Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma Cabozantinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
Cabozantinib, a small molecule directed to vascular endothelial growth factor receptors, MET and AXL, has shown to significantly improve the overall survival (OS) over placebo in the randomized phase 3 CELESTIAL trial in patients who had up to two lines of prior systemic therapy (including sorafenib) with progression on at least one in comparison to patients who received best supportive care.

Although cabozantinib shares similar targets with sorafenib/regorafenib, they present different toxicity profile. While the most common grade 3-4 Adverse Events reported for sorafenib were fatigue (4%), diarrhea (8%), hand-foot reaction (8%) and hypertension (2%); the most frequent grade 3-4 Adverse Events for cabozantinib were hand-foot reaction (3.6%), hypertension (3.4%) and elevation of AST (2.6%).

In clinical practice, regorafenib, ramucirumab and cabozantinib are approved by European Medicines Agency (EMA) as second-line treatment approved by EMA until now. However, more than 40% of candidate patients to 2nd line do not meet the RESORCE criteria or REACH-2 trial and are only candidates to cabozantinib treatment. However, investigators do not have safety data about those patients who are treated with other treatments than sorafenib in first line neither data about the real impact of sorafenib-intolerant patients according to the RESORCE trial definition.

For this reason, investigators propose to explore the role of cabozantinib in patients who were not considered in the CELESTIAL trial.

Detailed description:

Arms:
arm 1: Cabozantinib at 60 mg/day in monotherapy until symptomatic tumor progression, unacceptable adverse events, patient decision or death

Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Cabozantinib 60 mg/day. Cabozantinib dose will be modified upon development of adverse events.

Protocol document:
Prot_000.pdf: 
 
 
 
 
ACTION Clinical Study Protocol 
 
 
 
A phase II triAl of Cabozantinib for hepaTocellular 
carcInoma patients intOlerant to sorafenib treatment or 
first line treatment different to sorafeNib. (ACTION trial) 
 
NCT: NCT04316182 
 
 
 
 
 
 
 
 Version 4.0 – 15 July 2021 


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TITLE PAGE 
 
 
ACTION Clinical Study Protocol 
EUDRACT: 2019-004991-20 
 
 
A phase II triAl of Cabozantinib for hepaTocellular carcInoma patients intOlerant to 
sorafenib treatment or first line treatment different to sorafeNib. (ACTION trial) 
 
 
 
Version and status 
 Version 3.0 – 8 July 2020  
 
 
 
Version 3.1 – 27 August 2020 
                                           Version 4.0 – 15 July 2021 
 
 
 
Study Sponsor: Fundació Clinic per a la Recerca Biomèdica 
Principal Investigators: Maria Reig 
Affiliation: BCLC group. Liver Unit. ICMDM. CIBEREHD. IDIBAPS. Hospital Clínic 
c/ Villarroel, 170. Escala 11, 4ª planta. 08036. Barcelona. Spain 
Tel: 0034 93 227 9803 
Fax: +34 932275792 
email: mreig1@clinic.cat  
 
 
 
 
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable regulatory requirement. 
The information provided in this document is strictly confidential and is intended solely for the guidance of the clinical 
investigation. Reproduction or disclosure of this document – whether in part or full – to parties not associated with the clinical 
investigation or its use for any other purpose without prior written consent of the sponsor is not permitted. 
 


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SYNOPSIS 
Study Title (Full) 
 
A phase II triAl of Cabozantinib for hepaTocellular carcInoma patients intOlerant to sorafenib 
treatment or other First-Line treatment different to sorafenib (ACTION trial) 
Related Product 
 
CABOZANTINIB 
Indication 
 
Patients with HCC intolerant to sorafenib according to the RESORCE trial definition or those patients 
who received other first-line treatment. 
Phase of Study 
Phase IIa 
Countries 
Spain 
Retrospective or 
prospective study 
Prospective 
Planned number of 
sites/ subjects 
7 sites / 40 patients 
Blinding & Control 
non-randomized, non-blinded 
Study Type and Design 
 
Single arm, interventional, prospective study.  
Rationale  
 
Cabozantinib, a small molecule directed to vascular endothelial growth factor receptors, MET, and 
AXL, has shown to significantly improve the overall survival (OS) over placebo in the randomized 
phase 3 CELESTIAL trial in patients who had up to two lines of prior systemic therapy (including 
sorafenib) with progression on at least one in comparison to patients who received best supportive 
care (1).  
Although cabozantinib shares similar targets with sorafenib/regorafenib, they present different 
toxicity profile.  While the most common grade 3-4 AEs reported for sorafenib were fatigue (4%), 
diarrhea (8%), hand-foot reaction (8%) and hypertension (2%) (2); the most frequent grade 3-4 AEs for 
cabozantinib were hand-foot reaction (HFSR) (3.6%), hypertension (3.4%) and elevation of AST (2.6%) 
(1). 
In clinical practice, regorafenib, ramucirumab and cabozantinib are approved by EMA as second-line 
treatment approved by EMA until now (3). However, more than 40% of candidate patients to 2nd line 
do not meet the RESORCE criteria or REACH-2 trial and are only candidates to cabozantinib treatment. 
However, we do not have safety data about those patients who are treated with other treatments 
than sorafenib in first line neither data about the real impact of sorafenib-intolerant patients 
according to the RESORCE trial definition. 
For this reason, we propose to explore the role of cabozantinib in patients who were not considered in 
the CELESTIAL trial. 
 


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Primary Study Objective(s) 
 
To evaluate the safety profile established by rate of adverse events (AE) with Common Terminology 
Criteria for Adverse Events (CTCAE)≥3 excluding palmar-plantar erythordysthesia, rate of related-AEs 
and rate of death. The rate of AEs leading to treatment discontinuation. 
Secondary Study Objective(s) 
 
Overall survival (OS), objective response rate (ORR), time to progression (TTP), pattern of progression, 
post-progression survival (PPS), rate of patients who develop new extra-hepatic spread 
Operational/organizational aspects of the Study 
 
Multicenter study conducted by the BCLC in Spain with 7 relevant sites in HCC involved. Some study 
tasks will be outsourced to a national CRO (regulatory process, EDC system, monitoring plan, analysis, 
etc.) 
Study Population 
 
Patients with HCC intolerant to sorafenib according to the RESORCE trial definition or those patients 
who received other first-line treatment. 
Inclusion Criteria (detailed) 
 
1. HCC diagnosed according to criteria of American Association for the Study of Liver Diseases 
(AASLD )  definition in 2010. 
2. Intolerant to sorafenib according to RESORCE trial definition or patients who received 
treatment different to sorafenib as first-Line treatment . 
3. The subject has disease that is not amenable to a curative treatment approach (eg, 
transplant, surgery, radiofrequency ablation) 
4. Recovery to ≤ Grade 1 according to (CTCAE) v.5.0. from toxicities related to any prior 
treatments, unless the adverse events are clinically non-significant and/or stable on 
supportive therapy 
5. Respect the 15 days of first-line treatment washout before starting cabozantinib 
6. Age ≥ 18 years old on the day of consent 
7. ECOG performance status of 0 or 1 
8. Adequate hematologic function, based upon meeting the following laboratory criteria within 
              7 days before starting therapy: 
a. 
absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L) 
b. 
platelets ≥ 60,000/mm3 (≥ 60 x 109/L) 
c. 
hemoglobin ≥ 8 g/dL (≥ 80 g/L) 
9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days 
before starting therapy: 
a. 
Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance 
                            ≥ 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum  


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Creatinine x72 [mg/dL]) for males. (For females multiply by 0.85). 
 
AND 
b. 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine  
protein < 1 g 
10. Child-Pugh Score of A 
11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) within 7 days before starting therapy 
12. Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before starting therapy 
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < ≤ 5.0 upper limit of 
              normal (ULN) within 7 days before starting therapy 
14. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before starting therapy (if HbA1c results are 
unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL) 
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 
16. Capable of understanding and complying with the protocol requirements and signed informed 
consent 
17. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (eg, 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 
18. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming pregnant 
(ie, females who have had any evidence of menses in the past 12 months, with the exception 
of those who had prior hysterectomy). However, women who have been amenorrheic for 12 
or more months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, antiestrogens, ovarian suppression, low body weight, 
or other reasons. 
19. Subjects must consent to perform a tumor liver biopsy within 4 weeks before starting 
cabozantinib, allowing the acquisition of a tumor sample for performance of correlative 
studies. A formalin-fixed, paraffin embedded (FFPE) tumor tissue block of tumor sample 
should be stored at local sites for correlative studies. For these biopsies, subjects must have a 
soft tissue tumor lesion that can be biopsied at acceptable clinical risk, as judged by the 
investigator. Subjects must consent to the pre-treatment fresh liver biopsy as a condition of 
protocol participation. If adequate tissue is not obtained during the first procedure then a 
repeat biopsy should be considered based on the investigator’s assessment of clinical risk.  
However, biopsies at the time of radiological tumor progression are not required to meet 
eligibility.  Tumor biopsy is recommended at the time of tumor progression development. 
However, patients who develop radiologic tumor progression should have performance status 
0/1 and preserved liver function. Finally, patients with symptomatic tumor progression will 


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not be biopsied. 
Exclusion Criteria 
 
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma 
2. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone 
metastases or radionuclide treatment within 6 weeks of starting therapy (subject is excluded if 
there are any clinically relevant ongoing complications from prior radiation therapy) 
3. Prior cabozantinib treatment 
4. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before 
starting therapy. Eligible subjects must be without corticosteroid treatment at the time of 
starting therapy. 
5. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or 
warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation 
factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin for 
cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low 
dose LMWH are permitted. 
6. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions 
a. 
Cardiovascular disorders including: 
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious 
cardiac arrhythmias 
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or 
100 mm Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including TIA), myocardial infarction, or another ischemic event within 
6 months before starting therapy 
iv. Thromboembolic event within 3 months before starting therapy. Subjects with 
thromboses of portal/hepatic vasculature attributed to underlying liver 
disease and/or liver tumor are eligible 
b. 
 Gastrointestinal (GI) disorders including those associated with a high risk of  
perforation or fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel 
disease (eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis or appendicitis, acute pancreatitis or acute obstruction of the 
pancreatic duct or common bile duct, or gastric outlet obstruction  
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess 
within 6 months before starting therapy 
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed 


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prior to starting therapy 
c. 
Major surgery within 2 months before starting therapy. Complete healing from major  
surgery must have occurred 1 month before starting therapy. Complete healing from minor 
surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before 
starting therapy. Subjects with clinically relevant complications from prior surgery are not 
eligible 
d. 
Cavitating pulmonary lesion(s) or endobronchial disease 
e. 
Lesion invading a major blood vessel including, but not limited to:,   pulmonary artery, 
or aorta). Subjects with lesions invading the portal vasculature are eligible.  
f. 
Clinically significant bleeding risk including the following within 3 months of starting  
therapy: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or 
other signs indicative of pulmonary hemorrhage, or history of other significant bleeding if not 
due to reversible external factors 
g. 
Other clinically significant disorders such as: 
i. Active infection requiring systemic treatment, known infection with human 
immunodeficiency virus (HIV), or known acquired immunodeficiency 
syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection 
controlled with antiviral therapy are eligible. 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. Malabsorption syndrome 
iv.  Uncompensated/symptomatic hypothyroidism 
v.  Requirement for hemodialysis or peritoneal dialysis 
vi.  History of solid organ transplantation 
7. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding. 
Subjects treated with adequate endoscopic therapy (according to institutional standards) 
without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at 
least 6 months prior to study entry are eligible.  
8. Moderate or severe ascites. Note that controlled ascites with stable dose of diuretics in the 
last month is allowed.  
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days 
before starting therapy 
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the                 
average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
10. Inability to swallow tablets 
11. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations  
12. Pregnant or lactating females 
13. Diagnosis of another malignancy within 2 years before starting therapy, except for superficial 


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skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic 
therapy 
14. History of allergy to study drug components. 
15. Prisoners or subjects who are involuntarily incarcerated  
16.  Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg. 
infectious disease) illness 
17. Inability to comply with restrictions and prohibited activities/treatments. 
Test Treatment(s) (Description) 
 
Cabozantinib will be initiated at full dose (60 mg every day) which will be modified upon 
development of adverse events according to the manufacturer’s recommendations. Treatment will 
continue until symptomatic tumor progression, unacceptable adverse events, patient decision or 
death. 
 
Safety reporting  
 
All AEs that occur after the patient has signed informed consent until at least 30 days after the last 
dose of the study treatment must be recorded in the CRF. 
The documentation should be confirmed with a note in the patient's file. An abnormal laboratory 
result considered clinically significant—e.g. any which causes the patient's withdrawal from the 
study, requires treatment or causes obvious clinical manifestations, or which is assessed as relevant 
by the investigator—must be reported as an AE. Each event should be described in detail, together 
with the start and end dates, severity, relationship to the investigational medicinal product, 
measures taken and outcome. 
All actions taken concerning the study treatment to resolve the AE (drug withdrawal, drug 
suspension, dose reduction, unchanged dose, dose escalation, not applicable, not known) will be 
documented. 
Notice to the IECs of all relevant events (e.g. SAEs, Suspected Unexpected Serious Adverse Reactions  
[SUSARs]) will be given by the sponsor and/or investigator in accordance with the applicable 
regulations. 
The processing and communication of all relevant events (SAEs, SUSARs) to the authorities will be 
carried out by the sponsor in accordance with current legislation. 
The sponsor will inform all sites of relevant adverse events (e.g. SUSARs) in accordance with current 
legislation. 
Standard of Reference/Standard of Truth* 
 
Cabozantinib is a second-line treatment approved in HCC. However, in the CELESTIAL trial all patients 
received sorafenib as first-line treatment.  
Rationale for selection of a reference treatment 
 
In clinical practice, regorafenib, ramucirumab and cabozantinib are approved by EMA as second-line 
treatment until now (3). More than 40% of candidate patients to 2nd line do not meet the RESORCE 
criteria or REACH-2 trial and are only candidates to cabozantinib treatment. However, we do not 
have safety data about those patients who are treated with other treatments of sorafenib in first line 


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neither data about the real impact of sorafenib-intolerant patients according to the RESORCE trial 
definition.  
For this reason, our aim is to explore the role of cabozantinib in intolerant patients to first-line 
treatments or patients who received first line treatment different to sorafenib. 
 
 
Blinding 
 
Open-label due to the characteristic of the study. All patients will receive cabozantinib orally.  
Primary Outcome(s)  
 
Rate of AEs with CTCAE≥3 excluding palmar-plantar erythordysthesia, rate of AEs, rate of 
related-AEs and rate of death.  
Adverse events will be graded following version 5.0 of the CTCAE of the National Cancer Institute, 
during treatment and 30 days after the last dose before discontinuation. 
Secondary Outcome(s)  
 
Time to progression, pattern of progression, overall survival, post-progression survival, progression 
free survival, rate of patients who develop new extrahepatic spread. ORR  
Safety Outcomes  
 
Rate of AE, rate of related-AEs and rate of death.  
Adverse events will be graded following version 5.0 of the CTCAE of the National Cancer Institute, 
during treatment and 30 days after the last dose. 
Visit schedule 
 
Baseline evaluation and Follow-up included:  
All patients will be biopsied before starting cabozantinib. If the patient has a previous tissue sample, 
that material will be analyzed. However, this does not exclude the need to perform a biopsy within 
the month after initiation and at the time of developing radiologic tumor progression. 
Follow-up period 
 
Follow-up will include clinical and laboratory assessment every 2 weeks within the first 2 month, then 
every 4 weeks, tumor evaluation at week 4 and every 8 weeks thereafter. In addition, unscheduled 
visits will be made should they be needed (adverse events or symptoms). At each time point that the 
dose is changed we will perform a blood extraction to determine serum biomarkers. Moreover, a 
second extraction will be done 7 days after modifying the cabozantinib dose. Adverse events will be 
graded following version 5.0 of the CTCAE of the National Cancer Institute, during treatment and 30 
days after the last dose. Tumor evaluation during follow-up will be evaluated by CT-scan. Response 
and TP will be defined according to the RECIST criteria v1.1. Outcomes will be measured from the 
date of starting cabozantinib until the date of death regardless of cause of death. TTP will be defined 
as the time from the starting date of cabozantinib to disease progression (according to RECISTv1.1). 
PPS will be measured from the date of detecting progression at radiology until the date of death or 


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last follow-up.  Assessment will be done by radiologists in each center and then a central revision by 
radiologists with more than 10 years of experience in HCC and blinded to the evolution and outcome 
of the patients. Disease-control rate (DCR) will be defined as the percentage of patients who had a 
best-response rating of complete response (CR), partial response (PR) or stable disease (SD) 
(according to RECIST and BCLC-RECIST) maintained for at least 28 days after the first demonstration 
of best-response rating as per independent radiologic review. 
 
Statistical & Analytical Plan and Methodology 
 
The study will be analyzed using standard statistical methods to estimate rates and 95%CI (for ORR 
and other binary variables) by means of the Clopper-Pearson exact method, and the Kaplan-Meier 
method to describe the survival functions and the median and [95%CI]. A Statistical Analysis Plan, 
which will include all details regarding all analyses, the interim method, the handling of missing data 
and any plan for the analysis, will be finalized before the initiation of the study recruitment. 
The sample size calculation will be triggered by the primary outcome, i.e, the rate of adverse events 
(AE) with CTCAE≥3 excluding palmar-plantar erythordysthesia (critical AEs). The expected rate for this 
outcome was 56% in this population. The Simon's two-stage optimal design will be used to test the 
alternative hypothesis that with cabozantinib the rate of critical AEs will be reduced at least to 32.5% 
against the null hypothesis of 56%. In the first stage, 14 patients will be accrued and if there are 8 or 
more critical AES in these 14 patients, the study will be stopped for futility. Otherwise, 26 additional 
patients will be accrued for a total of 40. The null hypothesis will be rejected if 23 or fewer critical AEs 
are observed in 40 patients. This design yields a type I error rate of 2.5% one-sided and power of 80% 
when the true response rate is 67.5%. 
Planned Study Timelines:  
 
1. Enrolment rate (patients per month): 3 
2. Planned estimate of treatment(s) duration: 24months 
3. Submission date to health authority/ethics: Jan 2020 
4. Start of subject enrolment: March 2020 
5. End of Subject enrolment: Jul 2022 
6. All patients completed: Oct 2023 
7. End of Study: Jan 2024  
8. Report: Q2-Q3 2024   
9. Planned publication/presentation: Q1 2025 


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TABLE OF CONTENTS. 
TITLE PAGE .................................................................................................................................................................. 1 
SYNOPSIS .................................................................................................................................................................... 2 
1. 
INTRODUCTION ................................................................................................................................................ 13 
1.1 
HEPATOCELLULAR CARCINOMA ......................................................................................................................................... 13 
1.2 
CABOZANTINIB: BACKGROUND .......................................................................................................................................... 13 
1.2.1 
PHARMACOLOGY AND PHARMACOKINETICS ............................................................................................................ 13 
1.2.2 
CABOZANTINIB SAFETY SUMMARY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. ........................................ 16 
1.2.3 
SUMMARY OF CABOZANTINIB CLINICAL ACTIVITY IN HEPATOCELLULAR CARCINOMA ............................................ 16 
1.2.4 
RATIONALE FOR THE CURRENT STUDY ..................................................................................................................... 17 
1.2.4.1 
TREATMENT SCHEDULE ...................................................................................................................................................... 17 
2. 
STUDY OBJECTIVES ........................................................................................................................................... 17 
3. 
ETHICAL CONSIDERATIONS ............................................................................................................................... 17 
3.1 
GOOD CLINICAL PRACTICE .................................................................................................................................................. 17 
3.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ............................................................................... 18 
3.3 
INFORMED CONSENT .......................................................................................................................................................... 18 
4. 
STUDY DESIGN AND PLAN ................................................................................................................................ 19 
4.1 
TREATMENT PLAN ............................................................................................................................................................... 19 
4.1.1 
SCREENING PHASE .................................................................................................................................................... 19 
4.1.2 
CABOZANTINIB .......................................................................................................................................................... 20 
4.1.3 
END OF THE STUDY ................................................................................................................................................... 20 
4.1.4 
DISCONTINUATION OF CABOZANTINIB ..................................................................................................................... 21 
4.1.5 
POST STUDY DRUG STUDY FOLLOW-UP .................................................................................................................... 21 
4.1.6 
WITHDRAWAL OF CONSENT ..................................................................................................................................... 21 
4.1.7 
LOST TO FOLLOW-UP ................................................................................................................................................ 22 
5. 
PATIENT POPULATION ...................................................................................................................................... 22 
5.1 
INCLUSION CRITERIA ........................................................................................................................................................... 22 
5.1.1 
SIGNED WRITTEN INFORMED CONSENT ................................................................................................................... 22 
5.1.2 
TARGET POPULATION ............................................................................................................................................... 22 
5.2 
EXCLUSION CRITERIA .......................................................................................................................................................... 24 
5.2.1 
MEDICAL HISTORY AND CONCURRENT DISEASES ..................................................................................................... 24 
6. 
STUDY DRUG(S) AND CONCOMITANT MEDICATIONS ....................................................................................... 26 
6.1 
INVESTIGATIONAL PRODUCTS ............................................................................................................................................ 26 
6.1.1 
CABOZANTINIB .......................................................................................................................................................... 27 
6.1.2 
PACKAGING AND LABELING. ..................................................................................................................................... 27 
6.1.3 
HANDLING AND DISPENSING .................................................................................................................................... 27 
6.1.4 
DOSE MODIFICATIONS .............................................................................................................................................. 27 
6.1.4.1 
CABOZANTINIB DOSE MODIFICATIONS .............................................................................................................................. 27 
6.1.4.2 
GENERAL ............................................................................................................................................................................. 28 
6.1.4.3 
GASTROINTESTINAL DISORDERS ......................................................................................................................................... 29 
6.1.4.4 
HEPATOBILIARY DISORDERS ............................................................................................................................................... 30 
6.1.4.5 
HEMATOLOGICAL DISORDERS ............................................................................................................................................ 30 
6.1.4.6 
FATIGUE, ANOREXIA, AND WEIGHT LOSS ........................................................................................................................... 31 
6.1.4.7 
SKIN DISORDERS ................................................................................................................................................................. 31 


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6.1.4.8 
HYPERTENSION ................................................................................................................................................................... 33 
6.1.4.9 
THROMBOEMBOLIC EVENTS............................................................................................................................................... 34 
6.1.4.10 
PROTEINURIA ...................................................................................................................................................................... 35 
6.1.4.11 
CORRECTED QTc PROLONGATION ...................................................................................................................................... 35 
6.1.4.12 
HEMORRAGIC EVENTS ........................................................................................................................................................ 36 
6.1.4.13 
GI PERFORATION/FISTULA AND NON-GI FISTULA FORMATION ......................................................................................... 37 
6.1.4.14 
OSTEONECROSIS OF THE JAW ............................................................................................................................................. 37 
6.1.5 
CRITERIA TO RESUME CABOZANTINIB TREATMENT ................................................................................................. 38 
6.1.6 
PERMANENT DISCONTINUATION OF CABOZANTINIB DUE TO ADVERSE EVENTS ..................................................... 38 
6.1.7 
STOPPING RULES FOR CLINICAL DETERIORATION ..................................................................................................... 39 
6.1.7.1 
TREATMENT WITH CABOZANTINIB BEYOND DISEASE PROGRESSION ................................................................................ 40 
6.2 
CONCOMITANT TREATMENTS ............................................................................................................................................ 40 
6.2.1 
PERMITTED TREATMENTS ......................................................................................................................................... 40 
6.2.2 
PROHIBITED TREATMENTS ........................................................................................................................................ 41 
6.2.3 
SUPPORTIVE TREATMENTS ....................................................................................................................................... 41 
6.2.3.1 
PALLIATIVE LOCAL THERAPY ............................................................................................................................................... 42 
6.2.4 
TREATMENT OF HBV VIROLOGICAL BREAKTHROUGH AND ONGOING HCV ............................................................. 42 
6.3 
TREATMENT COMPLIANCE ................................................................................................................................................. 42 
6.4 
DESTRUCTION OF STUDY DRUG .......................................................................................................................................... 42 
7. 
STUDY PROCEDURES ........................................................................................................................................ 45 
7.1 
FLOW CHART/TIME AND EVENTS SCHEDULE ...................................................................................................................... 45 
7.2 
SAFETY ASSESSMENTS ........................................................................................................................................................ 48 
7.2.1 
ASSESSMENTS AND DOCUMENTATION OF ADVERSE EVENTS .................................................................................. 48 
7.2.2 
REPORTING OF SERIOUS ADVERSE EVENTS .............................................................................................................. 48 
7.2.3 
INVESTIGATOR’S NOTIFICATION TO THE SPONSOR .................................................................................................. 48 
7.2.4 
EXPECTED ADVERSE EVENTS ..................................................................................................................................... 49 
7.2.5 
PREGNANCIES ............................................................................................................................................................ 50 
7.2.6 
FURTHER SAFETY ....................................................................................................................................................... 50 
7.2.6.1 
PHYSICAL EXAMINATIONS .................................................................................................................................................. 50 
7.2.6.2 
VITAL SIGNS ........................................................................................................................................................................ 50 
7.2.6.3 
12-LEAD ECG ....................................................................................................................................................................... 51 
7.2.6.4 
LABORATORY ASSESSMENTS .............................................................................................................................................. 51 
7.3 
EFFICACY ASSESSMENTS ..................................................................................................................................................... 52 
7.4 
EXPLORATORY BIOMARKER, PERIPHERAL BLOOD AND TUMOR ASSESSMENTS ................................................................. 52 
8. 
ADVERSE EVENTS ............................................................................................................................................. 52 
8.1 
DEFINITIONS ....................................................................................................................................................................... 52 
8.1.1 
ADVERSE EVENT (AE) ................................................................................................................................................. 52 
8.1.2 
SERIOUS ADVERSE EVENT (SAE) ................................................................................................................................ 52 
8.1.3 
DEATH ....................................................................................................................................................................... 53 
8.1.4 
SPECIAL SITUATIONS ................................................................................................................................................. 54 
8.1.4.1 
PREGNANCY ........................................................................................................................................................................ 54 
8.1.4.2 
OVERDOSE .......................................................................................................................................................................... 54 
8.2 
COLLECTION AND REPORTING OF ADVERSE EVENTS, FATAL OUTCOMES AND SPECIAL SITUATIONS ................................. 54 
8.2.1 
COLLECTION OF SAFETY REPORTS ............................................................................................................................. 54 
8.2.2 
REPORTING OF SAFETY REPORTS .............................................................................................................................. 55 
8.2.3 
MANDATORY INFORMATION FOR REPORTING AN ADVERSE EVENT ........................................................................ 55 
8.3 
SAFETY CLASIFICATIONS ..................................................................................................................................................... 56 
8.3.1 
RELATIONSHIP OF EVENTS TO THE MEDICINAL PRODUCT ........................................................................................ 56 


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8.3.2 
SEVERITY OF EVENTS ................................................................................................................................................. 56 
8.3.3 
EXPECTEDNESS OF EVENTS ....................................................................................................................................... 57 
8.3.4 
SAFETY DATA LISTING ............................................................................................................................................... 57 
9. 
STATISTICAL METHODS .................................................................................................................................... 57 
9.1 
END-POINTS ........................................................................................................................................................................ 57 
9.2 
SAMPLE SIZE ....................................................................................................................................................................... 58 
9.3 
INTERIM ANALYSES ............................................................................................................................................................. 58 
10. 
STUDY CONDUCT CONFIDENTIAL ..................................................................................................................... 58 
10.1 ADHERENCE TO THE PROTOCOL ......................................................................................................................................... 59 
10.2 DATA MONITORING COMMITEE (DMC) .............................................................................................................................. 59 
11. 
DATA MANAGEMENT ....................................................................................................................................... 60 
11.1 DATA SOURCE ......................................................................................................................................................................... 60 
11.2 CONFIDENTIALITY .................................................................................................................................................................... 60 
11.3 WITHDRAWAL ......................................................................................................................................................................... 60 
12. 
LIST OF ABBREVIATIONS ................................................................................................................................... 61 
13. 
REFERENCE LIST ................................................................................................................................................ 64 
14. 
APPENDICES ..................................................................................................................................................... 66 
14.1 APPENDIX 1: ECOG PERFORMANCE STATUS ....................................................................................................................... 66 
14.2 APPENDIX 2: CHILD-PUGH SCALE ........................................................................................................................................ 67 
14.3 APPENDIX 3: RECIST 1.1 CRITERIA ....................................................................................................................................... 68 
14.4 APPENDIX 4: NCI CTCAE V.5.0 RECOMMENDATION FOR GRADING OF ADVERSE EVENTS .................................................. 73 
14.5 APPENDIX 5: MANAGEMENT OF SUSPECTED CABOZANTINIB TOXICITIES .......................................................................... 74 
14.6 APPENDIX 7: PATIENT-REPORTED QUALITY OF LIFE QUESTIONNAIRES .............................................................................. 75 
14.7 CYP3A4 AND CYP1A2 INHIBITORS/INDUCERS ............................................................................................................................. 87 
14.8 CLINICAL STUDY SAE REPORT FORM ................................................................................................................................... 88 
 
 


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1.  INTRODUCTION  
1.1 HEPATOCELLULAR CARCINOMA 
Hepatocellular carcinoma (HCC) is the third main cause of cancer-related death globally and has an 
incidence of around 850,000 new cases per year1 HCC represents nearly 90% of all cases of primary liver 
cancer and is the first cause of death in cirrhotic patients2. In Western countries, leading risk factors for 
HCC development are well known and include hepatitis B (HBV) and C virus (HCV) infection, alcohol intake 
and nonalcoholic fatty liver disease (NAFLD) associated with the metabolic syndrome1. The Barcelona Clinic 
Liver Cancer (BCLC) staging classification is the most accepted clinical algorithm for the stratification of 
patients according to prognosis and treatment allocation1. The systemic treatment in hepatocellular 
carcinoma is quickly evolving since the sorafenib breakthrough in 20073, the only available drug for 
advanced HCC for more than 10 years. New drugs were recently made available for these patients due to 
their benefit on the overall survival (OS). In first-line therapy, the lenvatinib vs sorafenib (REFLECT) trial4 
was a multicenter, randomized, 1st-line phase 3 trial in HCC demonstrating that both treatments are 
equally effective but with a different safety profile4. Very recently, the combination of atezolizumab (anti-
PDL1) and bevacizumab (IMbrave150 phase III trial5) has been reported to be superior than sorafenib. The 
first available second-line treatment with benefits in terms of survival was regorafenib6 and more recently 
cabozantinib7 and ramucirumab (REACH-2 trial8), all demonstrated to improve OS as compared to placebo 
in 3 phase III second-line randomized controlled trials (RCTs). Additionally, nivolumab9 and 
pembrolizumab10 have been granted an accelerated FDA approval in 2nd-line treatment based on radiologic 
tumor response. However, the phase III trial that compared pembrolizumab vs placebo in second-line is 
negative11. Specifically, the phase III CELESTIAL trial7 demonstrated that cabozantinib is safe and effective 
in terms of OS [hazard ratio (HR) for death, 0.76; 95%CI, 0.63 to 0.92] in patients intolerant to sorafenib 
but there was any definition of intolerance in that trial and also in patients who developed progression 
under  sorafenib.  
1.2 CABOZANTINIB: BACKGROUND 
A summary of the non-clinical pharmacology, toxicology, pharmaceutical and metabolism data on 
cabozantinib is provided in this section. Additional information can be found in the Investigator Brochures 
for cabozantinib. 
1.2.1 
PHARMACOLOGY AND PHARMACOKINETICS 
Cabozantinib shows a potent inhibitory activity against different receptor tyrosine kinases that are known 
to impact on tumor growth, metastasis, and angiogenesis. The primary targets of cabozantinib are MET, 
VEGFR2/KDR, and RET with cell-based IC50 (concentration associated with 50% inhibition) values of 8, 2 
and 85 nM, respectively12. In addition, cabozantinib suppressed phosphorylation of KIT, FLT3, and AXL with 
IC50 values of 5, 11, and 42 nM, respectively. The IC50 values in biochemical kinase assays do not always 
translate evenly in vivo. For example, cabozantinib exhibits comparable potency against MET and VEGFR2 
in cellular and in vivo assays, in spite of its apparent greater potency for inhibition of VEGFR2 in 
biochemical kinase assays. Hence, cabozantinib is a balanced inhibitor of MET and VEGFR2 that also 


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inhibits a number of other receptor tyrosine kinases implicated in tumor pathobiology, including RET, KIT, 
AXL, and FLT312. Data from pharmacodynamic experiments showed that cabozantinib inhibits MET and 
VEGFR2 in vivo. Oral administration of cabozantinib resulted in blockade of MET phosphorylation in human 
lung tumor xenografts grown in nude mice, blockade of MET phosphorylation in livers of mice, and 
blockade of VEGFR2 phosphorylation in mouse lung tissue. In addition, oral administration of cabozantinib 
resulted in blockade of phosphorylation of mutationally activated RET in human medullary thyroid cancer 
(MTC) xenografts grown in nude mice13. Treatment with cabozantinib results in anti-angiogenic effects in 
xenograft tumors, with disruption of the vasculature beginning within 24 hours after administration, and is 
associated with pro-apoptotic effects. These effects translate into significant tumor growth inhibition or 
tumor regression after cabozantinib treatment in multiple tumor models including MTC, breast cancer, 
lung carcinoma, and glioblastoma12. 
Overall, the preclinical data produced in vivo demonstrate that the target profile of cabozantinib translates 
into potent anti-angiogenic activity and potent antitumor efficacy both in soft tissue and in bone.  
A summary of cabozantinib pharmacology is contained in the Investigator’s Brochure, which should be 
reviewed in conjunction with this study protocol.  
A population PK analysis of cabozantinib was performed in using data collected from 289 subjects with 
solid tumors including metastatic medullary thyroid carcinoma (MTC) following oral administration of 140 
mg (FBE) daily doses as capsules14. The predicted effective half-life is approximately 55 hours, the oral 
volume of distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated to 
be 4.4 L/hr. The terminal half-life (for predicting drug washout) is approximately 120 hours. Following oral 
administration of cabozantinib, median time to peak cabozantinib plasma concentrations (Tmax) ranged 
from 2 to 5 hours post-dose. Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-
fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady 
state was achieved by Day 15. Cabozantinib is highly protein bound in human plasma (≥ 99.7%). A 
population PK analysis did not identify clinically relevant differences in clearance of cabozantinib between 
females and males or between Whites (89%) and non-Whites (11% [<4% were Asian]). Cabozantinib PK was 
not affected by age (20-86 years)14.  
A second PopPK analysis was conducted in subjects with renal cell carcinoma (RCC) who received repeated 
oral daily cabozantinib tablet dosing at 60 mg (with protocol-permitted dose reductions to 40 mg and 20 
mg) combined with healthy subjects who received a single oral tablet dose of 20, 40, or 60 mg. This 
analysis indicated that for a White male subject the predicted terminal plasma half-life of cabozantinib was 
approximately 99 h; the terminal phase volume of distribution (Vz) was approximately 319 L; and the CL/F 
at steady-state was estimated to be approximately 2.2 L/h. Female gender and Asian race were significant 
covariates on CL/F, and while the attributes were statistically significant, they were not deemed clinically 
meaningful given the magnitude of the effects. Further evaluation of the differences in the two PopPK 
analyses revealed that compared with other cancer patient groups (ie, RCC, castration-resistant prostate 
cancer [CRPC], glioblastoma multiforme [GB]), MTC subjects cleared cabozantinib faster and thus had 
lower dose-normalized steady-state plasma exposures. Several possible factors may underlie the higher 
cabozantinib clearance observed in the first PopPK analysis; however, an exact cause has yet to be 
identified.  


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Exposure of cabozantinib was assessed in Japanese subjects in capsule and tablet formulations (Study 
XL184-014)15. At steady state, exposure, AUC increased slightly less than dose proportionally from 40 to 80 
mg capsule doses and slightly more than dose proportionally from 40 to 60 mg tablet doses. There was no 
clinically relevant difference in exposure between capsule and tablet formulations. Steady-state plasma 
exposures in Japanese subjects administered 60-mg tablets were approximately 30% higher than reported 
in non-Japanese subjects administered 60-mg tablets (Study Report XL184-308)15. However, as this 
difference was within the range of inter-subject variability determined in Japanese (%CV= 34%) and non-
Japanese subjects (%CV=48%), no firm conclusions may be drawn regarding differences in cabozantinib 
exposures between these two subject populations.  
In the mass balance study, within a 48-day collection period after a single dose of 14Ccabozantinib in 
healthy subjects, approximately 81% of the total administered radioactivity was recovered with 54% in 
feces and 27% in urine. A PK study of cabozantinib in patients with renal impairment is ongoing. The results 
of a population PK analysis suggested that mild to moderate renal impairment (creatinine clearance value 
≥30 mL/min) does not have a clinically relevant effect on the clearance of cabozantinib. The PK evaluation 
of cabozantinib has not been completed in patients with hepatic impairment; preliminary data suggest that 
subjects with mild hepatic function impairment (Child-Pugh A) show a 61% higher plasma AUC0-∞ for 
cabozantinib as compared with matched healthy subjects (XL184-003)16. 
A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted conditions 
in healthy subjects administered a single 140 mg oral cabozantinib dose. Cabozantinib is a substrate of 
CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of the XL184 N-oxide metabolite by >80%. 
Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (ie, a <20% reduction). 
Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on 
cabozantinib metabolite formation. Cabozantinib AUC was increased 38% with coadministration of the 
strong CYP3A4 inhibitor ketoconazole and decreased 77% with coadministration of the strong CYP3A4 
inducer rifampin. 
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both 
CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of CYP3A4 
(estimated Kiapp = 282 μM) in human liver microsomal (HLM) preparations. IC50 values >20 μM were 
observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems14. 
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (ie, 75-100% of CYP1A1 
positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or 
CYP3A4 mRNA or isozyme-associated enzyme activities. Cabozantinib at steady-state plasma 
concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect on single-dose 
rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients with solid tumors. 
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a bi-
directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to 
increase plasma concentrations of co-administered substrates of P-gp. Additional results from this and 
other clinical PK trials may be found in the Investigator Brochure. 


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1.2.2 
CABOZANTINIB SAFETY SUMMARY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. 
The 41 subjects with advanced HCC treated with cabozantinib in phase II Study XL184-203 RDT17 received 
an initial dose of 100 mg/day (FBE). Fifty-nine percent of subjects required at least 1 dose reduction 
throughout both the Lead-in and Randomized Stages. The most frequently reported AEs during the study 
were consistent with those in subjects with other tumor types who received single-agent cabozantinib and 
included diarrhea (68%), fatigue (59%), palmar-plantar erythrodysesthesia (PPE) syndrome (54%), vomiting 
(42%), and nausea (39%). Common Grade 3 or higher AEs included diarrhea (22%), thrombocytopenia 
(17%), PPE syndrome (15%), aspartate aminotransferase (AST) increased (12%). 
The safety and efficacy were recently evaluated in the randomized, double-blind, placebo-controlled Phase 
3 study7. The 707 patients with HCC not susceptible to curative treatment and who had received sorafenib 
were randomized (2: 1) to receive cabozantinib (N = 470) or placebo (N = 237). Patients may have received 
prior systemic treatment for advanced disease in addition to sorafenib. Randomization was stratified by 
disease etiology (HBV [with or without HCV), HCV [without HBV] or other), geographic region (Asia, other 
regions) and by the presence of extrahepatic spread of the disease and / or macrovascular invasions. 
In the CELESTIAL study7 the most frequently reported AEs during the study were consistent with those in 
subjects with previous data with cabozantinib single-agent and included diarrhea (54%), decreased 
appetite (48%), PPE syndrome (46%), fatigue (45%), nausea (31%), hypertension (29%) and vomiting (26%). 
Common Grade 3 AEs included PPE syndrome (17%), hypertension (16%), Increase in AST/ALT level (11%), 
diarrhea (10%) and fatigue (10%). 
1.2.3 
SUMMARY OF CABOZANTINIB CLINICAL ACTIVITY IN HEPATOCELLULAR CARCINOMA  
The safety and efficacy were recently evaluated in the randomized, double-blind, placebo-controlled Phase 
3 study (CELESTIAL)7. The 707 patients with HCC not susceptible to curative treatment and who had 
received sorafenib were randomized (2: 1) to receive cabozantinib (N = 470) or placebo (N = 237). Patients 
may have received prior systemic treatment for advanced disease in addition to sorafenib. Randomization 
was stratified by disease etiology (HBV [with or without HCV), HCV [without HBV] or other), geographic 
region (Asia, other regions) and by the presence of extrahepatic spread of the disease and / or 
macrovascular invasions. 
The main efficacy variable was overall survival (OS). Secondary efficacy variables were progression-free 
survival (PFS) and objective response rate (ORT), evaluated by the researcher using the criteria for 
evaluation of solid tumor response (RECIST) 1.118. Tumor evaluations were performed every 8 weeks. The 
subjects continued the treatment of the blind study after the progression of the radiological disease, while 
experiencing a clinical benefit or even the need for a local systemic or anticancer therapy directed to the 
liver. The placebo crossing to cabozantinib was not allowed during the blind treatment phase. The 
CELESTIAL trial showed significantly longer OS in the cabozantinib arm compared to with placebo. Median 
OS was 10.2 months with cabozantinib and 8.0 months with placebo (HR for death, 0.76; 95% CI, 0.63 to 
0.92; P = 0.005). Median PFS was 5.2 months with cabozantinib and 1.9 months with placebo (HR for 
disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the ORR were 4% and less than 1%, 
respectively (P = 0.009). 


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1.2.4 
RATIONALE FOR THE CURRENT STUDY  
The systemic treatment for HCC has rapidly evolved in last years, having available in first-line sorafenib3 
and lenvatinib4 but very recently the IMbrave150 phase III trial5 has been presented as positive.  
Cabozantinib has been shown to be safe and effective in patient who progressed on sorafenib treatment7. 
Here, sorafenib intolerant patients were also included but no clear definition was applied to identify those 
patients.  Therefore, the aim of this study will be to test the safety of cabozantinib in patients sorafenib 
intolerant according to the RESORCE6 trial definition and in patients treated with first-line treatments other 
than sorafenib. 
1.2.4.1 
TREATMENT SCHEDULE  
Cabozantinib will be initiated at full dose (60 mg/day) and this dose will be modified upon development of 
adverse events according to the manufacturer’s recommendations. Cabozantinib will be continued at the 
dose that the patient can tolerate. Treatment will continue until symptomatic tumor progression, 
unacceptable adverse events, patient decision or death. 
2. STUDY OBJECTIVES  
The aim of this study will be to test the safety of cabozantinib in patients sorafenib intolerant according to 
the RESORE trial6 definition and in patients treated with first-line treatments other than sorafenib. Indeed, 
although a phase III trial (CELESTIAL)7 showed improved OS with acceptable toxicity in sorafenib intolerant 
patients or in those who progressed on sorafenib, no clear definition was applied to identify those 
patients.  The primary endpoints are the rate and type of AEs leading to treatment discontinuation, the 
rate and type of AEs, serious AEs (SAEs), rate of related-AE and rate of death. Secondary endpoints are 
time to progression, pattern of progression, overall survival, post-progression survival, rate of patients who 
develop new extra-hepatic spread and ORR. Radiologic tumor response will be defined according to the 
RECIST 1.118 and then will be evaluated by BCLC-RECIST19. Exploratory objectives are: i) to evaluate the role 
of tissue biomarkers (see Table 5 for timing-points) in determining the antitumoral activity of cabozantinib; 
ii) to describe the quality of life and iii) the gut microbiota composition at different time points. This study 
will collect blood and biopsy samples but the exploratory objectives will be done in a second study only if 
the study meets the safety end-point. 
3. ETHICAL CONSIDERATIONS 
3.1 GOOD CLINICAL PRACTICE  
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this 
study, are designed to ensure that the sponsor and investigator abide by Good Clinical Practice (GCP) 
guidelines as defined by the International Conference on Harmonization (ICH) and in accordance with the 
ethical principles underlying regulation (EU) Nº536/2014 of the European Parliament and the council of 16 
April 2014. The study will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating centers before 
start of the study, according to GCP, local laws, regulations and organizations.  When necessary, an 
extension, amendment or renewal of the EC/IRB approval must be obtained and also forwarded to the 


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Sponsor.  The responsible unit (e.g. EC/IRB, head of the study center/medical institution) must supply to 
the Sponsor, upon request, a list of the EC/IRB members involved in the vote and a statement to confirm 
that the EC/IRB is organized and operates according to GCP and applicable laws and regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of study conduct; 
the investigator may not modify or alter the procedures described in this protocol.   
Modifications to the study protocol will not be implemented by either the sponsor or the investigator 
without agreement by both parties.  However, the investigator or the sponsor may implement a deviation 
from, or a change of, the protocol to eliminate an immediate hazard(s) to the trial patients without prior 
IEC/IRB/sponsor approval/favorable opinion.  As soon as possible, the implemented deviation or change, 
the reasons for it and if appropriate the proposed protocol amendment should be submitted to the 
IEC/IRB/head of medical institution/sponsor.  Any deviations from the protocol must be explained and 
documented by the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 4.1.5 
3.2 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator must have written and dated approval/favorable opinion from the 
IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., advertisements), and any other 
written information to be provided to subjects. The investigator or the sponsor should also provide the 
IRB/IEC with a copy of the Investigator Brochure or product labeling information to be provided to subjects 
and any updates. The investigator or the sponsor should provide the IRB/IEC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
3.3 INFORMED CONSENT 
All relevant information on the study will be summarized in an integrated subject information sheet and 
informed consent form provided by the sponsor or the study center.  A sample subject information and 
informed consent form is provided as a document separate to this protocol. 
Based on this subject information sheet, the investigator or designee will explain all relevant aspects of the 
study to each subject / legal representative or proxy consenter (if the subject is under legal protection), 
prior to his/her entry into the study (i.e. before any examinations and procedures associated with the 
selection for the study are performed or any study-specific data is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB/IEC has been obtained. 
Each subject / legal representative or proxy consenter will have ample time and opportunity to ask 
questions and will be informed about the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
Only if the subject / legal representative or proxy consenter voluntarily agrees to sign the informed 
consent form and has done so, may he/she enter the study.  Additionally, the investigator and other 
information provider (if any) will personally sign and date the form.  The subject / legal representative or 
proxy consenter will receive a copy of the signed and dated form. 


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The signed informed consent statement is to remain in the investigator site file or, if locally required, in the 
patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are performed, 
the study record or subject´s clinical record must clearly show that informed consent was obtained prior to 
these procedures. 
The investigator will inform the subject/legal representative or proxy consenter of changes in a timely 
manner and will ask the subject to confirm his/her participation in the study by signing the revised IC form. 
Any revised written IC form and written information must receive the IEC/IRB`s approval/favorable opinion 
in advance of use. 
If the subject is not capable of providing a signature, a verbal statement of consent can also be given in the 
presence of an impartial witness (independent of the sponsor and the investigator).  This is to be 
documented by a signature from the informing physician as well as by a signature from the witness. 
The informed consent form and any other written information provided to patients / legal representatives 
or proxy consenters will be revised whenever important new information becomes available that may be 
relevant to the subject’s consent, or there is an amendment to the protocol that necessitates a change to 
the content of the subject information and / or the written informed consent form.  The investigator will 
inform the subject / legal representative or proxy consenter of changes in a timely manner and will ask the 
subject to confirm his/her participation in the study by signing the revised informed consent form.  Any 
revised written informed consent form and written information must receive the IEC/IRB`s approval / 
favorable opinion in advance of use. 
4. STUDY DESIGN AND PLAN 
The study is a prospective, multicenter, open-label, non-controlled phase IIa study evaluating cabozantinib 
for the treatment of patients with unresectable hepatocellular carcinoma sorafenib intolerant according to 
the RESORCE trial definition or who received other first-line treatments than sorafenib. Treated patients 
will be followed until death, withdrawal of consent or until the end of the duration of the study.  
4.1 TREATMENT PLAN 
4.1.1 
SCREENING PHASE 
Study entry is defined as the date that the Informed Consent has been signed by the patient. No patient 
may undergo any screening procedures that are not considered standard of care to assess his/her eligibility 
to receive protocol treatment, or commence protocol treatment, prior to signing the informed consent 
form. The time period between study entry and the commencement of protocol treatment is not to exceed 
28 days. Patients may only commence protocol treatment after all eligibility criteria have been confirmed. 
After signing the informed consent and upon documentation of eligibility, the patient will be allocated with 
an enrolment number and registered in an enrolment log. The patient identification number will be multi-
digit, to represent the investigational site and an enrolment number that will be unique to each subject. All 
patients referred for possible participation in this study must be assessed at screening to confirm the 
patient’s eligibility. All documentation supports the inclusion and exclusion criteria and screening 
investigation results are to be retained by the Investigator and made available for monitoring by the study 


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Sponsor including source data verification. All patients assessed as ineligible to be enrolled in the study 
after study entry are considered screening failures. The investigator will have their initials recorded on the 
Patient Screening Log and no further data will be collected for these patients. The Patient Screening Log 
will include the reason(s) for the patient not meeting the eligibility criteria and will be maintained by the 
site and copies retained by the study Sponsor. Patient who withdrew consent after study entry but before 
treatment for any reason will be considered screening failures and should be registered in the screening 
log.  
The study monitor should be contacted in the event of any query or uncertainty relating to a patient’s 
eligibility to receive protocol treatment: 
Dr. Marco Sanduzzi-Zamparelli 
BCLC group, Liver Unit, Hospital Clinic de Barcelona 
Email: msanduzzi@clinic.cat  
Phone: +34 932279803;  
Fax:+34 932275792 
Dr. Maria Reig 
BCLC group, Liver Unit, Hospital Clinic de Barcelona 
Email: mreig1@clinic.cat  
Phone: +34 932279803;  
Fax:+34 932275792 
4.1.2 
CABOZANTINIB 
The choice of dosage (starting dose of 60 mg) and schedule to be used in this trial is based on available 
data accumulated in previous Phase I, II and III trials and approved to treat HCC with cabozantinib. 
The study drug will be administered orally. The investigator or designated study personnel is responsible 
for dispensing the study drug to patients. 
Patients should be instructed to not eat anything for at least 2 hours before through 1 hour after taking 
cabozantinib. Subjects should be instructed to not make up vomited doses and to maintain the planned 
dosing schedule. Subjects should not make up for missed doses if more than 12 hours have elapsed 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 one the subject missed. 
Any unused study treatment must be returned to the study site for drug accountability and disposal.  
Cabozantinib will be initiated at full dose (60 mg/day) and the dose will be modified upon development of 
adverse events according to the manufacturer’s recommendations. Treatment will be continued until 
symptomatic tumor progression, unacceptable adverse events, patient decision or death. Criteria for 
cabozantinib dose reduction or escalation and to resume treatment are described in Section 6.1.4.1 
4.1.3 
END OF THE STUDY 
After discontinuation from study therapy, there is 1 follow-up visit required within seven days of 
discontinuation (on site visit), and additional survival follow-up (on-site or phone visits). The study will end 


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when survival follow-up collection has concluded. The last visit will be defined as the latest follow-up Visit. 
Additional survival follow-up may continue beyond the time of this analysis. 
4.1.4 
DISCONTINUATION OF CABOZANTINIB 
 Subjects MUST discontinue study medication: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Any clinical AE, abnormal laboratory test results or any illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of the 
subject. 
• Clinical deterioration  (Section 6.1.7) 
• Pregnancy 
• Termination of the study by the promoter 
• Specific criteria for discontinuation of outlined in (Section 6.1.6) 
• Loss of ability to freely provide consent through imprisonment or involuntary incarceration for 
treatment of either a psychiatric or physical (eg, infectious disease) illness. 
• Protocol defined disease progression unless subject is eligible for treatment beyond progression 
(Section 6.1.7.1). 
• In the case of pregnancy, the investigator must immediately notify the Medical Monitor/designee 
of this event. In most cases, the study drug will be permanently discontinued in an appropriate 
manner. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study drug, a discussion between the investigator and the Principal Investigator 
must occur.  
• All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in section. The only exception to this requirement is when a subject withdraws consent for 
all study procedures or loses the ability to consent freely (ie, is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). If a subject was withdrawn 
before completing the study, the reason for withdrawal must be entered on the appropriate CRF 
page. 
4.1.5 
POST STUDY DRUG STUDY FOLLOW-UP 
In this study, overall survival is a secondary endpoint. Subjects who discontinue study drug must continue 
to be followed for collection of survival follow-up data until death or the conclusion of the study. Survival 
follow-up visits should be planned every 3 months from Follow-Up Visit-1 and may be performed by phone 
contact or office visit. 
4.1.6 
WITHDRAWAL OF CONSENT 
Subjects who request to discontinue study treatment will remain in the study and must continue to be 
followed for protocol specified follow-up procedures. The only exception to this is when a subject 


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specifically withdraws consent for any further contact with him/her or persons previously authorized by 
subject to provide this information. Subjects should notify the Investigator of the decision to withdraw 
consent from future follow-up in writing, whenever possible. The Investigator should explain the 
withdrawal of consent in detail in the medical records, as to whether the withdrawal is from further 
treatment with study drug only or also from study procedures and/or post treatment study follow-up, and 
entered on the appropriate CRF page. 
4.1.7 
LOST TO FOLLOW-UP  
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. This 
includes follow-up with persons authorized by the subject as noted above. Lost to follow-up is defined by 
the inability to reach the subject after a minimum of three documented phone calls, faxes, or emails or 
whatsapp messages as well as lack of response by subject to one registered mail letter. All attempts should 
be documented in the subject’s medical records. If it is determined that the subject has died, the site will 
use permissible local methods to obtain the date and cause of death. If after all attempts, the subject 
remains lost to follow-up, then the last known alive date as determined by the investigator should be 
reported and documented in the subject’s medical records. 
5.  PATIENT POPULATION  
For entry into the study, the following criteria MUST be met. Eligibility criteria for this study have been 
carefully considered to ensure the safety of the study subjects and to ensure that the results of the study 
can be used. 
5.1 INCLUSION CRITERIA  
5.1.1 
SIGNED WRITTEN INFORMED CONSENT 
Willing, able and mentally competent to provide written informed consent. 
5.1.2 
TARGET POPULATION 
• HCC diagnosed according to criteria of American Association for the Study of Liver Diseases (AASLD) 
definition in 2010. 
• Intolerant to sorafenib according to RESORCE trial definition or patients who received treatment 
different to sorafenib as first-Line treatment. 
• The subject has disease that is not amenable to a curative treatment approach (eg, transplant, 
surgery, radiofrequency ablation) 
• Recovery to ≤ Grade 1 according to (CTCAE) v.5.0. from toxicities related to any prior treatments, 
unless the adverse events are clinically no significant and/or stable on supportive therapy 
• Respect the 15 days of first-line treatment washout before starting cabozantinib 
• Age ≥ 18 years old on the day of consent 
• ECOG performance status of 0 or 1 
• Adequate hematologic function, based upon meeting the following laboratory criteria within 


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7 days before starting therapy: 
a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L) 
b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L) 
c. hemoglobin ≥ 8 g/dL (≥ 80 g/L) 
•  Adequate renal function, based upon meeting the following laboratory criteria within 7 days before 
starting therapy: 
a. Serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 
mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum Creatinine 
x72 [mg/dL]) for males. (For females multiply by 0.85). 
AND 
b. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine 
protein <1g 
• Child-Pugh Score of A 
• Total bilirubin ≤ 2 mg/dL (≤ 34.2 μmol/L) within 7 days before starting therapy 
• Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before starting therapy 
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 upper limit of normal 
(ULN) within 7 days before starting therapy 
• Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before starting therapy (if HbA1c results are 
unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL) 
• Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 
• Capable of understanding and complying with the protocol requirements and signed informed 
consent 
• Sexually active fertile subjects and their partners must agree to use medically accepted methods of 
contraception (eg, 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 
• Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming pregnant (ie, 
females who have had any evidence of menses in the past 12 months, with the exception of those 
who had prior hysterectomy). However, women who have been amenorrheic for 12 or more 
months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior 
chemotherapy, antiestrogens, ovarian suppression, low body weight, or other reasons.   
• Subjects must consent to perform a tumor liver biopsy within 4 weeks before starting cabozantinib, 
allowing the acquisition of a tumor sample for performance of correlative studies. A 


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formalin-fixed, paraffin embedded (FFPE) tumor tissue block of tumor sample should be 
stored at local sites for correlative studies, as described in Section 7.4. For these biopsies, 
subjects must have a soft tissue tumor lesion that can be biopsied at acceptable clinical risk, 
as judged by the investigator. Subjects must consent to the pre-treatment fresh liver biopsy 
as a condition of protocol participation. If adequate tissue is not obtained during the first 
procedure then a repeat biopsy should be considered based on the investigator’s 
assessment of clinical risk.  However, biopsies at the time of radiological tumor progression 
are not required to meet eligibility.  Tumor biopsy is recommended at the time of tumor 
progression development. However, patients who develop radiologic tumor progression, 
should have performance status 0/1 and preserved liver function. Finally, patients with 
symptomatic tumor progression will not be biopsied. 
All patients on cabozantinib treatment must stop cabozantinib 5-7 days before performing the biopsy 
to avoid the risk of bleeding. They will be visited 5-7 days after the biopsy to re-start cabozantinib. 
5.2 EXCLUSION CRITERIA 
5.2.1 
MEDICAL HISTORY AND CONCURRENT DISEASES  
• Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma 
• Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone metastases) or 
radionuclide treatment within 6 weeks of starting therapy (subject is excluded if there are any 
clinically relevant ongoing complications from prior radiation therapy) 
• Prior cabozantinib treatment 
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy 
and/or surgery (including radiosurgery) and stable for at least 3 months before starting therapy. 
Eligible subjects must be without corticosteroid treatment at the time of starting therapy. 
• Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or 
warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation factor X 
(FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin for cardioprotection (per 
local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and lowdose LMWH are permitted. 
• The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, 
the following conditions: 
a. Cardiovascular disorders including: 
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac 
arrhythmias 
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or 100 mm 
Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including TIA), myocardial infarction, or another ischemic event within 6 
months before starting therapy 


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iv. Thromboembolic event within 3 months before starting therapy. Subjects with 
thromboses of portal/hepatic vasculature attributed to underlying liver disease 
and/or liver tumor are eligible 
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation. or 
fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease 
(eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or 
common bile duct, or gastric outlet obstruction  
ii.  Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 
6 months before starting therapy 
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to starting 
therapy 
c. Major surgery within 2 months before starting therapy. Complete healing from major 
surgery must have occurred 1 month before starting therapy. Complete healing from 
minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days 
before starting therapy. Subjects with clinically relevant complications from prior surgery 
are not eligible 
c. 
Cavitating pulmonary lesion(s) or endobronchial disease 
d. 
Lesion invading a major blood vessel including, but not limited to:, pulmonary artery, or 
aorta). Subjects with lesions invading the portal vasculature are eligible. 
e. 
Clinically significant bleeding risk including the following within 3 months of starting therapy: 
hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red blood, or other signs 
indicative of pulmonary hemorrhage, or history of other significant bleeding if not due to reversible 
external factors 
f. 
Other clinically significant disorders such as: 
i. Active infection requiring systemic treatment, known infection with human   
immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome 
(AIDS)-related illness. Subjects with active hepatitis virus infection controlled with 
antiviral therapy are eligible. 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. Malabsorption syndrome 
iv. Uncompensated/symptomatic hypothyroidism 
v. Requirement for hemodialysis or peritoneal dialysis 
vi. History of solid organ transplantation 


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•  Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding. 
Subjects treated with adequate endoscopic therapy (according to institutional standards) without 
any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months 
prior to study entry are eligible.  
• Moderate or severe ascites. Note that controlled ascites with stable dose of diuretics in the last 
month is allowed.  
 
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days before 
starting therapy 
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of 
these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
•  Inability to swallow tablets 
• Previously identified allergy or hypersensitivity to components of the study treatment formulations  
• Pregnant or lactating females 
• Diagnosis of another malignancy within 2 years before starting therapy, except for superficial skin 
cancers, or localized, low-grade tumors deemed cured and not treated with systemic  therapy 
• History of allergy to study drug components. 
• Prisoners or subjects who are involuntarily incarcerated  
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg. 
infectious disease) illness 
• Inability to comply with restrictions and prohibited activities/treatments. 
6. STUDY DRUG(S) AND CONCOMITANT MEDICATIONS  
6.1 INVESTIGATIONAL PRODUCTS 
An investigational product, also known as investigational medicinal product in some regions, is defined as a 
pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical 
study, including products already with a marketing authorization but used or assembled (formulated or 
packaged) differently than the authorized form, or used for an unauthorized indication, or when used to 
gain further information about the authorized form. The investigational product should be stored in a 
secure area according to local regulations. It is the responsibility of the investigator to ensure that 
investigational product is only dispensed to study subjects. Authorized personnel according to local 
regulations must dispense the investigational product only from official study sites. In this protocol, 
investigational products is cabozantinib. 


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6.1.1 
CABOZANTINIB   
Cabozantinib will be initiated at full dose (60 mg/day) and the dose will be modified upon development of 
adverse events according to the manufacturer’s recommendations and continued until symptomatic tumor 
progression, unacceptable adverse events, patient decision or death.  
6.1.2 
PACKAGING AND LABELING.  
Cabozantinib 60, 40 and 20 mg will be packaged in an open-label fashion and labeled for use in the ACTION 
clinical trial.  
6.1.3 
HANDLING AND DISPENSING  
The investigational products should be stored in a secure area according to local regulations. It is the 
responsibility of the investigator to ensure that investigational products are only dispensed to study 
subjects and only from official study sites by authorized personnel according to local regulations. The 
product storage manager should ensure that the study drugs are stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the manufacturer. If 
concerns regarding the quality or appearance of the study drug arise, the study drug should not be 
dispensed. Investigational products documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required processes.  
6.1.4 
DOSE MODIFICATIONS 
6.1.4.1 
CABOZANTINIB DOSE MODIFICATIONS   
Cabozantinib dose reduction  
Toxicities will be graded using the NCI CTC version 5.0 (see Appendix 4). All dose modifications will follow 
pre-defined dose levels as indicated below. 
The modifications of cabozantinib dosage will follow the following pre-defined dose levels: 
Table 1: Cabozantinib dose reduction 
Dose level 0 (standard dose) 
60 mg po 
1 tablet of cabozantinib every day 
Dose level -1 
40 mg po 
1 tablet of cabozantinib every day 
Dose level -2 
20 mg po 
1 tablet of cabozantinib every day 
Dose level -3 
20 mg po 
1 tablet of cabozantinib every 2 or 3 days 
If a patient experiences several toxicities and there are conflicting recommendations, the recommended 
dose adjustment, which reduces the dose to the lowest level, should be used. 
If a dose reduction has been performed, intra-subject dose re-escalation can be considered (up to the 
maximum of 60 mg daily dose) at the discretion of the treating investigator provided that the toxicities has 
resolved to at least CTC-Grade baseline levels. 


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Table 2 Dose Modification Criteria 
Toxicity 
Criteria Recommended Guidelines for 
Management 
Grade 1 AEs 
Continue study treatment if AE is tolerated 
Grade 2 AEs which are intolerable and 
cannot be adequately managed 
At the discretion of the investigator, study 
treatment should be dose reduced or interrupted. 
Note: It is recommended that dose interruptions 
be as brief as possible. 
Grade 3 (except clinically non-relevant 
laboratory abnormalities) 
Study treatment should be interrupted unless the 
toxicity can be easily managed with a dose 
reduction and optimal medical care. 
Grade 4 AEs (except clinically 
non-relevant laboratory abnormalities) 
Subjects should have their study treatment 
interrupted immediately. 
Discontinue study treatment unless the following 
criteria are met: 
Subject is deriving clear clinical benefit as 
determined by the investigator and agreed by the 
Sponsor.  
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care 
AE, adverse event. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to study treatment or had an unclear 
relationship to study treatment. 
b For dose reduction levels, see Table 1. 
6.1.4.2 
GENERAL 
The side effect profile of cabozantinib includes GI symptoms (such as nausea, vomiting, and 
diarrhea, mucositis/stomatitis), fatigue/asthenia, anorexia, weight loss, skin disorders including PPE 
syndrome, elevated liver function tests (including alanine aminotransferase [ALT] and AST), increased 
pancreatic enzymes with rare cases of overt pancreatitis, hypothyroidism, QTc prolongation, as well as 
side effects associated with inhibition of VEGF signaling. The latter of these include arterial and venous 
thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism (PE), transient ischemic 
attack, and myocardial infarction; hypertension; hemorrhagic events; proteinuria, wound 
complications, and rare cases of GI perforation, fistulae formation and rectal/perirectal abscess, 
osteonecrosis, and reversible posterior leukoencephalopathy (RPLS). Please refer to the Investigator’s 
Brochure for additional details. As with all investigational products, unknown AEs may occur. Subjects 
should be monitored closely throughout their study participation for all AEs. As with other agents in 
development, additional AEs are unknown. As of 22 October 2013, in studies with cabozantinib, 


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angioedema has been reported to occur in ~0.1% of subjects treated. The predicted effective plasma 
half-life of cabozantinib is 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 3-week 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.  
Management of fatigue, anorexia, diarrhea, nausea, skin disorders, vomiting, rash, hypertension, 
proteinuria, elevated ALT and AST, myelosuppression, mucositis, hypothyroidism, and cardiac disorders 
are presented in this section as these have been observed in previous studies with cabozantinib or 
represent common class effect toxicity. In addition, guidelines to minimize the risk for potential SAEs 
such as GI and non-GI perforation and fistula formation, hemorrhagic events, and osteonecrosis of the 
jaw (ONJ) are provided in this section. Please refer to the Investigator’s Brochure for additional practice 
guidelines and management 
      recommendations for side effects potentially related to cabozantinib treatment; available information 
on potential risk of congenital, familial, and genetic disorders; and guidelines on management of 
cabozantinib overdose. 
6.1.4.3 
 GASTROINTESTINAL DISORDERS 
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, oral pain, dyspepsia, 
stomatitis, and dysphagia. 
Diarrhea 
       Subjects should be instructed to notify their physician immediately at the first signs of poorly formed 
or loose stool or an increased frequency of bowel movements. Administration of management. Some 
subjects may require concomitant treatment with more than one antidiarrheal agent. When therapy 
with antidiarrheal agents does not control the diarrhea to tolerable levels, study treatment should be 
temporarily interrupted or dose reduced per Table 2. 
       In addition, general supportive measures should be implemented including continuous oral hydration, 
correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
       lactose-containing products, high fat meals and alcohol.  For more information please refer to the 
current Investigator’s Brochure. 
Nausea and Vomiting 
       Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and vomiting 
or as prophylaxis to prevent emesis, along with supportive care according to clinical practice guidelines. 
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists and 
dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids induce 
CYP3A4 and thus could lower cabozantinib exposure. Caution is also recommended with the use of 
nabilone, which is a weak inhibitor of CYP3A4. 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Removal of local factors should be instituted as 
indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. During study 


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treatment good oral hygiene and standard local treatments such as nontraumatic cleansing and oral 
rinses (eg, with a weak solution of salt and baking soda) should be maintained. The oral cavity should 
be rinsed and wiped after meals, and dentures should be cleaned and brushed often to remove plaque. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if 
oral infection is suspected and treat infection as clinically indicated. When stomatitis interferes with 
adequate nutrition and local therapy is not adequately effective, dose reduction or temporary 
withholding of study treatment should be considered. 
6.1.4.4 
HEPATOBILIARY DISORDERS 
Elevations of ALT, AST, and total bilirubin have been observed during treatment with cabozantinib. 
A subject who has ALT, AST, and total bilirubin ≤ 3.0 X ULN at baseline and who develops ≥ Grade 3 
elevated ALT, AST, or total bilirubin should have study treatment interrupted and the dose reduced as 
outlined in Tables Table 2. 
Subjects on this study may enter the study with elevations of AST/ALT up to 5 X ULN at baseline. Elevations 
of aminotransferases when hepatic tumors 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 total bilirubin concentration or coagulation factors. Cabozantinib treatment should 
be interrupted when transaminase increases are accompanied by progressive elevations of total 
bilirubin, and/or elevations of coagulation tests (eg, International Normalized Ratio [INR]). More 
frequent monitoring of transaminases should be considered and study treatment should be held until 
the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize at 
clinically acceptable levels. If hepatic toxicity resolves during a temporary hold and was deemed related 
to study treatment, then study treatment may be restarted at a reduced dose. Study treatment should 
be discontinued if hepatic dysfunction is not reversible despite temporary interruption of study 
treatment. Elevations > 3x ULN of ALT or AST concurrent with > 2xULN total bilirubin without other 
explanation can indicate drug-induced liver injury and drug should be permanently discontinued. If 
possible, hepatotoxic concomitant medications should be discontinued in subjects who develop 
increased values of ALT, AST, or total bilirubin. Evaluation of subjects with elevated transaminases or 
total bilirubin should be individualized and guided by the presence of specific risk factors such as 
illnesses which affect liver function (eg, infectious and non-infectious causes of hepatitis, liver cirrhosis, 
thrombosis of portal or hepatic vein), concomitant hepatotoxic medication, alcohol consumption, and 
cancer related causes. AEs which are based on hepatic dysfunction should be managed according to 
locally accepted clinical practice, including monitoring of appropriate laboratory functions. 
6.1.4.5 
HEMATOLOGICAL DISORDERS 
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications have been 
observed after administration of cabozantinib and may be managed with dose interruptions and/or 
dose reductions. Use of granulocyte colony-stimulating factor support for neutrophil recovery is 
allowed per investigator discretion. Complete blood counts with differentials and platelets should be 
performed during treatment if necessary. Subjects with hematologic toxicities may require additional 
or more frequent laboratory tests according to institutional guidelines. Febrile neutropenia or evidence 
of infection associated with neutropenia must be assessed immediately and treated aggressively 


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according to institutional guidelines. Dose reductions or dose interruptions for anemia are not 
mandated but can be applied as clinically indicated. Supportive care such as red blood cell transfusions 
may be given as clinically indicated. 
6.1.4.6 
FATIGUE, ANOREXIA, AND WEIGHT LOSS 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as anemia, 
deconditioning, emotional distress (depression and/or anxiety), nutrition, sleep disturbance, and 
hypothyroidism should be ruled out and/or these causes treated according to standard of care. 
Individual nonpharmacological and/or pharmacologic interventions directed to the contributing and 
treatable factors should be given. Pharmacological management with psychostimulants such as 
methylphenidate should be considered after disease specific morbidities have been excluded. Note: 
Chronic use of modafinil should be avoided because of its potential to reduce cabozantinib exposure 
(see Investigator’s Brochure). 
Dose reduction of study treatment should be considered when general or pharmacological measures have 
not been successful in reducing symptoms. Dose interruption may be considered for Grade ≥ 3 fatigue 
despite optimal management, at the investigator’s discretion. Anorexia and weight loss should be 
managed according to local standard of care including nutritional support. Pharmacologic therapy such 
as megestrol acetate should be considered for appetite enhancement. Should these interventions 
prove ineffective, dose hold and reductions may be considered for Grade ≥ 3 anorexia or weight loss. If 
anorexia and/or weight loss do not recur after a dose reduction, dose of study treatment may be re-
escalated to the previous dose. 
6.1.4.7 
SKIN DISORDERS 
Palmar-plantar erythrodysesthesia (PPE) syndrome PPE syndrome (also known as hand-foot syndrome), 
skin rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, and erythema have been reported in cabozantinib-treated 
subjects. All subjects on study should be advised on prophylactic skin care. This includes the use of 
hypoallergenic moisturizing creams, ointment for dry skin, and sunscreen with sun protection factor ≥ 
30; avoidance of exposure of hands and feet to hot water; protection of pressure-sensitive areas of 
hands and feet; and use of thick cotton gloves and socks to prevent injury and to keep the palms and 
soles dry. Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo). Early signs of PPE syndrome include tingling, numbness, and slight redness or 
mild hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles. The lateral sides of the fingers or peri-ungual zones may also be affected. Adequate 
interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, 
ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, 
including early dermatology referral. Treatment guidelines for PPE related to study drug (referred to as 
“study treatment”) are presented in Table 3. In the case of study treatment-related skin changes, the 
investigator may request that additional assessments be conducted with the subject’s consent. These 
assessments may include digital photographs of the skin changes and/or a biopsy of the affected skin 
and may be repeated until the skin changes resolve Wound Healing and Surgery VEGF inhibitors can 


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cause wound healing complications and wound dehiscence which may occur even long after a wound 
has been considered healed. Therefore, surgical and traumatic wounds must have completely healed 
prior to starting study treatment and be monitored for wound dehiscence or wound infection while the 
subject is being treated with study drug. Study treatment should be stopped at least 28 days prior to 
scheduled surgery. The decision to resume study treatment after surgery should be based on clinical 
judgment of adequate wound healing. Study treatment should be interrupted for any wound healing 
complication. Study treatment should be discontinued in subjects with serious or chronic wound 
healing complications.  
Table 3 Dose Modification Criteria and Recommended Guidelines for Treatment emergent 
PPE Syndrome 
CTCAE v.5.0 Grade 
Action To Be Taken 
Grade 1 
Study treatmenta may be continued at the 
current dose if PPE syndrome is clinically 
insignificant and tolerable. Otherwise, study 
treatment should be reduced to the next 
lower dose level. Start urea 20% cream twice 
daily AND clobetasol 0.05% cream once daily. 
Reassess at least weekly; if PPE syndrome 
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 PPE is 
tolerated. Study treatment should be dose 
reduced or interrupted if PPE is intolerable. 
Continue urea 20% cream twice daily and 
clobetasol 0.05% cream once daily and add 
analgesics 
(eg, 
gamma-aminobutyric 
acid 
agonists) for pain control if needed. 
Reassess at least weekly; if PPE does not 
improve within 2 weeks or worsens or affects 
self-care, 
proceed 
to 
the 
intervention 
guidelines for Grade 3. 
Grade 3 
Interrupt study treatmenta until severity 
decreases to Grade 1 or 0. Continue treatment 
of skin reaction with clobetasol 0.05% cream 
twice daily AND analgesics. Resume study drug 
at a reduced dose if PPE syndrome recovers to 


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Grade ≤ 1. Discontinue subject from study if 
intolerable PPE syndrome recurs at a reduced 
dose or if PPE syndrome does not improve 
within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-amino butyric acid; PPE, Palmar Plantar 
Erythrodysesthesia. 
a Study treatment includes both cabozantinib and matched placebo. 
6.1.4.8 
HYPERTENSION 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been reported in 
subjects treated with cabozantinib. Blood pressure (BP) should be monitored in a constant position at 
each visit (either sitting or supine) and every day at home by the patients himself.  
Treatment guidelines for hypertension deemed related to study drug are presented in Table 4. In general, 
subjects with known hypertension should be optimally managed prior to study entry. Decisions to 
decrease or hold the dose of study treatment must be based on BP readings taken by a medical 
professional and must be confirmed with a second measurement at least 5 minutes following the first 
measurement. Other than for hypertension requiring immediate therapy, the presence of new or 
worsened hypertension should be confirmed at a second visit before taking therapeutic action. It is 
recommended that this second visit occurs within 1 week. 
Table 4 Guidelines for the Management of Treatment-emergent Hypertension 
Criteria for Dose Modificationa 
Dose Modification 
> 150 mm Hg (systolic) and < 160 
mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 
mm Hg 
 
•Optimize antihypertensive treatment 
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 study treatment by 1 dose level 
• Add new or additional antihypertensive 
medications and/or increase dose of 
existing medications and monitor subject 
closely for hypotension. If optimized 


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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 BP (≥ 160 
mm Hg systolic or ≥ 110 mm Hg diastolic) 
are sustained and not adequately 
manageable or if BP is > 180 mm Hg 
systolic or > 120 mm 
Hg diastolic or if subject is symptomatic. 
• Restart study treatment at the most 
tolerable dose and reescalate only if 
BP falls to and is sustained at < 140 mm 
Hg systolic and < 90 mm Hg diastolic. 
Hypertensive emergencyb or 
hypertensive encephalopathy 
• Discontinue study treatment 
a  The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP > 150 mm Hg 
or diastolic BP > 100 mm Hg based on their clinical judgment and assessment of the individual subject. 
b Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of progressive or impending 
end-organ damage (ie, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, 
encephalopathy, kidney damage) 
6.1.4.9 
THROMBOEMBOLIC EVENTS 
Thromboembolic complications are frequent in cancer patients due to procoagulant changes induced by 
the malignancy or anticancer therapy including inhibitors of VEGF pathways. DVT and PE have been 
observed in clinical studies with cabozantinib; including fatal events (please refer to the Investigator’s 
Brochure). Subjects who develop a PE or DVT should have study treatment held until therapeutic 
anticoagulation with heparins (LMWH) is established. (Note: therapeutic anticoagulation with oral 
anticoagulants is prohibited.) Study treatment may be resumed in subjects with PE or DVT if it is 
determined that the event is uncomplicated, they are deriving benefit from study treatment, and that 
anticoagulation does not place them at a significant risk that outweighs the benefit of resuming 
treatment. During treatment with anticoagulants, subjects need to be monitored on an ongoing basis 
for bleeding risk and signs of bleeding. Subjects with life-threatening PE or DVT should have study 
treatment discontinued unless toxicity can be managed and subject is deriving clear clinical benefit as 


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determined by the investigator. Subjects who develop portal/hepatic vessel thrombosis may not require 
anticoagulation. The decision regarding anti-coagulation in such cases is at the discretion of the 
investigator and within the context of standard of care. Arterial thrombotic events (eg, transient 
ischemic attack, myocardial infarction) have been observed rarely in studies with cabozantinib. Subjects 
should be evaluated for preexisting risk factors for arterial thrombotic events such as diabetes mellitus, 
hyperlipidemia, hypertension, coronary artery disease, history of tobacco use, and cardiac or 
thromboembolic events that occurred prior to initiation of study treatment. Study treatment should be 
discontinued in subjects who develop an acute myocardial infarction or any other clinically significant 
arterial thromboembolic complication. 
6.1.4.10 
PROTEINURIA 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and other 
inhibitors of VEGF pathways. During each safety assessment visit, proteinuria will be quantified by 
measuring the urine protein-to-creatinine (UPCR) ratio performed by the central lab. In addition, urine 
dipstick analysis performed by the local lab will be done at least every 8 weeks and more as clinically 
indicated. Management of proteinuria will be based on UPCR results provided by the central lab. As 
dipstick results from the local labs may be available prior to the UPCR results from the central lab, they 
can be used by the investigator for interim management. In the case of proteinuria, if the dipstick 
analysis shows proteinuria ≥ 3+, study treatment should be interrupted until the UPCR results are 
available and more definitive management can be applied. 
6.1.4.11 
CORRECTED QTc PROLONGATION 
The effect of orally administered cabozantinib at 140 mg/day (FBE) on QTc interval was evaluated in a 
randomized, double-blinded, placebo-controlled Phase 3 study in patients with MTC (Study XL184-301). 
A mean increase in QT interval corrected by Fridericia (QTcF) of 10-15 ms was observed at 4 weeks after 
initiating cabozantinib. A concentration-QTc relationship could not be definitively established. Changes 
in cardiac wave form morphology or new rhythms were not observed. No cabozantinib treated patients 
on this study had a QTcF > 500 ms during the QT evaluation period. 
Only subjects with a baseline QTcF ≤ 500 ms are eligible for this study. Subjects will have ECGs performed 
at times designated by the protocol. If at any time on study there is an increase in QTcF interval to an 
absolute value > 500 ms, within 30 minutes after the initial ECG, 2 additional ECGs must be performed 
each with intervals approximately 3 minutes apart. If the average QTcF from the 3 ECGs is > 500 ms, the 
following actions must be taken: 
• Withhold study treatment 
• Immediately notify the Principal Investigator 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic hypotension, a 
significant ventricular arrhythmia on ECG) for a thorough cardiology evaluation and management 


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• Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• Check electrolytes, especially magnesium and potassium; correct abnormalities as clinically indicated 
• Check concomitant medications for any medication that may have contributed to QT prolongation, and if 
possible, discontinue these medications (see http://www.qtdrugs.org) 
• Send ECGs to central ECG laboratory (see ECG study manual) 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms 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 is not confirmed by the central ECG laboratory or a QTcF 
> 500 ms confirmed by the central laboratory returns to ≤ 500 ms 
• Study treatment has been interrupted through a minimum of 1 week following the return of the QTcF to 
≤ 500 ms 
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 
6.1.4.12 
HEMORRAGIC EVENTS 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib. In order to mitigate risk of severe hemorrhage, subjects should be evaluated for potential 
bleeding risk factors prior to initiating study treatment and monitored for bleeding events with serial 
complete blood counts and physical examination while on study. Risk factors for hemorrhagic events 
may include (but may not be limited to) the following: 
• Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, or abuts major blood 
vessels. The anatomic location and characteristics of tumor as well as the medical history must be 
carefully reviewed in the selection of subjects for study treatment. 
• Recent or concurrent radiation 
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases 
• Underlying medical conditions which affect normal hemostasis (eg, deficiencies in clotting factors and/or 
platelet function, or thrombocytopenia) 
• Concomitant medication with anticoagulants or other drugs which affect normal hemostasis 
• History of clinically significant hemoptysis 


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Discontinue study treatment in subjects who experience a severe bleeding complication. 
6.1.4.13 
GI PERFORATION/FISTULA AND NON-GI FISTULA FORMATION 
GI perforation/fistula and non-GI fistula formation have been reported with approved drugs that inhibit 
VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal pain, 
especially in subjects with known risk factors for developing GI perforation/fistula or non-GI fistula, to 
allow for early diagnosis. Such risk factors include (but may not be limited to) the following: 
GI perforation/fistula: 
• Intra-abdominal tumor/metastases invading GI mucosa 
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis or 
symptomatic cholangitis, or appendicitis 
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
• Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be confirmed 
prior to initiating study treatment. 
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal anti-
inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and effectively 
managed. 
Non-GI fistula: 
• Complications from radiation therapy have been identified as a possible predisposing risk factor for non-
GI fistula formation in subjects undergoing treatment with VEGF pathway inhibitors (eg, bevacizumab). 
Subjects are excluded from this study if there are any clinically relevant ongoing complications from 
prior radiation therapy (ie, radiation esophagitis or other inflammation of the viscera). 
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI perforation/fistula. 
6.1.4.14 
OSTEONECROSIS OF THE JAW 
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and bisphosphonates 
and denosumab in cancer patients. Additional risk factors for ONJ have been identified such as use of 
corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, smoking, dental or orofacial surgery 
procedures, and cancer disease itself. Osteonecrosis has been reported in subjects treated with 
cabozantinib, the details of which are provided in the current version of Investigator’s Brochure. As a 
preventive measure, invasive dental procedures should be avoided if possible. In cases where dental 
procedures are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure 
as well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on the 
duration of a temporary study treatment interruption. If clinically possible, study treatment should be held 
for approximately 4 weeks prior to a dental procedure and resumed after complete healing has occurred. 


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Subjects with any documented case of osteonecrosis should have study treatment interrupted, and 
appropriate clinical management should be initiated. Re-initiation of study treatment must be discussed 
with and approved by the Principal Investigator of the study. 
6.1.5 
CRITERIA TO RESUME CABOZANTINIB TREATMENT 
Subjects may resume treatment with cabozantinib when the drug-related AE(s) resolve to Grade ≤ 1 or 
baseline value, with the following exceptions: 
• Subjects may resume dosing in the presence of Grade 2 fatigue 
• Subjects who delayed dosing due to UPCR ≥ 2.0 or urine dipstick protein ≥ 3+ may resume dosing at 
one dose level reduction when 24 hours urine protein < 2.0 g or repeat UPCR < 2.0 
• Subjects who delayed dosing due to Grade 3 hypertension may resume dosing at the same dose or 
at one dose level reduction, at the discretion of the investigator, when hypertension has improved 
to Grade ≤ 2. 
• Subjects who delayed dosing due to Grade 4 lipase abnormalities (either asymptomatic or in the 
absence of radiographic findings) may resume dosing upon resolution to Grade ≤ 2. 
• Subjects who delayed dosing due to major surgery should not resume cabozantinib until complete 
wound healing has taken place. Following cabozantinib resumption, subjects should be monitored 
for wound dehiscence, wound infections, and other signs of impaired wound healing. 
If treatment is delayed 8 weeks for any reason, the participant must be permanently discontinued from 
study therapy, except in cases where permission to resume treatment is granted by the Medical Monitor 
or designee. 
6.1.6 
PERMANENT DISCONTINUATION OF CABOZANTINIB DUE TO ADVERSE EVENTS 
Cabozantinib administration should be discontinued if at least one of the following drug-related adverse 
event(s) occurs: 
• Subject no longer experiences clinical benefit as determined by the investigator. If study 
treatment is withdrawn for this reason, the date of this decision is to be recorded and every 
effort should be made to continue safety evaluations and collection of subsequent 
treatment information and follow-up information for survival. 
• Unacceptable side effects the investigator feels may be due to study treatment, including 
any subject with a GI or non-GI perforation/fistula 
• Any adverse event, laboratory abnormality or intercurrent illness, which, in the judgment of 
the Investigator, presents a substantial clinical risk to the subject with continuing study 
medication. 
• Any Grade 3 non-skin, drug-related adverse event lasting > 21 days  
Exception of grade 3 drug-related AE:  
− Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
• Any drug-related Grade 4 drug-related adverse event or laboratory abnormality, except for 
the following events which do not require discontinuation: 
− Grade 4 neutropenia < 7 days; 


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− Grade 4 lymphopenia or leukopenia; 
− Grade 4 amylase or lipase abnormalities that are not associated with symptoms or 
clinical manifestations of pancreatitis; 
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate 
management within 72 hours of their onset; 
• The investigator feels it is not in the best interest of the subject to continue on study 
• Participation in another clinical study using an investigational agent or investigational 
medical device  
• Necessity for treatment with non-protocol systemic anticancer therapy 
• Receipt of liver-directed local anti-cancer therapy (eg, transarterial tumor embolization or 
chemoembolization, radiofrequency or microwave ablation, percutaneous ethanol or acetic 
acid ablation, injection or infusion of drug eluting or radiation-emitting beads, cryoablation, 
radiation therapy, including stereotactic radiotherapy, or surgery) 
• Necessity for withholding study drug for greater than 8 weeks for AEs, unless continuation of 
treatment is approved by the Principal Investigator 
• Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to use 
medically accepted methods of contraception 
• Pregnancy of a female subject 
• Request by the Principal Investigator 
• Subject request to discontinue study treatment 
• Significant noncompliance with the protocol schedule in the opinion of the investigator or 
the Principal Investigator 
• The Principal Investigator should be notified of all discontinuations of study treatment as 
soon as possible. If a subject fails to return for the protocol-defined visits, an effort must be 
made to determine the reason. If the subject cannot be reached by telephone, at a 
minimum, a registered letter should be sent to the subject (or the subject’s legal guardian) 
requesting contact with the study site. 
• For subjects who withdraw or are withdrawn from study treatment, every effort must be 
made to continue protocol-specified evaluations and procedures through the post-
treatment follow-up and extended follow-up visits unless consent to participate in the study 
is also withdrawn. All subjects will be followed until death, unless consent to do so is 
specifically withdrawn by the subject or until a decision by the Principal Investigator is made 
to stop collection of these data. 
If the Investigator consider the option of continue with one of the investigations drugs, the decision to 
continue with one of the drug-study treatments beyond the criteria mentioned in this point of the protocol 
should be discussed with the Principal Investigator, Medical Monitor and documented in the study records.   
6.1.7 
STOPPING RULES FOR CLINICAL DETERIORATION   
Clinical deterioration will be assessed to have occurred after a clinical event that, in the Investigator’s 
opinion, is attributable to disease progression, is unlikely to reverse with continued study treatment and 


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therefore indicates that the subject is not benefiting from study treatment and cannot be managed by the 
addition of supportive care (such as bisphosphonates, bone directed radiotherapy, thoracentesis or 
paracentesis of accumulating effusions). The decision to continue or stop treatment should be discussed 
with the Principal Investigator and Medical Monitor as well as will be documented in the study files. 
Examples of events that may, in the Investigator’s opinion, indicate a lack of clinical benefit include, but are 
not limited to, the following: 
• Performance status decrease of at least 2 points from baseline despite transitory cabozantinib 
interruption for at least 4 weeks 
• Skeletal related events defined by spinal cord or nerve root compression. 
• Development of new central nervous system metastases or Grade 3 encephalopathy despite 
transitory cabozantinib interruption for at least 2 weeks  
• Any setting where the initiation of new anti-neoplastic therapy has been deemed beneficial to the 
patient. 
6.1.7.1 
TREATMENT WITH CABOZANTINIB BEYOND DISEASE PROGRESSION 
 In the absence of clinical deterioration, it is thus reasonable that subjects will be allowed to continue study 
therapy after an initial investigator-assessed RECIST 1.1 defined progression (based on a comparison with 
baseline or nadir scans or other tumor evaluations) as long as they meet the following criteria: 
• Investigator assessed clinical benefit 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases) 
• These criteria aim to ensure the risk/benefit of continuing treatment will continue to favor the 
subjects due to the current data available about the impact of the pattern of progression on post-
progression survival20–24. The assessment of clinical benefit should consider whether the subject is 
clinically deteriorating and unlikely to receive further benefit from continued treatment. The 
decision to start or continue with the drug-study treatments beyond initial investigator-assessed 
progression should be discussed with the Principal Investigator, Medical Monitor and documented 
in the study records.  If the decision is taken to continue cabozantinib treatment beyond 
progression, the subject will remain on the trial and continue to be treated and monitored 
according to the Time and Events Schedule in Section 8.  
6.2 CONCOMITANT TREATMENTS  
6.2.1 
PERMITTED TREATMENTS  
• Standard therapies for concurrent medical conditions. Prophylactic anti emetics may be 
administered according to standard practice. 
• Antiviral treatment for chronic HBV. 
• Megestrol acetate (Megace®) as supportive care 
• Bisphosphonates 
• Low dose aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 
mg/day), and low dose LMWH are permitted. The protocol does not restrict the use of heparins 


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at prophylactic doses. Therapeutic doses of heparins are allowed if clinically indicated for 
supportive treatment and the benefit outweighs the risk per the investigator’s discretion. 
During treatment with anticoagulants, subjects need to be monitored on an ongoing basis for 
bleeding risk and signs of bleeding. Therapeutic doses of oral anticoagulants (eg, warfarin or 
warfarin-related agents, thrombin or FXa inhibitors, antiplatelet agents such as clopidogrel) are 
not allowed. 
6.2.2 
PROHIBITED TREATMENTS  
• Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, 
hormonal therapy (unless hormonal replacement therapy was initiated prior the study 
inclusion) and experimental or approved therapies during this trial or within 30 days before 
starting to receive study medication, except prior therapy with sorafenib as detailed in the 
current protocol. 
• Any drug that targets angiogenesis, especially VEGF and VEGFR. 
• TKIs other than cabozantinib  
• Bone marrow transplant or stem cell rescue. 
• Patients taking narrow therapeutic index medications (e.g., warfarin, phenytoin, quinidine, 
carbamazepine, phenobarbital, cyclosporine, and digoxin) should be monitored proactively.  
• For anticoagulants and low dose aspirin see 6.2.1 section. 
Therapeutic monitoring should be performed consistent with the local clinical standard of care following 
dose modification of the agent. In general, patients should be closely monitored for side effects of all 
concomitant medications regardless of path of elimination. 
Additional information on potential drug interactions with cabozantinib is provided in Section 14.7 
6.2.3 
SUPPORTIVE TREATMENTS 
• Subjects may continue to receive hormonal replacement therapy if initiated prior to the study 
inclusion. 
• Bisphosphonates and RANK-L inhibitors are allowed for bone metastases. 
• It is the local imaging facility’s responsibility to determine, based on subject attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Imaging contraindications and contrast risks should be considered in 
this assessment. Subjects with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
subjects with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) < 30 
mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should not 
be given to this subject population. In addition, subjects are excluded from MRI if they have 
metallic implants, pacemakers, etc. The ultimate decision to perform MRI in an individual 
subject in this study rests with the site radiologist, the investigator and the standard set by the 
local Ethics Committee. 


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6.2.3.1 
PALLIATIVE LOCAL THERAPY 
Palliative local therapy for clinically symptomatic tumor sites (eg bone pain) including palliative 
(limited-field) radiation and palliative surgical resection may be considered if the following criteria 
are met: 
• The subject is considered to have progressed at the time of palliative therapy and meets criteria 
to continue with treatment beyond progression (Section 6.1.7.1). 
• The lesion for palliative local therapy is a non-target lesion 
• Tumor lesions requiring palliative local therapy should be evaluated for objective evidence of 
disease progression prior to the initiation of such therapy. 
• Palliative therapy must be clearly documented in the source records and case report form. 
Details in the source records should include: dates of treatment, anatomical site, dose 
administered and fractionation schedule, and adverse events. 
6.2.4 
TREATMENT OF HBV VIROLOGICAL BREAKTHROUGH AND ONGOING HCV 
Subjects will have ongoing assessments of HBV DNA as per local practice. If a subject has documented 
virologic breakthrough due to antiviral resistance, then this should be managed based on standardized 
guidelines.  
Initiation of direct acting antivirals (DAAs) for HCV is not allowed but if the investigator considers this 
option should discuss it with the PrincipaI Investigator and Medical Monitor. 
6.3 TREATMENT COMPLIANCE 
Study drug will be administered in the clinical facilities of each center and treatment compliance will be 
assessed by investigator report on the case report forms and Source Data Verification by Monitors. 
6.4 DESTRUCTION OF STUDY DRUG 
For this study, study drugs partially used study drug containers and syringes may should be destroyed on 
site. Cabozantinib containers must be destroyed as required for safety, or to meet local regulations (eg, 
cytotoxics or biologics). On-site destruction is allowed provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug.  
• On-site disposal practices and procedures agree with applicable laws and regulations, including any 
special requirements for controlled or hazardous substances. 
• Written procedures for on-site disposal are available and followed. The procedures must be filed 
with the site’s SOPs and a copy provided to the Sponsor upon request. 
• Records are maintained that allow for traceability of each container, including the date disposed of, 
quantity disposed, and identification of the person disposing the containers. The method of 
disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal vendor must be 
documented. 
• Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.  


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It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable national, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 


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Table 5: Study procedures 
  
 
 
 
 
Each cycle has 28 days. 
Screening1 
Cycles (+/- 72 hours) 
(Day 15 only for Cycle 1 and 2) 
First 
radiologic 
progression 
EOT (after last 
dose +7 days) 
Follow-up2 
 
 
Day 1 
 
Day 15 
(+/- 24 
hours) 
Day 28 
(+/- 72 
hours) 
 
 
 
Demographics 
x 
 
 
 
 
 
 
General Informed Consent 
x 
 
 
 
 
 
 
Inclusion/Exclusion criteria and 
Eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor and disease assessments 
 
Disease assessment by RECIST v1.1 
Every 8 weeks from Day 1 Cycle 2 
(+/- 7 days) 
X 
 
 
 
x 
 
 
 
Fresh tumor biopsy 
(See section 7.4) 
x 
 
 
 
x3 
 
 
 
 
Study procedures and examinations 
 
Physical examination 
x 
x 
x 
x 
x 
X 
 
ECOG performance status 
x 
x 
x 
x 
x 
X 
 
12-lead ECG4 
x 
 
 
 
 
X 
 
Vital signs5 
x 
x 
x 
x 
x 
X 
 
Assessment of AEs/SAEs 
x 
x 
x 
x 
x 
X 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
 
Diet and gut microbiota 
x 
 
 
 
 
Laboratory tests 
 
Serum chemistry6 
x 
x 
x 
x 
x 
x 
 
Hematology7 
x 
x 
x 
x 
x 
x 
 
Coagulation (PT, INR, PTT) 
x 
x 
x 
x 
x 
x 
 
HBsAg and HBsAb, HBcAb and       
HCV Ab; 
HBeAg and HBeAb, HBV DNA and 
HDV RNA and HDV Ab(HBV+ subjects 
only); 
HCV RNA (HCV+ subjects only) 
x 
 
 
 
 
x 
 
 
Thyroid function tests (TSH, free T3, 
free T4) 
x 
 
 
 
 
 
 
 
Urinalysis 
 
x 
x 
x 
x 
 
x 
 
Urine or serum pregnancy test 
(WOCBP) 
 
x 
 
 
 
 
 
 
 
 
Other procedures8 
 
Other laboratory blood tests and 
assays9 
 
X 
 
X 
Only in 
C1 
 
x 
 
 
Other liver tissue analysis10 
x 
 
 
x 
x 
 
 
Patient-reported Quality of Life (EQ-
5D, EORTC-QLQ C30, EORTC-HCC18 
and FACT-Hep)11 
 
x 
 
 
x 
x 
 
Other stool tests and assays12 Day 1 
 
x 
 
 
 
x 
 


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Cycle 4 and in case of OR or PD 
 
 
 
 
EOT: End of Treatment; OR: Objective Response; PD: Progressive Disease 
 
1 The time period between study entry and the commencement of protocol treatment is not to exceed 28 days. 
2 Follow-up visits could be on-site or phone visits after the last visit and will include survival data and liver cirrhosis complications evaluation every 3 
months. If the patient does not start any other treatment after end of treatment, radiologic follow-up with the same scheduled will be preferred. 
Laboratory tests will be performed at the discretion of the treating investigator until death or the end of the study. 
3 A biopsy will be performed at the time of progression whenever possible. 
4 Note: The ECG should be performed within the 7 days prior the randomization. If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be 
performed. If the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
5 Including height (only at screening visit) weight, body temperature, respiratory rate, seated blood pressure, heart rate and oxygen saturation (at 
rest and after mild exercise) 
6AST, ALT, GGT, Alkaline Phosphatase alkaline phosphatase, Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Albumin, Creatinine, Alpha alpha 
fetoprotein, Calcium, Sodium, Potassium, Glucose, Uric Acid, triglycerides, Total Protein, Lipase, Amylase, Magnesium, Phosphate, lactic 
dehydrogenase LDH, Chloride, Glomerular filtration rate. 
7Complete blood count with differential 
8 All the samples included in this section, will be centrally analyzed in a second-study  
9Other laboratory blood tests will include peripheral Blood Mononuclear Cells (PBMCs) immunophenotyping, serum biomarker analysis, 
polymorphism detection associated with treatment response/resistance, circulating-free DNA analysis, circulating mRNA/miRNA.  In case of any 
cabozantinib dose reduction a blood sample for PBMCs and serum biomarker analysis is recommended but no mandatory. Serum biomarker will be 
analyzed at each cabozantinib dose reduction. For details see the laboratory manual. 
10Other liver tissue analysis will include tumor and non-tumor infiltrated immune cell population characterization (fresh tissue from biopsy analyzed 
in situ in each recruiting center) and tumor and non-tumor cell transcriptome analysis (samples can be frozen and stored until analysis). Note that 
these samples will be obtained accordingly to the time point of “fresh tumor biopsy” but all the analysis will be performed in a second-study.  
11 Patient-reported Quality of Life (EQ-5D, EORTC-QLQ C30, EORTC-HCC18 and FACT-Hep) will be administered at Day 1 of Cycle 1 and Cycle 3, then 
at Day 1 every 3 cycle and at end of treatment s. 
12Other stool tests and assays will include gut microbiota composition and/or metabolomic analysis.   
7. STUDY PROCEDURES  
7.1 FLOW CHART/TIME AND EVENTS SCHEDULE 
Cabozantinib 
Informed consents must be signed to perform 
the liver biopsy before starting cabozantinib. 
Screening before starting: 
• Clinical and laboratory evaluation to 


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confirm all the inclusion and exclusion 
criteria to receive cabozantinib. 
• Respect the 15 days of first-line treatment 
washout before starting cabozantinib.   
• Chest and abdominal CT scan within 4 
weeks before starting therapy. 
• Liver biopsy within 4 weeks before 
starting therapy. 
Drug administration 
Cabozantinib will be given orally every day. All 
patients will start with 60 mg/day to be modified 
upon development of adverse events. 
Clinical evaluation at day 1 of every cycle and at 
day 15 of cycle 1 and 2.  
Unscheduled visits will be made should they be 
needed (adverse events or symptoms). 
Laboratory evaluation at day 1 of every cycle and 
at day 15 of cycle 1 and 2. 
Unscheduled laboratory evaluation will be made 
should they be needed (adverse events or 
symptoms). 
Radiological 
tumor 
evaluation 
at 
tumor 
evaluation at week 8 according to the RECIST 
criteria v1.1  
Dose modifications: 
Cabozantinib dose will be modified according to 
the manufacturer’s recommendations. 


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Serum biomarker determination: 
At baseline and at each time point accordingly to 
table 5, serum biomarker will be evaluated. 
Liver biopsy will be done if the patient develops 
radiologic tumor progression, performance status 
0/1 and preserved liver function. 
Patients with symptomatic tumor progression 
will not be biopsied. 
All patients on must stop cabozantinib 5-7 days 
before performing the biopsy to avoid the risk 
of bleeding. They will be visited 5-7 days after 
the biopsy to re-start cabozantinib.  
Patient-reported Quality of Life Questionnaires: 
The FACT-Hep (Version 4), EORTC- QLQ C30, 
EORTC-HCC18 and the EQ-5D should be self-
administered by the subject at the start of the 
visit, before the subject sees the investigator and 
before any study related procedures are done, so 
that any interaction between the patients and 
investigator or other health care provider will not 
influence the responses to the questionnaires.  
Questionnaires should be administered at Day 1 
of Cycle 1 and Cycle 3, then at Day 1 every 3 
cycles and at the End of Treatment (EOT) visit.  
The site personnel should complete the Patient 
Reported Outcomes Information Sheet. 
Diet and gut microbiota:  
At screening, specific points regarding patient 
usual diet and other factors potentially impacting 
on gut microbiota (domestic animals, smoking, 
medications) should be investigated by the 


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investigator in detail. 
7.2 SAFETY ASSESSMENTS  
7.2.1 
ASSESSMENTS AND DOCUMENTATION OF ADVERSE EVENTS 
All AEs occurring after the subject has signed the informed consent form (IC) up until the end of 
the safety follow-up period (30  7 days after permanently discontinuing cabozantinib 
administration) must be fully recorded in the subject’s CRF. 
Adverse event documentation is event-based (using the NCI-CTCAE version 5.0 guidelines): 
Adverse events should be collected past 30 days after the study treatment stop for all AEs that 
were ongoing at the end of treatment as well as new adverse events that in the opinion of the 
investigator could be related to study treatment. (Information may be obtained via phone call). 
Documentation must be supported by an entry in the subject’s file.  
Adverse events should be followed until resolution or stabilization unless, in the investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease.   
If any patient dies within 30 days of last dose of study drug, the investigator will inform the 
sponsor and record the cause of death in detail within 24 hours on a SAE form. 
A laboratory test abnormality considered clinically relevant, e.g. causing the subject to withdraw 
from the study, requiring treatment or causing apparent clinical manifestations, or judged relevant 
by the investigator, should be reported as an AE. Each event should be described in detail along 
with start and stop dates, severity, relationship to investigational product, action taken and 
outcome. 
Note that all the patients will receive the “alert card” reporting useful information in case of need 
such as the name of the clinical trial, the name and contacts of PI or collaborators. 
 
7.2.2 
REPORTING OF SERIOUS ADVERSE EVENTS 
The definition of SAE is given in Section 8.1.2. 
7.2.3 
INVESTIGATOR’S NOTIFICATION TO THE SPONSOR 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant contact 
details, is summarized in the investigator site file.  This information will be updated as needed. 
All SAEs occurring during the observation period defined in Section 8.2 must immediately (within 
24 hours of the investigator’s awareness) be reported to the recipient detailed in the manual. A 
SAE form must also be completed within 24 hours of the investigator awareness and forwarded to 
the designated recipient. Each SAE must be followed up until resolution or stabilization by 
submission of updated reports to the designated recipient. 


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In each case of a fatal or life-threatening reaction, the investigator must seek relevant follow-up 
information and must complete a follow-up report to be faxed to the sponsor as soon as possible 
but not later than 8 calendar days after the initial report is sent. 
An isolated laboratory abnormality that is assigned Grade 4, according to CTCAE v.5.0 definition, is 
not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Conference on Harmonization (ICH) criteria for an SAE. CTC Grade 4 baseline 
laboratory abnormalities that are part of the disease profile should not be reported as an SAE, 
specifically when they are allowed or not excluded by the protocol inclusion/exclusion criteria. If 
an investigator is in doubt about the applicable reporting obligations, he/she should consult with 
the study monitor for the Sponsor. CTC Grade 4 lab abnormalities will be documented in the 
laboratory data and will be reviewed on a regular basis. 
For all SAEs, the investigator is required to document in full, the course of the SAE and any therapy 
given, including any relevant findings/records in the report. 
It is not mandatory to report SAEs occurring after the protocol-defined observation period, 
however, at the investigator’s discretion these may be reported if considered potentially relevant. 
In such cases, the SAEs will be processed by the sponsor according to all applicable regulations. 
Notification to the IECs / IRBs 
Notification of the institutional ethical committees (IECs)/institutional review boards (IRBs) about 
all relevant events (e.g., SAEs, Suspected Unexpected Serious Adverse Reactions [SUSARs]) will be 
performed by the sponsor and/or by the investigator according to all applicable regulations. 
Notification to the authorities 
The processing and reporting of all relevant events (e.g. SAEs, SUSARs) to the authorities will be 
done by the sponsor according to all applicable regulations. 
Sponsor’s notification to the investigational site 
The sponsor will inform all investigational sites about reported relevant events (e.g. SUSARs) 
according to all applicable regulations. 
7.2.4 
EXPECTED ADVERSE EVENTS 
For this study, the applicable reference document is the most current version of the IB. 
Overview listings of frequent events that have occurred so far in the clinical development are 
shown in the current IB. If relevant new safety information is identified, the information will be 
integrated into an update of the IB and distributed to all participating sites. 
The expectedness of AEs will be determined by the sponsor according to the applicable reference 
document and according to all local regulations. 


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7.2.5 
PREGNANCIES 
The investigator must report to the sponsor any pregnancy occurring in a study subject during the 
subject’s participation in this study.  The report should be submitted within the same timelines as 
an SAE, although a pregnancy per se is not considered an SAE.  
For a study subject, the outcome of the pregnancy should be followed up carefully, and any 
outcome of the mother or the child should be reported. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain similar 
information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
7.2.6 
FURTHER SAFETY 
7.2.6.1 
PHYSICAL EXAMINATIONS 
Physical examinations will be performed according to the schedule summarized in the flow chart 
of Section  
For this examination, the investigator will assess/examine the following: 
− General appearances 
− Skin 
− Eyes 
− Ears, nose and throat 
− Head and neck 
− Lungs 
− Heart 
− Abdomen 
− Lymph nodes 
− Musculoskeletal system (including 
extremities and spine) 
− Neurological findings 
If indicated by the patient’s history, the following will be examined by specialists, if applicable: 
− Genito-urinary system 
− Gynecological organs 
− Rectum 
Depending on criteria of relative timing (before or after signing IC), the findings of the physical 
examination has to be recorded as medical/surgical history or as an AE. 
This includes review of all organ systems, examination of pertinent organ systems, vital signs, 
(heart rate, blood pressure (BP), and temperature). BP measurements (monitored weekly for the 
first 6 weeks of treatment) must be performed in a consistent manner using a manual cuff on the 
same arm. Have the subject sit comfortably for 5 minutes with feet on the floor and arm 
supported at heart level prior to taking the evaluation. The assessment must be made with the 
patients in the sitting position using the same arm for all evaluations. Two additional 
measurements, taken 5 minutes apart, should be conducted if the first BP is abnormal. 
7.2.6.2 
VITAL SIGNS 
Body weight/height, temperature, BP, respiratory and heart rate will be assessed according to the 
schedule summarized in Table the flow chart of Section 7.1 and in table 5 If clinically indicated 


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(e.g., excessive weight loss), it is at the investigator’s discretion to perform these measurements 
more frequently. 
Note that all the patients will receive a patient diary to report the dose of cabozantinib, BP, 
number of bowel movements each day and other additional comment by the patient. 
 
7.2.6.3 
12-LEAD ECG 
12-lead ECGs will be performed according to the schedule summarized in the Table 5. 
The study number, subject number, visit and the date of the ECG are noted on every ECG; all 
indications, which might lead to the identification of the subject, must be made illegible. 
The overall interpretation in ECG (normal/abnormal, clinical relevance) and the ECG diagnosis will 
be documented in the electronic case report form (eCRF). 
 
 
 
7.2.6.4 
LABORATORY ASSESSMENTS 
Laboratory analyses will be performed locally. 
• Complete blood count (CBC) with differential. This will include red blood cell count (RBC), 
hemoglobin, hematocrit, platelet count and white blood cell count (WBC). WBC must include 
differential neutrophil, lymphocyte, monocyte, basophil, and eosinophil absolute counts. 
• Chemistry and electrolyte panel:  This includes sodium, potassium, chloride, AST, ALT, GGT, 
bilirubin (total and direct), alkaline phosphatase, uric acid, total protein, albumin, calcium, 
lipase, amylase, triglycerides, phosphate, lactic dehydrogenase (LDH), glucose, creatinine, 
blood urea nitrogen (BUN).  
• Urine analysis.  
- 
Macroscopic appearance 
- 
Laboratory analysis:  Protein and creatinine on a random urine sample preferably taken at 
mid-morning for the quantification of proteinuria by urinary protein/creatinine ratio. This 
should be reported as the ratio of concentrations of total urine protein (in mg/dL) to 
urine creatinine (in g/dL). 
- 
Dipstick or laboratory analysis:  Bilirubin, erythrocytes or hemoglobin (blood), glucose, 
ketones, leukocytes, or leukocyte esterase, nitrite, pH.  
- 
A microscopic analysis should be performed if the appearance is turbid, or if protein, 
leukocytes, erythrocytes, or nitrite are out of normal range.  
• Thyroid function test (thyroid-stimulating hormone [TSH], free triiodothyronine [T3], free 
thyroxine [T4]).  
• Coagulation panel: PT or PT-INR and partial thromboplastin time (PTT).  


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• Alpha-fetoprotein (AFP) 
• Serum pregnancy test in woman of childbearing potential. Postmenopausal women who have 
not had periods for more than 1 year or surgically sterilized women will not be required to 
undergo a pregnancy test (this information should be recorded under medical history in the 
eCRF). 
The laboratory evaluations are not required at Day 1 of Cycle1 if these were completed within 7 
days of starting study drug treatment. 
7.3 EFFICACY ASSESSMENTS  
The following parameters will be evaluated: Time to progression, pattern of progression, overall 
survival, post-progression survival, rate of patients who develop new extra hepatic spread. 
7.4 EXPLORATORY BIOMARKER, PERIPHERAL BLOOD AND TUMOR ASSESSMENTS 
This study will collect blood and biopsy samples but the analysis will be done in a second study 
only if the study meets the safety end-point. 
Tumor and non-tumor tissue samples should be obtained by expert radiologists with 18 Gauge 
needle (Monopty, Bard Inc, Covington, UK) and will utilized to analyze tumor and non-tumor 
infiltrated immune cell population characterization (fresh tissue from biopsy analyzed in situ in 
each recruiting center) and tumor and non-tumor cell transcriptome analysis (samples can be 
frozen and stored until analysis). 
8. ADVERSE EVENTS 
8.1 DEFINITIONS 
Investigators should refer to the Safety Information section of the current cabozantinib IB.  As with 
any agent, there is always the potential for unexpected AEs, including hypersensitivity reactions.  
The IB will be updated if any new relevant safety data are obtained.   
8.1.1 
ADVERSE EVENT (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be the development of a new medical condition, or the 
deterioration of a pre-existing medical condition. This includes any unfavorable and unintended 
sign (e.g. tachycardia, enlarged liver), symptom (e.g. nausea, chest pain) or the abnormal results of 
an investigation (e.g. laboratory findings, electrocardiogram) temporally associated with the use of 
a medicinal product, whether or not considered related. 
8.1.2 
SERIOUS ADVERSE EVENT (SAE) 
An SAE is any AE occurring at any dose that: 
• results in death; 


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• Is life threatening, defined as 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; 
• results in hospitalisation or prolongation of existing hospitalisation, excluding admission for 
social or administrative reasons; 
o Hospitalisation is defined as any inpatient admission (even if less than 24 hours) 
(unless it occurs to ensure treatment compliance). For chronic or long term 
inpatients, inpatient admission also includes transfer within the hospital to an 
acute/intensive care inpatient unit. 
o Prolongation of hospitalisation is defined as any extension of an inpatient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for the initial admission, as determined by the investigator or treating 
physician. 
o 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. 
• results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions; 
• results in congenital anomaly/birth defect in the offspring of a subject who received the 
product; 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalisation but that when, based upon appropriate medical judgment, may jeopardise 
the subject and 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 hospitalisation, or the development of 
product dependency or product abuse. 
8.1.3 
DEATH 
All AEs resulting in death whilst using the medicinal product must be reported to Ipsen within 24 
hours of the Investigator’s knowledge of the event. All fatal outcomes should be considered as 
adverse events, even if this fatal outcome is not considered to be related to the medicinal product. 
The convention for recording death on the adverse event reporting form is as follows: 
• Adverse event term that led to death (e.g. multiple organ failure, pneumonia, myocardial 
infarction). 
• Outcome: fatal. 
• The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), 
in which case the adverse event term may be ‘Death’ or ‘Sudden death’. 


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8.1.4 
SPECIAL SITUATIONS 
This is any incidence of drug exposure during pregnancy or breast-feeding, overdose, off-label use, 
medication errors, occupational exposure, abuse, misuse or lack of therapeutic effectiveness 
whilst using the medicinal product. A ‘special situation’ should be collected by the Investigator and 
reported to Ipsen whether or not these ‘special situations’ are associated with an adverse event. 
8.1.4.1 
PREGNANCY 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the medicinal 
product has interfered with a contraceptive method. If pregnancy occurs whilst using the 
medicinal product, the outcome of the pregnancy will then need to be collected. This applies 
irrespective of whether the pregnancy is considered to be related to interference by the medicinal 
product with a contraceptive method. 
Information regarding any pregnancies must be collected on the adverse event report form, 
including those with normal progress and outcome. The investigator must instruct all female 
subjects to inform them immediately should they become pregnant whilst using the study 
medication. 
Reports of pregnancy must be reported to Ipsen within 24 hours of the Investigator’s knowledge. 
8.1.4.2 
OVERDOSE 
An overdose is any dose of the medicinal product given to a study participant that exceeds the 
dose described in the protocol. Overdoses are not considered AEs; however, all overdoses should 
be reported to Ipsen within 24 hours. An overdose should be reported even if it does not result in 
an AE. 
8.2 COLLECTION AND REPORTING OF ADVERSE EVENTS, FATAL OUTCOMES AND 
SPECIAL SITUATIONS  
Note 
From this point onwards, the term ‘Safety Report’ will collectively refer to all reports of 
AE, fatal outcomes and special situations.  
8.2.1 
COLLECTION OF SAFETY REPORTS 
All safety reports, whether they are serious/non-serious, related/unrelated, should be collected by 
the Investigator in the study source document during the course of the study. 
The Investigator must report all safety reports on the Clinical Study Serious Adverse Event (SAE) 
report form (080478-FOR) (Section 14.8) to Ipsen according to the timelines set out in section 
8.2.2. 


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8.2.2 
REPORTING OF SAFETY REPORTS 
In order to adhere to all applicable laws and regulations for reporting of a safety report, the 
Investigator should notify to the sponsor and sponsor will notify Ipsen within 24 hours of the study 
site staff becoming aware of the safety report. It is the Investigator’s responsibility to ensure that 
the reporting information and procedures are used and followed appropriately.  
Reporting Information for safety reports 
To report initial or follow-up information to Ipsen, a completed Clinical Study Serious 
Adverse Event (SAE) report form (080478-FOR) should be sent to the following within 24 
hours of becoming aware of the event: 
ANNA ROSET DALMAU, Local Pharmacovigilance Manger 
Email: pharmacovigilance.spain@ipsen.com, anna.roset@ipsen.com   
Phone: +34 936858153 / +34 617052107 
Fax: +34 93 685 10 11 
All adverse events will be processed by Ipsen according to their relevant Standard Operating 
Procedures. This includes the follow up of adverse event reports with the Investigator, as required. 
If an AE occurs with a “non Ipsen product”, the Investigator should consider informing the 
competent authority in the Member State where the event occurred or to the marketing 
authorisation holder of the suspected medicinal product, but not to both (to avoid duplicate 
reporting). 
8.2.3 
MANDATORY INFORMATION FOR REPORTING AN ADVERSE EVENT 
The following information is the minimum that must be provided to Sponsors and will be provided 
to Ipsen’s Pharmacovigilance contact within 24 hours for each adverse event: 
• Patient identifier 
• Product name 
• Adverse Event description including assessment of causal relationship and seriousness 
• Investigator name and contact details 
The additional information included in the adverse event report form must be provided to Ipsen as 
soon as it is available. 
The investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The investigator should also try to separate a primary adverse event considered as the 
foremost untoward medical occurrence from secondary adverse events which occurred as 
complications. The investigator should also provide the batch number and expiry date of the 
concerned product wherever possible. 


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8.3 SAFETY CLASIFICATIONS 
8.3.1 
RELATIONSHIP OF EVENTS TO THE MEDICINAL PRODUCT 
The following definitions should be considered when evaluating the relationship of AEs and SAEs 
to the study treatment: 
Relationship of Event to Study Treatment 
Not related 
 
An adverse event will be considered “not related” to the use of the 
medicinal drug if there is not a possibility that the event has been caused by 
the product under investigation. Factors pointing toward this assessment 
include, but are not limited to: the lack of reasonable temporal relationship 
between administration of the drug and the event, the presence of a 
biologically implausible relationship between the product and the adverse 
event (e.g., the event occurred before administration of drug), or the 
presence of a more likely alternative explanation for the adverse event. 
Related 
An adverse event will be considered “related” to the use of the medicinal 
drug if there is a possibility that the event may have been caused by the 
product under investigation. 
Factors that point toward this assessment include, but are not limited to: a 
positive 
rechallenge, 
a 
reasonable 
temporal 
sequence 
between 
administration of the drug and the event, a known response pattern of the 
suspected drug, improvement following discontinuation or dose reduction, a 
biologically plausible relationship between the drug and the adverse event, 
or a lack of an alternative explanation for the adverse event 
8.3.2 
SEVERITY OF EVENTS 
The following definitions should be considered when evaluating the severity of oncology events: 
Severity of Events 
Grade 
 
Definition 
 
1 
Mild adverse event 
2 
Moderate adverse event 
3 
Severe and undesirable adverse event 


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4 
Life-threatening or disabling adverse event 
5 
Death related to adverse event 
8.3.3 
EXPECTEDNESS OF EVENTS 
Expectedness of all AEs will be determined by Ipsen according to the SmPC. 
8.3.4 
SAFETY DATA LISTING 
A safety data listing will be obtained from the global safety database and will be included in the 
clinical study report. 
All collected adverse events will be summarized for inclusion as part of any interim safety analysis 
and in the clinical study report. 
9. STATISTICAL METHODS  
9.1 END-POINTS 
The study will be analyzed using standard statistical methods to estimate rates and 95%CI (for ORR 
and other binary variables) by means of the Clopper-Pearson exact method, and the Kaplan-Meier 
method to describe the survival functions and the median and [95%CI]. Indirect comparisons with 
will conducted with external data by assessing the 95%CI of the study estimates. A Statistical 
Analysis Plan, which will include all details regarding all analyses, the interim method, the handling 
of missing data and any plan for the analysis, will be finalized before the initiation of the study 
recruitment. 
Primary Outcome(s)  
• Rate of adverse events (AE) with Common Terminology Criteria for Adverse Events 
(CTCAE)≥3 excluding palmar-plantar erythordysthesia, rate of AEs, rate of related-AEs and 
rate of death. Rate of AEs leading to treatment discontinuation. 
• Adverse events will be graded following version 5.0 of the CTCAE of the National Cancer 
Institute, during treatment and 30 days after the last dose. 
Secondary Outcome(s)  
 
Time to progression, objective response rate, pattern of progression, overall survival, post-
progression survival, rate of patients who develop new extrahepatic spread. Serum and tissue 
marker characterization. 
Safety Outcomes  
This is a clinical trial were the main purpose is the assessment of safety, therefore, the primary 
and secondary outcomes were defined accordingly, as described above.   


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9.2 SAMPLE SIZE 
The sample size calculation will be triggered by the primary outcome, i.e, the rate of adverse 
events (AE) with CTCAE≥3 excluding palmar-plantar erythordysthesia (critical AEs). The expected 
rate for this outcome was 56% in this population1. The Simon's two-stage optimal design2 will be 
used to test the alternative hypothesis that with cabozantinib the rate of critical AEs will be 
reduced at least to 32.5% against the null hypothesis of 56% as previously observed. In the first 
stage, 14 patients will be accrued. If there are 8 or more critical AES in these 14 patients, the study 
will be stopped because of futility. Otherwise, 26 additional patients will be accrued for a total of 
40. The null hypothesis will be rejected if 23 or fewer critical AEs are observed in 40 patients. This 
design yields a type I error rate of 2.5% one-sided and power of 80% when the true response rate 
is 67.5%. 
All patients exposed to the study treatment (regardless of protocol adherence) will count be 
safety, and thus no need to sample size increases as per potential withdrawals are foreseen. 
9.3 INTERIM ANALYSES  
We plan to conduct 1 fixed pre-scheduled interim analyses for futility as per the Simon’s design as 
described in section 9.2. The interim analysis will be conducted after follow-up data from the first 
14 patients will be available after at least 30 days from study inclusion, or otherwise presenting an 
occurrence of the primary outcomes. The DSMB will consist of 3 members (2 hepatologists and 1 
nurse) and an agreed charter by all members will come into operation before the initiation of the 
study recruitment. To note, this interim futility analysis will have no impact on the type I error at 
the end of the trial, and thus alpha adjustment is not needed. 
10. STUDY CONDUCT CONFIDENTIAL 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; an 
abbreviated version with personnel relevant for the centers will be available in each center’s 
investigator site file. 
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the principal 
investigator at the site, or an appropriately qualified, trained and delegated individual of the 
investigational site. 
 
1 Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc 
JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, 
Schwab G, Kelley RK. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J 
Med. 2018 Jul 5;379(1):54-63. doi: 10.1056/NEJMoa1717002. 
2 Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 1989;10: 1-10 


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The principal investigator of each center must sign the protocol signature sheet before subject 
recruitment may start at the respective center.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the principal investigator before coming into effect at the 
respective center. 
A complete list of all participating centers and their investigators, as well as all required signature 
documents, will be maintained in the sponsor study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by local 
law, local co-sponsors will be nominated; they will be identified on the respective country-specific 
signature pages. 
10.1 ADHERENCE TO THE PROTOCOL 
The study shall be conducted as described in this protocol. The investigators should not implement 
any deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. If an amendment substantially alters the study design or increases the 
potential risk to the subject: (1) the consent form must be revised and submitted to the 
IRB(s)/IEC(s) for review and approval/favorable opinion; (2) the revised form must be used to 
obtain consent from subjects currently enrolled in the study if they are affected by the 
amendment; and (3) the new form must be used to obtain consent from new subjects prior to 
enrollment. If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
10.2 DATA SAFETY MONITORING BOARD (DSMB) 
A Data Safety Monitoring Board will be instituted in order to ensure ongoing safety of study 
patients with respect to a risk/benefit assessment during periodic data review meetings, review 
results from planned interim analyses and provide a formal recommendation for 
continuation/termination of the study and monitor study conduct to ensure the overall integrity of 
trial is maintained. One formal interim analysis is planned and will be performed as per separate 
DSMB charter. Recommendation for trial continuation will be guided by monitoring boundaries at 
formal interim analyses as well as safety evaluations at all safety data reviews (refer to Section for 
details on interim analyses). The committee will include at least 2 independent hepatologist and 
one independent nurse.  Data review meetings will be held periodically as per separate DSMB 
charter. Enrollment to the study will continue throughout the scheduled meetings of the DSMB. 
Decisions on trial termination, amendment or cessation of patient recruitment based on 
risk/benefit assessments will be made after recommendations from the DSMB have been assessed 
by the Sponsor. 


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11. DATA MANAGEMENT 
11.1 Data Source 
Each patient is pseudonymized by a unique central patient identification code, which is only used 
for study purposes. For the duration of the study and afterwards, only the patient’s treating 
physician or authorized site personnel is able to identify the patient based on the patient 
identification code. Uncoded patient data (which allows to directly identify a person) as well as the 
list allowing to connect the patient with the unique central patient identification code are only 
stored at the study site. As soon as the site has destroyed that list according to local legal 
requirements, no data processed within the study can be linked to a patient’s identity.  
11.2 Confidentiality 
Fundació Clinic per a la Recerca Biomèdica (FCRB) as well as all investigators ensure adherence to 
applicable data privacy protection regulation. Data are transferred in pseudonymized form only. 
The entire documentation made available to FCRB does not contain any data which, on its own 
account or in conjunction with other freely available data, can be used to re-identify natural 
persons. The investigators are obligated to ensure that no documents contain such data.  
11.3 Withdrawal 
Each patient may withdraw from the study at any time and without giving a reason. If a patient 
wants to terminate the study participation, no further data will be collected. In case a patient 
would like to withdraw the consent given earlier, he/she should inform his/her doctor and the site 
should document the withdrawal in the (electronic) Case Report Form as well as in the patient 
medical records. 


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12. LIST OF ABBREVIATIONS  
AASLSD 
American Association for the Study of Liver Diseases 
AE 
 
Adverse events 
AFP 
 
Alpha-fetoprotein 
AHA 
 
Alpha Hydroxy Acids 
APCs  
Antigen presenting cells 
BCLC  
Barcelona Clinic Liver Cancer 
BP 
 
Blood Pressure 
BSC 
 
Best supportive care 
BUN 
 
Blood urea nitrogen 
CBC 
 
Complete blood count 
CL 
 
Clearance 
CR 
 
Complete response 
CRC 
 
Colorectal cancer 
CRF 
 
Case Report Form 
CTCAE  
Common Terminology Criteria for Adverse Events 
DAAs  
Direct acting antivirals 
DAMP  
Damage associated molecular patterns 
DILI 
 
Drug-induced liver injury 
DSMB  
Data and safety monitoring board 
eCRF  
Electronic Case Report Form 
EDR 
 
Early dermatologic reactions 
eGFR  
Estimated Glomerular Filtration Rate 
EMT 
 
Epithelial mesenchymal transition 
FDA 
 
Food and Drug Administration 
FGFR  
Fibroblast growth factor receptor 
GCP 
 
Good Clinical Practice 


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GFR 
 
Glomerular filtration rate 
GIST 
 
GastroIntestinal Stromal Tumors 
GVHD  
Graft versus host disease 
HBV 
 
Hepatitis B virus 
HCC 
 
Hepatocellular carcinoma 
HCV 
 
Hepatitis C virus 
HFSR  
Hand-foot skin reaction 
HIF-1α  
Hypoxia-inducible factor 1α 
HIV 
 
Human inmunodeficiency virus 
HR 
 
Hazard ratio 
IC 
 
Informed consent form 
ICD 
 
Immunogenic cell death 
ICH 
 
International conference on harmonization 
IECs 
 
Institutional Ethical Committees 
IRBs 
 
Institutional Review Boards 
LDH 
 
Lactic dehydrogenase 
mAbs  
Monoclonal antibodies 
mCRC  
Metastasic colorectal cancer 
MDSC  
Myeloid-derived suppressor cells  
NAFLD  
Nonalcoholic fatty liver disease 
NF-B  
Nuclear factor B 
ORR 
 
Objective Response Rate 
OS 
 
Overall Survival 
PD 
 
Progressive Disease 
PDGFR  
Platelet-derived growth factor receptor 
PFS 
 
Progression free survival 
PK 
 
Pharmacokinetics 
PPS 
 
Post- Progression Survival 


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PR 
 
Parcial Response 
PTT 
 
Parcial thromboplastin time 
RBC 
 
Red blood cell count 
RCTs  
Randomized controlled trials 
SAEs 
 
Serious adverse events 
SD 
 
Stable Disease 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TAN 
 
Tumor associated neutrophils 
TNF-α  
Tumor necrosis factor α 
TRAEs  
Treatment- related AEs 
TSH 
 
Thyroid – stimulating hormone 
TTP 
 
Time to progression 
UPCR  
Urine protein/creatinine ratio 
VEGFR  
Vascular endothelial growth factor receptor 
 
 
 
 


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13. REFERENCE LIST  
1 
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018; 391: 1301–14. 
2 
Llovet JM, Zucman-Rossi J, Pikarsky E, et al. Hepatocellular carcinoma. Nat Rev Dis Prim 2016; 2: 
16018. 
3 
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 
2008; 359: 378–90. 
4 
Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with 
unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 
391: 1163–73. 
5 
Improved Survival in Hepatocellular Carcinoma | ESMO. https://www.esmo.org/Press-Office/Press-
Releases/ESMO-Asia-Congress-2019-IMbrave150-atezolizumab-bevacizumab-hepatocellular-
carcinoma-HCC-Cheng (accessed Dec 19, 2019). 
6 
Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed 
on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet 2017; 389: 56–66. 
7 
Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in Patients with Advanced and Progressing 
Hepatocellular Carcinoma. N Engl J Med 2018; 379: 54–63. 
8 
Zhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced 
hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 282–96. 
9 
FDA. HIGHLIGHTS OF PRESCRIBING INFORMATION (nivolumab). 2017. 
10 
FDA. HIGHLIGHTS OF PRESCRIBING INFORMATION (pembrolizumab). . 
11 
Finn RS, Ryoo B-Y, Merle P, et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab 
(Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular 
carcinoma (HCC). J Clin Oncol 2019; 37: 4004–4004. 
12 
Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, 
simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10: 
2298–308. 
13 
Bentzien F, Zuzow M, Heald N, et al. In vitro and in vivo activity of cabozantinib (XL184), an inhibitor 
of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid 2013; 23: 1569–77. 
14 
Miles D, Jumbe NL, Lacy S, Nguyen L. Population Pharmacokinetic Model of Cabozantinib in Patients 
with Medullary Thyroid Carcinoma and Its Application to an Exposure-Response Analysis. Clin 
Pharmacokinet 2016; 55: 93–105. 
15 
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell 
Carcinoma. N Engl J Med 2015; 373: 1814–23. 
16 
Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of 
cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol  
Off J Eur Soc Med Oncol 2017; 28: 2813–9. 
17 
Kelley RK, Verslype C, Cohn AL, et al. Cabozantinib in hepatocellular carcinoma: Results of a phase 2 


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placebo-controlled randomized discontinuation study. Ann Oncol 2017; 28: 528–34. 
18 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47. 
19 
Reig M, Darnell A, Forner A, Rimola J, Ayuso C, Bruix J. Systemic Therapy for Hepatocellular 
Carcinoma: The Issue of Treatment Stage Migration and Registration of Progression Using the BCLC-
Refined RECIST. Semin Liver Dis 2014; 34: 444–55. 
20 
Bruix Jordi FLG and RM. A critical insight into success and failure of systemic therapy for 
hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2019. 
21 
Reig M, Rimola J, Torres F, et al. Post-progression survival of patients with advanced hepatocellular 
carcinoma. Rationale for second line trial design. Hepatology 2013; : 2023–31. 
22 
Iavarone M, Cabibbo G, Biolato M, et al. Predictors of survival in patients with advanced 
hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 2015; 62: 784–91. 
23 
Ogasawara S, Chiba T, Ooka Y, et al. Post-progression survival in patients with advanced 
hepatocellular carcinoma resistant to sorafenib. Invest New Drugs 2016; 34: 255–60. 
24 
Reig M, Galle PR, Kudo M, et al. Pattern of progression in advanced HCC treated with 
ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2). J Clin Oncol 
2020; 38: 544–544. 
 
 


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14. APPENDICES  
14.1 APPENDIX 1: ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-diseasese performance without restriction. 
(Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work). (Karnofsky 
70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. (Karnofsky 50-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. (Karnofsky 30-40) 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. (Karnofsky 10-20) 
 


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14.2 APPENDIX 2: CHILD-PUGH SCALE  
 Points Scored for Observed Findings 
 
Points Scored for Observed Findings 
 
1 
2 
3 
Encephalopathy grade a 
None 
1 or 2 
3 or 4 
Ascites 
Absent 
Slight 
Moderate 
Serum bilirubin, mg/dL 
< 2 
2 to 3 
> 3.0 
Serum albumin, g/dL 
> 3.5 
2.8-3.5 
< 2.8 
Prothrombin time, sec (prolonged) 
< 4 
4-6 
> 6 
a  Encephalopathy grades: 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves  
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unarousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity 
 
Assessment as good operative risk (A) if 5 or 6 points; moderate risk (B) if 7 to 9 points, and poor operative risk (C) if 
10 to 15 points (developed for surgical evaluation of alcoholic cirrhotics). 
 


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14.3 APPENDIX 3: RECIST 1.1 CRITERIA 
Response and progression will be evaluated in this study using the RECIST criteria version 1.118. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used. 
Measurable Disease:  
Tumor lesions: Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI. If scans with slice 
thicknesses greater than 5mm are used, the minimum size should be twice the slice 
thickness. 
• 20 mm by chest x-ray 
• 10 mm calliper measurement by clinical examination (lesions which cannot be accurately 
measured with callipers should be recorded as non-measurable) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed.  
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components that can 
be evaluated by CT or MRI, can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Tumor lesions situated in a previously irradiated area are not considered measurable unless there 
has been demonstrated progression in the lesion. 
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to < 15mm short axis) are considered 
non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitic involvement of skin or lung, inflammatory breast disease, abdominal masses/ 
abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques and blastic bone lesions are all non-measurable. 
Target Lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs should be identified as target lesions and be recorded 
and measured at baseline. These 5 lesions should be selected on the basis of their size (lesion with 
the longest diameter), be representative of all involved organs and should be suitable for 
reproducible repeated measurements. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 


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sum diameters. If lymph nodes are to be included in the sum, then as noted above, only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression of the measurable dimension of the disease. If there 
are >5 measurable lesions, those not selected as target lesions will be considered together with 
non-measurable disease as non-target lesions. 
Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above the 5 listed as target lesions. including pathological lymph nodes (with short axis 
≥10 mm and < 15 mm) should be identified as non-target lesions and should also be recorded at 
baseline. Measurements are not required but these lesions should be noted at baseline and 
should be followed as “present”, “absent” or in rare cases “unequivocal progression”. In addition, 
it is possible to record multiple non-target lesions involving the same organ as a single item on the 
case record form (eg; ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Best Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment.  The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. While some non- target lesions may actually be measurable, they need not be measured 
and instead should be assessed only qualitatively at the time points specified in the protocol. 
All subjects will have their BEST RESPONSE on study classified as outlined below:  
Complete Response (CR): Disappearance of all clinical and radiological evidence of tumor (both 
target and non-target). Any pathological lymph nodes (whether target or non-target) must have a 
reduction in short axis to < 10mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as 
reference the baseline sum, no unequivocal progression of existing non target lesions and no 
appearance of new lesions. 
Stable Disease (SD): Steady state of disease. Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, no unequivocal progression of existing non target lesions and 
no appearance of new lesions. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5mm.  Unequivocal progression of existing non target lesions or the 
appearance of one or more new lesions will also constitute progressive disease. (Note: the 
appearance of one or more new lesions is also considered progression).  
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 nodes 
regress to below 10 mm on study.  This means that when lymph nodes are included as target 


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lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a 
normal lymph node is defined as having a short axis of <10mm. 
To achieve unequivocal progression in patients with measurable disease on the basis of the non-
target disease, there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of SD or PR in target disease, the overall tumor 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. 
In the absence of measurable disease, the same general concepts apply here as noted above. 
Response duration 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
Stable disease duration 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
 
 


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Table 8 Response for patients with target and non-target lesions 
Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
category also requires 
CR 
CR 
No 
CR 
 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not evaluated 
No 
PR 
 
PR 
Non-PD or not 
all evaluated 
No 
PR 
 
SD 
Non-PD or not 
all evaluated 
No 
SD 
documented after 8 wks.  
Not all 
evaluated 
Non-PD 
no 
NE 
 
PD 
Any 
Yes or No 
PD 
 
Any 
PD 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
Subjects with a global deterioration of 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 the objective progression even after 
discontinuation of treatment. 
 
Table 9: Response for patients with non-target lesions only 
Non-Target 
Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PD* 
Not evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* Non-CR/non-PD is preferred over “stable disease” for non-
target disease. 
Methods of Measurement 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
Clinical Lesions - Clinical lesions will only be considered measurable when they are superficial (e.g. 
skin nodules, palpable lymph nodes) and ≥ 10mm diameter as assessed using callipers. For the 


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case of skin lesions, documentation by colour photography including a ruler to estimate the size of 
the lesion is recommended. 
Chest X-ray - Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, chest CT is preferable. 
CT / MRI - CT is the best currently available and reproducible method to measure target lesions 
selected for response assessment. CT scans should be performed with cuts of 5 mm or less in slice 
thickness. When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable. This applies to the 
chest, abdomen and pelvis. Head & neck and extremities usually require specific protocols. 
Ultrasound - Ultrasound is not useful in assessment of lesion size and should not be used as 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised.  
Endoscopy / Laparoscopy - The utilization of these techniques for objective tumor evaluation is 
not advised.  
Cytology / Histology - These techniques can be used to differentiate between PR and CR in rare 
cases (for example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain). 
The central revision will be also done based on BCLC-RECIST19.  
 


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14.4 APPENDIX 4: NCI CTCAE V.5.0 RECOMMENDATION FOR GRADING OF ADVERSE 
EVENTS  
The full Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 Published 
November 27, 2017can be obtained at the following website: 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_re
ference_5x7.pdf 
 


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14.5 APPENDIX 5: MANAGEMENT OF SUSPECTED CABOZANTINIB TOXICITIES 
 
The management will be done according to manufacture recommendation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.6 APPENDIX 7: PATIENT-REPORTED QUALITY OF LIFE QUESTIONNAIRES 
Patient reported outcome measures 
Guidelines for Administration of the patient reported outcomes questionnaires 
These guidelines assume that an appropriate person has been designated to facilitate the self-
administration of the questionnaires. 
When and how should the questionnaire be administered? 
The FACT-Hep, EORTC-QLQ C30, EORTC-HCC18 and EQ-5D should be self-administered by the 
patient alone at the beginning of their scheduled visits at the clinic. These instruments should be 
administered at the start of the visit, before the patient sees the physician so that any interaction 
between the patient and physician will not influence the patient’s responses to the questionnaire.  
The questionnaire should also be administered before the patient is asked about adverse 
experiences and concurrent illnesses, again so that any discussions of health problems do not 
influence the patient’s responses. 
A quiet place should be provided for the patient to complete the questionnaire. It is important 
that the patient completes the questionnaire alone, without any advice from family members or 
friends who may accompany them. On average, it takes less than 15 around 25 minutes to 
complete the questionnaires. 
Foreign speaking patients: 
Patients must have basic fluency in the language of their country in order to complete the PRO 
instruments. If a patient is not able to speak/read the language of his/her country, please check if 
the patient has basic fluency in any of the languages in which the questionnaire is currently 
available. Copies of the alternative language questionnaire are available from the study manager. 
If the patient is illiterate, the person designated to facilitate the questionnaires should read the 
instructions, questions and answer alternatives to the patient verbatim and without providing 
interpretation.  
How should the Questionnaires be introduced? 
A sample script for introducing the questionnaire is given below. 
“Your doctor would like to better understand how you feel, how well you are able to do your usual 
activities, and how you rate your health. To help us better understand these things about you, 
please complete this questionnaire about your health.  The questionnaire is easy to fill out. The 
instructions are on the front cover (point to them). You should read (for illiterate patients: listen)1 
each question and then circle the appropriate number that matches your answer. Remember that 
this is not a test and there are no rights or wrong answers.  Choose the answer that best describes 
the way you feel.  I will quickly review the questionnaire when you are done to make sure that all 
the questions have been answered. You should answer these questions by yourself.  Your spouse 
or other family members should not help you when you answer the questionnaire.  I will be 


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nearby in case you want to ask me any questions.  Please return, the questionnaire to me when 
you have finished”. 
What to do if the patient asks for clarification? 
Some patients may ask the meaning of specific questions. If this happens, the staff member can 
assist the patient by re-reading the question for them verbatim.  If the patient asks what 
something means, do not try to explain what the question means, but tactfully suggest that the 
patient use his/her own interpretation of the question.  All patients should answer the questions 
based on what they think the questions mean, or the study results may be biased. 
Questionnaires completion:  
When the patient returns the questionnaire, check that all of the questions have been answered. 
If the questionnaire is not complete, point out to the patient that some of the questions were not 
answered.  If the patient does not quickly volunteer to answer these items, ask him/her whether 
she had any difficulty completing the questionnaire. If the patient says that he/she had trouble 
understanding a question, ask him/her why he/she had difficulty with that item.  Re-read the 
question for him/her verbatim, but do not attempt to explain or reword the question, as explained 
before.  If the patient is still unable to answer the question, accept the questionnaire as is. 
Some patients may be confused by the response choices.  They may want to respond with “I don’t 
know” or some other response choice that is not available.  If this happens, try to help the patient 
choose one of the response categories by saying something like: “I know that it may be difficult for 
you to choose an answer, but which of these answers do you think comes closest to the way that 
you are thinking or feeling?”  If the patient still cannot select an answer, accept the questionnaire 
as is. 
Occasionally, patients may not report having difficulty with a question or the response choices, but 
still may hesitate or refuse to answer an item or items.  If this happens, accept the questionnaire 
as is. 
If a patient asks for interpretation of his/her responses or asks for his/her scores on the 
questionnaire, tell him/her that you are not trained to score or interpret the questionnaire.  
Emphasize that their answers will be kept confidential. 
Completed questionnaires: 
Thank the patient once he/she has completed the questionnaire and you have checked it for 
completeness. 


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Patient reported outcomes (PRO) Information Sheet 
Instructions: 
− This information sheet is to be completed by the study nurse/investigator 
− This information sheet must be completed for all patients at each visit in which the 
protocol requires PRO assessment, whether or not the questionnaire has been 
completed by the patient. 
− When the patient returns the questionnaire 
- Please complete this information sheet 
- Please check that the patient has answered all the questions and no more than 
one answer 
 
Was the questionnaire provided to the patient at this visit 
 No 
 Yes 
If YES please continue 
If NO please go to question 5 
Date questionnaire completed 
 
/ 
/ 
 (dd/mm/yyyy) 
Was the questionnaire provided prior to clinical examination? 
 No 
 Yes 
Were all questions answered? 
 No 
 Yes 
If YES, please STOP 
If NO, specify reason questionnaire/questions were not answered  
 Patient felt too ill 
 Patient refused to complete questionnaire for reason other than illness 
 Patient did not keep appointment 
 Questionnaire not administered due to institution error 
 Questionnaire not available in the appropriate language 
 Other, please specify:____________________________  
 
 
 


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FACT-Hep (Version 4) 
 
Below is a list of statements that other people with your illness have said are important. By circling 
one (1) number per line, please indicate how true each statement has been for you during the past 
7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
 
 
 
GP1 
I have a lack of energy  
0 
1 
2 
3 
4 
 
GP2 
I have nausea  
0 
1 
2 
3 
4 
 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP4 
I have pain 
 
0 
1 
2 
3 
4 
 
GP5 
I am bothered by side effects of treatment
 
 
0 
1 
2 
3 
4 
 
GP6 
I feel ill  
0 
1 
2 
3 
4 
 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GS1 
I feel close to my friends 
 
0 
1 
2 
3 
4 
 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
 
GS3 
I get support from my friends  
0 
1 
2 
3 
4 
 
GS4 
My family has accepted my illness 
 
0 
1 
2 
3 
4 
 
GS5 
I am satisfied with family communication 
about my illness 
 
0 
1 
2 
3 
4 
 
GS6 
I feel close to my partner (or the person 
who is my main support) 
 
0 
1 
2 
3 
4 
 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question.  If you prefer 
not to answer it, please check this box      and go 
to the next section.  
 
 
 
 
 
GS7 
I am satisfied with my sex life  
0 
1 
2 
3 
4 


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By circling one (1) number per line, please indicate how true each statement has been for you during the 
past 7 days. 
 
 
EMOTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
GE1 
I feel sad 
 
 
0 
1 
2 
3 
4 
 
GE2 
I am satisfied with how I am coping with my 
illness  
 
0 
1 
2 
3 
4 
 
GE3 
I am losing hope in the fight against my 
illness  
 
0 
1 
2 
3 
4 
 
GE4 
I feel nervous  
 
0 
1 
2 
3 
4 
 
GE5 
I worry about dying 
 
 
0 
1 
2 
3 
4 
 
GE6 
I worry that my condition will get worse
 
 
 
0 
1 
2 
3 
4 
 
 
FUNCTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
 
 
 
GF1 
I am able to work (include work at home)
 
 
0 
1 
2 
3 
4 
 
GF2 
My work (include work at home) is fulfilling
 
 
0 
1 
2 
3 
4 
 
GF3 
I am able to enjoy life  
 
0 
1 
2 
3 
4 
 
GF4 
I have accepted my illness 
 
0 
1 
2 
3 
4 
 
GF5 
I am sleeping well 
 
 
0 
1 
2 
3 
4 
 
GF6 
I am enjoying the things I usually do for fun
 
 
 
0 
1 
2 
3 
4 
 
GF7 
 
I am content with the quality of my life right 
now 
 
 
0 
1 
2 
3 
4 
By circling one (1) number per line, please indicate how true each statement has been for you during the 
past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
 a bit 
Very 
much 
 
 
C1 
I have swelling or cramps in my stomach 
area 
 
0 
1 
2 
3 
4 


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C2 
I am losing weight 
 
0 
1 
2 
3 
4 
 
C3 
I have control of my bowels 
 
0 
1 
2 
3 
4 
 
C4 
I can digest my food well 
 
0 
1 
2 
3 
4 
 
C5 
I have diarrhea  
0 
1 
2 
3 
4 
 
C6 
I have a good appetite  
0 
1 
2 
3 
4 
 
Hep1 
I am unhappy about a change in my 
appearance 
 
0 
1 
2 
3 
4 
 
CNS7 
I have pain in my back  
0 
1 
2 
3 
4 
 
Cx6 
I am bothered by constipation  
0 
1 
2 
3 
4 
 
H17 
I feel fatigued 0 
0 
1 
2 
3 
4 
 
An7 
I am able to do my usual activities 
 
0 
1 
2 
3 
4 
 
Hep2 
I am bothered by jaundice or yellow color 
to my skin 
0 
1 
2 
3 
4 
 
Hep 3 
I have had fevers 
 
0 
1 
2 
3 
4 
 
Hep 4 
I have had itching 
 
0 
1 
2 
3 
4 
 
Hep 5 
I have had a change in the way food 
tastes  
0 
1 
2 
3 
4 
 
Hep 6 
I have had chills 
 
0 
1 
2 
3 
4 
 
HN 2 
My mouth is dry 
 
0 
1 
2 
3 
4 
 
Hep 8 
I have discomfort or pain in my stomach 
area 
 
0 
1 
2 
3 
4 
 


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EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. 
The information that you provide will remain strictly confidential. 
Please fill in your initials: 
 
Your birthdate (Day, Month, Year): 
Today's date (Day, Month, Year):31 
Not at All 
A 
Little 
Quite a 
Bit 
Very 
Much 
1. Do you have any trouble doing strenuous 
activities, like carrying a heavy shopping bag or a 
suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk 
outside of the house? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the 
day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, washing 
yourself or using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at 
A 
Quite 
Very 
All 
Little 
a Bit 
Much 
6. Were you limited in doing either your work or 
other daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or othe
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 


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12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 
 
During the past week: 
17. Have you had diarrhea? 
Not 
at All 
1 
A 
Little 
2 
Quite 
a Bit 
3 
Very 
Much 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in 
concentrating on things, like reading 
a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or 
medical treatment interfered with 
your social activities? 
1 
2 
3 
4 
28. Has your physical condition or 
medical treatment caused you 
financial difficulties? 
1 
2 
3 
4 
 


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EORTC QLQ – HCC18 
Patients sometimes report that they have the following symptoms or problems. Please indicate 
the extent to which you have experienced these symptoms or problems during the past week. 
Please answer by circling the number that best applies to you. 
During the past week: 
Not 
A 
Quite Very 
31. Did you feel thirsty? 
at 
all 
1 
little 
2 
a bit 
3 
much 
4 
32. Have you had problems with your sense of taste? 
1 
2 
3 
4 
33. Have you lost muscle from your arms or legs? 
1 
2 
3 
4 
34. Have you had abdominal swelling? 
1 
2 
3 
4 
35. Have you been concerned by the appearance of your abdomen? 
1 
2 
3 
4 
36. Have you been concerned by your skin or eyes being yellow 
(jaundiced)? 
1 
2 
3 
4 
37. Have you had itching? 
1 
2 
3 
4 
38. Have you had pain in your shoulder? 
1 
2 
3 
4 
39. Have you had abdominal pain? 
1 
2 
3 
4 
40. Have you had fevers? 
1 
2 
3 
4 
41. Have you had chills? 
1 
2 
3 
4 
42. Have you worried about getting enough nourishment? 
1 
2 
3 
4 
43. Have you felt full up too quickly after beginning to eat? 
1 
2 
3 
4 
44. Have you worried about your weight being too low? 
1 
2 
3 
4 
45. Have you been less active than you would like to be? 
1 
2 
3 
4 
46. Have you found it difficult to finish things? 
1 
2 
3 
4 
47. Have you needed to sleep during the day? 
1 
2 
3 
4 
During the past four weeks: 
48.   Has the disease or treatment had any effect on your sex life? 
1 
2 
3 
4 
 
 


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EQ-5D 
By placing a checkmark in one box in each group below, please indicate which statements best 
describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
❑ 
I have some problems in walking about 
 
❑ 
I am confined to bed 
 
❑ 
 
Self-Care 
I have no problems with self-care 
 
❑ 
I have some problems washing or dressing myself 
 
❑ 
I am unable to wash or dress myself 
 
❑ 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
❑ 
I have some problems with performing my usual activities 
 
❑ 
I am unable to perform my usual activities 
 
❑ 
 
Pain/Discomfort 
I have no pain or discomfort 
 
❑ 
I have moderate pain or discomfort 
 
❑ 
I have extreme pain or discomfort 
 
❑ 
 
Anxiety/Depression 
I am not anxious or depressed 
 
❑ 
I am moderately anxious or depressed 
 
❑ 
I am extremely anxious or depressed 
 
❑ 


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To help people say how good or bad a health state is, we have 
drawn a scale (rather like a thermometer) on which the best 
state you can imagine is marked 100 and the worst state you can 
imagine is marked 0. 
 
 
 
We would like you to indicate on this scale how good or bad 
your own health is today, in your opinion. Please do this by 
drawing a line from the box below to whichever point on the 
scale indicates how good or bad your health state is today
Your own 
health state 
today 


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87
14.7 CYP3A4 and CYP1A2 Inhibitors/Inducers 
http://medicine.iupui.edu/clinpharm/ddis/ 
Strong inhibitors and inducers (underlined) are not permitted during this study.   
CYP3A4 inhibitors 
CYP3A4 inducers 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
clarithromycin 
itraconazole 
ketoconazole 
nefazodone (withdrawn in the US) 
erythromycin 
grapefruit juice 
verapamil 
diltiazem 
cimetidine 
amiodarone 
fluvoxamine 
mibefradil (withdrawn in the US) 
troleandomycin 
rifampin 
carbamazepine 
phenobarbital 
phenytoin 
pioglitazone 
rifabutin 
St. John's wort 
 
 
 
 
 
 
 
 
 
 
 
 


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EudraCT No: 2019-004991-20  
Version: 4.0 
Date:  15 July 2021 
CONFIDENTIAL 
 
88
14.8 CLINICAL STUDY SAE REPORT FORM 
 

SAP_001.pdf: 
 
 
 
 
ACTION Statistical Analysis Plan 
 
 
 
A phase II triAl of Cabozantinib for hepaTocellular 
carcInoma patients intOlerant to sorafenib treatment or 
first line treatment different to sorafeNib. (ACTION trial) 
 
NCT: NCT04316182 
 
 
 
 
 
 
  
Date: 05-Nov-2021 


Medical Statistics Core Facility 
IDIBAPS - Hospital Clinic Barcelona 
bioestadistica@idibaps.org 
 
 
 
ACTION Statistical Analysis Plan   
 
05-Nov-2021 
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RESTRICTED 
 
 
Statistical Analysis Plan  
 
 
Medical Statistics Core Facility 
IDIBAPS (Institut d'Investigacions Biomèdiques August Pi i Sunyer) 
183, Mallorca Street. Floor 0, office 86. 08036 Barcelona. Spain 
Phone: +34 93 227 54 00 Ext 4383 
email: bioestadistica@idibaps.org 
 
 
 
 
 
Project 
TITLE: A phase II triAl of Cabozantinib for hepaTocellular 
carcInoma patients intOlerant to sorafenib treatment or first 
line treatment different to sorafeNib. (ACTION trial) 
 
CODE:  ACTION 
EudraCT Number:2019-004991-20 
 
Protocol Version and 
Date 
Version 4.0, Date: 15-Jul-2021 
  Sponsor  
Fundació Clínic per a la Recerca Biomèdica (FCRB) 
 
Principal Investigator 
 
Dr. María Reig 
 
BCLC group. Liver Unit. ICMDM. CIBEREHD. 
IDIBAPS. Hospital Clínic 
 
Institution 
Medical Statistics Core Facility 
IDIBAPS - Hospital Clínic de Barcelona 
 
 
 
SAP Version Date 
Final, Date: 05-Nov-2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




Medical Statistics Core Facility 
IDIBAPS - Hospital Clinic Barcelona 
bioestadistica@idibaps.org 
 
 
 
ACTION Statistical Analysis Plan   
 
05-Nov-2021 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ____________________________________________________________________ 3 
2 
STUDY PERSONNEL ______________________________________________________________________ 5 
2.1 
SPONSOR ____________________________________________________________________________ 5 
2.2 
PRINCIPAL INVESTIGATOR AND MEDICAL COORDINATOR _______________________________ 5 
2.3 
STATISTICIANS _______________________________________________________________________ 5 
3 
LIST OF ABBREVIATIONS ________________________________________________________________ 6 
4 
SCOPE OF ANALYSIS PLAN _______________________________________________________________ 7 
5 
SOFTWARE METHODS ___________________________________________________________________ 7 
6 
STUDY OBJECTIVES______________________________________________________________________ 7 
6.1 
PRIMARY OBJECTIVES ________________________________________________________________ 7 
6.2 
SECONDARY OBJECTIVES _____________________________________________________________ 7 
6.3 
EXPLORATORY OBJECTIVES ___________________________________________________________ 7 
7 
TRIAL CHARACERISTICS _________________________________________________________________ 7 
7.1 
STUDY DESIGN _______________________________________________________________________ 7 
7.2 
STUDY TREATMENTS _________________________________________________________________ 8 
7.2.1 
Cabozantinib _______________________________________________________________________ 8 
7.3 
DISCONTINUATION OF THE STUDY _____________________________________________________ 8 
7.3.1 
End of study _______________________________________________________________________ 8 
7.3.2 
Discontinuation of cabozantinib ________________________________________________________ 8 
7.3.3 
Post study drug study follow-up ________________________________________________________ 9 
7.3.4 
Withdrawal of consent _______________________________________________________________ 9 
7.3.5 
Lost to follow-up ____________________________________________________________________ 9 
7.4 
JUSTIFICATION OF SAMPLE SIZE _______________________________________________________ 9 
7.5 
INTERIM ANALYSES _________________________________________________________________ 10 
7.6 
STATISTICAL INTERIM AND MULTIPLICITY ADJUSTMENT _______________________________ 10 
7.7 
FLOW CHART OF TRIAL PROCEDURES _________________________________________________ 11 
8 
STATISTICAL ANALYSIS ________________________________________________________________ 13 
8.1 
ANALYSIS POPULATIONS _____________________________________________________________ 13 
8.2 
FLOW CHART ________________________________________________________________________ 13 
8.3 
ENDPOINTS DEFINITION ______________________________________________________________ 13 
8.3.1 
Primary outcomes __________________________________________________________________ 13 
8.3.2 
Secondary outcomes ________________________________________________________________ 13 
8.4 
VARIABLES _________________________________________________________________________ 14 
8.4.1 
Demographic characteristics, screening and baseline ______________________________________ 14 
8.4.2 
Safety variables and other evolution variables ____________________________________________ 14 
8.5 
STUDY ESTIMAND, HANDLING OF MISSING DATA AND CENSORING RULES _______________ 15 
8.5.1 
Censoring rules ____________________________________________________________________ 17 
8.6 
STATISTICAL METHODS ______________________________________________________________ 18 
8.6.1 
General Descriptive Analysis _________________________________________________________ 18 
8.6.2 
Specific Descriptive Analysis _________________________________________________________ 18 
8.6.3 
Definitions and derivation of data _____________________________________________________ 18 
8.6.4 
Demographic characteristics, screening and baseline ______________________________________ 19 
8.6.5 
Safety variables and other efficacy variables _____________________________________________ 19 
8.6.5.1 
Variables related to the primary outcomes _______________________________________________________ 19 
8.6.5.2 
Variables related to the secondary outcomes _____________________________________________________ 19 
8.6.5.2.1 
Binary variables ________________________________________________________________________ 19 
8.6.5.2.2 
Time to event endpoint ___________________________________________________________________ 20 
8.6.5.3 
Other variables ____________________________________________________________________________ 20 
8.6.5.3.1 
Tumor size____________________________________________________________________________ 20 
8.6.5.3.2 
Duration of response ___________________________________________________________________ 20 


Medical Statistics Core Facility 
IDIBAPS - Hospital Clinic Barcelona 
bioestadistica@idibaps.org 
 
 
 
ACTION Statistical Analysis Plan   
 
05-Nov-2021 
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8.6.5.3.3 
EQ-5D _______________________________________________________________________________ 20 
8.6.5.3.4 
FACT-Hep ___________________________________________________________________________ 21 
8.6.5.3.5 
EORTC-QLQ-C30 _____________________________________________________________________ 21 
8.6.5.3.6 
EORTC QLQ-HCC18 __________________________________________________________________ 21 
8.6.5.3.7 
Adverse events ________________________________________________________________________ 22 
8.6.5.3.8 
Concomitant medication ________________________________________________________________ 22 
8.7 
POST-HOC STATISTICAL ANALYSIS ___________________________________________________ 22 
9 
TABLES_________________________________________________________________________________ 23 
9.1 
DEMOGRAPHIC CHARACTERISTICS, SCREENING AND BASELINE. ___________________________________ 23 
9.2 
SAFETY VARIABLES AND OTHER EFFICACY VARIABLES. _________________________________________ 23 
10 
LISTINGS _____________________________________________________________________________ 24 
11 
FIGURES______________________________________________________________________________ 25 
12 
REFERENCES _________________________________________________________________________ 26 


Medical Statistics Core Facility 
IDIBAPS - Hospital Clinic Barcelona 
bioestadistica@idibaps.org 
 
 
 
ACTION Statistical Analysis Plan   
 
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2 
STUDY PERSONNEL 
 
2.1 
SPONSOR 
 
Sponsor: 
 
 
 
 
 
Fundació Clínic per a la Recerca Biomèdica * 
 
 
 
 
 
 
* 
Fundació Clínic per a la Recerca Biomèdica (FCRB) 
C/Roselló149-153 
 
2.2 
PRINCIPAL INVESTIGATOR AND MEDICAL COORDINATOR 
 
Principal Investigator: 
 
 
 
Dr. Maria Reig, MD, PhD ** 
 
 
 
 
 
 
 
mreig1@clinic.cat 
 
 
 
 
 
 
 
Medical Coordinator: 
 
 
 
Dr. Jordi Bruix, MD, PhD ** 
 
 
 
 
 
 
 
jbruix@clinic.cat 
 
 
 
 
 
 
 
 
 
 
 
** 
BCLC group. Liver Unit. ICMDM. CIBEREHD. 
IDIBAPS - Hospital Clinic Barcelona 
Hospital Clínic de Barcelona 
 
C/Villarroel 170, Esc. 11, 4ª planta 
08036 Barcelona, Spain 
 
Phone: +34 93 227 98 03 
 
2.3 
STATISTICIANS 
 
Project Statistician  
 
 
 
Ms. Gema Domenech, MSc *** 
 
 
 
 
 
 
 
gdomene1@clinic.ub.es 
 
Responsible of Statistical Analysis  
 
Mr. José Ríos, MSc *** 
 
 
 
 
 
 
 
jose.rios@idibaps.org 
 
 
*** 
Medical Statistics Core Facility 
 
IDIBAPS - Hospital Clinic Barcelona 
C/ Mallorca 183, Floor 0, office 86 
08036 Barcelona, Spain 
Phone: +3493 227 54 00 ext (4383) 


Medical Statistics Core Facility 
IDIBAPS - Hospital Clinic Barcelona 
bioestadistica@idibaps.org 
 
 
 
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3 
LIST OF ABBREVIATIONS 
ADO 
Available Data Only 
AE 
Adverse Events 
AESI 
Adverse Event of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
BCLC 
Barcelona Clinic Liver Cancer 
CI 
Confidence Interval 
CIBEREHD 
Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FACT-HEP 
Functional Assessment of Cancer Therapy – Hepatobiliary cancer 
HCC 
Hepatocelluar Carcinoma 
ICH 
International Conference on Harmonization 
ICMDM 
Institut Clínic de Malalties Digestives i Metabòliques 
IDIBAPS 
Institut d'investigacions Biomèdiques August Pi iSunyer 
LSM 
Leas Square Means 
MAR 
Missing At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Models for Repeated Measurements 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PEP 
Primary endpoint 
PP 
Per protocol 
PPS 
Post-progression survival 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SE 
Standard Error  
SD 
Standard Deviation 
SCReN 
Spanish Clinical Research Network 
TTP 
Time to progression 
VAS 
Visual Analogical Scale 


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4 
SCOPE OF ANALYSIS PLAN 
The statistical analysis will be carried out in accordance with the principles specified in the 
International Conference on Harmonization (ICH) Topic E9 (CPMP/ICH/363/96)1. This SAP will 
follow the general regulatory recommendations given in the ICHE91 guidance, as well as other 
specific guidance on methodological and statistical issues2. Also, it will stick to the 
recommendations given by the consensus documents of the scientific journals3,4,5 to improve 
reliability and value of medical research literature by promoting transparent and accurate reporting 
of clinical research studies. 
5 
SOFTWARE METHODS 
All tables and listings will be produced using SAS System6 (Release 9.4 or an upgraded version) 
and will be presented in WinWord documents. 
6 
STUDY OBJECTIVES 
6.1 
PRIMARY OBJECTIVES 
The aim of this study will be to test the safety of cabozantinib in patients sorafenib intolerant 
according to the RESORE trial7 definition and in patients treated with first-line treatments other 
than sorafenib. Indeed, although a phase III trial (CELESTIAL)¡Error! No se encuentra el origen de la referencia. 
showed improved OS with acceptable toxicity in sorafenib intolerant patients or in those who 
progressed on sorafenib, no clear definition was applied to identify those patients.  The primary 
endpoints are the rate and type of AEs leading to treatment discontinuation, the rate and type of 
AEs, serious AEs (SAEs), rate of related-AE and rate of death. 
6.2 
SECONDARY OBJECTIVES 
Secondary endpoints are time to progression, pattern of progression, overall survival, post-
progression survival, rate of patients who develop new extra-hepatic spread and ORR. Radiologic 
tumor response will be defined according to the RECIST 1.19 and then will be evaluated by BCLC-
RECIST10. 
6.3 
EXPLORATORY OBJECTIVES 
Exploratory objectives are:  
 To evaluate the role of tissue biomarkers (see section 7.7 for timing-points) in determining 
the antitumoral activity of cabozantinib. 
 To describe the quality of life. 
 The gut microbiota composition at different time points.  
This study will collect blood and biopsy samples but the exploratory objectives will be done in a 
second study only if the study meets the safety end-point. 
7 
TRIAL CHARACERISTICS 
7.1 
STUDY DESIGN 
The study is a prospective, multicenter, open-label, non-controlled phase IIa study evaluating 
cabozantinib for the treatment of patients with unresectable hepatocellular carcinoma sorafenib 
intolerant according to the RESORCE trial definition or who received other first-line treatments 
than sorafenib. Treated patients will be followed until death, withdrawal of consent or until the end 
of the duration of the study. 


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7.2 
STUDY TREATMENTS 
In this protocol investigational products is cabozantinib. 
 
See protocol section 6.1 for more information about dose modification rules for the study treatment. 
7.2.1 Cabozantinib 
Cabozantinib will be initiated at full dose (60 mg/day) and the dose will be modified upon 
development of adverse events according to the manufacturer’s recommendations and continued 
until symptomatic tumor progression, unacceptable adverse events, patient decision or death. 
7.3 
DISCONTINUATION OF THE STUDY 
7.3.1 End of study 
After discontinuation from study therapy, there is 1 follow-up visit required within seven days of 
discontinuation (on site visit), and additional survival follow-up (on-site or phone visits). The study 
will end when survival follow-up collection has concluded. The last visit will be defined as the 
latest follow-up Visit. Additional survival follow-up may continue beyond the time of this analysis. 
7.3.2 Discontinuation of cabozantinib 
Subjects MUST discontinue study medication: 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 Any clinical AE, abnormal laboratory test results or any illness which, in the opinion of the 
investigator, indicates that continued participation in the study is not in the best interest of 
the subject. 
 Clinical deterioration (see protocol section 6.1.7 for more details)  
 Pregnancy 
 Termination of the study by the promoter 
 Specific criteria for discontinuation of outlined in (see protocol section 6.1.6 for more 
details)  
 Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. 
 Protocol defined disease progression unless subject is eligible for treatment beyond 
progression (see protocol section 6.1.7.1 for more details). 
 In the case of pregnancy, the investigator must immediately notify the Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently 
discontinued in an appropriate manner. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study drug, a discussion between the 
investigator and the Principal Investigator must occur.  
 All subjects who discontinue should comply with protocol specified follow-up procedures as 
outlined in section. The only exception to this requirement is when a subject withdraws 


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consent for all study procedures or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness). If a 
subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate CRF page. 
7.3.3 Post study drug study follow-up 
In this study, overall survival is a secondary endpoint. Subjects who discontinue study drug must 
continue to be followed for collection of survival follow-up data until death or the conclusion of the 
study. Survival follow-up visits should be planned every 3 months from Follow-Up Visit-1 and may 
be performed by phone contact or office visit. 
7.3.4 Withdrawal of consent 
Subjects who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the Investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The Investigator 
should explain the withdrawal of consent in detail in the medical records, as to whether the 
withdrawal is from further treatment with study drug only or also from study procedures and/or post 
treatment study follow-up, and entered on the appropriate CRF page. 
7.3.5 Lost to follow-up 
All reasonable efforts must be made to locate subjects to determine and report their ongoing status. 
This includes follow-up with persons authorized by the subject as noted above. Lost to follow-up is 
defined by the inability to reach the subject after a minimum of three documented phone calls, 
faxes, or emails or whatsapp messages as well as lack of response by subject to one registered mail 
letter. All attempts should be documented in the subject’s medical records. If it is determined that 
the subject has died, the site will use permissible local methods to obtain the date and cause of 
death. If after all attempts, the subject remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the subject’s medical records. 
 
  
7.4 
JUSTIFICATION OF SAMPLE SIZE 
The sample size calculation will be triggered by the primary outcome, i.e, the rate of adverse events 
(AE) with CTCAE≥3 excluding palmar-plantar erythordysthesia (critical AEs). The expected rate 
for this outcome was 56% in this population¡Error! No se encuentra el origen de la referencia.. The Simon's two-
stage optimal design11 will be used to test the alternative hypothesis that with cabozantinib the rate 
of critical AEs will be reduced at least to 32.5% against the null hypothesis of 56% as previously 
observed. In the first stage, 14 patients will be accrued. If there are 8 or more critical AES in these 
14 patients, the study will be stopped because of futility. Otherwise, 26 additional patients will be 
accrued for a total of 40. The null hypothesis will be rejected if 23 or fewer critical AEs are 
observed in 40 patients. This design yields a type I error rate of 2.5% one-sided and power of 80% 
when the true response rate is 67.5%. 
All patients exposed to the study treatment (regardless of protocol adherence) will count be safety, 
and thus no need to sample size increases as per potential withdrawals are foreseen. 


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7.5 
INTERIM ANALYSES 
We plan to conduct 1 fixed pre-scheduled interim analyses for futility as per the Simon’s design as 
described in section 7.4. The interim analysis will be conducted after follow-up data from the first 
14 patients will be available after at least 30 days from study inclusion, or otherwise presenting an 
occurrence of the primary outcomes. The DSMB will consist of 3 members (2 hepatologists and 1 
nurse) and an agreed charter by all members will come into operation before the initiation of the 
study recruitment. To note, this interim futility analysis will have no impact on the type I error at 
the end of the trial, and thus alpha adjustment is not needed. 
The interim analyses will be performed by a statistician of the Medical Statistics core facility 
independent to the trial design, conduct of the trial and final analysis.  
A previous Data Review will be performed before lock of database for the interim analysis. Data 
Review Meeting with the sponsor in order to carry out the valid population to the interim analysis 
(according with section 7.4 and 7.5 specifications). 
The interim analysis report will be included the conclusions for the observed data according to the 
stopping roles in section 7.4 and complete list of adverse events characteristics by subject. 
7.6 
STATISTICAL INTERIM AND MULTIPLICITY ADJUSTMENT 
The analysis will follow the principles specified in the ICHE91 and the CPMP/EWP/908/9912  
Points to Consider on Multiplicity issues in Clinical Trials guidelines. 
The Simon's two-stage optimal design will be conducted in order to futility evaluation for this 
reason no multiplicity adjustments are needed. All statistical tests will be applied with 0.05 two-
sided significant level. 


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7.7 
FLOW CHART OF TRIAL PROCEDURES 
Each cycle has 28 days. 
Screening1 
Cycles (+/- 72 hours) 
(Day 15 only for Cycle 
1 and 2) 
First 
radiologic 
progression 
EOT (after 
last dose +7 
days) 
Follow-up2 
 
 
Day 1 
Day 15 
 
 
 
Demographics 
x 
 
 
 
 
 
General Informed Consent 
x 
 
 
 
 
 
Inclusion/Exclusion criteria and 
Eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor and disease assessments 
Disease assessment by RECIST 
v1.1 
Every 8 weeks from Day 1 Cycle 2 
(+/- 7 days) 
X 
 
 
 
 
 
 
Fresh tumor biopsy 
(See section 7.4) 
x 
 
 
x3 
 
 
 
 
Study procedures and examinations 
Physical examination 
x 
x 
x 
x 
X 
 
ECOG performance status 
x 
x 
x 
x 
X 
 
12-lead ECG4 
x 
 
 
 
X 
 
Vital signs5 
x 
x 
x 
x 
X 
 
Assessment of AEs/SAEs 
x 
x 
x 
x 
X 
 
Concomitant medications 
x 
x 
x 
x 
x 
 
Diet and gut microbiota 
x 
 
 
 
 
 
 
 
Laboratory tests 
Serum chemistry6 
x 
x 
x 
x 
x 
 
Hematology7 
x 
x 
x 
x 
x 
 
Coagulation (PT, INR, PTT) 
x 
x 
x 
x 
x 
 
HBsAg and HBsAb, HBcAb and      
HCV Ab; 
HBeAg and HBeAb, HBV DNA 
and HDV RNA and HDV 
Ab(HBV+ subjects only); 
HCV RNA (HCV+ subjects only) 
x 
 
 
 
x 
 
 
Thyroid function tests (TSH, free 
T3, free T4) 
x 
 
 
 
 
 
 
Urinalysis 
 
x 
x 
x 
 
x 
 
Urine or serum pregnancy test 
(WOCBP) 
 
x 
 
 
 
 
 
 
 
Other procedures8 
Other laboratory blood tests and 
assays9 
 
X 
 
X 
Only in C1 
x 
 
 
Other liver tissue analysis10 
x 
 
 
x 
 
 
Patient-reported Quality of Life 
(EQ-5D, EORTC-QLQ C30, 
EORTC-HCC18 and FACT-Hep)11 
 
x 
 
x 
x 
 
Other stool tests and assays12 Day 1 
Cycle 4 and in case of OR or PD 
 
x 
 
 
x 
 
 
EOT: End of Treatment; OR: Objective Response; PD: Progressive Disease 
 
1 The time period between study entry and the commencement of protocol treatment is not to exceed 28 days. 
2 Follow-up visits could be on-site or phone visits after the last visit and will include survival data and liver cirrhosis complications evaluation every 3 
months. If the patient does not start any other treatment after end of treatment, radiologic follow-up with the same scheduled will be preferred. 
Laboratory tests will be performed at the discretion of the treating investigator until death or the end of the study. 
3 A biopsy will be performed at the time of progression whenever possible. 
4 Note: The ECG should be performed within the 7 days prior the randomization. If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be 
performed. If the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
5 Including height (only at screening visit) weight, body temperature, respiratory rate, seated blood pressure, heart rate and oxygen saturation (at rest 
and after mild exercise) 


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6AST, ALT, GGT, Alkaline Phosphatase alkaline phosphatase, Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Albumin, Creatinine, Alpha alpha 
fetoprotein, Calcium, Sodium, Potassium, Glucose, Uric Acid, triglycerides, Total Protein, Lipase, Amylase, Magnesium, Phosphate, lactic 
dehydrogenase LDH, Chloride, Glomerular filtration rate. 
7Complete blood count with differential 
8 All the samples included in this section, will be centrally analyzed in a second-study  
9Other laboratory blood tests will include peripheral Blood Mononuclear Cells (PBMCs) immunophenotyping, serum biomarker analysis, 
polymorphism detection associated with treatment response/resistance, circulating-free DNA analysis, circulating mRNA/miRNA.  In case of any 
cabozantinib dose reduction a blood sample for PBMCs and serum biomarker analysis is recommended but no mandatory. Serum biomarker will be 
analyzed at each cabozantinib dose reduction. For details see the laboratory manual. 
10Other liver tissue analysis will include tumor and non-tumor infiltrated immune cell population characterization (fresh tissue from biopsy analyzed 
in situ in each recruiting center) and tumor and non-tumor cell transcriptome analysis (samples can be frozen and stored until analysis). Note that 
these samples will be obtained accordingly to the time point of “fresh tumor biopsy” but all the analysis will be performed in a second-study.  
11 Patient-reported Quality of Life (EQ-5D, EORTC-QLQ C30, EORTC-HCC18 and FACT-Hep) will be administered at Day 1 of Cycle 1 and Cycle 
3, then at Day 1 every 3 cycle and at end of treatment s. 
12Other stool tests and assays will include gut microbiota composition and/or metabolomic analysis. 
 


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8 
STATISTICAL ANALYSIS 
8.1 
ANALYSIS POPULATIONS 
There are only one population for this study: 
 Safety Set: All eligible patients who have received at least one dose of Cabozantinib will be 
included in the Safety population. 
The population will be fully defined and documented during the Data Review and before the 
database lock. The objective will be to carry out the population selection and definition of the final 
study population. 
The Safety population will be used for all analysis including the efficacy secondary endpoints.  
8.2 
FLOW CHART 
A flow diagram will be performed according to ICHE3 and the consort statement in order to 
summarize the number of patients at study losses by time at each stage. Patients screened, eligible, 
consented, randomized, receiving their allocated treatment, withdrawing/lost to follow up, and 
included in the population set defined in the section 8.1. 
8.3 
ENDPOINTS DEFINITION 
8.3.1 Primary outcomes 
The primary outcomes are related to safety assessment as follow: 
 Rate of adverse events (AE) with Common Terminology Criteria for Adverse Events 
(CTCAE)≥3 excluding palmar-plantar erythordysthesia, rate of AEs, rate of related-AEs and 
rate of death. Rate of AEs leading to treatment discontinuation. 
 Adverse events will be graded following version 5.0 of the CTCAE of the National Cancer 
Institute, during treatment and 30 days after the last dose. 
8.3.2 Secondary outcomes 
ORR will be the first relevant ranked secondary outcome: 
o 
Defined as a partial or complete response at any time, i.e. the best response from 
inclusion along all follow-up. 
The rest of secondary end points are: 
1. Time to progression (TTP): time to the first progression, defined as the time from the 
inclusion date to progression (i.e. date of progression event or censoring – date of inclusion 
+ 1).  
2. Pattern of progression: 
o Intrahepatic growth (IHG): increased size of intrahepatic target lesions or progression of 
intrahepatic "non-target" lesions at baseline. 
o New intrahepatic lesion (NIH): emergence of new intrahepatic lesions 
o Extrahepatic growth (EHG): increased size of extrahepatic target lesions, progression of 
extrahepatic "non-target" lesions at baseline or progression of the existing vascular 
invasion. 
3. Rate of patients who develop new extra-hepatic spread 


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4. Overall survival (OS): defined as the time from the inclusion date to death from any cause 
(i.e. date of death event or censoring – date of inclusion + 1).  
5. Post-progression survival (PPS), for those patients who progressed, the time from the 
progression date to death from any cause (i.e. date of death event or censoring – date of 1st 
progression  + 1).  
Please see description of the censoring rules for time to event variables in section 8.5.1. 
 
8.4 
VARIABLES 
8.4.1 Demographic characteristics, screening and baseline 
The following pre-treatment characteristics (only recruited pre-treatment) will be analysed: 
 Informed consent 
 Demographic data and vital signs 
 Clinical characteristics at HCC diagnosis 
 Clinical characteristics at study entry 
 Comorbidities 
 First line treatment 
 Selection criteria 
8.4.2 Safety variables and other evolution variables 
The safety variables and other evolution variables (recruited at different times) will be the follow:  
 Adverse Events evaluations for the primary outcomes: 
o Rate of AEs 
o Rate of SAEs 
o Rate of AEs (CTCAE)≥3 excluding palmar-plantar erythordysthesia 
o Rate of related-AEs 
o Rate of AEs leading to treatment discontinuation 
o Rate of death 
 Variables related to the secondary outcomes: 
o 
Objective Response Rate (ORR)  
o 
Rate of patients who develop new extrahepatic spread 
o 
Overall survival (OS) 
o 
Time to progression (TTP) 
o 
Pattern of progression.  
 Intrahepatic growth (IHG). 
 New intrahepatic lesion (NIH) 
 Extrahepatic growth (EHG) 
 New extrahepatic lesion (NEH): emergence of new extrahepatic lesions 
or emergence of vascular invasion  
o Post-progression survival (PPS) 
 BCLC staging system and CHILD-PUGH scale 
 Tumor disease assessment 
 Central test and stool test 
 Tumor biopsy 
 Physical examination 
 General examinations: vital signs, ECOG and oxygen saturation 


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 Laboratory test: 
o 
Urinalysis 
o 
Hematology 
o 
Biochemistry and electrolyte 
o 
Thyroid function 
o 
Specific laboratory test 
 EQ-5D 
 FACT-Hep 
 EORTC-QLQ-C30 
 EORTC QLQ-HCC18 
 Exitus information 
 Survival status by follow-up 
 Cabozantinib treatment information 
 Visit control (conducted yes/no) 
 Screen failure information 
 End of treatment  
 End of study  
 Concomitant medication 
 The rest of Adverse Events evaluations 
 Protocol deviations 
 
8.5 
STUDY ESTIMAND, HANDLING OF MISSING DATA AND CENSORING 
RULES 
The handling of missing data will follow the principles specified in the ICH-E9 and the 
CPMP/EWP/1776/99 Rev113. Guideline on Missing Data in confirmatory trials Guidelines.  As 
per the ICH E9(R1) (Addendum on estimands and sensitivity analysis in clinical trials 
EMA/CHMP/ICH/436221/2017)14, the plan for the assessment of the Primary endpoint (PEP) 
(in this study includes the main secondary outcome) is described here after using the 4 attributes 
of the estimand: 
1. Population: as described in protocol and section 8.1 of this SAP, all analyses will be carried 
out using Safety population.  
2. Endpoints: (please see details on the endpoints definitions in section 8.3) 
a. Non confirmatory primary endpoints (PEPs): the rate and type of: 
 Any AEs 
 Related-AEs 
 Rate of death 
 AEs leading to treatment discontinuation  
 Serious AEs (SAEs) 
 Rate of AEs (CTCAE)≥3 excluding palmar-plantar erythordysthesia 
b. Secondary endpoints (SEP):  
 ORR (main secondary outcome) 
 Overall survival (OS) 
 Time to progression (TTP) 


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 Pattern of progression 
 Post-progression survival (PPS) 
 Rate of patients who develop new extra-hepatic spread 
3. Intercurrent events (ICEs): the relevant intercurrent events expected to occur in this study 
includes the following situations and the method for handling will be the same for all of 
them due to the safety characteristics of the primary objective. The “Treatment Policy” 
strategy will be used, i.e., all observed data will be used regardless of the intercurrent event. 
a. No treatment initiation: exclusion from the analysis.  
b. Main estimand: any other situation regardless of the ICE (use of rescue medication, 
prohibited concomitant medication, treatment discontinuation, or any reason leading 
to study discontinuation): “Treatment Policy” strategy (i.e. all observed data will be 
considered regardless of any previous ICE). 
c. Supplementary estimand: for some relevant efficacy secondary endpoints, data after 
ICEs will be censored (see table below) and will be based on the while on treatment 
strategy. 
4. Population-level summary:  
a. Estimation of rates and 95%CI for the PEPs by means of Clopper-Pearson exact 
method will be used as the population-level summary (see sections 8.6.5.1 and  
8.6.5.2.1). 
b. Time to event variables will be described using the Kaplan-Meier method (see 
section 8.6.5.2.2). 
 
 
 
Primary 
Estimand 
Supplementary 
Estimand 
Primary endpoints 
 
 
Any AEs 
Related-AEs 
Rate of death 
AEs leading to treatment 
discontinuation  
Serious AEs (SAEs) 
Rate of AEs (CTCAE)≥3 
excluding palmar-plantar 
erythordysthesia 
Treatment policy 
None 
Secondary endpoints 
 
 
ORR (main secondary 
outcome) 
Treatment policy 
While on treatment* 
 
Overall survival (OS) 
Time to progression (TTP) 
Pattern of progression 
Treatment policy 
 
None 
Rate of patients who 
develop new extra-hepatic 
spread 
Post-progression survival 
(PPS) 
*(censored after treatment ICEs) 


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The ORR rate will be handled using the Treatment Policy strategy. In the unexpected case of 
missing due to no radiologic assessment was conducted, the composite strategy will be applied by 
imputing to ORR to failure. 
 
No formal imputations will be performed for any other variable. For the categorical variables the 
analyses will be based on the Available Data Only (ADO) approach. With regards to the continuous 
variables, mixed models15,16,17are robust to the presence of missing at random (MAR) and conducts 
the analysis with all participants despite the presence of missingness. Of note, this method 
calculates the estimations based on the variance-covariance structure but without any formal 
imputations. 
No formal imputation will be used for dates due to all post-inclusion dates are complete date. 
8.5.1 Censoring rules 
TTP:  
 Death without progression will be censored at the time of the last adequate radiological 
tumor assessment. 
 Progression documented between scheduled assessments: Event at date of adequate 
radiological tumor assessment 
 If a patient has not progressed at the time of database cutoff, the TTP of this patient will be 
censored at the last adequate tumor assessment before the database cutoff.  
 Documented progression or death after missing ≥2 consecutive post­baseline tumor 
assessments: date of last adequate tumor assessment before missed assessments or date of 
inclusion, whichever is later. 
 Patient lost to follow-up (or withdrew consent from study participation) before documented 
progression: date of last adequate tumor assessment. 
 Please see comment below on the “treatment policy” and “while on treatment” estimands 
Overall survival (OS):  
 If a patient is alive at the time of last contact before the database cutoff, the OS of this 
patient will be censored at the date of last contact.  
 Patient lost to follow-up (or withdrew consent from study participation) before death: date of 
last documented alive information 
 Please see comment below on the “treatment policy” and “while on treatment” estimands 
Post-progression survival (PPS) 
 Same rules as OS 
Handling of “treatment policy” and “while on treatment” estimands: If a patient discontinues study 
treatment or any other ICE is recorded before any event is documented, data from this patient will 
not be censored for the primary estimand (treatment policy). However, data will be censored for the 
supplementary estimand (while on treatment) at the last tumor assessment before the 
discontinuation of study treatment. 


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8.6 
STATISTICAL METHODS 
Non-inferential analysis will be performed due to the safety nature of the study. The following 
sections refer to descriptive statistics for the different variables of section 8.4. 
All analyses will be performed using Safety set. 
8.6.1 General Descriptive Analysis 
The results will be presented of standard methods18: 
 Continuous variables: Mean, 95%CI of Mean (95% mean confidence interval), SD (standard 
deviation), minimum, P25 (percentile 25), Median, P75 (percentile 75), maximum and N.  
 Categorical variables: total frequency and percentages and for each category.  
 Ordinal variables with few categories (less than 10) will be described using two tables: one 
including continuous variables descriptive parameters (as long as the interpretation is 
reasonable) and the other including categorical variables descriptive parameters. For ordinal 
variables with >10 categories, the same approximation used for continuous variables will be 
applied. 
Where applicable, these summaries will be provided by time-point (scheduled time-point) including 
the absolute differences from baseline. The data of unscheduled time-points will be only listed. 
Additionally, only for the size of tumor the relative difference from baseline will be also described. 
8.6.2 Specific Descriptive Analysis 
 
For the binary variables related to the primary and secondary outcomes, the estimation of rates and 
95% CI will be performed by means of Clopper-Pearson exact method. 
 
The Kaplan-Meier method will be used to describe the time to event endpoints, the median and their 
95% CI. Analysis will follow censoring rules as described in section 8.5.1. 
 
The continuous efficacy variable recruited by time-point will be analysed as a descriptively by 
means of the MMRM approach, fitting time-point as a fixed effect, and the subject and error terms 
as random. The dependent variable will be the absolute values (or absolute change from baseline 
when applicable). The within-patient variance-covariance matrix will be assumed to be 
unstructured. If this analysis fails to converge, the following structures will be tested in the 
following order until convergence: AR(1) (Auto-Regressive first order), Toeplitz and CS 
(Compound Symmetry). Time-point effects have been estimated by means of Least Square Means 
(LSM) and their standard error (SE) and 95% CI. Time-course evolutions have been estimated by 
LSM and their SE and 95%CI. The same analysis with a previous rank transformation applies to 
ordinal variables. 
8.6.3 Definitions and derivation of data 
 
The following definitions and derivations will be used for this study: 
 
 The analyses will be performed by visits and the baseline values for the calculation of the 
differences (absolute or relative) with respect to the baseline using the following strategy: 
o Baseline values will be defined as the last measurement taken before the first 
administration. 


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o The value of the baseline visit in case of measurement existing in that visit. 
o The value of the screening visit if there is no measurement in the baseline visit. 
 Start of the treatment period will be defined as the date of inclusion 
 Absolute differences from baseline for each visit: 
o Absolute differences = observed value - baseline value 
 Relative differences from baseline (only for the size or tumour): 
o Relative difference = [observed value-baseline value] / baseline value 
8.6.4 Demographic characteristics, screening and baseline 
Descriptive statistics and listings for each variable per visit (Screening Visit or Baseline Visit) will 
be performed.  
This analysis will be performed using Safety set on ADO approach. 
Results are presented by means of individual tables and listings for each of the variables described 
in section 8.6.1. 
The comorbidities will be tabulated and listed by type of comorbidity. The number of patients with 
at least one comorbidity globally and by type of comorbidity will be described. The following type 
of comorbidities will be considered: myocardial infarction, deep venous thrombosis, pulmonary 
embolism, transient ischemic attack, ischemic stroke, cerebral hemorrhage, lower GI bleeding, 
diabetes mellitus type I, diabetes mellitus type II, hypertension, heart failure, phlebitis, 
gastrointestinal ulcer, angina pectoris, esophageal varices, upper GI bleeding and others (the 
description of others will be only listed). 
8.6.5 Safety variables and other efficacy variables 
8.6.5.1 Variables related to the primary outcomes 
The binary variables related to primary outcomes (rate of AEs (CTCAE)≥3 excluding palmar-
plantar erythordysthesia, rate of AEs, rate if related AEs, rate of SAEs, and rate of  AEs leading to 
treatment discontinuation) will be described by means of rate and 95% CI calculated using the 
Clopper-Pearson exact method. 
These analyses will be performed Safety set on ADO approach. 
8.6.5.2 Variables related to the secondary outcomes 
The analyses performed for the variables related to the secondary endpoints are described in the 
following sections. 
8.6.5.2.1 
Binary variables 
The binary variables related to the secondary outcomes (see section 8.4.2 for more details) will be 
described by means of rate and 95% CI calculated using the Clopper-Pearson exact method. 
These binary variables are the following: 
 ORR defined as the best response. 
 Rate of patients who develop new extrahepatic spread. 
 Progression rate in general and by Pattern of progression (see section 8.3.2 for more details). 
These analyses will be performed using Safety set on ADO approach. For the ORR (as a best 
response) the missing data will be imputed as a failure. 
The timing of response will be plotted using a Swimmer plot. 


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8.6.5.2.2 
Time to event endpoint 
The Kaplan-Meier method will be used to describe the survival functions the median and their 95% 
CI for time to event variables. These analyses will follow censoring rules as described in section 
8.5.1.  
These variables are the follow: 
 Overall survival 
 Time to the first progression 
 Post-progression survival (in general and split by pattern progression) 
These analyses will be performed using Safety set on ADO approach. 
8.6.5.3 Other variables 
A descriptive analysis will be performed for all variables of section 8.4.2 with the appropriate 
descriptive statistics (see section 8.6.1). 
The continuous variables (laboratory parameters, vital signs and other continuous variables included 
in section 8.4.2) recruited by time (absolute values and absolute differences when applicable) will 
be analyzed by means of MMRM model specified in section 8.6.2. The same model with previous 
rank transformation will be applied to ordinal variables. 
These analyses will be performed using Safety set on ADO approach. 
The following sections describe the specific statistical analysis. 
8.6.5.3.1 
Tumor size 
The tumor size of target lesions (absolute values, absolute difference and relative differences) will 
be described by time-point. 
Also the absolute values and absolute differences will be analysed by means of MMRM model 
specified in section 8.6.2. 
The relative change in tumor size will be plotted by means of Spider plot and the best change in the 
tumor size using a waterfall plot. 
8.6.5.3.2 
Duration of response 
Additionally, the duration of response will be described with the appropriate descriptive statistics 
(see section 8.6.1).  
The timing of response will be plotted using a Swimmer plot. 
8.6.5.3.3 
EQ-5D 
The items of EuroQoL-5D questionnaire (mobility, self care, usual activities, pain discomfort and 
anxiety depression) will be analysed according to the EQ-5D-3L user guide19. All item responses 
will be transformed in responses of three levels and two levels, as follows: 
 Three levels: no problems, some problems and extreme problems 
 Two levels: no problems and problems. 
Descriptive statistical analyses by time-point will be performed for three levels response and for 
two levels response (as a continuous and as a categorical variable). Also, analyses by means of 
MMRM model with a previous rank transformation will be applied using three and two levels. 
VAS EQ-5D will be analysed by the same MMRM. 


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8.6.5.3.4 
FACT-Hep 
Questionnaire FACT-Hep (version 4)20 on clinical status included 45 items, 27 of which will be 
used for the determination of the following scale scores: 
 Subscales: 
o Physical Well-Being subscale, PWB 
o Social/Family Well-Being subscale, SWB 
o Emotional Well-Being subscale, EWB 
o Functional Well-Being subscale, FWB 
o Hepatobilliary Cancer subscale, HCS 
 FACT-G Total Score, FACTG 
 FACT-Hep Trial Outcome Index (TOI) 
 FACT-Hep total score 
 
The individual items will be described as a continuous and as a categorical variable (see section 
8.6.1) by time-point.  
The subscales and the different total scores will be also described as a continuous variable and the 
MMRM will be applied. 
8.6.5.3.5 
EORTC-QLQ-C30 
Questionnaire EORTC-QLQ-C30 (version 3)21 included 30 items and all of them will be used for 
the determination of the following scale scores: 
 Global health status/QoL, QL2 
 Functional scales: 
o Physical functioning, PF2 
o Role functioning, RF2 
o Emotional Functioning, EF 
o Cognitive functioning, CF 
o Social functioning, SF 
 Symptom scales 
o Fatigue, FA 
o Nausea and vomiting, NV 
o Pain, PA 
o Dyspnoea, DY 
o Insomnia, SL 
o Appetite loss, AP 
o Constipation, CO 
o Diarrhoea, DI 
o Financial difficulties, FI 
The individual items will be described as a continuous and as a categorical variable (see section 
8.6.1) by time-point.  
The scales scores will be also described as a continuous variable and the MMRM will be applied. 
8.6.5.3.6 
EORTC QLQ-HCC18 
Questionnaire EORTC-QLQ-HCC1822 is a supplementary questionnaire module to be employed in 
conjunction of QLQ-C30 (is a Hepatocellular Carcinoma Module), included 18 items and all of 
them will be used for the determination of the following scale scores: 
 Symptom scales 


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o Fatigue, FATI 
o Body image BI 
o Jaundice, JAUN 
o Nutrition, NUTR 
o Pain, PA 
o Fever, FEV 
 Single items 
o Abdominal swelling, AB 
o Sex life, SX 
The individual items will be described as a continuous and as a categorical variable (see section 
8.6.1) by time-point.  
The scale scores will be also described as a continuous variable and the MMRM will be applied. 
8.6.5.3.7 
Adverse events 
A summary of treatment-emergent adverse events (AEs), including the number of events reported, 
the number and percentage of patients reporting at least one event of each of the following: 
 Any AE 
 Any severe AE (grade greater or equal to 3 in the NCI CTCAE v5.0) 
 Any  AEs (CTCAE)≥3 excluding palmar-plantar erythordysthesia 
 Any treatment-related AE (with cabozantinib) 
 Any severe treatment-related AE  
 Any AE with outcome of death 
 Any serious AE 
 Any treatment-related serious AE 
 Any AE leading to discontinuation of the treatment permanently (cabozantinib)  
 Any treatment-related AE leading to discontinuation of the treatment permanently 
(regorafenib, nivolumab or both) 
The number and percentage of patients who experience one or more treatment-emergent AEs as 
well as the number of AE episodes will be tabulated by body system, preferred term (according to 
MedDRA v21.1), seriousness, intensity, action taken, outcome, relationship to the study drug and 
NCI CTCAE v5.0. 
8.6.5.3.8 
Concomitant medication 
The concomitant medication after randomization will be described by time-point and study product. 
Concomitant medication and its characteristics will be listed. The number of patients with at least 
concomitant medication globally and by ATC code (according to ATC classification index with the 
last version of WHO-DD at the end of last patient follow-up) will be described. 
 
8.7 
POST-HOC STATISTICAL ANALYSIS 
No subgroup analyses are planned in the protocol. 
Due to clinical relevance in this study of the first-line treatment a subgroup analysis is required by sponsor 
for the following groups: 
 
Sorafenib as first-line treatment 
 
Other than sorafenib as first-line treatment 


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The analyses related to the non confirmatory primary endpoints (PEPs) and secondary endpoints will be also 
performed by subgroup. 
 
9 
TABLES 
For the table of safety variable and other efficacy variables (where applicable according to section 8.7) the 
results will be present fall all subjects and by subgroup classification (within the same table).  
9.1 
Demographic characteristics, screening and baseline. 
Table 1. 
Study population.  
Table 2. 
Informed consent.  
Table 3. 
Demographic data and vital signs. 
Table 4. 
Clinical characteristics at HCC diagnosis.  
Table 5. 
Clinical characteristics at study entry.  
Table 6. 
Comorbidities. Number (%) of subjects reporting one or more Comorbidity (globally 
and by type of comorbidity).  
Table 7. 
First line treatment.  
Table 8. 
Selection criteria.  
9.2 
Safety variables and other efficacy variables. 
Table 9. 
Primary outcomes. Rate of AEs, SAEs, related-AEs, AEs leading to 
discontinuation, deaths  and 
AEs (CTCAE)≥3 excluding palmar-plantar 
erythordysthesia.  
Table 10. Secondary outcomes. ORR and time to ORR.  
Table 11. Secondary outcomes. Overall survival.  
Table 12. Secondary outcomes. Time to progression (TTP) 
Table 13.  Secondary outcomes. Pattern of progression.  
Table 14. Secondary outcomes. Post-progression survival.  
Table 15. Secondary outcomes. Rate of patient who develop new extrahepatic spread.  
Table 16. Duration of response. 
Table 17. BCLC staging system and CHILD-PUGH scale. 
Table 18. Tumor disease assessment (including tumor size). 
Table 19. Central test and stool test. Samples Yes/No. 
Table 20. Tumor biopsy. 
Table 21. Physical examination. 
Table 22. General examinations: vital signs, ECOG and oxygen saturation. 
Table 23. Laboratory test. Urinalysis.  
Table 24. Laboratory test. Hematology.  
Table 25. Laboratory test. Biochemistry and alectrolyte.  
Table 26. Laboratory test. Thyroid functions.  
Table 27. Laboratory test. Specific laboratory test.  
Table 28. EQ-5D. Individual items.  
Table 29. EQ-5D. Three level items.  
Table 30. EQ-5D. Two level items.  
Table 31. EQ-5D. EQ VAS.  
Table 32. FACT-Hep. Directly items. 
Table 33. FACT-Hep. Subscales. 
Table 34. FACT-Hep. Total scores. 
Table 35. EORTC-QLQ-C30. Directly items. 


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Table 36. EORTC-QLQ-C30. Subscales. 
Table 37. EORTC QLQ-HCC18. Directly items. 
Table 38. EORTC QLQ-HCC18. Subscales. 
Table 39. Exitus. 
Table 40. Survival status variables. 
Table 41. Cabozantinib treatment information. 
Table 42. Visit control. Last visit by patient. 
Table 43. Screen failure information. 
Table 44. End of treatment. 
Table 45. End of study. 
Table 46. Concomitant medication. Number (%) of subjects reporting one or more concomitant 
medication (globally and by type ATC code). 
Table 47. Adverse events. Summary of number (%) of subjects reporting one or more AE, 
severe AE, AE (CTCAE)≥3 excluding palmar-plantar erythordysthesia, treatment-
related AE, severe treatment-related AE, AE with death, serious AE, treatment-
related serious AE, AE leading to disc., treatment-related AE leading to disc.  
Table 48. Adverse events. Number (%) of subjects reporting one or more treatment-          
emergent adverse events (in general and by System Organ Class).  
Table 49. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by body system and preferred term.  
Table 50. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by seriousness.   
Table 51. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by severity.   
Table 52. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by action taken.  
Table 53. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by causality.  
Table 54. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by outcome.  
Table 55. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by severity, seriousness and causality.  
Table 56. Adverse events. Number (%) of subjects reporting one or more treatment-emergent 
adverse events and number of AE occurrences by NCI CTCAE v5.0. 
Table 57. Protocol deviations. Number (%) of subjects reporting one or more protocol 
deviation. 
 
10 LISTINGS 
Listing 1. Study population. 
Listing 2. Informed consent. 
Listing 3. Demographic data and vital signs. 
Listing 4. Clinical characteristics at HCC diagnosis.  
Listing 5. Clinical characteristics at study entry.  
Listing 6. Comorbidities. 
Listing 7. First line treatment. 
Listing 8. Selection criteria.  


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Listing 9. Primary outcomes. Rate of AEs, AE (CTCAE)≥3 excluding palmar-plantar 
erythordysthesia, SAEs, related-AEs, AEs leading to discontinuation, deaths. 
Listing 10. Secondary outcomes. ORR, time to ORR, time to progression, pattern of 
progression, Overall and post-progression survival and rate of patients who develop 
new extrahepatic spread. BCLC staging system and CHILD-PUGH scale. 
Listing 11. Duration of response 
Listing 12. Tumor disease assessment (including tumor size). 
Listing 13. Central test and stool test.  
Listing 14. Tumor biopsy. 
Listing 15. Physical examination. 
Listing 16. General examinations: vital signs, ECOG and oxygen saturation. 
Listing 17. Laboratory test. Urinalysis.  
Listing 18. Laboratory test. Hematology.  
Listing 19. Laboratory test. Biochemistry and electrolyte.  
Listing 20. Laboratory test. Thyroid functions.  
Listing 21. Laboratory test. Specific laboratory test.  
Listing 22. EQ-5D.  
Listing 23. FACT-Hep.  
Listing 24. EORTC QLQ-C30 
Listing 25. EORTQ QLQ-HCC18 
Listing 26. Exitus. 
Listing 27. Survival status variables. 
Listing 28. Cabozantinib treatment information.  
Listing 29. Visit control.  
Listing 30. Screen failure information. 
Listing 31. End of treatment. 
Listing 32. End of study. 
Listing 33. Subsequent treatments 
Listing 34. Concomitant medication.  
Listing 35. Adverse events. 
Listing 36. Protocol deviations. 
11 FIGURES 
 
Figure 1. 
Overall survival. Survival plot. 
Figure 2. 
Time to progression. Survival plot. 
Figure 3. 
Post-progression survival. Survival plot. 
Figure 4. 
Post-progression survival by pattern of progression. Survival plot. 
Figure 5. 
Relative change in tumor size. Spider plot. 
Figure 6. 
Best change in tumor size. Waterfall plot. 
Figure 7. 
Time to response. Swimmer plot. 
Figure 8. 
Duration of response. Survival plot. 


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