A Phase II, Multicentre, Open-label Study of Cabozantinib as 2nd Line Treatment in Subjects With Unresectable, Locally Advanced or Metastatic Renal Cell Carcinoma With a Clear-Cell Component Who Progressed After 1st Line Treatment With Checkpoint Inhibitors.
Phase: PHASE2
Conditions: Locally Advanced or Metastatic Renal Cell Carcinoma
Sponsor: Ipsen

IPSEN GROUP 
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A PHASE II, MULTICENTRE, OPEN-LABEL STUDY OF CABOZANTINIB AS 
2ND LINE TREATMENT IN SUBJECTS WITH UNRESECTABLE, LOCALLY 
ADVANCED OR METASTATIC RENAL CELL CARCINOMA WITH A CLEAR-CELL 
COMPONENT WHO PROGRESSED AFTER 1ST LINE TREATMENT WITH 
CHECKPOINT INHIBITORS 
 
STUDY PROTOCOL 
STUDY NUMBER: F-FR-60000-023 
CABOZANTINIB/XL184 
EudraCT number: 2018-002820-18 
 
Final Version 6.0 (including Amendment #4): 23 February 2022 
Final Version 5.0 (including Amendment #3): 03 March 2021 
Final Version 4.0 (including Amendment #2): 24 January 2020 
Final Version 3.0 (including Amendment #1): 28 November 2019 
Final Version 2.0: 26 April 2019 
 
Study Sponsor: 
Ipsen Pharma  
65 Quai Georges Gorse 
92650 Boulogne-Billancourt Cedex, France 
Tel: +33 (0) 1 58 33 50 00 
   
Sponsor Signatory:  
 
65 Quai Georges Gorse 
92650 Boulogne-Billancourt Cedex, France 
Tel: +33 (0) 1 58 33 50 00
Emergency Contact: 
Head Global Patient Safety,  
Ipsen Innovation 
ZI de Courtaboeuf, 5 Avenue du Canada 
91940 Les Ulis, France 
Mobile: +33 (0) 6 43 53 35 70 
 
For serious adverse event (SAE) reporting: 
Fax: 
+33 (0) 1 60 92 21 19 
E-mail: adverse.events@ipsen.com 
 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 
PPD

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SUMMARY OF CHANGES 
 
The current version of the protocol was released on 23 February 2022 and includes 
Amendment #4. The amendment forms were prepared and are provided in Appendix 8 to 
Appendix 11 (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
28 November 2019 
Appendix 8 
2 
24 January 2020 
Appendix 9 
3 
03 March 2021 
Appendix 10 
4 
23 February 2022 
Appendix 11 
 

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SYNOPSIS 
Name of Sponsor/company: Ipsen Pharma 
Name of finished product: Cabometyx 
Name of active ingredient(s): cabozantinib 
Title of study: A Phase II, Multicentre, Open-Label Study of Cabozantinib as 2nd Line 
Treatment in Subjects with Unresectable, Locally Advanced or Metastatic Renal Cell 
Carcinoma with a Clear-Cell Component Who Progressed After 1st Line Treatment with 
Checkpoint Inhibitors 
Study number:  F-FR-60000-023 
Number of planned centres: approximately 50 active centres 
Planned study period: 
Q1 2020 to Q4 2023 
Phase of development: 
Phase II  
Study type: Efficacy and Safety  
Objectives:  
The overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 
2nd line treatment in subjects with unresectable, locally advanced or metastatic renal cell 
carcinoma (RCC) with a clear-cell component, who progressed after prior checkpoint 
inhibitors (CPI) therapy with ipilimumab and nivolumab in combination or CPI combined 
with vascular endothelial growth factor (VEGF)-targeted therapy.  
 
Primary Study Objective:  
• 
To assess the efficacy of cabozantinib by the objective response rate (ORR) per 
Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by 
independent central review in cohort A. 
 
Secondary Study Objectives:  
• 
To assess other efficacy criteria of cabozantinib such as time to response (TTR), 
duration of response (DOR), disease control rate (DCR), progression-free survival 
(PFS) by independent central review and Investigator’s review; 
• 
To assess objective response rate (ORR) by independent central review and 
Investigator’s review in cohort B; 
• 
To assess ORR by Investigator’s review in cohort A;  
• 
To assess overall survival (OS); 
• 
To assess the ORR and PFS by Investigator’s review and OS in overall population 
(cohorts A+B); 
• 
To assess the change in disease-related symptoms as assessed by the Functional 
Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) 
questionnaire; 
• 
To assess the safety and tolerability of cabozantinib. 

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Study hypothesis:  
The hypothesis for the two cohorts of this study is that cabozantinib as 2nd line treatment 
will demonstrate a clinically significant increase of response rate as compared to historical 
control in subjects previously treated with CPI therapy. A therapy will be considered 
clinically meaningful if it provides a significant benefit in ORR (primary endpoint) over a 
standard rate of 10% (conservative threshold in reference to the response rate of everolimus 
in the METEOR study (exact 95% confidence interval (CI): 1.7-5.9)). 
Methodology: 
This is a Phase II, multicentre, open-label study to evaluate the efficacy and safety of 
cabozantinib 60 mg once daily (q.d.) in adults with unresectable, locally advanced or 
metastatic RCC with a clear-cell component that progressed, according to Investigator’s 
judgement, after prior CPI therapy (ipilimumab and nivolumab) alone or CPI combined 
with VEGF-targeted therapy. Approximately 114 eligible subjects will receive 
cabozantinib (two independent cohorts with 74 subjects* in cohort A and approximately 
40 subjects in cohort B). 
*The inclusion period will stop either when 74 subjects have been enrolled in cohort A or 
at the latest on 30 June 2022, whichever is reached first.  
 
Each subject’s study participation will consist of the following periods: 
 
Pre-treatment Period: Potential subjects will be screened to determine whether they meet 
the required eligibility criteria. Qualifying assessments will be performed within 15 days 
prior to first cabozantinib dose except when otherwise specified (detailed in study 
schedule). 
 
Treatment Period: Subjects who meet all eligibility criteria will be included in one of the 
two following cohorts based on their 1st line treatment and both cohorts will receive the 
same open-label treatment with cabozantinib (60 mg q.d.): 
 
• 
Cohort A: 74 subjects 
Cohort A will be composed of subjects who radiographically progressed after one prior 
line by CPI therapy with ipilimumab and nivolumab.  
 
• 
Cohort B: approximately 40 subjects 
Cohort B will be composed of subjects who radiographically progressed after one prior 
line by CPI therapy combined with VEGF-targeted therapy. 
  
In both cohorts, subjects can receive study treatment up to a maximum of 18 months after 
the last subject included in the study received the first cabozantinib dose (end of the study), 
but subjects may terminate study treatment earlier due to reasons such as disease 
progression, unacceptable toxicity or withdrawal of consent. 

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Subjects who discontinue treatment with cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend the End of Study Treatment visit (30 to 45 
days after the last dose of cabozantinib). Subjects who prematurely stop the study due to 
withdrawal of consent will be invited to attend the Early Study Withdrawal visit. 
 
Post-treatment Follow-up Period: Subjects who discontinue study treatment will be 
contacted during the Post-treatment Follow-up visits every 12 weeks ±15 days to assess 
survival status and collect information about subsequent anti-cancer therapy. During the 
follow-up period, any SAEs that occur more than 30 days after the date of the last 
cabozantinib dose, assessed as related to study treatment or study procedures will also be 
collected and followed until resolution or stability according to the Investigator. These 
assessments will be continued until the subject expires or until the end of the study 
(18 months after the last subject included in the study started cabozantinib treatment), 
whichever occurs first. Every effort will be made to collect these protocol-specific 
evaluations unless consent to participate in the study is withdrawn. 
Number of subjects planned: approximately 114 subjects: 74 subjects* in Cohort A and 
approximately 40 subjects in Cohort B 
* The inclusion period will stop either when 74 subjects have been enrolled in cohort A or 
at the latest on 30 June 2022, whichever is reached first.  
Diagnosis and criteria for inclusion:  
Inclusion criteria: 
All subjects must fulfil all the following criteria to be included in the study: 
(1) 
Subjects must provide a signed informed consent prior to any study-related 
procedures; 
(2) 
Male or female subjects must be aged ≥18 years on the day the informed consent is 
signed; 
(3) 
Subjects must have histologically confirmed unresectable, locally advanced (defined 
as disease not eligible for curative surgery or radiation therapy) or metastatic RCC 
with a clear-cell carcinoma component; 
(4) 
Subjects must have radiographic disease progression, according to Investigator’s 
judgement, following 1st line treatment with CPI (ipilimumab plus nivolumab) 
(Cohort A) or CPI in combination with VEGF-targeted therapy (Cohort B); 
(5) 
Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator; 
(6) 
Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1; 
(7) 
Subjects with treated brain metastases are eligible if metastases have been shown to 
be stable as per Investigator’s judgement;  
(8) 
Subjects must have adequate organ and marrow function, based upon meeting all of 
the following laboratory criteria within 15 days before baseline: 
(a) 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L). 
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 GI/L). 
(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 
× upper limit of normal (ULN). 

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(e) 
Total bilirubin ≤ 1.5 × ULN. For subjects with Gilbert’s disease ≤ 3 mg/dL (≤ 
51.3 μmol/L). 
(f) 
Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault equation  
(g) 
Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) 
creatinine or 24-hour urine protein < 1 g. 
(9) 
Subject must have recovered to baseline or ≤ Grade 1 per Common Terminology 
Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior 
treatments, unless adverse event(s) (AE(s)) are clinically nonsignificant and/or 
stable on supportive therapy as determined by the Investigator; 
(10) Subjects must have completed a steroid taper, if he/she experienced an immune-
related adverse event associated with previous CPI treatment; 
(11) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-
menopause and not surgically sterile) must provide a negative pregnancy test within 
7 days prior to the start of study treatment. If a urine test cannot be confirmed as 
negative, a negative serum pregnancy test is required; 
(12) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-
menopause and not surgically sterile) and their partners must agree to use highly 
effective methods of contraception that alone or in combination result in a failure 
rate of less than 1% per year when used consistently and correctly during the course 
of the study and for 120 days after the last dose of study treatment;  
(13) All male participants must agree to refrain from donating sperm and unprotected 
sexual intercourse with female partners during the study and for 120 days after the 
last dose of study treatment; 
(14) Subjects must be willing and able to comply with study requirements, remain at the 
investigational site for the required duration of each study visit and be willing to 
return to the investigational site for the follow-up evaluation, as specified in the 
protocol. 
(15) Subjects must be covered by social security or be the beneficiary of such a system 
(only applicable for French subjects). 
 
Exclusion criteria: 
Subjects will not be included in the study if the subject: 
(1) 
Inability to swallow tablets; 
(2) 
Was treated with any other investigational medicinal product (IMP) during a clinical 
study within the last 30 days before baseline; 
(3) 
Was previously treated with cabozantinib; 
(4) 
Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium 
used for Contrast Tomography (CT)-scan; 
(5) 
Presents untreated brain or leptomeningeal metastases, or current clinical or 
radiographic progression of known brain metastases; 
(6) 
Has a diagnosis of a serious cardiovascular disorder: 
(a) 
Congestive heart failure New York Heart Association class 3 or 4, unstable 
angina pectoris, or serious cardiac arrhythmias; 

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(b) 
Uncontrolled hypertension, defined as sustained blood pressure (BP) 
(>140 mm Hg systolic or >90 mm Hg diastolic pressure) despite optimal 
antihypertensive treatment; 
(c) 
Stroke (including transient ischaemic attack (TIA)), myocardial infarction 
(MI) or other ischaemic event, or thromboembolic event (e.g. deep venous 
thrombosis, pulmonary embolism) within 6 months before screening; 
(d) 
History of risk factors for torsades de pointes (e.g., long QT syndrome); 
(7) 
Is receiving a concomitant anticoagulation with coumarin agents (e.g. warfarin), 
direct thrombin inhibitor dabigatran, direct Factor Xa inhibitor betrixaban or platelet 
inhibitors (e.g. clopidogrel). 
Note: The following are allowed anticoagulants: prophylactic use of low-dose 
aspirin for cardioprotection (per local applicable guidelines), and low dose of low 
molecular weight heparin (LMWH). Therapeutic doses of LMWH or 
anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban 
in patients without known brain metastases who are on a stable dose of the 
anticoagulant for at least 1 week before baseline without clinically significant 
hemorrhagic complications from the anticoagulation regimen or the tumour. 
(8) 
Has a gastrointestinal (GI) disorder including those associated with a high risk of 
perforation or fistula formation: 
(a) 
Tumours invading the GI tract, active peptic ulcer disease, inflammatory 
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary 
duct, or gastric outlet obstruction; 
(b) 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before screening;  
Note: Complete healing of an intra-abdominal abscess must have been 
confirmed before screening. 
(9) 
Presents a corrected QT (QTc) interval calculated by the Fridericia formula 
(QTcF) > 500 msec within 1 month prior to baseline; 
Note: If a single electrocardiogram (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  
(10) Presents clinically significant haematuria, hematemesis, or haemoptysis of 
>0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g. 
pulmonary haemorrhage) within 3 months before screening; 
(11) Presents cavitating pulmonary lesion(s) or known endobronchial disease 
manifestation; 
(12) Presents lesions invading major pulmonary blood vessels; 
(13) Has been diagnosed with other clinically significant disorders such as: 
(a) 
Serious nonhealing wound/ulcer/bone fracture; 
(b) 
Malabsorption syndrome; 

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(c) 
Uncompensated/symptomatic hypothyroidism (subject with a history of 
autoimmune-related hypothyroidism who are on thyroid-replacement 
hormone are eligible for the study); 
(d) 
Moderate to severe hepatic impairment (Child-Pugh B or C); 
(e) 
Requirement for haemodialysis or peritoneal dialysis; 
(f) 
History of solid organ transplantation; 
(14) Has a predicted life expectancy of less than 3 months; 
(15) Has had prior surgery within 4 weeks prior to baseline. Note: If the subject has 
undergone major surgery, complete wound healing must have occurred 1 month 
prior to baseline. 
(16) Has had palliative radiation therapy for bone within 2 weeks or for radiation fields 
including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side 
effects must be complete prior to baseline; 
(17) Has a history of another active malignancy within 3 years from screening except for 
locally curable cancers that have been apparently cured, such as low-grade thyroid 
carcinoma, prostate cancer not requiring treatment (Gleason Grade ≤6), basal or 
squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ 
prostate, cervix or breast carcinoma or other treated malignancies with <5% chance 
of relapse according to the Investigator; 
(18) Has a history of allergy to study treatment components or agents with a similar 
chemical structure or any excipient used in the formulation as listed in the Summary 
of Product Characteristics (SmPC) document; 
(19) Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption; 
(20) Has a serious medical or psychiatric condition that render the subject unable to 
understand the nature, scope and possible consequences of the study, and/or presents 
an uncooperative attitude; 
(21) Is pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum 
pregnancy test will be performed up to 7 days prior to baseline for all female subjects 
of childbearing potential (i.e. less than or equal to 2 years post-menopause and not 
surgically sterile); 
(22) Is likely to require treatment during the study with drugs that are not permitted by 
the study protocol; 
(23) Has abnormal baseline findings, any other medical condition(s) or laboratory 
findings that, in the opinion of the Investigator, might jeopardise the subject’s safety. 
Test product, dose, mode of administration: 
All subjects will be treated with oral cabozantinib 60 mg q.d. In case of treatment-emergent 
toxicity, the Investigator may decide to reduce the dose to 40 mg or 20 mg according to the 
instructions specified in this protocol.  
The date of the first dose of cabozantinib is defined as baseline (Day 1, Visit 2) and 
screening and baseline visits can take place the same day as long as all eligibility 
criteria/parameters are available and checked prior to the first dose of cabozantinib. Doses 
will be self-administered at home by taking cabozantinib q.d. at the same time each day 

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(preferably at bedtime). Cabozantinib should not be taken with food. The subject should 
not eat anything for at least 2 hours before and 1 hour after taking cabozantinib. 
If a dose is missed, the missed dose should not be taken less than 12 hours before the next 
one.  
Duration of treatment: Subjects will receive study treatment, even after radiographic 
progression per RECIST 1.1, as long as the Investigator believes they continue to 
experience clinical benefit from study treatment and that this benefit outweighs potential 
risks, and up to the end of the study, defined as 18 months after the last subject included in 
the study received the first cabozantinib dose. Subjects may discontinue treatment due to 
disease progression, unacceptable toxicity, need for subsequent systemic anti-cancer 
treatment or any other reasons for treatment discontinuation listed in this protocol. 
Reference therapy, dose and mode of administration: No reference therapy. 

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Criteria for evaluation (endpoints): 
Efficacy: 
Primary Endpoint and Evaluation:  
• 
Objective response rate (ORR) in cohort A per RECIST 1.1 evaluated by 
independent central review.  
Secondary Endpoints and Evaluations: 
• 
Time to response (TTR) per RECIST 1.1 evaluated by independent central review; 
• 
Duration of response (DOR) per RECIST 1.1 evaluated by independent central 
review; 
• 
Disease control rate (DCR) per RECIST 1.1 by independent central review; 
• 
Progression-free survival (PFS) per RECIST 1.1 by independent central review; 
• 
Objective response rate (ORR) in cohort B per RECIST 1.1 evaluated by 
independent central review; 
• 
Overall survival (OS); 
• 
ORR, TTR, DOR, DCR and PFS per RECIST 1.1 according to local Investigator’s 
review; 
• 
Change in disease-related symptoms as assessed by the Functional Assessment of 
Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire. 
Safety: 
Safety assessments will start on the day of the Screening visit and will be carried out at 
minimum at every visit (every 2 weeks) up to Week 4 (Visit 4), and every 4 weeks 
thereafter. Safety will also be assessed at the End of Study Treatment visit (30 to 45 days 
after the last study treatment dose) and during the Post-treatment Follow-up period (every 
12 weeks (±15 days) by telephone call) up to 18 months after the last subject included in 
the study started cabozantinib treatment. Unscheduled visits for safety evaluations are 
allowed at any time. 
Routine safety evaluations throughout the study treatment period will include the recording 
of AEs, clinical laboratory (serum chemistry, haematology and urinalysis) test results, 
serum pregnancy tests (in females of childbearing potential), thyroid function tests, vital 
signs (BP and heart rate), ECG findings, physical examination findings and body weight 
measurements, and use of concomitant medication throughout the study treatment period. 
Information on new or worsening AEs and serious AEs (SAEs) will be collected from the 
date the informed consent is signed until the End of Study Treatment visit. This information 
will be collected at study visits, by telephone call to the subject or by spontaneous report 
by the subject. At baseline, AEs will be documented before and after cabozantinib dosing. 
Certain AEs and all SAEs that are ongoing 30 days after the date of the last cabozantinib 
dose are to be followed until resolution or until the Investigator considers the event is stable 
or irreversible. During the follow-up period, any SAEs that occur more than 30 days after 
the date of the last cabozantinib dose, assessed as related to study treatment or study 
procedures will also be collected and followed until resolution or stability according to the 
Investigator. 

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Statistical Methods: 
Sample size:  
With a true ORR proportion of 23%, a sample size of 68 subjects in cohort A will provide 
a statistical power of 80% to reject the null hypothesis of 10%, using a one-sample exact 
test for binomial distribution with a significance level of 0.025 (one-sided). Assuming 
approximately 7% non-evaluable subjects (i.e. subject who received at least one dose of 
study medication but did not provide a baseline for the tumour according to RECIST 1.1), 
up to a total of 74 subjects in cohort A will be included in the study. 
For cohort B, no formal sample size determination was performed as the enrolment will 
stop when the recruitment in cohort A will be reached. We anticipate approximately 40 
subjects recruited in cohort B.  
 
Statistical Methods: 
An interim and purely descriptive analysis will be conducted when 80% of the subjects 
(i.e. 59 subjects) of cohort A will be treated for at least 3 months. Both cohorts will be 
analysed at this cut-off date. The final analysis based on the primary endpoint (ORR) will 
be performed 12 months after the last subject received the first cabozantinib administration. 
A follow-up analysis based on OS will be conducted 18 months after the last subject 
received the first cabozantinib administration. The statistical testing will be carried out at 
the final analysis. 
The primary endpoint (ORR), defined as the proportion of subjects with complete response 
(CR) and partial response (PR) per RECIST 1.1 as determined by independent central 
review will be tested in cohort A using a one-sample exact test for binomial distribution. 
The proportion of subjects achieving ORR will be presented with their two-sided 95% CI 
using the Clopper-Pearson exact method. DCR estimates will be described with associated 
2-sided 95% CIs.  
Time-to-event endpoints (TTR, DOR, PFS and OS) will be analysed using the Kaplan-
Meier method. Median durations and associated 2-sided 95% CIs will be provided. Event 
rates at timepoints from either first dose of study treatment or first documented response 
will also be estimated with associated 2-sided 95% CIs. 
The FKSI-DRS score will be described at corresponding visits with associated change from 
baseline. The proportion of subjects with at least an increase of 1 point from baseline will 
also be reported. Comparisons between baseline and post-baseline scores will be performed 
using paired Student t-tests. 
All AEs will be coded according to the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be classified by preferred term (PT) and system 
organ class (SOC). AEs will be graded according to the National Cancer Institute (NCI) – 
Common Terminology Criteria for Adverse Events (NCI-CTCAE). The incidence of all 
reported AEs will be tabulated by cohort and overall. Summary tables will be presented by 
Grade 3 or 4, worst reported severity, drug relationship and AEs associated with premature 
withdrawal or dose modification of study medication. Subject deaths will be summarised, 
and primary cause of death will be reported by PT and SOC using MedDRA. Summary 
statistics (mean, median, standard deviation and range as appropriate) of values and 
changes or shifts from baseline will be presented by cohort and overall for vital signs, ECG 
variables, clinical laboratory tests at each assessment. For laboratory data, abnormal values 

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will be flagged in the data listings and a list of clinically significant abnormal values will 
be presented. 
Concomitant medications will be standardised using the World Health Organization drug 
dictionary and summarised by SOC and PT. 
 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES ................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................... 14 
LIST OF ABBREVIATIONS ................................................................................................ 19 
1 
BACKGROUND INFORMATION ............................................................................ 24 
1.1 
Renal Cell Carcinoma .................................................................................................. 24 
1.1.1 
Pathogenic Mechanisms in RCC ................................................................ 24 
1.1.2 
Approved Treatments for RCC ................................................................... 24 
1.2 
Cabozantinib ................................................................................................................. 25 
1.2.1 
Known and Potential Risks and Benefits of Cabozantinib to Human 
Subjects ........................................................................................................ 25 
1.2.1.1 
METEOR Study ............................................................................................ 25 
1.2.1.2 
CABOSUN Study .......................................................................................... 26 
1.3 
Checkpoint Inhibitor Therapy Alone and CPI Combined with Antiangiogenic 
Therapies as 1st Line Treatment in Renal Cell Carcinoma ....................................... 27 
1.4 
Rationale for Study Design .......................................................................................... 28 
1.5 
Selection of Cabozantinib Dose and Formulation ..................................................... 31 
1.6 
Population to be Studied .............................................................................................. 31 
1.7 
Compliance Statement .................................................................................................. 31 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 32 
2.1 
Purpose of the Study ..................................................................................................... 32 
2.2 
Study Objectives ........................................................................................................... 32 
2.2.1 
Primary Objective ........................................................................................ 32 
2.2.2 
Secondary Objectives .................................................................................. 32 
2.3 
Study Hypothesis ........................................................................................................... 32 
3 
STUDY DESIGN ........................................................................................................... 34 
3.1 
General Study Design and Study Schema .................................................................. 34 
3.2 
Endpoints ....................................................................................................................... 36 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 36 
3.2.2 
Secondary Efficacy Endpoints and Evaluation ......................................... 36 
3.2.3 
Safety Endpoints and Evaluation ............................................................... 36 
3.3 
Randomisation and Blinding ....................................................................................... 36 
3.4 
Maintenance of Randomisation and Blinding ............................................................ 36 
3.5 
Study Treatments and Dosage ..................................................................................... 36 
3.6 
Study Duration .............................................................................................................. 37 
3.7 
Source Data Recorded on The Electronic Case Report Form (eCRF) .................... 38 
3.8 
Independent Radiology Committee ............................................................................. 38 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 39 
4.1 
Inclusion Criteria .......................................................................................................... 39 
4.2 
Exclusion Criteria ......................................................................................................... 40 

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4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures .......... 42 
4.3.1 
Treatment Discontinuation and Study Withdrawal ................................... 42 
4.3.1.1 
Treatment Discontinuation .......................................................................... 42 
4.3.1.2 
Study Withdrawal ......................................................................................... 43 
4.3.2 
Early Study Termination ............................................................................ 43 
5 
STUDY PROCEDURES .............................................................................................. 45 
5.1 
Study Schedule .............................................................................................................. 45 
5.2 
Study Visits .................................................................................................................... 50 
5.2.1 
Procedures Before Study Treatment .......................................................... 50 
5.2.2 
Procedures During Study Treatment ......................................................... 50 
5.2.2.1 
End of Study Treatment Visit ....................................................................... 51 
5.2.2.2 
Early Study Withdrawal Visit ....................................................................... 51 
5.2.3 
Procedures After Study Treatment ............................................................. 51 
5.2.3.1 
Post-treatment Follow-up Period ................................................................ 51 
5.3 
Unscheduled Visits or Assessments ............................................................................. 51 
5.4 
Laboratory Assessments ............................................................................................... 52 
5.5 
Imaging .......................................................................................................................... 52 
5.6 
End of the Study ............................................................................................................ 52 
6 
TREATMENT OF SUBJECTS ................................................................................... 53 
6.1 
Investigational Medicinal Product Preparation, Storage, Security and 
Accountability ............................................................................................................... 53 
6.1.1 
Investigational Medicinal Product Storage and Security .......................... 53 
6.1.2 
Investigational Medicinal Product Preparation ........................................ 53 
6.1.3 
Investigational Medicinal Product Accountability .................................... 53 
6.2 
Study Drugs Administered ........................................................................................... 53 
6.2.1 
Administration of Cabozantinib ................................................................. 53 
6.2.1.1 
First Administration of Cabozantinib (baseline) ......................................... 54 
6.2.1.2 
Subsequent Dose Administration of Cabozantinib ...................................... 54 
6.2.2 
Cabozantinib Dose Modifications, Interruptions and Discontinuation.... 54 
6.2.3 
Cabozantinib Dose Reinstitution and Reescalation ................................... 56 
6.2.4 
Cabozantinib Warnings, Precautions and Guidelines for Management 
of Potential Adverse Events ........................................................................ 57 
6.3 
Prior and Concomitant Medication/Therapy ............................................................. 57 
6.3.1 
Allowed Therapies ....................................................................................... 57 
6.3.2 
Prohibited or Restricted Therapies ............................................................. 58 
6.3.3 
Potential Interactions with Cabozantinib................................................... 59 
6.4 
Lifestyle Restrictions/Recommendations .................................................................... 60 
6.5 
Procedures for Monitoring Subject Compliance ....................................................... 61 
7 
ASSESSMENT OF EFFICACY .................................................................................. 62 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 62 

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7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 62 
7.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data .......... 62 
7.3.1 
Tumour Assessments ................................................................................... 62 
7.3.2 
Overall Survival ........................................................................................... 63 
7.3.3 
Health-related Quality of Life .................................................................... 63 
8 
ASSESSMENT OF SAFETY ....................................................................................... 64 
8.1 
Adverse Events .............................................................................................................. 64 
8.1.1 
Definition of an Adverse Event .................................................................. 64 
8.1.2 
Categorisation of Adverse Events ............................................................... 64 
8.1.2.1 
Intensity Classification ................................................................................. 64 
8.1.2.2 
Causality Classification ............................................................................... 65 
8.1.2.3 
Assessment of Expectedness ......................................................................... 65 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 65 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 65 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 65 
8.1.3 
Recording and Follow-up of Adverse Events ............................................. 65 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 66 
8.1.5 
Pregnancy .................................................................................................... 68 
8.1.6 
Study Medication Errors ............................................................................. 69 
8.1.7 
Deaths .......................................................................................................... 69 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 69 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 70 
8.2 
Clinical Laboratory Tests ............................................................................................ 70 
8.2.1 
Pregnancy Test ............................................................................................ 71 
8.3 
Physical Examination ................................................................................................... 71 
8.4 
Vital Signs ...................................................................................................................... 72 
8.5 
Electrocardiography ..................................................................................................... 72 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 73 
10 
EXPLORATORY BIOMARKERS ............................................................................. 74 
11 
STATISTICS ................................................................................................................. 75 
11.1 Analysis Populations ..................................................................................................... 75 
11.1.1 
Populations Analysed .................................................................................. 75 
11.1.2 
Protocol Deviations ..................................................................................... 75 
11.2 Sample Size Determination .......................................................................................... 75 
11.3 Significance Testing and Estimations ......................................................................... 76 
11.4 Statistical/Analytical Methods ..................................................................................... 76 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 76 
11.4.2 
Subject Disposition and Withdrawals ......................................................... 76 
11.4.3 
Efficacy Evaluation ..................................................................................... 76 

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11.4.3.1 
Primary Efficacy Endpoint .......................................................................... 76 
11.4.3.2 
Secondary Efficacy Endpoints ..................................................................... 77 
11.4.3.3 
Primary Efficacy Endpoint Analysis ............................................................ 78 
11.4.3.4 
Secondary Efficacy Endpoint Analyses ........................................................ 78 
11.4.4 
Safety Evaluation ........................................................................................ 79 
11.5 Subgroup Analyses ....................................................................................................... 80 
11.6 Interim Analyses ........................................................................................................... 80 
12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 81 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 82 
13.1 Protocol Amendments and Protocol Deviations ........................................................ 82 
13.1.1 
Protocol Amendments ................................................................................. 82 
13.1.2 
Protocol Deviations and Exceptions........................................................... 82 
13.2 Information to Study Personnel .................................................................................. 83 
13.3 Study Monitoring .......................................................................................................... 83 
13.4 Investigator’s Regulatory Obligations ........................................................................ 84 
13.5 Audit and Inspection .................................................................................................... 84 
13.6 Data Quality Assurance ................................................................................................ 84 
14 
ETHICS ......................................................................................................................... 85 
14.1 Compliance with Good Clinical Practice (GCP) and Ethical Considerations ........ 85 
14.2 Informed Consent for Participation in the Study ...................................................... 85 
14.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 86 
14.4 Confidentiality Regarding Study Subjects ................................................................. 86 
15 
DATA HANDLING AND RECORD KEEPING ....................................................... 87 
15.1 Recording of Study Data .............................................................................................. 87 
15.2 Data Management ......................................................................................................... 87 
15.3 Record Archiving and Retention ................................................................................. 88 
16 
FINANCING AND INSURANCE ............................................................................... 89 
16.1 Contractual and Financial Details ............................................................................... 89 
16.2 Insurance, Indemnity and Compensation .................................................................. 89 
17 
REPORTING AND PUBLICATION OF RESULTS ................................................ 90 
17.1 Publication Policy ......................................................................................................... 90 
17.2 Clinical Study Report ................................................................................................... 91 
18 
REFERENCES .............................................................................................................. 92 
19 
LIST OF APPENDICES .............................................................................................. 94 
 
LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 3 

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Table 2 
Study Procedures and Assessments ................................................................... 46 
Table 3 
Dose Reductions of Cabozantinib ...................................................................... 55 
Table 4 
Dose Modifications of Cabozantinib for Treatment-related AEs ................... 56 
Table 5      Laboratory Assessments ..................................................................................... 71 
 
LIST OF FIGURES 
Figure 1 Study Design ............................................................................................................ 35 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
1st line 
First line 
2nd line 
Second line 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AKT 
Protein Kinase B 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve  
AXL 
Tyrosine-protein Kinase Receptor UFO 
b.i.d. 
Twice daily (in Latin: bis in die) 
BoD 
baseline sum of diameters 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C/A/P 
Chest/Abdomen/Pelvis 
CA 
Competent Authorities 
ccRCC 
Clear-Cell Renal Cell Carcinoma 
CFR 
Code of Federal Regulations (United States of America) 
chRCC 
Chromophobe Renal Cell Carcinoma 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CPI 
Checkpoint Inhibitor 
CR 
Complete Response 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CT 
Contrast Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP1A1 
Cytochrome P450 Family 1 Subfamily A Member 1 
CYP1A2 
Cytochrome P450 Family 1 Subfamily A Member 2 

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ABBREVIATION 
Wording Definition  
CYP2B6 
Cytochrome P450 Family 2 Subfamily B Member 6 
CYP2C19 
Cytochrome P450 Family 2 Subfamily C Member 19 
CYP2C8 
Cytochrome P450 Family 2 Subfamily C Member 8 
CYP2C9 
Cytochrome P450 Family 2 Subfamily C Member 9 
CYP2D6 
Cytochrome P450 Family 2 Subfamily D Member 6 
CYP3A4 
Cytochrome P450 Family 3 Subfamily A Member 4 
CYP450 
Cytochrome P450 
DILI 
Drug Induced Liver Injury 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FDA 
Food and Drug Administration 
FKSI-DRS 
Functional Assessment of Cancer Therapy-Kidney Cancer 
Symptom Index 
FT4 
Free Thyroxine 4 
GB 
Glioblastoma 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-stimulating Factor 
GGT 
γ-glutamyl transpeptidase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte Macrophage Colony-stimulating Factor 
HCG 
Human Chorionic Gonadotrophin 
HR 
Hazard Ratio 

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ABBREVIATION 
Wording Definition  
HRQOL 
Health-related Quality of Life 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMDC 
International Metastatic RCC Database Consortium 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio 
IRB 
Institutional Review Board 
IRC 
Independent Radiology Committee 
ITT 
Intention-to-treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
KPS 
Karnofsky Performance Status 
LDH 
Lactate Dehydrogenase 
LLN 
Lower Limit of Normal 
LMWH 
Low Molecular Weight Heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET  
Hepatocyte Growth Factor Receptor Protein 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance Imaging 
MRP2 
Multidrug Resistance-associated Protein 2 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTC 
Medullary Thyroid Cancer 
mTOR 
Mammalian Target of Rapamycin 
NA 
Not Applicable 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for 
Adverse Events 
NOS 
Not Otherwise Specified 
NPACT 
Non-protocol Anti-cancer Therapy 
NSAID 
Non-steroidal Anti-inflammatory Drug 
NSCLC 
Non-small Cell Lung Cancer 
ONJ 
Osteonecrosis of The Jaw 

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ABBREVIATION 
Wording Definition  
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 protein 
PD-L1 
Programmed Death-ligand 1 protein 
PEG 
Percutaneous Endoscopic Gastrostomy 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI3K 
Phosphoinositide 3-kinase 
PO 
Per Os (orally) 
PP Population 
Per Protocol Population 
PPES 
Palmar-Plantar Erythrodysaesthesia Syndrome 
PPI 
Proton Pump Inhibitor 
PR 
Partial Response 
pRCC 
Papillary Renal Cell Carcinoma 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
q.d. 
Once Daily (in Latin: quaque die) 
QTc 
Corrected QT Interval 
QTcF 
Fridericia’s Correction of QT Interval 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RET 
Proto-oncogene 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 

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ABBREVIATION 
Wording Definition  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-emergent Adverse Event 
TIA 
Transient Ischaemic Attack 
TKI 
Tyrosine Kinase Inhibitor 
TPR 
Time Point Response 
TSH 
Thyroid-stimulating Hormone 
TTF 
Time to Treatment Failure 
TTR 
Time to Response 
UE 
Unable to Evaluate 
ULN 
Upper Limit of Normal 
UPCR 
Urine Protein-to-Creatinine Ratio 
uRCC 
Unclassified Renal Cell Carcinoma 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR2 
VEGF Receptor 2 
VHL 
von Hippel-Lindau 
WHODRUG 
World Health Organization Drug 

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1 
BACKGROUND INFORMATION 
1.1 
Renal Cell Carcinoma 
Renal cell carcinoma (RCC) comprises a heterogeneous group of kidney cancers and is one of 
the ten most common cancers worldwide, with more than 300,000 new cases each year (1). The 
most common subtypes (≥5% incidence) include clear-cell RCC (ccRCC), papillary RCC 
(pRCC) and chromophobe RCC (chRCC). The other subtypes are either very rare (each with 
≤1% total incidence) or designated as unclassified RCC (uRCC, approximately 4% total 
incidence) when it is not possible to diagnose the tumour according to any other subtype. The 
ccRCC subtype is associated with most kidney cancer deaths and is predominant in metastatic 
disease (83-88%) (2). 
It is estimated that around 25-50% of subjects with localised disease eventually develop 
metastatic RCC (3) and that up to 30% of subjects considered disease-free after curative 
treatment for localised RCC will relapse (1). 
1.1.1 
Pathogenic Mechanisms in RCC 
Previous studies have contributed to a better understanding of the pathogenic mechanisms 
underlying RCC, which has not only helped explain why certain subjects with this disease 
become resistant to chemotherapy but has also provided relevant information to improve the 
median overall survival (OS) (4).  
The hepatocyte growth factor receptor protein (MET) and the vascular endothelial growth factor 
(VEGF) receptor 2 (VEGFR2) are receptor tyrosine kinases involved in tumour cell growth, 
invasiveness, metastasis and/or angiogenesis in multiple tumour types including RCC (5). 
Clear-cell renal carcinomas, which are defined by the presence of malignant epithelial cells 
with clear cytoplasm, commonly contain mutations in a gene whose activity controls the 
expression of both MET and VEGFR2, called the tumour suppressor von Hippel-Lindau (VHL) 
gene (6, 7). These mutations trigger an increase in the expression of VEGF and MET, thereby 
promoting increased angiogenesis, tumour cell proliferation, invasive growth and, ultimately, 
tumourigenesis (8). Indeed, high MET expression is associated with poor prognosis in subjects 
with RCC (9). VHL-deficient renal carcinoma cells have been shown to be more sensitive to 
MET targeting than similar cells in which VHL function has been restored (10). Moreover, 
circulating proteases that positively or negatively regulate the activation of the hepatocyte 
growth factor (a MET ligand) are frequently upregulated or downregulated, respectively, in 
RCC (7). 
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin 
(mTOR) pathway also contributes to the pathology of RCC by stimulating the expression of 
proangiogenic factors such as VEGF. 
1.1.2 
Approved Treatments for RCC 
Antiangiogenic therapies have been shown to have clinical benefit in subjects with advanced 
RCC. Several new marketed antiangiogenic agents are available as first line (1st line) 
treatments, such as the anti-VEGF antibody bevacizumab, tyrosine kinase inhibitors (TKIs) that 
target the VEGF pathway (sorafenib, sunitinib, pazopanib, axitinib) and mTOR inhibitors 
(temsirolimus and everolimus) (4). Cabozantinib, a multitarget antiangiogenic TKI that inhibits 
the VEGFR pathway (VEGFR-TKI), is also available as a 1st line treatment for intermediate- 
and poor-risk subjects with advanced RCC (11).  
Checkpoint inhibitor (CPI) therapy with ipilimumab and nivolumab is also an approved 
treatment for advanced RCC. Indeed, in January 2019, the European Medicines Agency (EMA) 

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granted ipilimumab and nivolumab Marketing Authorisation for 1st line treatment of 
intermediate- and poor-risk subjects with advanced RCC. European Commission approved 
pembrolizumab in combination with axitinib in August 2019 and for avelumab plus axitinib as 
first-line treatment for patients with advanced RCC in September 2019. 
 
There are also agents approved as second line (2nd line) treatment for RCC. These include 
multitarget antiangiogenic TKIs such as cabozantinib, lenvatinib and everolimus, and the CPI 
nivolumab. 
1.2 
Cabozantinib 
Cabozantinib (XL184) is a multitarget TKI that inhibits several proteins involved in the 
pathology of RCC, such as MET, VEGFR2, the tyrosine-protein kinase receptor UFO (AXL) 
and the proto-oncogene (RET). Cabozantinib is provided as both capsules and tablets, but the 
two formulations are not interchangeable. 
Cabometyx™ (cabozantinib tablets, 20, 40 and 60 mg) is currently approved by the EMA as a 
2nd line treatment for subjects with advanced RCC previously treated with VEGF-targeted 
therapy, and as a 1st line treatment for adults with advanced RCC with intermediate and poor 
risk. Cabometyx™ (cabozantinib tablets 40 mg) in combination with nivolumab, is indicated for 
the first-line treatment of advanced renal cell carcinoma in adults. 
Cabometyx™ (cabozantinib tablets, 20, 40 and 60 mg) is currently approved by the Food and 
Drug Administration (FDA) for the treatment of all subjects with advanced RCC regardless of 
previous therapies received. 
A more detailed description of the product is provided in the Summary of Product 
Characteristics (SmPC) document (11). 
1.2.1 
Known and Potential Risks and Benefits of Cabozantinib to Human Subjects 
A summary of the pharmacology of cabozantinib is provided in the Investigator’s Brochure 
supplied by the Sponsor (or designee). The Investigator’s Brochure should be reviewed in 
conjunction with this study protocol. 
In clinical studies, cabozantinib has been evaluated in multiple tumour types including MTC, 
castration-resistant prostate cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, 
non-small cell lung cancer (NSCLC), melanoma, differentiated thyroid cancer, RCC and 
glioblastoma (GB) multiforme (for details, please see the Investigator’s Brochure). 
1.2.1.1 
METEOR Study  
The safety and efficacy of cabozantinib were evaluated in a randomised, open-label, multicentre 
Phase III study (METEOR study) (12). In this study, 658 subjects with advanced RCC with a 
clear-cell component who had received prior treatment with at least one VEGFR-TKI were 
randomised (1:1) to receive cabozantinib (N = 330) or everolimus (N = 328). The included 
subjects could have received other prior therapies, including cytokines and antibodies against 
VEGF and the programmed death-1 (PD-1) receptor, or its ligands. Subjects with treated brain 
metastases were also allowed to enrol in the study. The primary endpoint was progression-free 
survival (PFS) assessed by a blinded independent radiology committee (IRC) among the first 
375 subjects randomised. Secondary efficacy endpoints were objective response rate (ORR) 
and OS. Tumour assessments were conducted every 8 weeks for the first 12 months, then every 
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The baseline demographic and disease characteristics were similar between the cabozantinib 
and everolimus arms. Most subjects were male (75%), with a median age of 62 years. 
Seventy-one percent received only one prior VEGFR-TKI therapy; 41% of subjects received 
sunitinib as their only prior VEGFR-TKI therapy. According to the Memorial Sloan Kettering 
Cancer Center (MSKCC) criteria for prognostic risk category (see Appendix 1), 46% of 
subjects had favourable prognostics (0 risk factors), 42% had intermediate prognostics (1 risk 
factor), and 13% had poor prognostics (2 or 3 risk factors). Fifty-four percent of subjects had 3 
or more organs with metastatic disease, including lung (63%), lymph nodes (62%), liver (29%), 
and bone (22%). The median duration of treatment was 7.6 months (range 0.3 - 20.5) in the 
cabozantinib arm and 4.4 months (range 0.21 – 18.9) in the everolimus arm. A statistically 
significant improvement in PFS was demonstrated for cabozantinib compared to everolimus in 
the primary PFS analysis population: 7.4 months versus 3.8 months, respectively (stratified 
hazard ratio (HR) 0.58, 95% confidence interval (CI): 0.45, 0.75; stratified log-rank 
p-value<0.0001). Similar results were observed in the intention-to-treat (ITT) population 
(658 subjects): 7.4 months versus 3.9 months, respectively (stratified HR 0.51, 95% CI: 0.41, 
0.62). 
A planned interim analysis of OS was conducted at the time of the PFS analysis and did not 
reach the interim boundary for statistical significance (202 events, unadjusted 95% CI: 0.51, 
0.90, p = 0.006) (12). In a subsequent unplanned interim analysis of OS, a statistically 
significant improvement was demonstrated for subjects randomised to cabozantinib compared 
to everolimus (320 events, median of 21.4 months versus 16.5 months, respectively; HR 0.66, 
95% CI: 0.53, 0.83, p = 0.0003). Similar OS results were observed in a follow-up analysis 
(descriptive) at 430 events. 
Exploratory analyses of PFS and OS in the ITT population have also shown consistent results 
in favour of cabozantinib compared to everolimus across different subgroups, such as age 
(<65 versus ≥65, sex, MSKCC risk group (favourable, intermediate, poor), Eastern Cooperative 
Oncology Group (ECOG) status (0 versus 1), time from diagnosis to randomisation (<1 year 
versus ≥1 year), tumour MET status (high versus low versus unknown), bone metastases 
(absence versus presence), visceral metastases (absence versus presence), visceral and bone 
metastases (absence versus presence), number of prior VEGFR-TKI therapies (1 versus ≥2), 
duration of first VEGFR-TKI therapy (≤6 months versus >6 months). 
The primary ORR analysis conducted by the IRC in the ITT population at the time of the 
primary analysis of PFS showed that the ORR for the cabozantinib and everolimus arms were 
17% (95% CI: 13, 22) and 3% (95% CI: 2, 6), respectively (unstratified p-value<0.0001). 
More details about the results obtained in this study can be found in the SmPC document (11). 
1.2.1.2 
CABOSUN Study  
The safety and efficacy of cabozantinib in treatment-naïve subjects with advanced or metastatic 
RCC were evaluated in a randomised, open-label, multicentre Phase II study (CABOSUN 
study) (13). In this study, 157 subjects with previously untreated locally advanced or metastatic 
RCC with a clear-cell component were randomised (1:1) to receive cabozantinib (N = 79) or 
sunitinib (N = 78). Included subjects had intermediate or poor risk disease as defined by the 
International Metastatic RCC Database Consortium (IMDC) risk group categories (see 
Appendix 2). Subjects were stratified by IMDC risk group and presence of bone metastases 
(yes/no). Approximately 75% of subjects had a nephrectomy prior to onset of treatment. 
For intermediate risk disease, one or two of the following risk factors were met, while for poor 
risk, three or more factors were met: time from diagnosis of RCC to systemic treatment <1 year, 

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Hgb below the lower limit of normal (LLN), corrected calcium above the upper limit of normal 
(ULN), Karnofsky Performance Status (KPS) lower than 80%, and neutrophil and platelet 
counts above the ULN. 
The primary endpoint was PFS. Secondary efficacy endpoints were ORR and OS. Tumour 
assessments were conducted every 12 weeks. 
The baseline demographic and disease characteristics were similar between the cabozantinib 
and sunitinib arms. Most subjects were male (78%) with a median age of 62 years. Subject 
distribution by IMDC risk groups included 81% of subjects with intermediate prognosis 
(1-2 risk factors) and 19% of subjects with poor prognosis (≥3 risk factors). Most 
subjects (87%) had ECOG performance status of 0 or 1, whereas 13% of subjects had an ECOG 
performance status of 2. Thirty-six percent of subjects had bone metastases. 
A statistically significant improvement in PFS was demonstrated for cabozantinib compared to 
sunitinib, as retrospectively assessed by a blinded IRC (14). Median PFS was 
8.6 months (95% CI: 6.8, 14) in the cabozantinib arm and 5.3 months (95% CI: 3, 8.2) in the 
sunitinib arm (HR 0.48, 95% CI: 0.31, 0.74, p = 0.0008). These results were consistent with 
those obtained in the Investigator analysis (13). 
Subjects with both positive and negative MET status experienced a favourable PFS effect with 
cabozantinib compared to sunitinib. Cabozantinib had greater antitumour activity in subjects 
with a positive MET status than in subjects with a negative MET status (HR 0.32 (0.16, 0.63) 
versus 0.67 (0.37, 1.23)) respectively. 
Cabozantinib treatment was associated with a trend for longer survival compared to sunitinib: 
median OS was 30.3 months (95% CI: 14.6, not estimable) in the cabozantinib arm and 
21.0 months (95% CI: 16.3, 27.0) in the sunitinib arm (HR 0.74, 95% CI: 0.47, 1.14). However, 
the CABOSUN study was not powered for the OS analysis and the data is immature. 
More details about the results obtained in this study can be found in the SmPC document (11). 
1.3 
Checkpoint Inhibitor Therapy Alone and CPI Combined with Antiangiogenic 
Therapies as 1st Line Treatment in Renal Cell Carcinoma 
While cabozantinib has provided strong positive results in multiple settings in metastatic RCC 
(12, 14), recent trials have demonstrated that CPI therapy alone or with different combinations 
of antiangiogenic agents have a beneficial effect in subjects with advanced or metastatic RCC. 
Therefore, treatment landscape has evolved, this raises the need to evaluate clinical benefit of 
subsequent VEGF targeted therapies to be used in 2nd line after 1st line systemic treatment 
containing CPI. 
 
Treatment with CPIs alone 
The Phase III Checkmate 214 study compared the effect of treatment with CPIs ipilimumab and 
nivolumab in combination versus sunitinib in untreated subjects with advanced or metastatic 
RCC. The co-primary endpoints were the ORR, PFS and OS among subjects with intermediate- 
and poor-prognosis.  
Treatment with ipilimumab and nivolumab in combination demonstrated superior ORR 
(42% (95% CI 37-47%) versus 27% (95% CI 22-31%), p<0.0001) and PFS (11.6 versus 
8.4 months, HR 0.82, p = 0.0331) compared to sunitinib. The median OS was not reached in 
subjects treated with the combination therapy but reached 26 months in subjects treated with 
sunitinib (p<0.0001). The complete response (CR) rate was 9% in the combination therapy arm 
compared to 1% in the sunitinib arm (15). 

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Treatment-related adverse events (AEs) occurred in 93% of subjects treated with ipilimumab 
and nivolumab and in 97% of subjects treated with sunitinib. Grade 3-5 AEs were less frequent 
among subjects treated with the combination therapy (46%) than those treated with 
sunitinib (63%). The most frequent AEs reported in the combination therapy arm were 
fatigue (37%), pruritus (28%) and diarrhoea (27%), whereas the most frequent AEs in the 
sunitinib arm were diarrhoea (52%), fatigue (49%) and palmar plantar erythema (43%). 
Treatment-related AEs leading to discontinuation were more frequent with ipilimumab and 
nivolumab (22%) than with sunitinib (12%). Importantly, the health-related quality of life was 
superior in the combination therapy arm (15). 
Although VEGFR-TKIs remain the current 1st line treatment for metastatic RCC, as defined by 
the principal expert committees in Europe and the United States, the recent approval of CPI 
therapy with ipilimumab and nivolumab in combination will likely become the new standard 
of care for subjects with metastatic RCC with intermediate- and poor-prognosis (16).  
 
Treatment with CPIs combined with antiangiogenic agents 
Interestingly, treatments that combine CPIs with antiangiogenic therapies may also provide a 
strong benefit to subjects with advanced or metastatic RCC. Firstly, these combination 
treatments allow a dual/multifaceted manipulation of the pathways involved in the development 
of RCC, which strengthens the anti-cancer strategy. Secondly, previous studies suggest that, in 
addition to their direct effect, antiangiogenic TKIs may enhance the effectiveness of CPI agents 
when administered concurrently (17, 18). 
As such, two new therapeutic options axitinib plus pembrolizumab and axitinib plus avelumab 
showed the efficacy and safety of combination therapy with CPI and TKI in untreated subjects 
with advanced RCC have been approved by EMA in August 2019 and in September 2019, 
respectively. Some clinical trials are ongoing: 
• 
A study evaluating the combination of lenvatinib and pembrolizumab versus sunitinib 
monotherapy in subjects with RCC (NCT02811861); 
• 
A study of cabozantinib in combination with nivolumab and ipilimumab in patients with 
previously untreated advanced or metastatic RCC (NCT03937219). 
Results from the study (NCT0314177) that assessed the combination of nivolumab (a 
programmed death-ligand 1/ PD-1 protein inhibitor) with cabozantinib versus sunitinib in 
untreated subjects with metastatic RCC (CkeckMate 9ER trial) showed that cabozantinib and 
atezolizumab in combination improved PFS and OS compared to sunitinib in subjects with 
untreated metastatic or advanced RCC (20).  
Together, the clinical trials mentioned in this section represent the evolution of the treatment 
landscape for 1st line treatment of subjects with advanced or metastatic RCC. The choice of 1st 
line treatment may impact on tumour growth and may therefore play a role on subsequent 
treatment activity, thus the results obtained in these trials provide valuable information to help 
establish the best therapeutic sequence to treat disease progression for subjects with this disease.   
1.4 
Rationale for Study Design 
Multitarget antiangiogenic TKI and CPI therapies represent two systemic treatment modalities 
that have been instrumental in the recent advances of anti-cancer treatment over the past several 
years. Studies with cabozantinib (Section 1.2) and CPI alone or in combination with different 
antiangiogenic inhibitors (Section 1.3) contribute to help determine the best treatment option 
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Antiangiogenic agents currently represent the preferable 1st line treatment option for patients 
with advanced and metastatic RCC with intermediate and poor prognosis. However, according 
to the European Association of Urology Guidelines Recommendations and European Society 
for Medical Oncology (ESMO) guidelines (21, 22) and based on recent approvals, CPI therapy 
with ipilimumab and nivolumab is likely to become the new standard of care for subjects with 
RCC with poor and intermediate prognosis and pembrolizumab and axitinib is likely to become 
the new standard of care for subjects with favourable prognosis. 
Importantly, the choice of 1st line treatment may impact on tumour growth and may therefore 
play a role on subsequent treatment activity, thus more trials are warranted to investigate the 
optimal treatment sequence for advanced and metastatic RCC (16). As such, as the pivotal 
clinical trials of VEGFR-TKIs in advanced or metastatic RCC in 2nd line were conducted before 
the availability of CPI therapies, there is an unmet need to assess the efficacy and safety of 
antiangiogenic therapies in subjects treated in 1st line with CPIs.  
Cabozantinib may be a potential 2nd line treatment for these subjects. In fact, preliminary data 
from retrospective analyses assessing the role of VEGFR-TKIs, including cabozantinib, given 
as early as 2nd line treatment after previous CPI therapy have shown promising results: 
• 
Powles et al. 2018 (23): this study reported outcomes based on prior therapy in the 
Phase III METEOR trial of cabozantinib versus everolimus in advanced RCC (12), 
including 5% of subjects who had received prior CPI therapy. In the prior 
anti-PD-1/PD-L1 subgroup, cabozantinib treatment was associated with improved PFS 
(HR 0.22, 95% CI 0.07-0.65), OS (HR 0.56, 95% CI 0.21-1.52) and ORR, as well as a 
higher rate of durable responses compared with everolimus; 
• 
Shah A. et al. 2018: this study assessed the effect of VEGFR-TKIs in 43 subjects with 
metastatic RCC after disease progression with CPI therapy. The authors reported an ORR 
of 42%, a median PFS of 10 months, an estimated 1-year OS of 87.5% 
(95% CI 74.6-100) and a disease control rate (DCR) of 100%. In this study, 
15 subjects (35%) received cabozantinib: 8 subjects presented stable disease, 6 subjects 
experienced partial response and 1 subject showed complete response (unpublished 
data); 
• 
McGregor B. et al. 2018: this study assessed the effect of cabozantinib in 69 subjects 
previously treated with CPI therapy with or without VEGF-targeted therapy. Overall, the 
authors reported an ORR of 36%, a median time to treatment failure (TTF) of 6.5 months 
and improved 1-year OS in subjects with favourable/intermediate risk compared to 
subjects with poor risk (67% (95% CI 50-80) versus 14% (95% CI 1-44)) (unpublished 
data). According to the authors, response rates were comparable to those in the METEOR 
trial (Section 1.2.1.1); 
• 
Graham J. et al. 2018: this study assessed the effect of several VEGFR-TKIs (including 
cabozantinib) versus mTOR inhibitors in 184 subjects previously treated with CPIs. In 
this study, cabozantinib was given as 2nd line treatment (6 subjects) or further 
(27 subjects). The authors reported significantly longer median times to treatment 
discontinuation in subjects treated with VEGFR-TKIs compared to those treated with 
mTOR inhibitors (5.3 versus 2.5 months, p = 0.002). The ORR was numerically higher 
in the VEGFR-TKIs group (19.8%) than in the mTOR inhibitors group (5.0%) 
(unpublished data); 
• 
Barata P. et al. 2018 (24): this study evaluated the effect of VEGFR-TKIs (including 
cabozantinib) in 28 subjects with metastatic RCC who progressed after CPI therapy. This 

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analysis included 3 subjects who received cabozantinib: 1 subject presented an ORR of 
33% and the other 2 subjects presented stable disease; 
• 
Auvray M. et al. 2019 (16): this study assessed the effect of VEGFR-TKIs in 
33 subjects treated with CPIs ipilimumab and nivolumab, as part of the Checkmate 214 
trial (15). In the overall population, median PFS from start of VEGFR-TKI therapy was 
8 months (95% CI 5-13). Interestingly, PFS in 2nd line was significantly longer in 
subjects with a long 1st line duration of response (DOR) to ipilimumab and nivolumab in 
combination (≥6 months) than in short responders to CPI (<6 months): 8 versus 5 months 
(p = 0.03). The OS rate was 54% at 12 months. These results suggest a sustained benefit 
of VEGFR-TKI treatment in subjects who progressed after CPI therapy.  
• 
Kalirai A. 2019 (27): reported results from the Canadian Kidney Cancer Information 
System: real world analysis of 102 patients treated with targeted therapy post CPI. Those 
who received first-line ipilimumab + nivolumab versus a VEGFi + CPI combination 
prior to second-line treatment had a median time to treatment failure of 8.0 vs 5.2 months 
(m) (HR=0.43, 95% CI: 0.13-1.44) and median OS of 16.5 m vs not reached (HR=0.76, 
95% CI: 0.11-5.24). Patients who received a VEGFi versus a mammalian target of 
rapamycin inhibitor (mTORi) as third-line TT had a median TTF of 7.6 vs 4.4 m 
(HR=0.52, 95% CI: 0.24-1.10) and median OS of 21.7 vs 16.2 m (HR=0.41, 95% CI: 
0.16-1.08). All third-line treatment patients received first-line VEGFi and second-line 
nivolumab. Of the third-line VEGFi treatment patients, 24 received axitinib (TTF 7.1 m, 
OS 21.7 m) and 22 received cabozantinib (data immature). Authors concluded that these 
results support the use of VEGFi after CPI in mRCC patients. 
• 
Ornstein MC 2018 (28) reported the results of a phase 2 Study of the Efficacy and Safety 
of axitinib given on an individualized schedule for mRCC, after treatment with PD-1 or 
PD-L1 Inhibitors: the study included 38 patients whose most recent therapy was anti PD-
1 (89%) or anti PD L1 (11%). In evaluable patients, the estimated median PFS is 9.2 
months, with 54% of patients still on axitinib. The ORR is 38.7%. The median highest 
dose per patient was 6mg BID (range, 5-9) and 44% of patients required dose reduction 
to < 5mg BID. There were no unexpected toxicities related to axitinib. 
Importantly, the safety profile observed in these studies was considered acceptable, which 
supports the positive effect of VEGFR-TKIs such as cabozantinib in subjects with advanced 
RCC who progressed after CPI therapy. However, the available data is still limited and 
validation of these promising findings in prospective clinical trials is thus required to confirm 
the key role of cabozantinib in a post-CPI setting. To generate the prospective data of 
cabozantinib in subjects who have been treated with CPI or CPI plus VEGF therapies for 
advanced or metastatic RCC, the Sponsor proposes to conduct a Phase II study in subjects with 
this disease. 
This is an international, multicentre, open-label Phase II trial of cabozantinib in subjects with 
advanced or metastatic RCC with a clear-cell component who progressed after 1st line treatment 
with CPI alone (ipilimumab and nivolumab in combination) or CPI combined with VEGF-
targeted therapy.  
The primary endpoint is ORR, defined as the proportion of subjects with CR or partial response 
(PR) per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, as determined by an 
independent central review in cohort A.  
Secondary endpoints are time to response (TTR), duration of response (DOR), DCR and PFS 
per RECIST 1.1 assessed both by independent central review and by local Investigator, ORR 

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per RECIST 1.1 also assessed by both independent central review (cohort B) and by local 
Investigator (cohort A and cohort B), OS and change in disease-related symptoms as assessed 
by the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS). 
Safety and tolerability of cabozantinib will also be monitored throughout the study. 
1.5 
Selection of Cabozantinib Dose and Formulation 
All approvals of cabozantinib (Cabometyx™) as a treatment for subjects with RCC include the 
60 mg dose as the recommended dose. 
Details on administration procedures and dosage are provided in Section 6.2. 
1.6 
 Population to be Studied 
The study will include adult subjects with unresectable, locally advanced or metastatic RCC 
with a clear-cell component who progressed after 1st line treatment with CPI alone (ipilimumab 
and nivolumab in combination) or CPI combined with VEGF-targeted therapy.  
1.7 
Compliance Statement 
The study will adhere to all local regulatory requirements and relevant company policies. The 
Sponsor will ensure that the countries where the data are transferred provide an adequate level 
of data protection. 
In case of data transfer outside the European Union (EU), the Sponsor will either ensure that 
the countries where data are transferred provide an adequate level of data protection or that the 
company receiving data has joined the EU-United States of America Privacy Shield Framework 
or will put in place a contract including standard contractual clauses adopted by the European 
Commission to ensure that the transfer of study information complies with applicable data 
protection legislation. Such a contract can be made available upon request. 
Before initiating the study, the Investigator/institution will have the following documents: 
written and dated approval/favourable opinion from the Independent Ethics Committee 
(IEC)/institutional review board (IRB) for the study protocol/amendment(s), written informed 
consent form, any consent form updates, subject emergency study contact cards, subject 
recruitment procedures (e.g. advertisements), any written information to be provided to subjects 
and a statement from the IEC/IRB that they comply with Good Clinical Practice (GCP) 
requirements. The IEC/IRB approval must identify the protocol version as well as the 
documents reviewed. 

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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Cabozantinib is currently approved in the United States as a treatment for adults with advanced 
RCC regardless of previous therapies received. In the EU, cabozantinib is approved for the 
treatment of advanced renal cell carcinoma (RCC) in treatment-naïve adults with intermediate 
or poor risk and following prior vascular endothelial growth factor (VEGF)-targeted therapy. 
Recent EMA approvals and several clinical trials are currently ongoing to investigate the effect 
of new treatment regimens containing CPI for patients with RCC (Section 1.3). These changes 
potentially transformed the treatment landscape and the available options for 1st line treatment 
of RCC. However, some of the patients may be refractory to these treatments, thus it is 
increasingly important to find potential 2nd line therapies for such patients. 
To date, no prospective clinical trial has tested the role of cabozantinib as a 2nd line treatment 
of subjects with advanced RCC who progressed after treatment with CPI therapy. Thus, the 
overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 2nd line 
treatment in subjects with unresectable, locally advanced or metastatic RCC with a clear-cell 
component who progressed after prior CPI therapy with ipilimumab and nivolumab in 
combination or CPI combined with VEGF-targeted therapy.  
2.2 
Study Objectives 
The overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 
2nd line treatment in subjects with unresectable, locally advanced or metastatic RCC with a 
clear-cell component who progressed after prior CPI therapy with ipilimumab and nivolumab 
in combination or CPI combined with VEGF-targeted therapy.  
2.2.1 
Primary Objective 
• 
To assess the efficacy of cabozantinib by the objective response rate (ORR) per Response 
Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by independent central 
review in cohort A. 
2.2.2 
Secondary Objectives 
• 
To assess other efficacy criteria of cabozantinib such as time to response (TTR), duration 
of response (DOR), disease control rate (DCR), progression-free survival (PFS) by 
independent central review and Investigator’s review; 
• 
To assess objective response rate (ORR) by independent central review and 
Investigator’s review in cohort B; 
• 
To assess ORR by Investigator’s review in Cohort A;  
• 
To assess overall survival (OS); 
• 
To assess the ORR and PFS by Investigator’s review and OS in overall population 
(cohorts A+B); 
• 
To assess the change in disease-related symptoms as assessed by the Functional 
Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS) 
questionnaire. 
• 
To access the safety and tolerability of cabozantinib. 
2.3 
Study Hypothesis 
The hypothesis for the two cohorts of this study is that cabozantinib as 2nd line treatment will 
demonstrate a clinically significant increase of response rate as compared to historical control 

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in subjects previously treated with CPI therapy. A therapy will be considered clinically 
meaningful if it provides a significant benefit in ORR (primary endpoint) over a standard rate 
of 10% (conservative threshold in reference to the response rate of everolimus in the METEOR 
study (12), exact 95% CI: 1.7-5.9). 

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3 
STUDY DESIGN 
3.1 
General Study Design and Study Schema 
This study will be conducted in approximately 50 active investigational sites across Germany, 
Switzerland, the Netherlands, France, UK, Austria and Spain. The list of countries and the 
number of investigational sites may change during the study depending on recruitment and 
availability of the first line combination therapies in each country. 
This is a Phase II, multicentre, open-label study to evaluate the efficacy and safety of 
cabozantinib 60 mg once daily (q.d.) in adults with unresectable, locally advanced or metastatic 
RCC with a clear-cell component who progressed after 1st line treatment with CPI alone 
(ipilimumab and nivolumab in combination) or CPI combined with VEGF-targeted therapy. 
Approximately 114 eligible subjects will receive cabozantinib (two independent cohorts with 
74 subjects* in cohort A and approximately 40 subjects in cohort B) (Figure 1). 
* The inclusion period will stop either when 74 subjects have been enrolled in cohort A or at 
the latest on 30 June 2022, whichever is reached first.  
 
Each subject’s study participation will consist of the following periods: 
 
Pre-treatment Period: Potential subjects will be screened to determine whether they meet the 
required eligibility criteria. Qualifying assessments will be performed within 15 days prior to 
first cabozantinib dose except when otherwise specified (detailed in study schedule in Table 2).  
 
Treatment Period: Subjects who meet all eligibility criteria will be included in one of the two 
following cohorts based on their 1st line treatment and both cohorts will receive the same 
open-label treatment with cabozantinib (60 mg q.d.): 
 
• 
Cohort A: 74 subjects 
Cohort A will be composed of subjects who radiographically progressed after one prior line by 
CPI therapy with ipilimumab and nivolumab. 
 
• 
Cohort B: approximately 40 subjects 
Cohort B will be composed of subjects who radiographically progressed after one prior line by 
CPI therapy combined with VEGF-targeted therapy. 
 
The timing of visits to the investigational site to perform all planned assessments is fixed from 
baseline and will be conducted as described in Section 5 (see Table 2 for schedule of 
assessments). 
The date of the first dose of cabozantinib is defined as baseline (Day 1, Visit 2). In both cohorts, 
subjects can receive study treatment up to the end of the study, defined as 18 months after the 
last subject included in the study started cabozantinib treatment (Section 5.6), but subjects may 
terminate treatment earlier due to reasons such as disease progression, unacceptable toxicity or 
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Efficacy evaluations will be performed as described in Section 7.3 (see Table 2 for schedule of 
assessments). These include radiographic tumour assessments which will be blindly reviewed 
by a central IRC (see Section 3.8) to evaluate efficacy endpoints (Section 7). 
Safety assessments will start on the date of the Screening visit and will be continued throughout 
the study as described in Section 8 (see Table 2 for schedule of assessments). Unscheduled 
safety evaluations are allowed at any time throughout the study (Section 5.3).
Subjects who discontinue study treatment with cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend the End of Study Treatment visit (30 to 45 days 
after the last dose of cabozantinib) (Section 5.2.2.1). Subjects who prematurely stop the study 
will be invited to attend the Early Study Withdrawal visit (Section 5.2.2.2).
Post-treatment Follow-up Period: Subjects who discontinue study treatment will be contacted 
during the Post-treatment Follow-up visits every 12 weeks ±15 days to assess survival status 
and collect information about subsequent anti-cancer therapy. During the follow-up period, any 
SAEs that occur more than 30 days after the date of the last cabozantinib dose, assessed as 
related to study treatment or study procedures will also be collected and followed until 
resolution or stability according to the Investigator. These assessments will be continued until 
the subject expires or until the end of the study (18 months after the last subject included in the 
study started cabozantinib treatment, Section 5.6), whichever occurs first. Every effort will be 
made to collect these protocol-specific evaluations unless consent to participate in the study is 
withdrawn. 
Specific details of study procedures are provided in Section 5. Details for treatment with 
cabozantinib are provided in Section 6.
Figure 1 Study Design
Abbreviations: CPI = Checkpoint inhibitor; PO = Orally; q.d. = Once daily; VEGF = Vascular endothelial growth factor 
*The inclusion period will stop either when 74 subjects have been enrolled in cohort A or at the latest on 30 June 2022, 
whichever is reached first. 

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3.2 
Endpoints 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
• 
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1 evaluated by independent central review in cohort A.  
3.2.2 
Secondary Efficacy Endpoints and Evaluation  
• 
Time to response (TTR) per RECIST 1.1 evaluated by independent central review; 
• 
Duration of response (DOR) per RECIST 1.1 evaluated by independent central review; 
• 
Disease control rate (DCR) per RECIST 1.1 by independent central review; 
• 
Progression-free survival (PFS) per RECIST 1.1 by independent central review; 
• 
Objective response rate (ORR) in cohort B per RECIST 1.1 evaluated by independent 
central review; 
• 
Overall survival (OS); 
• 
ORR, TTR, DOR, DCR and PFS per RECIST 1.1 according to local Investigator’s 
review; 
• 
Change in disease-related symptoms as assessed by the Functional Assessment of Cancer 
Therapy-Kidney Cancer Symptom Index (FKSI-DRS) questionnaire. 
The endpoints of ORR, TTR, DOR, DCR and PFS will be evaluated by tumour assessments 
(see Section 7.3.1). The OS will be assessed as described in Section 7.3.2.  
3.2.3 
Safety Endpoints and Evaluation 
The safety and tolerability of cabozantinib will be assessed throughout the study treatment 
period by evaluating AEs, clinical laboratory test results, vital signs measurements, 
electrocardiogram (ECG) and physical examination results, and use of concomitant medication 
(see Section 8).  
Summaries of AEs and SAEs will be tabulated by cohort and overall according to system organ 
class (SOC) and preferred term (PT) by overall incidence, worst reported severity, and 
relationship to study treatment. Selected laboratory test results will be summarised by cohort to 
evaluate worst post-baseline Common Terminology Criteria for Adverse Events (CTCAE) 
grade, as well as shifts or changes from baseline. 
3.3 
Randomisation and Blinding 
Not applicable. 
3.4 
Maintenance of Randomisation and Blinding 
Not applicable. 
3.5 
Study Treatments and Dosage 
The study treatment cabozantinib will be administered at a dose of 60 mg q.d. A subject’s daily 
dose may be reduced to 40 mg or 20 mg according to the Investigator’s clinical judgement as 
to whether this procedure will decrease the incidence or severity of AEs associated with 
cabozantinib (see Section 6.2.2). A detailed description of administration procedures is given 
in Section 6.2.1. 
Subjects will receive study treatment until discontinuation due to reasons such as disease 
progression, unacceptable toxicity, withdrawal of consent (see Section 5.2.2) or until the end of 
the study (18 months after the last subject included in the study started cabozantinib treatment, 
Section 5.6). 

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Cabozantinib will be packaged at Dreux, France. A sufficient quantity of cabozantinib and an 
acknowledgement of receipt form will be supplied to each investigational site.  
The Sponsor’s representative will receive a Certificate of Analysis for each batch of 
cabozantinib used in the study and Material Data Safety Sheets.  
The core label texts for all packaging units will be translated and/or adjusted to be in compliance 
with the applicable local regulatory requirements (e.g. Good Manufacturing Practice guidelines 
(Volume 4 Annex 13), national laws in force and in accordance with local languages.  
The Investigator or designee will only dispense cabozantinib to subjects included in this study. 
Each subject will only be given the study treatment if they carry his/her registration number. 
Dispensations for each subject will be documented in the electronic case report form (eCRF). 
At each cabozantinib dispensation (at scheduled and unscheduled visits, if applicable), 
treatment number(s) will be assigned by the Interactive Web Response System (IWRS), 
according to the appropriate dose (dose adaptation). The IWRS will also manage all logistical 
aspects of the study treatment (e.g. replacement, drug supplies and expiry dates) and the 
recording of drug accountability/destruction. This service provides the Investigator, 
investigational site coordinators and project team members with a service that is available 
24 hours a day, 7 days a week. Additional details may be found in the IWRS reference manual 
provided to each investigational site. In case of technical or dispensation queries, a 24-hour 
helpline is available (see supporting information in the Investigational Site File). If a subject 
discontinues the study before any intake of study treatment, his/her assigned treatment 
number(s) will not be reused. 
In addition to the information provided in the IWRS, drug accountability records documenting 
that each subject received the allocated study treatment will be maintained by the Investigator 
or delegate. 
3.6 
Study Duration 
The study is planned to start in the first quarter of 2020 and will start when the first subject 
provides a signed informed consent form. The inclusion period will stop either when the number 
of 74 enrolled subjects in Cohort A is reached or at the latest on 30 June 2022, whichever is 
reached first. For each subject, the study will start from the ICF signature and may last until the 
end of the study (18 months after the last subject included in the study received first 
cabozantinib dose). The period between the start and end of study will include both treatment 
and post-treatment follow-up periods, regardless of the duration of treatment (e.g. if a subject 
stops study treatment after 2 months, he/she will be followed-up for the remaining time up to 
the end of the study).  
It is estimated that subjects will receive study treatment for an average of 8 months. However, 
there is no minimum treatment duration for each subject. Study treatment may be discontinued 
due to several reasons, such as disease progression (i.e. a subject can discontinue study 
treatment after 2 weeks if disease has progressed), unacceptable toxicity or withdrawal of 
consent.  
The study will end 18 months after the last subject included in the study received the first 
cabozantinib dose. However, subjects who continue to benefit from the treatment after the end 
of the study will be supplied with Cabometyx® free of charge from Ipsen, according to local 
regulations and as long as there is safety and efficacy evidence to support the continuation of 
this treatment. Such subjects will be followed until at least 30 days after their last study 
treatment with cabozantinib administration. Information about cabozantinib administration and 

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any related SAEs will be collected during the period when Cabometyx® is supplied free of 
charge from Ipsen.  
3.7 
Source Data Recorded on The Electronic Case Report Form (eCRF) 
Data will be collected in the eCRF in compliance with FDA 21 Code of Federal Regulations 
(CFR) Part 11. As required by GCP guidelines, the monitor assigned by the Sponsor will verify, 
by direct reference to the source documents, that the data required by the protocol are accurately 
reported on the eCRF as defined in the monitoring plan.  
Source documents must, as a minimum, state that the subject is included in the clinical study, 
the date when the informed consent was obtained prior to participation in the study, the identity 
of the study, diagnosis and eligibility criteria, visit dates with subject status, cabozantinib 
administration, any AEs and associated concomitant medication. 
As required by Section 6.4.9 of the International Conference on Harmonisation (ICH-E6), if 
some items are recorded directly on the eCRF and are considered as source data, the 
identification of these data must be documented and agreed between the Investigator and the 
Sponsor. 
The definitions of source data and source documents are given below: 
• 
Source data: All original records and certified copies of original records of clinical 
findings, observations, or other activities necessary for the reconstruction and evaluation 
of the study. Source data are contained in source documents (original records or certified 
copies). 
• 
Source documents: Original documents, data and records (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, subject files and records 
kept at the pharmacy, at the laboratories and at medicotechnical departments involved in 
the clinical study). 
The subject must have consented to his/her medical records being viewed by the Sponsor’s 
authorised personnel and by local and possibly foreign, competent authorities. This information 
is included in the informed consent. 
3.8 
Independent Radiology Committee  
An IRC will be established to evaluate tumour scans and prior radiation history data of study 
subjects in a central, blinded and independent fashion. The IRC will be comprised of 
board-certified radiologists who will evaluate prior radiation history to validate the 
identification of target lesions, as well as determine radiographic response and progression after 
screening. All IRC assessments will be performed by batch (any additional details will be found 
in the IRC charter).  
Additional imaging results may be requested by the Sponsor for IRC review. 
Details regarding IRC member qualification, training, methods, procedures, and other issues 
relevant to committee operations will be described in the IRC Charter. 

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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
This study will include subjects with locally advanced or metastatic RCC with a clear-cell 
component that have progressed after 1st line CPI alone or CPI combined with VEGF-targeted 
therapy. The eligibility criteria for this study have been carefully considered to ensure the safety 
of the study subjects and to safeguard the integrity of the study results. It is imperative that all 
subjects fully meet all inclusion criteria and none of the exclusion criteria. 
4.1 
 Inclusion Criteria 
All subjects must fulfil all the following criteria to be included in the study: 
(1) 
Subjects must provide a signed informed consent prior to any study-related procedures; 
(2) 
Male or female subjects must be aged ≥18 years on the day the informed consent is 
signed; 
(3) 
Subjects must have histologically confirmed unresectable, locally advanced (defined as 
disease not eligible for curative surgery or radiation therapy) or metastatic RCC with a 
clear-cell carcinoma component; 
(4) 
Subjects must have radiographic disease progression, according to Investigator’s 
judgement following 1st line treatment with CPI (ipilimumab plus nivolumab) (Cohort A) 
or CPI in combination with VEGF-targeted therapy (Cohort B); 
(5) 
Subjects present ≥1 target lesion according to RECIST 1.1 per Investigator; 
(6) 
Subjects should have ECOG status 0-1; 
(7) 
Subjects with treated brain metastases are eligible if metastases have been shown to be 
stable as per Investigator’s judgement; 
(8) 
Subjects must have adequate organ and marrow function, based upon meeting all of the 
following laboratory criteria within 15 days before baseline: 
(a) 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L). 
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 GI/L). 
(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × 
upper limit of normal (ULN). 
(e) 
Total bilirubin ≤ 1.5 × ULN. For subjects with Gilbert’s disease ≤ 3 mg/dL (≤ 51.3 
μmol/L). 
(f) 
Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 
0.5 mL/sec) using the Cockcroft-Gault equation  
(g) 
Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) 
creatinine or 24-hour urine protein < 1 g. 
(9) 
Subject must have recovered to baseline or ≤ Grade 1 per CTCAE v5 from toxicities 
related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable 
on supportive therapy as determined by the Investigator; 
(10) Subject must have completed a steroid taper if he/she experienced an immune-related 
adverse event associated with previous CPI treatment; 
(11) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-
menopause and not surgically sterile) must provide a negative pregnancy test within 
7 days prior to the start of study treatment. If a urine test cannot be confirmed as negative, 
a negative serum pregnancy test is required; 

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(12) Female subjects of childbearing potential (i.e. less than or equal to 2 years post-
menopause and not surgically sterile) and their partners must agree to highly effective 
methods of contraception that alone or in combination result in a failure rate of less than 
1% per year when used consistently and correctly (see Appendix 3) during the course of 
the study and for 120 days after the last dose of study treatment;  
(13) All male participants must agree to refrain from donating sperm and unprotected sexual 
intercourse with female partners during the study and for 120 days after the last dose of 
study treatment; 
(14) Subjects must be willing and able to comply with study requirements, remain at the 
investigational site for the required duration of each study visit and be willing to return 
to the investigational site for the follow up evaluation, as specified in the protocol. 
(15) Subjects must be covered by social security or be the beneficiary of such a system (only 
applicable for French subjects). 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if the subject: 
(1) 
Inability to swallow tablets; 
(2) 
Was treated with any other investigational medicinal product (IMP) during a clinical 
study within the last 30 days before baseline; 
(3) 
Was previously treated with cabozantinib; 
(4) 
Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast medium used 
for Contrast Tomography (CT)-scan; 
(5) 
Presents untreated brain or leptomeningeal metastases, or current clinical or radiographic 
progression of known brain metastases; 
(6) 
Has a diagnosis of a serious cardiovascular disorder: 
(a) 
Congestive heart failure New York Heart Association class 3 or 4, unstable angina 
pectoris, or serious cardiac arrhythmias; 
(b) 
Uncontrolled hypertension, defined as sustained blood pressure (BP) 
(>140 mm Hg systolic or >90 mm Hg diastolic pressure) despite optimal 
antihypertensive treatment; 
(c) 
Stroke (including transient ischaemic attack (TIA)), myocardial infarction (MI) or 
other ischaemic event, or thromboembolic event (e.g. deep venous thrombosis, 
pulmonary embolism) within 6 months before screening; 
(d) 
History of risk factors for torsades de pointes (e.g., long QT syndrome); 
(7) 
Is receiving concomitant anticoagulation with coumarin agents (e.g. warfarin), direct 
thrombin inhibitor dabigatran, direct Factor Xa inhibitors betrixaban or platelet inhibitors 
(e.g. clopidogrel); 
Note: The following are allowed anticoagulants: prophylactic use of low-dose aspirin for 
cardioprotection (per local applicable guidelines), and low dose of low molecular weight 
heparin (LMWH). Therapeutic doses of LMWH or anticoagulation with direct factor Xa 
inhibitors rivaroxaban, edoxaban, or apixaban in patients without known brain 
metastases who are on a stable dose of the anticoagulant for at least 1 week before 
baseline without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumour. 

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(8) 
Has a gastrointestinal (GI) disorder including those associated with a high risk of 
perforation or fistula formation: 
(a) 
Tumours invading the GI tract, active peptic ulcer disease, inflammatory bowel 
disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction; 
(b) 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months before screening;  
Note: Complete healing of an intra-abdominal abscess must have been confirmed 
before screening. 
(9) 
Presents a corrected QT (QTc) interval calculated by the Fridericia formula (QTcF) > 
500 msec within 1 month prior to baseline; 
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  
(10) Presents clinically significant haematuria, hematemesis, or haemoptysis of >0.5 teaspoon 
(2.5 mL) of red blood, or other history of significant bleeding (e.g. pulmonary 
haemorrhage) within 3 months before screening; 
(11) Presents cavitating pulmonary lesion(s) or known endobronchial disease manifestation; 
(12) Presents lesions invading major pulmonary blood vessels; 
(13) Has been diagnosed with other clinically significant disorders such as: 
(a) 
Serious nonhealing wound/ulcer/bone fracture; 
(b) 
Malabsorption syndrome; 
(c) 
Uncompensated/symptomatic hypothyroidism (subject with a history of 
autoimmune-related hypothyroidism who are on thyroid-replacement hormone are 
eligible for the study); 
(d) 
Moderate to severe hepatic impairment (Child-Pugh B or C); 
(e) 
Requirement for haemodialysis or peritoneal dialysis; 
(f) 
History of solid organ transplantation; 
(14) Has a predicted life expectancy of less than 3 months; 
(15) Has had prior surgery within 4 weeks prior to baseline. Note: If the subject has undergone 
major surgery, complete wound healing must have occurred 1 month prior to baseline; 
(16) Has had palliative radiation therapy for bone within 2 weeks or for radiation fields 
including viscera within 4 weeks prior to baseline. Note: Resolution/healing of side 
effects must be complete prior to baseline; 
(17) Has a history of another active malignancy within 3 years from screening except for 
locally curable cancers that have been apparently cured, such as low-grade thyroid 
carcinoma, prostate cancer not requiring treatment (Gleason Grade ≤6), basal or 
squamous cell skin cancer, superficial bladder cancer, in situ melanoma, in situ prostate, 
cervix or breast carcinoma or other treated malignancies with <5% chance of relapse 
according to the Investigator; 

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(18) Has a history of allergy to study treatment components or agents with a similar chemical 
structure or any excipient used in the formulation as listed in the SmPC document; 
(19) Has rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption are also excluded; 
(20) Has a serious medical or psychiatric condition that renders the subject unable to 
understand the nature, scope and possible consequences of the study, and/or presents an 
uncooperative attitude; 
(21) Is pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum 
pregnancy test will be performed up to 7 days prior to baseline for all female subjects of 
childbearing potential (i.e. less than or equal to 2 years post-menopause and not 
surgically sterile); 
(22) Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol; 
(23) Has abnormal baseline findings, any other medical condition(s) or laboratory findings 
that, in the opinion of the Investigator, might jeopardise the subject’s safety.  
4.3 
Stopping Rules, Discontinuation and Withdrawal Criteria and Procedures  
4.3.1 
Treatment Discontinuation and Study Withdrawal  
In accordance with the Declaration of Helsinki (and with the applicable country’s acceptance 
of this declaration), each subject may discontinue study treatment or withdraw their consent to 
participate in the study at any time for any reason without prejudice.  
The Investigator also has the right to withdraw a subject from the study for any reason 
concerning the subject’s health or wellbeing or in case of lack of cooperation. 
Subjects who discontinue the study treatment or withdraw from study will not be replaced. 
If a subject fails to return for protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at least a registered letter should be sent 
to the subject (or the subject’s legal guardian) requesting contact with the investigational site. 
In case of suspected or confirmed COVID-19 (SARS-CoV-2) infection, the study drug 
administration may be temporarily discontinued depending on the subject clinical status. In 
some cases, the Investigator may request a participant be retested before the study drug 
administration is resumed.  
4.3.1.1 
Treatment Discontinuation 
If a subject decides to discontinue study treatment or the Investigator decides to discontinue a 
subject from the study treatment, this subject will be invited to undergo the assessments of the 
End of Study Treatment/Early Withdrawal visit (see Section 5.2.2) and to attend the 
Post-treatment Follow-up visits to assess safety, subsequent anti-cancer therapies and survival 
status assessments, unless the subject withdraws consent to remain in the study and refuses to 
have his/her data collected. If study treatment discontinuation occurs, the reason and date of 
this decision must be recorded in the eCRF. 
If the reason for study treatment discontinuation is an AE or a clinically significant laboratory 
test abnormality, monitoring will continue until the event has resolved or stabilised, until the 
subject is referred to a local health care professional, or until the determination of a cause 
unrelated to cabozantinib or study procedure is made. The specific AE or test result(s) must be 
recorded on the eCRF. If a subject is pregnant, please see Section 8.1.5. 
Reasons for study treatment discontinuation include: 

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• 
The subject no longer experiences clinical benefit as determined by the Investigator; 
• 
The subject requests to discontinue study treatment; 
• 
Unacceptable toxicity that the Investigator feels may be due to study treatment; 
• 
Study treatment needs to be interrupted for more than 6 weeks due to treatment-related 
AEs; 
• 
Refusal of sexually active fertile subjects (excluding subjects who have been sterilised) 
to use medically accepted methods of contraception; 
• 
Request by the Sponsor; 
• 
Subject needs treatment with another investigational agent or investigational medical 
device (not defined in the protocol); 
• 
Pregnancy. 
4.3.1.2 
Study Withdrawal 
If a subject decides to withdraw consent, no further study procedures or assessments will be 
performed or study data collected for this subject. However, all efforts will be made to complete 
and report the observations up to the time of withdrawal as thoroughly as possible. A complete 
final evaluation at the time of the subject’s withdrawal should be made (see Section 5.2.2.2) 
and the date and explanation as to why the subject is withdrawing or being withdrawn from the 
study must be recorded on the eCRF.  
In case of loss to follow-up, public records such as government vital statistics or obituaries will 
be analysed to assess the subjects’ survival status. 
Reasons for study withdrawal include:  
• 
Withdrawal of consent by the subject;  
• 
Request by the Sponsor or the Investigator; 
• 
Loss to follow-up (confirmed with two documented phone calls and a certified letter 
(delivery receipt request) without answer; 
• 
Subject’s significant noncompliance with protocol schedule (or other protocol violation) 
in the opinion of the Investigator or the Sponsor; 
• 
Subject’s death. 
4.3.2 
Early Study Termination  
There are no formal rules for the early termination of this study. During the conduct of the 
study, SAEs will be reviewed (see Section 8.1) as they are reported by the investigational site 
to identify safety concerns. A specific investigational site or a given cohort can be discontinued 
and the entire study may be terminated at any time if the Sponsor considers it necessary for any 
reason. In such case, only information regarding AEs, other cancer treatments and survival 
status will be collected for subjects who are still in the study at the time of study termination. 
Some possible reasons for the closure of an investigational site may include: 
• 
failure of the Investigator staff to comply with the protocol or with the GCP guidelines; 
• 
safety concerns; 
• 
inadequate subject recruitment. 
In case of premature discontinuation of an investigational site or the complete study, depending 
on the reason(s) for discontinuation, the Sponsor will notify the Investigator(s) affected in 
writing as to whether the ongoing subjects should continue the remaining cabozantinib dose 
administration(s). 

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In terminating the study, the Sponsor and the Investigator will assure that adequate 
consideration is given to the protection of the subjects’ interests. 

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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 2. 

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Table 2 
Study Procedures and Assessments 
 
Pre-treatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
Period d 
Assessment 
Screening  
Baseline a 
Week 2 
Week 4 
Week 8 
Every 
4 weeks  
End of Study Treatment 
Visit b or Early Study 
Withdrawal Visit c  
Follow-Up  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 to 
Visit X 
30 days after the last 
dose of treatment 
Every 12 weeks  
 
Before first 
cabozantinib 
intake 
Day 1 
Day 15 
(±2 Days) 
Day 29 
(±2 Days) 
Day 57 
(±2 Days) 
Day 85 to 
Day X 
(±5 Days) 
 
(+15 Days) 
(±15 Days) 
Informed consent form  
  X e 
 
 
 
 
 
 
 
Eligibility Criteria  
X 
X f 
 
 
 
 
 
 
Demography  
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
RCC history  
X 
 
 
 
 
 
 
 
Prior surgery/radiotherapy/ 
chemotherapy/medications 
related to RCC  
X 
 
 
 
 
 
 
 
Smoking habits/status 
X 
 
 
 
 
 
 
 
Physical examination  
≤15 Days prior to 
baseline  
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
Weight  
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
Vital signs  
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
ECOG performance status  
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
12-lead ECG  
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
 
X 
 
Every 
12 weeks 
X 
 

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Pre-treatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
Period d 
Assessment 
Screening  
Baseline a 
Week 2 
Week 4 
Week 8 
Every 
4 weeks  
End of Study Treatment 
Visit b or Early Study 
Withdrawal Visit c  
Follow-Up  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 to 
Visit X 
30 days after the last 
dose of treatment 
Every 12 weeks  
 
Before first 
cabozantinib 
intake 
Day 1 
Day 15 
(±2 Days) 
Day 29 
(±2 Days) 
Day 57 
(±2 Days) 
Day 85 to 
Day X 
(±5 Days) 
 
(+15 Days) 
(±15 Days) 
Haematology and blood 
biochemistry  
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
Coagulation assessments 
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
 
 
Urinalysis, microscopic urine 
examination and urine chemistry 
(including UPCR) g 
≤15 Days prior to 
baseline 
X 
(prior to 
first dose) f 
X 
X 
X 
Every 
4 weeks 
X 
 
Pregnancy test (female subjects 
only, if applicable) 
≤7 days prior to 
baseline 
X 
(prior to 
first dose) f 
Urinary and/or pregnancy blood tests are mandatory at 
every visit  
X 
 
Thyroid function test (FT4, 
TSH)  
≤15 days prior to 
baseline 
X 
(prior to 
first dose) f 
Every 4 weeks 
X 
 
Chest/Abdomen/Pelvis (C/A/P) 
CT/MRI 
 ≤28 days prior to 
baseline 
X f 
Every 12 weeks (±10 days) while on protocol treatment beginning at Week 12 
(i.e. Week 12, Week 24, Week 36, etc) until the end of study and additionally if 
clinically indicated 
X h 
Brain CT/MRI and Bone 
scintigraphy scan (only if 
indicative of metastases) 
 ≤28 days prior to 
baseline 
Only if indicative of brain and/or bone metastases at screening or if signs or symptoms 
suggestive of metastases develop 
X h (only if 
indicative of 
metastases)  
Cabozantinib intake i 
 
All subjects will be treated with oral cabozantinib 60 mg once daily (q.d.). In case of 
treatment-emergent toxicity, the Investigator may decide to reduce the dose to 40 mg or 20 mg 
 
Dispense/return of oral study 
drug and compliance accounting  
 
X 
 
X 
X 
X 
X 
 
AEs j, k 
X 
X 
X 
X 
X 
X 
X 
X k 

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Pre-treatment 
Period 
Treatment Period 
Post-treatment 
Follow-up 
Period d 
Assessment 
Screening  
Baseline a 
Week 2 
Week 4 
Week 8 
Every 
4 weeks  
End of Study Treatment 
Visit b or Early Study 
Withdrawal Visit c  
Follow-Up  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 to 
Visit X 
30 days after the last 
dose of treatment 
Every 12 weeks  
 
Before first 
cabozantinib 
intake 
Day 1 
Day 15 
(±2 Days) 
Day 29 
(±2 Days) 
Day 57 
(±2 Days) 
Day 85 to 
Day X 
(±5 Days) 
 
(+15 Days) 
(±15 Days) 
Prior and concomitant therapies l 
≤30 Days prior to 
baseline 
X l 
X l 
X l 
X l 
X l 
X l 
 
Other cancer treatment  
 
 
 
 
 
 
X 
Survival status  
 
 
 
 
 
 
X 
HRQOL 
(FKSI-DRS) m 
 
X 
(prior to 
first dose) 
Every 12 weeks while on protocol treatment beginning at Week 12 (i.e. 
Week 12, Week 24, Week 36, etc) until the End of Study Treatment visit or 
Early Study Withdrawal visit. 
 
Abbreviations: AEs = Adverse events; CT = Contrast tomography; ECG = Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = Electronic case report form; FKSI-
DRS = Functional Assessment of Cancer Therapy–Kidney Symptom Index–Disease-Related Symptoms; FT4 = Free thyroxine 4; HRQOL = Health-related quality of life; MRI = Magnetic 
Resonance Imaging; RCC = Renal cell carcinoma; SAE = Serious adverse event; TSH = Thyroid-stimulating hormone 
 
a Screening and baseline visits can take place the same day as long as all eligibility criteria/parameters are available and checked prior to the first dose of cabozantinib.  
b This visit will be held for subjects who have discontinued study treatment whatever the reason (e.g. disease progression or unacceptable toxicity).  
c All included subjects who prematurely stopped the study due to withdrawal of consent during study treatment period will attend the Early Study Withdrawal visit. 
d During the Post-treatment Follow-up period, subjects will be contacted every 12 weeks (±15 days) starting after the End of Study Treatment visit to assess survival status and document receipt 
of subsequent anti-cancer therapy. These assessments will be continued until the subject expires or the end of the study (18 months after the last subject included in the study received the first 
cabozantinib dose), whichever occurs first. 
e Informed consent must be provided before any study-specific procedures are performed; however, evaluations performed as part of routine care prior to informed consent can be used as Screening 
evaluations if permitted by the Institutional Review Board (IRB)/Ethics Committee (EC) policies of the investigational site.  
f These assessments are intended to confirm suitability for treatment after the Screening visit. There is no need to perform them again at baseline, unless the subject’s clinical status has changed 
(e.g. onset of new symptoms indicative of clinical deterioration). If these assessments are performed at screening and baseline visits, results must be available to be reviewed by the Investigator 
prior to first dose.  
g Microscopic urine examination to be performed at baseline and after that only at the discretion of the Investigator (results are not to be collected in the eCRF except in case of clinically abnormal 
findings, which are to be reported as an AE). Urine chemistry (24-hour urine protein or UPCR) may be performed at any scheduled or unscheduled visit at the discretion of the Investigator and 
based on results of routine urinalysis or as clinically indicated.  

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h Follow-up for radiographic progression, tumour assessment should be performed until radiographic progression confirmed by the Investigator only for subjects who have discontinued cabozantinib 
treatment before radiographic disease progression and who have not withdrawn consent.  
I Cabozantinib will be self-administered at home until study treatment is discontinued. 
j Information on new or worsening AEs will be collected from date of the signed informed consent until the end of study treatment, at each study visit, by telephone call or by spontaneous report 
by the subject. Any AEs and SAEs that are ongoing 30 days after the date of the last cabozantinib dose are to be followed until resolution or until the Investigator considers the event is stable or 
irreversible (see Section 8.1.3).  
k During the follow-up period, any SAEs that occur more than 30 days after the date of the last cabozantinib dose, assessed as related to study treatment or study procedures will also be collected 
and followed until resolution or stability according to the Investigator. 
l Information on prior and concomitant medication will be collected up to 30 days before baseline until 30 days after the date of the last cabozantinib dose.  
m The FACIT and all related works are owned and copyrighted by, and the intellectual property of David Cella, Ph.D. Permission for use of the FKSI-DRS questionnaire is obtained by contacting 
Dr. Cella at information@facit.org. 

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Based on an average treatment duration of 8 months and 12 visits, the total volume of blood 
drawn for all evaluations throughout this study will be approximately 144 mL for each subject 
(12 mL of blood per visit, this volume may depend on the laboratory used, treatment duration 
and number of visits).  
5.2 
Study Visits 
5.2.1 
Procedures Before Study Treatment 
All efficacy and safety assessments to be performed during the pre-treatment period are 
indicated in Table 2 (please see footnotes in the table for details) and described in Section 7 and 
Section 8, respectively.  
A signed and dated informed consent form may be obtained more than 15 days prior screening 
but must be provided before any study-specific procedures are performed. However, 
evaluations performed as part of routine care prior to the date of the signed informed consent 
form can be used as Screening evaluations if permitted by the IRB/Ethics Committee (EC) 
policies of the investigational site. Subjects will acknowledge and agree to the possible use of 
these data in the study by signing the informed consent form. 
All screened subjects will be allocated a subject number so that they can be identifiable 
throughout the study. The Investigator will maintain a list of screened subjects (i.e. who signed 
the informed consent form), subject numbers and names to ensure that all records may be found 
at a later date if required. In case a subject does not receive cabozantinib after the Screening 
visit, the primary reason will be recorded. 
5.2.2 
Procedures During Study Treatment  
All efficacy and safety assessments to be performed throughout the treatment period are 
indicated in Table 2 (please see footnotes in the table for details) and described in Section 7 and 
Section 8, respectively.  
Clinical status will be evaluated by the Investigator at each visit to the investigational site to 
confirm that the subject is suitable to continue study treatment and to make timely decisions 
regarding the interruption or restart of cabozantinib dosing. Tumour assessments from imaging 
visits will be reviewed by central review and by the local Investigator.  
Subjects may discontinue study treatment any time during the study due to reasons such as 
disease progression, intolerance to cabozantinib, need for subsequent systemic investigational 
drug therapy or other reasons for study treatment discontinuation listed in this protocol 
(Section 4.3.1). This implies that the duration of cabozantinib treatment may be different for 
each subject included (see Section 3.6 for details), but the study is planned to follow-up subjects 
up to 18 months after the last subject included in the study received the first cabozantinib dose. 
Subjects with radiographic progression per RECIST 1.1 evaluated by the Investigator may 
continue study treatment if the Investigator believes that there still is clinical benefit and that it 
outweighs potential risks. In this case, study treatment can be continued up to the end of the 
study (Section 5.6), unless the subject or the Investigator decides to discontinue study treatment 
due to unacceptable toxicity or needs subsequent systemic anti-cancer treatment.  
Subjects who discontinue study treatment with cabozantinib (e.g. due to radiographic 
progression or unacceptable toxicity) will be invited to attend the End of Study Treatment visit 
(Section 5.2.2.1).  
Subjects who discontinue study treatment due to withdrawal of consent will be invited to attend 
the Early Study Withdrawal visit (Section 5.2.2.2). 

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5.2.2.1 
End of Study Treatment Visit 
The End of Study Treatment visit will be carried out 30 to 45 days after the last cabozantinib 
dose (all necessary assessments to be performed at this visit are indicated in Table 2). After this 
date, the subject will enter the Post-treatment Follow-up period (Section 5.2.3.1).  
The Investigator will ask subjects to return any remaining cabozantinib tablets and check their 
compliance to study protocol. Efficacy evaluations should not be performed for subjects who 
do not attend the End of Study Treatment visit within 30 to 45 days after their last dose of 
cabozantinib. Subjects with ongoing AEs or clinically significant laboratory test abnormalities 
(as determined by the Investigator) will be monitored as described in Section 8.1.3 and 
Section 8.1.2.4, respectively. 
5.2.2.2 
Early Study Withdrawal Visit 
All included subjects who prematurely stop the study due to withdrawal of consent will be 
invited to attend the Early Study Withdrawal visit. Please see the footnotes in Table 2 for 
details. 
5.2.3 
Procedures After Study Treatment 
Subjects who discontinue study treatment with cabozantinib will be invited to enter the 
Post-treatment Follow-up period. All necessary assessments performed after treatment are 
indicated in Table 2.  
For subjects who have discontinued cabozantinib treatment before radiographic disease 
progression and who have not withdrawn consent, tumour assessment should be performed until 
radiographic progression confirmed by the Investigator. 
5.2.3.1 
Post-treatment Follow-up Period 
During the Post-treatment Follow-up period, subjects will be contacted every 
12 weeks (±15 days), starting after the End of Study Treatment visit, to assess survival status 
and record the receipt of subsequent anti-cancer therapy. During the follow-up period, any 
SAEs that occur more than 30 days after the date of the last cabozantinib dose, assessed as 
related to study treatment or study procedures will also be collected and followed until 
resolution or stability according to the Investigator. These assessments will be continued until 
the subject expires or until the end of the study (18 months after the last subject included in the 
study received the first cabozantinib dose, Section 5.6), whichever occurs first. Every effort 
will be made to collect these protocol-specific evaluations unless consent to participate in the 
study is withdrawn. All AEs will be documented and/or followed as described in Section 8.1.3 
and Section 8.1.4. 
At each contact, the Investigator (or designee) will determine if the subject has died, and if so, 
record the date and cause of death as best as can be determined. All efforts must be undertaken 
by the investigational sites to determine the date of death (or the date the subject was last known 
to be alive at the time of a data cut-off). This may include, but not necessarily be limited to, 
telephone calls, registered letters, and reviews of local obituaries and government death records. 
If a subject is lost to follow-up, multiple attempts to contact study subject or designee must be 
documented in the subject records. 
Every effort will be made to perform protocol-specific evaluations unless consent to participate 
in the study is withdrawn and the subject no longer allows data collection.  
5.3 
Unscheduled Visits or Assessments 
If the Investigator determines that a subject should be monitored more frequently or with 
additional laboratory parameter assessments than indicated by the protocol-defined visit 

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schedule, unscheduled visits or assessments are permitted. All laboratory assessments will be 
done by the local laboratory. If study treatment is interrupted, during the intervening time 
between the last dose and the time drug is restarted, the investigational site should perform 
unscheduled visits to monitor subject safety as needed and appropriateness for re-treatment with 
study treatment. 
5.4 
Laboratory Assessments 
The complete list of laboratory assessments to be performed in this study are indicated in 
Section 8.2.  
Based on an average treatment duration of 8 months and 12 visits, the total volume of blood 
drawn for all evaluations throughout this study will be approximately 144 mL for each subject 
(12 ml at each visit; this volume may depend on the laboratory used, treatment duration and 
number of visits).  
All samples will be analysed locally. 
5.5 
Imaging 
There will be no additional exposure to radiation. The imaging planned in this protocol is 
comparable to routine practice. 
5.6 
End of the Study 
The study will end 18 months after the last subject included in the study received the first 
cabozantinib dose. 
Subjects who continue to benefit from the treatment after the end of the study will be supplied 
with Cabometyx® free of charge from Ipsen, according to local regulations and as long as there 
is safety and efficacy evidence to support the continuation of this treatment. Such subjects will 
be followed until at least 30 days after their last study drug with cabozantinib administration. 
Information about cabozantinib administration and any related SAEs will be collected during 
the period when Cabometyx® is supplied free of charge from Ipsen.  

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6 
TREATMENT OF SUBJECTS 
6.1 
Investigational Medicinal Product Preparation, Storage, Security and 
Accountability 
6.1.1 
Investigational Medicinal Product Storage and Security 
The Investigator or an approved representative (e.g. pharmacist) will ensure that all bottles of 
cabozantinib tablets and any other study-related material is stored in a secured area, in 
accordance with applicable regulatory requirements. This medicinal product does not require 
any specific storage conditions. 
6.1.2 
Investigational Medicinal Product Preparation 
The Investigator or an approved representative (e.g. pharmacist) will ensure that all bottles of 
cabozantinib tablets are dispensed by qualified staff members. 
6.1.3 
Investigational Medicinal Product Accountability 
Cabozantinib tablets and any other study-related material is to be accounted for on the IMP 
accountability log provided by the Sponsor. It is essential that all unused supplies are retained 
for verification (by the Sponsor or Sponsor’s representative). The Investigator should ensure 
adequate records are maintained in the IMP accountability log. 
6.2 
Study Drugs Administered 
At the Screening visit, subjects will be allocated a subject number. Following confirmation of 
eligibility for the study, subjects will be included in one of the two following cohorts based on 
their previous therapy and both cohorts will receive the same open-label treatment with 
cabozantinib (60 mg q.d.): 
• 
Cohort A: 74 subjects 
Cohort A will be composed of subjects who radiographically progressed after one prior line by 
CPI therapy with ipilimumab and nivolumab.  
• 
Cohort B: approximately 40 subjects  
Cohort B will be composed of subjects who radiographically progressed after one prior line by 
CPI therapy combined with VEGF-targeted therapy. 
6.2.1 
Administration of Cabozantinib  
Cabozantinib tablets are meant to be taken orally only and cannot 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. This product cannot be taken with food, thus subjects must not 
eat 2 hours before and 1 hour after taking cabozantinib. 
The date of the first dose of cabozantinib is defined as baseline (Day 1, Visit 2). Subjects will 
take cabozantinib tablets q.d. at home, at the same time each day, preferably at bedtime. Any 
unused study treatment must be returned to the investigational site for drug accountability and 
disposal. If a dose is missed, the missed dose should not be taken less than 12 hours before the 
next one. 
The recommended dose is 60 mg q.d. as indicated in all approvals of cabozantinib 
(Cabometyx™). A dose of 60 mg should be maintained in the absence of treatment-emergent 
toxicity; however, management of suspected adverse drug reactions may require temporary 
interruption and/or dose reduction of cabozantinib therapy (see Table 4). When dose reduction 
is necessary, it is recommended to reduce to 40 mg q.d. and then to 20 mg q.d. Dose 
interruptions are recommended for management of CTCAE Grade 3 or greater toxicities or 

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intolerable Grade 2 toxicities. Dose reductions are recommended for events that, if persistent, 
could become serious or intolerable (see Section 6.2.2). 
The Sponsor will provide each Investigator with adequate supplies of cabozantinib bottles (30 
tablets each), which will be supplied as 60 mg, 40 mg and 20 mg yellow film-coated tablets. 
The 60 mg tablets are oval, the 40 mg tablets are triangle shaped and the 20 mg tablets are 
round.  
Exceptionally, in case there is a stock shortage of 60 mg tablets, the Sponsor will dispense a 
mix of bottles of cabozantinib in lower dose (e.g. 1 bottle of 20 mg + 1 bottle of 40 mg instead 
of 1 bottle of 60 mg). 
6.2.1.1 
First Administration of Cabozantinib (baseline) 
The required study assessments and blood collections should be done prior to any study 
treatment administration. The first intake of cabozantinib will be self-administered at home. On 
the first day of study treatment (defined as baseline), the subject should be fasted (water is 
allowed) for at least 2 hours before receiving cabozantinib. Upon completion of the 2-hour 
fasting, the subject should receive the 60 mg oral dose of cabozantinib with a full glass of water 
(at least 8 oz 240 mL) and then continue to fast for 1 hour. 
6.2.1.2 
Subsequent Dose Administration of Cabozantinib 
Subjects are to fast (with the exception of water) for at least 2 hours before taking their dose. 
After the 2-hour fast, subjects are to take cabozantinib with a full glass of water (minimum of 
240 mL) with no food intake for one more hour post-dose. If the subject’s schedule requires 
taking cabozantinib during the day, the subject is to be instructed to follow the same fasting 
recommendations. 
Subjects should be instructed to not make up for vomited doses and to maintain the planned 
dosing schedule. Subjects should not make up for missed doses if more than 12 hours elapse 
after the time the subject would usually take cabozantinib. In the event of missed doses, subjects 
should not take 2 doses to make up for the missed one. 
Subjects will receive cabozantinib as long as they continue to experience clinical benefit in the 
opinion of the Investigator and up to a maximum of 18 months after the last subject is included 
in the study or until unacceptable toxicity, need for subsequent systemic anti-cancer treatment 
or any other reasons for study treatment discontinuation listed in this protocol (Section 4.3). 
Section 6.2.2 provides the instructions for cabozantinib dose modification, interruption, or 
discontinuation due to AEs. 
6.2.2 
Cabozantinib Dose Modifications, Interruptions and Discontinuation  
Subjects will be monitored for AEs from the time of signing informed consent until 30 days 
after the date of the last dose of cabozantinib. Any SAE that the Investigator believes to be 
related to cabozantinib or study procedures can be reported at any time after the last dose with 
no time limitation during the follow-up period. Subjects will be instructed to notify their 
physician immediately for any occurring AE and unscheduled safety visits are allowed at any 
time. Causality assessment of AEs should include at minimum confounding factors such as 
disease and concomitant medications. The severity of all AEs will be graded by the Investigator 
according to the CTCAE version 5.0. 
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruptions): 

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• 
As a general approach, all AEs should be managed with supportive care at the earliest 
signs of toxicity considered. Should this be ineffective, dose reductions or interruptions 
should be considered to prevent worsening of toxicity; 
• 
The assigned dose for cabozantinib is 60 mg/day. Two reductions in dose levels of 
cabozantinib are permitted but these reductions must be incremental (see Table 3); 
• 
Dose modification criteria for cabozantinib are shown in Table 4. Dose reductions and/or 
interruptions should be implemented for unacceptable toxicity. Doses may be modified 
at any time during the study; 
• 
Dose modifications or interruptions may also occur in the setting of lower grade toxicity 
than that defined in Table 4, if the Investigator feels it is in the interest of a subject’s 
safety and will optimise drug tolerability; 
• 
Interruption of cabozantinib treatment due to AEs may occur at any time per Investigator 
discretion. If study treatment is interrupted due to AEs for more than 6 weeks, 
cabozantinib should be discontinued; 
• 
Dose interruptions for reason(s) other than AEs (e.g. surgical procedures) can be longer 
than 6 weeks but require Sponsor approval. The acceptable length of interruption will 
depend on agreement between Investigator and the Sponsor. 
Warnings, precautions and guidelines for the management of AEs (e.g. GI disorders, 
hepatobiliary disorders, blood system disorders, constitutional disorders, skin disorders, 
hypertension, thromboembolic events, proteinuria, QTc prolongation, hypophosphataemia, 
thyroid function disorders, haemorrhagic events, GI perforation/fistula and non-GI fistula 
formation and osteonecrosis of the jaw (ONJ)) are provided in Appendix 4. 
 
Table 3 
Dose Reductions of Cabozantinib 
Assigned dose 
First Dose Level Reduction 
Second Dose Level Reduction 
60 mg cabozantinib orally q.d. 
40 mg cabozantinib orally q.d. 
20 mg cabozantinib orally q.d. 
Abbreviations: q.d. = Once daily 
Cabozantinib should be discontinued if a dose of 20 mg q.d. (minimum dose) is not tolerated 

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Table 4 
Dose Modifications of Cabozantinib for Treatment-related AEs 
Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add 
supportive 
care 
as 
indicated. 
Continue 
cabozantinib treatment at the current dose level if AE 
is manageable and tolerable. 
Grade 2 AEs which are tolerable and are easily 
managed  
 
 
Grade 2 AEs which are intolerable and cannot be 
adequately managed 
Continue cabozantinib treatment at the current dose 
level with supportive care. 
 
 
At the discretion of the Investigator, cabozantinib 
should be dose reduced or interrupted. 
Note: It is recommended that dose holds be as brief as 
possible. 
Grade 3 
AEs 
(except 
clinically 
non-relevant 
laboratory abnormalities) 
Cabozantinib must be interrupted until the adverse 
reaction resolves to Grade ≤1. 
Note: It is recommended that dose holds be as brief as 
possible. 
Grade 4 
AEs 
(except 
clinically 
non-relevant 
laboratory abnormalities) 
Subjects should 
have cabozantinib interrupted 
immediately. 
Discontinue cabozantinib unless the following criteria 
are met: 
• 
Subject is deriving clear clinical benefit as 
determined by the Investigator; 
• 
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) 
and optimal medical care. 
Abbreviations: AE = Adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 6.2.4. For reinstitution 
of cabozantinib after dose interruption, please see Section 6.2.3.  
a Dose adjustment is only needed if toxicity is considered to be related or has an unclear relationship to cabozantinib treatment. 
6.2.3 
Cabozantinib Dose Reinstitution and Reescalation 
If toxicity decreases to CTCAE version 5.0 Grade ≤1 or to baseline values (or lower) and is 
considered to be unrelated to study treatment, then subjects may restart cabozantinib with no 
dose change. 
If toxicity decreases to CTCAE version 5.0 Grade ≤1 or to baseline values (or lower) and is 
considered to be possibly related to study treatment, then subjects may restart cabozantinib at a 
reduced dose (see Table 3 for dose reduction schedule). 
Subjects receiving a dose of 20 mg q.d. may be restarted at the same dose if deemed safe at the 
discretion of the Investigator. Subjects unable to tolerate a dose of 20 mg q.d. should 
discontinue study treatment. 
Re-escalation to the previous dose (but not higher than 60 mg/day) may be allowed at the 
discretion of the Investigator but no sooner than 2 weeks beyond resolution of the AEs that led 
to dose reduction. Dose re-escalation is not allowed for a drug-related dose reduction triggered 
by myelosuppression or by Grade 4 AEs affecting major organs (e.g. central nervous system 
(CNS), cardiac, hepatic, renal). 

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6.2.4 
Cabozantinib Warnings, Precautions and Guidelines for Management of Potential 
Adverse Events 
The side effect profile of cabozantinib includes, in descending order of frequency, diarrhoea, 
fatigue, decreased appetite, nausea, palmar-plantar erythrodysaesthesia syndrome (PPES), 
vomiting, weight decreased, hypertension, constipation, dysphonia  and asthenia (please refer 
to the Investigator’s Brochure for additional details). 
Subjects may also experience other medically important but less frequent AEs including arterial 
and venous thrombotic AEs (e.g. deep vein thrombosis (DVT), pulmonary embolism, TIA and 
MI), severe haemorrhagic events, proteinuria, wound healing complications, GI perforation, 
abscesses including intra-abdominal and pelvic abscess, GI and non-GI fistulae formation, 
osteonecrosis, and reversible posterior leukoencephalopathy syndrome (RPLS). 
All AEs associated with laboratory abnormalities experienced by ≥5% of subjects treated with 
cabozantinib in descending order of frequency were anaemia, AST increased, ALT increased, 
hypothyroidism, hypokalaemia, hypomagnesaemia, thrombocytopenia, hypocalcaemia, 
hypophosphataemia, lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, 
alkaline phosphatase (ALP) increased, hyponatraemia, and leukopenia.    
All AEs should be managed with supportive care at the earliest signs of toxicity and dose 
reductions or study treatment interruptions should be considered. Dose reductions are 
recommended for events that, if persistent, could become serious or intolerable. A more detailed 
approach for management of potential AEs is provided in Appendix 4.  
As with all investigational products, unknown AEs may occur. Subjects should be monitored 
closely for all AEs. The plasma effective half-life of cabozantinib is approximately 55 hours. 
Thus, when initiating therapy with cabozantinib, it will take most subjects 2-3 weeks to reach 
steady state after daily dosing. If AEs attributable to cabozantinib occur within the initial 
15-21-day period of dosing, early intervention with dose modifications may be justified for AEs 
that, if worsened, could potentially be dangerous or debilitating, since without a dose 
adjustment, systemic exposure of cabozantinib might be expected to increase after the onset of 
the AE. The terminal half-life of 120 hours determined in single dose studies is a predictor of 
drug washout following the last dose which is relevant when interrupting study treatment for 
AEs management. 
For general information regarding study medication error refer to Section 8.1.6. 
6.3 
Prior and Concomitant Medication/Therapy 
Any prior ongoing therapy at baseline and concomitant medications (received during 
cabozantinib administration) will be indicated on the eCRF, including dose and generic name 
or trade name. 
6.3.1 
Allowed Therapies 
The following concomitant medications are permitted during this study, but they must be 
closely monitored and every effort should be made to keep their dose and dose regimen constant 
throughout the course of the study: 
• 
Antiemetics and antidiarrheal medications are allowed prophylactically according to 
standard clinical practice if clinically indicated; 
• 
Granulocyte colony-stimulating factors (G-CSF) or granulocyte macrophage (GM)-CSF 
are allowed if used per clinical guidelines (e.g. American Society of Clinical Oncology 
(ASCO) or ESMO guidelines); 

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• 
Drugs used to control bone loss (e.g. bisphosphonates and denosumab) are allowed if 
started prior to screening activities but may not be initiated or exchanged during the 
course of the study and require sponsor approval; 
• 
Transfusions, hormone replacement, and short-term higher doses of corticosteroids 
should be utilised as indicated by standard clinical practice; 
• 
Individualised anticoagulation therapy is allowed if it can be provided safely and 
effectively under the following circumstances: 
- 
Prophylactic use of low-dose aspirin for cardioprotection (per local applicable 
guidelines), and low dose of LMWH are allowed if clinically indicated and the 
benefit outweighs the risk per the Investigator’s discretion; 
- 
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed in patients without known brain 
metastases who are on a stable dose of the anticoagulant for at least 1 week before 
baseline without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumour. 
- 
Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy must be followed. This includes, but is not limited to, 
subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (e.g. due to kidney dysfunction); 
- 
For restrictions on oral anticoagulants see Section 6.3.2. 
Potential drug interactions with cabozantinib are summarised in Section 6.3.3. 
6.3.2 
Prohibited or Restricted Therapies 
The following therapies are prohibited while the subject is on cabozantinib treatment: 
• 
Any investigational agent or investigational medical device; 
• 
Any drug or herbal product used specifically for the treatment of RCC; 
• 
Any coumarin agents (e.g. warfarin), direct thrombin inhibitor dabigatran, direct Factor 
Xa inhibitors betrixaban or platelet inhibitors (e.g. clopidogrel); 
• 
Any other systemic anti-cancer treatment (e.g. chemotherapy, immunotherapy, 
radionuclides) and local therapy such as surgery, ablation, or embolisation. 
 
The following therapies should be avoided while the subject is on cabozantinib treatment: 
• 
Palliative external radiation to bone metastasis for bone pain should not be performed 
while on study except if it is clinically unavoidable. Subjects who have such an 
intervention may be considered not evaluable (and may be assigned a censoring or 
progression date) for certain efficacy endpoints; 
• 
Erythropoietic stimulating agents (e.g. epoetin alfa and darbepoetin alfa) should not be 
used based on a report of increased risk of tumour recurrence/progression associated with 
erythropoietin (26); 
• 
Chronic co-administration of cabozantinib with strong inducers of the cytochrome P450 
Family 3 Subfamily A Member 4 (CYP3A4) family (e.g. phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, 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; 

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• 
Caution must be used when discontinuing study 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. 
ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations and should be avoided. Grapefruit 
and Seville oranges may also increase plasma concentrations of cabozantinib and should 
be avoided. 
Additional information on potential drug interactions with cabozantinib is provided in 
Section 6.3.3. 
6.3.3 
Potential Interactions with Cabozantinib  
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) showed that 
clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect 
on the area under the curve (AUC) of co-administered rosiglitazone, a cytochrome P450 Family 
2 Subfamily C Member 8 (CYP2C8) substrate. Therefore, cabozantinib is not anticipated to 
markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit 
other cytochrome P450 (CYP450) isozymes that have lower [I]/Ki values compared to CYP2C8 
(i.e. cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9), cytochrome P450 Family 
2 Subfamily C Member 19 (CYP2C19), cytochrome P450 Family 2 Subfamily D Member 6 
(CYP2D6), cytochrome P450 Family 1 Subfamily A Member 2 (CYP1A2), and CYP3A4). In 
vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for 
possible induction of Cytochrome P450 Family 1 Subfamily A Member 1(CYP1A1) at high 
cabozantinib concentrations (30 μM). 
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, cytochrome P450 Family 2 Subfamily B Member 6 (CYP2B6), or 
CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 77% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Chronic co-administration of cabozantinib with strong 
inducers of the CYP3A4 family (e.g. phenytoin, carbamazepine, rifampin, rifabutin,rifapentin, 
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib concentrations. 
The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce 
CYP3A4 should be used with caution because these drugs have the potential to decrease 
exposure (AUC) to cabozantinib. Selection of alternate concomitant medications with no or 
minimal CYP3A4 enzyme induction potential is recommended. 
Results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 
38% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in 
healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 
family (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations. Grapefruit and Seville oranges may also 
increase plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 
inhibitors should be avoided and other drugs that inhibit CYP3A4 should be used with caution 
because these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection 
of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential 
is recommended. 

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Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and 
inhibitors 
of 
selected 
CYP450 
isozyme 
pathways 
(http://medicine.iupui.edu/clinpharm/ddis/table.aspx).  
 
Protein Binding: Cabozantinib is highly bound (≥99.7%) to human plasma proteins (for details 
see the SmPC document (11), section 5.2). Therefore, highly protein-bound drugs should be 
used with caution with cabozantinib because there is a potential displacement interaction that 
could increase free concentrations of cabozantinib and/or a co-administered highly protein-
bound drug (and a corresponding increase in pharmacologic effect). 
 
Multidrug resistance-associated protein 2 (MRP2) inhibitors: In vitro data demonstrate that 
cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may lead to 
increased plasma concentration of cabozantinib. 
 
Bile salt-sequestering agents: Bile salt-sequestering agents such as cholestyramine and 
cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) 
resulting in potentially decreased exposure (for details see the SmPC document (11), 
section 5.2). The clinical significance of these potential interactions is unknown. 
 
Effect of cabozantinib on other medicinal products: The effect of cabozantinib on the 
pharmacokinetics of contraceptive steroids has not been investigated. As unchanged 
contraceptive effect may not be guaranteed, an additional contraceptive method, such as a 
barrier method, is recommended (see Appendix 3). 
 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting 
recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be 
a substrate for P-glycoprotein, but it does appear to have the potential to inhibit the 
P-glycoprotein transport activity. Therefore, cabozantinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-glycoprotein. Subjects should be 
cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, 
dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, 
sitagliptin, talinolol, tolvaptan) while receiving cabozantinib. Additional details related to these 
overall conclusions can be found in the Investigator’s Brochure. 
Concomitant administration of proton pump inhibitor (PPI) esomeprazole resulted in no 
clinically-relevant effect on cabozantinib plasma pharmacokinetics in healthy subjects. 
Therefore, concomitant use of gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, 
and antacids) is not contraindicated in subjects administered cabozantinib. Additional details 
regarding potential drug interactions with cabozantinib can be found in the Investigator’s 
Brochure. 
6.4 
Lifestyle Restrictions/Recommendations 
In addition to the restrictions already presented in the exclusion criteria (see Section 4.2), 
subjects will also be requested to avoid the following from 48 hours prior to baseline and until 
discharge from the study: 
• 
Seville oranges (see Section 6.3.3); 
• 
grapefruit (see Section 6.3.3). 

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A complete list of allowed and prohibited or restricted concomitant medication is provided in 
Section 6.3.  
6.5 
Procedures for Monitoring Subject Compliance 
The Investigator will be responsible for monitoring subject compliance. Subjects may be 
withdrawn from the study at any time if the Investigator or Sponsor determines that the subject 
is not in compliance with the study protocol. 
Administration compliance will be assessed at the investigational site using drug dispensing 
and return records, progress notes about dose reductions/holds and subject interview. These 
data will not be directly recorded in the eCRF; rather, the eCRF will capture intervals of 
constant dose and reasons for changes in dose level (e.g. a new record completed each time 
dose level changes, including periods where no dose was taken, and the reason for a dose level 
change).  
Deviations below 80% of the scheduled amount of cabozantinib intake will be regarded as a 
major protocol deviation. 
Where a subject is consistently noncompliant with cabozantinib intake they should be 
discontinued from study treatment/withdrawn from the study (see Section 4.3). 

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7 
ASSESSMENT OF EFFICACY 
For the timing of efficacy assessments in this study, please refer to the schedule in Table 2. 
7.1 
Primary Efficacy Endpoint and Evaluation 
• 
Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1 evaluated by independent central review in cohort A.  
7.2 
Secondary Efficacy Endpoints and Evaluations 
• 
Time to response (TTR) per RECIST 1.1 evaluated by independent central review; 
• 
Duration of response (DOR) per RECIST 1.1 evaluated by independent central review; 
• 
Disease control rate (DCR) per RECIST 1.1 by independent central review; 
• 
Progression-free survival (PFS) per RECIST 1.1 by independent central review; 
• 
Objective response rate (ORR) in cohort B per RECIST 1.1 evaluated by independent 
central review; 
• 
Overall survival (OS); 
• 
ORR TTR, DOR, DCR and PFS per RECIST 1.1 according to local Investigator’s 
review; 
• 
Change in disease-related symptoms as assessed by the Functional Assessment of Cancer 
Therapy-Kidney Cancer Symptom Index (FKSI-DRS). 
The endpoints of ORR, TTR, DOR, DCR and PFS will be evaluated by tumour assessments 
(see Section 7.3.1). The OS will be assessed as described in Section 7.3.2.  
7.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data 
Methods for assessing efficacy data are described below. The timing of efficacy assessments is 
provided in Table 2. 
Procedures for recording efficacy data are discussed in Section 15.1 and the statistical methods 
to be used in the analysis of the efficacy endpoints are provided in Section 11.4.3. 
7.3.1 
Tumour Assessments 
Radiographic tumour assessments will include contrast tomography (CT) and/or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, pelvis (C/A/P), brain, and bone 
scintigraphy scans. The same imaging modalities used at the Screening visit should be used for 
subsequent tumour assessments. For subjects who have discontinued cabozantinib treatment 
before radiographic disease progression and who have not withdrawn consent, tumour 
assessment should be performed until radiographic progression is confirmed by the 
Investigator. (see Table 2 for schedule of assessments). 
Tumour assessments will determine the study endpoints of ORR, TTR, DOR, DCR, and PFS. 
The review of radiographic images will be conducted by a blinded, central IRC (Section 3.8) 
by batch using RECIST 1.1 (see IRC charter). All radiographic tumour assessments (both 
scheduled and unscheduled) must be sent to the IRC. Prior radiation history data will also be 
reviewed by the IRC for selection of target lesions. 
Radiographic response and disease progression according to Investigator’s assessment will also 
be assessed by the local Investigator using RECIST 1.1 (see Appendix 5) for subject 
management and treatment decisions. 
All CT/MRI scans (C/A/P, brain) and scintigraphy scans (bone) are recommended to be 
performed using the study-specified imaging protocol (refer to the most recent version of the 

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imaging manual). To ensure image consistency, the same imaging modalities and acquisition 
protocols used at the Screening visit should be used for subsequent tumour assessments.  
If any doubt or ambiguities exist about radiographic progression, the Investigator is encouraged 
to continue study therapy if the subject presents acceptable tolerance and repeat the 
radiographic studies at the next scheduled time, thus delaying the determination of progression 
until the findings indicating radiographic progression are unequivocal. Radiographic 
progression determined by the Investigator does not warrant discontinuation of tumour 
assessments or study treatment (see Section 5.2.2). 
7.3.2 
Overall Survival 
Overall survival will be assessed during the Post-treatment Follow-up period (Section 5.2.3.1) 
every 12 weeks (±15 days) until the end of the study (18 months after the last subject included 
in the study started cabozantinib treatment). 
Information on subsequent non-protocol anti-cancer therapies will also be collected at the same 
time as this assessment. 
7.3.3 
Health-related Quality of Life 
Health-related quality of life parameters will be assessed using the paper version of the 
FKSI-DRS tool during the investigational site visits at baseline and then every 
12 weeks beginning at Week 12 until the End of Study Treatment visit or Early Study 
Withdrawal visit.  
The FACIT and all related works are owned and copyrighted by, and the intellectual property 
of David Cella, Ph.D. Permission for use of the FKSI-DRS questionnaire was obtained by 
contacting Dr. Cella at information@facit.org. For the questionnaire, please refer to Appendix 
6 (25). 

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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time the subject gives informed consent and 
throughout the study treatment (see Section 3.6 for a definition of study duration) and will be 
assessed by direct, nonleading questioning. The Sponsor will be responsible for the collection, 
assessment and reporting of safety data.  
Further details for AE reporting can be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
refers to symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, ECG). In clinical studies, an AE 
can include an undesirable medical condition occurring at any time, including run in or washout 
periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study treatment (as defined in Section 3.6 and Section 5.6). 
Natural progression or deterioration of the locally advanced or metastatic RCC with a clear-cell 
component under study will be recorded as part of the efficacy evaluation and should not be 
recorded as an AE/SAE. 
Death due to disease progression will be recorded as part of the efficacy evaluation and will not 
be regarded as an SAE. 
Signs and symptoms should not be reported as AEs/SAEs if they are clearly related to a relapse 
or an expected change or progression of the clear-cell component RCC. 
These signs and symptoms should only be reported as AEs/SAEs (depending on the 
Investigator’s judgement) if they are: 
• 
Judged by the Investigator to be unusually severe or accelerated clear-cell component 
RCC, or 
• 
If the Investigator considers the deterioration of clear-cell component RCC signs and 
symptoms to be caused directly by the IMP. 
If there is any uncertainty about an AE being due solely to clear-cell component RCC, it should 
be reported as an AE/SAE as appropriate. 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
Adverse events will be recorded and graded according to the current version of the National 
Cancer Institute (NCI)-CTCAE version 5.0 (effective in April 2018). In view of meta-analyses 
and for conversion purposes, the following conversion mapping will apply if the NCI-CTCAE 
scale is not available for a given AE: 
• 
NCI-CTCAE Grade 1 corresponds to mild, 
• 
NCI-CTCAE Grade 2 corresponds to moderate, 
• 
NCI-CTCAE Grade 3 corresponds to severe, 
• 
NCI-CTCAE Grade 4 corresponds to life threatening/disabling (events qualify as SAEs), 
• 
NCI-CTCAE Grade 5 corresponds to death related to AE (events qualify as SAEs). 

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Where:  
• 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Moderate: minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) (Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.). 
• 
Severe: or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL (Self-care 
ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
• 
Life threatening: urgent intervention indicated (also see Section 8.1.4).  
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports include good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IMP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not related: reports include good reasons and sufficient information (e.g. implausible 
time sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/event in this study will be the 
current Investigator’s Brochure. 
8.1.2.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation); 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject; 
• 
They are considered as clinically significant by the Investigator. 
8.1.2.5 
Abnormal Physical Examination Findings 
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings (abnormalities) will be recorded as AEs.  
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings judged by the Investigator as clinically significant (e.g. ECG changes, 
thyroid function disturbances) that result in a change in study drug dosage or administration 
schedule, or in the discontinuation of the study drug, or require intervention or diagnostic 
evaluation to assess the risk to the subject, should be recorded as AEs.  
8.1.3 
Recording and Follow-up of Adverse Events 
All observed or self-reported AEs, regardless of suspected causal relationship to IMP, will be 
recorded on the AE page(s) of the eCRF. Events involving drug reactions, accidents, illnesses 

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with onset during the treatment phase of the study or exacerbations of pre-existing illnesses 
should be recorded according to the NCI terminology.  
Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment. 
For all AEs, the Investigator must pursue and obtain adequate information both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification of the Sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the 
AE (i.e. treatment with cabozantinib or other illness). The Investigator is required to assess 
causality and record that assessment on the eCRF. Causality assessment of AEs should include 
at minimum confounding factors such as disease and concomitant medications.  
Follow-up of the AE after the date of cabozantinib discontinuation is required until the event 
or its sequelae resolve or stabilise at a level acceptable to the Investigator and the Sponsor’s 
clinical monitor or his/her designated representative. 
During the follow-up period, any SAE that occur more than 30 days after the date of the last 
cabozantinib dose, assessed as related to study treatment or study procedures will also be 
collected and followed until resolution or stability according to the Investigator. 
 
Follow-up of SAEs/ Grade 3 and 4 AEs leading to study treatment discontinuation: 
All SAEs that are ongoing at 30 days or later after the date of the last dose of study treatment 
and AEs assessed NCI-CTCAE Grade 3 or 4 that led to study treatment discontinuation that are 
ongoing 30 days after the last dose of study treatment are to be followed until either: 
• 
the AE has resolved; 
• 
the AE has improved to Grade 2 or lower; 
• 
the Investigator determines that the event has become stable or irreversible; 
The status of all other AEs that are ongoing 30 days after the last dose will be documented as 
of the last study visit for the subject. 
 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below), regardless of suspected relationship to IMP, must be reported 
immediately (within 24 hours of the Investigator’s knowledge of the event) using the email 
specified at the beginning of this protocol. If the immediate report is submitted by telephone, 
this must be followed by detailed written reports using the SAE report form. 
An SAE is any AE that: 
(1) 
Results in death; 
(2) 
Is life-threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death; 
(3) 
Results in in-patient hospitalisation or prolongation of existing hospitalisation, excluding 
admission for social or administrative reasons (see below); 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions; 
(5) 
Results in congenital anomaly/birth defect in the offspring of a subject who received the 
IMP; 

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(6) 
Is an important medical event that may not immediately result in death, be 
life-threatening or require hospitalisation but may be considered an SAE when, based 
upon appropriate medical judgement, it may jeopardise the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in in-patient hospitalisation, or the development of drug dependency or drug abuse. 
A suspected or confirmed coronavirus COVID-19 (SARS-CoV-2) infection must be 
reported as serious (seriousness criteria should be “other medically important serious 
event” if no other seriousness criteria are present (e.g. hospitalisation)). 
In addition to the above criteria, any additional AE that the Investigator considers serious should 
be immediately reported to the Sponsor and included in the corporate SAEs database system. 
When reporting SAEs, the following additional points should be noted: 
• 
When the diagnosis of an SAE is known or suspected, the Investigator should report a 
diagnosis or a syndrome rather than individual signs or symptoms. Signs and symptoms 
may be described in the event description. The Investigator should also try to separate a 
primary AE considered as the foremost medical occurrence from secondary AEs which 
occurred as complications; 
• 
Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding death is unknown. Terms such as “Unexplained Death” or “Death from 
Unknown Origin” may be used when the cause is unknown. In these circumstances, the 
cause of death must be investigated, and the diagnosis amended when the origin has been 
identified. If an autopsy is performed, the autopsy report should be provided;  
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long-term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the anticipated/required stay in relation to the original reason that 
led to the initial admission, as determined by the Investigator or treating physician.  
• 
While most hospitalisations necessitate reporting of an SAE, some hospitalisations do 
not require SAE reporting, as follows: 
- 
For protocol-specified hospitalisation in clinical studies, prolongation is defined 
as any extension beyond the length of stay described in the protocol; 
- 
Prolongation in the absence of a precipitating, treatment-emergent, clinical AE 
(i.e. not associated with the development of a new AE or worsening of a 
pre-existing condition) may meet the criteria for seriousness but is not an adverse 
experience and thus is not subject to immediate reporting to the Sponsor;  
- 
Pre-planned or elective treatments/surgical procedures should be noted in the 
subject’s Screening documentation. Hospitalisation for a pre-planned or elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described above. 
If a new elective treatment/surgical procedure is required for a subject during their 
participation in the study the elective treatment/surgical procedure should be 
considered a SAE; 

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- 
Events that result in hospital stays of fewer than 24 hours and that do not require 
admission (e.g. an emergency room visit for haematuria that results in a diagnosis 
of cystitis and discharge to home on oral antibiotics); 
• 
SAEs must be reported for any surgical or procedural complication resulting in 
prolongation of hospitalisation. 
When reporting an SAE, the following information is the minimum that must be provided to 
the Sponsor for each SAE within 24 hours of its occurrence: 
• 
study number; 
• 
centre number; 
• 
subject number; 
• 
Investigator’s name and contact details. 
Additional information includes the reason why the event is considered to be serious (i.e. the 
seriousness criteria), the Investigator’s assessment of the relationship of the event to study 
treatment, medications or other therapeutic measures used to treat the event, action taken with 
the study treatment because of the event, and the outcome/resolution of the event, which will 
be recorded on the SAE form.  
The additional information included in the SAE form must be provided to the Sponsor or 
representative as soon as it is available. The Investigator should always provide an assessment 
of causality for each event reported to the Sponsor. Upon receipt of the initial report, the 
Sponsor will ask for the Investigator’s causality assessment if it was not provided with the initial 
report. 
The Investigator must also report: 
• 
All SAEs that occur after informed consent and through 30 days after the date of the last 
cabozantinib dose (or the date the subject is deemed to be a screen failure). This 
information must be recorded on the AE page of the eCRF; 
• 
Any SAEs assessed as related to study treatment or study procedures. 
During the follow-up period, any SAE with a suspected causal relationship to cabozantinib 
administration occurring at any other time after completion of the study treatment (Section 5.6) 
must be reported promptly to the sponsor, within 24 hours. 
 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has interfered 
with a contraceptive method. If pregnancy occurs during the study, the outcome of the 
pregnancy will be collected and it will be necessary to discontinue administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the eCRF and should 
be reported to the Sponsor as an SAE. The Sponsor will request further information from the 
Investigator as to the course and outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form, which will be provided to the investigational sites upon request. 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. 
The Investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the study. The Investigator should counsel the subject, discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus. Monitoring of the 
subject should continue until conclusion of the pregnancy, which may involve follow-up after 
the subject’s involvement in the study has ended. 

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Pregnancies with a conception date within 120 days after the subject’s last dose of cabozantinib 
must also be reported to the Investigator for onward reporting to the Sponsor. 
Use of medically accepted methods of contraception is very important during the study and for 
4 months after study treatment. If a subject becomes pregnant during the study, she will be 
taken off study treatment. She will be followed through the end of her pregnancy and the infant 
should have a follow-up of at least 6 months after birth. If the Investigator becomes aware that 
the partner of a subject participating in the study is pregnant, this should be reported to the 
Sponsor. After the partner has given written consent, she should be counselled and followed as 
described above. Monitoring of the partner should continue until the end of the pregnancy. 
Abnormal pregnancy outcome/AE in foetus/neonate/child 
If there is an abnormal pregnancy outcome or an AE is reported in the foetus/neonate/child 
following exposure to cabozantinib, an attempt must be made to follow-up until one month after 
delivery. The information will be collected in the Clinica1.l Study SAE Report Form (080478-
FOR) for the mother and for the foetus/neonate/child. 
8.1.6 
Study Medication Errors 
Medication errors are defined as the administration of study drug medication outside or above 
the established dosing regimens specified in the protocol. 
Any overdose or study medication error that results in an AE or SAE (excluding missed doses) 
requires reporting within 24 hours to the Sponsor or designee.  
Any AEs or SAEs that occur as a result of an overdose have to be treated according to clinical 
standard practice. Please refer to the Investigator’s Brochure for additional management 
recommendations for an overdose of cabozantinib. 
8.1.7 
Deaths 
The convention for recording death is as follows:  
• 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, MI); 
• 
Outcome: fatal. 
For AEs leading to death, the NCI-CTCAE Grade 5 is the only appropriate grade (see 
Section 8.1.2.1). Deaths that cannot be attributed to an NCI-CTCAE term associated with 
Grade 5 or that cannot be reported within an NCI-CTCAE category as ‘Other’ have to be 
reported as one of these four AE options: 
• 
death not otherwise specified (NOS); 
• 
disease progression NOS; 
• 
multi-organ failure; 
• 
sudden death. 
8.1.8 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to cabozantinib or other reasons (see 
Section 4.3). 
If cabozantinib treatment is discontinued due to an AE or a clinically significant laboratory test 
abnormality, it must be reported immediately to the Sponsor’s designated representative. 
Monitoring will continue until the event has resolved or stabilised, until the subject is referred 
to a local health care professional, or until the determination of a cause unrelated to cabozantinib 
or study procedure is made. The specific AE or test result(s) must be recorded on the eCRF. In 

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all cases, the Investigator must ensure that the subject receives appropriate medical follow-up 
(see Section 8.1.3). 
8.1.9 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The Sponsor will ensure that processes are in place for the submission of reports of suspected 
unexpected serious adverse reactions (SUSARs) occurring during the study to the competent 
authorities, IECs and other Investigators concerned by the IMP. Reporting will be in accordance 
with the applicable regulatory requirements. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected at the frequency indicated in Table 2 for the 
evaluation of haematology, blood biochemistry, urinalysis, pregnancy tests and other clinical 
laboratory tests as safety measurements. A list of all laboratory analyses that will be measured 
in this study is provided in Table 5. 
All laboratory tests to establish eligibility must be done within 15 days prior to baseline 
(Table 2).  
All laboratory analyses will be performed and analysed by the local laboratory, including 
samples that are obtained at unscheduled visits whenever possible. All local laboratory results 
will be recorded on the eCRF and provided by the Investigator. The Investigator will review 
the safety laboratory test results, document the review and record any clinically relevant 
changes occurring or observed during the study in the AE section of the eCRF (see 
Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs). 
On days when a blood sample is collected, subjects must fast overnight (consumption of water 
is allowed).  
Abnormalities in any clinical laboratory test (including tests not required per protocol) that lead 
to a change in subject management (e.g. dose withheld or reduced, study treatment 
discontinued; requirement for additional medication or monitoring) are considered clinically 
significant for the purposes of this study and should be reported as AEs. If laboratory values 
constitute part of an event that meets criteria defining it as serious, the event (and associated 
laboratory values) must be reported as an SAE (see Section 8.1.4). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline levels or to a level deemed acceptable by the 
Investigator or until the abnormality is explained by an appropriate diagnosis.  

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Table 5      Laboratory Assessments 
Haematology  
- White blood cells with 
differential count (absolute 
neutrophil count (ANC), 
basophils, eosinophils, 
lymphocytes and monocytes  
- Haematocrit 
- Platelet count 
- Red blood cell count 
- Haemoglobin 
 
Coagulation  
- Prothrombin time/International 
normalised ratio (INR) 
- Partial thromboplastin time 
(PTT) 
 
Thyroid function  
- Thyroid-stimulating hormone 
(TSH)  
- Free Thyroxine 4 (FT4)  
Blood Chemistry  
- Albumin 
- Total alkaline phosphatase (ALP) 
- Alanine aminotransferase (ALT) 
- Aspartate aminotransferase (AST) 
- Blood urea nitrogen (BUN) 
- Chloride 
- Creatinine (estimation of creatinine 
clearance by Cockcroft and Gault)  
- γ-glutamyl transpeptidase (GGT) 
- Glucose 
- Potassium 
- Sodium 
- Corrected calcium 
- Total bilirubin (conjugated and 
unconjugated if total bilirubin is 
elevated) 
- Total protein 
 
Pregnancy Blood/Urine 
Test 
- β-human chorionic 
gonadotrophin (β-HCG) 
 
Urinalysis (Dipstick or 
Routine) a 
- pH 
- Protein 
- Glucose 
- Blood  
Microscopic Urine 
Examination a 
- At the discretion of the 
Investigator based on results 
or routine urinalysis or as 
clinically indicated 
 
Urine Chemistry (at the 
discretion of the Investigator 
and based on results of 
routine urinalysis or as 
clinically indicated) a 
- 24-hour urine protein or 
urine protein-to-creatinine 
ratio (UPCR) 
a Fresh urine samples will be collected to perform these assessments. 
8.2.1 
Pregnancy Test 
A β-HCG serum test and/or an HCG urine test will be performed for all female subjects of 
childbearing potential within 7 days prior to the baseline visit and at every visit thereafter up to 
the End of Study Treatment or Early Study Withdrawal visit (Table 2). Any subject becoming 
pregnant during the study will be withdrawn from the study. All pregnancies that occur during 
the study are to be reported as described in Section 8.1.5. 
8.3 
Physical Examination 
Physical examinations will be conducted as indicated in Table 2 as a safety measure. This 
assessment will include height (Screening visit only), weight, performance status, and an 
evaluation of the following systems: skin, head, eyes, ears, nose, throat, respiratory system, 
cardiovascular system, GI system, neurological condition, blood and lymphatic systems, and 
the musculoskeletal system.  
The ECOG performance status of the subject will be assessed at each scheduled safety 
assessment starting at screening (see reference table in Appendix 7). 
Any ongoing/intercurrent condition prior to first dose should be recorded in source documents 
and on the eCRF. 
Any clinically significant physical examination findings (abnormalities) observed during the 
treatment period will be reported as AEs. Any physical examination findings (abnormalities) 
persisting at the end of the treatment period will be followed by the Investigator until resolution 
or until reaching a clinically stable endpoint. 

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8.4 
Vital Signs 
Vital signs (BP and heart rate) will be assessed as indicated in Table 2 as safety measures. These 
assessments will be conducted with an automated device so that measurements are independent 
of the observer. Measurements of BP and heart rate will be performed after a 5-minute rest in 
sitting position and after standing up for 1 minute. Absolute values and change from baseline 
will be analysed. Any clinically significant abnormalities in the vital signs will be reported as 
an AE. 
8.5 
Electrocardiography 
Electrocardiography analyses will be conducted as indicated in Table 2 as a safety evaluation 
in this study.  
The ECGs will be recorded at the Screening visit, baseline and Week 4 (Visit 4). After the first 
8 weeks of study treatment, ECGs will be recorded at every 12 weeks up to the End of Study 
Treatment/Early Study Withdrawal visit. 
Twelve-lead ECGs will be recorded so that the different ECG intervals (RR, PR, QRS, QT 
intervals) can be measured automatically. The ECG will be recorded using a local ECG reader.  
Any clinically significant abnormalities will be recorded as AEs. 

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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics and pharmacodynamics will not be assessed in this study. 

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10 
EXPLORATORY BIOMARKERS  
Not applicable. 

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11 
STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in the statistical analysis plan (SAP), which will be dated and approved 
before the first subject is included. The SAP may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint and/or its analysis will also be 
reflected in a protocol amendment. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® 
(version 9.4 or higher). 
11.1 
Analysis Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent). 
• 
Included population: All subjects screened who fulfilled the inclusion and exclusion 
criteria.  
• 
Safety population: All included subjects who received at least one dose of study 
medication. 
• 
Efficacy population: All included subjects who received at least one dose of study 
medication and provided a baseline assessment for the tumour according to RECIST 1.1. 
• 
Per protocol (PP) population: All subjects in the efficacy population who have no 
impacting major protocol deviations (i.e. that could potentially affect the primary 
efficacy endpoint outcome for the subject) as described in the protocol deviations 
document. 
11.1.1 
Populations Analysed 
Analyses based on the primary and secondary efficacy endpoints will be performed on the 
efficacy population in each cohort separately.  
Sensitivity efficacy analyses will be based on PP population. Efficacy analyses in the PP 
population will be presented if there is a difference greater than 15% between efficacy 
population and PP population. 
The analyses of safety data will be performed based on the safety population in each cohort 
separately and overall. 
11.1.2 
Protocol Deviations 
Any major protocol deviation (see Section 13.1.2 for definition) will be described and its impact 
on inclusion in each analysis population (efficacy, PP and safety populations) for any subject 
will be specified. The final list of protocol deviations impacting the safety, efficacy and PP 
populations will be reviewed prior to database lock. The list may be updated, up to the point of 
database lock, to include any additional major protocol deviations impacting inclusion in the 
analyses populations. 
11.2 
Sample Size Determination 
For cohort A, the hypothesis for sample size computation is that cabozantinib will demonstrate 
a clinically significant increase in the response rate as compared to historical control in 2nd line 
treatment. A therapy will be considered clinically meaningful if it provides a significant benefit 
in ORR as assessed by independent central review over a standard rate of 10% (conservative 
threshold in reference to the response rate of everolimus in the METEOR study (12), exact 
95% CI: 1.7-5.9). Assuming approximately 7% non-evaluable subjects (i.e. subjects who 
received at least one dose of study medication but did not provide a baseline for the tumour 

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according to RECIST 1.1), 74 subjects in cohort A provides at least 80% power (at one-sided 
significance level (alpha) of 0.025) to reject the null hypothesis of 10% ORR in favour of an 
alternative hypothesis of 23% ORR.  
For cohort B, no formal sample size determination was performed as the enrolment will stop 
when the recruitment in cohort A will be reached. We anticipate approximately 40 subjects 
recruited in cohort B.  
11.3 
Significance Testing and Estimations 
ORR (primary endpoint) will be tested at the final analysis as described above using the one-
sided significance level (alpha) of 0.025. No statistical testing will be carried out at the interim 
analysis nor for secondary efficacy and safety endpoints. 
11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external contract research organisation (CRO), 
managed by the Sponsor’s biometry department. 
11.4.1 
Demographic and Other Baseline Characteristics 
Descriptive summary statistics (n, mean, standard deviation, median, minimum, maximum) or 
frequency counts of demographic and baseline data (medical history, concomitant disease and 
other assessments performed at the Screening visit) will be presented by cohort and overall for 
the safety population. 
11.4.2 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects in the screened, included, safety, efficacy and PP 
populations will be tabulated by cohort and overall. The reasons for subject exclusions from 
each of the populations will also be tabulated. In addition, the numbers of subjects who were 
screened, screened failed, treated, discontinued and completed each of the study periods (pre-
treatment period, treatment period, post-treatment follow-up period) will be tabulated by cohort 
and overall. Primary reasons for discontinuation of study treatment will be tabulated. 
11.4.3 
 Efficacy Evaluation 
11.4.3.1 Primary Efficacy Endpoint  
In line with the primary endpoint indicated in Section 7.1 (see also Appendix 5), the primary 
efficacy endpoint is: 
• 
Objective response rate (ORR) defined as the proportion of subjects who achieved a 
partial response (PR) or complete response (CR) at any timepoint as determined by 
independent central review per Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1 in cohort A.  
Details regarding the independent central review will be documented in the IRC charter 
finalised prior to the enrolment of the first subject. 
 
Below is the definition of the estimand used for the primary efficacy endpoint: 
Treatment: Cabozantinib 
Population: Subjects with unresectable, locally, advanced or metastatic RCC with a clear-cell 
component who progressed after prior CPI therapy with ipilimumab and nivolumab in 
combination (Cohort A). 
Endpoint: ORR defined as the proportion of PR and CR at any timepoint during treatment 
period as determined by independent central review per RECIST1.1. 

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Intercurrent events: 
•  
Study discontinuation without response (i.e. without PR or CR) during the treatment 
period (composite strategy) 
Subjects withdrawn from the study without response during the treatment period or subjects 
without any post-baseline tumour assessment are non-responders. 
•  
Treatment discontinuation prior to RECIST 1.1. progression (treatment policy strategy) 
The efficacy assessment at any timepoint prior to RECIST 1.1. progression is used regardless 
of whether the Cabozantinib is discontinued. 
•  
Subjects not treated (while on treatment strategy) 
Subjects will not be included in the primary efficacy analysis. 
•  
Subjects receiving non-protocol anti-cancer treatment (while on treatment strategy) 
Assessment of the response during the treatment period, i.e. until the initiation of non-protocol 
anti-cancer treatment. 
Population-level summary: ORR compared to the historical control value of 10%. 
 
11.4.3.2 Secondary Efficacy Endpoints  
In line with the secondary endpoints indicated in Section 7.2 (see also Appendix 5), the 
secondary efficacy endpoints are: 
• 
Time to response (TTR) defined as the time from start of study treatment to the date of 
first evidence of response (PR or CR as determined by independent central review per 
RECIST 1.1); 
• 
Duration of response (DOR) defined as the time from first documented response (PR or 
CR as determined by independent central review per RECIST 1.1) to either disease 
progression (as determined by independent central review per RECIST 1.1) or death due 
to any cause, whichever occurs first. Censoring rules will be similar to those applied for 
progression-free survival (PFS); 
• 
Disease control rate (DCR), defined as the proportion of subjects who achieved a PR, 
CR or SD as determined by independent central review per RECIST 1.1; 
• 
PFS defined as the time from start of study treatment to either disease progression (as 
determined by independent central review per RECIST 1.1) or death due to any cause, 
whichever occurs first; 
• 
Objective response rate (ORR) in cohort B defined as the proportion of subjects who 
achieved a partial response (PR) or complete response (CR) at any timepoint as 
determined by independent central review per RECIST 1.1; 
• 
Overall survival (OS) defined as the time from the start of treatment until death due to 
any cause; 
• 
ORR, TTR, DOR, DCR and PFS according to local Investigator’s review per 
RECIST 1.1; 
• 
Change in disease-related symptoms as assessed by the Functional Assessment of Cancer 
Therapy-Kidney Cancer Symptom Index (FKSI-DRS).  
All these secondary endpoints will be presented in each cohort separately. In addition, ORR 
and PFS according to local Investigator's review per RECIST 1.1 as well as OS will be 
presented in the overall population (cohort A + cohort B). 

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Below is the definition of the estimand used for the secondary efficacy endpoint of duration of 
response: 
Treatment: Cabozantinib 
Population: Subjects with unresectable, locally, advanced or metastatic RCC with a clear-cell 
component who progressed after prior CPI therapy with ipilimumab and nivolumab in 
combination (Cohort A) with a PR or CR at any timepoint during the treatment period. 
Endpoint: DOR defined as the time from first documented response (PR or CR as determined 
by independent central review per RECIST 1.1) to either disease progression (as determined by 
independent central review per RECIST 1.1) or death due to any cause, whichever occurs first. 
Intercurrent events: 
•  
Two or more missing scheduled tumour assessment prior to RECIST 1.1. progression 
(while on treatment strategy) 
Subjects will be censored at the date of the last tumour assessment prior to the missing 
assessment. 
•  
Subjects not treated (while on treatment strategy) 
Subjects will not be included in the efficacy analysis. 
•  
Subjects receiving non-protocol anti-cancer treatment prior to RECIST 1.1 progression 
(while on treatment strategy) 
Subjects will be censored at the date of the last tumour assessment prior to the initiation of non-
protocol anti-cancer treatment. 
•  
Treatment discontinuation prior to RECIST 1.1. progression (treatment policy strategy) 
Subjects will be censored at the date of the last tumour assessment. 
•  
Treatment discontinuation without any post-baseline tumour assessment (treatment 
policy strategy) after the first response to treatment 
Subjects will be censored at the time of first documented response. 
Population-level summary: median of DOR 2-sided 95% with CI. 
 
11.4.3.3 Primary Efficacy Endpoint Analysis 
The ORR as assessed by independent central review will be estimated in Cohort A and tested 
versus the threshold of 10% using a one-sample exact test for binomial distribution. A higher 
response rate over 10% will be considered statistically significant if the p-value for the one-
sided test is less than 0.025.  
The ORR estimates will be presented in statistical tables with their associated 2-sided 95% CIs 
using Clopper-Pearson exact method.  
11.4.3.4 Secondary Efficacy Endpoint Analyses 
The ORR according to Investigator’s assessment (cohort A and cohort B) and by independent 
central review (cohort B) will be presented with their associated 2-sided 95% CIs using 
Clopper-Pearson exact method. Discordance in ORR assessed by independent central review 
and by Investigator will be described.  
DCR estimates will be presented in statistical tables with associated 2-sided 95% CIs. 
Time-to-event endpoints (TTR, DOR, PFS and OS) will be analysed using the Kaplan-Meier 
method. The results will be presented for each Cohort A and B both in summary tables and 
graphically in Kaplan-Meier plots. Kaplan-Meier methodology will be used to characterise the 

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distribution of endpoints. Median durations and associated 2-sided 95% CIs will be provided. 
Event rates at timepoints from either first dose of study treatment or first documented response 
will also be estimated with associated 2-sided 95% CIs. 
General censoring rules for the analysis of PFS are described below: 
• 
Subjects who receive non-protocol anti-cancer therapy (NPACT) after start of 
cabozantinib and before experiencing an event will be right censored at the date of the 
last tumour assessment prior to the date of initiation of subsequent therapy; 
• 
Subjects who have not experienced an event (and are not otherwise censored) at the time 
of data cut-off will be right censored on the date of their last tumour assessment; 
• 
Subjects who miss two or more scheduled tumour assessments followed by an event will 
be right censored on the date of their most-recent tumour assessment prior to the missing 
assessments. 
Additional supportive analyses of PFS will be defined in the SAP using alternative event 
definitions and censoring schemes to account for partial or completely missing assessments, 
address bias due to tumour assessment timing, evaluate the impact of potentially informative 
censoring, and to address potential discrepancies between the documentation of progression per 
the Investigator and per the independent central review. 
For the 9-item subset of disease related symptoms of the FKSI-DRS, the total score will be 
calculated using the number of subjects having a baseline and at least one post-baseline 
completion score. Completion score will be defined as answering at least 5 of 9 items. 
Descriptive statistics will be performed at each timepoint and change from baseline. 
Comparisons between baseline and post-baseline scores will be performed using paired Student 
t-tests. The proportion of subjects with at least an increase of 1 point from baseline will also be 
reported. 
11.4.4 
Safety Evaluation 
The safety endpoints are indicated in Section 3.2.3. 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population in each cohort separately and overall. 
The number of subjects experiencing dose reduction, delay, and/or discontinuation due to an 
AE will be provided. 
All AEs will be coded according to the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and will be classified by PT and SOC. AEs will be graded 
according to the NCI-CTCAE. The incidence of all reported treatment-emergent AEs (TEAEs) 
and SAEs will be tabulated by cohort and overall.  
A TEAE is defined as any AE that occurs after first dose of study drug if: 
• 
it was not present prior to receiving the first dose of study drug, or 
• 
it was present prior to receiving the first dose of study drug but the intensity increased 
during the active phase of the study. 
The focus of analysis for this study will be the duration of the treatment period and 30 days 
after the date of last study drug administration. 
In addition, summary tables will be presented by Grade 3 or 4, worst reported severity, drug 
relationship and TEAEs associated with premature withdrawal or dose modification of study 
medication. 
Subject deaths will be summarised, and primary cause of death will be reported by PT and SOC 
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Adverse event listings will be presented by subject, SOC and PT. All TEAEs will be flagged in 
the AEs listings. 
Summary statistics (mean, median, standard deviation and range as appropriate) of values and 
changes or shifts from baseline will be presented by cohort and overall for vital signs, ECG 
variables and clinical laboratory tests at each assessment. For laboratory data, abnormal values 
will be flagged in the data listings and a list of clinically significant abnormal values will be 
presented. 
Concomitant medications will be standardised using the World Health Organization drug 
dictionary and summarised by anatomic therapeutic class (ATS) and preferred name. 
11.5 
Subgroup Analyses 
Subgroup analyses will be conducted by presenting the primary analysis of ORR (with point 
estimates and 95% CIs) for both independent central review and Investigator’s assessment in 
the following subgroups: 
• 
Age (<65 years, ≥65 years); 
• 
Gender (female, male); 
• 
MSKCC Risk Factors (favourable [0], intermediate [1], poor [2 or more]); 
• 
Heng criteria (favourable [0], intermediate [1-2], poor [3-6]); 
• 
Number of organs with metastases (1, 2, ≥3); 
• 
ECOG (0, 1); 
• 
Treatment duration on 1st anti-cancer therapy (<6 months, ≥6 months); 
11.6 
Interim Analyses 
An interim and purely descriptive analysis will be conducted when 80% of the subjects (i.e. 59 
subjects) of cohort A will be treated for at least 3 months. Both cohorts will be analysed at this 
cut-off date. The aim of this interim analysis is to describe the baseline characteristics, 
demographics, ORR as assessed by the Investigator at 3 months and any further efficacy 
parameters measured at the Month 3 visit. Further details will be provided in the SAP. The 
results of this interim analysis will not have any impact on the study conduct.  A final analysis 
based on the primary endpoint (ORR) will be performed 12 months after the last subject 
received the first cabozantinib administration. 
A follow-up analysis based on OS will be conducted 18 months after the last subject received 
the first cabozantinib administration. 
The statistical testing will be carried out at the final analysis. 
 

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12 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
Authorised personnel from external competent authorities (CAs) and Quality Assurance 
personnel authorised by the Sponsor may carry out inspections and audits. The purpose of an 
audit is to ensure that ethical, regulatory and quality requirements are fulfilled in all studies 
performed by the Sponsor. 
Auditors and inspectors must have direct access to study documents and investigational site 
facilities as specified in Section 13.4 and to any other locations involved in the study (e.g. 
laboratories). 
In the event of the investigational site being notified directly for a regulatory inspection, the 
Investigator must notify the Sponsor’s representative as soon as possible to assist with the 
preparations for the inspection. 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Protocol Amendments and Protocol Deviations 
13.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favourable opinion by the IEC/IRB, except when necessary to eliminate immediate 
safety concerns for the subjects or when the change involves only logistics or administration.  
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
• 
Non-substantial amendments are those that are not considered ‘substantial’ 
(e.g. administrative changes) and as such only need to be notified to the IECs or 
regulatory authorities for information purposes. 
• 
Substantial amendments are those considered ‘substantial’ to the conduct of the clinical 
study and are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects; 
- 
the scientific value of the study; 
- 
the conduct or management of the study;  
- 
the quality or safety of the study drug used in the study. 
Substantial amendments must be submitted to and approved by the IECs and relevant 
regulatory authorities, according to local regulations, prior to implementing changes. 
• 
Urgent amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
Sponsor with subsequent notification of the IECs and regulatory authorities. 
The principal Investigator and the Sponsor will sign all protocol amendments. 
13.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the Sponsor or Sponsor’s 
representative. 
A major protocol deviation is any significant divergence from the protocol, i.e. nonadherence 
on the part of the subject, the Investigator or the Sponsor to the protocol’s specific 
inclusion/exclusion criteria, primary objective evaluation criteria and/or GCP guidelines. 
Generally, a protocol deviation qualifies as major if: 
(1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject; 
(2) 
The deviation compromises the scientific integrity of the data collected in the study; 
(3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies or procedures on the part of the Investigator(s); 
(4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies or procedures; 
(5) 
The deviation is inconsistent with the Sponsor’s research, medical and/or ethical 
principles. 
See also Section 11.1.2 for details on the impact of major protocol deviations on the inclusion 
of subjects in each analysis population. 
A minor protocol deviation is any significant divergence from the protocol that does not impact 
the study results. 

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As a matter of policy, the Sponsor will not grant exceptions to protocol-specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is considered 
ethically, medically and scientifically justified for a particular subject, prior approval from the 
Sponsor and the responsible IRB/IEC, in accordance with the Standard Operating Procedure 
(SOP), is required before the subject is allowed to enter the study. If personnel from the 
investigation centre learns that a subject who did not meet protocol eligibility criteria was 
included in the study (protocol violation), they must immediately inform the Sponsor. Such 
subjects will be discontinued from the study, except in an exceptional instance following review 
and written approval by the Sponsor and the responsible IRB/IEC and according to the 
applicable SOP. The participation of these subjects in the study will be discussed between 
Sponsor and Investigator, taking into account subject safety and data reliability. The IRB/IEC 
will be informed if subject safety/protection is inadvertently affected. 
13.2 
Information to Study Personnel 
To ensure accurate, complete and reliable data, the Sponsor or its representatives will provide 
instructional material to the investigational sites, as appropriate. A study initiation visit will be 
conducted prior to the Screening visit to instruct the Investigators and study coordinators. This 
session will comprise instructions on the protocol, completion of the eCRF and all study-related 
procedures. The Investigator is responsible for providing information about the study to all staff 
members involved in the study or any element of subject management, both before starting any 
study procedures and during the course of the study (e.g. when new staff is involved). The 
Investigator must assure that all study staff members are qualified (education, experience and 
training) to perform their specific responsibilities. These study staff members must be listed on 
the study centre authorisation form, which includes a clear description of the responsibilities of 
each staff member. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
Investigator and for ensuring their compliance with the protocol. Additional information will 
be made available when new staff becomes involved in the study and as agreed with either the 
Investigator or the study monitor. 
13.3 
Study Monitoring 
The Investigator is responsible for the validity of all data collected at the investigational site. 
The Sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
the subjects are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP guidelines and regulatory 
requirements. 
Sponsor-assigned monitors will conduct regular investigational site visits. The Investigator will 
allow direct access to all relevant files (for all subjects) and clinical study supplies (dispensing 
and storage areas) for the verification of entries made in the eCRF and will assist with the 
monitor’s activities, if requested. Adequate time and space for monitoring visits should be made 
available by the Investigator. 
The investigational site must complete the eCRFs on an ongoing basis to allow regular review 
by the study monitor, both remotely (internet) and during investigational site visits. The 
Sponsor’s central study monitor will use functions of the electronic data capture (EDC) system 
to address any queries raised while reviewing the data entered by the investigational site 
personnel in a timely manner. 

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Whenever a subject’s name is revealed on a document required by the Sponsor (e.g. laboratory 
printouts) the name must be blacked out permanently by the investigational site personnel and 
annotated with the subject’s number as identification. 
A Steering Committee will be composed of Investigator and Sponsor representatives to 
supervise the overall scientific and operational management of the study.  
13.4 
Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP guidelines. This 
includes that the study may be audited at any time by a quality assurance personnel designated 
by the Sponsor or inspected by regulatory bodies. The Investigator must adhere to ICH GCP 
guidelines in addition to any applicable local regulations. 
If requested, the Investigator will provide the Sponsor, applicable regulatory agencies and 
applicable EC with direct access to any original source documents. 
The Investigator should demonstrate due diligence in the recruitment and screening of potential 
study subjects. The enrolment rate should be sufficient to complete the study as agreed with the 
Sponsor. The Sponsor should be notified of any projected delays that may impact the 
completion of the study. 
This clinical trial will be conducted in compliance with all international laws and regulations 
and national laws and regulations of the country(ies) in which the clinical trial is performed, as 
well as any applicable guidelines. 
13.5 
Audit and Inspection 
Authorised personnel from external CAs and Quality Assurance personnel authorised by the 
Sponsor may carry out inspections and audits (see Section 12). 
13.6 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the Investigator by the monitor for 
clarification/correction. The Investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 

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14 
ETHICS 
14.1 
Compliance with Good Clinical Practice (GCP) and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, the 
Declaration of Helsinki and ICH GCP guidelines.  
In addition, this study will adhere to all local regulatory requirements.  
Before initiating the study, the Investigator/institution should receive written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, cards with study contact in case of subject 
emergency, subject recruitment procedures (e.g. advertisements), any written information to be 
provided to subjects and a statement from the IEC/IRB showing that they comply with GCP 
requirements. The IEC/IRB approval must identify the protocol version as well as the 
documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval must be sought prior to implementation. Ethical approval 
on administrative changes will be obtained if required by the local/investigational site IEC/IRB. 
14.2 
Informed Consent for Participation in the Study 
Prior to screening, the Investigator or a person designated by the Investigator will explain the 
nature, purpose, benefits and risks of participation in the study to each subject, subject’s legally 
acceptable representative or impartial witness. Written informed consent must be obtained 
before to the subject enters the study (before initiation of any study-related procedure and 
administration of cabozantinib). Sufficient time will be given to discuss any questions raised 
by the subject. 
The Sponsor will provide a sample informed consent form. The final version-controlled form 
must be agreed to by the Sponsor and the IEC/IRB and must contain all elements included in 
the sample form, in language readily understandable by the subject. The Investigator will keep 
each subject’s original consent form, personally signed and dated by the subject or subject’s 
legally acceptable representative and by the person who conducted the informed consent 
discussion. The Investigator will provide a copy of their signed informed consent form to each 
subject. 
The informed consent form may need to be revised during the study should important new 
information become available that may be relevant to the subject’s safety or as a result of 
protocol amendments. In this instance, approval should always be given by the IEC/IRB. It is 
the Investigator’s responsibility to ensure that all subjects subsequently entered into the study 
and those currently in the study sign the amended form. This is documented in the same way as 
described above. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The Investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 

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14.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the Sponsor’s Regulatory Affairs group will ensure that all 
legal regulatory aspects are covered and obtain approval of the appropriate regulatory bodies, 
prior to study initiation in regions where an approval is required. 
The following documents should be submitted to the relevant EC for review and approval to 
conduct the study (this list may not be exhaustive): 
• 
protocol/amendment(s) approved by the Sponsor; 
• 
currently applicable Investigator’s Brochure or package labelling; 
• 
relevant Investigator’s curriculum vitae; 
• 
subject information and informed consent document(s) and form(s); 
• 
cards with study contact in case of subject emergency; 
• 
recruitment procedures/materials (advertisements), if any. 
The EC(s) will review all submission documents as required and a written favourable opinion 
for the conduct of the study should be made available to the Investigator before initiating the 
study. These documents must be dated, clearly identify the version number(s) and date(s) of the 
documents submitted/reviewed and include a statement from the EC showing that they comply 
with GCP requirements. 
The study may begin at the investigational site(s) only after receiving this dated and signed 
documentation containing the EC approval or favourable opinion. 
During the study, any update to the following documents will be sent to the EC, either for 
information or review and approval, depending on how substantial the modifications are: 
(1) Investigator’s Brochure; (2) reports of SAEs; (3) all protocol amendments and revised 
informed consent(s), if any. 
At the end of the study, the EC will be notified about study completion. 
14.4 
Confidentiality Regarding Study Subjects 
The Investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the Sponsor, subjects will be identified not by their 
names but by an identification code (e.g. identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons on 
behalf of the Sponsor, the quality assurance unit or regulatory authorities. Personal medical 
information will always be treated as confidential. 

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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Recording of Study Data 
The Investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest the accuracy and completeness of all data. If any changes are made to the 
eCRF after a form has been locked and electronically signed, the Investigator will be required 
to perform an additional e-signature to show agreement with any new information or changes 
to the eCRF. 
All corrections on the eCRF will be automatically tracked and the reason for the change is 
always required. In the eCRF, the audit trail function will make visible the changes made to 
each included item. 
15.2 
Data Management 
The EDC system will be utilised for collecting subject data. Each investigational site is required 
to have a computer and internet connection available for local clinical data entry. All entries in 
the eCRF will be made under the e-signature of the person performing the action. This electronic 
signature consists of an individual and confidential username and password combination. It is 
declared to be the legally binding equivalent of the handwritten signature. Only Sponsor-
authorised users will have access to the eCRF as appropriate to their study responsibilities. Users 
must have successfully undergone software application training prior to entering data into the 
eCRF. 
Data management will be conducted either by a CRO directed by the Sponsor’s data management 
department or by the Sponsor’s data management department. All data management procedures 
will be completed in accordance with the Sponsor and the SOPs of the contracted CRO. Prior to 
data being received in-house by the assigned CRO, they will be monitored at the investigational 
site (for further details see Section 13.3). The eCRF and other data documentation removed from 
the investigational site(s) will be tracked by the CRO and the monitor. 
The Sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and suitable queries are raised to resolve any missing or inconsistent data. The Investigator will 
receive data from the clinical study in an electronic format (PDF files), which will be an exact 
copy of the eCRF, and will include the full audit trail for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central study 
monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the Sponsor’s pharmacovigilance department (and vice-versa).  
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by the contracted CRO/a CRO directed by the Sponsor’s Biometry Group 
and reviewed and approved by the Sponsor. Prior and ongoing medications started before the 
study and concomitant medications (started at the time of cabozantinib administration) will be 
coded using World Health Organization Drug (WHODRUG) and AEs/medical history terms 
will be coded using MedDRA. 
Only data from included subjects will be reported in the eCRFs and collected in the Sponsor’s 
database. 
For screening failure subjects, the Unique Subject Identifier, the date of informed consent 
signature, the reason why the subject failed screening and the potential AEs which occurred 
during the Screening visit will be reported in the eCRFs and collected in the Sponsor’s database 

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(for complete list of data to be collected for screen failure patients, please refer to eCRF 
completion Guidelines). 
15.3 
Record Archiving and Retention 
During the initiation visits, the monitor must ensure the archiving facilities are adequate and 
archiving/retention responsibilities of the Investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. The Investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the investigational site. The Sponsor will inform the Investigator, 
in writing, as to when these documents no longer need to be retained. 
If the principal Investigator relocates or retires, or otherwise withdraws his/her responsibility 
for the maintenance and retention of study documents, the Sponsor must be notified (preferably 
in writing) so that adequate provision can be made for their future maintenance and retention. 

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16 
FINANCING AND INSURANCE 
16.1 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
their specific responsibilities in relation to the study. Financial remuneration will cover the cost 
per included subject based on the calculated costs to perform the study assessments in 
accordance with the protocol, and the specified terms of payment will be described in the 
contract. The contract should describe whether costs for pharmacy, laboratory and other 
protocol-required services are being paid directly or indirectly. 
16.2 
Insurance, Indemnity and Compensation 
The Sponsor will provide product liability insurance for all subjects included in the clinical 
study. Where required, a hospital-specific indemnity agreement will be used. 

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17 
REPORTING AND PUBLICATION OF RESULTS 
17.1 
Publication Policy 
The Sponsor is committed to disclosing information about the clinical trials it sponsors. Results 
will be communicated at scientific meetings and all reasonable efforts must be made to seek 
publication in a peer-reviewed scientific journal. Specific publication concepts, including data 
to be covered, target congress/journal and proposed authors, should be discussed with the 
appropriate Global Publications Manager and incorporated in the relevant publication plan 
before initiation. A dedicated Publications Committee, involving interested members of the 
study Steering Committee as well as the Global Publications Manager, may be established to 
plan specific publications. As a minimum, summary results of this study should be posted on 
the relevant clinical trial registry. When the trial has been conducted by a large multicentre 
group, the principal Investigator, the study steering committee (if applicable) and the Sponsor’s 
responsible physician should discuss and agree the selection of authors for planned publications 
in advance. They may decide to use a group name and nominate authors on behalf of the study 
group. All contributing Investigators will be listed in the acknowledgements together with any 
others who may have contributed but not sufficiently to qualify for authorship. 
Selection of authors for scientific publications will follow the International Committee of 
Medical Journal Editors guidelines (http://www.icmje.org/recommendations/browse/roles-and-
responsibilities/defining-the-role-of-authors-and-contributors.html). In particular, those named 
as authors, whether employed by a Sponsor’s affiliate or the Sponsor, or external Investigators, 
‘should have participated sufficiently in the work to take public responsibility for the content’. 
Authorship should be based on: 
• 
Substantial contributions to the conception and design, or acquisition of data, or analysis 
and interpretation of data; AND 
• 
Drafting the article or revising it critically for important intellectual content; AND 
• 
Final approval of the version to be published; AND 
• 
Agreement to be accountable for all aspects for the work, thereby ensuring that questions 
related to the accuracy or integrity of any part of the work were appropriately investigated 
and resolved. 
All authors of a publication should meet all four criteria. Each author must agree to their 
inclusion in the list of authors. Use of professional medical writing support may be employed.  
Resolution of scientific differences in the presentation or interpretation of study findings will 
be conducted along principles of honest scientific debate. The Sponsor shall be promptly 
notified of any amendments subsequently requested by referees or journal editors. 
All publications arising from this study will be reviewed by relevant functions at the Sponsor, 
coordinated by the Global Publications team. Requests and suggestions for changes will be 
discussed with all authors (and medical writer, if applicable). Resolution of scientific 
differences in the presentation or interpretation of study findings will be conducted along 
principles of honest scientific debate. The Sponsor’s review comments must be answered before 
a final version for submission can be approved by the author team. 
If patentability would be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical trial agreement concerned, (ii) the Sponsor consents to the publication, or (iii) 
the time period as may be agreed in the contractual arrangements, including clinical trial 
agreements, governing the relationship between the Sponsor and authors (or authors’ 

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institution) after receipt of the proposed publication by the Sponsor, whichever of (i), (ii) or (iii) 
occurs first. 
17.2 
Clinical Study Report  
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. The final CSR will include data on any subject that has signed the 
informed consent, regardless of whether the study is completed or prematurely terminated. 
Where appropriate, an abbreviated report may be prepared. The CSR will comply with any 
applicable regulatory requirements, national laws in force and will be in English. 
An analysis will be performed on the final response data 12 months after the last subject 
received the first cabozantinib administration. This analysis will be included in the final study 
report. An addendum to the report, including the analysis of data from the follow-up period, 
will be prepared 18 months after the last subject received the first cabozantinib administration. 

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18 
REFERENCES 
 
1 
Klatte, Tobias, Sabrina H. Rossi, and Grant D. Stewart. “Prognostic factors and 
prognostic models for renal cell carcinoma: a literature review.” World journal 
of urology (2018): 1-10.  
2 
Hsieh, James J., et al. “Renal cell carcinoma.” Nature reviews Disease primers 
3 (2017): 17009. 
3 
Janzen, Nicolette K., et al. “Surveillance after radical or partial nephrectomy 
for localized renal cell carcinoma and management of recurrent disease.” The 
Urologic clinics of North America 30.4 (2003): 843-852. 
4 
Gill, David M., et al. “Overview of current and future first-line systemic 
therapy for metastatic clear cell renal cell carcinoma.” Current treatment 
options in oncology 19.1 (2018): 6. 
5 
Carmeliet, Peter, and Rakesh K. Jain. “Molecular mechanisms and clinical 
applications of angiogenesis.” Nature 473.7347 (2011): 298.  
6 
Rini, Brian I. “Metastatic renal cell carcinoma: many treatment options, one 
patient.” Journal of Clinical Oncology 27.19 (2009): 3225-3234.  
7 
Giubellino, Alessio, W. Marston Linehan, and Donald P. Bottaro. “Targeting 
the Met signaling pathway in renal cancer.” Expert review of anti-cancer 
therapy 9.6 (2009): 785-793. 
8 
Nickerson, Michael L., et al. “Improved identification of von Hippel-Lindau 
gene alterations in clear cell renal tumours.” Clinical cancer research 14.15 
(2008): 4726-4734. 
9 
Gibney, G. T., et al. “c-Met is a prognostic marker and potential therapeutic 
target in clear cell renal cell carcinoma.” Annals of Oncology 24.2 (2012): 343-
349. 
10 
Bommi-Reddy, Archana, et al. “Kinase requirements in human cells: III. 
Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic 
lethal screen.” Proceedings of the National Academy of Sciences 105.43 
(2008): 16484-16489.  
11 
Cabometyx Product Information. October 2020. https://www.ema.europa.eu.  
12 
Choueiri TK, Escudier B, et al, for the METEOR investigators. Cabozantinib 
versus everolimus in advanced renal cell carcinoma (METEOR): final results 
from a randomised, open-label, phase 3 trial. Lancet Oncol 2016; published 
online June 5. http://dx.doi.org/10.1016/S1470-2045(16)30107-3. 
13 
Choueiri, Toni K., et al. “Cabozantinib versus sunitinib as initial targeted 
therapy for patients with metastatic renal cell carcinoma of poor or intermediate 
risk: the Alliance A031203 CABOSUN trial.” Journal of clinical oncology: 
official journal of the American Society of Clinical Oncology 35.6 (2017): 591-
597.  
14 
Choueiri, Toni K., et al. “Cabozantinib versus sunitinib as initial therapy for 
metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 
CABOSUN randomised trial): Progression-free survival by independent 
review and overall survival update.” European Journal of Cancer 94 (2018): 
115-125. 

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15 
Motzer, Robert J., et al. “Nivolumab plus ipilimumab versus sunitinib in 
advanced renal-cell carcinoma.” New England Journal of Medicine 378.14 
(2018): 1277-1290. 
16 
Auvray, Marie, et al. “Second-line targeted therapies after nivolumab-
ipilimumab failure in metastatic renal cell carcinoma.” European Journal of 
Cancer 108 (2019): 33-40. 
17 
Parekh, Hiral, and Brian I. Rini. “Emerging therapeutic approaches in renal cell 
carcinoma.” Expert review of anti-cancer therapy 15.11 (2015): 1305-1314.  
18 
Aoun, Fouad, et al. “Checkpoint inhibitors in bladder and renal cancers: results 
and perspectives.” Immunotherapy 7.12 (2015): 1259-1271.  
19 
Atkins, M. B., J. I. Clark, and D. I. Quinn. “Immune checkpoint inhibitors in 
advanced renal cell carcinoma: experience to date and future directions.” 
Annals of Oncology 28.7 (2017): 1484-1494.  
20 
Choueiri TK, et al. Oral presentation 6960. Presented at ESMO 2020.  
21 
Ljungberg, Börje, et al. “European Association of Urology Guidelines on Renal 
Cell Carcinoma: The 2019 Update.” European Urology (2019). 
22 
Escudier, Bernard, et al. “Renal cell carcinoma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up.” Annals of oncology (2019) 
updated on 30 November 2020. 
23 
Powles, Thomas, et al. “Outcomes based on prior therapy in the phase 3 
METEOR trial of cabozantinib versus everolimus in advanced renal cell 
carcinoma.” Br J Cancer 119 (2018): 663. 
24 
Barata, Pedro Coelho, et al. “The efficacy of VEGFR TKI therapy after 
progression on immune combination therapy in metastatic renal cell 
carcinoma.” British Journal of Cancer 119.2 (2018): 160. 
25 
Cella, David, et al. “Development and validation of a scale to measure disease-
related symptoms of kidney cancer.” Value in Health 10.4 (2007): 285-293. 
26 
Wright, James R., et al. “Randomized, double-blind, placebo-controlled trial of 
erythropoietin in non-small-cell lung cancer with disease-related anemia.” 
Journal of Clinical Oncology 25.9 (2007): 1027-1032. 
27 
Kalirai A, Wood L, Lalani A et al. Efficacy of targeted therapy (TT) after 
checkpoint inhibitors (CPI) in metastatic renal cell carcinoma (mRCC): Results 
from the Canadian Kidney Cancer Information System (CKCis). Journal of 
Clinical Oncology 37, no. 7_suppl (March 1 2019) 568-568. 
28 
Ornstein MC, Pal SK, Wood LS et al. Individualised axitinib regimen for 
patients with metastatic renal cell carcinoma after treatment with checkpoint 
inhibitors: a multicentre, single-arm, phase 2 study. Lancet Oncol 2019. 
29 
Eisenhauer, Elizabeth A., et al. “New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1).” European journal of cancer 
45.2 (2009): 228-247. 

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19 
LIST OF APPENDICES 
Appendix 1 Memorial Sloan Kettering Cancer Center (MSKCC) Criteria for 
prognostic risk category ............................................................................................ 95 
Appendix 2 International Metastatic RCC Database Consortium (IMDC) risk 
group category .......................................................................................................... 97 
Appendix 3 Methods of contraception ..................................................................... 99 
Appendix 4 Warnings, Precautions and Guidelines for The Management of 
Potential Cabozantinib Adverse Events .................................................................. 101 
Appendix 5 Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 ......... 114 
Appendix 6 FKSI-DRS Questionnaire ................................................................... 122 
Appendix 7 Performance Status Criteria ................................................................ 124 
Appendix 8 Amendment Form #1 .......................................................................... 126 
Appendix 9 Amendment Form #2 .......................................................................... 166 
Appendix 10 Amendment Form #3 ........................................................................ 170 

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Appendix 1 Memorial Sloan Kettering Cancer Center (MSKCC) Criteria for 
prognostic risk category   

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Appendix 2 International Metastatic RCC Database Consortium (IMDC) risk group 
category 

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Appendix 3 Methods of contraception 

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Female subjects of childbearing potential (i.e. less than or equal to 2 years post-menopause and 
not surgically sterile) and their partners must agree to use highly effective methods of 
contraception (that alone or in combination result in a failure rate of less than 1% per year when 
used consistently and correctly) during the course of the study and for 4 months after the last 
dose of study treatment.  
 
The interaction of cabozantinib with oral contraceptives has not been investigated and the 
contraceptive effect may not be guaranteed, therefore it is recommended that an additional 
contraceptive method such as a barrier method (e.g. condom or diaphragm) is used by your 
patient if they are using oral combined contraception or progestogen-only contraception.  
 
Effective methods of birth control include: 
• 
Hormonal contraception (oral, injectable, implantable, transdermal) plus a barrier 
method; 
• 
intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) plus a barrier 
method; 
• 
bilateral tubal occlusion (females); 
• 
vasectomized partner (males). 
 
Men with partners who can get pregnant will need to use one of the medically accepted methods 
of birth control listed above while in this study, as will their partner. All male subjects must 
refrain from donating sperm and sexual intercourse without condoms with female partners for 
the duration of study and for 120 days after the last dose of study drug.  
 

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Appendix 4 Warnings, Precautions and Guidelines for The Management of Potential 
Cabozantinib Adverse Events 

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1 
GASTROINTESTINAL DISORDERS 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess 
Prior to initiation of treatment with cabozantinib, subjects should be carefully evaluated for 
potential risk factors including (but not limited to) the following:  
• 
Tumours invading GI or respiratory tracts  
• 
Active peptic ulcer disease, inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s 
disease), diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis  
• 
History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess 
• 
Ongoing visceral complications from prior radiation therapy  
• 
Prior GI surgery (particularly when associated with delayed or incomplete healing)  
 
Complete healing following abdominal surgery and radiation therapy and/or resolution of intra-
abdominal abscess must be confirmed prior to initiating treatment with cabozantinib.  
After starting cabozantinib, subjects should be monitored for early signs of GI perforation such 
as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for 
developing GI perforation or fistula are present.  
Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with GI perforation or fistula. 
 
Diarrhoea 
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 diarrhoea are shown in Table A1. 1 .  

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Table A1. 1 Guidelines for Management of Treatment-Emergent Diarrhoea 
Status 
Management 
Tolerable Grade 1-2 
(duration <48 hours) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (e.g. loperamide 4 mg 
followed by 2 mg after each episode of diarrhoea [maximum: 16 mg 
loperamide per day]) 
• 
Dietary modifications (e.g. small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
- 
Diarrhoea resolving to baseline bowel habits: gradually add 
solid foods and discontinue or decrease antidiarrheal treatment 
after 12 hours diarrhoea-free interval 
- 
Diarrhoea not resolving: Continue/resume antidiarrheal 
treatment  
Intolerable Grade 2, 
Grade 2 >48 hours,  
or ≥Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend investigational site 
• 
Rule out infection (e.g. stool sample for culture) 
- 
Administer antibiotics as needed (e.g. if fever or Grade 3-4 
neutropenia persists >24 hours) 
• 
Administer fluids (1-1.5 L/day oral or intravenous (IV), as appropriate) 
for hydration or to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower grade diarrhoea consider 
hospitalisation and IV hydration 
• 
Re-assess after 24 hours 
- 
Diarrhoea resolving to baseline bowel habits or Grade ≤1: 
consider restarting study treatment at reduced dose 
- 
Diarrhoea not resolving:  
- 
Start and or continue antidiarrheal treatment (e.g. loperamide 
4 mg followed by 2 mg after each episode of diarrhoea 
(maximum: 16 mg loperamide per day)) 
- 
Consider starting 2nd line antidiarrheal or referral to 
gastroenterologist 
 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhoea 
as initial management. Some subjects may require concomitant treatment with more than one 
antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhoea to 
tolerable levels, study treatment should be temporarily interrupted, or dose reduced. When the 
diarrhoea 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 diarrhoea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasised. Regular examinations of the perianal region should be performed whenever 

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diarrhoea has occurred during treatment with cabozantinib. Infections of the perianal region 
should be treated per local guidelines. 
 
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. 
 
2 
NON-GASTROINTESTINAL FISTULA 
Non-GI fistula formation: Complications from radiation therapy has been identified as a 
possible predisposing risk factor for fistula formation in subjects undergoing treatment with 
cabozantinib. 
Subjects with any clinically relevant ongoing complications from prior radiation therapy (i.e. 
radiation esophagitis or other inflammation of the viscera) should not be treated with 
cabozantinib.  
Radiation therapy to the thoracic cavity (including mediastinum) should be avoided within 
3 months of starting treatment with cabozantinib (excluding local radiation for bone 
metastases). Fistula should be ruled out as appropriate in cases of onset of severe mucositis or 
difficulty swallowing after start of therapy. Discontinue cabozantinib and initiate appropriate 
management in subjects who have been diagnosed with a non-GI fistula. 
 
3 
HAEMORRHAGE 
Haemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be evaluated for potential bleeding risk factors prior to initiating 
cabozantinib treatment and should be monitored for bleeding events with serial complete blood 
counts and physical examination while on study. Risk factors for haemorrhagic events may 
include (but may not be limited to) the following:  
• 
Tumour of the lung with cavitary lesions or tumour lesions which invade or encase major 
blood vessels. Non-small cell lung cancer (NSCLC) with squamous cell differentiation 
is known for significant lung cavitations and centrally located tumours that may invade 
major blood vessels. Thus, the anatomic location and characteristics of tumour as well as 
the medical history should be carefully reviewed in the selection of subjects for treatment 
with cabozantinib;  
• 
Recent or concurrent radiation to the thoracic cavity;  
• 
Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease and 
ulcerative colitis;  
• 
Underlying medical conditions which affect normal haemostasis (e.g. deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia);  
• 
Concomitant medication with anticoagulants or other drugs which affect normal 
haemostasis;  
• 
History of clinically significant haemoptysis, hematemesis, or haematuria.  

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The risk of haemorrhage in cabozantinib-treated subjects with brain metastases has not been 
thoroughly analysed. Though the incidence of CNS haemorrhage events in a study of subjects 
with GB was higher than observed in general population of subjects with cancer treated with 
cabozantinib, it is not clear how the risk of haemorrhage in GB translates to a risk of 
haemorrhage for subjects with brain metastases. Currently, brain metastases of carcinomas are 
not contraindications to the use of cabozantinib, but subjects with brain metastases should be 
monitored with a high index of suspicion if symptoms that could be due to a CNS haemorrhage 
occur. 
Complete healing from radiation-induced side effects should have occurred before initiating 
cabozantinib treatment, and cabozantinib should be discontinued in subjects with serious and 
life-threatening bleeding events or recent haemoptysis (≥2.5 mL of red blood). 
 
4 
VASCULAR DISORDERS 
Thromboembolic events 
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced 
by the malignancy or anti-cancer therapy. Events of 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 held until therapeutic 
anticoagulation is established. Refer to the individual protocol for guidance on anticoagulation 
medication use. 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 study treatment per discretion 
of the Investigator and according to individual protocols. LMWHs are the preferred 
management agent for thrombotic events; Oral anticoagulants (including warfarin) are not 
allowed.  
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, hyperlipidaemia, 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.  
 
Aneurysms and artery dissections 
The use of VEGF pathway inhibitors in patients with or without hypertension may promote the 
formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk 
should be carefully considered in patients with risk factors such as hypertension or history of 
aneurysm. 
 
Hypertension 
Table A1. 2 provides treatment guidelines for hypertension deemed related to cabozantinib. 
Subjects with known hypertension should be optimally managed prior to entry into clinical 
trials with cabozantinib according to entry criteria of specific protocols. The subjects’ BP 
should be monitored in a constant position visit to visit, either sitting or supine in a relaxed 
setting. Decisions to decrease or hold the dose of study treatment must be based on BP readings 

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taken by a medical professional and must be confirmed with a second measurement at least 
5 minutes following the first measurement.  
 
Table A1. 2 Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimised anti-hypertensive therapy 
>150 mm Hg (systolic) a and <160 mm Hg 
OR 
>100 mm Hg (diastolic) and <110 mm Hg 
 
• 
Optimise antihypertensive medications by adding new 
or additional antihypertensive medications and/or 
increase dose of existing medications. 
• 
Reduce study treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) 
does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic 
• 
If subject is symptomatic interrupt study treatment 
≥160 mm Hg (systolic) 
OR 
≥110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
study treatment per Investigator’s discretion 
• 
Add new or additional anti-hypertensive medications 
and/or increase dose of existing medications and 
monitor subject closely for hypotension. If optimised 
antihypertensive therapy (usually to include 3 agents) 
does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic, study treatment should be dose 
reduced further or interrupted 
• 
Study treatment should be dose interrupted if upper 
limits of systolic BP (≥160 mm Hg) are sustained and 
not adequately manageable or if systolic BP is 
>180 mm Hg or diastolic BP >110 mm Hg, or if 
subject is symptomatic 
• 
Re-start study treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at 
<150 mm Hg systolic and <100 mm Hg diastolic 
Hypertensive emergency c 
• 
Discontinue study treatment 
BP = Blood pressure. 
a The Investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 or 
diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols. 
c Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending end-
organ damage (e.g. MI/ischaemia, intracranial haemorrhage, cerebral ischaemia, pulmonary oedema, encephalopathy, 
kidney damage). 
 
5 
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 

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(e.g. with a weak solution of salt and baking soda) should be maintained. Lips should be kept 
moisturised 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. 
 
6 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Wound healing and surgery 
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 28 days prior to scheduled surgery. The 
decision to resume treatment with cabozantinib after surgery should be based on clinical 
judgment of adequate wound healing.  
 
Palmar-plantar erythrodysaesthesia syndrome 
Palmar-plantar erythrodysaesthesia syndrome (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 summarised in Table A1. 3. 

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Table A1. 3 Dose Modification Criteria and Recommended Guidelines for Treatment-emergent Hand-
Foot Syndrome (PPES) 
Common Terminology 
Criteria for Adverse Events 
(CTCAE) version 5.0 Grade 
Action to Be Taken 
Grade 1 
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced to 
the next lower dose level.a Start urea 20% cream twice daily (b.i.d.) AND 
clobetasol 0.05% cream once daily (q.d). Reassess at least weekly; if PPES 
worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2 
Study treatment may be continued if PPES is tolerated. Study treatment 
should be dose reduced or interrupted if PPES is intolerable. Continue urea 
20% cream b.i.d. AND high potency steroid cream (e.g. clobetasol 0.05%) 
q.d. and add analgesics (e.g. NSAIDs/gamma-aminobutyric acid agonists) 
for pain control if needed. Reassess at least weekly; if PPES worsens or 
affects self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with high potency steroid cream (e.g. clobetasol 
0.05%) b.i.d. 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. 
NSAID = Non-steroidal anti-inflammatory drug; PPES = Palmar-plantar erythrodysaesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
 
7 
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. 
 
8 
OSTEONECROSIS 
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 
ONJ.  
Perform an oral examination prior to initiation of cabozantinib and periodically during 
cabozantinib therapy. Advise subjects regarding oral hygiene practice and to quickly report 
symptoms to the Investigator. Caution should be used in subjects receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental procedures are 
unavoidable, treatment with cabozantinib should be held for at least 4 weeks prior to the 
procedure and resumed after complete wound healing has occurred. Bone healing may often 
require a protracted time.  

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If ONJ occurs, cabozantinib treatment should be held and should not be restarted until the 
condition has sufficiently healed and the Sponsor has approved the re-initiation of therapy. 
 
9 
PROTEINURIA 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring 
urine protein/creatinine ratio (UPCR). Table A1. 4 provides treatment guidelines for proteinuria 
deemed related to cabozantinib.  
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria 
>3.5 g per day in combination with low blood protein levels, high cholesterol levels, high 
triglyceride levels, and oedema). 
 
Table A1. 4 Management of Proteinuria Related to 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-hour protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤2 mg/mg or 
urine protein ≤2 g/24 hours on 24-hour urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR >2 mg/mg on 
repeat UPCR testing or urine protein >2 g/24 hours on 24-hour urine 
collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to <2 mg/mg. Consider holding cabozantinib treatment if 
UPCR remains >2 mg/mg despite a dose reduction until UPCR 
decreases to <2 mg/mg. Restart cabozantinib treatment at a reduced 
dose after a dose hold unless otherwise approved by sponsor. 
• 
Repeat UPCR within 7 days and once per week. If UPCR <1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done within 
1 week of first reading.) If UPCR remains >1 mg/mg and <2 mg/mg 
for 1 month or is determined to be stable (<20% change) for 1 month, 
check urine protein/creatinine per protocol or as clinically indicated. 
≥3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Hold cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein.  
• 
If ≥3.5 mg/mg on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to 
<2 mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until the 
UPCR decreases to <1 mg/mg. If UPCR remains >1 mg/mg and 
<2 mg/mg for 1 month or is determined to be stable (<20% change) for 
1 month, check urine protein/creatinine per protocol or as clinically 
indicated. 
Nephrotic syndrome 
• 
Discontinue all study treatment 
UPCR = Urine protein/creatinine ratio. 

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10 
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 and ataxia have been observed in clinical studies 
with cabozantinib. In addition, hepatic encephalopathy has been observed in HCC clinical 
studies with cabozantinib. The development of any new or progressive, unexplained 
neurological symptoms should be assessed for underlying causes. 
RPLS has been reported and 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. 
 
11 
HEPATIC EVENTS 
Investigators should monitor for Drug induced lived injury (DILI) diligently and report any 
potential events.  
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 (e.g. liver cirrhosis, thrombosis of portal or hepatic vein, HCC, hepatitis), concomitant 
hepatotoxic medication, alcohol consumption, and cancer related causes.  
If not otherwise specified in individual protocols, cabozantinib should be interrupted for related 
CTCAE Grade 3 or higher hepatic injury (transaminase increase to > 5 × ULN) and when 
transaminase increases are accompanied by progressive elevations of total bilirubin, and/or 
elevations of coagulation tests (e.g. International Normalized Ratio [INR]). More frequent 
monitoring of transaminases should be considered and cabozantinib should be held until the 
aetiology 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 DILI. Study drug should be permanently discontinued in cases 
determined to be DILI according to Hy’s Law review. 
 
12 
INFECTIONS AND INFESTATIONS 
Infections are commonly observed in cancer subjects. Predisposing risk factor include a 
decreased immune status (e.g. after myelosuppressive anti-cancer therapies, splenectomy), 
destructive growth of the underlying malignancy including bone marrow infiltration with 
suppression of normal haematopoiesis, as well as the presence of intravenous (IV) devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be held until adequate healing has taken place. 
 
13 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Haematological toxicities (i.e. neutropenia and thrombocytopenia) and associated 
complications have been observed after administration of cabozantinib and may be managed 

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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 haematological toxicities are not mandated but can be 
applied as clinically indicated. Supportive care for thrombocytopenia or anaemia, such as 
transfusions, may be managed according to institutional guidelines. The use of colony-
stimulating growth factors should be considered unless prohibited by a specific protocol. 
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. 
 
14 
FATIGUE 
Common causes of fatigue, such as anaemia, 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 by a 
particular protocol. 
 
15 
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. 
 
16 
CORRECTED QT PROLONGATION 
The effect of orally administered cabozantinib 140 mg q.d. on QTc interval was evaluated in a 
placebo-controlled study in subjects with MTC. A mean increase of 10-15 ms in QTcF 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. There were no events of torsades de pointes reported.  
Unless otherwise specified in certain protocols, only subjects with a baseline QTcF ≤500 msec 
are eligible for cabozantinib research studies. Cabozantinib should be used with caution in 
subjects with QT prolongation risk, a history of QT interval prolongation, or who are taking 
antiarrhythmics or other drugs known to prolong the QT interval. Concomitant treatment with 
strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be 
avoided.  
If at any time on study there is an increase in QTcF to an absolute value >500 ms or an increase 
of >60 ms above baseline, two additional 12-lead ECGs must be performed with intervals not 
less than 3 minutes apart within 30 minutes after the initial ECG.  
If the average QTcF from the three ECGs is >500 ms or increased by >60 ms above baseline, 
the following actions must be taken:  
• 
Withhold study treatment;  
• 
Immediately notify the Sponsor;  
• 
Hospitalise symptomatic subjects (e.g. with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
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• 
Consider cardiology consultation for asymptomatic subjects for evaluation and 
management; 
• 
Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities 
as clinically indicated;  
• 
Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org);  
• 
Repeat ECG triplicates hourly until the average QTcF is ≤500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert.  
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced dose level 
if all of the following conditions are met:  
• 
Symptoms are determined to be unrelated to the QT interval prolongation;  
• 
The QTcF value >500 ms or increase of >60 ms above baseline is not confirmed 
according to protocol procedures;  
• 
Study treatment has been interrupted through a minimum of 1 week following the return 
of the QTcF to ≤500 msec or return to ≤60 ms above baseline;  
• 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved; 
Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment.  
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then 
every 2 weeks for 1 month, then according to the protocol-defined time points.  
All study treatment must be permanently discontinued if either of the following applies:  
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation;  
• 
Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of 
study treatment at a reduced dose.  
• 
 
17 
ENDOCRINE DISORDERS 
Treatment-emergent increases in thyroid-stimulating hormone (TSH) have been observed with 
cabozantinib treatment. Currently available data are insufficient to determine the mechanism of 
thyroid function test alterations and its clinical relevance. Routine monitoring of thyroid 
function and assessments for signs and symptoms associated with thyroid dysfunction is 
recommended before initiation and during treatment with cabozantinib. Management of thyroid 
dysfunction (e.g. symptomatic hypothyroidism) should follow accepted clinical practice 
guidelines. 
 
18 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on 
nonclinical GLP-compliant toxicology studies. The development of new or progressive, 
unexplained musculoskeletal symptoms such as pain or weakness should be assessed for 
underlying causes.  
Rhabdomyolysis has been reported. Cabozantinib should be discontinued in subjects with 
serious and life-threatening rhabdomyolysis and interrupted if less severe forms occur when 

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there are no other clear causes. Re-initiation of cabozantinib treatment must be discussed with 
and approved by the sponsor. Therapy of rhabdomyolysis should include supportive care and 
standard medical intervention. 
 
19 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Dyspnoea has been reported in clinical studies with cabozantinib. Symptoms should be 
managed according to locally accepted clinical practice including an assessment for underlying 
causes. Pulmonary embolism should be considered as possible causes for new onset dyspnoea 
given the risk of thrombosis associated with inhibition of VEGF signalling. Furthermore, fistula 
formation and pneumonia have been reported in subjects treated with cabozantinib and should 
be considered as clinically indicated in subjects presenting with pulmonary symptoms. 
 
20 
ELECTROLYTE ABNORMALITIES 
Electrolyte abnormalities, including hypocalcaemia, hypokalaemia, hypomagnesaemia, and 
hypophosphataemia have been noted in subjects treated with cabozantinib. In some cases, these 
have been Grade 3 or 4 and/or serious. These laboratory values should be evaluated routinely. 
Deficits should be corrected when an electrolyte abnormality is noted in order to avoid 
worsening. Correction of electrolyte abnormalities should be accompanied by increased 
frequency of monitoring. 

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Appendix 5 Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 

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Adapted from (29).
TUMOUR MEASURABILITY
At baseline, tumour lesions/lymph nodes will be categorized as measurable or non-measurable 
as described below. All measurable and non-measurable lesions should be assessed at screening 
and at subsequent protocol-specified tumour assessment timepoints. Additional assessments 
may be performed as clinically indicated for suspicion of progression.
DEFINITION OF MEASURABLE LESIONS
Tumour Lesions
Tumour lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size as follows:
•
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval ൑5 mm)
•
10-mm caliper measurement by clinical examination (lesions that cannot be accurately 
measured with calipers should be recorded as non-measurable)
•
20 mm by chest X-ray
Malignant Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in 
the short axis when assessed by CT scan (CT scan slice thickness recommended to be ൑5 
mm). At baseline and follow-up, only the short axis will be measured and followed. Additional 
information on lymph node measurement is provided below (see "Identification of Target and 
Non-Target Lesions" and "Calculation of Sum of Diameters").
DEFINITION OF NON-MEASURABLE LESIONS
Non-measurable tumour lesions encompass small lesions (longest diameter  10 mm or
pathological lymph nodes with short axis ≥10 mm but  15 mm) as well as truly non-
measurable lesions. Lesions considered truly non-measurable include leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement 
of skin or lung, peritoneal spread, and abdominal mass/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques.
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment, as outlined below.
Bone Lesions:
•
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, and 
plain films are not considered adequate imaging techniques for measuring bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions.
•
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 

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considered measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 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. 
 
Lesions with Prior Local Treatment: 
• 
Tumour lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
 
METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks 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 the study. 
Imaging-based evaluation should always be the preferred option. 
 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm in 
diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by colour photography, including a ruler to estimate the size of the lesion, is 
suggested. 
 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. In this guideline, the definition of measurability of lesions on CT scan is 
based on the assumption that CT slice thickness is ≤ 5 mm. When CT scans have slice thickness 
of  5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI 
is also acceptable. 

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If prior to enrolment it is known that a patient is unable to undergo CT scans with intravenous 
(IV) contrast because of allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (without IV contrast) will be used to evaluate the patient at baseline and during the 
study should be guided by the tumour type under investigation and the anatomic location of the 
disease. For patients who develop contraindications to contrast after baseline contrast CT is 
done, the decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be 
performed should also be based on the tumour type and the anatomic location of the disease, 
and should be optimized to allow for comparison with the prior studies if possible. Each case 
should be discussed with the radiologist to determine if substitution of these other approaches 
is possible and, if not, the patient should be considered not evaluable from that point forward. 
Care must be taken in measurement of target lesions and interpretation of non-target disease or 
new lesions on a different modality, since the same lesion may appear to have a different size 
using a new modality. 
 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOUR MARKERS, CYTOLOGY, 
HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumour markers, cytology, and histology cannot be used 
for objective tumour evaluation. 
 
ASSESSMENT OF TUMOUR BURDEN 
To assess objective response or future progression, it is necessary to estimate the overall tumour 
burden at baseline and use this as a comparator for subsequent measurements. 
 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
that, for instances in which patients have only one or two organ sites involved, a maximum of 
two lesions (one site) and four lesions (two sites), respectively, will be recorded. Other lesions 
(albeit measurable) in those organs will be considered non-target lesions. 
 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and should be representative of all involved organs, but in addition should lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance the next largest lesion 
that can be measured reproducibly should be selected. 
 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumour. As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumour. Lymph node size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT, this is almost always the axial plane; for MRI, 
the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node that is reported as being 20 mm ( 30 mm has a short 

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axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should 
be recorded as the node measurement. All other pathological nodes (those with short axis ≥ 10 
mm but  15 mm) should be considered non-target lesions. Nodes that have a short axis of  10 
mm are considered non-pathological and should not be recorded or followed. 
 
All lesions (or sites of disease) not selected as target lesions (measurable or non-measurable), 
including pathological lymph nodes, should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required. It is possible to record multiple non-
target lesions involving the same organ as a single item on the Case Report Form (CRF) (e.g., 
"multiple enlarged pelvic lymph nodes" or "multiple liver metastases"). 
 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for non-lymph node lesions, short axis for lymph 
node lesions) will be calculated for all target lesions at baseline and at each subsequent tumour 
assessment as a measure of tumour burden. 
 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the node 
regresses to  10 mm during the study. Thus, when lymph nodes are included as target lesions, 
the sum of diameters may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of  10 mm. 
 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and non-lymph node) recorded at baseline 
should have their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g., 2 mm). However, sometimes lesions or lymph nodes that are recorded as target 
lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measurement and may report them as being too small to measure. When this 
occurs, it is important that a value be recorded on the CRF, as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned and "too small to measure" should be ticked. (Note: It 
is less likely that this rule will be used for lymph nodes since they usually have a 
definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well and "too small to measure" should also be ticked). 
 
To reiterate, however, if the radiologist is able to provide an actual measurement, that should 
be recorded, even if it is + 5 mm, and in that case "too small to measure" should not be ticked. 
 
Measuring Lesions That Split or Coalesce on Treatment 

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When non-lymph node lesions fragment, the longest diameters of the fragmented portions 
should be added together to calculate the sum of diameters. Similarly, as lesions coalesce, a 
plane between them may be maintained that would aid in obtaining maximal diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they are 
no longer separable, the vector of the longest diameter in this instance should be the maximum 
longest diameter for the coalesced lesion. 
 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node non-
target lesions should be monitored for reduction to  10 mm in short axis. 
Non-target lesions should be noted at baseline and should be identified as "present" or "absent" 
and (in rare cases) may be noted as "indicative of progression" at subsequent evaluations. In 
addition, if a lymph node lesion shrinks to a non-malignant size (short axis  10 mm), this 
should be captured on the CRF as part of the assessment of nontarget lesions. 
 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumour response for target lesions are 
provided below: 
• 
Complete response (CR): Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
• 
Partial response (PR): At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
• 
Progressive disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints (including 
baseline) 
In addition to the relative increase of 20%, the sum of diameters must also demonstrate 
an absolute increase of ≥ 5 mm. 
• 
Stable disease (SD): Neither sufficient shrinkage to qualify for CR or PR nor sufficient 
increase to qualify for PD 
 
CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumour response for the group of nontarget 
lesions are provided below. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the timepoints 
specified in the schedule of activities. 
• 
CR: Disappearance of all non-target lesions and (if applicable) normalization of tumour 
marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumour marker level above the normal limits 
• 
PD: Unequivocal progression of existing non-target lesions 
 

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SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of substantial 
worsening in non-target lesions in a magnitude that, even in the presence of SD or PR in target 
lesions, the overall tumour burden has increased sufficiently to merit discontinuation of therapy. 
A modest increase in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. The designation of overall progression solely on the 
basis of change in non-target lesions in the face of SD or PR in target lesions will therefore be 
extremely rare. 
 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumour (for example, some 
"new" bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient's baseline lesions show PR or CR. For example, necrosis of a liver 
lesion may be reported on a CT scan report as a "new" cystic lesion, which it is not. 
 
A lesion identified during the study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. 
 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is 
definitely a new lesion, progression should be declared using the date of the initial scan. 
 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table A5.1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 

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Table A5.1 
Criteria for Overall Response at a Single Timepoint: Patients with Target Lesions (with 
or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR= complete response, NE= not evaluable, PD= progressive disease, PR= partial response, SD= stable disease 
 
 
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint. If measurements are made on only a subset of target lesions at a 
timepoint, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesions would 
not change the assigned timepoint response. This would be most likely to happen in the case of 
PD. For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
during the study only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion. 
 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
"symptomatic deterioration." Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response; it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target lesions as shown in 
Table A5.1. 
 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 

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Appendix 6 FKSI-DRS Questionnaire  

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Appendix 7 Performance Status Criteria 

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Table A1. 1 Performance Status Criteria 
 

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Appendix 8 Amendment Form #1 
 

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[…] 
6 
Synopsis (Methodology)  
[…] 
Each subject’s study participation will consist of the 
following periods: 
 
 
Pre-treatment Period: Potential subjects will be 
screened to determine whether they meet the 
required eligibility criteria. Qualifying assessments 
at the Screening visit will be performed within 15 
days prior to first cabozantinib dose except when 
otherwise specified. Eligible subjects will be 
included in the study on the day of the Screening 
visit. 
 
 
[…] 
Subjects 
who 
discontinue 
treatment 
with 
cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend the 
End of Study Treatment visit (30 days (+15 days) 
after the last dose of cabozantinib). Subjects who 
prematurely stop the study due to withdrawal of 
consent will be invited to attend the Early Study 
Withdrawal visit. 
[…] 
Each subject’s study participation will consist 
of the following periods: 
 
 
Pre-treatment Period: Potential subjects will 
be screened to determine whether they meet the 
required 
eligibility 
criteria. 
Qualifying 
assessments will be performed within 15 days 
prior to first cabozantinib dose except when 
otherwise 
specified 
(detailed 
in 
study 
schedule).  
 
 
 
[…] 
Subjects who discontinue treatment with 
cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend 
the End of Study Treatment visit (30 to 45 days 
after the last dose of cabozantinib). Subjects 
who prematurely stop the study due to 
withdrawal of consent will be invited to attend 
the Early Study Withdrawal visit. 
 
7-8 and 
38-39 
Synopsis (Inclusion criteria) 
and Section 4.1 
All subjects must fulfil all the following criteria to 
be included in the study: 
All subjects must fulfil all the following criteria 
to be included in the study: 

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[…] 
(8) 
Subjects must have adequate organ and 
marrow function, based upon meeting all of 
the following laboratory criteria within 10 
days before study entry: 
(a) 
Absolute neutrophil count (ANC) ≥ 
1500/mm3 (≥ 1.5 GI/L). 
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 GI/L). 
(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) < 
3.0 × upper limit of normal (ULN). 
(e) 
Total bilirubin ≤ 1.5 × ULN. For 
subjects with Gilbert’s disease ≤ 3 
mg/dL (≤ 51.3 μmol/L). 
(f) 
Fasting serum triglycerides ≤ 2.5 × 
ULN AND total cholesterol ≤ 300 
mg/dL (≤ 7.75 mmol/L). Lipid-
lowering medication is allowed. 
(g) 
Serum creatinine ≤ 2.0 × ULN or 
calculated creatinine clearance ≥ 30 
mL/min (≥ 0.5 mL/sec) using the 
Cockcroft-Gault equation  
(h) 
Urine 
protein-to-creatinine 
ratio 
(UPCR) ≤ 1 mg/mg (≤ 113.2 
mg/mmol) creatinine or 24-hour urine 
protein < 1 g. 
 
 
[…] 
(8) 
Subjects must have adequate organ and 
marrow function, based upon meeting all 
of the following laboratory criteria within 
15 days before baseline: 
(a) 
Absolute neutrophil count (ANC) 
≥ 1500/mm3 (≥ 1.5 GI/L). 
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 
GI/L). 
(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine aminotransferase (ALT) 
and aspartate aminotransferase 
(AST) < 3.0 × upper limit of 
normal (ULN). 
(e) 
Total bilirubin ≤ 1.5 × ULN. For 
subjects with Gilbert’s disease ≤ 3 
mg/dL (≤ 51.3 μmol/L). 
(f) 
Fasting serum triglycerides ≤ 2.5 × 
ULN AND total cholesterol ≤ 300 
mg/dL (≤ 7.75 mmol/L). Lipid-
lowering medication is allowed. 
(g) 
Serum creatinine ≤ 2.0 × ULN or 
calculated creatinine clearance ≥ 
30 mL/min (≥ 0.5 mL/sec) using 
the Cockcroft-Gault equation  
(h) 
Urine protein-to-creatinine ratio 
(UPCR) ≤ 1 mg/mg (≤ 113.2 
mg/mmol) creatinine or 24-hour 
urine protein < 1 g. 
[…] 

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[…] 
(12) Female subjects of childbearing potential (i.e. 
less than or equal to 2 years post-menopause 
and not surgically sterile) must agree to use 
medically accepted methods of contraception 
(e.g. barrier methods, including 
male 
condom, female condom, or diaphragm with 
spermicidal gel) during the course of the 
study and for 4 months after the last dose of 
study treatment;  
(12) Female subjects of childbearing potential 
(i.e. less than or equal to 2 years post-
menopause and not surgically sterile) 
and their partners must agree to use 
highly 
effective 
methods 
of 
contraception 
that 
alone 
or 
in 
combination result in a failure rate of 
less than 1% per year when used 
consistently 
and 
correctly 
(see 
Appendix 3) during the course of the 
study and for 4 months after the last dose 
of study treatment;  
[…] 
(15) Subjects must be covered by social 
security or be the beneficiary of such a 
system (only applicable for French 
subjects). 
8-9 and 
39-40-
41 
Synopsis (Exclusion criteria) 
and Section 4.2 
Subjects will not be included in the study if the 
subject: 
(1) 
Has a diagnosis of predominant non clear-cell 
RCC; 
(2) 
Inability to swallow tablets; 
(3) 
Was treated with any other investigational 
medicinal product (IMP) within the last 
30 days before study entry; 
(4) 
Was previously treated with cabozantinib; 
 
 
Subjects will not be included in the study if the 
subject: 
 
 
 
(1) 
Inability to swallow tablets; 
(2) 
Was 
treated 
with 
any 
other 
investigational medicinal product (IMP) 
within the last 30 days before baseline; 
(3) 
Was 
previously 
treated 
with 
cabozantinib; 

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(5) 
Presents untreated brain or leptomeningeal 
metastases, or current clinical or radiological 
progression of known brain metastases; 
 
 
(6) 
Has a diagnosis of a serious cardiovascular 
disorder: 
(a) 
Congestive heart failure New York 
Heart Association 
class 3 or 4, 
unstable angina pectoris, or serious 
cardiac arrhythmias; 
(b) 
Uncontrolled hypertension, defined as 
sustained 
blood 
pressure 
(BP) 
(>140 mm Hg systolic or >90 mm Hg 
diastolic pressure) despite optimal 
antihypertensive treatment; 
(c) 
Stroke (including transient ischaemic 
attack (TIA)), myocardial infarction 
(MI) or other ischaemic event, or 
thromboembolic event (e.g. deep 
venous 
thrombosis, 
pulmonary 
(4) 
Has a contraindication to Magnetic 
Resonance Imaging (MRI) or contrast 
medium 
used 
for 
Contrast 
Tomography (CT)-scan; 
(5) 
Presents 
untreated 
brain 
or 
leptomeningeal metastases, or current 
clinical or radiographic progression of 
known brain metastases; 
(6) 
Has 
a 
diagnosis 
of 
a 
serious 
cardiovascular disorder: 
(a) 
Congestive heart failure New York 
Heart Association class 3 or 4, 
unstable 
angina 
pectoris, 
or 
serious cardiac arrhythmias; 
(b) 
Uncontrolled 
hypertension, 
defined 
as 
sustained 
blood 
pressure 
(BP) 
(>140 mm Hg 
systolic or >90 mm Hg diastolic 
pressure) 
despite 
optimal 
antihypertensive treatment; 
(c) 
Stroke 
(including 
transient 
ischaemic 
attack 
(TIA)), 
myocardial infarction (MI) or 
other 
ischaemic 
event, 
or 
thromboembolic event (e.g. deep 
venous thrombosis, pulmonary 
embolism) within 6 months before 
screening; 

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embolism) within 6 months before 
study entry; 
(d) 
History of risk factors for torsades de 
pointes (e.g., long QT syndrome); 
 
 
 
 
 
 
 
 
 
(7) 
Is receiving a concomitant anticoagulation 
with oral anticoagulants (e.g. warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet 
inhibitors (e.g. clopidogrel). 
Note: Low-dose aspirin for cardioprotection 
(per local applicable guidelines), low-dose 
warfarin (<1 mg/day), and low dose, low 
molecular weight heparin (LMWH) are 
permitted.  
 
 
 
(d) 
History of risk factors for torsades 
de 
pointes 
(e.g., 
long 
QT 
syndrome); 
 
 
(7) 
Is 
receiving 
a 
concomitant 
anticoagulation with oral anticoagulants 
(e.g.  warfarin, direct thrombin and 
Factor 
Xa 
inhibitors) 
or 
platelet 
inhibitors (e.g. clopidogrel). 
Note: 
Low-dose 
aspirin 
for 
cardioprotection (per local applicable 
guidelines), and low dose, low molecular 
weight heparin (LMWH) are permitted.  
 
(8) 
Has a gastrointestinal (GI) disorder 
including those associated with a high 
risk of perforation or fistula formation: 
(a) 
Tumours invading the GI tract, 
active 
peptic 
ulcer 
disease, 
inflammatory 
bowel 
disease, 
diverticulitis, 
cholecystitis, 
symptomatic 
cholangitis 
or 
appendicitis, acute pancreatitis or 
acute obstruction of the pancreatic 
or biliary duct, or gastric outlet 
obstruction; 
(b) 
Abdominal fistula, GI perforation, 
bowel 
obstruction, 
or 
intra-

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(8) 
Has a gastrointestinal (GI) disorder including 
those associated with a high risk of 
perforation or fistula formation: 
(a) 
Tumours invading the GI tract, active 
peptic ulcer disease, inflammatory 
bowel 
disease, 
diverticulitis, 
cholecystitis, symptomatic cholangitis 
or appendicitis, acute pancreatitis or 
acute obstruction of the pancreatic or 
biliary 
duct, 
or 
gastric 
outlet 
obstruction; 
(b) 
Abdominal fistula, GI perforation, 
bowel obstruction, or intra-abdominal 
abscess within 6 months before study 
entry;  
Note: Complete healing of an intra-
abdominal abscess must have been 
confirmed before study entry. 
 
 
 
 
 
 
 
 
(9) 
Presents a corrected QT (QTc) interval 
calculated 
by 
the 
Fridericia 
formula 
abdominal 
abscess 
within 
6 months before screening;  
Note: Complete healing of an 
intra-abdominal abscess must have 
been confirmed before screening. 
 
 
(9) 
Presents a corrected QT (QTc) interval 
calculated by the Fridericia formula 
(QTcF) > 500 msec within 1 month prior 
to baseline; 
Note: If a single electrocardiogram 
(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  
    
(10) Presents 
clinically 
significant 
haematuria, 
hematemesis, 
or 
haemoptysis of >0.5 teaspoon (2.5 mL) 
of red blood, or other history of 
significant bleeding (e.g. pulmonary 
haemorrhage) within 3 months before 
screening; 
 

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(QTcF) > 500 msec within 1 month prior to 
study entry; 
Note: If a single electrocardiogram (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  
 
 
 
(10) Presents clinically significant haematuria, 
hematemesis, 
or 
haemoptysis 
of 
>0.5 teaspoon (2.5 mL) of red blood, or other 
history 
of 
significant 
bleeding 
(e.g. 
pulmonary haemorrhage) within 3 months 
before study entry; 
 
 
 
[…] 
(15) Has had prior surgery within 4 weeks prior to 
study entry. Note: If the subject has 
undergone major surgery, complete wound 
healing must have occurred 1 month prior to 
study entry. 
 
 
[…] 
(15) Has had prior surgery within 4 weeks 
prior to baseline. Note: If the subject has 
undergone major surgery, complete 
wound healing must have occurred 
1 month prior to baseline. 
(16) Has had palliative radiation therapy for 
bone within 2 weeks or for radiation 
fields including viscera within 4 weeks 
prior 
to 
baseline. 
Note: 
Resolution/healing of side effects must 
be complete prior to baseline; 
 
(17) Has 
a 
history 
of 
another 
active 
malignancy 
within 
3 years 
from 
screening except for locally curable 
cancers that have been apparently cured, 
such as low-grade thyroid carcinoma, 
prostate cancer not requiring treatment 
(Gleason Grade ≤6), basal or squamous 
cell skin cancer, superficial bladder 
cancer, in situ melanoma, in situ prostate, 
cervix or breast carcinoma or other 
treated malignancies with <5% chance of 
relapse according to the Investigator; 
[…] 

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(16) Has had palliative radiation therapy for bone 
within 2 weeks or for radiation fields 
including viscera within 4 weeks prior to 
study entry. Note: Resolution/healing of side 
effects must be complete within 4 weeks 
prior to study entry; 
 
(17) Has a history of another active malignancy 
within 3 years from study entry except for 
locally curable cancers that have been 
apparently cured, such as low-grade thyroid 
carcinoma, prostate cancer not requiring 
treatment (Gleason Grade ≤6), basal or 
squamous cell skin cancer, superficial 
bladder cancer, in situ melanoma, in situ 
prostate, cervix or breast carcinoma or other 
treated malignancies with <5% chance of 
relapse according to the Investigator; 
 
 
[…] 
(21) Is pregnant or breastfeeding. A β-human 
chorionic 
gonadotrophin 
(HCG) 
serum 
pregnancy test will be performed up to 7 days 
prior to study entry for all female subjects of 
childbearing potential (i.e. less than or equal 
to 2 years post-menopause and not surgically 
sterile); 
(21) Is pregnant or breastfeeding. A β-human 
chorionic gonadotrophin (HCG) serum 
pregnancy test will be performed up to 
7 days prior to baseline for all female 
subjects of childbearing potential (i.e. 
less than or equal to 2 years post-
menopause and not surgically sterile); 
 

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11 
Synopsis (Criteria for 
evaluation (endpoints)) 
Efficacy: 
Secondary Endpoints(s) and Evaluation(s): 
• 
Best overall response (BOR) per RECIST 1.1 
evaluated by independent central review; 
• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
[…] 
• 
ORR, BOR, TTR, DOR, DCR and PFS per 
RECIST 1.1 according to local Investigator’s 
review; 
Safety: 
Safety assessments will start on the day of the 
Screening visit and will be carried out at minimum 
at 
every 
visit 
(every 
2 weeks) 
up 
to 
Week 4 (Visit 4), and every 4 weeks thereafter. 
Safety will also be assessed at the End of Study 
Treatment visit (30 days (+15 days)) after the last 
study treatment dose) and during the Post-treatment 
Follow-up period (every 12 weeks (±15 days) by 
telephone call) up to 18 months after the last subject 
included in the study started cabozantinib treatment. 
Unscheduled visits for safety evaluations are 
allowed at any time. 
Efficacy: 
Secondary Endpoints(s) and Evaluation(s): 
• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
[…] 
• 
ORR, TTR, DOR, DCR and PFS per 
RECIST 1.1 
according 
to 
local 
Investigator’s review; 
 
 
 
Safety: 
Safety assessments will start on the day of the 
Screening visit and will be carried out at 
minimum at every visit (every 2 weeks) up to 
Week 4 (Visit 4), and every 4 weeks thereafter. 
Safety will also be assessed at the End of Study 
Treatment visit (30 to 45 days after the last 
study 
treatment 
dose) 
and 
during 
the 
Post-treatment 
Follow-up 
period 
(every 
12 weeks (±15 days) by telephone call) up to 
18 months after the last subject included in the 
study 
started 
cabozantinib 
treatment. 
Unscheduled visits for safety evaluations are 
allowed at any time. 
12 
Synopsis (Statistical 
methods) 
Statistical Methods: 
Analyses will be performed at two intermediate data 
cut offs: 1) when 60% of subjects (i.e. 75 subjects) 
Statistical Methods: 
An intermediate analysis will be conducted 
when 60% of subjects (i.e. 75 subjects) of the 

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of the first recruiting cohort reaching the target 
number of subjects (either Cohort A or Cohort B) 
have reached 12 months of study follow-up. 2) 
when 60% of subjects (i.e. 75 subjects) of the 
second recruiting cohort reaching the target number 
of subjects (either Cohort A or Cohort B) have 
reached 12 months of study follow up. In addition, 
at this cut-off date, all subjects at 12 months of 
study follow up in the first recruiting cohort will be 
analysed. A final analysis will be performed after 
database lock, i.e. 18 months after the last subject 
received the first cabozantinib administration. At 
intermediate analysis, no statistical testing with 
alpha spending approach will be performed. The 
statistical testing will only be carried out at the final 
analysis. 
The primary endpoint (ORR), defined as the 
proportion of subjects with complete response (CR) 
and partial response (PR) per RECIST 1.1 as 
determined by independent central review and 
confirmed by a subsequent visit ≥28 days later, will 
be tested in each cohort using a one-sample exact 
test for binomial distribution. The proportion of 
subjects achieving ORR will be presented with their 
two-sided 95% CI using the Clopper-Pearson exact 
method. Best overall response (BOR) will be 
descriptively summarised and DCR estimates will 
be described with associated 2-sided 95% CIs. 
[…] 
first recruiting cohort reaching the target 
number of subjects (either Cohort A or 
Cohort B) have reached 12 months of study 
follow-up. Both cohorts will be analysed at 
this cut-off date. The final analysis based on 
the primary endpoint (ORR) will be 
performed 12 months after the last subject 
received 
the 
first 
cabozantinib 
administration. A follow-up analysis based 
on OS will be conducted 18 months after the 
last subject received the first cabozantinib 
administration. At the intermediate analysis, no 
statistical testing will be performed. The 
statistical testing will only be carried out at the 
final analysis. 
The primary endpoint (ORR), defined as the 
proportion of subjects with complete response 
(CR) and partial response (PR) per RECIST 1.1 
as determined by independent central review 
and confirmed by a subsequent visit ≥28 days 
later, will be tested in each cohort using a one-
sample exact test for binomial distribution. The 
proportion of subjects achieving ORR will be 
presented with their two-sided 95% CI using the 
Clopper-Pearson exact method. DCR estimates 
will 
be 
described 
with 
associated 
2-sided 95% CIs. 
[…] 

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19-20 
LIST OF 
ABBREVIATIONS 
[…] 
BOR: Best Overall Response 
[…] 
[…] 
 
 
DILI: Drug Induced Liver Injury 
[…] 
24-25 
1.1.2 
[…] 
Checkpoint inhibitor (CPI) therapy with ipilimumab 
and nivolumab is also an approved treatment for 
advanced RCC. Indeed, in January 2019, the 
European Medicines Agency (EMA) granted 
ipilimumab 
and 
nivolumab 
Marketing 
Authorisation for 1st line treatment of intermediate- 
and poor-risk subjects with advanced RCC. 
[…] 
Checkpoint inhibitor (CPI) therapy with 
ipilimumab and nivolumab is also an approved 
treatment for advanced RCC. Indeed, in January 
2019, the European Medicines Agency (EMA) 
granted ipilimumab and nivolumab Marketing 
Authorisation 
for 
1st 
line 
treatment 
of 
intermediate- and poor-risk subjects with 
advanced RCC. In September 2019, European 
Commission approved pembrolizumab in 
combination with axitinib and CHMP 
adopted positive opinion for avelumab plus 
axitinib as first-line treatment for patients 
with advanced RCC. 
28 
1.3 
[…] 
As such, several clinical trials have been underway 
to determine the efficacy and safety of a 
combination therapy with CPI and antiangiogenic 
TKI agents in untreated subjects with advanced 
RCC (19). These clinical trials include several 
Phase III trials, as follows: 
• 
An ongoing study evaluating the combination 
of cabozantinib and nivolumab versus 
[…] 
As such, several clinical trials have been 
underway to determine the efficacy and safety 
of a combination therapy with CPI and 
antiangiogenic TKI agents in untreated subjects 
with advanced RCC (19). These clinical trials 
include several Phase III trials, as follows: 
• 
An 
ongoing 
study 
evaluating 
the 
combination 
of 
cabozantinib 
and 

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sunitinib monotherapy in subjects with RCC 
(NCT03141177); 
• 
A study that assessed the combination of 
axitinib and pembrolizumab versus sunitinib 
monotherapy 
in 
subjects 
with 
RCC 
(NCT02853331); 
• 
An ongoing study evaluating the combination 
of lenvatinib and pembrolizumab versus 
sunitinib monotherapy in subjects with RCC 
(NCT02811861); 
• 
A study that assessed the combination of 
axitinib and avelumab versus sunitinib 
monotherapy 
in 
subjects 
with 
RCC 
(NCT02684006); 
• 
A study that assessed the combination of 
atezolizumab with or without an anti-VEGF 
agent (bevacizumab) versus sunitinib in 
untreated subjects with metastatic RCC 
(NCT02420821). 
Some of these studies have already provided 
promising results for the treatment of advanced 
RCC. The study that assessed axitinib plus 
pembrolizumab versus sunitinib monotherapy in 
subjects with RCC (KEYNOTE-426 trial) showed 
that subjects treated with the combination therapy 
experienced significantly longer OS and PFS and 
higher ORR compared to those treated with 
sunitinib (20).  
nivolumab versus sunitinib monotherapy 
in subjects with RCC (NCT03141177); 
• 
An 
ongoing 
study 
evaluating 
the 
combination 
of 
lenvatinib 
and 
pembrolizumab 
versus 
sunitinib 
monotherapy in subjects with RCC 
(NCT02811861); 
• 
A study that assessed the combination of 
atezolizumab 
with 
or 
without 
an 
anti-VEGF agent (bevacizumab) versus 
sunitinib in untreated subjects with 
metastatic RCC (NCT02420821). 
 

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The assessment of axitinib and avelumab versus 
sunitinib monotherapy in untreated subjects with 
RCC (JAVELIN Renal 101) showed that PFS was 
significantly longer in the combination therapy arm 
compared to the sunitinib arm (21).  
 
29 
1.4 
[…] 
Antiangiogenic agents currently represent the 
preferable 1st line treatment option for patients with 
advanced and metastatic RCC with intermediate 
and poor prognosis. However, according to the 
European Association of Urology Guidelines 
Recommendations and European Society for 
Medical Oncology (ESMO) guidelines (22, 23) and 
based on the results of the Phase III Checkmate-214 
study (15), CPI therapy with ipilimumab and 
nivolumab is likely to become the new standard of 
care for subjects with RCC with poor and 
intermediate prognosis 
[…] 
Antiangiogenic agents currently represent the 
preferable 1st line treatment option for patients 
with advanced and metastatic RCC with 
intermediate and poor prognosis. However, 
according to the European Association of 
Urology Guidelines Recommendations and 
European Society for Medical Oncology 
(ESMO) guidelines (22, 23) and based on 
recent 
approvals, 
CPI 
therapy 
with 
ipilimumab and nivolumab is likely to become 
the new standard of care for subjects with RCC 
with poor and intermediate prognosis and 
pembrolizumab and axitinib is likely to 
become the new standard of care for subjects 
with favourable prognosis. 
 
30-31 
1.4  
[…] 
 
 
 
 
[…] 
• 
Kalirai A. 2019 (28): reported results 
from the Canadian Kidney Cancer 
Information 
System: 
real 
world 
analysis of 102 patients treated with 
targeted therapy post CPI. Those who 

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received 
first-line 
ipilimumab 
+ 
nivolumab versus a VEGFi + CPI 
combination 
prior 
to 
second-line 
treatment had a median time to 
treatment failure of 8.0 vs 5.2 months 
(m) (HR=0.43, 95% CI: 0.13-1.44) and 
median OS of 16.5 m vs not reached 
(HR=0.76, 
95% 
CI: 
0.11-5.24). 
Patients who received a VEGFi versus 
a mammalian target of rapamycin 
inhibitor (mTORi) as third-line TT 
had a median TTF of 7.6 vs 4.4 m 
(HR=0.52, 95% CI: 0.24-1.10) and 
median OS of 21.7 vs 16.2 m (HR=0.41, 
95% CI: 0.16-1.08). All third-line 
treatment patients received first-line 
VEGFi and second-line nivolumab. Of 
the 
third-line 
VEGFi 
treatment 
patients, 24 received axitinib (TTF 7.1 
m, OS 21.7 m) and 22 received 
cabozantinib 
(data 
immature). 
Authors concluded that these results 
support the use of VEGFi after CPI in 
mRCC patients. 
• 
Ornstein MC 2018 (29) reported the 
results of a phase 2 Study of the 
Efficacy and Safety of axitinib given on 
an individualized schedule for mRCC, 
after treatment with PD-1 or PD-L1 
Inhibitors: the study included 38 

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patients whose most recent therapy 
was anti PD-1 (89%) or anti PD L1 
(11%). In evaluable patients, the 
estimated median PFS is 9.2 months, 
with 54% of patients still on axitinib. 
The ORR is 38.7%. The median 
highest dose per patient was 6mg BID 
(range, 5-9) and 44% of patients 
required dose reduction to < 5mg BID. 
There were no unexpected toxicities 
related to axitinib. 
[…] 
Secondary endpoints are time to response 
(TTR), duration of response (DOR), DCR and 
PFS per RECIST 1.1 assessed both by 
independent central review and by local 
Investigator, ORR per RECIST 1.1 assessed by 
local Investigator, OS and change in disease-
related symptoms as assessed by the Functional 
Assessment of Cancer Therapy-Kidney Cancer 
Symptom Index (FKSI-DRS). Safety and 
tolerability of cabozantinib will also be 
monitored throughout the study. 
 

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[…] 
Secondary endpoints are best overall response 
(BOR), time to response (TTR), duration of 
response (DOR), DCR and PFS per RECIST 1.1 
assessed both by independent central review and by 
local Investigator, ORR per RECIST 1.1 assessed 
by local Investigator, OS and change in disease-
related symptoms as assessed by the Functional 
Assessment of Cancer Therapy-Kidney Cancer 
Symptom 
Index 
(FKSI-DRS). 
Safety 
and 

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tolerability of cabozantinib will also be monitored 
throughout the study. 
32 
2.1 
[…] 
Several clinical trials are currently ongoing to 
investigate the effect of new treatment regimens 
containing CPI for patients with RCC (Section 1.3). 
If positive, the results from these trials will 
changethe available options for 1st line treatment of 
RCC. However, some of the patients may be 
refractory to these treatments, thus it is increasingly 
important to find potential 2nd line therapies for such 
patients. 
[…] 
Recent EMA approvals and several clinical 
trials are currently ongoing to investigate the 
effect of new treatment regimens containing 
CPI for patients with RCC (Section 1.3). These 
changes 
potentially 
transformed 
the 
treatment landscape and the available options 
for 1st line treatment of RCC. However, some of 
the patients may be refractory to these 
treatments, thus it is increasingly important to 
find potential 2nd line therapies for such 
patients. 
32 
2.2.2  
• 
To 
assess 
other 
efficacy 
criteria 
of 
cabozantinib such as best overall response 
(BOR), time to response (TTR), duration of 
response (DOR), disease control rate (DCR), 
progression-free 
survival 
(PFS) 
by 
independent and Investigator’s review; 
[…] 
• 
To assess other efficacy criteria of 
cabozantinib such as time to response 
(TTR), duration of response (DOR), 
disease control rate (DCR), progression-
free survival (PFS) by independent and 
Investigator’s review; 
• 
To assess objective response rate 
(ORR) by Investigator’s review; 
[…] 
33-34 
3.1  
This study will be conducted in approximately 
50 active investigational sites across Germany, 
Switzerland, 
the 
Netherlands, 
France, 
UK, 
Belgium, Austria and Spain. The list of countries 
and the number of investigational sites may change 
during the study depending on recruitment and 
This study will be conducted in approximately 
50 active investigational sites across Germany, 
Switzerland, the Netherlands, France, UK, 
Austria and Spain. The list of countries and the 
number of investigational sites may change 
during the study depending on recruitment and 

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availability of the CPI combination (ipilimumab 
and nivolumab) in each country. 
[…] 
 
Pre-treatment Period: Potential subjects will be 
screened to determine whether they meet the 
required eligibility criteria. Qualifying assessments 
at the Screening visit will be performed within 
15 days prior to first cabozantinib dose except when 
otherwise specified. Eligible subjects will be 
included in the study on the day of the Screening 
visit. 
[…]Subjects who discontinue study treatment with 
cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend the 
End of Study Treatment visit (30 days (+15 days)) 
after the last dose of cabozantinib) (Section 5.2.2.1). 
Subjects who prematurely stop the study will be 
invited to attend the Early Study Withdrawal visit 
(Section 5.2.2.2). 
[…] 
 
availability of the CPI combination (ipilimumab 
and nivolumab) in each country. 
[…] 
 
Pre-treatment Period: Potential subjects will 
be screened to determine whether they meet the 
required 
eligibility 
criteria. 
Qualifying 
assessments will be performed within 15 days 
prior to first cabozantinib dose except when 
otherwise specified (detailed in study schedule 
in Table 2).  
[…] 
Subjects who discontinue study treatment with 
cabozantinib due to disease progression or 
unacceptable toxicity will be invited to attend 
the End of Study Treatment visit (30 to 45 days 
after the last dose of cabozantinib) (Section 
5.2.2.1). Subjects who prematurely stop the 
study will be invited to attend the Early Study 
Withdrawal visit (Section 5.2.2.2). 
 
 
 
[…] 
[Figure 1 updated] 
34-35 
3.2.2  
• 
Best overall response (BOR) per RECIST 1.1 
evaluated by independent central review; 
• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
 

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• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
[…] 
• 
ORR, BOR, TTR, DOR, DCR and PFS per 
RECIST 1.1 according to local Investigator’s 
review; 
[…] 
The endpoints of ORR, BOR, TTR, DOR, DCR and 
PFS will be evaluated by tumour assessments (see 
Section 7.3.1). The OS will be assessed as described 
in Section 7.3.2.  
[…] 
• 
ORR, TTR, DOR, DCR and PFS per 
RECIST 1.1 
according 
to 
local 
Investigator’s review; 
 
[…] 
The endpoints of ORR, TTR, DOR, DCR and 
PFS will be evaluated by tumour assessments 
(see Section 7.3.1). The OS will be assessed as 
described in Section 7.3.2.  
35 
3.2.3  
Summaries of AEs and SAEs will be tabulated by 
cohort according to system organ class (SOC) and 
preferred term (PT) by overall incidence, worst 
reported severity, and relationship to study 
treatment.  
Summaries of AEs and SAEs will be tabulated 
by cohort and overall according to system 
organ class (SOC) and preferred term (PT) by 
overall incidence, worst reported severity, and 
relationship to study treatment.  
36 
3.6 
The study is planned to start in the third quarter of 
2019 and will start when the first subject provides a 
signed informed consent form.  
The study is planned to start in the fourth 
quarter of 2019 and will start when the first 
subject provides a signed informed consent 
form.  
37 
3.8  
An IRC will be established to evaluate tumour scans 
and prior radiation history data of study subjects in 
a central, blinded and independent fashion. The IRC 
will be comprised of board-certified radiologists 
who will evaluate prior radiation history to validate 
the identification of target lesions, as well as 
determine radiographic response and progression 
after study entry.  
An IRC will be established to evaluate tumour 
scans and prior radiation history data of study 
subjects in a central, blinded and independent 
fashion. The IRC will be comprised of 
board-certified radiologists who will evaluate 
prior 
radiation 
history 
to 
validate 
the 
identification of target lesions, as well as 

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determine 
radiographic 
response 
and 
progression after screening.  
41 
4.3.1.1 
If a subject decides to discontinue study treatment 
or the Investigator decides to discontinue a subject 
from the study treatment, this subject will be invited 
to undergo the assessments of the End of Study 
Treatment/Early 
Withdrawal 
visit 
(see 
Section 5.2.2) and to attend the Post-treatment 
Follow-up visits safety, subsequent anti-cancer 
therapies and survival status assessments, unless the 
subject withdraws consent to remain in the study 
and refuses to have his/her data collected. If study 
treatment discontinuation occurs, the reason and 
date of this decision must be recorded in the eCRF. 
If a subject decides to discontinue study 
treatment or the Investigator decides to 
discontinue a subject from the study treatment, 
this subject will be invited to undergo the 
assessments 
of 
the 
End 
of 
Study 
Treatment/Early 
Withdrawal 
visit 
(see 
Section 5.2.2) and to attend the Post-treatment 
Follow-up visits to assess safety, subsequent 
anti-cancer therapies and survival status 
assessments, unless the subject withdraws 
consent to remain in the study and refuses to 
have his/her data collected. If study treatment 
discontinuation occurs, the reason and date of 
this decision must be recorded in the eCRF. 
44-45-
46-47 
Table 2 
 
 
 
 
 
 
 
Assessment column: 
• 
Urinalysis, microscopic urine examination 
and urine chemistryg 
• 
Brain CT/MRI Bone CT scan (only if 
indicative of metastases) 
[Table 2 updated] 
Footnote f added at baseline column for 
eligibility 
criteria, 
physical 
examination, 
weight, vital signs and ECOG performance 
status assessments. 
Assessment column: 
• 
Urinalysis, 
microscopic 
urine 
examination 
and 
urine 
chemistry 
(including UPCR)g 
• 
Brain CT/MRI and Bone scintigraphy 
scan (only if indicative of metastases) 
 

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Pre-treatment Period column for Prior and 
concomitant therapies line:  
≤15 Days prior to Screening 
 
 
Footnote: 
e Informed consent may be obtained more than 
15 days prior to study entry but must be provided 
before any study-specific procedures are performed; 
however, evaluations performed as part of routine 
care prior to informed consent can be used as 
Screening 
evaluations 
if 
permitted 
by 
the 
Institutional 
Review 
Board 
(IRB)/Ethics 
Committee (EC) policies of the investigational site. 
 
f These assessments are intended to confirm 
suitability for treatment after the Screening visit. If 
these assessments have been performed during the 
Screening visit and within 15 days (or ≤7 days for 
pregnancy test and ≤28 days for CT/MRI scans) 
prior to first cabozantinib dose (baseline/Day 1), 
there is no need to perform them again at baseline, 
unless the subject’s clinical status has changed (e.g. 
onset of new symptoms indicative of clinical 
 
Pre-treatment Period column for Prior and 
concomitant therapies line:  
≤30 Days prior to Screening 
 
Footnote  
e Informed consent may be obtained more than 
15 days prior to screening but must be provided 
before any study-specific procedures are 
performed; however, evaluations performed as 
part of routine care prior to informed consent 
can be used as Screening evaluations if 
permitted by the Institutional Review Board 
(IRB)/Ethics Committee (EC) policies of the 
investigational site. 
 
f These assessments are intended to confirm 
suitability for treatment after the Screening 
visit. There is no need to perform them again at 
baseline, unless the subject’s clinical status has 
changed (e.g. onset of new symptoms indicative 
of clinical deterioration). If these assessments 
are performed at screening and baseline visits, 
results must be available to be reviewed by the 
Investigator prior to first dose.  
 
g Microscopic urine examination to be 
performed at baseline and after that only at the 
discretion of the Investigator (results are not to 

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deterioration). If these assessments are performed at 
baseline, results must be available to be reviewed by 
the Investigator prior to first dose.  
g Microscopic urine examination to be performed at 
baseline and after that only at the discretion of the 
Investigator (results are not to be collected in the 
eCRF except in case of clinically abnormal findings, 
which are to be reported as an AE). Urine chemistry 
(24-hour urine protein) may be performed at any 
scheduled or unscheduled visit at the discretion of 
the Investigator and based on results of routine 
urinalysis or as clinically indicated. 
 
 
 
i Follow-up for radiological progression, tumour 
assessment should be performed until radiological 
progression confirmed by the Investigator only for 
subjects who have discontinued cabozantinib 
treatment before radiological disease progression 
and who have not withdrawn consent. 
m Information on prior and concomitant medication 
will be collected up to 30 days before study entry 
until 30 days after the date of the last cabozantinib 
dose. 
be collected in the eCRF except in case of 
clinically abnormal findings, which are to be 
reported as an AE). Urine chemistry (24-hour 
urine protein or UPCR) may be performed at 
any scheduled or unscheduled visit at the 
discretion of the Investigator and based on 
results of routine urinalysis or as clinically 
indicated. 
 
i Follow-up for radiographic progression, 
tumour assessment should be performed until 
radiographic progression confirmed by the 
Investigator only for subjects who have 
discontinued cabozantinib treatment before 
radiographic disease progression and who 
have not withdrawn consent. 
m Information on prior and concomitant 
medication will be collected up to 30 days 
before screening until 30 days after the date of 
the last cabozantinib dose. 
48 
5.2.1 
[…] 
A signed and dated informed consent form may be 
obtained more than 15 days prior study entry but 
must be provided before any study-specific 
[…] 
A signed and dated informed consent form may 
be obtained more than 15 days prior screening 
but must be provided before any study-specific 

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procedures are performed. However, evaluations 
performed as part of routine care prior to the date of 
the signed informed consent form can be used as 
Screening 
evaluations 
if 
permitted 
by 
the 
IRB/Ethics Committee (EC) policies of the 
investigational site. Subjects will acknowledge and 
agree to the possible use of these data in the study 
by signing the informed consent form. 
After informed consent is obtained, subjects that 
meet all the inclusion criteria and none of the 
exclusion criteria will be included in the study. 
Included subjects will be assigned to Cohort A or 
Cohort B according to their 1st line therapy to treat 
RCC (Section 3.1). Subjects will undergo the 
required screening assessments outlined in Table 2 
to determine eligibility (see Section 4 for inclusion 
and exclusion criteria). Screening assessments must 
be performed within 15 days prior to first dose 
unless otherwise stated (as indicated in Table 2, 
certain assessments must be obtained closer to study 
entry).  
procedures 
are 
performed. 
However, 
evaluations performed as part of routine care 
prior to the date of the signed informed consent 
form can be used as Screening evaluations if 
permitted by the IRB/Ethics Committee (EC) 
policies of the investigational site. Subjects will 
acknowledge and agree to the possible use of 
these data in the study by signing the informed 
consent form. 
 
49 
5.2.2.1 
The End of Study Treatment visit will be carried out 
30 days (+15 days) after the last cabozantinib dose 
(all necessary assessments to be performed at this 
visit are indicated in Table 2). After this date, the 
subject will enter the Post-treatment Follow-up 
period (Section 5.2.3.1).  
The Investigator will ask subjects to return any 
remaining cabozantinib tablets and check their 
compliance to study protocol. Efficacy evaluations 
The End of Study Treatment visit will be carried 
out 30 to 45 days after the last cabozantinib 
dose (all necessary assessments to be performed 
at this visit are indicated in Table 2). After this 
date, the subject will enter the Post-treatment 
Follow-up period (Section 5.2.3.1).  
The Investigator will ask subjects to return any 
remaining cabozantinib tablets and check their 
compliance 
to 
study 
protocol. 
Efficacy 

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should not be performed for subjects who do not 
attend the End of Study Treatment visit within 30 
days (+15 days) after their last dose of cabozantinib. 
Subjects with ongoing AEs or clinically significant 
laboratory test abnormalities (as determined by the 
Investigator) will be monitored as described in 
Section 8.1.3 and Section 8.1.2.4, respectively. 
evaluations should not be performed for 
subjects who do not attend the End of Study 
Treatment visit within 30 to 45 days after their 
last dose of cabozantinib. Subjects with ongoing 
AEs or clinically significant laboratory test 
abnormalities 
(as 
determined 
by 
the 
Investigator) will be monitored as described in 
Section 8.1.3 and Section 8.1.2.4, respectively. 
 
49 
5.2.3 
[…] 
For subjects who have discontinued cabozantinib 
treatment before radiological disease progression 
and who have not withdrawn consent, tumour 
assessment should be performed until radiological 
progression confirmed by the Investigator. 
[…] 
For 
subjects 
who 
have 
discontinued 
cabozantinib treatment before radiographic 
disease progression and who have not 
withdrawn consent, tumour assessment should 
be performed until radiographic progression 
confirmed by the Investigator. 
54 
6.2.2 
Table 4 
First column: 
Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 Grade 
[Table 4 updated] 
First column: 
Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 Grade 
55 
6.2.4 
[…] 
Subjects may also experience other medically 
important but less frequent AEs including arterial 
and venous thrombotic AEs (e.g. deep vein 
thrombosis (DVT), pulmonary embolism, TIA and 
MI), severe haemorrhagic events, proteinuria, 
wound healing complications, GI perforation, 
abscesses including intra-abdominal and pelvic 
[…] 
Subjects may also experience other medically 
important but less frequent AEs including 
arterial and venous thrombotic AEs (e.g. deep 
vein thrombosis (DVT), pulmonary embolism, 
TIA and MI), aneurysms and artery 
dissections, 
severe 
haemorrhagic 
events, 
proteinuria, wound healing complications, GI 

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abscess, GI and non-GI fistulae formation, ONJ, and 
reversible posterior leukoencephalopathy syndrome 
(RPLS) also known as Posterior Reversible 
Encephalopathy Syndrome (PRES). 
perforation, 
abscesses 
including 
intra-
abdominal and pelvic abscess, GI and non-GI 
fistulae 
formation, 
ONJ, 
and 
reversible 
posterior 
leukoencephalopathy 
syndrome 
(RPLS) also known as Posterior Reversible 
Encephalopathy Syndrome (PRES). 
60 
7.2 
• 
Best overall response (BOR) per RECIST 1.1 
evaluated by independent central review; 
• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
 
[…] 
• 
ORR, BOR, TTR, DOR, DCR and PFS per 
RECIST 1.1 according to local Investigator’s 
review; 
 
[…] 
The endpoints of ORR, BOR, TTR, DOR, DCR and 
PFS will be evaluated by tumour assessments (see 
Section 7.3.1). The OS will be assessed as described 
in Section 7.3.2.  
 
 
 
 
• 
Time to response (TTR) per RECIST 1.1 
evaluated by independent central review; 
[…] 
• 
ORR, TTR, DOR, DCR and PFS per 
RECIST 1.1 
according 
to 
local 
Investigator’s review; 
 
[…] 
The endpoints of ORR, TTR, DOR, DCR and 
PFS will be evaluated by tumour assessments 
(see Section 7.3.1). The OS will be assessed as 
described in Section 7.3.2.  
60 
7.3.1 
Radiographic tumour assessments will include 
contrast 
tomography 
(CT) 
and/or 
magnetic 
resonance imaging (MRI) scans of the chest, 
abdomen, pelvis (C/A/P), brain, bone scans. The 
same imaging modalities used at the Screening visit 
should be used for subsequent tumour assessments. 
Radiographic tumour assessments will include 
contrast tomography (CT) and/or magnetic 
resonance imaging (MRI) scans of the chest, 
abdomen, pelvis (C/A/P), brain, and bone 
scintigraphy 
scans. 
The 
same 
imaging 
modalities used at the Screening visit should be 

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For subjects who have discontinued cabozantinib 
treatment before radiological disease progression 
and who have not withdrawn consent, tumour 
assessment should be performed until radiological 
progression is confirmed by the Investigator. (see 
Table 2 for schedule of assessments). 
 
 
 
 
[…] 
All CT/MRI scans (C/A/P, brain) and CT scans 
(bone) are recommended to be performed using the 
study-specified imaging protocol (refer to the most 
recent version of the imaging manual). To ensure 
image consistency, the same imaging modalities 
and acquisition protocols used at the Screening visit 
should be used for subsequent tumour assessments.  
used for subsequent tumour assessments. For 
subjects who have discontinued cabozantinib 
treatment 
before 
radiographic 
disease 
progression and who have not withdrawn 
consent, 
tumour 
assessment 
should 
be 
performed until radiographic progression is 
confirmed by the Investigator. (see Table 2 for 
schedule of assessments). 
 
[…] 
All CT/MRI scans (C/A/P, brain) and 
scintigraphy scans (bone) are recommended to 
be performed using the study-specified imaging 
protocol (refer to the most recent version of the 
imaging manual). To ensure image consistency, 
the same imaging modalities and acquisition 
protocols used at the Screening visit should be 
used for subsequent tumour assessments.  
 
63-64 
8.1.3 
All observed or self-reported AEs, regardless of 
treatment group or suspected causal relationship to 
IMP, will be recorded on the AE page(s) of the 
eCRF. Events involving drug reactions, accidents, 
illnesses with onset during the treatment phase of 
the study or exacerbations of pre-existing illnesses 
should be recorded according to the NCI 
terminology.  
[…] 
All observed or self-reported AEs, regardless of 
suspected causal relationship to IMP, will be 
recorded on the AE page(s) of the eCRF. Events 
involving drug reactions, accidents, illnesses 
with onset during the treatment phase of the 
study or exacerbations of pre-existing illnesses 
should be recorded according to the NCI 
terminology.  
 
[…] 

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Follow-up of the AE after the date of cabozantinib 
discontinuation is required until the event or its 
sequelae resolve or stabilise at a level acceptable to 
the Investigator and the Sponsor’s clinical monitor 
or his/her designated representative. 
 
Follow-up of the AE after the date of 
cabozantinib discontinuation is required until 
the event or its sequelae resolve or stabilise at a 
level acceptable to the Investigator and the 
Sponsor’s clinical monitor or his/her designated 
representative. 
Any AE with a suspected causal relationship 
to cabozantinib administration occurring at 
any other time after completion of the study 
(Section 5.6) must be reported promptly, 
within 24 hours. 
 
Follow-up of SAEs/ Grade 3 and 4 AEs 
leading to study treatment discontinuation: 
All SAEs that are ongoing at 30 days or later 
after the date of the last dose of study 
treatment and AEs assessed NCI-CTCAE 
Grade 3 or 4 that led to study treatment 
discontinuation that are ongoing 30 days 
after the last dose of study treatment are to 
be followed until either: 
• 
the AE has resolved; 
• 
the AE has improved to Grade 2 or 
lower; 
• 
the Investigator determines that the 
event 
has 
become 
stable 
or 
irreversible; 
The status of all other AEs that are ongoing 
30 days 
after 
the 
last 
dose 
will 
be 

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documented as of the last study visit for the 
subject. 
66 
8.1.4 
[…] 
Any AE/SAE with a suspected causal relationship 
to cabozantinib administration occurring at any 
other time after completion of the study must be 
reported promptly, within 24 hours. 
[…] 
Any SAE with a suspected causal relationship 
to cabozantinib administration occurring at any 
other time after completion of the study 
(Section 5.6) must be reported promptly, within 
24 hours. 
 
67 
8.1.5 
 
[…] 
Abnormal 
pregnancy 
outcome/AE 
in 
foetus/neonate/child 
If there is an abnormal pregnancy outcome 
or 
an 
AE 
is 
reported 
in 
the 
foetus/neonate/child following exposure to 
cabozantinib, an attempt must be made to 
follow-up until one month after delivery. The 
information will be collected in the Clinica1.l 
Study SAE Report Form (080478-FOR) for 
the mother and for the foetus/neonate/child. 
68 
8.2 
[…] 
All laboratory tests to establish eligibility must be 
done within 15 days prior to study entry (Table 2).  
[…] 
All laboratory tests to establish eligibility must 
be done within 15 days prior to screening 
(Table 2). 
69 
8.2 
Table 5 
Blood Chemistry column: 
 […] 
[Table 5 updated] 
Blood Chemistry column: 
 […] 

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- Triglycerides (fasted) 
 Lactate Dehydrogenase (LDH) 
- Triglycerides (fasted) 
 
69 
8.3 
[…] 
The ECOG performance status of the subject will be 
assessed at each scheduled safety assessment 
starting at baseline (see reference table in Appendix 
7). 
[…] 
The ECOG performance status of the subject 
will be assessed at each scheduled safety 
assessment starting at screening (see reference 
table in Appendix 7). 
74 
11.3 
ORR (primary endpoint) will be tested as described 
above using the one-sided significance level (alpha) 
of 0.025. The null hypothesis will be rejected at the 
final analysis if the result is statistically significant. 
No statistical testing for statistical comparisons will 
be carried out at the intermediate analysis nor for 
secondary efficacy and safety endpoints 
ORR (primary endpoint) will be tested at the 
final analysis as described above using the one-
sided significance level (alpha) of 0.025. No 
statistical testing will be carried out at the 
intermediate analysis nor for secondary efficacy 
and safety endpoints 
74-75 
11.4.3.2 
In line with the secondary endpoints indicated in 
Section 7.2 (see also Appendix 5), the secondary 
efficacy endpoints are: 
• 
Best overall response (BOR) defined as the 
best response among CR, PR, stable disease 
(SD) or progressive disease (PD) as 
determined by independent central review 
per RECIST 1.1; 
• 
Time to response (TTR) defined as the time 
from start of study treatment to the date of 
first evidence of response (PR or CR as 
determined by independent central review 
per RECIST 1.1); 
[…] 
In line with the secondary endpoints indicated 
in Section 7.2 (see also Appendix 5), the 
secondary efficacy endpoints are: 
 
 
 
 
 
 
 
• 
Time to response (TTR) defined as the 
time from start of study treatment to the 
date of first evidence of response (PR or 

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• 
ORR, BOR, TTR, DOR, DCR and PFS 
according to local Investigator’s review per 
RECIST 1.1; 
[…] 
CR as determined by independent central 
review per RECIST 1.1); 
 
[…] 
• 
ORR, TTR, DOR, DCR and PFS 
according to local Investigator’s review 
per RECIST 1.1; 
[…] 
75 
11.4.3.4 
The ORR according to Investigator’s assessment 
will be analysed in the same way as ORR assessed 
by independent central review without statistical 
testing. 
Discordance 
in 
ORR 
assessed 
by 
independent central review and by Investigator will 
be described.  
The BOR will be descriptively summarised. DCR 
estimates will be presented in statistical tables with 
associated 2-sided 95% CIs. 
 
The 
ORR 
according 
to 
Investigator’s 
assessment will be analysed in the same way as 
ORR assessed by independent central review 
without statistical testing. Discordance in ORR 
assessed by independent central review and by 
Investigator will be described.  
DCR estimates will be presented in statistical 
tables with associated 2-sided 95% CIs. 
 
76 
11.4.4 
[…] 
A TEAE is defined as any AE that occurs after first 
dose of study drug until 30 days after the date of last 
study drug administration if: 
• 
it was not present prior to receiving the first 
dose of study drug, or  
• 
it was present prior to receiving the first dose 
of study drug but the intensity increased 
during the active phase of the study. 
[…] 
A TEAE is defined as any AE that occurs after 
first dose of study drug if: 
• 
it was not present prior to receiving the 
first dose of study drug, or 
• 
it was present prior to receiving the first 
dose of study drug but the intensity 
increased during the active phase of the 
study. 

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The focus of analysis for this study will be the 
duration of the treatment period and 30 days 
after 
the 
date 
of 
last 
study 
drug 
administration. 
77 
11.5 
[…] 
• 
ECOG (0, 1) which will be converted from 
ECOG status; 
[…] 
[…] 
• 
ECOG (0, 1); 
[…] 
77 
11.6 
There are no formal interim analyses with stopping 
rules for efficacy or futility planned for this study. 
However, intermediate analyses are planned as 
follows:  
• 
The first intermediate analysis will be 
conducted when 60% of subjects (i.e. 
75 subjects) of the first recruiting cohort 
reaching the target number of subjects (either 
Cohort A 
or 
Cohort B) 
have 
reached 
12 months of study follow-up;  
• 
The second intermediate analysis will be 
conducted when 60% of subjects (i.e. 
75 subjects) of the second recruiting cohort 
reaching the target number of subjects (either 
Cohort A 
or 
Cohort B) 
have 
reached 
12 months of study follow-up. In addition, at 
this cut off date, all subjects in the first 
recruiting cohort at 12 months of study 
There are no formal interim analyses with 
stopping rules for efficacy or futility planned for 
this study. However, one intermediate analysis 
is planned as follows:  
The intermediate analysis will be conducted 
when 60% of subjects (i.e. 75 subjects) of the 
first recruiting cohort reaching the target 
number of subjects (either Cohort A or 
Cohort B) have reached 12 months of study 
follow-up; Both cohorts will be analysed at 
this cut-off date.    
 
 
 
 
 
 

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follow-up will be analysed. A final analysis 
will be performed after database lock, i.e. 
18 months after the last subject received the 
first cabozantinib administration. 
 
 
 
 
 
 
 
A follow-up analysis based on OS will be conducted 
after database lock, i.e. 18 months after the last 
subject 
received 
the 
first 
cabozantinib 
administration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A final analysis based on the primary 
endpoint (ORR) will be performed 12 months 
after the last subject received the first 
cabozantinib administration. 
A follow-up analysis based on OS will be 
conducted 18 months after the last subject 
received the first cabozantinib administration. 
The statistical testing will only be carried out 
at the final analysis. 
 
82 
14.2 
Prior to study entry, the Investigator or a person 
designated by the Investigator will explain the 
nature, purpose, benefits and risks of participation 
in the study to each subject, subject’s legally 
Prior to screening, the Investigator or a person 
designated by the Investigator will explain the 
nature, 
purpose, 
benefits 
and 
risks 
of 
participation in the study to each subject, 

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acceptable representative or impartial witness. 
Written informed consent must be obtained before 
to the subject enters the study (before initiation of 
any study-related procedure and administration of 
cabozantinib). Sufficient time will be given to 
discuss any questions raised by the subject. 
subject’s legally acceptable representative or 
impartial witness. Written informed consent 
must be obtained before to the subject enters the 
study (before initiation of any study-related 
procedure and administration of cabozantinib). 
Sufficient time will be given to discuss any 
questions raised by the subject. 
 
88 
17.2 
[…] 
As indicated in Section 11.6, an analysis will be 
performed on the final response data after the last 
subject has completed the treatment period. This 
analysis will be included in the final study report. 
An addendum to the report, including the analysis 
of data from the follow-up period, will be prepared 
after the last subject completes the follow-up period. 
 
[…] 
As indicated in Section 11.6, the intermediate 
analysis will be conducted when 60% of 
subjects of the first recruiting cohort 
reaching the target number of subjects have 
reached 12 months of study follow-up. This 
analysis will be included in the interim study 
report. An analysis will be performed on the 
final response data after the last subject has 
completed the treatment period. This analysis 
will be included in the final study report. An 
addendum to the report, including the analysis 
of data from the follow-up period, will be 
prepared after the last subject completes the 
follow-up period. 
90 
18 
[references deleted] 
20 
Rini, 
Brian 
I., 
et 
al. 
“Pembrolizumab 
plus 
Axitinib 
versus Sunitinib for Advanced 
Renal Cell 
Carcinoma.” 
New 
[references added] 
28 
Kalirai A, Wood L, Lalani A et 
al. Efficacy of targeted therapy 
(TT) after checkpoint inhibitors 
(CPI) in metastatic renal cell 
carcinoma (mRCC): Results 

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England Journal of Medicine 
(2019). 
21 
Motzer, Robert J., et al. “Avelumab 
plus axitinib versus sunitinib for 
advanced renal cell carcinoma.” 
New England Journal of Medicine 
(2019). 
 
from the Canadian Kidney 
Cancer Information System 
(CKCis). Journal of Clinical 
Oncology 37, no. 7_suppl 
(March 1 2019) 568-568. 
29 
Ornstein MC, Pal SK, Wood 
LS et al. Individualised axitinib 
regimen 
for 
patients 
with 
metastatic renal cell carcinoma 
after treatment with checkpoint 
inhibitors: 
a 
multicentre, 
single-arm, phase 2 study. 
Lancet Oncol 2019. 
92-93 
Appendix 
 
[Appendix 1 Memorial Sloan Kettering Cancer 
Center (MSKCC) Criteria for prognostic risk 
category added] 
94-95 
Appendix 2 
 
[Appendix 2 International Metastatic RCC 
Database Consortium (IMDC) risk group 
category added] 
96-97 
Appendix 3 
 
[Appendix 3 Methods of contraception added] 
102 
Appendix 4 (4 Vascular 
disorders) 
 […] 
 
 […] 
Aneurysms and artery dissections 
The use of VEGF pathway inhibitors in 
patients with or without hypertension may 
promote the formation of aneurysms and/or 
artery 
dissections. 
Before 
initiating 
cabozantinib, this risk should be carefully 

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considered in patients with risk factors such 
as hypertension or history of aneurysm. 
104 
Appendix 4 
(6 Skin and subcutaneous 
tissue disorders) 
Table A1.3 
First column: 
Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 Grade 
[Table A1.3 updated] 
First column: 
Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 Grade 
107 
Appendix 4 (11 Hepatic 
events) 
Elevations of aminotransferases when hepatic 
tumours are present may not require study treatment 
dose modifications if there are no progressive 
changes in the aminotransferases (less than a 
doubling) and if there are no progressive elevations 
in serum total bilirubin concentration or coagulation 
factors. 
Subjects 
with 
right 
upper quadrant 
abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) 
performed immediately and reviewed before 
administration of the next dose of study drug. 
 
Investigators should monitor for Drug 
induced lived injury (DILI) diligently and 
report any potential events.  
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 
(e.g. liver cirrhosis, thrombosis of portal or 
hepatic vein, HCC, hepatitis), concomitant 
hepatotoxic 
medication, 
alcohol 
consumption, and cancer related causes.  
If not otherwise specified in individual 
protocols, 
cabozantinib 
should 
be 
interrupted for related CTCAE Grade 3 or 
higher hepatic injury (transaminase increase 
to > 5 × ULN) and when transaminase 
increases are accompanied by progressive 
elevations 
of 
total 
bilirubin, 
and/or 
elevations 
of 
coagulation 
tests 
(e.g. 
International Normalized Ratio [INR]). 
More frequent monitoring of transaminases 
should be considered and cabozantinib 

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should be held 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 
DILI. Study drug should be permanently 
discontinued in cases determined to be DILI 
according to Hy’s Law review. 
112 
Appendix 5 
Definitions 
Baseline: Baseline is defined as the most recent 
assessment performed prior to study entry. In this 
study, baseline is equivalent to the Screening visit. 
Baseline assessments must be performed within the 
period defined in the protocol eligibility criteria. 
[…] 
Definitions 
Baseline: Baseline is defined as the most recent 
assessment performed prior to study entry. 
Baseline assessments must be performed within 
the period defined in the protocol eligibility 
criteria. 
[…] 

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121 
Appendix 7 
 
[Appendix 7 updated] 

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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-60000-023 
AMENDED 
PROTOCOL 
VERSION 
NUMBER 
& 
DATE 
 
Final (including Amendment #1): 28 November 2019 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
 
- Main changes of the protocol amendment #1 are linked to requests 
from Regulatory European authorities and ECs. 
- Correction of minor inconsistencies and typos. 
- Update of background and rationale parts due to new treatments 
approved in RCC 
OTHER ACTION REQUIRED? CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 

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Appendix 9 Amendment Form #2 

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condoms, 
diaphragms, 
and spermicides (creams 
or gels that contain a 
chemical to kill sperm); or 
• 
intrauterine device (IUD) 
or intrauterine hormone-
releasing system (IUS) 
plus a barrier method; 
• 
bilateral tubal occlusion 
(females); 
• 
vasectomized 
partner 
(males). 
 
[…] 
The interaction of cabozantinib 
with oral contraceptives has not 
been investigated and this may 
mean your oral contraceptive 
could be ineffective, therefore it 
is 
recommended 
that 
an 
additional contraceptive method 
such as a barrier method (e.g. 
condom or diaphragm) is used if 
you are taking oral combined 
contraception or progestogen
only contraception.  
hormone-releasing 
system (IUS) plus a 
barrier method; 
• 
bilateral 
tubal 
occlusion (females); 
• 
vasectomized partner 
(males). 
 

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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-60000-023 
AMENDED 
PROTOCOL 
VERSION 
NUMBER 
& 
DATE 
 
Final (including Amendment #2): 24 January 2020 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
 
- Main change of the protocol amendment #2 is linked to requests 
from Regulatory European authorities: re-wording of the 
contraceptive methods on a precautionary basis. 
OTHER ACTION REQUIRED? CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 

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Appendix 10 Amendment Form #3 
 

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3 
Coordinatin
g 
investigator’
s agreement 
page 
 
[Page deleted] 
4 
Synopsis 
(number of 
planned 
centres) 
50 active centres 
Approximately  
50 active centres 
5-6 
Synopsis 
(Methodolog
y) 
[…]q 
Post-treatment Follow-up Period: Subjects who discontinue study 
treatment will be contacted during the Post-treatment Follow-up 
visits every 12 weeks ±15 days to assess survival status and collect 
information about subsequent anti-cancer therapy. 
[…] 
Post-treatment Follow-up Period: Subjects 
who discontinue study treatment will be 
contacted during the Post-treatment Follow-up 
visits every 12 weeks ±15 days to assess survival 
status and collect information about subsequent 
anti-cancer therapy. During the follow-up 
period, any SAEs that occur more than 
30 days after the date of the last cabozantinib 
dose, assessed as related to study treatment or 
study procedures will also be collected and 
followed 
until 
resolution 
or 
stability 
according to the Investigator. 
6-7 
and 
37-38 
Synopsis 
(Inclusion 
criteria) and 
Section 4.1 
[…] 
(8) 
Subjects must have adequate organ and marrow function, 
based upon meeting all of the following laboratory criteria 
within 15 days before baseline: 
(a) 
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 
GI/L). 
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 GI/L). 
[…] 
(8) 
Subjects must have adequate organ and 
marrow function, based upon meeting all 
of the following laboratory criteria within 
15 days before baseline: 
(a) 
Absolute neutrophil count (ANC) ≥ 
1500/mm3 (≥ 1.5 GI/L). 

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(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) < 3.0 × upper limit of normal 
(ULN). 
(e) 
Total bilirubin ≤ 1.5 × ULN. For subjects with Gilbert’s 
disease ≤ 3 mg/dL (≤ 51.3 μmol/L). 
(f) 
Fasting serum triglycerides ≤ 2.5 × ULN and total 
cholesterol ≤ 300 mg/dL (≤ 7.75 mmol/L). Lipid
lowering medication is allowed. 
(g) 
Serum creatinine ≤ 2.0 × ULN or calculated creatinine 
clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the 
Cockcroft-Gault equation  
(h) 
Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 
113.2 mg/mmol) creatinine or 24-hour urine protein < 1 
g. 
 
 
 
[…] 
(12) Female subjects of childbearing potential (i.e. less than or 
equal to 2 years post-menopause and not surgically sterile) and 
their partners must agree to use highly effective methods of 
contraception (that alone or in combination result in a failure 
rate of less than 1% per year when used consistently and 
correctly) during the course of the study and for 4 months after 
the last dose of study treatment;  
(b) 
Platelets ≥ 100,000/mm3 (≥ 100 
GI/L). 
(c) 
Haemoglobin ≥ 9 g/dL (≥ 90 g/L). 
(d) 
Alanine aminotransferase (ALT) 
and 
aspartate 
aminotransferase 
(AST) < 3.0 × upper limit of normal 
(ULN). 
(e) 
Total bilirubin ≤ 1.5 × ULN. For 
subjects with Gilbert’s disease ≤ 3 
mg/dL (≤ 51.3 μmol/L). 
(f) 
Serum creatinine ≤ 2.0 × ULN or 
calculated creatinine clearance ≥ 30 
mL/min (≥ 0.5 mL/sec) using the 
Cockcroft-Gault equation  
(g) 
Urine protein-to-creatinine ratio 
(UPCR) ≤ 1 mg/mg (≤ 113.2 
mg/mmol) creatinine or 24-hour 
urine protein < 1 g. 
 
[…] 
(12) Female subjects of childbearing potential 
(i.e. less than or equal to 2 years post-
menopause and not surgically sterile) and 
their partners must agree to use highly 
effective methods of contraception that 
alone or in combination result in a failure 
rate of less than 1% per year when used 
consistently and correctly) during the 
course of the study and for 120 days after 
the last dose of study treatment;  

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7-8 
and 
38-39 
Synopsis 
(Exclusion 
criteria) and 
Section 4.2 
[…] 
(2) 
Was treated with any other investigational medicinal product 
(IMP) within the last 30 days before baseline; 
 
[…] 
(7) 
Is receiving a concomitant anticoagulation with oral 
anticoagulants (e.g. warfarin, direct thrombin and Factor Xa 
inhibitors) or platelet inhibitors (e.g. clopidogrel). 
Note: Low-dose aspirin for cardioprotection (per local 
applicable guidelines), and low dose, low molecular weight 
heparin (LMWH) are permitted.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[…] 
(2) 
Was treated with any other investigational 
medicinal product (IMP) during a 
clinical study within the last 30 days 
before baseline; 
[…] 
(7) 
Is receiving a concomitant anticoagulation 
with coumarin agents (e.g. warfarin), 
direct thrombin inhibitor dabigatran, 
direct Factor Xa inhibitor betrixaban or 
platelet inhibitors (e.g. clopidogrel). 
Note: 
The 
following 
are 
allowed 
anticoagulants: prophylactic use of 
low-dose aspirin for cardioprotection (per 
local applicable guidelines), and low dose 
of 
low 
molecular 
weight 
heparin 
(LMWH). Therapeutic doses of LMWH 
or anticoagulation with direct factor Xa 
inhibitors rivaroxaban, edoxaban, or 
apixaban in patients without known 
brain metastases who are on a stable 
dose of the anticoagulant for at least 1 
week before baseline without clinically 
significant hemorrhagic complications 
from the anticoagulation regimen or the 
tumour. 
 
[…] 

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[…] 
(13) Has been diagnosed with other clinically significant disorders 
such as: 
(a) 
Serious nonhealing wound/ulcer/bone fracture; 
(b) 
Malabsorption syndrome; 
(c) 
Free thyroxine 4 (FT4) outside the laboratory normal 
reference range;  
(d) 
Uncompensated/symptomatic hypothyroidism; 
(e) 
Moderate to severe hepatic impairment (Child-Pugh B 
or C); 
(f) 
Requirement for haemodialysis or peritoneal dialysis; 
(g) 
History of solid organ transplantation; 
(13) Has been diagnosed with other clinically 
significant disorders such as: 
(a) 
Serious 
nonhealing 
wound/ulcer/bone fracture; 
(b) 
Malabsorption syndrome; 
(c) 
Uncompensated/symptomatic 
hypothyroidism (subject with a 
history of autoimmune-related 
hypothyroidism 
who 
are 
on 
thyroid-replacement 
hormone 
are eligible for the study); 
(d) 
Moderate 
to 
severe 
hepatic 
impairment (Child-Pugh B or C); 
(e) 
Requirement for haemodialysis or 
peritoneal dialysis; 
(f) 
History 
of 
solid 
organ 
transplantation; 
9 
Synopsis 
(Test 
product, 
dose, mode 
of 
administrati
on) 
[…] 
The date of the first dose of cabozantinib is defined as baseline 
(Day 1, Visit 2) and should occur within 15 days after the Screening 
visit. Doses will be self-administered at home by taking cabozantinib 
q.d. at the same time each day (preferably at bedtime). Cabozantinib 
should not be taken with food. The subject should not eat anything 
for at least 2 hours before and 1 hour after taking cabozantinib. 
[…] 
The date of the first dose of cabozantinib is 
defined as baseline (Day 1, Visit 2) and 
screening and baseline visits can take place 
the same day as long as all eligibility 
criteria/parameters are available and checked 
prior to the first dose of cabozantinib. Doses 

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will be self-administered at home by taking 
cabozantinib q.d. at the same time each day 
(preferably at bedtime). Cabozantinib should not 
be taken with food. The subject should not eat 
anything for at least 2 hours before and 1 hour 
after taking cabozantinib. 
10 
Synopsis 
(Criteria for 
evaluation 
(endpoints)) 
Safety 
[…] 
Routine safety evaluations throughout the study will include the 
recording of AEs, clinical laboratory (serum chemistry, haematology 
and urinalysis) test results, serum pregnancy tests (in females of 
childbearing potential), thyroid function tests, vital signs (BP and 
heart rate), ECG findings, physical examination findings and body 
weight measurements, and use of concomitant medication throughout 
the study. 
Information on new or worsening AEs will be collected from the date 
the informed consent is signed until the End of Study Treatment visit 
(treatment related serious AEs (SAEs) are to be reported at any time, 
including after the study is finished). This information will be 
collected at study visits, by telephone call to the subject or by 
spontaneous report by the subject. At baseline, AEs will be 
documented before and after cabozantinib dosing. Certain AEs and 
all SAEs that are ongoing 30 days after the date of the last 
cabozantinib dose are to be followed until resolution or until the 
Investigator considers the event is stable or irreversible. Any 
AE/SAEs assessed as related to study treatment or study procedures, 
even SAEs that occur more than 30 days after the date of the last 
cabozantinib dose, will also be collected and followed until 
resolution or stability according to the Investigator. 
Safety 
[…] 
Routine safety evaluations throughout the study 
treatment period will include the recording of 
AEs, clinical laboratory (serum chemistry, 
haematology and urinalysis) test results, serum 
pregnancy tests (in females of childbearing 
potential), thyroid function tests, vital signs (BP 
and heart rate), ECG findings, physical 
examination 
findings 
and 
body 
weight 
measurements, 
and 
use 
of 
concomitant 
medication throughout the study treatment 
period. 
Information on new or worsening AEs and 
serious AEs (SAEs) will be collected from the 
date the informed consent is signed until the End 
of Study Treatment visit. This information will 
be collected at study visits, by telephone call to 
the subject or by spontaneous report by the 
subject. At baseline, AEs will be documented 
before and after cabozantinib dosing. Certain 
AEs and all SAEs that are ongoing 30 days after 
the date of the last cabozantinib dose are to be 
followed until resolution or until the Investigator 

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considers the event is stable or irreversible. 
During the follow-up period, any SAEs that 
occur more than 30 days after the date of the last 
cabozantinib dose, assessed as related to study 
treatment or study procedures will also be 
collected and followed until resolution or 
stability according to the Investigator. 
11 
Synopsis 
(Statistical 
Methods) 
Sample size:  
With a true ORR proportion of 19%, a sample size of 117 subjects in 
each cohort will provide a statistical power of 80% to reject the null 
hypothesis of 10%, using a one-sample exact test for binomial 
distribution with a significance level of 0.025 (one-sided). Assuming 
approximately 7% non-evaluable subjects, a total of 125 subjects per 
cohort will be included in the study. 
 
 
 
 
 
 
 
Statistical Methods: 
[…] 
The primary endpoint (ORR), defined as the proportion of subjects 
with complete response (CR) and partial response (PR) per 
RECIST 1.1 as determined by independent central review and 
confirmed by a subsequent visit ≥28 days later, will be tested in each 
cohort using a one-sample exact test for binomial distribution. 
Sample size:  
With a true ORR proportion of 19%, a sample 
size of 117 subjects in each cohort will provide a 
statistical power of 80% to reject the null 
hypothesis of 10%, using a one-sample exact test 
for binomial distribution with a significance 
level 
of 
0.025 (one-sided). 
Assuming 
approximately 7% non-evaluable subjects (i.e. 
subject who received at least one dose of study 
medication but did not provide a baseline for 
the tumour according to RECIST 1.1), a total 
of 125 subjects per cohort will be included in the 
study. 
 
Statistical Methods: 
[…] 
The primary endpoint (ORR), defined as the 
proportion of subjects with complete response 
(CR) and partial response (PR) per RECIST 1.1 
as determined by independent central review will 
be tested in each cohort using a one-sample exact 
test for binomial distribution. 

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[…] 
Summary statistics (mean, median, standard deviation and range as 
appropriate) of values and changes or shifts from baseline will be 
presented by cohort and overall for vital signs, ECG variables, 
clinical laboratory tests etc. at each assessment. For laboratory data, 
abnormal values will be flagged in the data listings and a list of 
clinically significant abnormal values will be presented. 
 
[…] 
Summary statistics (mean, median, standard 
deviation and range as appropriate) of values and 
changes or shifts from baseline will be presented 
by cohort and overall for vital signs, ECG 
variables, clinical laboratory tests etc. at each 
assessment. For laboratory data, abnormal values 
will be flagged in the data listings and a list of 
clinically significant abnormal values will be 
presented. 
24 
1.1.2 
[…] 
Checkpoint inhibitor (CPI) therapy with ipilimumab and nivolumab 
is also an approved treatment for advanced RCC. Indeed, in January 
2019, the European Medicines Agency (EMA) granted ipilimumab 
and nivolumab Marketing Authorisation for 1st line treatment of 
intermediate- and poor-risk subjects with advanced RCC. In 
September 2019, European Commission approved pembrolizumab in 
combination with axitinib and CHMP adopted positive opinion for 
avelumab plus axitinib as first-line treatment for patients with 
advanced RCC. 
[…] 
Checkpoint 
inhibitor 
(CPI) 
therapy 
with 
ipilimumab and nivolumab is also an approved 
treatment for advanced RCC. Indeed, in January 
2019, the European Medicines Agency (EMA) 
granted ipilimumab and nivolumab Marketing 
Authorisation 
for 
1st 
line 
treatment 
of 
intermediate- and poor-risk subjects with 
advanced RCC. European Commission approved 
pembrolizumab in combination with axitinib in 
August 2019 and for avelumab plus axitinib as 
first-line treatment for patients with advanced 
RCC in September 2019. 
24 
1.2 
Cabozantinib (XL184) is a multitarget TKI that inhibits several 
proteins involved in the pathology of RCC, such as MET, VEGFR2, 
the tyrosine-protein kinase receptor UFO (AXL) and the proto-
oncogene (RET). Cabozantinib is provided as both capsules and 
tablets, but the two formulations are not interchangeable. 
Cabozantinib (XL184) is a multitarget TKI that 
inhibits several proteins involved in the 
pathology of RCC, such as MET, VEGFR2, the 
tyrosine-protein kinase receptor UFO (AXL) and 
the proto-oncogene (RET). Cabozantinib is 

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Cometriq® (cabozantinib capsules, 20 and 80 mg) was approved as a 
treatment for subjects with progressive, metastatic medullary thyroid 
cancer (MTC) on 29 November 2012 by the Food and Drug 
Administration (FDA), and on 21 March 2014 by the EMA.  
Cabometyx™ (cabozantinib tablets, 20, 40 and 60 mg) is currently 
approved by the EMA as a 2nd line treatment for subjects with 
advanced RCC previously treated with VEGF-targeted therapy, and 
as a 1st line treatment for adults with advanced RCC with 
intermediate and poor risk. 
Cabometyx™ (cabozantinib tablets, 20, 40 and 60 mg) is currently 
approved by the FDA for the treatment of all subjects with advanced 
RCC regardless of previous therapies received. 
provided as both capsules and tablets, but the two 
formulations are not interchangeable. 
Cabometyx™ (cabozantinib tablets, 20, 40 and 
60 mg) is currently approved by the EMA as a 
2nd line treatment for subjects with advanced 
RCC previously treated with VEGF-targeted 
therapy, and as a 1st line treatment for adults with 
advanced RCC with intermediate and poor risk. 
Cabometyx™ (cabozantinib tablets, 20, 40 and 
60 mg) is currently approved by the Food and 
Drug Administration (FDA) for the treatment 
of all subjects with advanced RCC regardless of 
previous therapies received. 
 
27 
1.3 
Treatment with CPIs combined with antiangiogenic agents 
[…] 
As such, several clinical trials have been underway to determine the 
efficacy and safety of a combination therapy with CPI and 
antiangiogenic TKI agents in untreated subjects with advanced RCC 
(19). These clinical trials include several Phase III trials, as follows: 
An ongoing study evaluating the combination of cabozantinib and 
nivolumab versus sunitinib monotherapy in subjects with RCC 
(NCT03141177); 
• 
An ongoing study evaluating the combination of lenvatinib 
and pembrolizumab versus sunitinib monotherapy in subjects 
with RCC (NCT02811861); 
Treatment 
with 
CPIs 
combined 
with 
antiangiogenic agents 
[…] 
As such, two new therapeutic options axitinib 
plus pembrolizumab and axitinib plus  
avelumab showed the efficacy and safety of 
combination therapy with CPI and TKI in 
untreated subjects with advanced RCC have 
been approved by EMA in August 2019 and in 
September 2019, respectively. Some clinical 
trials are ongoing: 
• 
A study evaluating the combination of 
lenvatinib and pembrolizumab versus 
sunitinib monotherapy in subjects with 
RCC (NCT02811861); 

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• 
A study that assessed the combination of atezolizumab with or 
without an anti VEGF agent (bevacizumab) versus sunitinib in 
untreated subjects with metastatic RCC (NCT02420821). 
Results from the study that assessed the combination of atezolizumab 
(a programmed death-ligand 1 (PD L1)/ PD-1 protein inhibitor) with 
or without an anti-VEGF agent (bevacizumab) versus sunitinib in 
untreated subjects with metastatic RCC (IMmotion151 trial) showed 
that cabozantinib and atezolizumab and bevacizumab in combination 
improved PFS compared to sunitinib in subjects with untreated 
metastatic or advanced RCC (20). A recent safety analysis showed 
that atezolizumab and bevacizumab in combination showed a 
tolerable safety profile in subjects with metastatic RCC with less 
toxicity compared to sunitinib. The toxicities observed were 
consistent with each agent alone, and no new AEs were identified in 
this analysis (21). 
• 
A study of cabozantinib in combination 
with nivolumab and ipilimumab in 
patients 
with 
previously 
untreated 
advanced 
of 
metastatic 
RCC 
(NCT03937219). 
Results from the study (NCT0314177) that 
assessed the combination of nivolumab (a 
programmed death-ligand 1/ PD-1 protein 
inhibitor) with cabozantinib versus sunitinib in 
untreated 
subjects 
with 
metastatic 
RCC 
(CkeckMate 
9ER 
trial) 
showed 
that 
cabozantinib and atezolizumab in combination 
improved PFS and OS compared to sunitinib in 
subjects with untreated metastatic or advanced 
RCC (20).  
 
29 
1.4 
The primary endpoint is ORR, defined as the proportion of subjects 
with a confirmed CR or partial response (PR) per Response 
Evaluation Criteria in Solid Tumours (RECIST) 1.1, as determined 
by an independent central review. 
The primary endpoint is ORR, defined as the 
proportion of subjects with CR or partial 
response (PR) per Response Evaluation Criteria 
in Solid Tumours (RECIST) 1.1, as determined 
by an independent central review. 
30 
1.7 
[…] 
In case of data transfer outside the European Union (EU), the Sponsor 
will either ensure that the countries where data are transferred 
provide an adequate level of data protection or that the company 
receiving data has joined the EU-United States of America Privacy 
Shield Framework or will put in place a contract including standard 
contractual clauses adopted by the European Commission to ensure 
that the transfer of study information complies with applicable data 
[…] 
In case of data transfer outside the European 
Union (EU), the Sponsor will either ensure that 
the countries where data are transferred provide 
an adequate level of data protection or that the 
company receiving data will put in place a 
contract including standard contractual clauses 
adopted by the European Commission to ensure 

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protection legislation. Such a contract can be made available upon 
request. 
that the transfer of study information complies 
with applicable data protection legislation. Such 
a contract can be made available upon request. 
31 
2.1 
Cabozantinib is currently approved in the United States as a treatment 
for adults with advanced RCC regardless of previous therapies 
received. In the EU, cabozantinib is approved as a 1st line treatment 
for adults with advanced RCC with intermediate and poor risk and as 
a 2nd line treatment for subjects previously treated with (VEGF) 
targeted therapy. 
 
Cabozantinib is currently approved in the United 
States as a treatment for adults with advanced 
RCC regardless of previous therapies received. 
In the EU, cabozantinib is approved for the 
treatment of advanced renal cell carcinoma 
(RCC) 
in 
treatment-naïve 
adults 
with 
intermediate or poor risk and following prior 
vascular endothelial growth factor (VEGF)-
targeted therapy. 
32-33 
3.1 
This study will be conducted in approximately 50 active 
investigational sites across Germany, Switzerland, the Netherlands, 
France, UK, Austria and Spain. The list of countries and the number 
of investigational sites may change during the study depending on 
recruitment and availability of the CPI combination (ipilimumab and 
nivolumab) in each country. 
 
 
[…] 
The date of the first dose of cabozantinib is defined as baseline 
(Day 1, Visit 2) and should occur within 15 days after the Screening 
visit. 
 
[…] 
Post-treatment Follow-up Period: Subjects who discontinue study 
treatment will be contacted during the Post-treatment Follow-up 
This study will be conducted in approximately 
50 active investigational sites across Germany, 
Switzerland, the Netherlands, France, UK, 
Austria and Spain. The list of countries and the 
number of investigational sites may change 
during the study depending on recruitment and 
availability of the first line combination 
therapies in each country. 
 
[…] 
The date of the first dose of cabozantinib is 
defined as baseline (Day 1, Visit 2). 
 
[…] 
Post-treatment Follow-up Period: Subjects who 
discontinue study treatment will be contacted 

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visits every 12 weeks ±15 days to assess survival status and collect 
information about subsequent anti-cancer therapy. Any AE/serious 
AEs (SAEs) assessed as related to cabozantinib or study procedures, 
even SAEs that occur more than 30 days after the date of the last 
cabozantinib dose, will also be collected and followed until 
resolution or stability according to the Investigator. 
during the Post-treatment Follow-up visits every 
12 weeks ±15 days to assess survival status and 
collect information about subsequent anti-cancer 
therapy. During the follow-up period, any 
SAEs that occur more than 30 days after the 
date of the last cabozantinib dose, assessed as 
related to study treatment or study procedures 
will also be collected and followed until 
resolution 
or 
stability 
according 
to 
the 
Investigator. 
[Figure 1 updated] 
34 
3.2.3 
The safety and tolerability of cabozantinib will be assessed 
throughout the study by evaluating AEs, clinical laboratory test 
results, vital signs measurements, electrocardiogram (ECG) and 
physical examination results, and use of concomitant medication (see 
Section 8).  
The safety and tolerability of cabozantinib will 
be assessed throughout the study treatment 
period by evaluating AEs, clinical laboratory 
test 
results, 
vital 
signs 
measurements, 
electrocardiogram 
(ECG) 
and 
physical 
examination results, and use of concomitant 
medication (see Section 8).  
35 
3.5 
[…] 
In addition to the information provided in the IWRS, drug 
accountability paper records documenting that each subject received 
the allocated study treatment will be maintained by the Investigator. 
[…] 
In addition to the information provided in the 
IWRS, drug accountability records documenting 
that each subject received the allocated study 
treatment will be maintained by the Investigator 
or delegate. 
35 
 
3.6 
The study is planned to start in the fourth quarter of 2019 and will 
start when the first subject provides a signed informed consent form. 
The inclusion period is estimated to last approximately 24 months, 
but this may be extended if necessary. For each subject, the study will 
start from their first cabozantinib administration and may last until 
The study is planned to start in the fourth quarter 
of 2019 and will start when the first subject 
provides a signed informed consent form. The 
inclusion 
period 
is 
estimated 
to 
last 
approximately 24 months, but this may be 

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the end of the study (18 months after the last subject included in the 
study received first cabozantinib dose). 
 
 
 
[…] 
Such subjects will be followed until at least 30 days after their last 
study treatment with cabozantinib administration. Information about 
cabozantinib administration, AEs and any SAEs will be collected 
during this period. 
extended if necessary. For each subject, the study 
will start from the ICF signature and may last 
until the end of the study (18 months after the last 
subject included in the study received first 
cabozantinib dose). 
 
[…] 
Such subjects will be followed until at least 
30 days after their last study treatment with 
cabozantinib administration. Information about 
cabozantinib administration and any related 
SAEs will be collected during the period when 
Cabometyx® is supplied free of charge from 
Ipsen. 
35 
3.7 
Data will be collected in the eCRF in compliance with FDA 21 Code 
of Federal Regulations (CFR) Part 11. As required by GCP 
guidelines, the monitor assigned by the Sponsor will verify, by direct 
reference to the source documents, that the data required by the 
protocol are accurately reported on the eCRF. 
 
Data will be collected in the eCRF in compliance 
with FDA 21 Code of Federal Regulations (CFR) 
Part 11. As required by GCP guidelines, the 
monitor assigned by the Sponsor will verify, by 
direct reference to the source documents, that the 
data required by the protocol are accurately 
reported on the eCRF as defined in the 
monitoring plan.  
40 
4.3.1 
[…] 
[…] 
In case of suspected or confirmed COVID-19 
(SARS-CoV-2) infection, the study drug 
administration 
may 
be 
temporarily 
discontinued depending on the subject clinical 
status. In some cases, the investigator may 

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request a participant be retested before the 
study drug administration is resumed.  
44 to 
47 
Table 2 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment period column: 
Prior to Screening 
 
Pre-treatment period column and Line AEs: 
≤ 15 Days prior to Screening 
 
Footnote: 
a All assessments should be performed and the corresponding results 
obtained prior to first dose of cabozantinib to ensure subjects meet 
the eligibility criteria. 
[…] 
Assessment column: 
[…] 
• 
Smoking habits/status 
 
Pre-treatment period column and Line 4:  
Before first cabozantinib intake 
 
Pre-treatment period column and Smoking 
habits/status line:  
X  
 
Pre-treatment period column: 
Prior to baseline 
 
Pre-treatment period column and Line AEs: 
X  
 
Footnote: 
a Screening and baseline visits can take place 
the same day as long as all eligibility 
criteria/parameters are available and checked 
prior to the first dose of cabozantinib.  
[…] 

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e Informed consent may be obtained more than 15 days prior to 
screening but must be provided before any study-specific procedures 
are performed; however, evaluations performed as part of routine 
care prior to informed consent can be used as Screening evaluations 
if permitted by the Institutional Review Board (IRB)/Ethics 
Committee (EC) policies of the investigational site.  
 
[…] 
l During the Post-treatment Follow-up period, any AE/SAEs assessed 
as related to cabozantinib or study procedures, even SAEs that occur 
more than 30 days after the date of the last cabozantinib dose, will 
also be collected and followed until resolution or stability according 
to the Investigator. 
m Information on prior and concomitant medication will be collected 
up to 30 days before screening until 30 days after the date of the last 
cabozantinib dose.  
e Informed consent must be provided before any 
study-specific 
procedures 
are 
performed; 
however, evaluations performed as part of 
routine care prior to informed consent can be 
used as Screening evaluations if permitted by the 
Institutional 
Review 
Board 
(IRB)/Ethics 
Committee (EC) policies of the investigational 
site.  
 
[…] 
l During the follow-up period, any SAEs that 
occur more than 30 days after the date of the 
last cabozantinib dose, assessed as related to 
study treatment or study procedures will also be 
collected and followed until resolution or 
stability according to the Investigator. 
m Information on prior and concomitant 
medication will be collected up to 30 days before 
baseline until 30 days after the date of the last 
cabozantinib dose.  
48 
5.2.1 
[…] 
All screened subjects will be allocated a subject number so that they 
can be identifiable throughout the study. The Investigator will 
maintain a list of screened subjects (i.e. who signed the informed 
consent form), subject numbers and names to ensure that all records 
may be found at a later date if required. Under no circumstances will 
subjects be screened more than once. In case a subject does not 
receive cabozantinib after the Screening visit, the primary reason will 
be recorded. 
[…] 
All screened subjects will be allocated a subject 
number so that they can be identifiable 
throughout the study. The Investigator will 
maintain a list of screened subjects (i.e. who 
signed the informed consent form), subject 
numbers and names to ensure that all records 
may be found at a later date if required. In case a 
subject does not receive cabozantinib after the 

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Screening visit, the primary reason will be 
recorded. 
48 
5.2.2 
[…] 
Subjects should receive their first dose of cabozantinib within 
15 days after the Screening visit.  
 
[…] 
Subjects with radiographic progression per RECIST 1.1 evaluated by 
the Investigator may continue study treatment if the Investigator 
believes that there still is clinical benefit and that it outweighs 
potential risks. In this case, study treatment can be continued up to 
the end of the study (Section 5.6), unless the subject decides to 
discontinue study treatment due to unacceptable toxicity or needs 
subsequent systemic anti-cancer treatment.  
 
 
 
 
[…] 
Subjects with radiographic progression per 
RECIST 1.1 evaluated by the Investigator may 
continue study treatment if the Investigator 
believes that there still is clinical benefit and that 
it outweighs potential risks. In this case, study 
treatment can be continued up to the end of the 
study (Section 5.6), unless the subject or the 
investigator decides to discontinue study 
treatment due to unacceptable toxicity or needs 
subsequent systemic anti-cancer treatment.  
49 
5.2.3.1 
[…] 
Any AE/SAEs assessed as related to cabozantinib or study 
procedures, even SAEs that occur more than 30 days after the date of 
the last cabozantinib dose, will also be collected and followed until 
resolution or stability according to the Investigator. 
[…] 
During the follow-up period, any SAEs that 
occur more than 30 days after the date of the 
last cabozantinib dose, assessed as related to 
study treatment or study procedures will also be 
collected and followed until resolution or 
stability according to the Investigator. 
50 
5.6 
[…] 
Such subjects will be followed until at least 30 days after their last 
study drug with cabozantinib administration. Information about 
[…] 
Such subjects will be followed until at least 
30 days after their last study drug with 
cabozantinib administration. Information about 

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cabozantinib administration, AEs and any SAEs will be collected 
during this period. 
cabozantinib administration and any related 
SAEs will be collected during the period when 
Cabometyx® is supplied free of charge from 
Ipsen. 
51 
6.2.1 
[…] 
The date of the first dose of cabozantinib is defined as baseline 
(Day 1, Visit 2) and should occur within 15 days after the Screening 
visit). Subjects will take cabozantinib tablets q.d. at home, at the same 
time each day, preferably at bedtime. Any unused study treatment 
must be returned to the investigational site for drug accountability 
and disposal. If a dose is missed, the missed dose should not be taken 
less than 12 hours before the next one. 
The assigned dose is 60 mg q.d. as indicated in all approvals of 
cabozantinib (Cabometyx™). 
[…] 
The date of the first dose of cabozantinib is 
defined as baseline (Day 1, Visit 2). Subjects 
will take cabozantinib tablets q.d. at home, at the 
same time each day, preferably at bedtime. Any 
unused study treatment must be returned to the 
investigational site for drug accountability and 
disposal. If a dose is missed, the missed dose 
should not be taken less than 12 hours before the 
next one. 
The recommended dose is 60 mg q.d. as 
indicated in all approvals of cabozantinib 
(Cabometyx™). 
52 
6.2.1.1 
The required study assessments and blood collections should be done 
prior to any study treatment administration. Subjects should receive 
their first dose of cabozantinib within 15 days after the Screening 
visit. 
The required study assessments and blood 
collections should be done prior to any study 
treatment administration.  
52 
6.2.1.2 
After baseline, all subsequent doses of cabozantinib will also be self-
administered at home. Subjects should fast for at least 2 hours after 
eating the evening meal (water is allowed) before taking the study 
treatment. After the 2-hour fasting and before going to bed, subjects 
are to take cabozantinib with a full glass of water (at least 8 oz or 240 
mL) with no food intake for 1 hour post-dose. If the subject’s 
schedule requires taking cabozantinib during the day, the subject 
should be instructed to follow the same fasting recommendations. 
Subjects are to fast (with the exception of 
water) for at least 2 hours before taking their 
dose. After the 2-hour fast, subjects are to take 
cabozantinib with a full glass of water 
(minimum of 240 mL) with no food intake for 
one more hour post-dose. If the subject’s 
schedule requires taking cabozantinib during the 

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The subject should take cabozantinib at approximately the same time 
every day and adhere to the fasting requirements described in this 
section. 
day, the subject is to be instructed to follow the 
same fasting recommendations. 
 
52 
6.2.2 
Subjects will be monitored for AEs from the time of signing informed 
consent until 30 days after the date of the last dose of cabozantinib. 
Any SAE that the Investigator believes to be related to cabozantinib 
or study procedures can be reported at any time after the last dose 
with no time limitation. 
Subjects will be monitored for AEs from the time 
of signing informed consent until 30 days after 
the date of the last dose of cabozantinib. Any 
SAE that the Investigator believes to be related 
to cabozantinib or study procedures can be 
reported at any time after the last dose with no 
time limitation during the follow-up period. 
55 
6.2.4 
The side effect profile of cabozantinib includes, in descending order 
of frequency, diarrhoea, fatigue, decreased appetite, nausea, weight 
decrease, palmar-plantar erythrodysaesthesia syndrome (PPES), 
vomiting, 
constipation, 
hypertension, 
dysgeusia, 
dysphonia, 
asthenia, and dyspnoea (please refer to the Investigator’s Brochure 
for additional details). 
Subjects may also experience other medically important but less 
frequent AEs including arterial and venous thrombotic AEs (e.g. deep 
vein thrombosis (DVT), pulmonary embolism, TIA and MI), 
aneurysms and artery dissections, severe haemorrhagic events, 
proteinuria, wound healing complications, GI perforation, abscesses 
including intra-abdominal and pelvic abscess, GI and non-GI fistulae 
formation, ONJ, and reversible posterior leukoencephalopathy 
syndrome 
(RPLS) 
also 
known 
as 
Posterior 
Reversible 
Encephalopathy Syndrome (PRES). 
The side effect profile of cabozantinib includes, 
in descending order of frequency, diarrhoea, 
fatigue, decreased appetite, nausea, palmar-
plantar erythrodysaesthesia syndrome (PPES), 
vomiting, weight decreased, hypertension, 
constipation, dysphonia  
and 
asthenia 
(please refer to the Investigator’s Brochure for 
additional details). 
Subjects may also experience other medically 
important but less frequent AEs including 
arterial and venous thrombotic AEs (e.g. deep 
vein thrombosis (DVT), pulmonary embolism, 
TIA and MI), severe haemorrhagic events, 
proteinuria, wound healing complications, GI 
perforation, abscesses including intra-abdominal 
and pelvic abscess, GI and non-GI fistulae 
formation, 
osteonecrosis, 
and 
reversible 
posterior 
leukoencephalopathy 
syndrome 
(RPLS). 

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56 
6.3.1 
[…] 
• 
Individualised anticoagulation therapy with heparin is allowed 
if it can be provided safely and effectively under the following 
circumstances: 
- 
Low dose heparins for prophylactic use are allowed if 
clinically indicated and the benefit outweighs the risk 
per the Investigator’s discretion; 
- 
Therapeutic doses of LMWH at the time of first dose are 
allowed if the subject has no evidence of brain 
metastasis, has been on a stable dose of LMWH for at 
least 12 weeks, and has had no complications from a 
thromboembolic event or the anticoagulation regimen; 
 
Therapeutic doses of LMWH after first dose are allowed 
if clinically indicated (e.g. for the treatment of deep 
venous thrombosis) and the benefit outweighs the risk 
per the Investigator’s discretion; 
- 
Accepted clinical guidelines regarding appropriate 
management while receiving anticoagulation therapy 
with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse 
drug reactions, monitoring laboratory parameters, dose 
adjustments (e.g. due to kidney dysfunction); 
[…] 
• 
Individualised anticoagulation therapy is 
allowed if it can be provided safely and 
effectively 
under 
the 
following 
circumstances: 
- 
Prophylactic use of low dose 
heparins for cardioprotection per 
local applicable guidelines),  and 
low dose of LMWH are allowed if 
clinically indicated and the benefit 
outweighs 
the 
risk 
per 
the 
Investigator’s discretion; 
- 
Therapeutic doses of LMWH or 
anticoagulation with direct factor 
Xa 
inhibitors 
rivaroxaban, 
edoxaban, 
or 
apixaban 
are 
allowed 
in 
patients 
without 
known brain metastases who are 
on 
a 
stable 
dose 
of 
the 
anticoagulant for at least 1 week 
before baseline without clinically 
significant 
hemorrhagic 
complications 
from 
the 
anticoagulation regimen or the 
tumour. 
- 
Accepted 
clinical 
guidelines 
regarding appropriate management 
while receiving anticoagulation 

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therapy must be followed. This 
includes, but is not limited to, 
subject 
education 
regarding 
potential adverse drug reactions, 
monitoring laboratory parameters, 
dose adjustments (e.g. due to 
kidney dysfunction); 
56 
6.3.2 
[…] 
• 
Any oral anticoagulants (e.g. warfarin or other coumarin 
related agents, direct thrombin or direct FXa inhibitors, or 
antiplatelet agents such as clopidogrel, or chronic use of 
aspirin above low dose levels for cardioprotection per local 
applicable guidelines); 
• 
Any other systemic anti-cancer treatment (e.g. chemotherapy, 
immunotherapy, 
radionuclides) 
and 
local 
anti-cancer 
treatment such as surgery, ablation, or embolisation. 
 
[…] 
• 
Chronic co-administration of cabozantinib with strong 
inducers of the cytochrome P450 Family 3 Subfamily A 
Member 4 (CYP3A4) family (e.g. dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentin, 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; 
[…] 
• 
Any coumarin agents (e.g. warfarin), 
direct thrombin inhibitor dabigatran, 
direct FXa inhibitors betrixaban, or 
antiplatelet inhibitor (e.g. clopidogrel); 
Any other systemic anti-cancer treatment (e.g. 
chemotherapy, immunotherapy, radionuclides) 
and local therapy such as surgery, ablation, or 
embolisation. 
 
 
 
 
[…] 
• 
Chronic co-administration of cabozantinib 
with strong inducers of the cytochrome 
P450 Family 3 Subfamily A Member 4 
(CYP3A4) 
family 
(e.g. 
phenytoin, 
carbamazepine, 
rifampin, 
rifabutin, 
rifapentin, phenobarbital, and St. John’s 
Wort) 
may 
significantly 
decrease 

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cabozantinib concentrations and should be 
avoided. 
Selection 
of 
alternate 
concomitant medications with no or 
minimal CYP3A4 enzyme induction 
potential is recommended; 
57-58 
6.3.3 
Cytochrome P450: Data from a clinical drug interaction study (Study 
XL184-008) 
showed 
that 
clinically 
relevant 
steady-state 
concentrations of cabozantinib appear to have no marked effect on 
the area under the curve (AUC) of co-administered rosiglitazone, a 
cytochrome P450 Family 2 Subfamily C Member 8 (CYP2C8) 
substrate. Therefore, cabozantinib is not anticipated to markedly 
inhibit CYP2C8 in the clinic, and by inference, is not anticipated to 
markedly inhibit other cytochrome P450 (CYP450) isozymes that 
have lower [I]/Ki values compared to CYP2C8 (i.e. cytochrome P450 
Family 2 Subfamily C Member 9 (CYP2C9), cytochrome P450 
Family 2 Subfamily C Member 19 (CYP2C19), cytochrome P450 
Family 2 Subfamily D Member 6 (CYP2D6), cytochrome P450 
Family 1 Subfamily A Member 2 (CYP1A2), and CYP3A4). In vitro 
data indicate that cabozantinib is unlikely to induce cytochrome P450 
enzymes, except for possible induction of CYP1A1 at high 
cabozantinib concentrations (30 μM). 
[…] 
Chronic co-administration of cabozantinib with strong inducers of 
the CYP3A4 family (e.g. dexamethasone, phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) 
may significantly decrease cabozantinib concentrations. 
[…] 
Protein Binding: Cabozantinib is highly bound (≥99.7%) to human 
plasma proteins. 
Cytochrome P450: Data from a clinical drug 
interaction study (Study XL184-008) showed 
that 
clinically 
relevant 
steady-state 
concentrations of cabozantinib appear to have no 
marked effect on the area under the curve (AUC) 
of co-administered rosiglitazone, a cytochrome 
P450 Family 2 Subfamily C Member 8 
(CYP2C8) substrate. Therefore, cabozantinib is 
not anticipated to markedly inhibit CYP2C8 in 
the clinic, and by inference, is not anticipated to 
markedly inhibit other cytochrome P450 
(CYP450) isozymes that have lower [I]/Ki 
values compared to CYP2C8 (i.e. cytochrome 
P450 Family 2 Subfamily C Member 9 
(CYP2C9), 
cytochrome 
P450 
Family 
2 
Subfamily 
C 
Member 
19 
(CYP2C19), 
cytochrome P450 Family 2 Subfamily D 
Member 6 (CYP2D6), cytochrome P450 Family 
1 Subfamily A Member 2 (CYP1A2), and 
CYP3A4). 
In 
vitro 
data 
indicate 
that 
cabozantinib is unlikely to induce cytochrome 
P450 enzymes, except for possible induction of 
Cytochrome P450 Family 1 Subfamily A 
Member 1(CYP1A1) at high cabozantinib 
concentrations (30 μM). 

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[…] 
Effect of cabozantinib on other medicinal products: The effect of 
cabozantinib on the pharmacokinetics of contraceptive steroids has 
not been investigated. As unchanged contraceptive effect may not be 
guaranteed, an additional contraceptive method, such as a barrier 
method, is recommended. 
 
[…] 
Chronic co-administration of cabozantinib with 
strong inducers of the CYP3A4 family (e.g. 
phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, and St. John’s Wort) 
may 
significantly 
decrease 
cabozantinib 
concentrations. 
[…] 
Protein Binding: Cabozantinib is highly bound 
(≥99.7%) to human plasma proteins (for details 
see the SmPC document (11), section 5.2). 
[…] 
Effect of cabozantinib on other medicinal 
products: The effect of cabozantinib on the 
pharmacokinetics of contraceptive steroids has 
not 
been 
investigated. 
As 
unchanged 
contraceptive effect may not be guaranteed, an 
additional contraceptive method, such as a 
barrier method, is recommended (see Appendix 
3). 
60 
 
7.3.1 
[…] 
Tumour assessments will determine the study endpoints of ORR, 
TTR, DOR, DCR, and PFS. The review of radiographic images will 
be conducted by a blinded, central IRC (Section 3.8) by batch (see 
IRC charter). 
[…] 
Tumour assessments will determine the study 
endpoints of ORR, TTR, DOR, DCR, and PFS. 
The review of radiographic images will be 
conducted by a blinded, central IRC (Section 
3.8) by batch using RECIST 1.1 (see IRC 
charter). 

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61 
 
7.3.3 
[…] 
Permission for use of the FKSI-DRS questionnaire is obtained by 
contacting Dr. Cella at information@facit.org. 
[…] 
Permission 
for 
use 
of 
the 
FKSI-DRS 
questionnaire was obtained by contacting Dr. 
Cella at information@facit.org. 
62 
8.1 
Adverse events will be monitored from the time the subject gives 
informed consent and throughout the study (see Section 3.6 for a 
definition of study duration) and will be assessed by direct, 
nonleading questioning. 
Adverse events will be monitored from the time 
the subject gives informed consent and 
throughout the study treatment (see Section 3.6 
for a definition of study duration) and will be 
assessed by direct, nonleading questioning. 
62 
8.1.1 
[…] 
This definition includes events occurring from the time of the subject 
giving informed consent until the end of the study (as defined in 
Section 3.6 and Section 5.6). 
 
 
[…] 
Signs and symptoms should not be reported as AEs/SAEs if they are 
clearly related to a relapse or an expected change or progression of 
the baseline clear-cell component RCC. 
[…] 
This definition includes events occurring from 
the time of the subject giving informed consent 
until the end of the study treatment (as defined 
in Section 3.6 and Section 5.6). 
 
[…] 
Signs and symptoms should not be reported as 
AEs/SAEs if they are clearly related to a relapse 
or an expected change or progression of the 
clear-cell component RCC. 
64 
8.1.3 
[…] 
Any AE with a suspected causal relationship to cabozantinib 
administration occurring at any other time after completion of the 
study (Section 5.6) must be reported promptly, within 24 hours. 
[…] 
During the follow-up period, any SAE that 
occur more than 30 days after the date of the 
last cabozantinib dose, assessed as related to 
study treatment or study procedures will also 
be collected and followed until resolution or 
stability according to the Investigator. 

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64-
65-66 
8.1.4 
All SAEs (as defined below), regardless of treatment group or 
suspected relationship to IMP, must be reported immediately (within 
24 hours of the Investigator’s knowledge of the event) using the 
email specified at the beginning of this protocol. 
 
[…] 
(6) 
Is an important medical event that may not immediately result 
in death, be life-threatening or require hospitalisation but may 
be considered an SAE when, based upon appropriate medical 
judgement, it may jeopardise the subject or may require 
medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalisation, or 
the development of drug dependency or drug abuse. 
 
 
 
 
 
 
 
 
 
 
 
All SAEs (as defined below), regardless of 
suspected relationship to IMP, must be reported 
immediately 
(within 
24 hours 
of 
the 
Investigator’s knowledge of the event) using the 
email specified at the beginning of this protocol. 
[…] 
(6) 
Is an important medical event that may not 
immediately 
result 
in 
death, 
be 
life-threatening or require hospitalisation 
but may be considered an SAE when, 
based 
upon 
appropriate 
medical 
judgement, it may jeopardise the subject 
or may require medical or surgical 
intervention to prevent one of the 
outcomes 
listed 
in 
this 
definition. 
Examples of such medical events include 
allergic bronchospasm requiring intensive 
treatment in an emergency room or at 
home, blood dyscrasias or convulsions 
that 
do 
not 
result 
in 
in-patient 
hospitalisation, or the development of 
drug dependency or drug abuse. A 
suspected or confirmed coronavirus 
COVID-19 (SARS-CoV-2) infection 
must be reported as serious (seriousness 
criteria should be “other medically 
important serious event” if no other 
seriousness criteria are present (e.g. 
hospitalisation)). 
 

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[…] 
• 
While most hospitalisations necessitate reporting of an SAE, 
some hospitalisations do not require SAE reporting, as 
follows: 
- 
For protocol-specified hospitalisation in clinical studies, 
prolongation is defined as any extension beyond the 
length of stay described in the protocol; 
- 
Prolongation in the absence of a precipitating, 
treatment-emergent, clinical AE (i.e. not associated with 
the development of a new AE or worsening of a 
pre-existing condition) may meet the criteria for 
seriousness but is not an adverse experience and thus is 
not subject to immediate reporting to the Sponsor;  
- 
Pre-planned or elective treatments/surgical procedures 
should 
be 
noted 
in 
the 
subject’s 
Screening 
documentation. Hospitalisation for a pre-planned or 
elective treatment/surgical procedure should not be 
reported as an SAE unless there are complications or 
sequelae which meet the criteria for seriousness 
described above; 
 
 
 
 
 
[…] 
• 
While most hospitalisations necessitate 
reporting 
of 
an 
SAE, 
some 
hospitalisations do not require SAE 
reporting, as follows: 
- 
For 
protocol-specified 
hospitalisation in clinical studies, 
prolongation is defined as any 
extension beyond the length of stay 
described in the protocol; 
- 
Prolongation in the absence of a 
precipitating, treatment-emergent, 
clinical AE (i.e. not associated with 
the development of a new AE or 
worsening 
of 
a 
pre-existing 
condition) may meet the criteria for 
seriousness but is not an adverse 
experience and thus is not subject to 
immediate reporting to the Sponsor;  
- 
Pre-planned 
or 
elective 
treatments/surgical 
procedures 
should be noted in the subject’s 
Screening 
documentation. 
Hospitalisation for a pre-planned or 
elective 
treatment/surgical 
procedure should not be reported as 
an 
SAE 
unless 
there 
are 
complications or sequelae which 
meet the criteria for seriousness 

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[…] 
The Investigator must also report: 
• 
All SAEs that occur after informed consent and through 
30 days after the date of the last cabozantinib dose (or the date 
described above. If a new elective 
treatment/surgical procedure is 
required for a subject during 
their participation in the study 
the elective treatment/surgical 
procedure should be considered a 
SAE; 
 
 
[…] 
The Investigator must also report: 
• 
All SAEs that occur after informed 
consent and through 30 days after the date 
of the last cabozantinib dose (or the date 
the subject is deemed to be a screen 
failure). This 
information must be 
recorded on the AE page of the eCRF; 
• 
Any SAEs assessed as related to study 
treatment or study procedures. 
During the follow-up period, any SAE with a 
suspected causal relationship to cabozantinib 
administration occurring at any other time after 
completion of the study (Section 5.6) must be 
reported promptly to the sponsor, within 
24 hours. 

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the subject is deemed to be a screen failure). This information 
must be recorded on the AE page of the eCRF; 
• 
Any AE/SAEs assessed as related to study treatment or study 
procedures, including SAEs occurring more than 30 days after 
the date of the last cabozantinib dose. 
If the subject does not meet the eligibility criteria during the 
Screening visit, then SAEs only need to be reported from the time the 
subject signs the informed consent until the day when the subject has 
been determined to not be eligible for study participation.  
Any SAE with a suspected causal relationship to cabozantinib 
administration occurring at any other time after completion of the 
study (Section 5.6) must be reported promptly, within 24 hours. 
67 
8.1.6 
[…] 
Any overdose or study medication error that results in an AE or SAE 
(excluding missed doses) requires reporting within 24 hours to the 
Sponsor or designee. Forms for reporting medication errors will be 
provided to the investigational sites. 
[…] 
Any overdose or study medication error that 
results in an AE or SAE (excluding missed 
doses) requires reporting within 24 hours to the 
Sponsor or designee.  
68 
8.2 
[…] 
All laboratory tests to establish eligibility must be done within 
15 days prior to screening (Table 2).  
 
[…] 
On days when a blood sample is collected, subjects must fast 
overnight (no caloric intake for at least 8 hours, consumption of water 
is allowed).  
[…] 
All laboratory tests to establish eligibility must 
be done within 15 days prior to baseline (Table 
2).  
 
[…] 
On days when a blood sample is collected, 
subjects must fast overnight (consumption of 
water is allowed) 
69 
8.2 
Table 5 
[Table 5 updated] 

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Blood Chemistry column: 
[…] 
- Glucose (fasted) 
[…] 
 Total cholesterol (fasted) 
- Triglycerides (fasted) 
Blood Chemistry column: 
[…] 
- Glucose  
  
69 
8.2.1 
A β-HCG serum test and/or an HCG urine test will be performed for 
all female subjects of childbearing potential within 7 days prior to the 
Screening visit and at every visit thereafter up to the End of Study 
Treatment or Early Study Withdrawal visit (Table 2). 
A β-HCG serum test and/or an HCG urine test 
will be performed for all female subjects of 
childbearing potential within 7 days prior to the 
baseline visit and at every visit thereafter up to 
the End of Study Treatment or Early Study 
Withdrawal visit (Table 2). 
73 
11.1 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed 
the informed consent). 
 
The following populations will be used during 
statistical analyses: 
• 
Screened 
population: 
All 
subjects 
screened (i.e. who signed the informed 
consent). 
• 
Included 
population: 
All 
subjects 
screened who fulfilled the inclusion and 
exclusion criteria.  
73 
11.1.2 
Any major protocol deviation (see Section 13.1.2 for definition) will 
be described and its impact on inclusion in each analysis population 
(efficacy, PP and safety populations) for any subject will be 
specified. The final list of protocol deviations impacting the safety, 
efficacy and PP populations will be reviewed prior to database lock. 
The list may be updated, up to the point of database lock, to include 
Any 
major 
protocol 
deviation 
(see 
Section 13.1.2 for definition) will be described 
and its impact on inclusion in each analysis 
population (efficacy, PP and safety populations) 
for any subject will be specified. The final list of 
protocol deviations impacting the safety, 
efficacy and PP populations will be reviewed 
prior to database lock. The list may be updated, 

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any additional major protocol deviations impacting inclusion in the 
PP population. 
up to the point of database lock, to include any 
additional major protocol deviations impacting 
inclusion in the analyses populations. 
73-74 
11.2 
[…] 
Assuming approximately 7% non-evaluable subjects, 125 subjects in 
each cohort provides at least 80% power (at one-sided significance 
level (alpha) of 0.025) to reject the null hypothesis of 10% ORR in 
favour of an alternative hypothesis of 19% ORR. In total, 
250 subjects need to be included in the study. 
[…] 
Assuming 
approximately 
7% non-evaluable 
subjects (i.e. subjects who received at least one 
dose of study medication but did not provide 
a baseline for the tumour according to 
RECIST 1.1), 125 subjects in each cohort 
provides at least 80% power (at one-sided 
significance level (alpha) of 0.025) to reject the 
null hypothesis of 10% ORR in favour of an 
alternative hypothesis of 19% ORR. In total, 
250 subjects need to be included in the study. 
74 
11.4.1 
Descriptive summary statistics (n, mean, standard deviation, median, 
minimum, maximum) or frequency counts of demographic and 
baseline data (medical history, concomitant disease and other 
assessments performed at the Screening visit) will be presented by 
cohort and overall for the screened and safety populations. 
 
Descriptive summary statistics (n, mean, 
standard 
deviation, 
median, 
minimum, 
maximum) or frequency counts of demographic 
and baseline data (medical history, concomitant 
disease and other assessments performed at the 
Screening visit) will be presented by cohort and 
overall for the safety population. 
74 
11.4.2 
The numbers and percentages of subjects in the screened, safety, 
efficacy and PP populations will be tabulated by cohort and overall. 
The reasons for subject exclusions from each of the populations will 
also be tabulated. In addition, the numbers of subjects who were 
screened, screened failed, treated, discontinued and completed each 
of the study periods (pre-treatment period, treatment period, 
post-treatment period) will be tabulated by cohort and overall. 
The numbers and percentages of subjects in the 
screened, included, safety, efficacy and PP 
populations will be tabulated by cohort and 
overall. The reasons for subject exclusions from 
each of the populations will also be tabulated. In 
addition, the numbers of subjects who were 
screened, screened failed, treated, discontinued 
and completed each of the study periods (pre-

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Primary reasons for discontinuation of study treatment will be 
tabulated. 
treatment 
period, 
treatment 
period, 
post-treatment follow-up period) will be 
tabulated by cohort and overall. Primary reasons 
for discontinuation of study treatment will be 
tabulated. 
74 
11.4.3.1 
[…] 
• 
Objective response rate (ORR) defined as the proportion of 
subjects who achieved a partial response (PR) or complete 
response (CR) at any timepoint as determined by independent 
central review per Response Evaluation Criteria in Solid 
Tumours (RECIST) 1.1, confirmed by a subsequent visit ≥28 
days later.  
[…] 
• 
Objective response rate (ORR) defined as 
the proportion of subjects who achieved a 
partial 
response 
(PR) 
or 
complete 
response (CR) at any timepoint as 
determined by independent central review 
per Response Evaluation Criteria in Solid 
Tumours (RECIST) 1.1.  
74-75 
11.4.3.2 
[…] 
• 
Duration of response (DOR) defined as the time from first 
documented response (PR or CR as determined by 
independent central review per RECIST 1.1 that is 
subsequently confirmed) to either disease progression (as 
determined by independent central review per RECIST 1.1) or 
death due to any cause, whichever occurs first. If the response 
is not confirmed, it will not be included. Censoring rules will 
be similar to those applied for progression-free survival (PFS); 
[…] 
• 
Duration of response (DOR) defined as 
the time from first documented response 
(PR or CR as determined by independent 
central review per RECIST 1.1) to either 
disease progression (as determined by 
independent 
central 
review 
per 
RECIST 1.1) or death due to any cause, 
whichever occurs first. Censoring rules 
will be similar to those applied for 
progression-free survival (PFS); 
76 
11.4.3.4 
[…] 
Additional supportive analyses of PFS will be defined in the SAP 
using alternative event definitions and censoring schemes to account 
for partial or completely missing assessments, address bias due to 
tumour assessment timing, evaluate the impact of potentially 
[…] 
Additional supportive analyses of PFS will be 
defined in the SAP using alternative event 
definitions and censoring schemes to account for 
partial or completely missing assessments, 

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informative censoring, and to address potential discrepancies 
between the documentation of progression per the Investigator and 
per the independent central review. These analyses will be performed 
using the same statistical methods described for the primary analysis. 
address bias due to tumour assessment timing, 
evaluate the impact of potentially informative 
censoring, and to address potential discrepancies 
between the documentation of progression per 
the Investigator and per the independent central 
review. 
 
76 
11.4.4 
[…] 
Summary statistics (mean, median, standard deviation and range as 
appropriate) of values and changes or shifts from baseline will be 
presented by cohort and overall for vital signs, ECG variables, 
clinical laboratory tests etc. at each assessment. For laboratory data, 
abnormal values will be flagged in the data listings and a list of 
clinically significant abnormal values will be presented. 
Concomitant medications will be standardised using the World 
Health Organization drug dictionary and summarised by SOC and 
PT. 
 
[…] 
Summary statistics (mean, median, standard 
deviation and range as appropriate) of values and 
changes or shifts from baseline will be presented 
by cohort and overall for vital signs, ECG 
variables, clinical laboratory tests at each 
assessment. For laboratory data, abnormal values 
will be flagged in the data listings and a list of 
clinically significant abnormal values will be 
presented. 
Concomitant medications will be standardised 
using the World Health Organization drug 
dictionary and summarised by anatomic 
therapeutic class (ATS) and preferred name. 
77 
11.5 
Subgroup analyses will be conducted by presenting the primary 
analysis of ORR (with point estimates and 95% CIs) for both 
independent central review and Investigator’s assessment in the 
following subgroups: 
• 
Age (<65 years, ≥65 years); 
• 
Gender (female, male); 
Subgroup analyses will be conducted by 
presenting the primary analysis of ORR (with 
point 
estimates 
and 
95% CIs) 
for 
both 
independent central review and Investigator’s 
assessment in the following subgroups: 
• 
Age (<65 years, ≥65 years); 
• 
Gender (female, male); 

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• 
MSKCC Risk Factors (favourable [0], intermediate [1], poor 
[2 or more]); 
• 
Heng criteria (favourable [0], intermediate [1-2], poor [3-6]); 
• 
Number of organs with metastases (1, 2, ≥3); 
• 
ECOG (0, 1); 
• 
Treatment duration on 1st anti-cancer therapy (<6 months, 
≥6 months); 
• 
Tumour MET status (high, low, unknown); 
• 
PD L1 status (negative, positive, unknown). 
• 
MSKCC Risk Factors (favourable [0], 
intermediate [1], poor [2 or more]); 
• 
Heng criteria (favourable [0], intermediate 
[1-2], poor [3-6]); 
• 
Number of organs with metastases (1, 2, 
≥3); 
• 
ECOG (0, 1); 
• 
Treatment duration on 1st anti-cancer 
therapy (<6 months, ≥6 months); 
 
84-85 
15.2 
[…] 
For screening failure subjects, only the Unique Subject Identifier, the 
date of informed consent signature, the reason why the subject failed 
screening and the potential AEs which occurred during the Screening 
visit will be reported in the eCRFs and collected in the Sponsor’s 
database. 
[…] 
For screening failure subjects, the Unique 
Subject Identifier, the date of informed consent 
signature, the reason why the subject failed 
screening and the potential AEs which occurred 
during the Screening visit will be reported in the 
eCRFs and collected in the Sponsor’s database 
(for complete list of data to be collected for 
screen failure patients, please refer to eCRF 
completion Guidelines). 
85 
15.3 
During the pre-treatment period and initiation visits, the monitor 
must 
ensure 
the 
archiving 
facilities 
are 
adequate 
and 
archiving/retention responsibilities of the Investigator have been 
discussed.  
During the initiation visits, the monitor must 
ensure the archiving facilities are adequate and 
archiving/retention 
responsibilities 
of 
the 
Investigator have been discussed.  
88 
17.2 
[…] 
This analysis will be included in the interim study report. An analysis 
will be performed on the final response data after the last subject has 
completed the treatment period. This analysis will be included in the 
[…] 
This analysis will be included in the interim 
study report. An analysis will be performed on 
the final response data 12 months after the last 

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final study report. An addendum to the report, including the analysis 
of data from the follow-up period, will be prepared after the last 
subject completes the follow up period. 
subject 
received 
the 
first 
cabozantinib 
administration. This analysis will be included 
in the final study report. An addendum to the 
report, including the analysis of data from the 
follow-up period, will be prepared 18 months 
after the last subject received the first 
cabozantinib administration. 
89-90 
18 
11 
Cabometyx 
Product 
Information. 
https://www.medicines.org.uk/emc/product/7631/s
mpc 
12 
Choueiri, Toni K., et al “Cabozantinib versus 
everolimus in advanced renal-cell carcinoma.” New 
England Journal of Medicine 373.19 (2015): 1814
1823. 
 
 
 
 
 
 
 
 
 
 
[…] 
20 
Motzer, Robert J., et al. “IMmotion151: a 
randomized phase III study of atezolizumab plus 
11 
Cabometyx® 
Product 
Information, 
October 
2020. 
https://www.ema.europa.eu 
12 
Choueiri TK, Escudier B, et al, 
for 
the 
METEOR 
investigators. 
Cabozantinib 
versus everolimus in advanced 
renal 
cell 
carcinoma 
(METEOR):final results from 
a 
randomised, 
open-label, 
phase 3 trial. Lancet Oncol 
2016; published online June 5. 
http://dx.doi.org/10.1016/S147
0-2045(16)30107-3. 
[…] 
20 
Choueiri TK, et al. Oral 
presentation 6960. Presented 
at ESMO 2020.  
[…] 
22 
Escudier, Bernard, et al. “Renal 
cell carcinoma: ESMO Clinical 
Practice 
Guidelines 
for 

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bevacizumab vs sunitinib in untreated metastatic 
renal cell carcinoma (mRCC).” Journal of Clinical 
Oncology 2018 36:6_suppl, 578 578. 
21 
Suarez, C., et al. “873P Safety and tolerability of 
atezolizumab (atezo) plus bevacizumab (bev) vs 
sunitinib (sun) in untreated metastatic renal cell 
carcinoma 
(mRCC): 
Pooled 
analysis 
of 
IMmotion150 and IMmotion151.” Annals of 
Oncology 29. suppl_8 (2018): mdy283 082 
diagnosis, treatment and follow-
up.” Annals of oncology (2019) 
updated on 30 November 
2020. 
107 
Appendix 4 
10  Nervous system disorders 
[…] 
RPLS also known PRES has been reported and 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. 
10  Nervous system disorders 
[…] 
RPLS has been reported and 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. 
112 to 
118 
Appendix 5 
 
[Appendix 5 updated] 

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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-60000-023 
AMENDED 
PROTOCOL 
VERSION 
NUMBER 
& 
DATE 
 
Final (including Amendment #3): 03 March 2021 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
Reason(s) for changes 
 
- Update of inclusion and exclusion criteria 
- Correction of minor inconsistencies and typos. 
- Update of background and rationale parts due to new treatments 
approved in RCC 
- Update of AE management part due to the availability of new 
Investigator’s Brochure. 
- Addition of some clarifications 
OTHER ACTION REQUIRED? CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
STATISTICAL & ANALYSIS PLAN 
(SAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 
 

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Appendix 11 Amendment Form #4 
 
 
 

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Amendment 4 (23 February 2022) 
This amendment is considered to be substantial based on the criteria set forth in the regulation 
(EU) No 536/2014. 
 
Overall Rationale for the Amendment: 
Since the set-up of Cabopoint study, increasing clinical data is supporting a higher targeted 
ORR in the post IO 2L setting compared to the initial statistical assumptions for Cabopoint. 
Beside this increasing supporting data, the evaluation by investigator assessment of the first 
21 subjects of cohort A is demonstrating a ORR >30%.  Based on the significant 
underperformance of the study enrolment, an amendment of the study including a new statistical 
assumption is the only possibility to proceed with Cabopoint, alternative would have been to 
stop study enrolment due to underperformance. 
With an adapted statistical assumption based on latest clinical data, it will be possible to finalize 
the study in a meaningful scientifically and timeline manner.   
 
Summary change table from previous version of the protocol 
 

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Synopsis (Primary 
Study Objective) and 
Section 2.2.1 
• 
To assess the efficacy of 
cabozantinib 
by 
the 
objective response rate 
(ORR) 
per 
Response 
Evaluation Criteria in 
Solid 
Tumours 
(RECIST) 1.1 evaluated 
by independent central 
review. 
 
• 
To assess the efficacy of 
cabozantinib by the objective 
response 
rate 
(ORR) 
per 
Response Evaluation Criteria in 
Solid Tumours (RECIST) 1.1 
evaluated 
by 
independent 
central review in cohort A. 
 
Removal of cohort B from the primary 
objective/endpoint as no more hypothesis is 
defined for cohort B. 

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Synopsis (Secondary 
Study Objective) and 
Section 2.2.2 
 
• 
To assess other efficacy 
criteria of cabozantinib 
such as time to response 
(TTR), 
duration 
of 
response (DOR), disease 
control 
rate 
(DCR), 
progression-free survival 
(PFS) by independent 
and 
Investigator’s 
review; 
• 
To 
assess 
objective 
response rate (ORR) by 
Investigator’s review; 
• 
To assess overall survival 
(OS) 
 
 
• 
To assess other efficacy criteria 
of cabozantinib such as time to 
response (TTR), duration of 
response (DOR), disease control 
rate (DCR), progression-free 
survival (PFS) by independent 
central 
review 
and 
Investigator’s review; 
• 
To assess objective response 
rate (ORR) by independent 
central 
review 
and 
Investigator’s review in cohort 
B; 
• 
To 
assess 
ORR 
by 
Investigator’s review in cohort 
A 
• 
To assess overall survival (OS) 
• 
To assess the ORR and PFS by 
Investigator’s review and OS 
in 
overall 
population 
(cohorts A+B) 
Description of cohort B in the secondary 
objective/endpoint as no more hypothesis is 
defined for cohort B. 
To add Investigator review of ORR and 
PFS and to add OS assessment for cohorts 
A and B. 

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Synopsis 
(Methodology) and 
Section 3.1 
This is a Phase II, multicentre, 
open-label study to evaluate the 
efficacy 
and 
safety 
of 
cabozantinib 60 mg once daily 
(q.d.) 
in 
adults 
with 
unresectable, locally advanced 
or metastatic RCC with a clear-
cell component that progressed, 
according 
to 
Investigator’s 
judgement, after prior CPI 
therapy 
(ipilimumab 
and 
nivolumab) 
alone 
or 
CPI 
combined with VEGF-targeted 
therapy. 
Approximately 
250 eligible 
subjects 
will 
receive 
cabozantinib 
(two 
independent cohorts with 125 
subjects in each cohort). 
 
 
 
[…] 
Treatment Period: […] 
• 
Cohort A: 125 subjects 
Cohort A will be composed of 
subjects who radiographically 
progressed after one prior line 
by CPI therapy with ipilimumab 
and nivolumab.  
This is a Phase II, multicentre, open-
label study to evaluate the efficacy and 
safety of cabozantinib 60 mg once 
daily (q.d.) in adults with unresectable, 
locally advanced or metastatic RCC 
with a clear-cell component that 
progressed, according to Investigator’s 
judgement, after prior CPI therapy 
(ipilimumab and nivolumab) alone or 
CPI combined with VEGF-targeted 
therapy. Approximately 114 eligible 
subjects will receive cabozantinib (two 
independent cohorts with 74 subjects* 
in cohort A and approximately 40 
subjects in cohort B). 
*The inclusion period will stop 
either when 74 subjects have been 
enrolled in cohort A or at the latest 
on 
30 June 2022, 
whichever 
is 
reached first.  
 
[…] 
Treatment Period: […] 
• 
Cohort A: 74 subjects 
Cohort A will be composed of subjects 
who radiographically progressed after 
one prior line by CPI therapy with 
ipilimumab and nivolumab.  
Modification of number of eligible subjects 
to reflect the sample size recalculation 
performed following the underperformance 
of the study enrolment. 

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• 
Cohort B: 125 subjects 
Cohort B will be composed of 
subjects who radiographically 
progressed after one prior line 
by CPI therapy combined with 
VEGF-targeted therapy. 
 
• 
Cohort B: 
approximately 
40 subjects 
Cohort B will be composed of subjects 
who radiographically progressed after 
one prior line by CPI therapy 
combined 
with 
VEGF-targeted 
therapy. 
 
Synopsis (Number of 
subjects planned) 
250 subjects: 125 subjects in 
Cohort A and 125 subjects in 
Cohort B 
approximately 
114 
subjects: 
74 
subjects* 
in 
Cohort 
A 
and 
approximately 40 subjects in Cohort 
B 
*The inclusion period will stop 
either when 74 subjects have been 
enrolled in cohort A or at the latest 
on 
30 June 2022, 
whichever 
is 
reached first.  
 
Modification of number of eligible subjects 
to reflect the sample size recalculation 
performed following the underperformance 
of the study enrolment. 
Synopsis (Inclusion 
criteria) and Section 
4.1 
(10) 
Subjects 
must 
have 
completed a steroid taper, if 
he/she must have had an 
immune-related adverse event 
associated with immune CPI; 
(10) Subjects must have completed a 
steroid taper, if he/she experienced an 
immune-related 
adverse 
event 
associated 
with 
previous 
CPI 
treatment; 
Reworded for better clarity. 

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Synopsis (Criteria for 
evaluation 
(endpoints)), Section 
3.2, Section 7.1, 
Section 7.2, Section 
11.4.3.1 and Section 
11.4.3.2 
Primary 
Endpoint 
and 
Evaluation:  
• 
Objective response rate 
(ORR) per RECIST 1.1 
evaluated by independent 
central review.  
Secondary 
Endpoints 
and 
Evaluations: 
[…] 
 
 
Primary Endpoint and Evaluation:  
• 
Objective response rate (ORR) 
in cohort A per RECIST 1.1 
evaluated 
by 
independent 
central review.  
Secondary Endpoints and Evaluations: 
[…] 
• 
Objective 
response 
rate 
(ORR) 
in 
cohort 
B 
per 
RECIST 1.1 
evaluated 
by 
independent central review; 
 
 
Removal of cohort B from the primary 
objective/endpoint and description of cohort 
B in secondary objectives/endpoints as no 
more hypothesis is defined for cohort B. 
To add that ORR for cohort B will be 
assessed by independent review. 

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Synopsis (Statistical 
Methods) 
Sample size:  
With a true ORR proportion of 
19%, a sample size of 117 
subjects in each cohort will 
provide a statistical power of 
80% 
to 
reject 
the 
null 
hypothesis of 10%, using a one-
sample exact test for binomial 
distribution with a significance 
level of 0.025 (one-sided). 
Assuming approximately 7% 
non-evaluable 
subjects 
(i.e. 
subject who received at least 
one dose of study medication 
but did not provide a baseline 
for the tumour according to 
RECIST 1.1), a total of 125 
subjects per cohort will be 
included in the study. 
A minimum sample size fixed at 
70% for subjects previously 
treated more than 6 months by 
first anti cancer therapy will be 
applied in the study for each 
cohort. 
This 
will 
provide 
meaningful 
descriptive 
summaries 
with 
sufficient 
accuracy and precision in this 
subgroup of subjects. 
 
Sample size:  
With a true ORR proportion of 23%, a 
sample size of 68 subjects in cohort A 
will provide a statistical power of 80% 
to reject the null hypothesis of 10%, 
using a one-sample exact test for 
binomial 
distribution 
with 
a 
significance level of 0.025 (one-sided). 
Assuming 
approximately 
7% non-
evaluable subjects (i.e. subject who 
received at least one dose of study 
medication but did not provide a 
baseline for the tumour according to 
RECIST 1.1), up to a total of 
74 subjects in cohort A will be 
included in the study. 
For cohort B, no formal sample size 
determination was performed as the 
enrolment will stop when the 
recruitment in cohort A will be 
reached. 
We 
anticipate 
approximately 40 subjects recruited 
in cohort B.  
 
 
 
 
 
Statistical Methods: 
Modification of number of eligible subjects 
to reflect the sample size recalculation 
performed following the underperformance 
of the study enrolment. 
The scope of the interim analysis has been 
revised. 
Addition of text to describe secondary 
endpoint analysis of ORR. 

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Statistical Methods: 
An intermediate analysis will be 
conducted 
when 
60% 
of 
subjects (i.e. 75 subjects) of the 
first recruiting cohort reaching 
the target number of subjects 
(either Cohort A or Cohort B) 
have reached 12 months of 
study follow-up. Both cohorts 
will be analysed at this cut-off 
date. The final analysis based on 
the primary endpoint (ORR) 
will be performed 12 months 
after the last subject received the 
first 
cabozantinib 
administration. 
A 
follow-up 
analysis based on OS will be 
conducted 18 months after the 
last subject received the first 
cabozantinib administration. At 
the intermediate analysis, no 
statistical 
testing 
will 
be 
performed. 
The 
statistical 
testing will only be carried out 
at the final analysis. 
The primary endpoint (ORR), 
defined as the proportion of 
subjects with complete response 
(CR) and partial response (PR) 
per RECIST 1.1 as determined 
An interim and purely descriptive 
analysis will be conducted when 
80% of the subjects (i.e. 59 subjects) 
of cohort A will be treated for at least 
3 months. Both cohorts will be 
analysed at this cut-off date. The final 
analysis based on the primary endpoint 
(ORR) will be performed 12 months 
after the last subject received the first 
cabozantinib administration. A follow-
up analysis based on OS will be 
conducted 18 months after the last 
subject received the first cabozantinib 
administration. The statistical testing 
will be carried out at the final analysis. 
The primary endpoint (ORR), defined 
as the proportion of subjects with 
complete response (CR) and partial 
response (PR) per RECIST 1.1 as 
determined by independent central 
review will be tested in cohort A using 
a one-sample exact test for binomial 
distribution.  
The proportion of subjects achieving 
ORR will be presented with their two-
sided 95% CI using the Clopper-
Pearson exact method. DCR estimates 
will be described with associated 
2-sided 95% CIs.  
 

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by independent central review 
will be tested in each cohort 
using a one-sample exact test 
for binomial distribution.  
The proportion of subjects 
achieving 
ORR 
will 
be 
presented with their two-sided 
95% CI using the Clopper-
Pearson exact method. DCR 
estimates will be described with 
associated 2-sided 95% CIs. 
1.2 
Cabometyx™ 
(cabozantinib 
tablets, 20, 40 and 60 mg) is 
currently approved by the EMA 
as a 2nd line treatment for 
subjects with advanced RCC 
previously treated with VEGF-
targeted therapy, and as a 
1st line treatment for adults with 
advanced 
RCC 
with 
intermediate and poor risk.  
 
Cabometyx™ (cabozantinib tablets, 20, 
40 and 60 mg) is currently approved by 
the EMA as a 2nd line treatment for 
subjects 
with 
advanced 
RCC 
previously treated with VEGF-targeted 
therapy, and as a 1st line treatment for 
adults with advanced RCC with 
intermediate 
and 
poor 
risk. 
Cabometyx™ (cabozantinib tablets 
40 mg) 
in 
combination 
with 
nivolumab, is indicated for the first-
line treatment of advanced renal cell 
carcinoma in adults. 
 
Addition of details regarding indication of 
Cabometyx™ in combination with 
nivolumab. 

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Section 1.4 
[…] 
The primary endpoint is ORR, 
defined as the proportion of 
subjects with CR or partial 
response (PR) per Response 
Evaluation Criteria in Solid 
Tumours (RECIST) 1.1, as 
determined by an independent 
central review. 
Secondary endpoints are time to 
response (TTR), duration of 
response (DOR), DCR and PFS 
per RECIST 1.1 assessed both 
by independent central review 
and by local Investigator, ORR 
per RECIST 1.1 assessed by 
local 
Investigator, OS and 
change 
in 
disease-related 
symptoms as assessed by the 
Functional 
Assessment 
of 
Cancer Therapy-Kidney Cancer 
Symptom Index (FKSI DRS). 
Safety 
and 
tolerability 
of 
cabozantinib 
will 
also 
be 
monitored throughout the study. 
[…] 
The primary endpoint is ORR, defined 
as the proportion of subjects with CR 
or partial response (PR) per Response 
Evaluation Criteria in Solid Tumours 
(RECIST) 1.1, as determined by an 
independent central review in cohort 
A.  
Secondary endpoints are time to 
response (TTR), duration of response 
(DOR), DCR and PFS per RECIST 1.1 
assessed both by independent central 
review and by local Investigator, ORR 
per RECIST 1.1 also assessed by both 
independent central review (cohort 
B) and by local Investigator (cohort A 
and  cohort B, OS and change in 
disease-related symptoms as assessed 
by the Functional Assessment of 
Cancer 
Therapy-Kidney 
Cancer 
Symptom Index (FKSI-DRS). Safety 
and tolerability of cabozantinib will 
also be monitored throughout the 
study. 
 
Removal of cohort B from the primary 
objective/endpoint and description of cohort 
B in secondary objectives/endpoints as no 
more hypothesis is defined for cohort B. 
Section 3.1 
 
[Figure 1 updated] 
This figure was updated to reflect the 
changed planned subject numbers for each 
cohort. 

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Section 3.6 
The study is planned to start in 
the fourth quarter of 2019 and 
will start when the first subject 
provides a signed informed 
consent form. The inclusion 
period is estimated to last 
approximately 24 months, but 
this 
may 
be 
extended 
if 
necessary. For each subject, the 
study will start from the ICF 
signature and may last until the 
end of the study (18 months 
after the last subject included in 
the 
study 
received 
first 
cabozantinib dose). The period 
between the start and end of 
study 
is 
estimated 
to 
be 
approximately 42 months and 
will include both treatment and 
post 
treatment 
follow 
up 
periods, 
regardless 
of 
the 
duration of treatment (e.g. if a 
subject stops study treatment 
after 2 months, he/she will be 
followed-up for the remaining 
time up to the end of the study). 
The study is planned to start in the first 
quarter of 2020 and will start when the 
first 
subject 
provides 
a 
signed 
informed consent form. The inclusion 
period will stop either when the 
number of 74 enrolled subjects in 
Cohort A is reached or at the latest 
on 30 June 2022, whichever is 
reached first. For each subject, the 
study will start from the ICF signature 
and may last until the end of the study 
(18 months after the last subject 
included in the study received first 
cabozantinib 
dose). 
The 
period 
between the start and end of study will 
include 
both 
treatment 
and 
post-treatment 
follow-up 
periods, 
regardless of the duration of treatment 
(e.g. if a subject stops study treatment 
after 
2 months, 
he/she 
will 
be 
followed-up for the remaining time up 
to the end of the study).  
 
Update of study timelines. 
Section 5.1 
 
[Table 2 modified] 
Tumour tissue line deleted 
Footnote h deleted 
Deletion of tumour tissue analysis because 
the substudy is cancelled.  

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Section 6.2 
[…] 
• 
Cohort A: 125 subjects 
Cohort A will be composed of 
subjects who radiographically 
progressed after one prior line 
by CPI therapy with ipilimumab 
and nivolumab.  
• 
Cohort B: 125 subjects  
Cohort B will be composed of 
subjects who radiographically 
progressed after one prior line 
by CPI therapy combined with 
VEGF-targeted therapy. 
 
[…] 
• 
Cohort A: 74 subjects 
Cohort A will be composed of subjects 
who radiographically progressed after 
one prior line by CPI therapy with 
ipilimumab and nivolumab.  
• 
Cohort B: 
approximately 
40 subjects  
Cohort B will be composed of subjects 
who radiographically progressed after 
one prior line by CPI therapy 
combined 
with 
VEGF-targeted 
therapy. 
Modification of number of eligible subjects 
to reflect the sample size recalculation 
performed following the underperformance 
of the study enrolment. 
Section 10 
At selected sites, tumour tissue 
(archived 
before 
1st 
line 
treatment) may be obtained at 
any time (archived biopsy) for a 
biomarker 
sub-study 
(exploratory analysis) of MET 
and PD L1 expression (status) 
associated with RCC prognosis 
or the mechanism(s) of action of 
study 
treatment. 
Details 
regarding 
the 
preparation, 
processing, and shipping of 
samples can be found in the 
biomarkers manual. 
Not applicable. 
 
Substudy cancelled. 

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Section 11.2 
For each cohort, the hypothesis 
for sample size computation is 
that 
cabozantinib 
will 
demonstrate 
a 
clinically 
significant 
increase 
in 
the 
response rate as compared to 
historical control in 2nd line 
treatment. 
 
[…] 
Assuming approximately 7% 
non-evaluable 
subjects 
(i.e. 
subjects who received at least 
one dose of study medication 
but did not provide a baseline 
for the tumour according to 
RECIST 1.1), 125 subjects in 
each cohort provides at least 
80% 
power 
(at 
one-sided 
significance level (alpha) of 
0.025) 
to 
reject 
the 
null 
hypothesis of 10% ORR in 
favour 
of 
an 
alternative 
hypothesis of 19% ORR. In 
total, 250 subjects need to be 
included in the study.  
A minimum sample size fixed at 
70% for subjects previously 
treated more than 6 months by 
first anti cancer therapy will be 
For cohort A, the hypothesis for 
sample size computation is that 
cabozantinib 
will 
demonstrate 
a 
clinically significant increase in the 
response rate as compared to historical 
control in 2nd line treatment. 
 
 
[…] 
Assuming 
approximately 
7% non-
evaluable subjects (i.e. subjects who 
received at least one dose of study 
medication but did not provide a 
baseline for the tumour according to 
RECIST 1.1), 74 subjects in cohort A 
provides at least 80% power (at one-
sided significance level (alpha) of 
0.025) to reject the null hypothesis of 
10% ORR in favour of an alternative 
hypothesis of 23% ORR.  
For cohort B, no formal sample size 
determination was performed as the 
enrolment will stop when the 
recruitment in cohort A will be 
reached. 
We 
anticipate 
approximately 40 subjects recruited 
in cohort B. 
Modification of number of eligible subjects 
to reflect the sample size recalculation 
performed following the underperformance 
of the study enrolment.  

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applied in the study for each 
cohort. 
This 
will 
provide 
meaningful 
descriptive 
summaries 
with 
sufficient 
accuracy and precision in this 
subgroup of subjects. 
Section 11.3 
ORR (primary endpoint) will be 
tested at the final analysis as 
described above using the one-
sided significance level (alpha) 
of 0.025. No statistical testing 
will be carried out at the 
intermediate analysis nor for 
secondary efficacy and safety 
endpoints. 
ORR (primary endpoint) will be tested 
at the final analysis as described above 
using the one-sided significance level 
(alpha) of 0.025. No statistical testing 
will be carried out at the interim 
analysis nor for secondary efficacy and 
safety endpoints. 
 
Modification of ‘intermediate’ to ‘interim’ 
analysis. 

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Section 11.4.3.1 
 
Below is the definition of the 
estimand used for the primary 
efficacy endpoint: 
Treatment: Cabozantinib 
Population: 
Subjects 
with 
unresectable, locally, advanced or 
metastatic RCC with a clear-cell 
component who progressed after 
prior CPI therapy with ipilimumab 
and nivolumab 
in combination 
(Cohort A). 
Endpoint: ORR defined as the 
proportion of PR and CR at any 
timepoint during treatment period 
as 
determined 
by 
independent 
central review per RECIST1.1. 
Intercurrent events: 
•  
Study 
discontinuation 
without response (i.e. without PR or 
CR) during the treatment period 
(composite strategy) 
Subjects withdrawn from the study 
without 
response 
during 
the 
treatment period or subjects without 
any 
post-baseline 
tumour 
assessment are non-responders. 
•  
Treatment 
discontinuation 
prior to RECIST 1.1. progression 
(treatment policy strategy) 
Addition of estimands to follow ICH E9 
guidelines and the addendum on estimands. 

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The efficacy assessment at any 
timepoint prior to RECIST 1.1. 
progression is used regardless of 
whether 
the 
Cabozantinib 
is 
discontinued. 
•  
Subjects not treated (while on 
treatment strategy) 
Subjects will not be included in the 
primary efficacy analysis. 
•  
Subjects 
receiving 
non-
protocol 
anti-cancer 
treatment 
(while on treatment strategy) 
Assessment of the response during 
the treatment period, i.e. until the 
initiation 
of 
non-protocol 
anti-
cancer treatment. 
Population-level summary: ORR 
compared to the historical control 
value of 10% 
Section 11.4.3.2 
 
All these secondary endpoints will be 
presented in each cohort separately. 
In 
addition, 
ORR 
and 
PFS 
according to local Investigator’s 
review per RECIST 1.1 as well as OS 
will be presented in the overall 
population (cohort A + cohort B). 
Clarification of the secondary endpoint 
analysis. 

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Section 11.4.3.2 
 
Below is the definition of the 
estimand used for the secondary 
efficacy endpoint of duration of 
response: 
Treatment: Cabozantinib 
Population: 
Subjects 
with 
unresectable, locally, advanced or 
metastatic RCC with a clear-cell 
component who progressed after 
prior CPI therapy with ipilimumab 
and nivolumab 
in combination 
(Cohort A) with a PR or CR at any 
timepoint during the treatment 
period. 
Endpoint: DOR defined as the time 
from first documented response (PR 
or CR as determined by independent 
central review per RECIST 1.1) to 
either 
disease 
progression 
(as 
determined by independent central 
review per RECIST 1.1) or death 
due to any cause, whichever occurs 
first. 
Intercurrent events: 
•  
Two 
or 
more 
missing 
scheduled tumour assessment 
prior 
to 
RECIST 
1.1. 
progression 
(while 
on 
treatment strategy) 
Addition of estimands to follow ICH E9 
guidelines and the addendum on estimands. 

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Subjects will be censored at the date 
of the last tumour assessment prior 
to the missing assessment. 
•  
Subjects not treated (while on 
treatment strategy) 
Subjects will not be included in the 
efficacy analysis. 
•  
Subjects 
receiving 
non-
protocol 
anti-cancer 
treatment prior to RECIST 
1.1 progression (while on 
treatment strategy) 
Subjects will be censored at the date 
of the last tumour assessment prior 
to the initiation of non-protocol anti-
cancer treatment. 
•  
Treatment 
discontinuation 
prior 
to 
RECIST 
1.1. 
progression (treatment policy 
strategy) 
Subjects will be censored at the date 
of the last tumour assessment. 
•  
Treatment 
discontinuation 
without 
any 
post-baseline 
tumour assessment (treatment 
policy strategy) after the first 
response to treatment 
Subjects will be censored at the time 
of first documented response. 

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Population-level summary: median 
of DOR 2-sided 95% with CI. 
 
Section 11.4.3.3 
The ORR as assessed by 
independent central review will 
be estimated in each Cohort A 
and B and tested versus the 
threshold of 10% using a one-
sample exact test for binomial 
distribution. In each cohort, a 
higher response rate over 10% 
will be considered statistically 
significant if the p value for the 
one-sided test is less than 0.025. 
The ORR as assessed by independent 
central review will be estimated in 
Cohort A and tested versus the 
threshold of 10% using a one-sample 
exact test for binomial distribution. A 
higher response rate over 10% will be 
considered statistically significant if 
the p-value for the one-sided test is less 
than 0.025.  
 
Removal of cohort B from the primary 
objective/endpoint as no more hypothesis is 
defined for cohort B. 
Section 11.4.3.4 
The 
ORR 
according 
to 
Investigator’s assessment will 
be analysed in the same way as 
ORR assessed by independent 
central 
review 
without 
statistical testing. Discordance 
in 
ORR 
assessed 
by 
independent central review and 
by 
Investigator 
will 
be 
described. 
The ORR according to Investigator’s 
assessment (cohort A and cohort B) 
will 
be 
presented 
with 
their 
associated 2-sided 95% CIs using 
Clopper-Pearson 
exact 
method. 
Discordance in ORR assessed by 
independent central review and by 
Investigator will be described.  
 
Description of cohort A and B in secondary 
objectives/endpoints as no more hypothesis 
is defined for cohort A and cohort B. 

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Section 11.6 
There are no formal interim 
analyses with stopping rules for 
efficacy or futility planned for 
this 
study. 
However, 
one 
intermediate analysis is planned 
as follows:  
The intermediate analysis will 
be conducted when 60% of 
subjects (i.e. 75 subjects) of the 
first recruiting cohort reaching 
the target number of subjects 
(either Cohort A or Cohort B) 
have reached 12 months of 
study follow up. Both cohorts 
will be analysed at this cut off 
date.    
[…] 
The statistical testing will only 
be carried out at the final 
analysis. 
 
 
An interim and purely descriptive 
analysis will be conducted when 
80% of the subjects (i.e. 59 subjects) 
of cohort A will be treated for at least 
3 months. Both cohorts will be 
analysed at this cut-off date. The aim 
of this interim analysis is to describe 
the 
baseline 
characteristics, 
demographics, ORR as assessed by 
the Investigator at 3 months and any 
further 
efficacy 
parameters 
measured at the Month 3 visit. 
Further details will be provided in 
the SAP. The results of this interim 
analysis will not have any impact on 
the study conduct.   
 
 
[…] 
The statistical testing will be carried 
out at the final analysis. 
 
Revision of the scope of the interim 
analysis. 

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Section 17.2 
[…] 
As indicated in Section 11.6, the 
intermediate analysis will be 
conducted 
when 
60% of 
subjects of the first recruiting 
cohort 
reaching 
the 
target 
number 
of 
subjects 
have 
reached 12 months of study 
follow-up. This analysis will be 
included in the interim study 
report. 
 
 
No interim CSR will be provided. 
 
 
Other documents impacted 
 
Informed consent form  
Yes  
  No  
 
Case report form (CRF)  
Yes  
  No  
 
Statistical analysis plan (SAP)  
Yes  
  No