serious adverse events will be reported immediately to the IRB. All 
study participant information will be kept in a confidential manner by the assigning of a random 
number to each study participant. All data will be kept confidential as per institutional guidelines 
and policies. Any breach of confidentiality is a serious matter and conflicts with institutional 
policies and will be reported to the IRB. A cumulative summary of all adverse events occurring 
on this study and a report of the data safety and monitoring plan will be submitted to the IRBs 
with the annual renewal reports.
Monitoring plan of Subsite(s): 
At the time of study initiation at a non-Emory site, the Emory Sponsor, Winship regulatory 
specialist, and Winship research coordinators will perform a site initiation teleconference. 
During this teleconference, the Emory team will review the study, enrollment, reporting, and 
regulatory compliance. The participating site will have internal monitoring meetings. These 
meetings, which will include the participating site investigator, the clinical research coordinator 
and the regulatory affairs coordinator, will meet at least on a monthly basis to review and discuss 
study data to ensure subject safety. The research coordinators will maintain a spreadsheet, which 
will be de-identified and will summarize all the patient data for subjects actively being treated on 
the trial as well as a roadmap detailing pending tests/treatments for each individual subject. The 
spreadsheet will be shared with the Emory PI via e-mail monthly. Teleconferences will be 
conducted weekly between the PI at Emory and the research team at the participating site(s). The 
purpose of the meetings is to discuss the enrollment, regulatory updates, monitor toxicities, and 
evaluate the progress of the trial. A record of the teleconferences will be kept in the regulatory 
binder. Scheduled teleconferences may stop after all patients have completed assigned protocol 
therapy and the PI at Emory will communicate with participating sites via email as needed. This 
communication will also be maintained in the regulatory binder. Chart reviews will be performed 
on selected cases by the participating site staff to confirm that the data collection is accurate.

Winship’s MSC will perform an on-site or remote monitoring visit within the first three months 
of enrollment of the first subject. Quarterly monitoring visits will occur (annually once onsite 
and three times remotely) until subject follow-up is terminated. In situations where the one 
annual onsite monitoring visit cannot be completed at non-Emory sites due to institutional 
restrictions, the visit will still occur, however, it will be completed remotely.  Monthly reviews 
of data in OnCore will be conducted to ensure compliance or identify discrepancies.  
27. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS
The investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents, subjects should be 
identified by identification codes and not by their names. The investigator should keep a subject 
enrollment log showing codes, names, and addresses. The investigator should maintain 
documents not for submission to Exelixis or designees (eg, subjects’ written consent forms) in 
strict confidence.
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review.
28. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide any such publication to Exelixis, Inc. for review 
at least sixty (60) days before submission and also comply with any provisions regarding 
publication that are agreed to between the PI’s institution (eg, institution name.) and Exelixis, 
Inc. in the Clinical Trial Agreement related to this study. The results will be made public within 
24 months of the end of data collection. However, if a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. In any event, a full report of the outcomes 
should be made public no later than three (3) years after the end of data collection. Authorship 
for abstracts and manuscripts resulting from this study will be determined in accordance to 
guidelines established by the International Committee of Medical Journal Editors.

29. REFERENCES
1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29. Epub 2014/01/09.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015;65(1):5-29.
3. Chung CH, Guthrie VB, Masica DL, Tokheim C, Kang H, Richmon J, et al. Genomic alterations in head and neck 
squamous cell carcinoma determined by cancer gene-targeted sequencing. Annals of oncology : official journal of the 
European Society for Medical Oncology / ESMO. 2015.
4. Saba NF, Khuri FR. Optimizing systemic therapy in squamous cell carcinoma of the head and neck with a focus on 
targeted agents. Current opinion in oncology. 2009;21(3):232-7.
5. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber RS, Morrison W, et al. Concurrent Chemotherapy and 
Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. The New England Journal of Medicine. 
2003;349(22):2091-8.
6. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent 
radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 
2004;350(19):1937-44.
7. Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, et al. Cisplatin and fluorouracil 
alone or with docetaxel in head and neck cancer. N Engl J Med. 2007;357(17):1705-15. Epub 2007/10/26.
8. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, et al. Human papillomavirus and survival of 
patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35. Epub 2010/06/10.
9. Ang MK, Patel MR, Yin XY, Sundaram S, Fritchie K, Zhao N, et al. High XRCC1 protein expression is associated 
with poorer survival in patients with head and neck squamous cell carcinoma. Clinical cancer research : an official 
journal of the American Association for Cancer Research. 2011;17(20):6542-52. Epub 2011/09/13.
10.
Urba SG, Forastiere AA. Systemic therapy of head and neck cancer: most effective agents, areas of promise. 
Oncology (Huntington). 1989;3(4):79-88; discussion 
11.
Kies MS, Levitan N, Hong WK. Chemotherapy of head and neck cancer. Otolaryngologic Clinics of North 
America. 1985;18(3):533-41.
12.
Couteau C, Chouaki N, Leyvraz S, Oulid-Aissa D, Lebecq A, Domenge C, et al. A phase II study of 
docetaxel in patients with metastatic squamous cell carcinoma of the head and neck. Br J Cancer. 1999;81(3):457-62.
13.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy 
plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116-27. Epub 2008/09/12.
14.
Cohen EEW, Rosen F, Stadler WM, Recant W, Stenson K, Huo DZ, et al. Phase II trial of ZD1839 in 
recurrent or metastatic squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 
2003;21(10):1980-7.
15.
Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in 
development and cancer. The EMBO journal. 2000;19(13):3159-67. Epub 2000/07/06.
16.
Kim HH, Vijapurkar U, Hellyer NJ, Bravo D, Koland JG. Signal transduction by epidermal growth factor and 
heregulin via the kinase-deficient ErbB3 protein. The Biochemical journal. 1998;334 ( Pt 1):189-95. Epub 1998/08/07.
17.
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature reviews 
Cancer. 2005;5(5):341-54. Epub 2005/05/03.
18.
Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment 
of cancer. J Clin Oncol. 2003;21(14):2787-99. Epub 2003/07/16.
19.
Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: 
mechanisms of activation and signalling. Exp Cell Res. 2003;284(1):31-53.
20.
Noble ME, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure. 
Science. 2004;303(5665):1800-5.
21.
Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, et al. Epidermal growth factor 
receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res. 
2001;7(7):1850-5.
22.
Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 
1999;82(2-3):241-50.
23.
Chen Z, Ke LD, Yuan XH, Adler-Storthz K. Correlation of cisplatin sensitivity with differential alteration of 
EGFR expression in head and neck cancer cells. Anticancer Res. 2000;20(2A):899-902.

24.
D'Amico TA, Massey M, Herndon JE, 2nd, Moore MB, Harpole DH, Jr. A biologic risk model for stage I 
lung cancer: immunohistochemical analysis of 408 patients with the use of ten molecular markers. J Thorac Cardiovasc 
Surg. 1999;117(4):736-43.
25.
Scher HI, Sarkis A, Reuter V, Cohen D, Netto G, Petrylak D, et al. Changing pattern of expression of the 
epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms. Clin 
Cancer Res. 1995;1(5):545-50.
26.
Gorgoulis V, Aninos D, Mikou P, Kanavaros P, Karameris A, Joardanoglou J, et al. Expression of EGF, 
TGF-alpha and EGFR in squamous cell lung carcinomas. Anticancer Res. 1992;12(4):1183-7.
27.
al-Kasspooles M, Moore JH, Orringer MB, Beer DG. Amplification and over-expression of the EGFR and 
erbB-2 genes in human esophageal adenocarcinomas. Int J Cancer. 1993;54(2):213-9.
28.
Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor 
receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53(15):3579-
84.
29.
Grandis JR FD, Melhem MF, Gooding WE, Drenning SD, Morel PA. Human leukocyte antigen class I allelic 
and haplotype loss in squamous cell carcinoma of the head and neck: clinical and immunogenetic consequences. Clin 
Cancer Res. 2000;6(7):2794-802.
30.
Huang SM BJ, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, 
apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59(8):1935-40.
31.
Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by 
epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor 
monoclonal antibody. Proceedings of the National Academy of Sciences of the United States of America. 
1983;80(5):1337-41. Epub 1983/03/01.
32.
Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal 
antibodies to human epidermal growth factor receptors. Molecular biology & medicine. 1983;1(5):511-29. Epub 
1983/12/01.
33.
Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J. Growth inhibition of human tumor cells in 
athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer research. 1984;44(3):1002-7. 
Epub 1984/03/01.
34.
Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, et al. Monoclonal anti-epidermal growth factor 
receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor 
binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. The Journal of 
biological chemistry. 1984;259(12):7755-60. Epub 1984/06/25.
35.
Bonner JA, Harari PM, Giralt J. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and 
neck. . N Engl J Med 2006;354(6):567-78.
36.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy 
plus cetuximab in head and neck cancer. N Engl J Med 2008;Sep 11;359(11):1116-27.
37.
Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, uncontrolled, 
multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent 
and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(16):2171-7.
38.
Bardelli A, Janne PA. The road to resistance: EGFR mutation and cetuximab. Nature medicine. 
2012;18(2):199-200.
39.
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, et al. Identification of a mutation in 
the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal 
cancer. Nature medicine. 2012;18(2):221-3.
40.
Krumbach R, Schuler J, Hofmann M, Giesemann T, Fiebig HH, Beckers T. Primary resistance to cetuximab 
in a panel of patient-derived tumour xenograft models: activation of MET as one mechanism for drug resistance. 
European journal of cancer. 2011;47(8):1231-43.
41.
Wheeler SE, Suzuki S, Thomas SM, Sen M, Leeman-Neill RJ, Chiosea SI, et al. Epidermal growth factor 
receptor variant III mediates head and neck cancer cell invasion via STAT3 activation. Oncogene. 2010;29(37):5135-
45.
42.
Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment 
strategies. Nat Rev Clin Oncol. 2010;7(9):493-507.

43.
Hansen AR, Siu LL. Epidermal growth factor receptor targeting in head and neck cancer: have we been just 
skimming the surface? J Clin Oncol. 2013;31(11):1381-3.
44.
Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, et al. Mechanisms of 
acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 2008;Jun 26;27(28):3944-56 
45.
Lee JW, Soung YH, Kim SY, Nam HK, Park WS, Nam SW, et al. Somatic mutations of EGFR gene in 
squamous cell carcinoma of the head and neck. Clinical cancer research : an official journal of the American 
Association for Cancer Research. 2005;11(8):2879-82.
46.
Iglesias-Bartolome R, Martin D, Gutkind JS. Exploiting the Head and Neck Cancer Oncogenome: 
Widespread PI3K-mTOR Pathway Alterations and Novel Molecular Targets. Cancer discovery. 2013;3(7):722-5.
47.
Leeman RJ, Lui VW, Grandis JR. STAT3 as a therapeutic target in head and neck cancer. Expert opinion on 
biological therapy. 2006;6(3):231-41.
48.
Sen M, Thomas SM, Kim S, Yeh JI, Ferris RL, Johnson JT, et al. First-in-human trial of a STAT3 decoy 
oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer discovery. 2012;2(8):694-705.
49.
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nature reviews Molecular cell biology. 
2001;2(2):127-37.
50.
Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, et al. Mechanisms of 
acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27(28):3944-56.
51.
Vlacich G, Coffey RJ. Resistance to EGFR-targeted therapy: a family affair. Cancer cell. 2011;20(4):423-5.
52.
Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine 
kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445(7126):437-41.
53.
Jiang N, Saba NF, Chen ZG. Advances in Targeting HER3 as an Anticancer Therapy. Chemotherapy 
research and practice. 2012;2012:817304.
54.
Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, et al. An ErbB3 antibody, MM-121, is active 
in cancers with ligand-dependent activation. Cancer research. 2010;70(6):2485-94.
55.
Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, et al. An activated ErbB3/NRG1 autocrine loop 
supports in vivo proliferation in ovarian cancer cells. Cancer cell. 2010;17(3):298-310.
56.
Jiang N, Wang D, Hu Z, Shin HJ, Qian G, Rahman MA, et al. Combination of Anti-HER3 Antibody MM-
121/SAR256212 and Cetuximab Inhibits Tumor Growth in Preclinical Models of Head and Neck Squamous Cell 
Carcinoma. Mol Cancer Ther. 2014;April 18 PMID: 24748655.
57.
Qian G, Jiang N, Wang D, Newman S, Kim S, Chen Z, et al. Heregulin and HER3 are prognostic biomarkers 
in oropharyngeal squamous cell carcinoma. Cancer 2015;Oct 15;121(20):3600-11.
58.
Qian G, Jiang N, Wang D, Newman S, Kim S, Chen Z, et al. Heregulin and HER3 are prognostic biomarkers 
in oropharyngeal squamous cell carcinoma. Cancer 2015 Oct 15;121(20):3600-11. 2015.
59.
Sato Y, Yashiro M, N T. Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-
amplified cancer cells. Cancer Sci. 2013;Dec;104(12):1618-25. .
60.
Xia W, Petricoin EF 3rd, Zhao S, Liu L, Osada T, Cheng Q, et al. An heregulin-EGFR-HER3 autocrine 
signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res. 
2013;15(5):R85.
61.
Shames DS, Carbon J, Walter K, Jubb AM, Kozlowski C, Januario T, et al. High heregulin expression is 
associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of 
the head and neck. PLoS One 2013;8(2):e56765.
62.
Saba NF, Qian G, Ning J, Kim S, Chen Z, Garcia G, et al. Expressions of EGFR, HER2, and HER3 and their 
correlations with clinical characteristics in oropharyngeal squamous cell carcinoma (OPSCC). J Clin Oncol. 2014;Vol 
32, No 15_suppl (May 20 Supplement), 2014: 6068.
63.
Di Renzo MF, Narsimhan RP, Olivero M, Bretti S, Giordano S, Medico E, et al. Expression of the Met/HGF 
receptor in normal and
neoplastic human tissues. . Oncogene 1991;6; 1997–2003.
64.
Comoglio PM, C: B. The HGF receptor family: Unconventional signal transducers for invasive cell
growth. . Genes Cells 1996;1: 347–354, .
65.
PM: C. Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant
cells. Exs. 1993;65: 131–165, .
66.
Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic 
inhibition. Cancer metastasis reviews. 2003;22(4):309-25.

67.
Nisa L, Aebersold DM, Giger R, Zimmer Y, Medova M. Biological, diagnostic and therapeutic relevance of 
the MET receptor signaling in head and neck cancer. Pharmacology & therapeutics. 2014;143(3):337-49.
68.
Skead G, Govender D. Gene of the month: MET. Journal of clinical pathology. 2015;68(6):405-9.
69.
Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Therapeutic advances in medical 
oncology. 2011;3(1 Suppl):S7-S19.
70.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to 
gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039-43.
71.
Tanizaki J, Okamoto I, Sakai K, Nakagawa K. Differential roles of trans-phosphorylated EGFR, HER2, 
HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification. British journal of 
cancer. 2011;105(6):807-13.
72.
Yun C, Gang L, Rongmin G, Xu W, Xuezhi M, Huanqiu C. Essential role of Her3 in two signaling 
transduction patterns: Her2/Her3 and MET/Her3 in proliferation of human gastric cancer. Molecular carcinogenesis. 
2015;54(12):1700-9.
73.
Duh FM, Scherer SW, Tsui LC, Lerman MI, Zbar B, L S. Gene structure of the human MET protooncogene. 
Oncogene 1997;15: 1583–1586, .
74.
Liu Y. The human hepatocyte growth factor receptor gene: Complete structural organization and promoter
characterization. . Gene 1998;215: 159–169, .
75.
Seki T, Hagiya M, Shimonishi M, Nakamura T, Shimizu, Scherer SW. Organization of the human hepatocyte 
growth factorencoding gene. . Gene 1991;102: 213–219, .
76.
Mars WM, Zarnegar R, Michalopoulos GK. Activation
of hepatocyte growth factor by the plasminogen activators uPA and tPA. . Am J Pathol 1993;143: 949–958, .
77.
Ma PC, Tretiakova MS, MacKinnon AC, Ramnath N, Johnson C, Dietrich S, et al. Expression and mutational 
analysis of MET in human solid cancers. Genes Chromosomes Cancer. 2008;Dec;47(12):1025-37.
78.
Sattler M, Reddy MM, Hasina R, Gangadhar T, R. S. The role of the c-Met pathway in lung cancer and the 
potential for targeted therapy. Ther Adv Med Oncol 2011;Jul;3(4):171-84. .
79.
Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M, et al. The MET Receptor 
Tyrosine Kinase Is a Potential Novel Therapeutic Target for Head and Neck Squamous Cell Carcinoma. Cancer Res 
2009;69: (7). April 1,.
80.
Kwon MJ, Kim DH, Park HR, Shin HS, Kwon JH, Lee DJ, et al. Frequent hepatocyte growth factor 
overexpression and low frequency of c-Met gene amplification in human papillomavirus-negative tonsillar squamous 
cell carcinoma and their prognostic significances. Human Pathol 2014;Jul;45(7):1327-38.
81.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to 
gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;May 18;316(5827):1039-43.
82.
Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. Targeting MET as a strategy to overcome 
crosstalk-related resistance to EGFR inhibitors. The lancet oncology. 2009;10(7):709-17.
83.
Price KA, Cohen EE. Mechanisms of and therapeutic approaches for overcoming resistance to epidermal 
growth factor receptor (EGFR)-targeted therapy in squamous cell carcinoma of the head and neck (SCCHN). Oral 
oncology. 2015;51(5):399-408.
84.
Seiwert TY, Jagadeeswaran R, Faoro L, Janamanchi V, Nallasura V, El Dinali M, et al. The MET receptor 
tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer research. 
2009;69(7):3021-31.
85.
Di Renzo MF, Olivero M, Martone T, Maffe A, Maggiora P, Stefani AD, et al. Somatic mutations of the 
MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene. 2000;19(12):1547-55.
86.
Ghadjar P, Blank-Liss W, Simcock M, Hegyi I, Beer KT, Moch H, et al. MET Y1253D-activating point 
mutation and development of distant metastasis in advanced head and neck cancers. Clinical & experimental 
metastasis. 2009;26(7):809-15.
87.
Sun S, Wang Z. Head neck squamous cell carcinoma c-Met(+) cells display cancer stem cell properties and 
are responsible for cisplatin-resistance and metastasis. International journal of cancer Journal international du cancer. 
2011;129(10):2337-48.
88.
Albers AE, Chen C, Koberle B, Qian X, Klussmann JP, Wollenberg B, et al. Stem cells in squamous head 
and neck cancer. Critical reviews in oncology/hematology. 2012;81(3):224-40.

89.
Steinway SN, Dang H, You H, Rountree CB, Ding W. The EGFR/ErbB3 Pathway Acts as a Compensatory 
Survival Mechanism upon c-Met Inhibition in Human c-Met+ Hepatocellular Carcinoma. PloS one. 
2015;10(5):e0128159.
90.
Corso S, Ghiso E, Cepero V, Sierra JR, Migliore C, Bertotti A, et al. Activation of HER family members in 
gastric carcinoma cells mediates resistance to MET inhibition. Molecular cancer. 2010;9:121.
91.
Arteaga CL. HER3 and mutant EGFR meet MET. Nature medicine. 2007;13(6):675-7.
92.
Swanson MS, Sinha UK. Rationale for combined blockade of PD-1 and CTLA-4 in advanced head and neck 
squamous cell cancer—review of current data. Oral Oncology 2015;Jan;51(1):12-5.
93.
Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. PD-1-expressing tumor-
infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;Jan 
1;73(1):128-38.
94.
Melkane AE, Auperin A, Saulnier P, Lacroix L, Vielh P, Casiraghi O, et al. Human papillomavirus 
prevalence and prognostic implication in oropharyngeal squamous cell carcinomas. Head Neck. 2014;Feb;36(2):257-
65.
95.
Gillison ML, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab (nivo) vs 
investigator’s choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): 
CheckMate-141. AACR 2016 abstract # CT099. 2016.
96.
Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of 
pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-
012): an open-label, multicentre, phase 1b trial. The Lancet Oncology. 2016;17(7):956-65. Epub 2016/06/02.
97.
Chow LQ, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor Activity of Pembrolizumab 
in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: 
Results From the Phase Ib KEYNOTE-012 Expansion Cohort. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2016. Epub 2016/09/21.
98.
Geng L, Donnelly E, McMahon G, Lin PC, Sierra-Rivera E, Oshinka H, et al. Inhibition of vascular 
endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res. 
2001;61(6):2413-9. Epub 2001/04/06.
99.
Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, et al. Anti-Vascular 
endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer 
Res. 2000;60(19):5565-70. Epub 2000/10/18.
100.
Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase 
inhibitors: an emerging toxic effect of targeted therapy. Nature reviews Clinical oncology. 2009;6(4):219-28. Epub 
2009/04/01.
101.
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, double-blind, placebo-
controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. Journal of clinical oncology 
: official journal of the American Society of Clinical Oncology. 2007;25(9):1027-32. Epub 2007/02/22.

APPENDIX A:
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence of 
disease.
0
Normal activity. Fully active, able to 
carry on all predisease performance 
without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (eg, light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but is 
able to care for most of his/her needs.
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.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed > 50% of the time. Capable 
of only limited self-care, confined to 
bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed or 
chair.
10
Moribund, fatal processes progressing 
rapidly.
5
Dead
0
Dead
ECOG, Eastern Cooperative Oncology Group