Phase 2 Study of Cabozantinib Combined With Pembrolizumab in Metastatic or Recurrent Gastric and Gastroesophageal Adenocarcinoma (mGC)
Phase: PHASE2
Conditions: Gastric Adenocarcinoma, GastroEsophageal Cancer
Sponsor: University of California, Irvine

Protocol #: UCI 18-124 
MP 10/11//2022 
 
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PROTOCOL  
Phase 2 Study of cabozantinib combined with pembrolizumab in metastatic or recurrent gastric 
and gastroesophageal Adenocarcinoma (mGC) 
 
Principal Investigator:  
Farshid Dayyani, MD, PhD 
 
 
 
 
University of California Irvine  
 
 
 
 
Department of Medicine/Division of Hematology/Oncology 
 
 
 
 
101 The City Dr South, Orange, CA 92868 
 
 
 
 
(Phone) 714-456-8161  
 
 
 
 
(Fax) 714-456-2242 
 
 
 
 
Email: fdayyani@hs.uci.edu 
 
 
Sub-Investigator(s): 
 
 
 
 
 
 
Fa Chyi Lee, MD 
 
 
 
 
Jason Zell, DO 
 
 
 
 
Jennifer B. Valerin, MD 
 
 
 
 
Kristen Neumann, NP  
 
 
 
 
May Cho, MD 
 
 
 
 
Department of Medicine/Division of Hematology/Oncology 
 
 
 
 
 
 
 
 
 
 
Biostatistician: 
 
Thomas Taylor, PhD 
 
 
 
 
Principal Statistician 
 
 
 
 
University of California Irvine 
 
 
 
 
222 Irvine Hall, Irvine, CA 92697 
 
 
 
 
Phone: (949) 824-6903  
 
 
 
 
Email: thtaylor@uci.edu  
 
 
 
 
 
 
Coordinating Center:   
UC Irvine Chao Family Comprehensive Cancer Center 
 
 
 
 
101 The City Drive South, Orange CA 92868 
 
 
 
 
Contact: Jessica Spolarich, Clinical Research Manager 
 
 
 
 
Phone: 714-509-2450  
 
 
 
 
Email: uci18124@hs.uci.edu 
 
 
 
 
 
Study Drug: 
 
 
Cabozantinib [Cabometyx©] 
 
Funding Source:  
Exelixis, Inc., UCI CFCCC  
 
How is the Agent Supplied?:  Exelixis, Inc. 
 
Current Version:  
 
10/11/22 
 
Previous Version: 
 
06/07/22 
 
 
 
 
08/02/21 
 
 
 
 
10/19/20 
 
 
 
 
07/14/20 
 
 
 
 
05/28/20 
 
 
 
 
04/07/20 
 
 
 
 
02/24/20 
 
 
 
 
11/18/19 
 
 
 
 
09/16/19 

Protocol #: UCI 18-124 
MP 10/11//2022 
 
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The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: ______________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 
 

Protocol #: UCI 18-124 
MP 10/11//2022 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 6 
STUDY SCHEMA ........................................................................................................................ 7 
STUDY SUMMARY ..................................................................................................................... 7 
1.0 
BACKGROUND AND RATIONALE .............................................................................. 8 
1.1 
Disease Background ........................................................................................................ 8 
1.2 
Study Agent(s) Background and Associated Known Toxicities ..................................... 12 
1.3 
Other Agents .................................................................................................................. 21 
1.4 
Rationale ........................................................................................................................ 27 
2.0 
STUDY OBJECTIVES ................................................................................................... 28 
2.1 
Primary Objectives ......................................................................................................... 28 
2.2 
Secondary Objectives .................................................................................................... 28 
2.3 
Endpoints ....................................................................................................................... 28 
3.0 
PATIENT ELIGIBILITY .................................................................................................. 28 
3.1 
Inclusion Criteria ............................................................................................................ 28 
3.2 
Exclusion Criteria ........................................................................................................... 30 
4.0 
TREATMENT PLAN ....................................................................................................... 33 
4.1 
Treatment Dosage and Administration .......................................................................... 33 
4.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 35 
4.3 
Pembrolizumab adjustment for toxicity .......................................................................... 36 
4.4 
Cabozantinib adjustment for toxicity .............................................................................. 38 
4.5 
Concomitant Medications/Treatments ........................................................................... 47 
4.6 
Duration of Therapy ....................................................................................................... 47 
4.7 
Duration of Follow Up .................................................................................................... 48 
4.8 
Removal of Patients from Protocol Therapy .................................................................. 48 
4.9 
Patient Replacement ..................................................................................................... 48 
5.0 
STUDY PROCEDURES ................................................................................................. 48 
5.1 
Screening/Baseline Procedures .................................................................................... 48 
5.2 
Registration Procedures for participating sites only ...................................................... 49 
5.3 
Procedures During Treatment ....................................................................................... 50 
5.4 
Follow-up Procedures .................................................................................................... 50 

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5.5 
Time and Events Table .................................................................................................. 50 
5.6 
Removal of Subjects from Study ................................................................................... 52 
6.0 
Measurement of Effect ................................................................................................. 52 
6.1 
Antitumor Effect- Solid Tumors ...................................................................................... 52 
6.2 
Safety/tolerability ........................................................................................................... 57 
7.0 
ADVERSE EVENTS ....................................................................................................... 57 
7.1 
Experimental Therapy .................................................................................................... 57 
7.2 
Adverse Event Monitoring ............................................................................................. 68 
7.3 
Definitions ...................................................................................................................... 68 
7.4 
Reporting Requirements ................................................................................................ 71 
7.5 
Additional Reporting of Events to the CFCCC DSMB and Sponsor Investigator .......... 73 
7.6 
Other Reporting Requirements to Exelixis .................................................................... 75 
8.0 
DRUG INFORMATION .................................................................................................. 75 
8.1 
Cabozantinib .................................................................................................................. 75 
8.2 
Pembrolizumab .............................................................................................................. 76 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................ 77 
9.1 
Study Design/Study Endpoints ...................................................................................... 77 
9.2 
Sample Size and Accrual .............................................................................................. 78 
9.3 
Data Analyses Plans ...................................................................................................... 79 
10.0 
STUDY MANAGEMENT ............................................................................................ 79 
10.1 
Conflict of Interest .......................................................................................................... 79 
11.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 79 
10.3 
Required Documentation (for multi-site studies) ........................................................... 80 
10.4 
Data Completion ............................................................................................................ 80 
10.5 
Data Management and Monitoring/Auditing .................................................................. 80 
10.6 
Adherence to the Protocol ............................................................................................. 81 
10.7 
Amendments to the Protocol ......................................................................................... 81 
10.8 
Record Retention ........................................................................................................... 82 
10.9 
Obligations of Investigators ........................................................................................... 82 
10.10 Publications of Data and Protection of Trade Secrets ................................................... 82 

Protocol #: UCI 18-124 
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10.11 Conditions for Terminating the Study ............................................................................ 82 
11.0 
REFERENCES ............................................................................................................ 82 
12.0 
APPENDICES .............................................................................................................. 85 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
GC 
Gastroesophageal Adenocarcinoma 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PFS-6 
Progression Free Survival at 6 months 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 
 
 

Protocol #: UCI 18-124 
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STUDY SCHEMA 
 
 
 
 
 
 
 
STUDY SUMMARY  
Title 
Phase 2 Study of cabozantinib combined with pembrolizumab in 
metastatic or recurrent gastric and gastroesophageal Adenocarcinoma 
(mGC) 
Short Title 
Cabozantinib and pembrolizumab in 2L+ gastric and gastroesophageal 
adenocarcinomas 
Protocol Number 
UCI 18-124 
Phase 
2 
Operational Changes 
during the COVID-19 
Pandemic 
For the duration of the COVID-19 pandemic and in response to 
directives from the Vice Chancellor for Research and the UCI Human 
Research Protections Program, the Chao Family Comprehensive 
Cancer Center’s Stern Center for Cancer Clinical Trials and Research 
will be modifying operations as outlined in Interim Standard Operating 
Procedure “Clinical Trial Enrollment and Operations during the COVID-
19 Pandemic” dated 06April2020. 
In addition, the University of California Irvine Medical Center Pharmacy 
Services has issued guidance regarding the shipment of Investigational 
Drug Product directly to clinical trial participants when in-person clinic 
visits are not feasible or recommended.  This new process is described 
in “Investigational Drug Services: Emergent Shipment of Investigational 
Product Policy” dated 23March2020. 
Current versions of these SOP and Policy documents may be obtained 
at the following URL: \\hs.uci.edu\myshare\Cancer Center 
Research\COVID-19\Research\SOPs and Guidelines 
Methodology 
Open label, single arm 
Study Duration 
3 years 
Study Center(s) 
Single Center 
Objectives 
Primary objective: To estimate the efficacy of cabozantinib combined 
with pembrolizumab in patients with advanced gastric and 
gastroesophageal adenocarcinoma (GC) Primary Endpoint: 6 months 
progression-free survival (PFS-6) Secondary Objective: efficacy, safety, 
Secondary Endpoint: overall survival, objective response rate, adverse 
events 
 
 
Cabozantinib 40mg po daily day 1-21  
Pembrolizumab 200mg iv over 30 minutes day 1 
 
q 21 days  
CR, PR, or SD 
Continue protocol treatment 
PD 
Discontinue protocol treatment 

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Number of Subjects 
Up to 27 subjects  
Diagnosis and Main 
Inclusion Criteria 
• Histologically proven unresectable or recurrent gastric or 
gastroesophageal adenocarcinoma • At least one prior chemotherapy 
regimen including a fluoropyrimidine and/or platinum agent • At least one 
line of treatment with a PD-1 or PD-L1 inhibitor in patients with PD-L1 
CPS score >=10% • Age ≥ 18 years • Performance status (Eastern 
Cooperative Oncology Group) ≤ 2 • Adequate bone marrow function 
(ANC≥1000/mcL); and platelet count ≥ 60,000/mcL • Adequate liver 
function (total serum bilirubin level within normal institutional limits (or 
<3mg/dL in patients with Gilbert's disease) and serum transaminases 
≤3xULN or ≤5xULN if liver metastasis is present); • Adequate renal 
function (serum creatinine level < 1.5xULN) • An expected survival 
period of>3 months • Patients with known MSI-High or dMMR tumors 
must have disease progression after at least one line of immunotherapy 
Study Product(s), Dose, 
Route, Regimen 
Cabozantinib 40 mg p.o. daily days 1-21  
Pembrolizumab 200 mg i.v. day 1 every 21 days 
Study Duration  
The study will consist of a screening period of up to 28 days, a treatment 
period (21 day cycles), and a follow up period of up to 18 months after 
enrollment of the last patient or until death, whichever occurs first. 
Subjects will be allowed to continue treatment on study until disease 
progression, unacceptable toxicity or withdrawal of consent.  
Statistical Methodology 
Main objective is to estimate the efficacy of the combination regimen with 
PFS-6 as a primary endpoint. The null hypothesis in this heavily pre-
treated population is a PFS-6 of 5%. The alternative hypothesis assumes 
a PFS-6 of 20% or more. A 2-stage approach will be used. If PFS-6 is 
seen in at least 2 out of the first 19 patients, the cohort will be expanded 
to a total of 27 patients. If the PFS-6 is achieved in at least 4 patients in 
the expanded cohort, that would be sufficient evidence to reject the null 
hypothesis of 5% in favor of the alternative hypothesis of 20% or more. 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Gastric cancer is the 5th leading cancer and the 3rd leading cause of cancer-related 
deaths worldwide[1]. The incidence of GC varies with different geographic regions, with 
over 70% of GCs occurring in developing countries[2]. Gastric cancer often presents as 
advanced disease upon diagnosis, comprising approximately 40% of newly diagnosed 
cases in the United States (US) and Europe, and approximately 20% in Japan and 
Korea, where early detection is common[2]. 
 
Gastric cancer, including GEJ carcinoma, is a heterogeneous disease with several 
established risk factors, including environmental, genetic, and behavioral risks. There has 
been a steady decline in GC mortality attributable to dietary and lifestyle changes 
worldwide and to decreasing infection with Helicobacter pylori, which is considered the 
main cause of GC/GEJ in Asian countries[3]. However, the incidence of GEJ tumors has 
increased considerably due to increases in risk factors such as obesity and 
gastroesophageal reflux disease[1]. 
 
Gastroesophageal junction cancer anatomically straddles the distal esophagus and 
proximal stomach. Due to its anatomic location and given that, like GC, the majority of 
GEJ tumors are adenocarcinomas, GEJ tumors are frequently grouped together with GC. 

Protocol #: UCI 18-124 
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Adenocarcinoma is further classified into 2 distinct types: intestinal (well-differentiated) or 
diffuse (undifferentiated)[4]. 
 
Until optimal, tumor-specific treatment strategies are defined, advanced and metastatic 
GEJ cancer is treated and managed in a similar fashion to GC[5]. Platinum compounds 
(oxaliplatin and cisplatin) and fluoropyrimidines (5-fluorouracil, capecitabine, and 
tegafur/gimeracil/oteracil potassium [S1]) are generally considered as first-line (1L), 
standard-of-care treatment options in metastatic GC and GEJ cancer across geographic 
regions[6][7]. These platinum/fluoropyrimidine combinations are also generally accepted 
as active comparators in Phase 2 or Phase 3 randomized studies by health authorities 
worldwide[2]. The different biological characteristics and treatment approaches among 
regions result in different survival outcomes, with median overall survival (mOS) 
durations of 12 to 14 months in Asian countries and 8 to 11 months in the United States 
(US) and Europe[6][7]. 
 
While these cytotoxic agents are clinically active, with a 30% to 50% objective response 
rate (ORR) in the 1L GC treatment setting, this clinical activity is accompanied by 
significant toxicity. Grade 3/4 toxicities up to 77% have been reported for doublet 
regimens and > 80% for triplet regimens[8][9][10][11]. Hematological toxicity is the major 
problem; Grade 3/4 neutropenia has been reported in approximately 40% of participants 
treated with platinum doublets, and has increased to 82% when docetaxel was added on. 
Renal toxicity and neuropathy are the main reasons for discontinuation of platinum 
treatment. Gastrointestinal complaints are also common. Additionally, despite ORRs of 
30% to 50%, chemotherapy has resulted in few participants achieving complete response 
(CR). 
 
Since it is increasingly unlikely to induce longterm remission in patients by a first-line 
treatment only, a potential way forward could be to expand the lines of treatment from the 
first- to the second-line and beyond[12]. Indeed, currently roughly 50% of patients 
progressing after firstline maintain acceptable general conditions and are still good 
candidates to receive further therapies[12]. Also, the benefit of second-line chemotherapy 
has been convincingly established in randomised trials[13][14][15], and more recently, 
the anti-vascular endothelial growth factor receptor 2 (VEGFR-2) ramucirumab has been 
shown to improve survival either as single agent over BSC[16] or combined with 
paclitaxel over paclitaxel alone in pretreated patients[17]. 
 
Monochemotherapy versus BSC 
 
Three are the landmark phase III randomised trials that successfully explored the role of 
second-line monochemotherapy in patients with GC. 
 
The German Arbeitsgemeinschaft Internistische Onkologie trial compared a 3-week 
schedule of irinotecan 250 mg/m² (escalated up to 350 mg/m² depending on toxicity) with 
BSC in patients with Eastern Cooperative Oncology Group performance status (ECOG 
PS) 0–2 who had received prior fluoropyrimidine/platinum combination and whose 
disease progressed during or within 6 months following first line[18]. Although the study 
was terminated prematurely due to poor accrual, among 40 enrolled patients the median 
OS was significantly longer in the irinotecan arm than in the BSC arm (4 vs 2.4 months, 
HR=0.48, p=0.023). The UK COUGAR-2 trial enrolled 168 patients to receive either 
docetaxel 75 mg/m² every 3 weeks plus BSC for a maximum of six cycles or BSC 
alone[19]. The median OS was improved with docetaxel compared with BSC (5.2 vs 3.6 
months, HR=0.67, p=0.01). Despite a higher incidence of grade 3–4 neutropenia, 
infection and febrile neutropenia, patients receiving docetaxel experienced less pain, 
nausea, vomiting and constipation and decreased dysphagia and abdominal pain. 

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A Korean trial tried to answer the question about the optimal cytotoxics to be used in 
second line[20]. In this study, 202 patients with ECOG PS 0–1 and failing one or two prior 
chemotherapy lines were randomised in a 2:1 ratio to either salvage chemotherapy 
(docetaxel 60 mg/m² every 3 weeks or irinotecan 150 mg/m² every 2 weeks upon 
investigator’s choice) or BSC. The administration of second-line chemotherapy resulted 
in a significant improvement in OS compared with BSC (5.3 vs 3.8 months, HR=0.657, 
p=0.007), while no survival difference was recorded between docetaxel and irinotecan 
(5.2 vs 6.5 months, p=0.116). Even side effects were similar in both treatment arms. 
 
A meta-analysis of patient-level data from the abovementioned trials including a total of 
410 patients underscored the median OS gain of roughly 2 months for second-line 
monochemotherapy as compared with BSC, with a significant reduction in the risk of 
death by 37% (HR=0.63, p<0.0001). This benefit was conferred by both irinotecan and 
docetaxel and was of similar magnitude through patients of different ethnic origin[21]. Of 
note, when we consider these results we have to remember that the docetaxel benefit is 
limited to a 3-week schedule at a higher dose, while the weekly lower dose regimen did 
not seem to yield a similar advantage[15]. 
 
On the contrary, a weekly paclitaxel regimen provided an OS comparable to that 
achieved with irinotecan in 219 patients refractory to standard first-line treatment (9.5 vs 
8.4 months, HR=1.13, p=0.38)[14]. 
 
Combination chemotherapy versus monochemotherapy 
 
Unlike the first-line setting, combination chemotherapy failed to demonstrate a survival 
benefit over single.-agent in pretreated AGC. In a small Korean phase II trial, irinotecan 
monotherapy was as effective as FOLFIRI in terms of ORR (17.2% vs 20%, p=0.525), 
median PFS (2.2 vs 3.0 months, p=0.481) and OS (5.8 vs 6.7 months, p=0.514); grade 
3–4 toxicity was also superimposable between treatment arms[13]. In another Japanese 
phase III study comparing biweekly irinotecan (60 mg/m²) plus cisplatin (30 mg/m²) to 
biweekly irinotecan alone (150 mg/m²) in 130 patients refractory to S1-based first-line 
chemotherapy, PFS was significantly prolonged in the combination arm (3.8 vs 2.8 
months, HR 0.68, p=0.0398) but OS did not differ[22]. A meta-analysis of 10 randomised 
trials confirmed that doublet chemotherapy does not significantly improve OS compared 
with single agent, while resulting in more grade 3–4 myelosuppression, diarrhoea and 
fatigue, suggesting monochemotherapy as standard of care in this setting[23]. 
 
Ramucirumab: single agent and combinatorial approach 
 
In spite of negative results coming from first-line trials, the therapeutic exploitation of 
angiogenesis turned out to be effective in second line. Ramucirumab, a fully human 
immunoglobulin IgG1 monoclonal antibody targeting VEGFR-2, has been shown to 
significantly improve survival in two pivotal international phase III double-blind, placebo-
controlled trials. In the REGARD trial, 355 patients whose disease progressed within 
4 months of fluoropyrimidine or platinum-containing first-line chemotherapy or within 
6 months of completion of adjuvant therapy, and with an ECOG PS of 0–1, were 
randomised in a 2:1 ratio to either ramucirumab 8 mg/kg or placebo, intravenously every 
2 weeks.16 Patients receiving ramucirumab had an improvement in both OS (5.2 vs 3.8 
months, HR=0.776, p=0.047) and PFS (2.1 vs 1.3 months, HR=0.48, p<0.0001), with a 
reduction in the risk of death by 22% compared with placebo[16]. Also, the disease 
control rate was significantly higher in the experimental arm (49% vs 23%), although 
objective responses were infrequent with ramucirumab. The survival benefit remained 
significant after adjusting for main prognostic variables such as PS, tumour location and 

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peritoneal disease. The efficacy of ramucirumab alone was comparable to that reported 
in phase III trials of second-line chemotherapy, with a more favourable toxicity profile. 
 
Similarly, in the RAINBOW trial, which is the largest second-line trial in GC, the addition 
of ramucirumab to weekly paclitaxel significantly prolonged either median OS (9.6 vs 7.4 
months, HR=0.807, p=0.017) or PFS (4.4 vs 2.9 months, HR=0.635, p<0.0001) when 
compared with paclitaxel monotherapy in 665 patients[17]. A decrease in the risk of death 
by 19% was seen and a significantly greater proportion of patients attained an objective 
response in the combination group than in the single-agent group (28% vs 16%, 
p=0.0001). These results are noteworthy especially in the light of poor risk feature of 
patients enrolled as demonstrated by the rate of peritoneal metastases higher than 40% 
in both the experimental and control arms. In a preplanned subgroup analysis, Asian 
patients derived less survival benefit than non-Asian. A dilution effect by poststudy 
discontinuation treatment as well as difference in pharmacokinetics has been advocated 
to explain this discrepant outcome. Interestingly, the survival benefit was achieved while 
maintaining patient quality of life, delaying symptom worsening and functional status 
deterioration[24]. The toxicity of ramucirumab was tolerable and, as expected, higher in 
the combination regimen. In the single-agent trial the most common AE was an increased 
risk of grade 3 or higher hypertension (8% vs 3%), while when combined with paclitaxel, 
ramucirumab resulted in significantly increased rates of grade 3–4 neutropenia (40.7% vs 
18.8%), though this did not translate into higher incidence of febrile neutropenia. 
Antiangiogenic class side effects such as proteinuria, bleeding and gastrointestinal 
perforations were mainly infrequent, mild in grade and more commonly noted in the 
combination arm. 
 
Thirdline and later lines of therapy 
 
Until recently, no randomized trials with cytotoxics were available to show a survival 
benefit in 3L+ patients with mGAC. The TAGS trial was a global phase 3 study of adult 
patients with mGC who had received ≥ 2 prior regimens of chemotherapy. Patients were 
randomized 2:1 to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-
day cycle) or placebo, plus best supportive care. Median overall survival was 5·7 months 
(95% CI 4·8-6·2) in the trifluridine/tipiracil group and 3·6 months (3·1-4·1) in the placebo 
group (hazard ratio 0·69 [95% CI 0·56-0·85]; one-sided p=0·00029, two-sided 
p=0·00058)[25]. 
 
Immunotherapy Experience with Pembrolizumab 
 
KEYNOTE-059 was a global, open-label, single-arm, multicohort study in patients with 2+ 
lines of prior treatment[26]. Treatment consisted of pembrolizumab 200mg every 3 
weeks. ORR was the primary endpoint and ranged from 6.4% (PD-L1 negative 
population) to 15.5% (PD-L1 positive population). Median response duration was 
reported as 16.3 months in patients with PD-L1 positive tumors. 
 
KEYNOTE-061was a global randomized phase 3 trial of single agent pembrolizumab 
200mg every 3 weeks vs. standard dose paclitaxel in patients with advanced gastric or 
gastro-esophageal junction cancer that progressed on first-line chemotherapy with a 
platinum and fluoropyrimidine[27]. Primary endpoints were overall survival and 
progression-free survival in patients with a programmed cell death ligand 1 (PD-L1) 
combined positive score (CPS) of 1 or higher. Median overall survival was 9·1 months 
(95% CI 6·2-10·7) with pembrolizumab and 8·3 months (7·6-9·0) with paclitaxel (hazard 
ratio [HR] 0·82, 95% CI 0·66-1·03; one-sided p=0·0421). Median progression-free 
survival was 1·5 months (95% CI 1·4-2·0) with pembrolizumab and 4·1 months (3·1-4·2) 
with paclitaxel (HR 1·27, 95% CI 1·03-1·57). In the total population, grade 3-5 treatment-

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MP 10/11//2022 
 
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related adverse events occurred in 42 (14%) of the 294 patients treated with 
pembrolizumab and 96 (35%) of the 276 patients treated with paclitaxel. Pembrolizumab 
reduced the risk of death by 18% vs. paclitaxel in patients with previously treated G/GEJ 
cancer and PD-L1 CPS ≥1, although this difference was not statistically significant. In 
post-hoc analysis, the pembrolizumab treatment effect for OS was greater for CPS ≥5 
(HR 0.73; 95% CI 0.52-1.03) and ≥10 (HR 0.64; 95% CI 0.41-1.02). 
 
The pivotal Phase 3 KEYNOTE-062 trial[28] evaluated pembrolizumab, as monotherapy 
and in combination with chemotherapy (cisplatin and either 5-fluorouracil or capecitabine) 
for the first-line treatment of advanced gastric or gastroesophageal junction (GEJ) 
adenocarcinoma. In the monotherapy arm of the study, pembrolizumab met a primary 
endpoint by demonstrating noninferiority to chemotherapy, the current standard of care, 
for overall survival (OS) in the entire intention-to-treat (ITT) population of patients whose 
tumors expressed PD-L1 (Combined Positive Score [CPS] ≥1). In the combination arm of 
KEYNOTE-062, pembrolizumab plus chemotherapy was not found to be superior for OS 
(CPS ≥1 or CPS ≥10) or progression-free survival (PFS) (CPS ≥1) compared with 
chemotherapy alone. The safety profile of pembrolizumab was consistent with that 
previously observed in gastric cancer. 
  
 
From the currently available data the clinical benefit rate from immunotherapy with 
pembrolizumab appears to be dependent on the PD-L1 expression level, but in general 
between 6%-30%. While the responses were durable, in the intent to treat population the 
6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 months. Therefore, 
the majority of patients treated with immunotherapy will eventually experience disease 
progression. These findings highlight the remaining unmet need for the majority of 
patients who either are refractory or develop disease progression following treatment with 
single agent checkpoint inhibitors. 
 
Proposed strategy to overcome resistance to immunotherapy with Cabozantinib  
 
Cabozantinib, a dual MET and VEGFR inhibitor [29], has been safely combined with PD-
1 and PD-L1 inhibitors in solid tumors[30][31]. A recently reported study examined the 
efficacy of cabozantinib in patients with RCC who progressed on immune checkpoint 
blockade. Overall, cabozantinib showed promising activity with an ORR of 33% and DCR 
of 79%, with a median TTF of 6.6 months[32]. We hypothesize that cabozantinib, based 
on preclinical and clinical observations so far, might contribute to overcoming resistance 
to PD-1 blockade in mGC. The proposed trial would be in line with regards to medical 
strategy and anticipated trends for treatment of mGC. It is highly likely that in the short to 
mid-term the frontline treatment for mGC patients will become a combination of doublet 
fluoropyrimidine/platinum chemotherapy and checkpoint inhibitors (with trastuzumab if 
Her- 2 positive [NCT03382600, NCT02901301, NCT02872116]). Nevertheless, the 
majority of these patients are expected to eventually progress, which highlights the future 
unmet need of 2L+ treatment options after standard doublet+IO failure. 
 
 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
Cabozantinib (Cabometyx®) is an orally available multiple tyrosine kinase receptor 
(Figure 1). In vitro biochemical and/or cellular assays have shown that cabozantinib 
inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, 
TYRO3, MER, KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are 
involved in both normal cellular function and pathologic processes such as oncogenesis, 

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metastasis, tumor angiogenesis, drug resistance,and maintenance of the tumor 
microenvironment. 
 
Figure 1 Molecular Structure of Cabozantinib 
 
• 
Pharmacodynamics 
 
The exposure-response or –safety relationship for cabozantinib is unknown.  
 
Cardiac Electrophysiology 
 
The effect of orally administered cabozantinib on QTc interval was evaluated in a 
randomized, double-blinded, placebo-controlled study in patients with medullary 
thyroid cancer administered a dose of 140 mg. A mean increase in QTcF of 10 - 15 
ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc 
relationship could not be definitively established. Changes in cardiac wave form 
morphology or new rhythms were not observed. No cabozantinibtreated patients in 
this study had a confirmed QTcF > 500 ms nor did any cabozantinib-treated patients 
in the RCC study (at a dose of 60 mg). 
 
• 
Pharmacokinetics 
 
Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold 
mean cabozantinib accumulation (based on AUC) compared to a single dose 
administration; steady state was achieved by Day 15. 
 
Absorption 
 
Following oral administration of cabozantinib, median time to peak cabozantinib 
plasma concentrations (Tmax) ranged from 2 to 3 hours post-dose.  
 
A 19% increase in the Cmax of the tablet formulation (CABOMETYX) compared to 
the capsule formulation (COMETRIQ®) was observed following a single 140 mg 
dose. A less than 10% difference in the AUC was observed between cabozantinib 
tablet (CABOMETYX) and capsule (COMETRIQ) formulations. 
 
Cabozantinib Cmax and AUC values increased by 41% and 57%, respectively, 
following a highfat meal relative to fasted conditions in healthy subjects administered 
a single 140 mg oral dose of an investigational cabozantinib capsule formulation. 
 
Distribution 
 

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The oral volume of distribution (Vz/F) of cabozantinib is approximately 319 L. 
Cabozantinib is highly protein bound in human plasma (≥ 99.7%). 
 
Elimination 
 
The predicted terminal half-life is approximately 99 hours and the clearance (CL/F) at 
steadystate is estimated to be 2.2 L/hr. 
 
Metabolism 
 
Cabozantinib is a substrate of CYP3A4 in vitro. 
 
Excretion 
 
Approximately 81% of the total administered radioactivity was recovered within a 48-
day collection period following a single 140 mg dose of an investigational 14C-
cabozantinib formulation in healthy subjects. Approximately 54% was recovered in 
feces and 27% in urine. Unchanged cabozantinib accounted for 43% of the total 
radioactivity in feces and was not detectable in urine following a 72 hour collection. 
 
Specific Populations 
 
The following patient characteristics did not result in a clinically relevant difference in 
the pharmacokinetics of cabozantinib: age (32-86 years), sex, race (Whites and non-
Whites), or mild to moderate renal impairment (eGFR greater than or equal to 30 
mL/min/1.73 m2 as estimated by MDRD (modification of diet in renal disease 
equation)). The pharmacokinetics of cabozantinib is unknown in patients with worse 
than moderate renal impairment (eGFR less than 29 mL/min/1.73m2) as estimated 
by MDRD equation or renal impairment requiring dialysis. 
 
Hepatic Impairment 
Based on a population pharmacokinetic analysis of cabozantinib in healthy subjects 
and patients with cancer, no clinically significant differences in the mean cabozantinib 
exposure were observed between subjects with normal liver function (total bilirubin 
and AST ≤ ULN) and those with mild hepatic impairment (total bilirubin ≤ ULN and 
AST > ULN or total bilirubin > 1 to 1.5x ULN and any AST value). In a dedicated 
pharmacokinetic study, cabozantinib exposure (AUC0-INF) increased by 63% in 
patients with moderate hepatic impairment (Child-Pugh B). Patients with severe 
hepatic impairment have not been studied. 
 
Pediatric Population 
The pharmacokinetics of cabozantinib has not been studied in the pediatric 
population 
 
Drug Interactions 
 
CYP3A4 Inhibition on Cabozantinib 
Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) 
to healthy subjects increased single-dose plasma cabozantinib exposure (AUC0-inf) 
by 38%. 
 
CYP3A4 Induction on Cabozantinib 

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Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to 
healthy subjects decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 
77%. 
 
Cabozantinib on CYP2C8 substrates 
No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) 
plasma exposure (Cmax and AUC) was observed when co-administered with 
cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily for a 
minimum of 21 days) in patients with solid tumors. 
 
Gastric pH modifying agents on Cabozantinib 
No clinically-significant effect on plasma cabozantinib exposure (AUC) was observed 
following co-administration of the proton pump inhibitor (PPI) esomeprazole (40 mg 
daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers. 
 
 
In vitro Studies 
 
Metabolic Pathways 
Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by > 80%. 
Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., 
a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, 
CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. 
 
Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this 
potential interaction concluded that concurrent use did not result in a clinically 
relevant effect on CYP2C8 substrate exposure. Given this finding, other less 
sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, 
CYP2C19, and CYP3A4) were not evaluated in a clinical study because, although a 
clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib 
does not inhibit CYP1A2 and CYP2D6 isozymes in vitro. 
 
Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this 
finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 or CYP3A4. 
 
 
Drug Transporter Systems 
Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has 
the potential to increase plasma concentrations of co-administered substrates of P-
gp. The clinical relevance of this finding is unknown. 
 
Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential 
to increase plasma concentrations of cabozantinib. The clinical relevance of this 
finding is unknown. 
 
 
• 
Nonclinical Toxicology 
 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Cabozantinib was not carcinogenic in a 26-week carcinogenicity study in rasH2 
transgenic mice. 
 

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Cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) 
assay and was not clastogenic in both the in vitro cytogenetic assay using human 
lymphocytes or in the in vivo mouse micronucleus assay. 
 
Based on nonclinical findings, male and female fertility may be impaired by treatment 
with CABOMETYX. In a fertility study in which cabozantinib was administered to male 
and female rats at doses of 1, 2.5, and 5 mg/kg/day, male fertility was significantly 
compromised at doses equal to or greater than 2.5 mg/kg/day (approximately 13-fold 
of human AUC at the recommended dose), with a decrease in sperm counts and 
reproductive organ weights. In females, fertility was significantly reduced at doses 
equal to or greater than 1 mg/kg/day (5-fold of human AUC at the recommended 
dose) with a significant decrease in the number of live embryos and a significant 
increase in pre- and post-implantation losses. 
 
Observations of effects on reproductive tract tissues in general toxicology studies 
were supportive of effects noted in the dedicated fertility study and included 
hypospermia and absence of corpora lutea in male and female dogs in a 6-month 
repeat dose study at plasma exposures (AUC) approximately 0.5-fold (males) and 
<0.1-fold (females) of those expected in humans at the recommended dose. In 
addition, female rats administered 5 mg/kg/day for 14 days (approximately 9-fold of 
human AUC at the recommended dose) exhibited ovarian necrosis. 
 
 
• 
CLINICAL STUDIES 
 
CELESTIAL 
CELESTIAL (NCT01908426) was a phase 3 randomized trial (2:1) of cabozantinib 
60mg daily or matching placebo in 707 patients who had received previous treatment 
with sorafenib, and had disease progression after at least one systemic treatment for 
hepatocellular carcinoma (up to two lines of previous lines of therapy were 
allowed)[33]. The primary endpoint, overall survival, was significantly longer with 
cabozantinib (10.2 months) compared to placebo (8.0 months). Median progression-
free survival was also improved (5.2 months vs. 1.9 months).  Objective response 
rate with cabozantinib was reported in 4% of the patients (1% in patients who 
received placebo). Grade 3 or 4 adverse events occurred in 68% of patients in the 
cabozantinib group and in 36% in the placebo group. The most common high-grade 
events were palmar–plantar erythrodysesthesia (17% with cabozantinib vs. 0% with 
placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level 
(12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). 
 
METEOR 
METEOR (NCT01865747) was a randomized (1:1), open-label, multicenter study of 
CABOMETYX versus everolimus conducted in patients with advanced RCC who had 
received at least 1 prior antiangiogenic therapy. Patients had to have a Karnofsky 
Performance Score (KPS) ≥ 70%. Patients were stratified by the number of prior 
VEGFR tyrosine kinase inhibitors and Memorial Sloan Kettering Cancer Center 
(MSKCC) Risk Group. 
 
Patients (N=658) were randomized to receive CABOMETYX (N=330) administered 
orally at 60 mg daily or everolimus (N=328) administered orally at 10 mg daily. The 
majority of the patients were male (75%), with a median age of 62 years. Sixty-nine 
percent (69%) received only one prior anti-angiogenic therapy. Patient distribution by 
MSKCC risk groups was 46% favorable (0 risk factors), 42% intermediate (1 risk 
factor), and 13% poor (2 or 3 risk factors). Fifty-four percent (54%) of patients had 3 

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or more organs with metastatic disease, including lung (63%),lymph nodes (62%), 
liver (29%), and bone (22%).  
 
The main efficacy outcome measure was progression-free survival (PFS) assessed 
by a blinded independent radiology review committee among the first 375 subjects 
randomized. Other efficacy endpoints were objective response rate (ORR) and 
overall survival (OS) in the Intent-toTreat (ITT) population. Tumor assessments were 
conducted every 8 weeks for the first 12 months, then every 12 weeks thereafter. 
Patients received treatment until disease progression or experiencing unacceptable 
toxicity. Patients on both arms who had disease progression could continue 
treatment at the discretion of the investigator.  
 
Statistically significant improvements in PFS, OS, and ORR were demonstrated for 
CABOMETYX compared to everolimus (Figures 2 and 3 and Tables 1 and 2). 
 
 
Figure 2: Progression-Free Survival in Study 1 (First 375 Randomized) 
 
 
Table 1: Progression-Free Survival in Study 1 (First 375 Randomized) 
 
 

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Figure 3: Overall Survival in Study 1 (ITT) 
 
 
 
Table 2. Overall Survival and Objective Response Rate in Study 1 (ITT) 
1 stratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs 2 or more) and MSKCC prognostic 
criteria for previously treated patients with RCC (0 vs 1 vs 2 or 3) as stratification factors (per IVRS data) 
2 chi-squared test 
 
CABOSUN 
 
CABOSUN (NCT01835158) was a randomized (1:1), open-label, multicenter study of 
CABOMETYX versus sunitinib conducted in patients with advanced RCC who had 
not received prior therapy. Patients were randomized to receive CABOMETYX 
(N=79) 60 mg orally daily or sunitinib (N=78) 50 mg orally daily (4 weeks on 
treatment followed by 2 weeks off) until disease progression or unacceptable toxicity. 
All patients were required to have intermediate or poor risk disease as defined by the 
International Metastatic RCC Database Consortium (IMDC) risk group categories. 
Patients were stratified by IMDC risk group and presence of bone metastases 
(yes/no). 
 
The majority of patients were male (78%), with a median age of 63 years. Patient 
distribution by IMDC risk groups was 81% intermediate (1-2 risk factors) and 19% 
poor (≥3 risk factors). Thirty-six percent (36%) patients had bone metastases. Forty-
six percent (46%) of patients were ECOG 0, 41% ECOG 1, and 13% ECOG 2. 

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The major efficacy outcome measure was progression-free survival (PFS) by a 
retrospective blinded independent radiology review committee (BIRC). 
 
A statistically significant improvement in PFS, as assessed by a blinded independent 
radiology review committee, was demonstrated for CABOMETYX compared to 
sunitinib (Figure 4, Table 3). The OS results are presented in Figure 5 and Table 3; 
ORR results are presented in Table 3. 
 
 
Figure 4: Progression-Free Survival in CABOSUN (ITT) 
 
 
Table 3. Progression-free Survival, Overall Survival and Objective Response Rate in 
CABOSUN (ITT) 
1 as assessed by a retrospective blinded independent radiology review committee (BIRC) 
2 estimated from stratified Cox proportional hazards model with stratification factors IMDC risk group and 
presence of bone metastases and treatment as covariate 
3 two-sided stratified log-rank test with stratification factors IMDC risk group and presence of bone 
metastases 
4 no multiplicity adjustments were made for overall survival or ORR 
 

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Figure 5: Overall Survival in CABOSUN (ITT) 
 
• 
How Supplied / Storage Handling 
 
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. The 60-mg tablets are oval and 
the 20-mg tablets are round. Doses of 40 mg will comprise two 20-mg tablets. The 
components of the tablets are listed in Table 4.  
Table 4: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/wa 
Cabozantinib Drug Substance (25% drug load as free base) 
Active 
Ingredient 
31.68 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose Anhydrous (60M) 
Filler 
19.42 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.00 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
6.00 
Colloidal Silicon Dioxide 
Glidant 
0.30 
Magnesium Stearate 
Lubricant 
0.75 
Opadry® yellow film coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide 
yellow 
Film 
Coating 
4.00 
aweight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose 
 
 
• 
Cabozantinib Administration 
 

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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 4.2 and 4.4 below. 
 
1.3 
 Other Agents 
• 
Pembrolizumab [Keytruda®] 
 
• 
Mechanism of Action 
 
 
Pembrolizumab is a highly selective humanized mAb designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an 
IgG4/kappa isotype with a stabilizing sequence alteration in the Fc region. 
 
• 
Intravenous Infusion 
 
Pembrolizumab DS for IV infusion is produced at several locations to yield: a partially 
formulated aqueous solution stored under refrigerated (2°C to 8°C) conditions at a 
concentration of 40.0 to 50.0 mg/mL in 10 millimolar (mM) histidine buffer, pH 5.2 to 5.8; 
and a fully formulated aqueous solution stored frozen (–40°C°±5°C) at a concentration of 
22.5 to 27.5 mg/mL in 10 mM histidine buffer, pH 5.2 to 5.8, containing 7% sucrose and 
0.02% polysorbate 80. The drug substance solution from both sources is a clear to 
opalescent liquid. 
 
The manufacturing process for pembrolizumab is a suspension cell culture process that 
uses commercially available animal component-free medium. The contents of the 
production bioreactor are initially filtered to remove intact cells and cell debris, and then 
0.2 micron (μm) filtered into presterilized bags. 
 
The purification process for pembrolizumab drug substance consists of chromatography, 
viral inactivation, viral filtration, ultrafiltration/diafiltration, formulation (only for the fully 
formulated DS stored frozen), and a final 0.2 μm filtration step. 
 
Two DP dosage forms are available for pembrolizumab for IV infusion: a white to off-
white lyophilized powder, 50 mg/vial, and a liquid, 100 mg/vial, both in Type I glass vials 
intended for single use only. The drug products are manufactured using facilities and 
practices under GMP requirements. 
 
• 
Nonclinical Pharmacology 
 
Pembrolizumab potently blocks binding to both ligands, PD-L1 and PD-L2, with IC50 
values below 1 nM. Pembrolizumab binds to human and Cynomolgus monkey PD-1 with 
comparable affinity, and blocks the binding of human and Cynomolgus monkey PD-1 to 

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PD-L1 and PD-L2 with comparable potency. Pembrolizumab does not cross-react with 
dog, rat, or mouse PD-1. 
 
Pembrolizumab enhances T-cell responses in human donor blood cell cultures, with a 
half-maximal effective concentration of approximately 0.1 to 0.3 nM. Pembrolizumab 
strongly enhances T-lymphocyte immune responses in cultured blood cells from healthy 
human donors, cancer patients, and Cynomolgus monkeys. The antibody potentiates 
existing immune responses only in the presence of antigen-receptor stimulation and does 
not nonspecifically activate all T-cells. 
 
Pembrolizumab does not bind Ig superfamily members CD28, CTLA-4, or ICOS. In in 
vitro PBMC and whole blood cytokine release assays, the cytokine levels induced by 
pembrolizumab were low, and comparable to those induced by trastuzumab. 
Pembrolizumab does not induce ADCC or CDC. 
 
Safety pharmacology evaluations conducted as part of the 1- and 6-month toxicity and 
TK studies in Cynomolgus monkeys showed no pembrolizumab–related effects on any 
parameter evaluated (ECGs, general veterinary and physical examinations with body 
temperature and blood pressure, clinical observations, and histopathology of tissues from 
the cardiovascular, respiratory, renal, and nervous systems). 
 
The KDs of pembrolizumab binding to human and Cynomolgus monkey PD-1 were 
determined by measurement of kinetic rate constants (on/off) in a solid phase format 
(ForteBio BLI). ForteBio BLI measurements demonstrated that pembrolizumab binds 
human PD-1 with a fast association rate, dissociates very slowly, and has a high affinity 
of 29 pM [Table 5]. 
 
The ability of pembrolizumab to block the binding of PD-1 ligands, PD-L1 and PD-L2, to 
human or Cynomolgus monkey PD-1 was measured using a competitive binding assay 
and detection by fluorometric microvolume assay technology. Pembrolizumab potently 
blocks binding to both PD-1 ligands with IC50 values below 1 nM [Table 4]. 
 
 
Table 5 Characterization of Pembrolizumab Binding to PD-1 
1/Ms=1 per molar per sec; BLI=biolayer-interferometry; FMAT=fluorometric microvolume assay technology; 
IC50=half maximal inhibitory concentration; kassoc=association rate constant; KD=dissociation constant; 
kdissoc=dissociation rate constant; N/A=not applicable; PD-1=programmed cell death 1; PD-L1=programmed 
cell death ligand 1; PD-L2=programmed cell death ligand 2; pM=picomolar; s=second. 
 
• 
Metabolism 
 
No traditional metabolism studies were conducted with pembrolizumab per current ICH 
S6 (R1) guidance on preclinical safety evaluation of biotechnology-derived 
pharmaceuticals.  
 

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However, in vivo studies were conducted in C.B17 SCID mice to demonstrate the lack of 
Fab-arm or half molecule exchange for pembrolizumab. IgG4 wild-type molecules can 
undergo in vitro and in vivo molecular rearrangement called Fab-arm (or half molecule) 
exchange by swapping their half molecule with other IgG4 half molecules, thereby 
generating bispecific or hybrid antibodies [4-3], [4-4]. A point mutation (S228P) in the 
core hinge region in IgG4 has been shown to be sufficient to prevent the Fab-arm 
exchange [4-3], [4-4]. The results supported that pembrolizumab, which has a hinge 
mutation from S to P at Position 228, did not form detectable hybrid antibodies with co-
administered wild type IgG4 molecules in vivo in SCID mice (PK007). This observation is 
consistent with the results of extensive in vitro characterization of pembrolizumab 
(PK007) and indicates that pembrolizumab is not likely to engage in Fab-arm exchange in 
humans. 
 
• 
Excretion 
 
No specific studies were performed with pembrolizumab. 
 
• 
Toxicology and Toxicokinetics 
 
All pivotal toxicity studies were conducted in accordance with the principles of GLP. 
Unless otherwise indicated, all studies were conducted at Merck Research Laboratories, 
West Point, Pennsylvania, U.S.A. or Laboratoires Merck Sharp & Dohme-Chibret, Centre 
de Recherche, Riom, France. The U.S.A. and France are members of the OECD and 
therefore part of the OECD Mutual Acceptance of Data system. GLP compliance 
statements are included in all GLP study reports. 
 
• 
Specific populations 
 
The following factors had no clinically important effect on the CL of pembrolizumab: age 
(range: 15 to 94 years), sex, race (89% White), renal impairment (eGFR ≥ 15 
mL/min/1.73 m2), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) 
and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor 
burden. The impact of moderate or severe hepatic impairment on the pharmacokinetics 
of pembrolizumab is unknown. 
 
Pediatric Patients: Pembrolizumab concentrations with weight-based dosing at 2 mg/kg 
every 3 weeks in pediatric patients (2 to 17 years) are comparable to those of adults at 
the same dose. 
 
• 
NONCLINICAL TOXICOLOGY 
 
• 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
No studies have been performed to test the potential of pembrolizumab for 
carcinogenicity or genotoxicity. 
 
Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month 
repeat-dose toxicology studies in monkeys, there were no notable effects in the male and 
female reproductive organs; however, most animals in these studies were not sexually 
mature. 
• 
Animal Toxicology and/or Pharmacology 
 
In animal models, inhibition of PD-1 signaling resulted in an increased severity of some 
infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 

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knockout mice exhibit markedly decreased survival compared with wild-type controls, 
which correlated with increased bacterial proliferation and inflammatory responses in 
these animals. PD-1 knockout mice have also shown decreased survival following 
infection with lymphocytic choriomeningitis virus (LCMV). Administration of 
pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection 
resulted in two out of four animals with significantly increased levels of serum ALT, AST, 
and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab. 
 
• 
CLINICAL STUDIES 
 
Pembrolizumab has been studied in clinical trials alone or in combination with 
chemotherapy in a wide range of malignancies. Below the clinical studies pertinent to 
gastric cancer.  
 
• 
Microsatellite Instability-High Cancer 
 
The efficacy of KEYTRUDA was investigated in patients with MSI-H or mismatch repair 
deficient (dMMR), solid tumors enrolled in one of five uncontrolled, open-label, multi-
cohort, multi-center, single-arm trials. Patients with active autoimmune disease or a 
medical condition that required immunosuppression were ineligible across the five trials. 
Patients received either KEYTRUDA 200 mg every 3 weeks or KEYTRUDA 10 mg/kg 
every 2 weeks. Treatment continued until unacceptable toxicity or disease progression 
that was either symptomatic, rapidly progressive, required urgent intervention, or 
occurred with a decline in performance status. A maximum of 24 months of treatment 
with KEYTRUDA was administered. For the purpose of assessment of anti-tumor activity 
across these 5 trials, the major efficacy outcome measures were ORR as assessed by 
blinded independent central radiologists’ (BICR) review according to RECIST v1.1, and 
duration of response. 
 
 
Table 6. MSI High Trials. 
CRC = colorectal cancer 
PCR = polymerase chain reaction 
IHC = immunohistochemistry 
 

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A total of 149 patients with MSI-H or dMMR cancers were identified across the five trials. 
Among these 149 patients, the baseline characteristics were: median age 55 years (36% 
age 65 or older); 56% male; 77% White, 19% Asian, 2% Black; and ECOG PS 0 (36%) or 
1 (64%). Ninety-eight percent of patients had metastatic disease and 2% had locally 
advanced, unresectable disease. The median number of prior therapies for metastatic or 
unresectable disease was two. Eighty-four percent of patients with metastatic CRC and 
53% of patients with other solid tumors received two or more prior lines of therapy. The 
identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was 
prospectively determined using local laboratory-developed, polymerase chain reaction 
(PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR. Fourteen of 
the 149 patients were retrospectively identified as MSI-H by testing tumor samples from a 
total of 415 patients using a central laboratory developed PCR test. Forty-seven patients 
had dMMR cancer identified by IHC, 60 had MSI-H identified by PCR, and 42 were 
identified using both tests. 
 
Efficacy results are summarized in Tables 7 and 8. 
 
 
Table 7: Efficacy Results for Patients with MSI-H/dMMR Cancer 
NR- not reached 
 
 
Table 8: Response by Tumor Type 
CR = complete response 
PR = partial response 
SD = stable disease 
PD = progressive disease 
NE = not evaluable 
 
• 
Gastric Cancer 
 
The efficacy of KEYTRUDA was investigated in KEYNOTE-059 (NCT02335411), a 
multicenter, nonrandomized, open-label multi-cohort trial that enrolled 259 patients with 

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gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on at least 
2 prior systemic treatments for advanced disease. Previous treatment must have 
included a fluoropyrimidine and platinum doublet. HER2/neu positive patients must have 
previously received treatment with approved HER2/neu-targeted therapy. Patients with 
active autoimmune disease or a medical condition that required immunosuppression or 
with clinical evidence of ascites by physical exam were ineligible. Patients received 
KEYTRUDA 200 mg every 3 weeks until unacceptable toxicity or disease progression 
that was symptomatic, rapidly progressive, required urgent intervention, occurred with a 
decline in performance status, or was confirmed at least 4 weeks later with repeat 
imaging. Patients without disease progression were treated for up to 24 months. 
Assessment of tumor status was performed every 6 to 9 weeks. The major efficacy 
outcome measures were ORR according to RECIST v1.1, as assessed by blinded 
independent central review, and duration of response. 
 
Among the 259 patients, 55% (n = 143) had tumors that expressed PD-L1 with a 
combined positive score (CPS) of ≥ 1 and microsatellite stable (MSS) tumor status or 
undetermined MSI or MMR status. PD-L1 status was determined using the PD-L1 IHC 
22C3 pharmDx Kit. The baseline characteristics of these 143 patients were: median age 
64 years (47% age 65 or older); 77% male; 82% White, 11% Asian; and ECOG PS of 0 
(43%) and 1 (57%). Eighty-five percent had M1 disease and 7% had M0 disease. 
Fiftyone percent had two and 49% had three or more prior lines of therapy in the 
recurrent or metastatic setting. 
 
For the 143 patients, the ORR was 13.3% (95% CI: 8.2, 20.0); 1.4% had a complete 
response and 11.9% had a partial response. Among the 19 responding patients, the 
duration of response ranged from 2.8+ to 19.4+ months, with 11 patients (58%) having 
responses of 6 months or longer and 5 patients (26%) having responses of 12 months or 
longer. 
 
Among the 259 patients enrolled in KEYNOTE-059, 7 (3%) had tumors that were 
determined to be MSI-H. An objective response was observed in 4 patients, including 1 
complete response. The duration of response ranged from 5.3+ to 14.1+ months. 
 
• 
Combination of cabozantinib with pembrolizumab 
 
The combination of pembrolizumab (Keytruda) and cabozantinib (Cabometyx) has 
antitumor activity in patients with previously treated metastatic renal cell carcinoma 
(RCC) and is tolerated at their separate approved doses for this indication, based on the 
findings from a dose-escalation cohort of a phase I study[34]. Among 8 patients enrolled 
with RCC of any histology, the best objective response was a partial response in 2 
patients and stable disease in 4 patients; 2 patients experienced progressive disease. 
The maximum-tolerated dose (MTD) was identified as 60 mg of oral cabozantinib daily 
plus 200 mg of pembrolizumab intravenously every 3 weeks. No dose-limiting toxicities 
(DLTs) were observed with cabozantinib at 40 mg when used in combination with 
pembrolizumab in patients evaluable for DLT. One patient required a dose reduction from 
60 mg of cabozantinib to 40 mg after cycle 5. 
 
Eligible patients in the phase I study (NCT03149822) had documented RCC of any 
histology, measurable or evaluable disease based on RECIST v1.1 criteria, adequate 
organ function, and an ECOG performance status of 0 or 1. Patients received 
pembrolizumab and cabozantinib in a standard 3+3 dose escalation to determine the 
DLT, MTD, and objective response rate. Cabozantinib was dosed at 40 mg and 60 mg 
daily in the first and second cohorts, respectively. Pembrolizumab was dosed at 200 mg 
every 3 weeks in all cohorts. The original study design included only pretreated patients 

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but after cabozantinib was approved in the first-line setting in patients with intermediate- 
and poor-risk disease, the protocol permitted patients with newly diagnosed metastatic 
RCC. 
 
The DLT assessment window was 21 days; dose-escalation patients who did not 
complete the DLT assessment window for any reason other than a DLT were considered 
non-evaluable for DLT and were replaced. Scans were obtained every 9 weeks, and 
treatment could continue beyond progression. Two patients in the cabozantinib 40-mg 
cohort were not evaluable for DLT due to nonadherence and were therefore replaced 
with 3 patients who were treated at the 60-mg dose. 
In the first cohort (n = 5), 4 patients had clear cell histology and 1 had non-clear cell 
RCC; all had prior nephrectomy. The median age was 54 years. Four were intermediate 
risk and 1 was poor risk by Memorial Sloan Kettering Cancer Center (MSKCC) risk 
criteria. Three patients in cohort 1 received 1 prior systemic treatment and 2 patients 
received ≥2. Moreover, 3 patients received prior tyrosine kinase inhibitor (TKI) only and 2 
received prior TKI plus immunotherapy. 
 
In cohort 2 (n = 3), the median age of the 3 patients was 47 years. All 3 had clear cell 
histology, all had prior nephrectomy, and all were MSKCC intermediate risk. Two 
received 1 prior systemic treatment and 1 received ≥2. Two patients received prior TKI 
only and 1 received prior TKI and immunotherapy. 
 
Patients in the study were not selected for programmed cell death ligand 1 (PD-L1) 
expression. No correlation with PD-L1 status and response was seen in tumor samples 
tested. 
1.4 
Rationale 
 
Gastric cancer is the third leading cause of cancer mortality and the fifth most common 
malignancy worldwide[35]. Currently, fluoropyrimidine and platinum-based combinations 
are the most commonly used first line treatment regimens. Patients who progress after 
1st line chemotherapy have few standard treatment options. Paclitaxel and ramucirumab 
(anti- VEGFR2 mAb) improve OS in 2nd line in metastatic gastric cancer[17]. The phase 
III ONO-4538-12 (ATTRACTION 2) trial has demonstrated an improved overall survival 
for nivolumab compared with placebo for patients with heavily pretreated gastric 
cancer[36]. In the Keynote-59 trial, pembrolizumab produced an ORR of 11.6% in 3L+ 
mGC, although the response rate was higher (15.5% vs. 6.4%) in patients with PD-L1 
positive compared to PD-L1 negative tumors (defined as CPS score of at least 1%)[26]. 
While the responses were durable, in the intent to treat population the 6-months PFS (6-
PFS) was only 14.1% and the median PFS was 2.0 months. These findings highlight the 
remaining unmet need for the majority of patients who either are refractory or develop 
disease progression following treatment with single agent checkpoint inhibitors. 
Cabozantinib has been safely combined with PD-1 and PD-L1 inhibitors in solid 
tumors[30], [31]. A recently reported study examined the efficacy of cabozantinib in 
patients with RCC who progressed on immune checkpoint blockade. Overall, 
cabozantinib showed promising activity with an ORR of 33% and DCR of 79%, with a 
median TTF of 6.6 months[32]. We hypothesize that cabozantinib, based on preclinical 
and clinical observations so far, might contribute to overcoming resistance to PD-1 
blockade in mGC. The proposed trial would be in line with regards to medical strategy 
and anticipated trends for treatment of mGC. It is highly likely that in the short to mid-term 
the frontline treatment for mGC patients will become a combination of doublet 
fluoropyrimidine/platinum chemotherapy and checkpoint inhibitors (with trastuzumab if 
Her- 2 positive[NCT03382600, NCT02901301, NCT02872116]). Nevertheless, the 

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majority of these patients are expected to eventually progress, which highlights the future 
unmet need of 2L+ treatment options after standard doublet+IO failure. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To estimate the efficacy of cabozantinib in combination with pembrolizumab in 
patients with advanced gastric and gastroesophageal adenocarcinoma who have 
progressed at least on one line of therapy 
2.2 
Secondary Objectives  
 
2.2.1 
To describe the adverse events associated with cabozantinib in combination with 
pembrolizumab in patients with advanced gastric and gastroesophageal 
adenocarcinoma 
 
2.2.2 
In patients with measurable disease, to describe any preliminary evidence of 
anti-tumor activity by assessment of objective response as determined by 
RECIST v1.1 in patients with advanced gastric and gastroesophageal 
adenocarcinoma 
 
2.3 
Endpoints 
The primary endpoint is 6 months progression-free survival (PFS-6). 
The secondary endpoints are rates of drug-related grade 3-5 adverse events experienced 
during and up to four weeks after completion of study treatment. These will be assessed 
via NCI’s CTCAE v5.0 toxicity criteria. Other secondary endpoints are best objective 
response rate by RECIST v1.1 in patients with measurable disease and overall survival. 
3.0 
PATIENT ELIGIBILITY 
3.1 
Inclusion Criteria 
 
 
3.1.1   Patients must have histologically or cytologically confirmed gastric or 
gastroesophageal adenocarcinoma 
 
 
3.1.2     Must have locally advanced, recurrent, or metastatic disease not amenable to 
curative intent surgery. 
 
 
3.1.3 
Must have progressed, or not tolerated, at least one line of treatment with a 
platinum and/or fluoropyrimidine containing regimen. At least one cycle of 
combination chemotherapy including a platinum (oxaliplatin, cisplatin, 
carboplatin) and/or fluoropyrimidine (capecitabine or 5-Fluorouracil) based 
regimen for advanced disease. Combination regimens with 
platinum/fluoropyrimidine containing a taxane and or a checkpoint inhibitor are 
allowed. Patients progressing within six months of perioperative chemotherapy or 
definitive chemoradiation for localized disease are eligible. Patients who have 
exhausted all other standard of care options are also eligible. 
 
 
3.1.4 
Must have received and progressed on one previous line of treatment containing 
a checkpoint inhibitor (if PD-L1 CPS score unknown or ≥ 10%). Patients with PD-

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L1 CPS score < 10% are eligible independent of whether they have received 
previous checkpoint inhibitors. 
 
 
 
3.1.5 
Age ≥ 18 years.  
Because no dosing or adverse event data are currently available on the use of 
cabozantinib in patients <18 years of age, children are excluded from this study 
but will be eligible for future pediatric single-agent trials, if applicable. 
 
  
3.1.6   Performance status: ECOG performance status ≤2 (Appendix A). 
 
 
 
3.1.7  
Life expectancy of greater than 3 months 
       
 
 
3.1.8     Adequate organ and marrow function as defined below: 
 
Leukocytes 
≥ 2,000/mcL 
absolute neutrophil count 
≥ 1000/mcL 
platelets 
≥ 60,000/mcl 
total bilirubin 
within normal institutional limits (or 
<3mg/dL in patients with Gilbert’s 
disease) 
AST(SGOT)/ALT(SPGT) 
≤ 3 X institutional upper limit of 
normal or ≤ 5 X if liver metastases 
are present 
creatinine 
< 1.5 X upper limit of normal  
hemoglobin 
≥ 8 g/dL 
Serum albumin 
≥ 2.8 g/dL 
Urine protein/creatinine ration (UPCR) 
≤ 1 mg/mg 
 
 
3.1.9  
The effects of cabozantinib on the developing human fetus at the recommended 
therapeutic dose are unknown.  For this reason, women of child-bearing potential 
and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry, for the duration of study 
participation, and for 4 months following completion of therapy. Should a woman 
become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
 
3.1.9.1 A female of child-bearing potential is any woman (regardless of 
sexual orientation, having undergone a tubal ligation, or 
remaining celibate by choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral 
oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the 
preceding 12 consecutive months). 
 
3.1.10 Ability to swallow tablets 
 
3.1.11  Ability to understand and the willingness to sign a written informed consent. 
 
3.1.12  Patients with known MSI-High or dMMR tumors must have disease progression 
after at least one line of immunotherapy 
 

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3.2 
Exclusion Criteria 
 
3.2.1 
Patients who have had chemotherapy within 2 weeks prior to entering the study  
 
3.2.2 
All toxicities attributed to prior anti-cancer therapy other than alopecia must have 
resolved to grade 1 or baseline  
 
3.2.3 
Patients may not be receiving any other investigational agents. 
 
3.2.4 
Patients with known brain metastases or cranial epidural disease unless 
accurately treated with radiotherapy and/or surgery (including radiosurgery) and 
stable for at least 4 weeks before first dose of study treatment. These individuals 
should be excluded from this clinical trial because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that would 
confound the evaluation of neurologic and other adverse events. Eligible subjects 
must be neurologically asymptomatic and without corticosteroid treatment at the 
time of the first dose of study treatment.   
 
3.2.5 
History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to pembrolizumab, cabozantinib or other agents used in 
study. Patients with documented previous immune related toxicities which led to 
discontinuation of a checkpoint inhibitor.  
 
3.2.6 
Concomitant anticoagulation with oral anticoagulants (eg, warfarin), direct 
thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitors betrixaban, or 
platelet inhibitors (eg, clopidogrel).  
Allowed anticoagulants are the following: 
 
a. Prophylactic use of low-dose aspirin for cardio-protection (per local 
applicable guidelines) and low-dose low molecular weight heparins (LMWH). 
b. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in subjects without known brain 
metastases who are on a stable dose of the anticoagulant for at least 1 week 
before first dose of study treatment without clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor. 
 
3.2.7 
The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) 
test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study 
treatment.  
 
3.2.8 
Uncontrolled intercurrent illness including, but not limited to, the following 
conditions:  
 
a. ongoing or active infection 
b. symptomatic congestive heart failure 
c. uncontrolled hypertension defined as sustained blood pressure (BP) > 150 
mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive 
treatment 
d. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), 
or other ischemic event, or thromboembolic event (eg, deep venous 
thrombosis, pulmonary embolism) within 6 months before first dose 
e. unstable angina pectoris 
f. 
cardiac arrhythmia 

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g. evidence of tumor invading GI tract, active peptic ulcer disease, inflammatory 
inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction 
of the pancreatic duct or common bile duct, or gastric outlet obstruction. 
h. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed 
before first dose. 
i. 
Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 
teaspoon (2.5 ml) of red blood, or other history of significant bleeding (eg, 
pulmonary hemorrhage) within 12 weeks before first dose. 
j. 
Cavitating pulmonary lesion(s) or known endotracheal or endobronchial 
disease manifestation. 
k. Lesions invading any major blood vessels. 
l. 
Other clinically significant disorders that would preclude safe study 
participation: 
i. 
Serious non-healing wound/ulcer/bone fracture 
ii. 
Uncompensated/symptomatic hypothyroidism  
iii. 
Moderate to severe hepatic impairment (Child-Pugh B or C)  
m. psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.9 
Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of 
brain metastasis) within 2 weeks before first dose of study treatment. Minor 
surgeries within 10 days before first dose. Subjects must have complete wound 
healing from major surgery or minor surgery before first dose of study treatment. 
Subjects with clinically relevant ongoing complications from prior surgery are not 
eligible. 
 
3.2.10 Prior treatment with cabozantinib 
 
3.2.11 Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 28 days before first dose of study treatment. 
 
    Corrected QT (QTc) = QT / ∛RR 
 
QT: duration of QT interval 
RR: duration of RR interval  
 
 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two 
additional ECGs at intervals of approximately 3 min must be performed within 30 
min after the initial ECG, and the average of these three consecutive results for 
QTcF will be used to determine eligibility. 
 
3.2.12 Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 2 weeks before first dose of study treatment. 
 
3.2.13 History of another primary cancer within the last 3 years with the exception of 
non-melanoma skin cancer, early-stage prostate cancer, or curatively treated 
cervical carcinoma in-situ and not treated with systemic therapy. 
 
3.2.14 Inability to comply with study and follow-up procedures as judged by the 
Investigator 
 

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3.2.15 Patients must not be pregnant or nursing due to the potential for congenital   
 
 
  
abnormalities and the potential of this regimen to harm nursing infants.  
 
 
 
3.2.16 Has squamous cell or undifferentiated gastric cancer. 
 
3.2.17 Has received prior cytotoxic, biologic or other systemic anticancer therapy 
including investigational agents within 2 weeks prior to randomization. 
 
3.2.18 Radiation therapy for bone metastasis within 2 weeks, any other radiation 
therapy within 4 weeks before 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. 
 
3.2.19 Has received a live vaccine within 30 days prior to the first dose of study 
intervention. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, 
rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
3.2.20 Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid 
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study 
intervention. 
 
3.2.21 Has severe hypersensitivity (Grade ≥ 3) to pembrolizumab or cabozantinib and/or 
any of their excipients. 
 
3.2.22 Has an active autoimmune disease that has required systemic treatment in past 
2 years (i.e., with use of disease‐modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment and is allowed. 
 
3.2.23 Has a history of (non‐infectious) pneumonitis that required steroids or has current 
pneumonitis. 
 
3.2.24 Has an active infection requiring systemic therapy. 
 
3.2.25 Has a known history of human immunodeficiency virus (HIV) infection. 
 
 
Note: No HIV testing is required unless mandated by local health authority. 
 
3.2.26 Has a known history of active tuberculosis (TB; Bacillus tuberculosis). 
 
3.2.27 Has a history or current evidence of any condition (eg, known deficiency of the 
enzyme dihydropyrimidine dehydrogenase), therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's 
participation for the full duration of the study, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator. 
 
 

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3.3  
Inclusion of Women, Minorities, Vulnerable Populations Both men and women and 
members of all races and ethnic groups are eligible for this trial. Non-English speaking, 
deaf, hard of hearing and illiterate individuals are eligible for this trial. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
 
4.1.1 
Patients will be treated with cabozantinib 40 mg p.o. on days 1-21 and 
pembrolizumab 200 mg i.v. on day 1 every 21 days.  
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Cabozantinib 
None 
40 mg daily 
 
At least 1 
hour before 
or at least 2 
hours after 
eating 
Days 1-21 
3 weeks 
(21 
days) 
 
Pembrolizumab 
Supportive care 
for infusion 
reactions per 
institutional 
guidelines 
200 mg in  
50 
cc 
NS 
0.9% over 30 
min 
IV  
Day 1 
 
 
4.1.2 
Concomitant Medications   
 
 
4.1.2.1  Allowed Therapy:  
 
 
• 
Antiemetics and antidiarrheal medications are allowed prophylactically according to 
standard clinical practice if clinically indicated.  
• 
Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per 
clinical guidelines (e.g., ASCO or ESMO guidelines).  
• 
Bisphosphonates or RANK-L inhibitors can be used to control bone loss or hypocalcemia 
if the benefit outweighs the risk per the Investigator’s discretion. 
 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates 
(Section 7.1.2). Oral examinations are recommended at screening to determine eligibility 
and periodically during the study. In addition, subjects should be advised regarding oral 
hygiene practice and to quickly report symptoms to the Investigator. Frequent monitoring 
for potentially overlapping toxicities with study treatment is recommended. Withhold 
cabozantinib for at least 3 weeks prior to scheduled dental surgery or invasive dental 
procedures, if possible. Withhold cabozantinib for development of ONJ until complete 
resolution 
• 
Transfusions and hormone replacement should be utilized as indicated by standard 
clinical practice. 
• 
Inhaled, intranasal, intra-articular, and topical corticosteroids are allowed if minimal 
systemic absorption. Systemic corticosteroids are allowed for control of infusion reactions 
or irAEs and must be tapered to a dose level ≤ 10 mg/day of prednisone equivalent 
before next administration of the IO agent. Prophylactic steroid treatment for subjects 
with contrast allergies prior to tumor imaging is allowed.   

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• 
Individualized anticoagulation therapy with heparin or direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and effectively 
under the following circumstances: 
• 
At the time of first dose of study treatment: 
 
Low dose low molecular weight heparins (LMWH) for prophylactic use 
are allowed if clinically indicated and the benefit outweighs the risk per 
the Investigator’s discretion. 
 
Therapeutic doses of LMWH or the direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed if the subject has no 
evidence of brain metastasis, has been on a stable dose of the 
anticoagulant for at least 1 week, and has had no clinically significant 
hemorrhagic complications from the anticoagulation regimen or the 
tumor. See Section 4.1.2.2 for prohibited anticoagulants. 
• 
After first dose of study treatment: 
 
Low dose low molecular weight heparins (LMWH) for prophylactic use 
are allowed if clinically indicated and the benefit outweighs the risk per 
the Investigator’s discretion. 
 
Therapeutic doses of LMWH or the direct factor Xa oral inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed if clinically indicated 
(e.g., for the treatment of DVT), and the benefit outweighs the risk per 
the Investigator’s discretion. See section 7.1.2 for management of 
thromboembolic complications while on study. See section 4.1.2.2 for 
prohibited anticoagulants. Accepted clinical guidelines regarding 
appropriate management while receiving any kind of anticoagulation 
therapy must be followed. This includes, but is not limited to, subject 
education regarding the potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (e.g., due to kidney 
dysfunction). Caution is warranted in settings associated with an 
increased risk for bleeding such as gastrointestinal cancers, urothelial 
cancers, gastrointestinal mucosal abnormality (e.g., mucositis), renal or 
hepatic impairment, thrombocytopenia, arterial hypertension, or prior 
history of gastrointestinal bleed. For direct factor Xa inhibitors, the 
potential for drug-drug interaction with other concomitant medications, as 
well as gastrointestinal absorption, should be considered. Aspirin and 
other nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used 
concomitantly with heparin or factor Xa inhibitors due to the increased 
risk for bleeding complications. The risks and benefits of the use of 
anticoagulants should be reassessed on a regular basis. For more 
information regarding the use of anticoagulants, refer to the prescribing 
information of the anticoagulant and accepted clinical practice guidelines. 
 
4.1.2.2  Prohibited or Restricted Therapy: 
 
The following therapies are prohibited until study treatment has been permanently 
discontinued: 
• 
Any investigational agent or investigational medical device. 
• 
Oral anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors 
(e.g., dabigatran), direct factor Xa inhibitor betrixaban, platelet inhibitors (e.g., 
clopidogrel), and chronic use of aspirin above low dose levels for cardio-protection 
per local applicable guidelines), until 4 weeks after cabozantinib has been 
permanently discontinued. 
• 
Any non-protocol systemic anticancer treatment (e.g., chemotherapy, 
immunotherapy, radionuclides, drugs or herbal products used specifically for the 
treatment of the cancer under investigation). 

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• 
Immunosuppressive agents including immunosuppressive doses of systemic 
corticosteroids with exceptions as stated in Section 4.1.2.1. 
• 
Live vaccines are prohibited while on study and until 5 months after last dose of IO 
agent (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow 
fever, varicella, and TY21a typhoid vaccines). The use of inactivated (killed) 
vaccines for the prevention of infectious disease is permitted. 
• 
Metamizole (dipyrone) because of its potential for causing agranulocytosis. 
 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• 
Local anticancer treatment including palliative radiation, ablation, embolization, or 
surgery with impact on tumor lesions should not be performed until radiographic 
progression per RECIST 1.1 has been established.  
• 
Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not 
be used based on a report of increased risk of tumor recurrence/progression 
associated with erythropoietin (Wright et al 2007). 
• 
Concomitant medications that are known to prolong the QTc interval should be 
avoided in subjects who receive cabozantinib until they have permanently 
discontinued cabozantinib treatment (refer to http://www.qtdrugs.org for a list of 
drugs which have the potential to prolong the QTc interval). 
• 
Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., 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, as 
this could significantly increase the exposure to cabozantinib.  
• 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., 
boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, 
telaprevir, telithromycin, and voriconazole) may increase cabozantinib 
concentrations and should be avoided. Grapefruit, star fruit, and Seville oranges 
may also increase plasma concentrations of cabozantinib and should be avoided. 
 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.5). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 5.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
Cabozantinib and pembrolizumab have class specific safety profiles based on their 
mechanism of action but may also cause AEs that overlap. For management of AEs 
which can be clearly attributed to cabozantinib or pembrolizumab, independent dose 
modification for either agent is allowed. Examples of VEGFR TKI associated AEs caused 
by cabozantinib are hypertension and hand-foot syndrome. Examples of immune-related 
AEs caused by pembrolizumab are pneumonitis and endocrinopathies. For AEs without 
clear attribution to either study treatment, management of toxicity should include dose 
modifications of both agents per the discretion of the investigator. Examples of 
overlapping AEs are diarrhea and transaminase increases. 
 

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Dose Modification Table  
 
Dose Level  
Agent  
Dose 
1 (starting dose) 
Cabozantinib 
40 mg 
1 (starting dose) 
Pembrolizumab 
200 mg 
 
 
 
-1 (50% reduction) 
Cabozantinib 
20 mg 
 
 
 
-2  
Cabozantinib 
20 mg every other day 
 
 
 
Toxicities:  
 
Toxicity Dose Reductions 
NCI CTC Grade 
Cabozantinib 
Pembrolizumab 
Grade 0-2 
No change from original starting 
dose  
No change from original starting dose 
(unless described in 4.2.1) 
Intolerable grade 2 
or grade 3  
Hold until resolved to < Grade 1 
then resume to dose level 1 or -1, 
depending on physician 
assessment 
Hold until resolved to < Grade 2, then 
resume at dose level 1 
(unless described in 4.2.1) 
Second episode of 
grade 3 or 
intolerable grade 2 
 
first episode of 
grade 4 toxicity 
Hold until resolved to < Grade 1 
then reduce to dose level one 
less than previous (i.e. -1 or -2) 
 
Discontinue permanently  
(unless investigator determines 
patient is deriving clear clinical 
benefit) 
Discontinue permanently 
(unless described in 4.2.1) 
Third episode of 
grade 3  
Remove subject from trial 
Not applicable 
 
4.3 
Pembrolizumab adjustment for toxicity 
No dosage reductions of pembrolizumab are recommended; treatment is withheld or 
discontinued to manage toxicities. 
  
Colitis (immune-mediated): 
 
Grade 2 or 3: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 
mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 
1 toxicity after corticosteroid taper. 
 
Grade 4: Permanently discontinue pembrolizumab; administer corticosteroids 
(prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).  
 
Dermatologic toxicity (immune-mediated): 
 
Grade 3 severe skin reactions or suspected Stevens-Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN): Withhold pembrolizumab and refer for specialized care for 
assessment and treatment; may require corticosteroids (based on the severity). 
 

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Grade 4 severe skin reactions or confirmed SJS or TEN: Permanently discontinue 
pembrolizumab and refer for specialized care for assessment and treatment; may require 
corticosteroids (based on the severity). 
 
Endocrinopathies (immune-mediated): 
 
Grade 3 or 4: Withhold pembrolizumab until clinically stable. 
 
Hyperglycemia, severe: Also administer antihyperglycemics. 
 
Hyperthyroidism, severe (grade 3) or life-threatening (grade 4): Manage with thionamides 
and beta blockers as appropriate; may resume upon recovery to grade 0 or 1 toxicity or 
discontinue. 
 
Hypophysitis, grade 2 (symptomatic): Also administer corticosteroids (followed by a 
taper) and hormone-replacement therapy if appropriate; may resume upon recovery to 
grade 0 or 1 toxicity or discontinue. 
 
Hypophysitis, grade 3 or 4: Withhold or discontinue pembrolizumab (based on severity); 
also administer corticosteroids (followed by a taper) and hormone-replacement therapy 
as clinically indicated. 
 
Nephritis (immune-mediated): 
 
Grade 2: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 
mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 
1 toxicity after corticosteroid taper. 
 
Grade 3 or 4: Permanently discontinue pembrolizumab; administer corticosteroids 
(prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).  
 
Pneumonitis (immune-mediated): 
 
Grade 2: Withhold pembrolizumab; administer corticosteroids (prednisone 1 to 2 
mg/kg/day [or equivalent] followed by a taper); may resume upon recovery to grade 0 or 
1 toxicity after corticosteroid taper. 
 
Grade 3 or 4 or recurrent grade 2: Permanently discontinue pembrolizumab; administer 
corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper). 
 
Other immune-mediated toxicities: 
 
Grade 2 or grade 3 (based on the severity and type of reaction): Withhold 
pembrolizumab; 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). 
 
Grade 3 (based on the severity and type of reaction) or grade 4: Permanently discontinue 
pembrolizumab; also administer corticosteroids (may consider other systemic 
immunosuppressants if not controlled by corticosteroids [based on limited data]). 
 

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Recurrent immune-mediated adverse reactions, grades 3 or 4: Permanently discontinue 
pembrolizumab; also administer corticosteroids (may consider other systemic 
immunosuppressants if not controlled by corticosteroids [based on limited data]). 
 
Inability to taper corticosteroids: Permanently discontinue pembrolizumab if unable to 
reduce corticosteroid dose to prednisone <10 mg/day (or equivalent) within 12 weeks 
after last pembrolizumab dose (may consider other systemic immunosuppressants if not 
controlled by corticosteroids [based on limited data]). 
 
Persistent grade 2 or 3 adverse reaction (excluding endocrinopathy) that does not 
recover to grade 0 or 1 within 12 weeks after the last pembrolizumab dose: Permanently 
discontinue pembrolizumab; also administer corticosteroids (may consider other systemic 
immunosuppressants if not controlled by corticosteroids [based on limited data]). 
 
Infusion-related reaction: 
 
Grade 1 or 2: Interrupt infusion or slow the infusion rate. 
Grade 3 or 4: Permanently discontinue pembrolizumab. 
4.4 Cabozantinib adjustment for toxicity 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, 
weight decreased, PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, 
asthenia, and dyspnea.  
 
Subjects may also experience other medically important but less frequent AEs including 
arterial thrombotic AEs (e.g., deep vein thrombosis [DVT], pulmonary embolism, transient 
ischemic attack [TIA], and myocardial infarction [MI], severe hemorrhagic events, 
proteinuria, wound healing complications, gastrointestinal (GI) perforation, abscesses 
including intra-abdominal and pelvic abscess, GI and non-GI fistula formation, 
osteonecrosis, and reversible posterior leukoencephalopathy syndrome (RPLS). 
 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of 
subjects treated with cabozantinib in descending order of frequency were anemia, AST 
increased, ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, 
thrombocytopenia, hypocalcemia, hypophosphatemia, lactate dehydrogenase (LDH) 
increased, lipase increased, neutropenia, hyponatremia, ALP increased, hyponatremia, 
and leukopenia. 
 
Many adverse events may occur early (within the first few weeks) in the course of 
treatment with cabozantinib, as cabozantinib is expected to reach steady state exposure 
at approximately 2 weeks following first dose. Events that generally have an early onset 
include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPES, abdominal 
pain, mucosal inflammation, constipation, diarrhea, and vomiting. 
 
Adverse events should be managed with supportive care at the earliest signs of toxicity. 
Dose reductions and treatment interruptions should be considered. Dose reductions are 
recommended for events that, if persistent, could become serious or intolerable (Section 
4.2). 
 
Cabozantinib should be discontinued for the following AEs: visceral perforation or fistula 
formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic 
syndrome, hypertensive emergency, persistent uncontrolled hypertension despite optimal 
medical management, and reversible posterior leukoencephalopathy syndrome (RPLS). 

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Gastrocintestinal Disorders 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After 
starting treatment with 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 [37] are present. Discontinue 
cabozantinib and initiate appropriate management in subjects who have been diagnosed 
with GI perforation or fistula. 
 
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. 
Guidelines for the evaluation and management of diarrhea are shown in Table 9. 
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, cabozantinib should be temporarily interrupted or 
dose reduced. When the diarrhea is controlled, retreatment with cabozantinib may be 
acceptable per investigator decision. 
 
In addition, general supportive measures should be implemented such as continuous oral 
isotonic hydration, correction of fluid and electrolyte abnormalities, small frequent meals, 
and stopping lactose-containing products, high-fat meals, and alcohol. 
 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions 
which increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene 
should be emphasized. Regular examinations of the perianal region should be performed 
whenever diarrhea has occurred during treatment with cabozantinib. Infections of the 
perianal region should be treated per local guidelines. 
 
Table 9:  
Management of Diarrhea Associated with Cabozantinib 

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Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (eg, loperamide 4 mg 
followed by 2 mg after each episode of diarrhea [maximum: 16 mg 
loperamide per day]) 
• 
Dietary modifications (eg, small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add solid 
foods and discontinue or decrease antidiarrheal treatment after 
12 h diarrhea-free interval 
o 
Diarrhea not resolving: Continue/resume antidiarrheal treatment  
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend clinic 
• 
Rule out infection (eg, stool sample for culture) 
o 
Administer antibiotics as needed (eg, if fever or Grade 3-4 
neutropenia persists > 24 h) 
• 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration 
or to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower grade diarrhea consider 
hospitalization and IV hydration 
• 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: 
consider restarting study treatment at reduced dose 
o 
Diarrhea not resolving: Start and or continue antidiarrheal 
treatment (eg, loperamide 4 mg followed by 2 mg after each 
episode of diarrhea [maximum: 16 mg loperamide per day]). 
Consider starting second line antidiarrheal or referral to 
gastroenterologist 
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for 
treatment or prophylaxis of nausea and vomiting, along with supportive care. Dehydration 
and electrolyte abnormalities may be associated with vomiting and monitoring for and 
correction of fluid and electrolyte disturbances should be implemented. Antiemetic 
medications should be assessed for potential drug interactions (refer to Section 7.1.3 for 
further details). 
 
Non-Gastrointestinal Fistula 
Complications from radiation therapy especially of the thoracic cavity including 
mediastinum have been identified as a possible predisposing risk factor for non-GI fistula 
formation in subjects undergoing treatment with VEGF pathway inhibitors. 
 
Discontinue cabozantinib and initiate appropriate management in subjects who have 
been diagnosed with a non GI fistula. 
 
Hemorrhage 
Hemorrhagic events, including serious and sometimes fatal events, have been reported 
with cabozantinib. Subjects should be monitored for bleeding events with serial complete 
blood counts and physical examination while on study. The risk of hemorrhage in 
cabozantinib-treated subjects with brain metastases has not been thoroughly analyzed. 
Subjects enrolled with treated and stable brain metastases should be monitored with a 
high index of suspicion if symptoms that could be due to a CNS hemorrhage occur. 

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Cabozantinib should be discontinued in subjects with serious and life-threatening 
bleeding events or recent hemoptysis (≥ 2.5 mL of red blood). 
 
Thromboembolic events 
Refer to section 7.1.2 
 
Hypertension 
Table 10 provides treatment guidelines for hypertension deemed related to cabozantinib. 
Blood pressure should be monitored in a constant position visit to visit, either sitting or 
supine in a relaxed setting. Decisions to reduce or interrupt the dose of study treatment 
must be based on BP readings taken by a medical professional and must be confirmed 
with a second measurement at least 5 minutes following the first measurement.  
 
Cabozantinib should be discontinued in subjects with hypertensive emergency. 
 
Table 10: 
Management of Hypertension Associated with 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 cabozantinib treatment by one dose level if 
optimal antihypertensive therapy (usually to include 3 
agents) does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic 
• If subject is symptomatic interrupt cabozantinib treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
cabozantinib 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, cabozantinib treatment should 
be dose reduced further or interrupted 
• 
Cabozantinib 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 cabozantinib 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 cabozantinib 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 BP with clinical evidence of progressive or impending 
end-organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary 
edema, encephalopathy, kidney damage). 

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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 non-traumatic and non-irritating 
cleansing, and oral rinses (eg, with a weak solution of salt and baking soda) should be 
maintained. Lips should be kept moisturized with lip balm. The use of lipstick, lip-gloss, 
and Vaseline should be avoided. 
 
Local treatment should be instituted at the earliest onset of symptoms. Obtain 
bacterial/viral culture if oral infection is suspected and treat infection as clinically 
indicated. 
 
Skin and Subcutaneous Tissue Disorders 
Wound healing and surgery: Refer to section 7.1.2 
 
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot 
syndrome), skin rash (including blister, erythematous rash, macular rash, skin exfoliation, 
dermatitis acneiform, and papular rash), pruritus, dry skin, erythema, pigmentary 
changes, and alopecia have been reported with cabozantinib. All subjects on study 
should be advised on prophylactic measures including the use of emollients, removal of 
calluses, avoidance of exposure of hands and feet to hot water leading to vasodilatation, 
protection of pressure-sensitive areas of hands and feet, and use of cotton gloves and 
socks to prevent injury and keep the palms and soles dry. 
 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical 
red and swollen areas on the palms and soles. The lateral sides of the fingers or 
periungual 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. Analgesics may be required for pain control. 
 
Aggressive management of symptoms is recommended, including early dermatology 
referral. Treatment recommendations in response to PPES are summarized in Table 11. 
 

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Table 11: 
Management of Hand-Foot Syndrome (PPES) Associated with 
Cabozantinib 
CTCAE v.5.0 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if PPES is 
clinically insignificant and tolerable. Otherwise, cabozantinib 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  
Cabozantinib treatment may be continued if PPES is tolerated. 
Cabozantinib should be dose reduced or interrupted if PPES is intolerable. 
Continue urea 20% cream twice daily AND high potency steroid cream (eg, 
clobetasol 0.05%) 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 cabozantinib treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with high potency steroid cream (eg, 
clobetasol 0.05%) 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. 
 
Osteonecrosis 
Refer to section 7.1.2  
 
Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by 
measuring UPCR. Table 12 provides treatment guidelines for proteinuria deemed related 
to cabozantinib.  
 
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome 
(proteinuria > 3.5 grams per day in combination with low blood protein levels, high 
cholesterol levels, high triglyceride levels, and edema).  
 

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Table 12: 
Management of Proteinuria Associated with Cabozantinib 
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-h protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine 
collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider interrupting 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 interruption. 
• 
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) 
• 
Interrupt cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt 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 cabozantinib treatment 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 
 
Nervous System Disorders  
Cabozantinib appears to represent minimal risk of adverse neurological effects based on 
nonclinical Good Laboratory Practice (GLP)-compliant toxicology studies. Dysphonia, 
dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory 
impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy 
have been observed in clinical studies with cabozantinib. The development of any new or 
progressive, unexplained neurological symptoms should be assessed for underlying 
causes. 
 
RPLS has been reported. RPLS should be considered in any subject presenting with 
seizures, headache, visual disturbances, confusion or altered mental function. 
Cabozantinib treatment should be discontinued in subjects with RPLS. 
 
Hepatocellular Toxicity  
Elevation of aminotransferases (ALT and AST): Evaluation of subjects with elevated 
transaminases or bilirubin should be individualized and guided by the presence of 
specific risk factors such as liver conditions (eg, liver cirrhosis, metastases to the liver, 
thrombosis of portal or hepatic vein, hepatocellular carcinoma, hepatitis), concomitant 
hepatotoxic medication, alcohol consumption, and cancer related causes.  

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Cabozantinib should be interrupted for related CTCAE Grade 3 or higher hepatic injury 
(transaminase increase to > 5 x ULN) and when transaminase increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation 
tests (eg, International Normalized Ratio [INR]). More frequent monitoring of 
transaminases should be considered and cabozantinib should be interrupted until the 
etiology of the abnormalities is determined and these abnormalities are corrected or 
stabilize at clinically acceptable levels. Cabozantinib should be discontinued if hepatic 
dysfunction is not reversed despite interruption of study treatment. Elevations of 
aminotransferases when hepatic metastases are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than a 
doubling) and if there are no progressive elevations in serum bilirubin concentration or 
coagulation factors. Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total 
bilirubin without other explanation (such as initial findings of cholestasis and obstructive 
disease, viral hepatitis, pre-existing or acute liver disease, or another drug capable of 
causing the observed injury) can indicate drug-induced liver injury (DILI). Study drug 
should be permanently discontinued in cases determined to be DILI according to Hy’s 
Law review. 
 
Infections and Infestations 
Refer to section 7.1.2 
 
Blood and Lymphatic System 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. Subjects with hematologic 
toxicities may require additional or more frequent laboratory tests according to 
institutional guidelines. 
 
Dose reductions or dose interruptions for hematological toxicities are not mandated but 
can be applied as clinically indicated. Supportive care for thrombocytopenia or anemia, 
such as transfusions, may be managed according to institutional guidelines. The use of 
colony-stimulating growth factors should be considered. 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. 
 
Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress 
(depression and/or anxiety), poor nutrition, dehydration, sleep disturbance, and 
hypothyroidism should be ruled out and treated according to standard of care. 
Pharmacological management should be considered after disease specific morbidities 
have been excluded when not prohibited. 
 
Weight Loss  
Anorexia and weight loss should be managed according to local standard of care 
including nutritional support. Pharmacologic therapy should be considered for appetite 
enhancement when not prohibited by a particular protocol. 
 
Corrected QT 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 

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study had a QTcF > 500 ms. Review of the larger safety database (~5000 subjects 
exposed to cabozantinib in clinical trials and in post-marketing experience) confirmed the 
absence of safety concerns associated with QT prolongation. There were no events of 
torsades de pointes reported. 
 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 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, 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, the following actions must be 
taken: 
• 
Interrupt cabozantinib treatment 
• 
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. Cabozantinib 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 is not confirmed  
• 
Cabozantinib treatment has been interrupted through a minimum of 1 week 
following the return of the QTcF to ≤ 500 ms. 
• 
QT prolongation can be unequivocally associated with an event other than 
cabozantinib administration and is treatable/has been resolved  
 
Following reinitiation of study treatment, ECGs must be done as clinically indicated. 
Cabozantinib 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 after reinitiation of study treatment at a 
reduced dose 
 
Electrolyte Disorders 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with cabozantinib, and serum 
electrolyte levels should be monitored frequently while receiving cabozantinib. Clinically 
relevant electrolyte disorders should be managed according to the dose modification 
guidelines as outlined in Section 4.2 or as clinically indicated. Standard clinical practice 
guidelines should be used for management of electrolyte disorders and may include oral 
or intravenous replacement. 

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Endocrine Disorders 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed 
with cabozantinib treatment. Currently available data are insufficient to determine the 
mechanism of thyroid function test alterations and its clinical relevance. Management of 
thyroid dysfunction (eg, symptomatic hypothyroidism) should follow accepted clinical 
practice guidelines. 
 
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. 
4.5 
Concomitant Medications/Treatments 
Cabozantinib 
 
Strong CYP3A4 Inhibitors 
Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inhibitor 
increased the exposure of cabozantinib, which may increase the risk of exposure-related 
adverse reactions. Avoid coadministration of CABOMETYX with strong CYP3A4 
inhibitors. Reduce the dosage of CABOMETYX if coadministration with strong CYP3A4 
inhibitors cannot be avoided. Avoid grapefruit, grapefruit juice, star fruit and Seville 
oranges which may also increase exposure of cabozantinib. 
 
Strong CYP3A Inducers 
Coadministration of a cabozantinib capsule formulation with a strong CYP3A4 inducer 
decreased the exposure of cabozantinib, which may reduce efficacy. Avoid 
coadministration of CABOMETYX with strong CYP3A4 inducers. Avoid St. John’s Wort 
which may also decrease exposure of cabozantinib. 
 
Pembrolizumab 
 
Glucocorticoids 
Steroids in excess of a daily dose of 10mg prednisone equivalent have to be avoided due 
to immunosuppressive effects which can counteract the efficacy of pembrolizumab. 
 
Thalidomide Analogues 
Pembrolizumab may enhance the adverse/toxic effect of Thalidomide Analogues. 
Specifically, mortality may be increased when this combination is used for treatment of 
refractory multiple myeloma. Avoid combination. 
4.6 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until: 
• 
Disease progression as defined radiographic progression by RECIST v1.1 
criteria OR death OR symptomatic progression as clinically determined by 
the treating physician  
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Treatment held for more than 28 days 
• 
Patient decides to withdraw from the study, OR 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 

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4.7 
Duration of Follow Up 
Patients will be followed every 3 months until death or 18 months after the last patient is 
enrolled, whichever occurs first. Patients removed from treatment for unacceptable 
adverse events will be followed until resolution or stabilization of the adverse event. 
Follow-up after removal from treatment is every 3 months (either clinic visit or phone call).   
4.8 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 5.6 apply. 
Notify the Principal Investigator via email (fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu), and document the reason for study removal and the date the 
patient was removed in the Case Report Form. The patient should be followed-up per 
protocol.  
4.9 
Patient Replacement 
Patients will not be replaced 
5.0 
STUDY PROCEDURES 
 
Telemedicine Visits 
In-person visits are the preferred study visit method for collection of the assessments and 
procedures. Study visits conducted by phone or videoconferencing technology (i.e., “virtual” or 
“telemedicine” visits), including adverse event assessments for patients, may be substituted for 
protocol-required in-person visits, if the site investigator determines that the phone/virtual visit is 
adequate to achieve the central purpose of the visit. 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained as long as these assessments 
are completed within 28 days prior to registration. 
 
All screening procedures must be performed within 28 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Screening Confirmation 
Patient information should be entered into Oncore within 1 business day of 
consent. Sites are responsible for assigning subject ID. Sites will be assigned a 
unique site code. Subject IDs should follow a format with the unique site code 
followed by the sequential patient ID. For example, Site Code-Sequential Number 
(i.e. for UCI’s first patient the subject ID will be 01-01). (Refer to Oncore SOP for 
Oncore data entry instructions) 
5.1.3 Medical history 
Complete medical, oncology and surgical history, history of infections 
5.1.4 Demographics 
Age, gender, race, ethnicity 

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5.1.5 Review subject eligibility criteria 
5.1.6 Review previous and concomitant medications 
5.1.7 Physical exam  
5.1.8 Vital signs  
Temperature, pulse respirations, blood pressure, height, and weight (height only 
at screening)  
5.1.9 ECOG Performance status 
5.1.10 
Hematology 
Complete blood count with differential (CBC) 
5.1.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, hemoglobin, 
electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, TSH, 
fT3, fT4, total bilirubin, urine protein/creatinine ratio, PT/INR and PTT,. 
 
Tumor Markers (Optional) 
Carcinoembryonic antigen (CEA) and cancer-related antigen 19-9 (CA 19-9). 
5.1.12 
Urine studies 
Urine dipstick; if ++ or higher, random urine protein and creatinine, urine protein 
to creatinine ratio  
5.1.13 
12-lead ECG 
5.1.14 
Pregnancy test (for females of child bearing potential) 
See section 3.1.8.1 for definition.  
5.1.15 
Tumor assessment 
To be performed with computed tomography of the chest with contrast only (if 
contrast allergy, CT chest may be done without contrast), and abdomen/pelvis 
with contrast per physician discretion. CT abdomen/pelvis may be replaced with 
MRI Abdomen/pelvis per clinical judgement of the treating physician. Additional 
imaging is indicated at baseline if there is clinical suspicion for other organ 
involvement (e.g.. MRI or CT brain and bone scan). 
Imaging is to be performed at baseline within 28 days of starting treatment 
 
5.1.16 
Serious Adverse Events Assessment 
5.2 
Registration Procedures for participating sites only 
Prior to confirmation of registration the below items must be emailed via secure email to 
the initiating site for review and approval. 
 

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1. Redacted source documentation required to confirm eligibility (including but 
not limited to): 
a. Pathology report 
b. Physical exam including ECOG, medical and oncology history 
c. All screening labs 
2. Signed eligibility criteria  
 
All items must be emailed via secure email to (fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu) UCI CFCCC at least 3 business days before planned treatment 
start date. 
 
Upon receipt of all required documents, UCI CFCCC will provide confirmation of 
registration. Subjects may not begin study treatment without confirmation of registration.  
5.3 
Procedures During Treatment 
5.3.1 
Prior to Each Treatment Cycle 
• Physical exam, vital signs 
• Hematology 
• Serum chemistries 
• Adverse events 
• Study drug accountability 
• Review previous and concomitant medications 
• Pregnancy Test (if applicable)  
 
Site must maintain an accurate and timely record of dispensing of study drug to 
subject, and receipt of all study drug and pill diaries. 
 
5.3.2 
Within 30 days after treatment termination 
• Physical exam, vital signs 
• Hematology 
• Serum chemistries 
• Adverse events 
• Review previous and concomitant medications 
• Pregnancy Test (if applicable)  
5.3.3 
Tumor Assessments 
• To be completed every 8 weeks (+/- one week) during first year of treatment 
and every 3 months (+/- one week) after the first year until patient comes off 
study  
5.4 
Follow-up Procedures 
Patients will be followed every three months after completion of (or early withdrawal from) 
study treatment until death or up to 18 months after the last patient is enrolled, whichever 
comes first.  
• 
Review of systems and determination of live status (either in clinic during 
standard visit or by phone) 
5.5 
Time and Events Table 
 

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Baseline evaluations are to be conducted within 1 week prior to administration of protocol therapy.  
Scans and x-rays must be done ≤4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation 
of the next cycle of therapy. 
 
 
 
Baseline 
-28 to -1 
days 
C1D1 +/- 
3 days 
At every 
cycle (21 
days) +/- 3 
days 
q 8 
Weeks 
for first 
year, q 
3 
months 
after the 
first year 
+/- 1 
week 
Off 
Treatment 
Follow-
up (q 3 
months 
until 
death or 
up to 18 
months 
after last 
patient is 
enrolled, 
whicheve
r occurs 
first) +/- 
14 days 
Assessment 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and PE  
X 
X 
X 
 
X 
 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
Performance 
Status 
X 
X 
X 
 
X 
 
Adverse Events  
X** 
X 
X 
 
X 
 
Tumor 
Measurements 
X 
 
 
X 
 
 
CT CAP or CT 
chest/MRI 
Abd/Pelvis 
X 
 
 
X 
 
 
CBC / CMP / UA / 
UPCR 
X 
X 
X 
 
X 
 
PT/INR, PTT 
X 
X 
X*** 
 
 
 
TFTs (TSH, free 
T3, free T4) 
X 
X 
X*** 
 
 
 
CEA and CA 19-9 
(optional)**** 
 
 
X 
 
 
 
12-lead ECG 
X 
X 
X*** 
 
X 
 
Pregnancy Test* 
X 
X 
X*** 
 
X 
 
Review of 
systems 
 
 
 
 
 
X 
Study Drug 
Accountability 
 
 
X 
 
X 
 
*Urine or serum pregnancy test is done according to local institutional standard and should 
be obtained ONLY in women of child-bearing potential.  
** Only Serious Adverse Events will be assessed and reported during baseline 
*** To be done Day 1 of Weeks 3, 6, 9 and then every 4-6 weeks 
**** This is an optional component and should only be collected if done according to local 

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institutional standards. 
5.6 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Patient voluntarily withdraws from treatment (follow-up permitted);  
5.5.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.5.3 
Patient is unable to comply with protocol requirements; 
5.5.4 
Subjects who cannot tolerate the minimum protocol-specified dose of study 
treatment will have study treatment discontinued; 
5.5.5 
Patient demonstrates disease progression or subject no longer experiences 
clinical benefit as determined by the investigator (unless continued treatment with 
study drug is deemed appropriate at the discretion of the investigator); 
5.5.6 
Patient experiences toxicity, intercurrent illness, or specific conditions in section 
4.2 that makes continuation in the protocol unsafe; 
5.5.7 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.5.8 
Patient becomes pregnant or patient is breastfeeding (pregnancy to be reported 
along same timelines as a serious adverse event); 
5.5.9 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.10 Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception during the course of the study and for 4 months after 
discontinuation of study treatment 
5.5.11 Subjects who cannot tolerate the minimum protocol-specified dose of study 
treatment will have study treatment discontinued 
5.5.12 If a 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 of the toxicity and with 
agreemtn of the investigator 
5.5.13 Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol 
5.5.14 Lost to follow-up. If a research subject cannot be located to document survival 
after 3 attempts including 1 mailed certified letter, the subject may be considered 
“lost to follow-up.” All attempts to contact the subject during the two years must 
be documented and approved by the Data Monitoring Committee. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
 

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Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
6.1.1 
Definitions 
Evaluable: All patients receiving cycle 1, day 1 of the protocol treatment.  
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response. Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for response. 
These patients will have their response classified according to the definitions 
stated below. (Note: Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of 
the lesions.  
 
6.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with 
spiral CT scan. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
 
 
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions 
 

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Target lesions. All measurable lesions up to a maximum of 3 lesions per organ 
and 6 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 28 days before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT and MRI. These techniques should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to tumors of the 
chest, abdomen, and pelvis. MRI is also acceptable in certain situations (e.g. for 
body scans).  Scans will be done within 28 days prior to cycle 1 and after that 
every 8 weeks (+/- 7 days) until end of treatment. 
 
Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or 
stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 

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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. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD 
of target lesions, taking as reference the smallest sum 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. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): 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 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at 
least once >4 
wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 

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disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation of 
treatment. 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target 
Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment 
of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised 
 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
 
 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression or death, whichever occurs first. 
 
Progression is defined as death, radiographic progression as defined in 6.1.4.3, 
or clinical deterioration attributed to disease progression as judged by the 
investigator. 
 
 

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6.2 
Safety/tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug. The study will use the CTCAE version 5.0 for reporting of non-hematologic adverse 
events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for hematologic 
adverse events. 
7.0 
ADVERSE EVENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list 
of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether 
the event requires expedited (via AdEERS) reporting in addition to routine reporting.   
 
7.1 
Experimental Therapy 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
7.1.1 
Contraindications 
Cabozantinib and pembrolizumab have no known contraindications. 
 
7.1.2 
Special Warnings and Precautions for Use 
Cabozantinib 
 
Dermatologic toxicity: Palmar-plantar erythrodysesthesia syndrome (PPES) 
was commonly observed in clinical trials; severe PPES (≥ grade 3) also occurred. 
May require treatment interruption, dosage reduction, and/or discontinuation. 
 
GI toxicity: Diarrhea was commonly observed in cabozantinib-treated patients in 
clinical trials. May require therapy interruption and/or dosage reduction. 
Cabozantinib is associated with a moderate emetic potential; antiemetics are 
recommended to prevent nausea/vomiting. [US Boxed Warning]: Cometriq: 
Serious GI perforations and fistulas have been reported when used for medullary 
thyroid cancer; discontinue for GI perforation or fistula formation. May be fatal. 
Tracheal/esophageal fistulas were also noted; some cases were fatal. GI 
fistula/perforation (including fatal perforations) were also reported in patients 
treated with cabozantinib. Monitor for signs/symptoms of perforations and 
fistulas, including abscess and sepsis. May require therapy discontinuation. 
 
Hemorrhage: [US Boxed Warning]: Cometriq: Serious and occasionally fatal 
hemorrhage (including hemoptysis and gastrointestinal) has occurred with 
cabozantinib when used for medullary thyroid cancer. Monitor for 
signs/symptoms of bleeding and do not administer to patients with severe 
hemorrhage or a recent history of hemorrhage or hemoptysis. Severe 
hemorrhage has also been reported in patients with renal cell cancer and 
hepatocellular carcinoma, including grade 3 or higher events. Do not administer 
to patients who have a recent history of hemorrhage, including hemoptysis, 
hematemesis, or melena. Discontinue for grade 3 or 4 hemorrhagic events. 
 
Hypertension: Treatment emergent hypertension was commonly seen in clinical 
trials (including grade 3 or higher toxicity and hypertensive crisis). Do not initiate 
cabozantinib in patients with uncontrolled hypertension. Monitor blood pressure 
prior to therapy initiation and regularly thereafter; withhold for hypertension that is 

Protocol #: UCI 18-124 
MP 10/11//2022 
 
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uncontrolled with appropriate medical management. May require cabozantinib 
dosage reduction and/or therapy discontinuation. 
 
Infections and infestations: Infections are commonly observed in cancer 
subjects. Predisposing risk factor include a decreased immune status (e.g., after 
myelosuppressive anticancer therapies, splenectomy), destructive growth of the 
underlying malignancy including bone marrow infiltration with suppression of 
normal hematopoiesis, as well as the presence of IV devices. Infections and 
abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until complete healing has taken place. 
 
Osteonecrosis of the jaw: Osteonecrosis has been reported in subjects treated 
with cabozantinib. Additional risk factors include use of bisphosphonates and 
denosumab, chemotherapy and anti-angiogenic drugs, use of corticosteroids, 
local radiotherapy, and dental or orofacial surgery procedures. Osteonecrosis of 
the jaw (ONJ) 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 osteonecrosis. Perform an oral examination prior to initiation 
of cabozantinib and periodically during cabozantinib treatment. 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 interrupted for at least 3 
weeks prior to the procedure and resumed after complete wound healing has 
occurred. Bone healing may often require a protracted time. Withhold 
cabozantinib for development of ONJ until complete resolution. 
 
Proteinuria: Proteinuria occurred in patients receiving cabozantinib in clinical 
trials; nephrotic syndrome was also reported (rare). Monitor urine protein 
regularly and discontinue therapy if nephrotic syndrome develops. 
 
Reversible posterior leukoencephalopathy syndrome: Reversible posterior 
leukoencephalopathy syndrome (RPLS) has occurred with cabozantinib. Monitor 
for signs/symptoms of RPLS (seizures, headache, visual disturbances, confusion 
or altered mental function); if diagnosis confirmed, discontinue therapy. 
 
Thromboembolic events: Thromboembolic events are frequent in cancer 
subjects due to procoagulant changes induced by the malignancy or anticancer 
therapy. DVT and pulmonary embolism have been observed in clinical studies 
with cabozantinib, including fatal events. Subjects who develop a pulmonary 
embolism and/or DVT should have study treatment interrupted until therapeutic 
anticoagulation is established. Treatment with cabozantinib may be resumed in 
subjects with pulmonary embolism or DVT if it is determined that the event is 
uncomplicated and that the subject is 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 and 
according to individual protocols. Therapeutic doses of LMWH or the direct factor 
Xa oral inhibitors rivaroxaban, edoxaban, or apixaban are allowed for 
management of thrombotic events. Other oral anticoagulants including coumarin 
agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor 
Xa inhibitor betrixaban, platelet inhibitors (e.g., clopidogrel), and chronic use of 
aspirin above low dose levels for cardioprotection per local applicable guidelines 
are not allowed, until 4 weeks after cabozantinib has been permanently 

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discontinued. See Section 4.1.2  for additional restrictions on anticoagulation 
therapy. 
 
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with 
cabozantinib. Subjects should be evaluated for pre-existing risk factors for 
arterial thrombotic events such as diabetes mellitus, hyperlipidemia, 
hypertension, coronary artery disease, history of tobacco use, and cardiac and/or 
thromboembolic events that occurred prior to initiation of study treatment. Further 
treatment with cabozantinib should be discontinued in subjects who develop an 
acute MI, cerebral infarction, or any other clinically significant arterial 
thromboembolic complication. 
 
Wound healing impairment: Cabozantinib has the potential to cause wound 
healing complications and wound dehiscence which may even occur long after a 
wound has been considered healed. Therefore, surgical and traumatic wounds 
must not only be completely healed prior to starting cabozantinib treatment but 
must also be monitored for wound dehiscence, wound infection and other signs 
of impaired wound healing while the subject is being treated with cabozantinib. If 
dehiscence occurs, cabozantinib treatment should not be restarted until complete 
healing has taken place. Treatment with cabozantinib should be stopped at least 
3 weeks prior to elective surgery. Do not administer cabozantinib for at least 2 
weeks after major surgery and until complete wound healing. 
 
Pembrolizumab 
 
Dermatologic toxicity: Immune-mediated rashes, including Stevens-Johnson 
syndrome (SJS), toxic epidermal necrolysis (TEN, some fatal), exfoliative 
dermatitis, and bullous pemphigoid may occur with pembrolizumab. Monitor for 
suspected severe skin reactions and exclude other causes. Based on the 
severity of the dermatologic toxicity, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids. Withhold pembrolizumab for 
signs/symptoms of SJS or TEN and refer for specialized care for assessment 
and management. Permanently discontinue pembrolizumab if SJS or TEN is 
confirmed. 
 
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, 
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 3.5 months 
(range: 10 days to 16.2 months) and the median duration was 1.3 months (range: 
1 day to over 8 months). In many patients, colitis was managed with high-dose 
systemic corticosteroids for a median duration of 7 days (range: 1 day to 5.3 
months), followed by a corticosteroid taper. Most patients with colitis experienced 
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 1.3 months (range: 8 days to 21.4 months); 
the median duration was 1.8 months (range: 8 days to over 20 months). Hepatitis 

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MP 10/11//2022 
 
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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] forgrade 3 or higher, each followed by a taper), and withhold or 
discontinue therapy based on the severity of liver enzyme elevations. Systemic 
corticosteroids were used to manage immune-mediated hepatitis in many 
patients; the median duration of high-dose corticosteroid therapy was 5 days 
(range: 1 to 26 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. Pembrolizumab/axitinib combination 
therapy may result in higher frequencies of grades 3 and 4 ALT and AST 
elevations (compared to pembrolizumab monotherapy). The median time to 
onset of ALT elevation was 2.3 months (range: 7 days to ~20 months) for 
pembrolizumab/axitinib combination therapy, and over half of patients with ALT 
elevation required systemic corticosteroids; resolution of grades 2 to 4 ALT 
elevation occurred in most patients. When rechallenged with either 
pembrolizumab, axitinib, or both, over half of patients did not experience 
recurrence of ALT elevation to >3 times ULN. Monitor liver enzymes at baseline 
and then periodically during treatment; consider more frequent liver enzyme 
monitoring than for pembrolizumab (or axitinib) monotherapy. If liver enzymes 
are elevated, withhold pembrolizumab and axitinib, and consider corticosteroids 
as needed. 
 
Hypersensitivity: Hypersensitivity and anaphylaxis have been observed (rare). 
 
Hypophysitis: Immune-mediated hypophysitis occurred (grades 2, 3, and 4). 
The median time to onset was 3.7 months (range: 1 day to 12 months) and the 
median duration was 4.7 months (range: 8 days to over 12 months). Most cases 
were managed with systemic corticosteroids. Nearly half of patients with 
hypophysitis experienced resolution. 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 was 3.2 to 5.1 months (range: 12 days to 12.8 months) 
and the median duration was 3.3 months (range: 12 days to over 16 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). 
Most patients required systemic corticosteroids. The median duration of 
corticosteroid use was 3 to 15 days (range: 1 day to 4 months), followed by a 
taper. Nephritis resolved in approximately one-third to one-half of affected 
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 grade 3, grade 4, and fatal cases. In patients with NSCLC, a higher 
incidence of pneumonitis was reported in patients who had received prior 

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thoracic radiation. The median time to development was 3.3 months (range: 2 
days to ~19 months) and the median duration was 1.5 months (range: 1 day to 
over 17 months). Many patients required initial management with high-dose 
systemic corticosteroids; the median duration of initial corticosteroid therapy was 
5 to 8 days (range: 1 day to ~10 months) followed by a corticosteroid taper. 
Pneumonitis resolved in half of the affected patients. 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. Pneumonitis occurred more 
frequently in patients with a history of prior thoracic radiation. 
 
Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and 
thyroiditis have occurred. The median onset for hyperthyroidism was 1.4 months 
(range: 1 day to ~22 months) and the median duration was 2.1 months (range: 3 
days to over 15 months). Hyperthyroidism resolved in nearly three-fourths of 
affected patients. Hypothyroidism occurred with a median onset of 3.5 months 
(range: 1 day to 19 months) and median duration was not reached (range: 2 days 
to over 27 months). Hypothyroidism resolved in one-fifth of affected patients. The 
incidence of new or worsening hypothyroidism was higher in patients with 
squamous cell cancer of the head and neck. 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. Thyroiditis occurred with a median onset of 1.2 months 
(range 0.5 to 3.5 months). 
 
Other immune-mediated toxicities: Other clinically relevant immune-mediated 
disorders have been observed (may involve any organ system or tissue, and may 
be severe or fatal), including rash, exfoliative dermatitis, bullous pemphigoid, 
uveitis, arthritis, vasculitis, myositis, Guillain-Barré syndrome, pancreatitis, 
hemolytic anemia, sarcoidosis, serum sickness, myasthenia gravis, myelitis, 
myocarditis, and encephalitis. While immune-mediated toxicity generally occurs 
during treatment with pembrolizumab, adverse reactions may also develop after 
therapy discontinuation. 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. 
7.1.3 
Interaction with other medications 
 
Cabozantinib 
 
Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 

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Bisphosphonate Derivatives: Angiogenesis Inhibitors (Systemic) may enhance 
the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for 
osteonecrosis of the jaw may be increased.  Risk C: Monitor therapy 
 
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Risk C: Monitor therapy 
 
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk X: Avoid combination 
 
CYP3A4 Inducers (Moderate): May decrease the serum concentration of 
CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy 
 
CYP3A4 Inducers (Strong): May decrease the serum concentration of 
Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with 
cabozantinib if possible. If combined, cabozantinib dose adjustments are 
recommended and vary based on the cabozantinib product used and the 
indication for use. See monograph for details. Risk D: Consider therapy 
modification 
 
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 
Substrates (High risk with Inhibitors). Risk C: Monitor therapy 
 
CYP3A4 Inhibitors (Strong): May increase the serum concentration of 
Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with 
cabozantinib if possible. If combined, cabozantinib dose adjustments are 
recommended and vary based on the cabozantinib product used and the 
indication for use. See monograph for details. Risk D: Consider therapy 
modification 
 
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate 
when possible. If concomitant therapy cannot be avoided, monitor clinical effects 
of the substrate closely (particularly therapeutic effects). Risk D: Consider 
therapy modification 
 
Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates 
(High risk with Inducers). Management: Concurrent use of enzalutamide with 
CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use 
of enzalutamide and any other CYP3A4 substrate should be performed with 
caution and close monitoring. Risk D: Consider therapy modification 
 
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Risk C: Monitor therapy 
 
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 

Protocol #: UCI 18-124 
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Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates 
(High risk with Inhibitors). Risk C: Monitor therapy 
 
Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates 
(High risk with Inhibitors). Risk C: Monitor therapy 
 
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 
Substrates (High risk with Inhibitors). Risk X: Avoid combination 
 
Grapefruit Juice: May increase the serum concentration of Cabozantinib. Risk X: 
Avoid combination 
 
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk X: Avoid combination 
 
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Risk C: Monitor therapy 
 
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Management: Avoid concurrent use of lorlatinib with any 
CYP3A4 substrates for which a minimal decrease in serum concentrations of the 
CYP3A4 substrate could lead to therapeutic failure and serious clinical 
consequences. Risk D: Consider therapy modification 
 
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates 
(High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, 
and monitor for increased concentrations/toxicity, during and 2 weeks following 
treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy 
modification 
 
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Management: Doses of CYP3A4 substrates may need to be 
adjusted substantially when used in patients being treated with mitotane. Risk D: 
Consider therapy modification 
 
MRP2 Inhibitors: May increase the serum concentration of Cabozantinib. Risk C: 
Monitor therapy 
 
Netupitant: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 
substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 
substrates should be monitored more closely when used with pitolisant. Risk D: 
Consider therapy modification 
 

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Rifabutin: May decrease the serum concentration of Cabozantinib. Risk C: 
Monitor therapy 
 
Rifapentine: May decrease the serum concentration of Cabozantinib. Risk C: 
Monitor therapy 
 
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Risk C: Monitor therapy 
 
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High 
risk with Inducers). Risk C: Monitor therapy 
 
Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Risk C: Monitor therapy 
 
St John's Wort: May decrease the serum concentration of Cabozantinib. Risk X: 
Avoid combination 
 
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High 
risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that 
are considered to have a narrow therapeutic index should be avoided due to the 
increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with 
stiripentol requires closer monitoring. Risk D: Consider therapy modification 
 
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates 
(High risk with Inducers). Risk C: Monitor therapy 
 
Pembrolizumab 
 
Thalidomide Analogues: Pembrolizumab may enhance the adverse/toxic effect of 
Thalidomide Analogues. Specifically, mortality may be increased when this 
combination is used for treatment of refractory multiple myeloma.  Risk X: Avoid 
combination. 
7.1.4 
Adverse Reactions 
 
Cabozantinib 
 
 
>10%: 
 
Cardiovascular: Hypertension (30% to 61%) 
 
Central nervous system: Fatigue (41% to 56%), mouth pain (36%), voice 
disorder (19%), headache (11% to 18%), dizziness (11% to 14%) 
 
Dermatologic: Palmar-plantar erythrodysesthesia (42% to 50%), hair 
discoloration (34%), skin rash (19% to 23%), xeroderma (11% to 19%), 
alopecia (16%), erythema (11%) 
 
Endocrine & metabolic: Increased lactate dehydrogenase (84%), 
increased serum triglycerides (53%), hypocalcemia (8% to 52%), 
hypoalbuminemia (36% to 51%), hypophosphatemia (25% to 48%), 
weight loss (17% to 48%), hyperglycemia (37%), hypomagnesemia (19% 

Protocol #: UCI 18-124 
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to 31%), hyponatremia (10% to 30%), increased gamma-glutamyl 
transferase (27%), hypokalemia (18% to 23%), hypothyroidism (8% to 
21%) 
 
Gastrointestinal: Diarrhea (54% to 74%), stomatitis (13% to 51%; grades 
3/4: 2% to 5%), nausea (31% to 50%), decreased appetite (46% to 
48%), dysgeusia (12% to 34%), vomiting (24% to 32%), constipation 
(25% to 27%), abdominal pain (23% to 27%), mucositis (14% to 19%), 
increased serum amylase (16%), dysphagia (13%), dyspepsia (10% to 
12%) 
 
Genitourinary: Proteinuria (2% to 12%) 
 
Hematologic & oncologic: Lymphocytopenia (25% to 53%; grades 3/4: 
1% to 16%), neutropenia (31% to 43%; 35%; grades 3/4: 2% to 7%), 
leukopenia (35%), thrombocytopenia (25% to 35%; grades 3/4: 1%), 
anemia (17% to 31%; grades 3/4: 1% to 5%) 
 
Hepatic: Increased serum aspartate aminotransferase (73% to 86%), 
increased serum alanine aminotransferase (68% to 86%), increased 
serum alkaline phosphatase (35% to 52%), hyperbilirubinemia (25%) 
 
Neuromuscular & skeletal: Asthenia (19% to 22%), arthralgia (11% to 
14%), limb pain (9% to 14%), muscle spasm (8% to 13%) 
 
Renal: Increased serum creatinine (58%) 
 
Respiratory: Dyspnea (12% to 19%), cough (18%) 
 
 
1% to 10%: 
 
Cardiovascular: Hypotension (7%), venous thromboembolism (6% to 
7%), syncope (grades 3/4: 5%), pulmonary embolism (4%), arterial 
thromboembolism (1% to 2%), vascular disease (grades 3/4: 1%) 
 
Central nervous system: Anxiety (9%), paresthesia (7%), peripheral 
sensory neuropathy (7%), pain (grades 3/4: 5%), peripheral neuropathy 
(5%), depression (grades 3/4: 4%), confusion (grades 3/4: 1%) 
 
Dermatologic: Hyperkeratosis (7%), dermal ulcer (grades 3/4: 3%) 
 
Endocrine & metabolic: Dehydration (7%), hyperkalemia (grades 3/4: 
1%) 
 
Gastrointestinal: Hemorrhoids (9%), gastrointestinal hemorrhage (3%), 
gastrointestinal perforation (1% to 3%), gastrointestinal fistula (1%) 
 
Hematologic & oncologic: Increased hemoglobin (8%), hemorrhage 
(grade ≥3: 5%) 
 
Neuromuscular & skeletal: Musculoskeletal chest pain (9%), back pain 
(grades 3/4: 4%), ostealgia (grades 3/4: 3%), osteonecrosis of the jaw 
(≤1%) 

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Renal: Acute renal failure (grades 3/4: 4%) 
 
Respiratory: Pulmonary infection (grades 3/4: 4%) 
 
Miscellaneous: Fistula (nongastrointestinal: 4%; includes 
tracheal/esophageal), wound healing impairment (≤2%) 
 
 
<1%, postmarketing, and/or case reports: Cholestatic hepatitis, hypertensive 
crisis, nephrotic syndrome, pancreatitis, reversible posterior 
leukoencephalopathy syndrome, seizure 
 
Pembrolizumab 
 
 
>10%: 
 
Cardiovascular: Peripheral edema (14% to 15%), cardiac arrhythmia 
(11%) 
 
Central nervous system: Fatigue (23% to 43%), pain (22%), headache 
(11% to 14%) 
 
Dermatologic: Pruritus (11% to 28%), skin rash (13% to 24%), vitiligo 
(13%) 
 
Endocrine & metabolic: Hyperglycemia (19% to 49%), hypoalbuminemia 
(27% to 44%), hypertriglyceridemia (33% to 43%), hyponatremia (10% to 
38%), hypophosphatemia (19% to 29%), hypocalcemia (15% to 27%), 
decreased serum bicarbonate (22%), hypercholesterolemia (20%), 
hypokalemia (15% to 20%), hypoglycemia (13% to 19%), hypothyroidism 
(9% to 15%), hypercalcemia (14%), hyperkalemia (13%), weight loss 
(10% to 11%) 
 
Gastrointestinal: Diarrhea (13% to 28%), decreased appetite (16% to 
25%), constipation (14% to 22%), abdominal pain (13% to 22%), nausea 
(11% to 22%), vomiting (12% to 19%) 
 
Genitourinary: Urinary tract infection (15% to 19%), hematuria (12% to 
13%) 
 
Hematologic & oncologic: Anemia (17% to 54%; grades 3/4: 4% to 24%), 
lymphocytopenia (24% to 47%; grades 3/4: 1% to 18%), leukopenia 
(35%; grades 3/4: 9%), neutropenia (24% to 30%; grades 3/4: 7% to 
11%), thrombocytopenia (27%; grades 3/4: 4%), hemorrhage (19%; 
grades 3/4: 5%), increased INR (19%), prolonged partial thromboplastin 
time (14%) 
 
Hepatic: Increased serum alkaline phosphatase (17% to 42%), increased 
serum transaminases (27% to 34%), increased serum aspartate 
aminotransferase (20% to 34%), increased serum alanine 
aminotransferase (9% to 27%), increased liver enzymes (13%) 
 

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Immunologic: Graft versus host disease (followed by allogeneic 
hematopoietic stem cell transplantation: 26%) 
 
Infection: Infection (16%) 
 
Neuromuscular & skeletal: Musculoskeletal pain (21% to 32%), arthralgia 
(10% to 18%), back pain (11% to 12%), asthenia (10% to 11%) 
 
Renal: Increased serum creatinine (11% to 35%) 
 
Respiratory: Upper respiratory tract infection (13% to 28%), cough (14% 
to 26%), dyspnea (10% to 23%), flu-like symptoms (11%) 
 
Miscellaneous: Fever (11% to 28%) 
 
1% to 10%: 
 
Cardiovascular: Facial edema (10%), pericarditis (4%), pericardial 
effusion (2%) 
 
Central nervous system: Peripheral neuropathy (2% to 10%) 
 
Endocrine & metabolic: Hyperthyroidism (3% to 10%), thyroiditis (≤2%) 
 
Gastrointestinal: Colitis (2%) 
 
Hepatic: Hyperbilirubinemia (10%), hepatic sinusoidal obstruction 
syndrome (followed by allogeneic hematopoietic stem cell 
transplantation: 9%), ascites (grades 3/4: 8%), hepatitis (≤3%) 
 
Immunologic: Antibody development (2%; neutralizing: <1%) 
 
Neuromuscular & skeletal: Arthritis (2%), myositis (≤1%) 
 
Ophthalmic: Uveitis (≤1%) 
 
Renal: Acute renal failure (2%) 
 
Respiratory: Pneumonitis (2% to 3%) 
 
Miscellaneous: Infusion-related reaction (≤9%) 
 
Frequency not defined: 
 
Cardiovascular: Cardiac failure, cardiac tamponade, edema, myocardial 
infarction, septic shock 
 
Central nervous system: Confusion, polyneuropathy 
 
Dermatologic: Maculopapular rash 
 
Infection: Herpes zoster 
 
Respiratory: Pleural effusion, pneumonia, respiratory failure 

Protocol #: UCI 18-124 
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Miscellaneous: Fistula, physical health deterioration 
 
<1%, postmarketing, and/or case reports: Anaphylaxis, chronic inflammatory 
demyelinating polyradiculoneuropathy (Maleissye 2016), diabetic ketoacidosis, 
encephalitis, Guillain-Barré syndrome, hemolytic anemia, hypersensitivity 
reaction, hypophysitis, myasthenia gravis, myelitis, myocarditis, nephritis, organ 
transplant rejection (solid), pancreatitis, sarcoidosis, type 1 diabetes mellitus, 
vasculitis 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of Subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of patient safety 
and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
7.3 
Definitions 
  
7.3.1 Event Definitions 
Adverse event (AE) - An adverse event is any untoward medical experience or 
change of an existing condition that occurs during or after treatment, whether or 
not it is considered to be related to the protocol intervention.  
 
Unexpected Adverse Event [Modified from the definition of unexpected adverse 
drug experience in FDA regulations at 21 CFR 312.32 (a)] – An adverse event is 
unexpected if it is not listed in the investigator’s brochure and/or package insert; 
is not listed at the specificity or severity that has been observed; is not consistent 
with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or 
predisposed risk factor of the research participant experiencing the adverse 
event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an 
unexpected event OR is an expected natural progression of any underlying 
disease, disorder, condition, or predisposed risk factor of the research participant 
experiencing the adverse event. 
 
Serious Adverse Event (SAE) [21 CFR 312.32] - defined as any expected or 
unexpected adverse event that result in any of the following outcomes: 
• 
Death 

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• 
Is life-threatening experiences (places the subject at immediate risk of 
death from the event as it occurred) 
• 
Unplanned hospitalization equal or greater than 24 hours)) or 
prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
Any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the outcomes listed above (examples of 
such events include allergic bronchospasm requiring intensive treatment 
in the emergency room or at home, blood dyscrasias of convulsions that 
do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse). 
 
Unanticipated problem (UP) - Any incident, experience or outcome that meets 
all three of the following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: 
a) the research procedures described in the protocol-related documents 
such as the IRB approved research protocol, informed consent 
document or Investigator Brochure (IB); and b) the characteristics of the 
subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly 
related means there is a reasonable possibility that the incident, 
experience, or outcomes may have been caused by the drugs, devices 
or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of 
harm (including physical, psychological, economic, or social harm) than 
previously known or recognized. 
 
Protocol Violation- A protocol violation is an accidental or unintentional change 
to or noncompliance with the IRB-approved protocol that increases risk or 
decreases benefit and/or affects the subject's rights, safety, welfare, and/or the 
integrity of the data. Examples of incidents that may be considered violations 
include: enrolling a participant who does not meet the inclusion criteria; obtaining 
verbal consent before the initiation of study procedures when the IRB requires 
signed, written informed consent; and failure to collect screening labs before 
initiation of study procedures [Reference: Policy #57 UCI HRPP Policy and 
Procedure Glossary].  
 
Protocol Deviation- a protocol deviation is an accidental or unintentional change 
to the research protocol that does not increase risk or decrease benefit or have a 
significant effect on the participant’s rights, safety or welfare, or on the integrity of 
the data. Deviations may result from the action of the participant, researcher, or 
staff. Examples: a rescheduled study visit, an omitted routine safety lab for a 
participant with previously normal values; or failure to collect an ancillary self-
report questionnaire data (e.g., quality of life) [Reference: Policy #57 UCI HRPP 
Policy and Procedure Glossary].  
7.3.2 Characteristics and Severity of Adverse Events 
 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The 
CTCAE v5 is available at: 

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https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_
50  
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
o 
Expectedness”:  AEs can be ‘Unexpected’ or ‘Expected’   
-Unexpected: (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the IRB-approved documents, 
such as the protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
o Attribution of the AE: 
 Related – The AE is clearly related to the study treatment. 
 Not Related – The AE is clearly NOT related to the study treatment. 
 
7.3.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.3.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.3.3.2 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 
7.3.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
 
 
 
 
Following events do not satisy criteria for SAE: 
 
 
 
 
Hospitalizations for preplanned procedures 
 
 
 
 
Hospitalization for study-related treatment and procedures 

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7.3.3.4 
Results in persistent or significant disability or incapacity. 
7.3.3.5 
Is a congenital anomaly/birth defect 
7.3.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
7.4 
Reporting Requirements 
 
Adverse events, serious adverse events, deviations, violations, and unanticipated problems must be 
entered into the clinical trial management system (CTMS), OnCore, and must also be reported to the 
following entities according to the timelines mentioned in the chart below. Serious adverse events 
collection will start at the time patient signs consent until 30 days after the end of treatment. Adverse 
events will be collected from the time the research patient begins treatment until 30 days after the end of 
treatment. All adverse events/serious adverse events should be followed until resolution or stabilization.  
 
 
 
 
 
 
 
 

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Event Type  
Coordinating Center/Medical 
Monitor 
UCI IRB  
Exelixis, Inc. 
CFCCC DSMB 
Unanticipated 
Problem  
Within 24 hours from date the site 
is aware of the event, the site 
should enter this information into 
OnCore. An email notification 
should also be sent via email to 
fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu.    
Within 5 
business days 
submit an 
Unanticipated 
Problem 
Report (UP). 
Current policy 
can be found 
here. 
Within 1 business day of learning of the 
event. Submit a MedWatch Form to 
Exelixis via fax (650-837-7392) or email 
(drugsafety@exelixis.com). All follow up 
information must be sent to Exelixis within 
1 business day of PI’s receipt of new 
information. Please refer to section 7.6 for 
further information.  
Within 5 days from date PI is 
aware of the event. This 
information must be reported 
into OnCore.  
AEs and SAEs (non-
Unanticipated 
Problem)  
Please refer to section 7.5 for 
reporting timeframes on AEs and 
SAEs    
N/A  
 Please refer to section 7.6 for other 
reportable events 
Please refer to section 7.5  for 
clarification on reporting 
timeframes for AEs and SAEs  
Non-compliance  
N/A 
N/A 
N/A 
Please refer to section 7.5 for 
reportable 
deviations/violations  
Serious or 
continuing non-
compliance  
Within 24 hours via email to 
fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu    
Within 5 
business days 
submit a New 
Information 
Report 
N/A 
Within 5 days from date PI is 
aware of the event.  
Prospective/Planned 
Deviations  
At least 5 business days prior to 
the event via email to 
fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu for approval.   
At least 48 
hours prior to 
date the 
request is 
needed by. 
Submit a  
Prospective 
Deviation 
Request form 
N/A  
At the time of progress 
review as aggregate reports  
 

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7.5 
Additional Reporting of Events to the CFCCC DSMB and Sponsor Investigator  
 
Adverse Event/ Serious Adverse Events  
Event Type  
Reporting Timeframe to 
CFCCC DMSB  
(Notification is done by 
entering this information into 
OnCore within the timelines 
below) 
Reporting Timeframe to 
Coordinating Center 
(Notification is done via email 
to fdayyani@hs.uci.edu and 
uci18124@hs.uci.edu within 
the timelines below) 
Serious Adverse Events (all attributions) that meet all of the following 
criteria: 
 
Unexpected 
 
Grades 3-5 
 
Occurring during treatment or within 30 days of the end 
of treatment* 
5 business days from date the 
PI is aware of the event 
24 hours from date the site is 
aware of the event. 
Adverse Events that meet all of the following criteria: 
 
Unexpected 
 
Study related (possibly, probably, or definitely) 
 
Grades 3-4 
 
Occurring during treatment or within 30 days of the end 
of treatment* 
5 business days from date the 
PI is aware of the event 
24 hours from date the site is 
aware of the event. 
All other Adverse Events and Serious Adverse Events should be reported 
as noted in the ‘Recording of Events’ section 
Prior to each scheduled 
progress review.  
5 business days from the date 
the site is aware of the event 
* Investigators are not obligated to actively seek information regarding the occurrence of new AEs or SAEs beginning after the 30-day post-treatment period. However, if the 
investigator learns of such an event and that event is deemed relevant to the study, he/she should promptly document and report the event. 
 

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Deviations/Violations 
Event Type  
Reporting Timeframe to CFCCC DSMB 
(Notification is done by entering this 
information into OnCore within the 
timelines below) 
Reporting Timeframe to 
Coordinating Center (Or other entity 
monitoring/coordinating the trial) 
Violations as defined above (e.g. wrong dosage of drug 
administered, safety procedures not being conducted at specific 
time points). 
5 business days from the date the PI is 
aware of the event 
24 hours from the date the site is 
aware of the event 
Deviations as defined above, including: 
 Planned deviations (e.g. rescheduling a visit that will be 
out of window due to a holiday) 
 
Unplanned deviations (e.g. rescheduled visit, a missed 
routine safety laboratory test for a participant with 
previously normal values) 
Prior to each scheduled progress 
review  
5 business days from the date the site 
is aware of the event  

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7.6 
Other Reporting Requirements to Exelixis  
o 
Pregnancy/Lactation Exposure 
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. Pregnancy (in subject or partner) or lactation exposure, although not 
an SAE, should be reported to Exelixis. Forms 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. 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. 
 
o 
Medication Errors/Overdose 
Any overdose, or study drug administration error that results in an AE, even if it does not meet the 
definition of serious, requires reporting within one (1) business day to Exelixis. 
8.0 
DRUG INFORMATION 
8.1 
Cabozantinib 
 
 
 
 
A list of the adverse events and potential risks associated with cabozantinib can be found in Section 7.1.   
 
• 
Other names for the drug(s):  
CABOMETYX 
COMETRIQ 
 
• 
Classification - type of agent: 
Antineoplastic Agent, Tyrosine Kinase Inhibitor; 
Antineoplastic Agent, Vascular Endothelial Growth Factor (VEGF) Inhibitor 
 
• 
Mode of action: 
Cabozantinib is a potent inhibitor of proinvasive receptor tyrosine kinases (RTKs), including AXL, 
FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3; induces 
apoptosis of cancer cells and suppresses tumor growth, metastasis, and angiogenesis 
 
• 
Storage and stability: 
Store CABOMETYX at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C 
(59°F to 86°F)  
 
• 
Protocol dose:  
40 mg daily continuous  
 
• 
Preparation: 
N/A 
 
• 
Route of administration for this study: 
Oral  
 
• 
Incompatibilities: 
None  
 
• 
Availability: 
Provided by supporter 

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• 
Agent Ordering 
Exelixis 
Sub-site(s) will order agent through Exelixis and will receive the agent will ship directly to the sites.  
 
• 
Side effects:  
The most commonly reported (≥ 25%) adverse reactions are: diarrhea, fatigue, nausea, decreased 
appetite, hypertension, palmar-plantar erythrodysesthesia (PPE), weight decreased, vomiting, 
dysgeusia, and stomatitis. 
 
• 
Agent Accountability 
 
Accountability for the study drug at the study center is the responsibility of the 
Investigator. The Investigator will ensure that the study drug is used only in accordance with this 
protocol. Where allowed, the Investigator may choose to assign drug accountability responsibilities to 
a pharmacist or other appropriate individual. 
 
The Investigator or delegate will maintain accurate drug accountability records indicating the drug’s 
delivery date to the site, inventory at the study center, use by each patient, and destruction.  
 
These records will adequately document that the patients were provided the doses as specified in the 
protocol and should reconcile all study drug received from Exelixis. 
 
Study drug must not be used for any purpose other than the present study. Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
 
Patients will receive instructions for home administration of cabozantinib according to the regimen 
description above. Cabozantinib is to be taken 1 hour before or 2 hours after meals. If doses of 
cabozantinib are missed or held, the patient should not make up for the missed doses.  
 
Patients will be given a study medication diary to complete at home for cabozantinib. Compliance with 
the dosing regimen will be assessed based on completion of the drug diary and return of unused drug 
(or empty bottles).  
 
IMP Destruction 
IMP will be destroyed by the sponsor according to their SOPs. Destruction logs should be made 
available to Exelixis at the end of the study. 
IMP Returns 
Exelixis will not accept returned IMP 
8.2 
Pembrolizumab 
 
 
 
 
 
A list of the adverse events and potential risks associated with Irinotecan can be found in Section 7.1.   
 
• 
Other names for the drug(s):  
KEYTRUDA 
 
• 
Classification - type of agent: 
Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody; 
Antineoplastic Agent, Immune Checkpoint Inhibitor; 
Antineoplastic Agent, Monoclonal Antibody  
 
• 
Mode of action: 
Pembrolizumab is a highly selective anti-PD-1 humanized monoclonal antibody which inhibits 

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programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block PD-1 
ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the negative immune 
regulation caused by PD-1 receptor signaling[38]. Anti-PD-1 antibodies (including pembrolizumab) 
reverse T-cell suppression and induce antitumor responses. 
 
• 
Storage and stability: 
• 
KEYTRUDA for injection (white to off-white lyophilized powder): Carton containing one 50 mg 
single-dose vial (NDC 0006-3029-02) Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).. 
 
• 
KEYTRUDA injection (clear to slightly opalescent, colorless to slightly yellow solution): Carton 
containing one 100 mg/4 mL (25 mg/mL), single-dose vial (NDC 0006-3026-02) Carton containing 
two 100 mg/4 mL (25 mg/mL), single-dose vials (NDC 0006-3026-04) Store vials under 
refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do 
not shake. 
 
• 
Protocol dose:  
200 mg on day 1 every 21 days 
 
• 
Preparation: 
Dilute in 50mL 0.9% Sodium Chloride IVPB 
 
• 
Route of administration for this study: 
Intravenous infusion  
 
• 
Incompatibilities: 
None  
 
• 
Availability: 
Commercially available 
 
• 
Agent Ordering 
Provided locally by the trial site 
 
• 
Side effects:  
Most common adverse reactions (reported in ≥20% of patients) were: 
KEYTRUDA as a single agent: fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, 
nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
This is a single-arm, open label, phase-II trial designed as a pilot to see if the treatment regimen is worthy 
of further study.   Specifically, the trial is designed as the first stage of a Simon two-stage, minimax 
design[39].  The goal is to gather evidence on efficacy or futility of the study treatment in this study 
population, while monitoring toxicity.   The two-stage approach offers economy and exposes the fewest 
possible participants to potential harm without substantial benefit, with control of the probability of errors 
in decisions.  
 
Primary Endpoint:  For efficacy the primary endpoint is progression-free survival at six months (PFS-6), 
dating from the first dose of study treatment.  Progression is defined and determined as given in Section 
61.6.  For toxicity, the primary endpoint is the number of participants showing serious toxicity during their 
participation in the trial.  Serious toxicities are given in Section 7.0. 

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Efficacy Null Hypothesis:  Based on current outcomes for this study population[25][26], the null 
hypothesis is that 5% of evaluable patients will be progression-free at six months. 
 
Efficacy Alternative Hypothesis:  Based on our clinical judgment and aspirations, we anticipate that 20% 
(or more) of evaluable participants will be progression-free at six months.  In our view, 20% progression-
free at six months is the smallest advance that would be judged clinically worthwhile. 
 
Secondary endpoints: 
• 
Overall survival, defined as time from starting treatment to death from any cause. 
• 
Objective response rate in patients with measurable disease as defined in section 6.0 
• 
Safety as described in the adverse events in section 7.0 
9.2 
Sample Size and Accrual 
Sample Size:  Given null- and alternative-hypothesis proportions of 0.05 and 0.20, respectively, 
approximately 20 evaluable subjects will signal futility/efficacy with 80-percent power and five percent risk 
of type-I error.  Under these conditions the table below gives the number of evaluable subjects required, 
the smallest number of patients progression-free at six months to signal efficacy, and the probability of 
correctly declaring futility. 
 
Design 
Approach 
Sample 
Size 
Responses 
Signal Efficacy 
 
Probability 
Correctly 
Asserting 
Futility 
Minimax 
19 
>=2 
0.75 
 
 
As may be seen, the minimax approach requires 19 evaluable subjects for this project.  If at least two 
participants are progression-free at six months, then the treatment regimen is considered worthy of 
further study. Given that result, then, in a separate study to complete stage two of the design, an 
additional eight evaluable subjects would be run. If at least four of the total of 27 evaluable were 
progression-free at six months that would be sufficient evidence to reject the null hypothesis of five 
percent in favor of the alternative hypothesis of 20 percent. The probability of declaring futility when in fact 
the null hypothesis (viz., 5%) is true is at least 75 percent.  
 
No more than nine patients with PD-L1 CPS = 1-9% who are immunotherapy naïve will be enrolled. 
 
Continuous Monitoring for Excess Toxicity:  All participants in trial are monitored for serious toxicity for the 
duration of their participation in the study.  Serious toxicities are given in Section 7.    A sequential 
Pocock-type boundary will inform decisions to continue or stop accrual for excess toxicity, as accrual 
proceeds (Ivanova, 2005).  The table below shows the cumulative number of participants enrolled and the 
corresponding cumulative number of serious toxicities that will signal the underlying risk of serious toxicity 
exceeds 33 percent (5% risk of type-1 error).   
 
Threshold Number of Cumulative Toxicities that Signal Excess Toxicity as a Function of Cumulative 
Number Enrolled* 
 
Cumulative 
Number 
Enrolled 
Threshold Number 
Showing Serious 
Toxicity to Stop 
Accrual 
1 
- 
2 
- 
3 
- 

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4 
4 
5 
5 
6 
5 
7 
6 
8 
7 
9 
7 
10 
7 
11 
8 
12 
8 
13 
9 
14 
9 
15 
10 
16 
10 
17 
11 
18 
11 
19 
12 
20 
12 
* Pocock –type boundary with maximum acceptable probability of toxicity set to 33 percent and type-1 risk of five percent[40]. 
9.3 
Data Analyses Plans 
The primary endpoint (PFS-6) will be calculated at 6 months after the last patient enrolled has started 
treatment, or at the time of progression of the last patient enrolled, whichever occurs first.  
 
Participants will be characterized on host and demographic factors, with continuous measures given as 
means or medians and categorical measures given as percents.  Consistent with the phase-II nature of 
the research, we will examine the data in many ways to illuminate future research priorities.  We will 
estimate survival curves for progression-free and overall survival, and attempt to identify systematic 
differences between those who respond to treatment and those who do not.  Survival will be estimated by 
Kaplan-Meier methods.  If assumptions are met, we will model survival using Cox proportional- hazards, 
eliminating ties by subtracting a small, randomly generated amount from the observed times[41].  As may 
be indicated, we will transform data to correspond better to analytic requirements, using logit transforms 
for percent data[42] and log or some other approach for continuous measures.  As the goals of these 
secondary analyses are to inform decisions about future research, no formal statistical hypothesis-testing 
will be done, probabilities from statistical tests will augment clinical judgment in interpretation, and we will 
not regard overall, study-wise, error rates for these secondary analyses. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by their own 
institution’s COI committee. All investigators will follow the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations. The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation of the study 
and will be given the opportunity to review the consent form. Each consent form must include all the 

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relevant elements currently required by the FDA Regulations and local or state regulations. Once this 
essential information has been provided to the patient and the investigator is assured that the patient 
understands the implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient and by the person who conducted the informed consent discussion. 
10.3 
Required Documentation (for multi-site studies) 
Before the study can be initiated at any site, the following documentation must be provided to UCI 
CFCCC. 
 
• 
A copy of the official IRB approval letter for the protocol and informed consent 
• 
IRB membership list 
• 
CVs and medical licensure for the principal investigator and any associate investigators who will be 
involved in the study 
• 
Form FDA 1572 appropriately filled out and signed with appropriate documentation  
• 
Financial Disclosure statements for the PI and participating investigators, as necessary 
• 
A copy of the IRB-approved consent form and HIPAA form 
• 
IRB member list with their occupations and institutional affiliations or a general assurance number will 
be acceptable.  
• 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
• 
Signed protocol signature page  
10.4 
Data Completion 
10.4.1 OnCore Date Entry  
 
Data, as indicated by Sponsor, will be entered into OnCore – UC Irvine’s Clinical Trial 
Management system. The Investigator is responsible for ensuring all entries are accurate and 
correct. The Investigator must maintain accurate source data that support OnCore data entry. All 
data will be entered as per Sponsor’s specification and timeframe.  
 
10.4.2 Recording of Events 
All investigator initiated treatment trials require that adverse events, serious adverse events, 
deviations, and unanticipated problems be entered into the clinical trial management system 
(CTMS), OnCore.  All entries must be entered in OnCore within the timelines specified in sections 
7.5-7.6 of being aware of the adverse event, serious adverse event, violation, deviation, or 
unanticipated problem.  Adverse events and violations/deviations and adverse events that are 
unanticipated problems that require prompt reporting to the DSMB must be entered into OnCore 
according to the timelines as specified in section 7.4-7.6. 
10.5 
Data Management and Monitoring/Auditing 
10.5.1 Quality Assurance 
Quality assurance activities will be conducted as per UC Irvine Chao Family Comprehensive 
Cancer Center’s Quality Assurance Monitoring and Auditing Plan and at the discretion of the 
CFCCC Data and Safety Monitoring Board in order to ensure patient safety and data integrity 
oversight. By conducting internal monitoring and auditing, the CFCCC will ensure compliance 
with high quality standards and all applicable regulations, guidelines, and institutional policies. 
Trial monitoring and auditing may be completed remotely or on-site by the Quality Assurance 

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Officer. Participating sites may follow their own internal quality assurance policies in order to 
maintain patient safety and data integrity oversight. The investigator must permit study-related 
monitoring/auditing and provide access to study-related materials.  
 
10.5.2 Data and Safety Monitoring Plan 
This is a risk level 2 study, as defined in the Chao Family Comprehensive Cancer Center 
(CFCCC) Data and Safety Monitoring Plan (DSMP) because it is a study in which the IND is 
exempt by the FDA.   
 
The Principal Investigator (PI), co-investigator, clinical research coordinator, and statistician are 
responsible for monitoring of data and safety for this study.  For studies that have stopping rules 
for safety and efficacy, the PI will be responsible for the implementation and make changes as 
applicable. The CFCCC Data and Safety Monitoring Board (DSMB) is an independent body 
responsible for the safety of study subjects as well as the data integrity of the protocol.  Data and 
safety will be reported to the DSMB with submission of progress reports that include aggregated 
reports of adverse events, serious adverse events, deviations, and violations.  In addition, certain 
adverse events, serious adverse events, deviations, violations, and unanticipated problems will 
be reported promptly to the DSMB for review according to Section 7.4 and Section 7.5.   
 
10.6 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study patient requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol. 
 
Due to restrictions instituted during the COVID-19 pandemic, planned clinic visits may be performed via 
telemedicine at the discretion of the Principal Investigator, following the guidelines established in the 
CFCCC Standard Operating procedure “Interim Standard Operating Procedure: Clinical Trial Enrollment 
and Operations during the COVID-19 Pandemic” (URL: \\hs.uci.edu\myshare\Cancer Center 
Research\COVID-19\Research\SOPs and Guidelines).  Whenever possible, on-site clinic visits will be 
replaced by telemedicine visits between the clinic staff and on-study patients. 
 
Emergency Modifications may be enacted if needed to ensure the safety, and well-being of the study 
patients.  Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB approval.  For any such emergency modification 
implemented, an IRB modification form must be completed within five (5) business days of making the 
change. 
 
All other planned deviations or violations from the protocol must have prior approval by the Principal 
Investigator and the IRB. Please refer to Section 7.4 for more information on how protocol deviations and 
violations are defined. It will also provide instructions on when and who to contact and obtain approval 
from for prospective deviations. Protocol deviations should also be reported in accordance with UCI IRB, 
UCI CFCCC Stern Center policies and the participating site’s IRB policies.  
10.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented by 
the Principal Investigator. It should also be noted that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a revised consent form might be required. 
Protocol modifications or amendments must be reviewed and approved by Exelixis prior to 
implementation. 
 
The written amendment, and if required the amended consent form, must be sent to the IRB for approval 
prior to implementation.  

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10.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator must retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region. In all 
other cases, study documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with 
Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal Investigator 
is responsible for personally overseeing the treatment of all study patients. The Principal Investigator 
must assure that all study site personnel, including sub-investigators and other study staff members, 
adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both 
during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be reviewed 
by the Principal Investigator and will require his/her final signature to verify the accuracy of the data. 
10.10 
Publications 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 Exelixis with a copy of any proposed publication or release: (a) 
for abstracts, slide presentations or posters, at least five (5) business day prior to submission (in the case 
of abstracts) or first public presentation (in the case of slide presentations and posters); and (b) at least 
thirty (30) days in advance of first submission and each subsequent submission in the case of 
manuscripts 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. 
10.11 
Conditions for Terminating the Study 
At any time, the study may be terminated by the study sponsor, the sponsoring institution, or by Exelixis. 
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. Upon study termination, the 
investigator(s) shall cease enrolling subjects into the study, and shall discontinue conduct of the study as 
soon as is medically practicable. 
11.0 
REFERENCES 
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ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or 

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gastroesophageal junction adenocarcinoma,” Ann. Oncol., vol. 27, no. 4, pp. 673–679, Apr. 2016. 
[25] 
K. Shitara et al., “Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer 
(TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial,” Lancet Oncol., vol. 19, no. 11, pp. 1437–
1448, Nov. 2018. 
[26] 
C. S. Fuchs et al., “Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated 
Advanced Gastric and Gastroesophageal Junction Cancer,” JAMA Oncol., vol. 4, no. 5, p. e180013, May 2018. 
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K. Shitara et al., “Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal 
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[Online]. Available: http://abstracts.asco.org/239/AbstView_239_251955.html. [Accessed: 20-Jul-2019]. 
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Clin. Pharmacokinet., vol. 56, no. 5, pp. 477–491, May 2017. 
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plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) 
malignancies,” Ann. Oncol., vol. 28, no. suppl_5, Sep. 2017. 
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Engl. J. Med., vol. 379, no. 1, pp. 54–63, Jul. 2018. 
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M. E. Keeler et al., “Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell 
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Y.-K. Kang et al., “Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory 
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12.0 
APPENDICES 
APPENDIX A 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor 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 (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 

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5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APPENDIX B 
 
Pill Diary 
 

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APPENDIX C 
Patient Information Cabozantinib 

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