The Efficacy of Cabozantinib in Advanced SAlivary Gland Cancer Patients, a Phase II Clinical Trial
Phase: PHASE2
Conditions: Salivary Gland Cancer
Sponsor: Radboud University Medical Center

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PROTOCOL TITLE The efficacy of Cabozantinib in Advanced SAlivary gland cancer 
Patients, a phase II clinical trial’ (Cabo ASAP) 
Protocol ID 
MOHN14 
Short title 
Cabo ASAP 
EudraCT number  
2018-000682-36 
Version 
3.0 
Date 
21-06-2018 
Coordinating investigator/project 
leader 
 
Carla M.L. van Herpen, MD, PhD 
Radboud University Medical Center 
Geert Grooteplein zuid 8 
6525 GA Nijmegen 
P.O. Box 9101 
+ 31 243667251 
Carla.vanHerpen@radboudumc.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
Carla M.L. van Herpen, MD, PhD 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboud University Medical Center 
Geert Grooteplein Zuid 8 
6525 GA Nijmegen 
P.O. Box 9101 
https://www.radboudumc.nl 
Subsidising party 
Ipsen Pharmaceuticals / Exelixis 
Independent expert (s) 
Dr. A.J. Croockewit  
Geert Grooteplein Zuid 8  
Postbus 9101  
6500 HB Nijmegen  
Sandra.Croockewit@radboudumc.nl  
Tel: +31 243618800 
Pharmacy 
Pharmacy Department  
Radboud University Medical Center 
Geert Grooteplein Zuid 10  
6525 GA Nijmegen  
Licence number: 4095 F 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Principal Investigator 
Carla M.L. van Herpen, MD, PhD 
Geert Grooteplein Zuid 8  
Postbus 9101  
6525 GA Nijmegen  
Carla.vanHerpen@radboudumc.nl  
Tel: +31 243667251  
 
16-03-2018 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 7 
2. 
OBJECTIVES ................................................................................................................. 8 
3. 
STUDY DESIGN ............................................................................................................ 9 
4. 
STUDY POPULATION ..................................................................................................11 
4.1 
Population (base) ...................................................................................................11 
4.2 
Inclusion criteria .....................................................................................................12 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................15 
5.1 
Investigational product/treatment ............................................................................15 
5.2 
Use of co-intervention (if applicable) ......................................................................15 
5.3 
Escape medication (if applicable) ...........................................................................15 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................16 
6.1 
Name and description of investigational product(s) ................................................16 
6.2 
Summary of findings from non-clinical studies ........................................................16 
6.3 
Summary of findings from clinical studies ...............................................................16 
6.4 
Summary of known and potential risks and benefits ...............................................16 
6.5 
Description and justification of route of administration and dosage .........................17 
6.6 
Dosages, dosage modifications and method of administration ...............................17 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................17 
6.8 
Drug accountability .................................................................................................17 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................18 
8. 
METHODS ....................................................................................................................19 
8.1 
Study parameters/endpoints ...................................................................................19 
8.1.1 
Main study parameter/endpoint .......................................................................19 
8.2 
Secondary study parameters/endpoints (if applicable) ...........................................19 
8.2.1 
Other study parameters (if applicable) .............................................................20 
8.3 
Randomisation, blinding and treatment allocation ..................................................20 
8.4 
Study procedures ...................................................................................................21 
8.5 
Withdrawal of individual subjects ............................................................................22 
8.5.1 
Specific criteria for withdrawal (if applicable) ...................................................22 
8.6 
Replacement of individual subjects after withdrawal ...............................................22 
8.7 
Follow-up of subjects withdrawn from treatment .....................................................22 
8.8 
Premature termination of the study .........................................................................22 
9. 
SAFETY REPORTING ..................................................................................................23 
9.1 
Temporary halt for reasons of subject safety ..........................................................23 
9.2 
AEs, SAEs and SUSARs ........................................................................................23 
9.2.1 
Adverse events (AEs) ......................................................................................23 
9.2.2 
Serious adverse events (SAEs) .......................................................................23 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................23 
9.3 
Annual safety report ...............................................................................................24 

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9.4 
Follow-up of adverse events ...................................................................................24 
 
Monitoring ..................................................................................................................25 
10. 
STATISTICAL ANALYSIS ..........................................................................................26 
10.1 
Primary study parameter(s) ....................................................................................26 
10.2 
Secondary study parameter(s) ...............................................................................26 
10.3 
Other study parameters ..........................................................................................26 
10.4 
Interim analysis ......................................................................................................26 
11. 
ETHICAL CONSIDERATIONS ...................................................................................28 
11.1 
Regulation statement .............................................................................................28 
11.2 
Recruitment and consent........................................................................................28 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................28 
11.4 
Benefits and risks assessment, group relatedness .................................................28 
11.5 
Compensation for injury .........................................................................................28 
11.6 
Incentives ...............................................................................................................28 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................29 
12.1 
Handling and storage of data and documents ........................................................29 
12.2 
Monitoring and Quality Assurance ..........................................................................29 
12.3 
Amendments ..........................................................................................................29 
12.4 
Annual progress report ...........................................................................................29 
12.5 
Temporary halt and (prematurely) end of study report ............................................30 
12.6 
Public disclosure and publication policy ..................................................................30 
13. 
STRUCTURED RISK ANALYSIS...............................................................................31 
13.1 
Potential issues of concern .....................................................................................31 
13.2 
Synthesis ...............................................................................................................32 
14. 
REFERENCES ..........................................................................................................34 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
 
 
ACC 
ADT 
ABR form, General Assessment and Registration form, is the application form 
that is required for submission to the accredited Ethics Committee (In Dutch, ABR 
= Algemene Beoordeling en Registratie) 
Adenoid cystic carcinoma 
Androgen deprivation therapy 
AE 
Adverse Event 
AR 
Adverse Reaction 
CCMO 
 
ctDNA 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
Circulating tumor DNA 
CV 
DoR 
Curriculum Vitae 
Duration of response 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
 
ORR 
OS 
PFS 
QoL 
SDC 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
Objective response rate 
Overall survival 
Progression free survival 
Quality of life 
Salivary duct carcinoma 
(S)AE 
SGC 
(Serious) Adverse Event  
Salivary gland cancer 
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-
tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Salivary gland cancer (SGC) is a rare cancer with 24 histological subtypes. 
Treatment options for locally advanced and/or metastatic SGC are limited. The tyrosine 
kinase inhibitor cabozantinib suppresses tumor growth, angiogenesis, and metastasis, and 
has been approved for renal cell carcinoma and thyroid cancer. Cabozantinib may also be of 
value in advanced SGC because c-MET, one of the targets of cabozantinib, is frequently 
overexpressed in SGC. 
Objectives: To assess the objective response rate (ORR), progression free survival (PFS), 
overall survival (OS), duration of response (DoR), toxicity, and quality of life (QoL) of patients 
with advanced SGC treated with cabozantinib in 3 cohorts: salivary duct carcinoma (SDC), 
adenoid cystic carcinoma (ACC), other SGC’s. 
Study design: Single arm, single center, phase II clinical trial 
Study population: Patient with c-MET positive, locally advanced, recurrent, and/or 
metastatic SGC.  
Intervention: Cabozantinib tablets 60 mg once daily until progressive disease, intolerable 
toxicity, or investigator and/or patient decision to withdraw for a maximum duration of 2 
years. 
Main study parameters/endpoints: study endpoints are in line with the objectives.  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
Burden and risks: Patients will use the study medication for a maximum duration of 2 years. 
During these 2 years, patients will make 17 study related visits. 12 CT scans will be made 
and patients will be asked to fill in questionnaires 7 times. The safety of Cabometyx is well 
known because of studies in renal cell carcinoma.  
Benefit: Because Cabometyx has not been tested in SGC patients before, the chance of 
responding to treatment is unknown. The Simon 2-stage design will be used to prevent 
exposure of too many patients to ineffective treatment without discarding a potential effective 
treatment because of treatment failure in some patients. 
Group relatedness: The study does not involve minors and/or incapacitated subjects. 
 

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1. INTRODUCTION AND RATIONALE 
SGC is a rare cancer. The annual incidence rate ranges from 0.4-2.6 cases per 100,000 
people. Besides, SGC’s are histological diverse. Twenty-four histological types can be 
distinguished.1 Primary treatment consists of resection of the affected salivary gland and a 
neck dissection, mostly followed by postoperative radiotherapy. Treatment options for 
patients with locally recurrent and/or metastatic disease (later: advanced disease) systemic 
treatment options are limited to androgen deprivation therapy (ADT) and HER2-targeted 
therapies in selected cases. Chemotherapy may be used for palliation, but the effect is 
limited. Therefore, new treatment options for advanced SGC are urgently warranted. 
 
Cabozantinib is an oral, small-molecule inhibitor of tyrosine kinases, including c-MET, 
VEGFR, and AXL. In preclinical models, cabozantinib has been shown to suppress tumor 
growth, angiogenesis, and metastasis.2 In clinical practice, it has been approved for 
treatment of advanced renal cell carcinoma in patients who received prior anti-angiogenic 
therapy (cabometyx® tablets),3 and treatment of progressive, metastatic medullary thyroid 
cancer (Cometriq® capsules).4 Next to this, it has shown promising results in bone 
metastases of castration-resistant prostate cancer.5 
 
Cabozantinib may also be of value in the treatment of advanced SGC because c-MET, one 
of the targets of cabozantinib, is frequently overexpressed in SGC. In ACC, c-MET 
overexpression has been shown in 53.2% of patients.6 In SDC, c-MET overexpression has 
been shown in 39.7% of patients.7  
  
No data are available on the efficacy of cabozantinib in SGC. We will conduct a phase II, 
single arm clinical trial to investigate the efficacy of cabozantinib in c-MET positive SGC. 
Three patient groups will be included: (1) advanced SDC, (2) advanced ACC, and (3) 
advanced SGC of other subtypes. As ACC can originate in the salivary glands, but also in 
other parts of the body, such as lung, trachea, breast and cervix, these patients can also be 
included in the study and will be analyzed in the cohort with advanced ACC patients. 
 
Before and during treatment we will collect blood samples for future analysis of circulating 
tumor DNA (ctDNA). ctDNA is cell-free DNA in the blood circulation which originates from the 
tumor. Analysis of ctDNA may be of value for early response prediction. In colorectal cancer, 
treatment response and failure can be predicted by a decrease and increase of ctDNA.8 In 
this study, we will draw blood for ctDNA analysis using Roche cell-free DNA tubes before 
start of treatment, after 2 weeks, after 4 weeks, and before every evaluation CT-scan. 
Samples will be analyzed for ctDNA levels to evaluate whether treatment response and 
failure can be predicted. 
 
 
 
 

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2. OBJECTIVES 
Objectives will be analyzed separately in all 3 cohorts of c-MET positive, advanced SGC: (1) 
SDC, (2) ACC originated in the salivary glands or other sites of the body, (3) other SGC’s 
 
Primary Objective 
 
Assess the ORR. ORR is defined as the sum of the complete remissions plus partial 
responses.9 The best response will be used in each patient.  
 
Secondary Objectives 
 
Assess the PFS. PFS will be defined as time from study enrollment until disease 
progression or death.  
 
Assess the OS. OS will be defined as time from study enrollment until date of death of 
any cause. 
 
Asses the DoR. DoR is defined as time from study enrollment until date of documented 
tumor progression or death 
 
Assess the toxicity of cabozantinib. Toxicity will be scored according to NCI CTC 
common criteria v 4.0.10 
 
Assess the QoL of patients treated with cabozantinib using EORTC questionnaires. 
 
Assess the response rate by using continuous tumor shrinkage end-points, as was 
advocated by Billingham et al11 and Wason et al.12 
 
ctDNA will be assessed to evaluate whether response and disease progression can be 
predicted. 
 
More details about the definitions and analysis of primary and secondary outcomes are 
described in chapter 8.1. 
 

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3. STUDY DESIGN 
Design: single arm, single center, phase II clinical trial 
 
Duration: inclusion is expected to take aproximately two years  
 
Setting: single center study (Radboud University Medical Center, Nijmegen, the Netherlands) 
 
Assessments 
During the study patients will be seen every 2 weeks for the first 8 weeks, then every 4 
weeks for the first 6 months, then every 8 weeks in the first year, and every 12 weeks in the 
second year. The following assessments will be done: 
 
History / 
physical exam 
Blood  
analysis 
CtDNA 
Urine 
ECG 
Imaging 
Questionarres 
Toxicity 
Any other 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Week 0 
X 
X 
X 
X 
X 
X  
X 
 
X 
Week 2 
X 
X 
X 
X 
X 
 
 
X 
X 
Week 4 
X 
X 
X 
 
 
 
 
X 
X 
Week 6 
X 
X 
 
 
 
 
 
X 
X 
Week 8 
X 
X 
X 
 
 
X 
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X 
X 
Week 12 
X 
X 
 
 
 
 
 
X 
X 
Week 16 
X 
X 
X 
 
 
X 
X 
X 
X 
Week 20 
X 
X 
 
 
 
 
 
X 
X 
Week 24 
X 
X 
X 
 
 
X 
X 
X 
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Week 32 
X 
X 
X 
 
 
X 
 
X 
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Week 40 
X 
X 
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X 
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Week 48 
X 
X 
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X 
 
X 
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Week 56 
X 
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X 
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Week 68 
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X 
 
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Week 80 
X 
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X 
 
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Week 92 
X 
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X 
 
X 
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Week 104 
X 
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X 
 
X 
X 
At PD 
X  
X  
X  
 
 
X  
X 
X  
X  
1. History / physical exam 
o Standard history and physical examination 
2. Blood analysis 
o Hematology: haemoglobin, blood cell count (RBC, WBC count and differential, 
platelets) 
o Biochemistry: AST, ALT, AP, GGT, LD, bilirubin, creatinine, urea, Na, K, Ca, P, 
Mg, albumin, . TSH and free T4 in week 0. 
3. ctDNA 
o blood sample for ctDNA analysis 
4. Urine 
o protein/creatinine ratio 

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5. ECG 
o Standard ECG 
6. Imaging  
o CT- or MR-scanning of primary tumor area and regional lymph nodes 
o Chest plus abdominal CT 
 An independent endpoint review committee will be installed to verify 
responses according to RECIST version 1.1.13 
7. Questionnaires:  
o EORTC QLQ-C30 
o EORTC QLQ-H&N35 
o PSSHN 
o VAS 
8. Toxicity  
o Toxicity profile according to NCI CTC common criteria v 4.0 
9. Any other 
o Any other diagnostic procedure that the investigator deems necessary 
 
 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Study population:  
Patients with c-MET positive, advanced SGC 
 
c-MET positivity 
o Immunohistochemistry  
 
c-MET expression will be evaluated by immunohistochemical staining on a 
biopsy of the primary tumor (in case of locally advanced or locally 
recurrent disease) or a biopsy of metastasis (in case of metastatic 
disease). The D1C2 antibody (Cell Signaling®) will be used.  
 
The staining pattern will be scored as cytoplasmic and membranous 
staining using a semiquantitive scoring system (negative / weak / 
moderate / strong). Weak, moderate and strong cytoplasmic and/or 
membranous staining will be regarded as c-MET positive disease. 
o NGS 
 
C-MET mutations and amplifications will be assessed using Next-
Generation Sequencing (NGS) of Formalin-Fixed, Paraffin-Embedded 
(FFPE) tissue using Single Molecule Molecular Inversion Probes 
(smMIP’s).14  
 
MET (NCBI Reference Sequence NM_001127500.2) will be sequenced in 
the following regions: codon 168, 375, 982-1027, 1230-1284, 1304. 
 
Advanced SGC 
o Advanced SGC is defined as either/or 
 
Locally advanced SGC 
 
Locally recurrent SGC 
 
Metastatic SGC 
 
Patients will be analyzed in 3 cohorts (see statistical plan for more information) 
o SDC: n=9/17 patients 
o ACC: n=9/17 patients 
 
In this cohort, patients with advanced ACC originating from the salivary 
glands and ACC originating from other body parts will be included. 
o Other SGC’s: n=9 patients 
 
Source population:  
Study participants will be drawn from the following source population: 
 
Patients with SGC who are treated at the Department of Medical Oncology of the 
Radboudumc.  
 
Patients with SGC who are reffered to the Department of Medical Oncology of the 
Radboudumc in order to evaluatie eligability to particpate in this study. 
 
Patients with SGC who heard or read about this study and contact the investigators to 
ask whether they can take part in the study. Potential participants will not be actively 
recruited. However, there will be a message on the website of Dutch Salivary Gland 
Cancer Patient Platform: http://speekselklierkanker.org/. This message is added to this 
submission (see ‘E3 Wervingsmateriaal’).  
 
 
 

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4.2 Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria: 
 
Disease specific 
o locally advanced, recurrent, and/or metastatic SGC (excluding sarcomas and 
mesenchymal tumors) 
o c-MET positive disease (see paragraph 4.1) 
o Measurable disease per RECIST version 1.1 
o Cohort-specific criteria 
 
SDC cohort: 
 
Direct inclusion (no objective tumor growth prior to inclusion 
needed) 
 
ACC cohort:  
 
Inclusion after objective growth in the last three months or 
complaints due to the disease 
 
Other SGC’s  
 
Inclusion after objective growth in the last three months or 
complaints due to the disease 
 
General conditions 
o Age ≥18 years 
o Eastern Cooperative Oncology Group performance status of 0 or 1. 
o Normal number of neutrophils and thrombocytes 
o Liver function: 
 
ALT and AST < 2.5 x upper limit of normal (ULN)  
 
Total bilirubin ≤ 1.5 x ULN (except for Gilbert’s syndrome) 
 
Serum albumin ≥28 g/L 
o Renal function:  
 
Creatinine < 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min 
 
Urine protein/creatinine ratio ≤113.1 mg/mmol (≤1 mg/mg) or 24-hour 
urine protein <1 g 
o Hemoglobin A1c (HbA1c) ≤ 8% or a fasting serum glucose ≤ 9 mmol/l 
 
 
 

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4.3 Exclusion criteria 
 
General conditions 
o A known allergy for cabozantinib or its components 
o Long QT-syndrome 
o Pregnancy or lactation 
o Patients (M/F) with reproductive potential not implementing adequate 
contraceptives measures 
o Known brain metastases or cranial epidural disease unless adequately treated 
with radiotherapy and/or surgery and stable for at least 3 months before 
inclusion 
o Major surgery within 3 months before randomization. Complete wound healing 
from major surgery must have occurred 1 month before inclusion and from 
minor surgery at least 10 days before inclusion 
o Uncontrolled illness including, but not limited to 
 
Cardiovascular disorders including symptomatic congestive heart 
failure, unstable angina pectoris, or serious cardiac arrhythmias 
 
Uncontrolled hypertension defined as sustained systolic BP > 150 mm 
Hg, or diastolic BP > 100 mm Hg 
 
Stroke (including TIA), myocardial infarction, or other ischemic event 
within 6 months before inclusion 
 
Serious active infections 
 
Concomitant treatments 
o Concomitant (or within 4 weeks before inclusion) administration of any other 
experimental drug under investigation. 
o Concurrent treatment with any other anti-cancer therapy. 
o Concomitant anticoagulation.  
 
Low dose aspirin for cardioprotection and low dose LMWH are 
permitted. 
o Radiation therapy within the last 4 weeks before inclusion 
 
 
 

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4.4 Sample size calculation 
The Simon two-stage design15 will be used, with a null hypothesis of at most 5% 
response rate (not warranting further investigation) and an alternative hypothesis of at 
least 25% response rate (leading to further investigation). The statistical error rates of the 
design are α = 0.05 and β = 0.80. The first stage consists of 9 patients per cohort ((1) 
SDC, (2) ACC) evaluable for response. If 0 responses out of the first 9 evaluable patients 
are observed, the study will be stopped with the conclusion that the drug should not be 
further investigated. In any other situation, the study will be continued until 17 patients are 
evaluable for response per cohort. If ≤2 responses out of these 17 patients are observed 
the study will accept the null hypothesis, with the conclusion that the drug should not be 
investigated further. If >2 responses out of 17 patients are observed, the null hypothesis 
will be rejected with the conclusion that the drug should be further investigated. In the 
third cohort (other SGC) 9 patients will be included to evaluate the efficacy of 
cabozantinib in other subtypes of c-MET positive SGC. Because different subtypes are 
included in this cohort, these results are hypothesis forming but will not be used for 
statistical analysis. Therefore, this study cohort will be closed after the first stage with 9 
patients. 
 
Feasibility analysis: 
The Radboud university medical center is a tertiary referral center for head and neck 
cancer and SGC in particular, receiving referrals from all other academic medical centers 
and the Dutch Cancer Institute in the Netherlands. In 2016 and 2017 approximately 80-90 
new locally recurrent or metastatic SGC patients (40% SDC, 40% ACC, 20% other 
SGC’s) visited our outpatient department. Next to this, we closely collaborate with the 
SGC patient network in the Netherlands. Therefore we believe it is feasible to enroll 17 
SDC patients, 17 ACC patients and 9 other SGC patients in two years.  
 

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5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
Patients will use cabozantinib tablets (Cabometyx®) once daily until progressive disease, 
intolerable toxicity, or investigator and/or patient decision to withdraw for a maximum 
duration of 2 years. 
 
Starting dose 
o 60 mg once daily 
o Liver function disorder: 40 mg once daily 
o Renal impairment: Cabozantinib should be used with caution in patients with 
mild or moderate renal impairment, but no dose reduction is necessary 
 
Dose reductions 
o Grade 3 or greater toxicities or intolerable grade 2 toxicities: temporary 
interrupt treatment untill side effects recovered to grade 1 toxicity or less. 
Resume therapy at 40 mg once daily if necessary and at 20 mg once daily at a 
subsequent episode 
o Dose reductions are recommended for events that, if persistent, could become 
serious or intolerable. 
 
Missed dose 
o  If there are still 12 hours or more before the next dose is due, then the missed 
dose should be taken as soon as possible. The next dose should be taken at 
the normal time.  
o If the next dose is due in less than 12 hours, then the missed dose should not 
be taken. The next dose should be taken at the normal time. 
 
Method of administration 
o Cabometyx is for oral use. The tablets should be swallowed whole and not 
crushed.  
o Patients should be instructed to not eat anything for at least 2 hours before 
through 1 hour after taking Cabometyx.\ 
 
5.2 Use of co-intervention (if applicable) 
 
No co-intervention is allowed during the study period. 
 
Concomitant medicinal products that are strong inhibitors of CYP3A4 (i.e. azoles, 
erytromycine, antiretroviral drugs, grapefruit juice) should be used with caution, and 
chronic use of concomitant medicinal products that are strong inducers of CYP3A4 
(rifampicine, certain anti-epileptics, st. John’s wort) should be avoided. 
 
5.3 Escape medication (if applicable) 
Not applicable 

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product(s) 
Cabometyx 20/40/60 mg film-coated tablets. See chapter 1, 2 and 3 of the Summary of 
product characteristics for more information. 
 
6.2 Summary of findings from non-clinical studies 
In nonclinical toxicology studies of cabozantinib in rodents and non-rodents, 
histopathological changes associated with cabozantinib administration were observed in 
gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, adrenal, and 
reproductive tract tissues, and secondary changes were observed in bone and pancreas. 
Cabozantinib tested negative in bacterial and mammalian cell genotoxicity assays in vitro. 
In reproductive toxicity studies, cabozantinib was embryotoxic in rats, produced fetal soft 
tissue changes in rabbits, produced fetal external malformations in rats, and decreased 
fertility in male and female rats. The metabolite present at highest concentrations in 
humans administered cabozantinib, EXEL-1644, was negative in an in vitro bacterial 
genotoxicity bioassay and caused no systemic tissue toxicity in rats. In a 2-year rat 
carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased 
incidence of benign pheochromocytoma, alone or in combination with malignant 
pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla in 
both sexes. No clinical cases of pheochromocytoma have occurred to date. No 
carcinogenic signal was observed in a rasH2 transgenic mouse model following 
cabozantinib dosing for 26 weeks. See chapter 4 of the IB and paragraph 5.3 in the 
Summary of product characteristics for more information. 
 
6.3 Summary of findings from clinical studies 
17 clinical studies of cabozantinib for oncology indications including four Phase 1 studies, 
one Phase 1b/2 study, four Phase 2 studies, five Phase 3 studies (a placebo-controlled 
study in subjects with medullary thyroid cancer, two active-controlled studies in subjects 
with CRPC, one ongoing open-label, active-controlled study in subjects with renal cell 
carcinoma, and one ongoing and enrolling double-blinded placebo-controlled study in 
subjects with hepatocellular carcinoma, one ongoing and enrolling Phase 4 study in 
medullary thyroid cancer, one ongoing maintenance “roll-over” study, and one expanded 
access study (Table 5-1 in the IB) are done. In addition, there are eleven clinical 
pharmacology studies (Table 5-2 in the IB); nine were conducted in healthy subjects 
alone, one study was conducted that included healthy subjects and subjects with renal 
impairment, and one study was conducted that included healthy subjects and subjects 
with hepatic impairment. In addition to these company-sponsored clinical studies, twenty-
nine externally-sponsored studies and seventeen National Cancer Institute -Cancer 
Therapy Evaluation Program (CTEP) trials have enrolled subjects in oncology indications. 
Study results are summarized in paragraph 5.5 of the IB and paragraph 5.1 of the 
Summary of product characteristics. 
 
6.4 Summary of known and potential risks and benefits 
Cabozantinib has a well known safety profile, with 2467 patients treated within a clinical 
trial. Adverse event experienced by ≥20% of these patients are listed in table 1-1 of the 

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IB. Serious adverse events experienced by ≥1% of these patients are listed in table 1-2 of 
the IB. Benefits of cabozantinib in other cancers are described in paragraph 5.5 of the IB. 
 
6.5 Description and justification of route of administration and dosage 
Cabozantinib tablets are meant to be taken orally only and not to be crushed for 
dissolving in liquid or administered through other routes including percutaneous 
endoscopic gastrostomy (PEG) tubes. Cabozantinib tablets should not be administered to 
subjects who do not have adequate swallowing capacity. Cabozantinib is meant to be 
taken without food (subjects should not eat for at least 2 hour before and at least 1 hour 
after taking cabozantinib) with a full glass (at least 240 ml) of water. If a dose is missed, 
the missed dose should not be taken less than 12 h before the next dose. Dosage is 
described in paragraph 5.1 of this protocol and table 1 in the Summary of product 
characteristics (page 4). 
 
6.6 Dosages, dosage modifications and method of administration 
Starting dose of cabometyx is 60 mg once daily (40 mg once daily in case of liver function 
disorders). Recommended dose modifications are described in paragraph 5.1 of this 
protocol and table 1 in the Summary of product characteristics (page 4). The trial 
medication will be stored at the trial pharmacy and can be ordered by filling in an AKF-
form. Subsequently, the research nurse of the medical oncology department will hand the 
medication over to the patient on the outpatient department. 
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Preparation and labeling of the commercially available medicinal product will be 
performed by the pharmacy department according to in-house SOP and IB. 
 
6.8 Drug accountability 
Drug accountability will be registered per patient and overall. For ‘per patient drug 
accountability’ a drug dispensing log will be used (see the attachment). In this log, drug 
dispension and returned drugs will be registered. A drug accountability log will be used for 
an overview of all dispensed and returned drugs (see the attachment).  

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
  
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
 
Assess the ORR  
o Response will be measured according to RECIST version 1.1.13  
o ORR is defined as the sum of the complete remissions plus partial 
responses.9 
o The best response will be used in each patient.  
o An independent endpoint review committee will be installed to verify 
responses. 
 
8.2 Secondary study parameters/endpoints (if applicable) 
 
Assess the PFS 
o PFS is defined as time from study enrollment until disease progression or 
death.  
o Outcome will be scored as ‘progressed’ or ‘censored’ according to the FDA 
guidance for industry of clinical trial endpoints.9 
 
Assess the OS 
o OS is defined as time from study enrollment until date of death of any cause. 
o Analysis of OS will be done at the end of the study (study related follow-up will 
be until 3 years after start of treatment) 
 
Asses the DoR 
o DoR is defined as time from study enrollment until date of documented tumor 
progression or death 
o Only patients with a CR or PR will be included in the assessment of DoR. 
 
Assess the toxicity of cabozantinib in SGC patients 
o Toxicity will be scored according to NCI CTC common criteria v 4.0. 
 
Assess the QoL of SGC patients treated with cabozantinib 
o QoL will be assessed using the EORTC QLQ-C30, EORTC QLQ-H&N35, 
PSSHN and VAS questionnaires. 
 
Assess the response rate of patients with advanced SGC treated with cabozantinib by 
using continuous tumor shrinkage end-points, as was advocated by Billingham et al11 
and Wason et al.12 
 
ctDNA will be assessed to evaluate whether treatment response and disease 
progression can be predicted. 
 
 
 
 
 

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8.2.1 Other study parameters (if applicable) 
 
History 
o Birth date 
o Gender 
o General medical history 
o Medication use 
o Allergies 
o SGC history: diagnosis date, location primary tumor, TNM stage at 
diagnosis, ex-PA?, AR-status, HER2-status, type of surgery, date of 
surgery, postoperative radiotherapy, date of radiotherapy, adjuvant 
systemic therapy, location of recurrence, date of recurrence, palliative 
treatments 
 
Clinical examination:  
o Vital signs 
o Body weight 
 
Laboratory tests: Hematology, biochemistry, urine (see assessments) 
 
ECG: QT time, abnormalities 
 
 
8.3 Randomisation, blinding and treatment allocation 
This is a single arm study, so randomisation, blinding and treatment allocation are not 
applicable. 
 
 
 

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8.4 Study procedures 
In chapter 3 (study design) we describe which assessments will be done and when. 
Below we describe what this means for a patient who decides to participate: how many 
study related visits will be made, how much blood will be drawn, how much radiation will 
be used etcetera. 
 
 
Treatment 
o A patient will use Cabometyx tablets once daily for a maximum of 2 years 
 
OPD visits 
o A patient will visit the OPD at week 0 (baseline), 2, 4, 6, 8, 12, 16, 20, 24, 32, 
40, 48, 56, 68, 80, 92, 104 if he/she is on treatment for the maximum duration 
of 2 years. This means 17 planned study related visits in 2 years. 
 
Laboratory tests 
o Blood will be drawn by venapuncture at every visit.  
o At every visit, the following blood will be drawn:  
 
First tube is always discarded 3 ml tube 
 
Hematology  3 ml EDTA tube 
 
Biochemistry  3 ml lithium-heparin tube 
 
ctDNA  3x 8.5 ml Roche cell free DNA tubes 
 
total: 34.5 ml of blood per visit 
 
Urine analysis 
o A urine portion will be analyzed for protein/creatinine ratio before start of 
treatment, after 2 weeks, and when clinically indicated. 
 
ECG 
o An ECG will be made before start of treatment, after 2 weeks, and when 
clinically indicated. 
 
Imaging 
o A neck-, chest-, and abdominal CT scan will be made in week 0, 8, 16, 24, 32, 
40, 48, 56, 68, 80, 92 and week 104 if a patient stay on treatment during the 
maximum of 2 years. So 12 CT-scans of approximately 15 mSv will be made, 
resulting in a yearly exposure of 90 mSv. Taking the terminal disease into 
account, this corresponds to a effective dose in healthy adults of 9 mSv, which 
is a moderate risk. In our opinion, this exposure is justified concerning the 
relevance of the study. See the radiation ethic form for further details. 
 
Questionnaires 
o Questionairres will be taken 7 times (at baseline, week 8, week 16, week 24, 
week 40, week 56 and at PD) 
o The follow questionnaires will be taken: 
 
EORTC QLQ-C30: 30 questions 
 
EORTC QLQ-H&N35: 35 questions 
 
PSSHN16: 3 questions 
 
VAS: 1 question 
 
Total: 30+35+3+1=69 questions 
 
 
 

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8.5 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for 
urgent medical reasons. 
8.5.1 Specific criteria for withdrawal (if applicable) 
Not applicable 
 
8.6 Replacement of individual subjects after withdrawal 
If a participant decides to withdraw before start of treatment with Cabometyx, another 
patient will be recruited to replace this participant. If a participant withdraws after start of 
treatment, this patient will be regarded as ‘lost to follow-up’ and won’t be replaced. 
 
8.7 Follow-up of subjects withdrawn from treatment 
All participants who received at least one dose of Cabometyx, will have study related 
follow-up for 3 years after the start of the study in order to establish PFS en OS. If a 
participant withdraws before start of Cabometyx, there will be no study related follow-up. 
Once study related follow-up is finished, patients will get follow-up as standard medical 
care. 
 
8.8 Premature termination of the study 
The Simon 2-stage design of this study prevents unnecessary exposure of an ineffective 
treatment. After the first stage (9 patients in each cohort) an interim analysis will be done 
to see whether continuation of the trial is indicated. See the sample size calculation for 
more details. 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the investigational product. All 
adverse events reported spontaneously by the subject or observed by the investiga-
tor or his staff will be recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
 
results in death; 
 
is life threatening (at the time of the event); 
 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
 
results in persistent or significant disability or incapacity; 
 
is a congenital anomaly or birth defect; or 
 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events.  
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
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2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in the Investigator’s Brochure. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 
 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 
A list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 
A report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
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MonitoringCabometyx is registered in advanced renal cell carcinoma. Additional toxicity is 
not expected in SGC. Therefore a DSMB deemed unnecessary.The study will be 
monitored according to the NFU guideline ‘Kwaliteitsborging mensgebonden onderzoek 
2.0’. For this study with a moderate risk, moderate intensive monitoring will be applied 
(see page 18 of the NFU guideline).  
  
 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
Following Simon’s design (as described in section 4.4) for RECIST v1.1, the null 
hypothesis will be rejected if more than 2 responses out of 17 patients are observed; in 
that case the conclusion is that the drug should be further investigated. This design yields 
a type I error rate of 0.047 and power 0.81 when the true response rate is 0.25.  A 95% 
CI for the overall response rate per RECIST v1.1 will be calculated using the binomial 
distribution. Next to this, responses (CR, PR, SD and PD) will be described using simple 
descriptive statistics. 
 
10.2 Secondary study parameter(s)  
 
Assess the PFS 
o PFS will be estimated by a Kaplan-Meier curve 
 
In SDC patients, PFS will be compared to PFS in AR-positive SDC 
patients which received ADT17,18 and HER2-positive SDC patients 
which received docetaxel plus trastuzumab.19 
 
In ACC patients, PFS will be compared to PFS in ACC patients which 
received mitoxantrone monotherapy,20,21 vinorelbine monotherapy,22 
epirubicin monotherapy,23 or cisplatin plus anthracycline combination 
therapies24 
 
In other SGC patients, PFS will be described per individual case. 
 
Assess the OS 
o OS will be estimated by a Kaplan-Meier curve 
 
In SDC patients, OS will be compared to a historical cohort of patients 
receiving best supportive care and a cohort receiving ADT.18 
 
In ACC patients, median OS after disease recurrence is 6.4 years, and 
median OS after metastasis is 3.7 years.25 OS of our study patients will 
be compared to these data and to OS data of phase II studies in ACC 
mentioned above (assess the PFS).  
 
In other SGC patients, survival will be described per individual case 
 
Toxicity and QoL questionnaires will be described using simple descriptive statistics. 
 
Assess the response rate of patients with advanced SGC treated with cabozantinib by 
using continuous tumor shrinkage end-points, as was advocated by Billingham et al11 
and Wason et al.12 
 
Tumor shrinkage will be shown in a waterfall plot. 
 
10.3 Other study parameters 
Background variable will be described using simple desricptive statistics and will be 
presented in a table.  
 
10.4 Interim analysis 
 
According to the Simon 2-stage design, interim analysis of treatment efficacy will be 
done after 9 patients in each cohort. Treatment efficacy will be established by the 
response rate, in which a treatment response is defined as a complete remission or 
partial response, based on RECIST version 1.1 criteria. In case of 0 response, this 

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cohort will be terminated. In case of ≥1 response(s), 8 additional patients will be 
included in stage 2. This interim analysis will be performed by the researcher. The 
monitor will check the responses, in order to establish whether patients can be 
included in stage 2.  
 
For OS, a planned interim analysis will be done after a median follow-up of 3 years. 
The monitor will analyze interim safety and efficacy data in according to the NFU 
guideline ‘Kwaliteitsborging mensgebonden onderzoek 2.0’, for moderate risk studies. 
Next to this, the monitor will check if the study can proceed to stage 2, based on 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki 
(version 8, 19 October 2013), in accordance with the Medical Research Involving Human 
Subjects Act (WMO), the personal data protection act (Wet Bescherming 
Persoonsgegevens), and the Medical Treatment Agreement Act (WGBO). 
 
11.2 Recruitment and consent 
Patients will be informed about the study by their treating physician during normal patient 
care. Detailed information about the study can be offered by the investigators during 
normal patient care or by phone call. If a patient decides to participate, the baseline study 
visit will be planned, which starts with reviewing inclusion and exclusion criteria and 
signing the IC.  
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable 
 
11.4 Benefits and risks assessment, group relatedness 
Benefits: because cabometyx has not been tested in SGC patients before, the chance of 
responding to treatment is unknown. The Simon 2-stage design will be used in order to 
prevent exposure of too many patients to ineffective treatment without discarding a 
potential effective treatment because of treatment failure in some patients. 
Risk assessment: Safety of Cabometyx is well known because of studies in renal cell 
carcinoma.3 The most common serious adverse reactions associated with cabozantinib 
are abdominal pain (3%), pleural effusion (3%), diarrhoea (2%), and nausea (2%). The 
most frequent adverse reactions of any grade (experienced by at least 25% of patients) 
included diarrhoea (74%), fatigue (56%), nausea (50%), decreased appetite (46%), 
palmar-plantar erythrodysaesthesia syndrome (PPES) (42%), hypertension (37%), 
vomiting (32%), weight decreased (31%), and constipation (25%).26  
Group relatedness: the study does not involve minors and/or incapacitated subjects 
 
11.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives  
Travel expenses and parking costs will be paid. 
 
 
 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Patient identification 
During registration an unique patient record ID will be allocated to the patients. This 
record ID will be used for identification of the patients and should be reported on all case 
record forms (CRFs). Data and patient material will be handled confidentially and if 
possible anonymously. When it is necessary to trace data or material to an individual 
subject, we will use a subject identification number list to link the data to the subject. This 
list will be safeguarded by the Principle Investigator. The handling of personal data 
complies with the Dutch Personal Data Protection Act (in Dutch: De Wet Bescherming 
Persoonsgegevens, WBP). 
 
Data management 
Data will be collected on electronic Case Report Forms (CRF) to document eligibility, 
safety and efficacy parameters, compliance to treatment schedules and parameters 
necessary to evaluate the study endpoints. The e-CRF will be completed on site by the 
local investigator or an authorized staff member. All CRF entries must be based on 
source documents. Guidelines for completing the CRF will be provided by the Trial office 
Hematology-Oncology, Nijmegen. Access to the e-CRF will be provided by the Trial office 
Hematology-Oncology, Nijmegen only to authorized site staff members. Training 
materials will be provided by the Trial office Hematology-Oncology, 
Nijmegen. 
 
12.2 Monitoring and Quality Assurance  
Source data verification of the CRFs and check of the Investigator Study File documents 
will be performed by the clinical research monitor of the Radboudumc, according to the 
procedures The NFU guideline “Kwaliteitsborging mensgebonden onderzoek 2.0’’ for 
studies with a moderate risk. 
 
12.3 Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
 
the safety or physical or mental integrity of the subjects of the trial; 
 
the scientific value of the trial; 
 
the conduct or management of the trial; or 
 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
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first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
12.6 Public disclosure and publication policy 
Prior to initiation, the study will be submitted to clinicaltrials.gov. All the results will 
officially be published. Ipsen will provided with a copy of any manuscript, paper or poster 
not less than thirty (30) days prior to their submission to a scientific journal or 
presentation at scientific meetings and a reasonably detailed summary or abstract of any 
other oral or written publication not less than thirty (30) days prior to their submission or 
presentation. ln case the investigator receives no response within thirty (30) days the 
investigator will be free to publish. Upon request by Ipsen, presentation, submission for 
publication or other disclosure, will be withhold for an additional ninety (90) days to allow 
Ipsen to seek patent protection. 
 
 
 

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13. STRUCTURED RISK ANALYSIS  
 
13.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
Cabozantinib is an inhibitor of multiple receptor tyrosine kinases. The targets of 
cabozantinib include several tyrosine kinases known to play important roles in tumor cell 
proliferation and/or tumor neovascularization, namely MET (hepatocyte growth factor 
[HGF] receptor), vascular endothelial growth factor receptor 2 (VEGFR2, also known as 
KDR), AXL, and RET. Other recognized targets of cabozantinib include ROS1, TRKA, 
TRKB, TYRO3, MER, two additional members of the VEGFR family (VEGFR1, VEGFR3), 
and the closely-related tyrosine kinases KIT and FLT-3. In vivo pharmacodynamic activity 
of cabozantinib against MET, VEGFR2, AXL, and RET has been demonstrated in 
preclinical studies and has been associated with tumor growth inhibition and tumor 
regression. In preclinical studies, cabozantinib treatment has also been shown to inhibit 
tumor angiogenesis and tumor invasiveness and metastasis. Next to this, MET 
expression has been shown in 53.2% of ACC patients6 and 39.7% SDC patients.7 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
Cabozantinib has been studied in humans in different cancers (see chapter 5 of the IB) 
and has been approved for metastatic medullary thyroid cancer and advanced renal cell 
carcinoma. The safety profile of cabozantinib and the efficacy in other cancers is 
therefore well known. Cabozantinib has not been studied in SGC before. We will use a 2-
stage design in order to minimize sample size in case of low-activity. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
Anti-tumor activity is shown in other cancers in humans (paragraph 5.5 of the IB). 
Currently, no SGC cell cultures or organoid cultures are available to test cabozantinib 
efficacy in SGC in vitro. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Cabozantinib is a multikinase receptor tyrosine kinase. These targets (see 13.1a) inhibit 
different factors in cancer progression, such as cell proliferation and tumor 
neovascularisation. However, these targets are not tumor-specific and therefore induce 
certain side effects. These side effects are extensively studied in human beings in 
previous studies in other cancers. Anticipated adverse events and management of 
adverse events are described in paragraph 6.2 of the IB 
 
e. Analysis of potential effect 
Because cabozantinib has not been studied in SGC before, potential efficacy can’t be 
predicted. The Simon 2-stage design will be used to minimize exposure of patients to this 
treatment in case of low-acitivity.  
 
f. Pharmacokinetic considerations 
Following oral administration of cabozantinib capsules or tablets, Tmax ranged from 2 to 5 
hour post-dose. The terminal half-life (for predicting drug washout) is approximately 120 

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hour. Repeat daily dosing of cabozantinib capsules at 140 mg for 19 days resulted in a 4- 
to 5-fold higher mean cabozantinib accumulation (based on AUC) compared with a single 
dose administration; steady state was achieved by Day 15. Cabozantinib is highly protein 
bound in human plasma (≥ 99.7%). 
 
A PopPK analysis of cabozantinib was performed using data collected from 289 
cabozantinib-treated subjects with solid tumors following oral administration of 140-mg 
capsule daily doses. The predicted effective half-life for that formulation at that dose was 
approximately 55 h, V/F is approximately 349 L, and CL/F at steady-state was estimated 
to be 4.4 L/h. This PopPK analysis did not identify clinically relevant differences in 
clearance of cabozantinib between females and males or between Whites (89%) and 
non-Whites (11% [<4% were Asian]). Cabozantinib PK was not affected by age (20-86 
years). 
 
More information about the pharmacokinetics can be found in paragraph 5.2 of the IB. 
 
g. Study population 
The study population are patients with locally advanced and/or metastatic SGC. This is a 
life-treatening condition and at the moment of inclusion the condition is unstable, because 
SDC is an aggressive tumor and for the others types of SGC objective growth is needed 
prior to inclusion. Next to this, treatment options are very limited in this situation (see 
introduction). Women with child bearing potential could be included in the study, but have 
to take contraceptive measures in order to participate. 
 
h. Interaction with other products 
In summary, currently available data suggest that cabozantinib: (1) is not anticipated to 
markedly induce or inhibit CYP enzymes at clinically-relevant plasma concentrations; (2) 
is a substrate for CYP3A4; (3) may have the potential to inhibit the P-gp transport activity 
but is not a substrate of P-gp; and (4) is a substrate of drug-transporter MRP2. More 
information can be found in paragraph 6.4 of the IB. 
 
i. Predictability of effect 
Treatment effect will be measured with CT-scans every 8 weeks using RECIST criteria. It 
is not possible to predict treatment effect reliable before the first evaluation CT scan. In 
this study, we will collect blood samples for ctDNA analysis. The ctDNA samples will be 
analyzed in order to establish whether disease response can be predicted before the first 
evaluation CT-scan using ctDNA. 
 
j. Can effects be managed? 
In general side effects can be managed by either supportive treatment and/or dose 
reductions. Specific management of side effects is described in paragraph 6.2 of the IB. If 
side effect occur, the Radboudumc has 24-hour facilities including a level 3 intensive care 
to manage side effects. 
 
13.2 Synthesis 
To sum up, SGC is a rare cancer with few treatment options in case of disease 
recurrence or distant metastases. New treatment options are therefore urgently 

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warranted. Because c-MET overexpression is established in ACC and SDC, treatment 
with the tyrosine kinase inhibitor cabozantinib (which targets MET, among others) could 
be a new treatment option.  
In order to minimize risk of this experimental treatment, we took certain measures. First of 
all, only patients with a reasonable health (see inclusion criteria) can be included. Second, 
we use the Simon 2-stage design in order to minimize exposure of patients in case of 
minimal efficacy. Third, we took standard precautions such as a moderate monitoring 
according to NFU guidelines. And Finally, we will only include c-MET positive tumors in 
order to increase the chance of treatment efficacy. In case of treatment efficacy in c-MET 
positive salivary gland tumors, a future study may investigate the efficacy of cabozantinib 
in all salivary gland tumors, as cabozantinib has more targets then only c-MET. 
In our opinion, the remaining risks of this therapy are acceptable for patients participating 
in the study, taking the lack of other treatment options, well-known safety profile of 
cabozantinib, and safety measures into account. According to the NFU risk classification, 
this study has a moderate risk (moderate chance of moderate damage). 
 
 
 
 
 
 

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