A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination With Atezolizumab Versus Sorafenib in Subjects With Advanced Hepatocellular Carcinoma Who Have Not Received Previous Systemic Anticancer Therapy
Phase: PHASE3
Conditions: Hepatocellular Carcinoma
Sponsor: Exelixis

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XL184-312 Protocol Amendment 5.0
Page 1 of 229
CLINICAL STUDY PROTOCOL
A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) 
in Combination with Atezolizumab versus Sorafenib in Subjects 
with Advanced Hepatocellular Carcinoma Who Have Not Received 
Previous Systemic Anticancer Therapy
PROTOCOL NUMBER:
XL184–312
STUDY TREATMENT:
Cabozantinib in Combination with Atezolizumab vs 
Sorafenib
IND NUMBER:
140,189
EudraCT NUMBER: 
2018-003354-24 
SPONSOR:
Exelixis, Inc.
1851 Harbor Bay Parkway 
Alameda, CA 94502 
MEDICAL MONITOR:
DATE FINAL (Version 0.0):
31 August 2018
DATE AMENDED:
12 April 2019
PROTOCOL AMENDMENT 1.0
09 April 2020
PROTOCOL AMENDMENT 2.0
14 May 2021
PROTOCOL AMENDMENT 3.0
28 March 2022
PROTOCOL AMENDMENT 4.0
24 January 2023
PROTOCOL AMENDMENT 5.0
1&71&7
PPD

XL184-312 Protocol Amendment 5.0
Page 2 of 229
PROTOCOL APPROVAL PAGE
PROTOCOL TITLE: 
A Randomized, Controlled Phase 3 Study of Cabozantinib 
(XL184) in Combination with Atezolizumab versus 
Sorafenib in Subjects with Advanced Hepatocellular 
Carcinoma Who Have Not Received Previous Systemic 
Anticancer Therapy
PROTOCOL NUMBER:
XL184-312 
STUDY TREATMENT:
Cabozantinib in Combination with Atezolizumab versus 
Sorafenib  
IND NUMBER:
140,189 
EudraCT NUMBER: 
2018-003354-24 
SPONSOR:
Exelixis, Inc. 
1851 Harbor Bay Parkway 
Alameda, CA 94502 
MEDICAL MONITOR:
DATE FINAL (Version 0.0):
31 August 2018
DATE AMENDED:
12 April 2019
PROTOCOL AMENDMENT 1.0
09 April 2020
PROTOCOL AMENDMENT 2.0
14 May 2021
PROTOCOL AMENDMENT 3.0
28 March 2022
PROTOCOL AMENDMENT 4.0
24 January 2023
PROTOCOL AMENDMENT 5.0
Approval of protocol by Sponsor: 
PPD
PPD
PPD

XL184-312 Protocol Amendment 5.0
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INVESTIGATOR SIGNATURE PAGE
PROTOCOL TITLE: 
A Randomized, Controlled Phase 3 Study of Cabozantinib 
(XL184) in Combination with Atezolizumab versus 
Sorafenib in Subjects with Advanced Hepatocellular 
Carcinoma Who Have Not Received Previous Systemic 
Anticancer Therapy
PROTOCOL NUMBER:
XL184-312 
STUDY TREATMENT:
Cabozantinib in Combination with Atezolizumab versus 
Sorafenib
IND NUMBER:
140,189 
EudraCT NUMBER: 
2018-003354-24 
SPONSOR:
Exelixis, Inc. 
1851 Harbor Bay Parkway 
Alameda, CA 94502 
MEDICAL MONITOR:
DATE FINAL (Version 0.0):
31 August 2018
DATE AMENDED:
12 April 2019
PROTOCOL AMENDMENT 1.0
09 April 2020
PROTOCOL AMENDMENT 2.0
14 May 2021
PROTOCOL AMENDMENT 3.0
28 March 2022
PROTOCOL AMENDMENT 4.0
24 January 2023
PROTOCOL AMENDMENT 5.0
By my signature below, I hereby state that I have read, and agree to abide by, the instructions, 
conditions, and restrictions of the protocol or protocol amendment referenced above. 
________________________________________________________________ 
Name of Investigator (print) 
________________________________________________________________ 
Name of Investigator (signature) 
 
 
 
 
 
Date
PPD

 
XL184-312 Protocol Amendment 5.0 
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PROTOCOL SYNOPSIS  
TITLE 
A Randomized, Controlled Phase 3 Study of Cabozantinib (XL184) in Combination with 
Atezolizumab versus Sorafenib in Subjects with Advanced Hepatocellular Carcinoma Who Have 
Not Received Previous Systemic Anticancer Therapy 
PROTOCOL NUMBER 
XL184-312 
CLINICAL PHASE 
Phase 3 
RATIONALE 
Liver cancer is the second most frequent cause of cancer deaths worldwide (Ferlay et al 2015). 
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting 
for approximately 90% of cases. In 2015, 854,000 new liver cancer cases were reported 
worldwide and 810,000 deaths occurred (Global Burden of Disease Liver Cancer 2017; EASL 
2018). The estimated incidence and mortality rates of liver cancer in the USA in 2016 were 
approximately 42,000 and 30,000 cases, respectively (American Cancer Society 2018); incidence 
and mortality in the EU in 2012 were 52,000 and 48,000 cases, respectively (Ferlay et al 2013).  
Surgical resection and transplantation are potential curative treatment modalities for HCC. 
Ablative therapies (eg, radiofrequency ablation [RFA], microwave ablation [MWA], and 
percutaneous ethanol injection [PEI]) are being used for early stage unresectable HCC. 
Transarterial chemoembolization (TACE) is used generally for intermediate stage disease. The 
current standard of care for first line treatment of advanced unresectable HCC is sorafenib, which 
is a small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR) and other 
protein kinases. In a randomized placebo-controlled Phase 3 study (SHARP), sorafenib improved 
the primary endpoint of overall survival (OS) in subjects with advanced HCC (Child-Pugh A) 
who had not received prior systemic therapy (Llovet et al 2008). Median OS was 10.7 months in 
the sorafenib arm and 7.9 months in the placebo arm (hazard ratio [HR] 0.69; 95% confidence 
interval [CI] 0.55, 0.87; p-value < 0.001). A similar HR was observed (with a shorter duration of 
OS than in the SHARP trial) in a corresponding placebo-controlled Phase 3 trial conducted in an 
Asian-Pacific population in which infection with hepatitis B virus (HBV) was the main cause of 
HCC: median OS was 6.5 months vs 4.2 months (HR 0.68; 95% CI: 0.50, 0.93; p-value = 0.014) 
(Cheng et al 2009). Recently, the VEGFR-targeting tyrosine kinase inhibitor (TKI) lenvatinib was 
shown to be non-inferior to sorafenib in a Phase 3 study enrolling subjects with advanced HCC 
who had not received prior systemic therapy (Kudo et al 2018) leading to US and EU approval in 
this population. In that study, median OS for lenvatinib was 13.6 months compared with 12.3 
months for sorafenib (HR 0.92; 95% CI 0.79, 1.06).  
Cabozantinib is an orally bioavailable small molecule TKI that potently inhibits VEGFR, MET, 
AXL, and RET, as well as a number of other receptor tyrosine kinases (RTKs) that have also 
been implicated in tumor pathobiology, including KIT and FLT3. Cabozantinib suppresses MET 

 
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and VEGFR2 signaling, rapidly inducing apoptosis of endothelial and tumor cells, resulting in 
tumor regression in a variety of xenograft models. Cabozantinib capsules (140 mg) are approved 
in the United States for the treatment of patients with progressive, metastatic medullary thyroid 
cancer (MTC) and in the European Union for the treatment of patients with progressive, 
unresectable locally advanced or metastatic MTC (Cometriq™ US prescribing information [US 
PI] and European Medicines Agency Summary of Product Characteristics [EMA SmPC]). 
Cabozantinib tablets (60 mg) are approved in the United States, Europe, and other regions for 
advanced renal cell carcinoma (RCC; different patient populations depending on region; 
Cabometyx™ US PI and EMA SmPC). Based on the results from the studies below, cabozantinib 
tablets (60 mg) as a single agent have also been approved in the US and EU for the treatment of 
HCC in patients who have previously been treated with sorafenib (Cabometyx US PI and EMA 
SmPC). 
The clinical activity and safety of single agent cabozantinib (60 mg, tablets) in HCC has been 
demonstrated in a randomized placebo-controlled Phase 3 study (CELESTIAL) in subjects who 
had received prior therapy with sorafenib (subjects were required to have progressed during or 
following prior systemic therapy and up to 2 prior lines of systemic therapy were allowed; Abou-
Alfa et al 2018). The primary endpoint of the study was OS. At the second pre-planned interim 
analysis, the prespecified event-driven primary efficacy endpoint analysis of the 707 subjects 
enrolled at the data cutoff (470 cabozantinib, 237 placebo) demonstrated a statistically significant 
improvement in OS for subjects in the cabozantinib arm compared with placebo (Intent-to-Treat 
[ITT] population): the HR, adjusted for stratification factors, was 0.76 (95% CI 0.63, 0.92; 
stratified log-rank p-value = 0.0049; critical p-value to reject the null hypothesis of equal OS = 
0.021). The Kaplan-Meier estimates for median duration of OS were 10.2 months in the 
cabozantinib arm vs 8.0 months in the placebo arm. The secondary endpoint analysis of 
progression-free survival (PFS) as determined by the investigator yielded a median duration of 
PFS of 5.2 months in the cabozantinib arm and 1.9 months in the placebo arm. The HR, adjusted 
for stratification factors, was 0.44 (95% CI 0.36, 0.52, stratified log-rank p-value < 0.0001). 
Investigator-determined objective response rate (ORR) was 4% and 0.4% for subjects in the 
cabozantinib and placebo arms, respectively (unstratified Fisher exact test p-value = 0.0059); all 
were partial responses (PRs). In addition, there was a high rate of stable disease (SD) in the 
cabozantinib arm relative to placebo (60% vs 33%). Adverse events reported for ≥ 20% of 
subjects in the cabozantinib arm by decreasing frequency were diarrhea, decreased appetite, 
palmar-plantar erythrodysesthesia (PPE), fatigue, nausea, hypertension, vomiting, aspartate 
aminotransferase (AST) increased, and asthenia. Grade 3 or 4 adverse events (AEs) regardless of 
causality were reported for 68% of subjects in the cabozantinib arm and 36% in the placebo arm. 
Grade 3 or 4 AEs reported for ≥ 5% of subjects in the cabozantinib arm by decreasing frequency 
were PPE, hypertension, AST increased, fatigue, diarrhea, asthenia, and decreased appetite. The 
results of this study formed the basis for regulatory applications to the US FDA and EMA to 
approve cabozantinib for treatment of patients with advanced HCC who have received prior 
therapy. Earlier clinical evaluation of cabozantinib in HCC was conducted in a Phase 2 study that 
included both previously-treated and treatment-naïve subjects with advanced HCC (n=41; Kelley 
et al 2017). Progression-free survival from first dose throughout the study was estimated for all 
HCC subjects using a piecewise method; median PFS was 5.2 months. Tumor regression 
appeared independent of prior sorafenib exposure.  

 
XL184-312 Protocol Amendment 5.0 
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Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody which potently and 
selectively inhibits binding of programmed death ligand 1 (PD-L1) on tumor cells and tumor 
infiltrating immune cells in the tumor microenvironment (McDermott et al 2016). Through this 
interaction, atezolizumab interrupts the negative regulatory effects of PD-L1 on T-cell 
proliferation and function that result from PD-L1 binding to programmed death receptor 1 (PD-1) 
and B7.1 (CD80) expressed on T lymphocytes and other immune cells. The result is an increase 
in the susceptibility of tumor cells to T-cell-mediated immune response, an effect that has been 
demonstrated in clinical activity across several tumor types. 
Atezolizumab injection, for intravenous (IV) use (1200 mg once every 3 weeks [q3w]), has been 
approved in the United States and the European Union for the treatment of patients with advanced 
urothelial carcinoma (UC) after prior platinum containing chemotherapy or in a subset patients 
who are considered cisplatin-ineligible (different patient populations are indicated depending on 
region; Rosenberg et al 2016, Balar et al 2017). Atezolizumab is also approved for patients with 
locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy 
(Fehrenbacher et al 2016; Tecentriq™ US PI and EMA SmPC). Recently, atezolizumab was also 
granted accelerated approval in the US for treatment in combination with paclitaxel protein-
bound for adult patients with unresectable locally advanced or metastatic triple negative breast 
cancer (TNBC) whose tumors express PD-L1 (Schmid et al 2018) and was also approved for 
first-line treatment in combination with carboplatin and etoposide in adult patients with 
extensive-stage small cell lung cancer (ES-SCLC; Horn et al 2018, Tecentriq US PI). Treatment 
with atezolizumab is generally well-tolerated but can be associated with immune-related adverse 
events (irAEs).  
The clinical activity and safety of atezolizumab has been evaluated in subjects with advanced 
HCC either as single agent or in combination therapy. In a Phase 1b study of atezolizumab 
(1200 mg q3w) in combination with the anti-VEGF targeting antibody bevacizumab, 103 subjects 
with advanced HCC naïve to systemic therapy had been enrolled at the data cutoff of 26 July 
2018 (NCT02715531; Pishvaian et al 2018). Among 73 efficacy-evaluable subjects, the median 
survival follow-up was 7.2 months. The ORR by independent radiology facility (IRF) was 27% 
(with 4 complete responses [CRs]) per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) and was 34% (with 8 CRs) per modified RECIST (mRECIST); ORR by 
Investigator per RECIST 1.1 was 32% with 1 CR. Confirmed responses were reported across the 
patient population regardless of HCC etiology, geographic region, baseline alpha-fetoprotein 
(AFP) levels, or extrahepatic spread of tumor. The investigator-assessed median PFS per RECIST 
1.1 was 14.9 months, and the IRF-assessed median PFS per RECIST 1.1 was 7.5 months. Median 
estimates for duration of response (DOR) and OS were not yet reached at the data cutoff of 
26 July 2018. Among the 103 safety evaluable subjects, treatment-related Grade 3 or 4 AEs were 
reported in 28 subjects (27%), most commonly hypertension (n = 10 [10%]). Five (5) Grade 5 
AEs were observed, 2 of which were assessed as treatment related (one sepsis, one pneumonitis). 
A total of 19 subjects (18%) experienced treatment-related serious adverse events (SAEs). 
Adverse events of special interest (AESIs) of any grade for atezolizumab were reported for 54% 
of subjects, and AESIs of any grade for bevacizumab were reported for 47% of subjects. 
Immune-related AESIs for atezolizumab of ≥ Grade 3 requiring corticosteroid treatment included 
pneumonitis (2 subjects), autoimmune encephalitis, drug-induced liver injury (DILI), colitis, AST 
increased, γ-glutamyltranspeptidase (GGT) increased, diabetes mellitus, and pancreatitis (1 
subject each). The high response rate observed suggested that the combination of atezolizumab 

 
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with bevacizumab has synergistic activity in advanced HCC and compared favorably to early 
single-agent atezolizumab data in treatment-naïve HCC. Limited information is currently 
available for atezolizumab as a single agent in patients with advanced HCC. A total of 12 subjects 
were enrolled in two Phase 1 studies. In these two studies, few responses were observed: one 
study with 5 subjects had no responses (NCT01375842), and one study with 7 subjects had two 
confirmed responses per investigator assessment (NCT02825940).  
Targets of cabozantinib are also implicated in promoting tumor immune suppression including 
TYRO3, MER, and AXL (TAM family kinases). Preclinical studies (Kwilas et al 2014, Lu et al 
2017) and clinical observations on circulating immune suppressive cells and immune effector 
cells in cancer patients (Apolo et al 2014) suggest that cabozantinib promotes an immune-
permissive environment that may present an opportunity for synergistic effects from combined 
treatment with immune checkpoint inhibitors (ICIs). A Phase 1b study (NCT03170960) is 
currently evaluating the combination of cabozantinib with atezolizumab in multiple tumor 
cohorts. In the dose escalation stage of the study, cabozantinib dose levels of 40 mg and 60 mg 
once daily (qd) were evaluated in 6 subjects each (atezolizumab was administered at 1200 mg IV 
q3w for all subjects). At both cabozantinib dose levels in the dose-limiting toxicity (DLT) 
evaluation period of the dose escalation stage of the study there were no DLTs or SAEs (n=12 
subjects total). The majority of AEs were of Grade 1 or 2 including irAEs. Grade 3 AEs included 
five events of hypertension, two events each of diarrhea and hypophosphatemia, and one event 
each of pulmonary embolism, hyperglycemia, GGT increased, AST increased, ALT increased, 
lymphocyte count decreased, lipase increased, muscular weakness, nephritis, and myositis 
(verbatim term). No Grade 4 or 5 AEs were reported. Among 10 subjects with clear cell RCC 
enrolled in the dose escalation stage, the investigator-assessed confirmed ORR was 70% with 
1 CR and 6 PRs. Cabozantinib 40 mg in combination with atezolizumab 1200 mg was selected as 
the recommended dose for the Expansion Stage cohorts because of its favorable safety profile 
over a prolonged time on study treatment with minimal dose reductions and encouraging 
preliminary efficacy, which was deemed to optimize the benefit/risk of the combination. The 
study is ongoing and currently enrolling expansion cohorts in multiple solid tumor types 
including subjects with advanced HCC who have not received prior systemic anticancer therapy. 
As of 05 February 2019, 157 additional subjects had been enrolled in the expansion cohorts 
evaluating cabozantinib (40 mg, qd) + atezolizumab (1200 mg IV q3w); information on the 
141 subjects evaluable for safety as of 29 January 2019 is provided in Section 1.4. 
Targeting the VEGF signaling pathway with small molecule TKIs has improved the clinical 
outcome of patients with advanced HCC; however, the OS has been modest with a median OS 
between 10.7 and 13.6 months (SHARP trial, Llovet et al 2008; REFLECT trial, Kudo et al 
2018). More recently ICI therapies are being evaluated as potential new treatment strategy in 
HCC. Both cabozantinib and atezolizumab have shown encouraging clinical activity in advanced 
HCC. Based on the potential synergistic effects the combination of cabozantinib with 
atezolizumab appears to be a promising treatment opportunity for subjects with advanced HCC. 
Therefore, further evaluation of cabozantinib in combination with atezolizumab in subjects with 
previously untreated advanced HCC is warranted.  
This Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with 
atezolizumab (approximately 370 subjects) versus the standard of care sorafenib (approximately 
185 subjects) in subjects with advanced HCC who have not received previous systemic anticancer 
therapy. A single-agent cabozantinib arm (approximately 185 subjects) will be enrolled in which 

 
XL184-312 Protocol Amendment 5.0 
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subjects will receive single-agent cabozantinib in order to determine its contribution to the overall 
safety and efficacy of the combination with atezolizumab in this patient population.  
It is planned to include up to 148 subjects from mainland China in this study to assess safety and 
efficacy in the China subpopulation. In the event enrollment in mainland China is incomplete by 
the time the global enrollment phase has been completed, a Mainland China Extension Phase will 
be implemented to complete enrollment and facilitate subpopulation analyses as needed. The 
global population will include all subjects enrolled during the global enrollment phase (including 
subjects enrolled at sites in mainland China during that phase), and the China subpopulation will 
include all subjects enrolled at sites in China (ie, during both the global enrollment phase and the 
Mainland China Extension Phase). 
XL184-312 Protocol Amendment 2.0 introduced considerations and study-related measures 
necessary due to the COVID-19 pandemic. XL184-312 Protocol Amendment 3.0 expanded the 
COVID-19-related guidance to include instructions for managing subjects who become infected 
on study, considerations for administration of COVID-19 vaccines, and confirmation that the 
COVID-19 accommodations are temporary and will be repealed back to standard study conduct 
when conditions allow. 
OBJECTIVES 
The primary objective of this study is to evaluate the efficacy of cabozantinib in combination 
with atezolizumab versus sorafenib in subjects with advanced HCC who have not received 
previous systemic anticancer therapy. A secondary objective is to evaluate the activity of single-
agent cabozantinib compared with sorafenib in this patient population. 
Primary efficacy endpoints: 
• 
Duration of PFS per RECIST 1.1, by Blinded Independent Radiology Committee (BIRC) 
for the experimental arm (cabozantinib + atezolizumab) vs the control arm (sorafenib) 
• 
Duration of OS for the experimental arm (cabozantinib + atezolizumab) vs the control 
arm (sorafenib) 
Secondary efficacy endpoint: 
• 
PFS per RECIST 1.1 by BIRC for the single-agent cabozantinib arm vs the control arm 
(sorafenib) 
Additional endpoints: 
• 
ORR, time to progression (TTP), and DOR per RECIST 1.1 by BIRC and Investigator  
• 
Evaluation of radiographic response per modified RECIST (mRECIST) 
• 
Safety through the evaluation of AEs, including irAEs and other AESIs.  
• 
Characterization of the pharmacokinetics (PK) of cabozantinib in subjects with 
previously untreated HCC  
• 
Immunogenicity of atezolizumab given in combination with cabozantinib  
• 
Change in serum AFP from baseline 
• 
Correlation of biomarker analyses with clinical outcomes 

 
XL184-312 Protocol Amendment 5.0 
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• 
Health-related quality of life (HRQOL) as assessed by the EuroQol Health questionnaire 
instrument (EQ-5D-5L) 
• 
Healthcare resource utilization 
STUDY DESIGN 
This is a multicenter, randomized, open-label, controlled Phase 3 trial of cabozantinib in 
combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not 
received previous systemic anticancer therapy. The multiple primary efficacy endpoints are PFS 
and OS for the experimental arm (cabozantinib + atezolizumab) vs the control arm (sorafenib). 
Additionally there will be a third arm to evaluate the safety and clinical activity of single-agent 
cabozantinib. Approximately 740 eligible subjects with advanced HCC were planned to be 
randomized in a 2:1:1 ratio at approximately 250 sites in this trial in the global enrollment phase 
of the study. However, enrollment commenced under a randomization ratio of 6:3:1 per the 
original protocol design, and there was a dynamic transition in randomization allocation over 
time. As a result, the needed enrollment of 185 subjects in the single-agent cabozantinib arm was 
not expected to be reached at the planned total global enrollment phase sample size of 740 
subjects. Therefore, to ensure complete enrollment in the single-agent cabozantinib arm, the total 
global enrollment phase was extended to accrue a total of approximately 840 subjects. After 
completion of the global enrollment phase, additional subjects (up to 148) may be enrolled in a 
Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. If initiated, subjects recruited in the Mainland China Extension Phase will be 
randomized according to the same 2:1:1 scheme as subjects in the global enrollment phase. The 
global population will include all subjects enrolled during the global enrollment phase (including 
subjects enrolled at sites in mainland China during that phase), and the China subpopulation will 
include all subjects enrolled at sites in China (ie, during both the global enrollment phase and the 
Mainland China Extension Phase).  
The sample size for the global study may be increased up to an additional 25% if a review of the 
accumulating data suggests that the COVID-19 pandemic has caused the rate of study dropout or 
non-compliance to increase to a degree that the ability to adequately evaluate study endpoints 
may be undermined. The Mainland China Extension Phase will not be expanded beyond 
148 subjects.  
Special accommodations during the global COVID-19 pandemic are described in Appendix M. 
The trial consists of the following phases:  
Pre-Treatment Period: Potential subjects will be screened to determine if they meet the required 
eligibility criteria. Qualifying screening assessments must be performed within 28 days before 
randomization unless otherwise specified. 
Guidance for diagnosis of HCC in cirrhotic patients by imaging is provided in Section 5.8.6.1. 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in a 
2:1:1 manner to receive study treatment as follows:  
Experimental arm (at least 370 subjects):  
cabozantinib (40 mg oral, qd) +  
atezolizumab (1200 mg infusion, q3w) 

 
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Control arm (at least 185 subjects):  
sorafenib (400 mg, twice a day [bid]) 
Single-Agent Cabozantinib Arm (approximately 185 subjects):  
cabozantinib (60 mg qd)  
Randomization will be stratified by the following factors established at screening: 
• 
Disease etiology (HBV [with or without hepatitis C virus {HCV}], HCV [without HBV], or 
Other) 
• 
Region (Asia, Other) 
• 
Presence of extrahepatic disease and/or macrovascular invasion (Yes, No) 
Subjects will receive study treatment as long as they continue to experience clinical benefit in the 
opinion of the Investigator or until there is unacceptable toxicity, the need for subsequent 
systemic anticancer treatment, or any other reasons for the treatment discontinuation listed in the 
protocol. Treatment may continue after radiographic progression per RECIST 1.1 according to 
the criteria outlined in Section 5.8.6.3. Subjects on the experimental arm (cabozantinib and 
atezolizumab) are allowed to discontinue one component of the study treatment but continue to 
receive the other. Escalation of cabozantinib from 40 mg qd to 60 mg qd in the experimental arm 
is allowed after Sponsor approval for subjects who are tolerating the 40 mg cabozantinib dose 
level well and have been treated on this dose level for at least 4 weeks. In general, subjects who 
develop clinically relevant adverse events (eg, Grade 3 or 4 AEs) are not allowed to dose escalate 
cabozantinib from 40 qd to 60 mg qd. Crossover from the control to experimental therapy will not 
be allowed unless study transitions to a Crossover Phase (see below). 
Crossover Phase: The study may transition to a Crossover Phase if the analysis of the multiple 
primary endpoint of OS for the global ITT population (ie, not including subjects enrolled in the 
Mainland China Extension Phase) shows statistically significant and clinically meaningful 
evidence of improvement.  
The Crossover Phase will only be implemented upon decision by the Sponsor and following any 
required discussion with regulatory authorities following review of the data. Crossover may be 
implemented independently and at different points in time for study sites and subjects in mainland 
China compared to other sites and subjects in the global study. If the decision is made to enter the 
Crossover Phase, study sites will have 8 weeks to determine eligibility and begin administration 
of crossover treatment (cabozantinib + atezolizumab combination) to eligible subjects 
randomized to the control arm (sorafenib) or the single-agent cabozantinib arm; subsequently no 
further crossover will be allowed.  
• 
Subjects randomized to the sorafenib control arm or the single-agent cabozantinib arm will 
have the option to cross over to receive the cabozantinib + atezolizumab combination if they 
meet predefined eligibility criteria.  
• 
Subjects randomized to the cabozantinib + atezolizumab experimental arm who are still 
receiving study treatment and subjects randomized to the sorafenib control arm or the single-
agent cabozantinib arm who are still receiving study treatment and do not cross over to the 
combination treatment (cabozantinib + atezolizumab) may continue on their originally 
assigned study treatment until a criterion for protocol-defined discontinuation has been met.  

 
XL184-312 Protocol Amendment 5.0 
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• 
Subjects randomized to the cabozantinib + atezolizumab experimental arm who are in the 
Post-Treatment Period and subjects randomized to the sorafenib control arm or the 
single-agent cabozantinib arm who do not cross over to cabozantinib + atezolizumab and are 
in the Post-Treatment Period will continue with post treatment assessments. 
The study is expected to have completed enrollment in the global enrollment phase at the time of 
transitioning to the Crossover Phase for those subjects, but accrual of subjects in the Mainland 
China Extension Phase may still be ongoing at that point. In the Crossover Phase safety 
assessments and efficacy assessments will be performed per the schedule of assessments. PK, 
biomarker, health-related quality of life (HRQOL), and healthcare resource utilization 
assessments will be discontinued. 
Post-Treatment Period: A first Post-Treatment Follow-up visit (FU-1) for safety evaluation 
(including subjects in the Maintenance Phase [below]) is to occur 30 (+14) days after the date of 
the decision to permanently discontinue study treatment (defined as the later of the date of the 
decision to permanently discontinue study treatment or the date of the last dose of study 
treatment). A second Post-Treatment Follow-up visit (FU-2) for safety evaluation will be 
conducted approximately 100 days (±14 days) after the date of the decision to permanently 
discontinue study treatment. Further details for follow-up and data collection requirements for 
AEs, SAEs, and AESIs are summarized in Appendix K.  
Radiographic tumor and HRQOL assessments are to continue, regardless of whether study 
treatment is given, reduced, held, or discontinued until a protocol-defined criterion for ending 
radiographic assessments is met (see Section 5.8.6.2). Consequently these assessments may be 
required in the Post-Treatment Follow-up Period for some subjects. 
In addition, subjects are to be contacted every 12 weeks (± 14 days) after FU-2 to assess survival 
status and document receipt of subsequent anticancer therapy. This follow-up will continue until 
the subject expires or the Sponsor decides to discontinue collection of these data; however, these 
assessments are not required in the Maintenance Phase (below). Every effort must be made to 
perform these evaluations unless consent for non-interventional study assessment is withdrawn. 
Mainland China Extension Phase: After completion of the global enrollment phase, additional 
subjects (up to 148) may be enrolled in a Mainland China Extension Phase at sites in mainland 
China for evaluation in a China subpopulation. The Pre-Treatment, Treatment, and 
Post-Treatment Periods of the study will be conducted in the same manner in the Mainland China 
Extension Phase as for subjects who were enrolled in the global enrollment phase.  
Study Completion: The study will be considered complete if the null hypothesis is rejected for the 
primary endpoint of OS (experimental vs control arm) in either of the planned interim analyses or 
if the final planned analysis for OS has been conducted (irrespective of the results), all other 
planned formal inference tests have been performed (eg, for secondary efficacy endpoints), and 
any required supportive analyses for China are completed. 
Maintenance Phase/Treatment after Study Completion: The purpose of the Maintenance Phase is 
to continue to provide long-term access to study drug(s) to subjects who are deriving clinical 
benefit even after evaluation of the study objectives has been completed (Study Completion, see 
above). When sufficient data have been collected to adequately evaluate all study endpoints, 
subjects who continue study treatment may enter the study Maintenance Phase. Upon initiation of 
the Maintenance Phase, the Sponsor considers the safety and efficacy profile of the experimental 

 
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treatment regimen within this study to have been sufficiently established and data analyses 
required for regulatory purposes to have been completed. If a Crossover Phase has been 
implemented, the Maintenance Phase may not begin before the Week 9 Day 1 (W9D1) visit has 
elapsed in the Crossover Phase for the last subject randomized to sorafenib or single-agent 
cabozantinib who crossed over to receive cabozantinib + atezolizumab. The Sponsor is to notify 
the sites if or when the study will enter the Maintenance Phase or if an alternative post-Study 
Completion option will be implemented (Section 6.3). 
In the Maintenance Phase, subjects will continue to receive study treatment until they meet the 
protocol-required criteria for treatment discontinuation. Subjects are to undergo periodic safety 
assessments (including local laboratory tests) and tumor assessments. The nature and frequency 
of these assessments during the Maintenance phase are to be performed per institutional standard 
of care and guidance from the Sponsor. It is the Investigator’s responsibility to ensure that subject 
visits occur frequently enough and adequate assessments are performed to ensure subject safety.  
In order to continue to collect important safety information for subjects enrolled in the study 
during the Maintenance Phase, reporting of SAEs; certain AEs (including irAEs and other AESIs 
[whether serious or not], and AEs leading to dose modifications or treatment discontinuation); 
and other reportable events (DILI, pregnancy, and medication errors with sequelae) is to continue 
per protocol requirements specific to the Maintenance Phase. 
The study clinical database will be closed upon initiation of the Maintenance Phase. Important 
safety information (noted above) collected in the Maintenance Phase will be captured in the 
safety database. Only data collected prior to implementation of Maintenance Phase will be 
reported in a clinical study report. 
End of Trial: End of trial is defined as the last scheduled visit or scheduled procedure for the last 
subject (including Maintenance Phase assessments). 
NUMBER OF SUBJECTS 
Approximately 740 eligible subjects were planned to be randomized 2:1:1 to receive cabozantinib 
in combination with atezolizumab (n=370), sorafenib (n=185), or single-agent cabozantinib 
(n=185) in the global enrollment phase of the study. However, enrollment commenced under a 
randomization ratio of 6:3:1 per the original protocol design, and there was a dynamic transition 
in randomization allocation over time. As a result, the needed enrollment of 185 subjects in the 
single-agent cabozantinib arm was not expected to be reached at the planned total global 
enrollment phase sample size of 740 subjects. Therefore, to ensure complete enrollment in the 
single-agent cabozantinib arm, the total global enrollment phase was extended to accrue a total of 
approximately 840 subjects. 
The sample size for the global study may be increased up to an additional 25% if a review of the 
accumulating data suggests that the COVID-19 pandemic has caused the rate of study dropout or 
non-compliance to increase to a degree that the ability to adequately evaluate study endpoints 
may be undermined. 
After completion of the global enrollment phase, additional subjects (up to 148) may be enrolled 
in a Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. The Mainland China Extension Phase will not be expanded beyond 148 subjects. 
The global population will include all subjects enrolled during the global enrollment phase 

 
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(including subjects enrolled at sites in mainland China during that phase), and the China 
subpopulation will include all subjects enrolled at sites in China (ie, during both the global 
enrollment phase and the Mainland China Extension Phase). 
TARGET POPULATION 
To be eligible for the study the subject must meet all of the inclusion and none of the exclusion 
criteria. The Sponsor will not grant exceptions to these eligibility criteria: 
Inclusion Criteria 
1. Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic 
patients by multiphase imaging using CT or MRI per the American Association for the Study 
of Liver Diseases (AASLD) (Marrero et al 2018) or European Association for the Study of 
the Liver (EASL 2018) guidelines.  
Note: Sites must receive Sponsor accreditation for imaging-based diagnosis of HCC prior to 
implementing this methodology. In addition, subjects who do not meet the AASLD or EASL 
guidelines for imaging diagnosis of HCC or who do not have cirrhosis must have histological 
or cytological diagnosis of HCC.  
2. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, 
surgery, ablation therapy) or locoregional therapy (eg, TACE). 
3. The subject is receiving antiviral therapy per local standard of care if the subject has active 
HBV infection (defined by HBsAg positive); the subject must have HBV DNA < 500 IU/mL. 
4. Measurable disease per RECIST 1.1 as determined by the Investigator.  
5. Barcelona Clinic Liver Cancer (BCLC) stage Category B or C (Appendix I).  
6. Child-Pugh Score of A (Appendix J). 
7. Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events 
(CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically 
nonsignificant and/or stable on supportive therapy as determined by the Investigator.  
8. Age eighteen years or older on the day of consent. 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
10. Adequate organ and marrow function, based upon meeting all of the following laboratory 
criteria within 14 days prior to randomization: 
a. Absolute neutrophil count (ANC) ≥ 1500/µL (≥ 1.5 × 109/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection.  
b. White blood cell (WBC) count ≥ 2000/µL (≥ 2.0 × 109/L). 
c. Platelets ≥ 60,000/µL (≥ 60 × 109/L) without transfusion within 2 weeks before screening 
laboratory sample collection.  
d. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening 
laboratory sample collection.  

 
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e. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization (if HbA1c results 
are unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL) 
f. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 5 × upper limit 
of normal (ULN).  
g. Total bilirubin ≤ 2 mg/dL (≤ 34.2 µmol/L). 
h. Serum albumin ≥ 2.8 g/dL (≥ 28 g/L). 
i. 
Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 
mL/sec) using the Cockcroft-Gault equation (see Table 3). 
j. 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h protein 
≤ 1 g. 
11. Capable of understanding and complying with the protocol requirements and must have 
signed the informed consent document prior to any screening assessment except those 
procedures performed as standard of care within the screening window. 
12. Sexually active fertile subjects and their partners must agree to use highly effective methods 
of contraception that alone or in combination result in a failure rate of less than 1% per year 
when used consistently and correctly (see Appendix H) during the course of the study and for 
5 months after the last dose of study treatment. A barrier method (eg, condom) is also 
required. 
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects 
are considered to be of childbearing potential unless one of the following criteria is met: 
documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea 
in a woman > 45 years-of-age in the absence of other biological or physiological causes. In 
addition, females < 55 years-of-age must have a serum follicle stimulating hormone (FSH) 
level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of 
medical records, medical examination, or medical history interview by study site staff.  
 
Exclusion Criteria 
1. Known fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular 
cholangiocarcinoma. 
2. Prior systemic anticancer therapy for advanced HCC including but not limited to 
chemotherapy, small molecule kinase inhibitors, and ICIs. Subjects who have received local 
intratumoral or arterial chemotherapy are eligible.  
3. Documented hepatic encephalopathy (HE) within 6 months before randomization (see 
Section 6.6.2.4 for a case definition of HE). 
4. Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) 
within 6 months before randomization. 
5. Subjects who have received any local anticancer therapy including surgery, PEI, RFA, 
MWA, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) 
within 28 days prior to randomization 

 
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6. Radiation therapy for bone metastasis within 2 weeks, any other external beam radiation 
therapy within 8 weeks prior to randomization. Subjects with clinically relevant ongoing 
complications from prior radiation therapy are not eligible. 
7. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 8 weeks prior to 
randomization. Subjects who are neurologically symptomatic or are receiving systemic 
corticosteroid treatment at the planned time of randomization are not eligible. 
8. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and 
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed 
anticoagulants:  
• 
Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low 
molecular weight heparins (LMWH)  
9. Administration of a live, attenuated vaccine within 30 days prior to randomization. 
10. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT) or 
triphasic liver magnetic resonance imaging (MRI) because of allergy or other 
contraindication to both CT and MRI contrast agents. 
11. The subject has uncontrolled, significant intercurrent or recent (within the last 3 months 
before randomization [unless otherwise specified below]) illness including, but not limited to, 
the following conditions: 
a. Cardiovascular and cardiac disorders: 
i. 
Congestive heart failure (CHF) class III or IV as defined by the New York Heart 
Association, unstable angina pectoris, serious cardiac arrhythmias.  
ii. 
Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg 
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. 
iii. 
Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or 
other ischemic event or thromboembolic event (eg, deep vein thrombosis [DVT], 
pulmonary embolism) within 6 months before randomization. 
iv. 
History of risk factors for torsades de pointes (eg, long QT syndrome).  
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, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction.  
ii. 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months prior to randomization. Complete healing of an intra-abdominal 
abscess must be confirmed prior to randomization. 
iii. 
Gastric or esophageal varices that are untreated or incompletely treated with bleeding 
or high risk for bleeding. Subjects treated with adequate endoscopic therapy 

 
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(according to institutional standards) without any episodes of recurrent GI bleeding 
requiring transfusion or hospitalization for at least 6 months before randomization are 
eligible. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) 
of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 
3 months before randomization.  
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. 
e. Lesions invading major blood vessel, including, but not limited to: inferior vena cava, 
pulmonary artery, or aorta. Subjects with lesions invading the intrahepatic vasculature, 
including portal vein, hepatic vein, and hepatic artery, are eligible.  
f. Other clinically significant disorders such as: 
i. 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, 
antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix D for a more 
comprehensive list of autoimmune diseases and immune deficiencies). Subjects with 
the following conditions are eligible for the study: 
• 
A history of autoimmune-related hypothyroidism and on thyroid replacement 
hormone  
• 
Controlled Type 1 diabetes mellitus and on an insulin regimen 
• 
Asthma that requires intermittent use of bronchodilators 
• 
Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only provided all of following are true: 
o Rash covers < 10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high potency or oral corticosteroids within the 
previous 12 months  
ii. 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days 
before randomization. 
Note: Inhaled, intranasal, intra-articular, and topical corticosteroids and 
mineralocorticoids are permitted.  
Transient use of systemic corticosteroids for allergic conditions such as contrast 
allergy is allowed. 
iii. 
Active infection requiring systemic treatment, known history of infection with human 
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 

 
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(AIDS)-related illness, or a known positive test for tuberculosis due to tuberculosis 
infection. Subjects with active hepatitis B virus infection controlled with antiviral 
therapy are eligible (see Inclusion Criterion 3). Subjects with active, uncontrolled 
hepatitis C virus infection are eligible provided liver function meets eligibility criteria 
and are receiving management of the disease per local institutional practice (note: 
antiviral treatment for HCV is allowed with Sponsor approval). Subjects with history 
of COVID-19 must have recovered from the disease at least 30 days prior to 
randomization. 
iv. 
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan  
v. 
Serious non-healing wound/ulcer/bone fracture.  
vi. 
Malabsorption syndrome. 
vii. 
Symptoms of thyroid dysfunction with thyroid function test corroboration (Note: 
asymptomatic subjects with an isolated abnormal free thyroxine [FT4] are eligible)  
viii. 
Moderate to severe hepatic impairment (Child-Pugh B or C [Appendix J]). 
ix. 
Requirement for hemodialysis or peritoneal dialysis. 
x. 
History of solid organ transplant including liver transplant, or allogeneic stem cell 
transplant. 
12. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before 
randomization. Minor surgeries within 10 days before randomization. Subjects must have 
complete wound healing from major surgery or minor surgery before randomization. Subjects 
with clinically relevant ongoing complications from prior surgery are not eligible. 
13. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per 
electrocardiogram (ECG) within 14 days before randomization.  
Note: If a single ECG shows a QTcF with an absolute value > 480 ms, two additional ECGs 
at intervals of approximately 3 min must be performed within 30 min after the initial ECG, 
and the average of these three consecutive results for QTcF will be used to determine 
eligibility  
14. History of psychiatric illness likely to interfere with ability to comply with protocol 
requirements or give informed consent 
15. Pregnant or breastfeeding females. 
16. Inability to swallow tablets. 
17. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe hypersensitivity to monoclonal antibodies. Subjects with 
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption are also excluded. 

 
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18. Any other active malignancy at time of randomization or diagnosis of another malignancy 
within 2 years before randomization that requires active treatment, except for superficial skin 
cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.  
 
ESTIMATED LENGTH OF SUBJECT PARTICIPATION 
It is estimated that subjects will receive study treatment for an average of approximately 
6 months. Subjects will be followed until death, withdrawal of consent for non-interventional 
study assessments, or Sponsor decision to no longer collect survival data. 
ESTIMATED STUDY DATES 
It is estimated that approximately 25 months will be required to randomize 740 subjects at 
approximately 250 global sites for the global enrollment phase of the study. The number of events 
required for the final analyses of the primary PFS (257 events among the first 372 randomized 
subjects within the cabozantinib + atezolizumab combination and sorafenib arms) and primary 
OS (368 events among the 555 randomized subjects within the cabozantinib + atezolizumab 
combination and sorafenib arms) is expected to be observed around approximately 18 months and 
around 38 months, respectively, after the first subject is randomized.  
After completion of the global enrollment phase, additional subjects (up to 148) may be enrolled 
in a Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. It is estimated that randomization of the subjects in mainland China during the 
global enrollment phase and Mainland China Extension Phase will require at least 21 months.  
The true intervals required to meet the milestones above may be longer or shorter due to 
divergence from assumptions, including non-constant accrual rate due to the time required for all 
study sites to become active, or due to the impact of the global COVID-19 pandemic on subject 
enrollment and other aspects of study conduct.  
INVESTIGATIONAL REGIMEN DOSE/ ROUTE/ DURATION 
Subjects in the experimental arm will take oral study medication (40 mg of cabozantinib: 2 tablets 
containing 20 mg each of cabozantinib) once daily. Atezolizumab will be administered IV every 
3 weeks at 1200 mg dose.  
Dose reduction levels of cabozantinib will be allowed in the experimental arm (20 mg qd and 
20 mg every other day [qod]). Dose reductions for atezolizumab will not be allowed and AEs will 
be managed by dose delays. Escalation of cabozantinib from 40 mg qd to 60 mg qd is allowed 
after Sponsor approval for subjects who are tolerating the 40 mg cabozantinib dose level well and 
have been treated on this dose level for at least 4 weeks. In general, subjects who develop 
clinically relevant adverse events (eg, Grade 3 or 4 AEs) are not allowed to dose escalate 
cabozantinib from 40 qd to 60 mg qd. 
Subjects in the control arm will take sorafenib orally (2 tablets containing 200 mg each of 
sorafenib) twice daily. Dose interruptions and reductions will be allowed as per local prescribing 
information.  
Subjects in the single-agent cabozantinib arm will take 60 mg of cabozantinib qd (1 tablet of 
60 mg of cabozantinib). Two dose reduction levels of cabozantinib will be allowed in this arm 

 
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(40 mg daily and 20 mg daily). Subjects may be allowed to re-escalate following a dose reduction 
according to the guidance provided in Section 6.6.1. 
Subjects will continue study treatment as long as they continue to experience clinical benefit in 
the opinion of the Investigator (see Section 5.8.6.3) or until unacceptable toxicity, the need for 
alternative anticancer treatment, or other reasons for treatment discontinuation. Continuation of 
one component of the combination study in the experimental arm (cabozantinib and 
atezolizumab) while discontinuing the other will be allowed as per protocol defined guidelines.  
SAFETY ASSESSMENTS 
Safety will be assessed on a schedule based on the date of the first dose (W1D1) and every 
3 weeks thereafter. Routine safety follow-up visits will be performed 30 (+14) days (FU-1) and 
approximately 100 (± 14) days (FU-2) after the date of the decision to permanently discontinue 
study treatment. Further details for follow-up and data collection requirements for AEs, SAEs, 
and AESIs are summarized in Appendix K.  
Routine safety evaluations will include physical examination, vital signs, performance status, 
12-lead ECG, hematology, serum chemistries, coagulation tests, urine tests (including UPCR), 
serum pregnancy tests (in females of childbearing potential), and thyroid function tests. Adverse 
event seriousness, severity grade, relationship to study treatment, and relationship to immune 
effects (ie, irAEs) will be assessed by the Investigator. Severity grade will be defined by the 
National Cancer Institute (NCI) CTCAE v5. 
An Independent Data Monitoring Committee (IDMC) will be established to monitor safety of the 
study on a regular basis. The IDMC will operate independently from the Sponsor and the clinical 
investigators. 
EFFICACY ASSESSMENTS 
Subjects will be monitored for radiographic response and progression per RECIST 1.1. For 
determining radiographic endpoints, radiographic assessments will be assessed by the BIRC and 
Investigator; radiographic assessment by the Investigator will be used for treatment decisions. 
Overall survival will be assessed at scheduled visits and every 12 weeks (± 14 days). Subjects 
will be followed until death, withdrawal of consent for non-interventional study assessments, or 
Sponsor decision to no longer collect these data. 
TUMOR ASSESSMENTS 
Study Eligibility by Imaging-Based Diagnosis: Clinical diagnosis of HCC by multiphase imaging 
using CT or MRI in subjects with cirrhosis according to AASLD or EASL HCC guidelines is 
acceptable for study eligibility. Diagnostic imaging hallmarks of HCC include arterial phase 
enhancement, tumor size, washout, enhancing capsule, and threshold growth. If the subject does 
not have cirrhosis or these imaging criteria cannot be assessed or are not met, histological or 
cytological diagnosis of HCC is required for study participation. Ultrasound, angiography, 
fluorodeoxyglucose (FDG)-positron emission tomography (PET), or AFP cannot be used for 
clinical diagnosis of HCC. Accreditation for HCC diagnostic imaging, as described in the 
amended study imaging manual, is required before a site can enroll subjects diagnosed with HCC 
via imaging alone. Diagnostic scans may be used for screening if they meet the criteria described 

 
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in Section 5.8.6.2. For detailed guidance regarding diagnosis of HCC by imaging refer to the 
amended study imaging manual. 
Chest / Abdomen / Pelvis (CAP): CT of CAP or CT chest and MRI abdomen/pelvis will be 
performed in all subjects at screening (prior to randomization). Tumor assessments after 
randomization should be performed every 6 weeks (± 7 days) though Week 49. After Week 49, 
these assessments will be performed every 12 weeks (± 7 days). CT/MRI of the CAP should 
include a noncontrast study of at least the liver followed by contrast with triphasic CT imaging of 
the liver or liver MRI with gadolinium enhanced imaging including triphasic liver.  
Other Sites: All other known or suspected sites of disease, including in the brain or bone, are to 
be imaged by CT/MRI at screening (prior to randomization). Any lesions identified, including 
bone lesions with a soft tissue component, are to be followed at subsequent tumor assessments as 
described for CAP above using the same modality as at screening. New suspected lesion sites 
identified after randomization, including suspected sites of bone or brain lesions, should be 
assessed by CT/MRI. MRI is the preferred method for brain lesion assessment. If CT of the brain 
is performed instead of MRI, ambiguous results must be confirmed by MRI. (Note: in order to 
meet the eligibility requirements of the study, brain metastasis must have been treated and stable 
for at least 8 weeks before randomization. Subjects without documented brain metastasis during 
the screening assessment are not required to undergo post-randomization brain imaging unless 
clinically indicated.) 
Tumor assessments should continue on the protocol-defined schedule regardless of whether study 
treatment is given, reduced, held, or discontinued until a protocol-defined criterion for ending 
radiographic assessments is met (see Section 5.8.6.2). Treatment may continue after radiographic 
progression per RECIST 1.1 as long as the Investigator believes that the subject is still receiving 
clinical benefit from study treatment and that the potential benefit of continuing study treatment 
outweighs potential risks (see Section 5.8.6.3). The same imaging modalities used at screening 
are to be used for subsequent tumor assessments after randomization. 
Radiographic response and disease progression will be determined using RECIST 1.1. 
Investigators are encouraged, if any doubt or ambiguities exist about radiographic progression, to 
continue study treatment if the subject is tolerating it acceptably, repeat radiographic tumor 
imaging at the next scheduled time point, and delay determination of progression until the 
findings indicating radiographic progression are unequivocal.  
Radiographic tumor assessments are to continue until the later of Investigator-determined 
radiographic progression per RECIST 1.1 or study treatment is permanently discontinued. 
For the purpose of determining radiographic study endpoints, central review of radiographic 
images will be conducted by a BIRC. All radiographic tumor assessments will be sent to the 
BIRC, which also will review prior radiation history data and prior local therapy information for 
the purpose of selection of target lesions.  
TUMOR MARKER ASSESSMENTS 
Tumor marker samples (AFP) will be collected at screening, predose on W1D1, and after first 
dose of study treatment as described in the schedule of assessments (Appendix A). The tumor 
marker assessments will not be used to determine PD in this study. The samples will be analyzed 
by a central laboratory. 

 
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PHARMACOKINETIC ASSESSMENTS 
Blood samples will be obtained from all subjects in the experimental arm and the single-agent 
cabozantinib arms for cabozantinib PK. Samples will be collected for plasma cabozantinib 
concentration measurement predose on Week 1 Day 1 (W1D1), W4D1, W7D1, W10D1, and 
W13D1. The results will be used to confirm exposure to cabozantinib and to further characterize 
the population PK and exposure-response relationships for cabozantinib in this population.  
Blood samples will be obtained from all subjects in the experimental arm for atezolizumab PK. 
Samples will be collected for serum atezolizumab concentration measurement predose on W1D1, 
W4D1, W7D1, W10D1, W13D1 and FU visits. The results may be used to confirm exposure to 
atezolizumab.  
Collection of PK samples may be halted early or sampling frequency may be reduced at the 
discretion of the Sponsor. 
IMMUNOGENICITY ASSESSMENTS 
Blood samples will be obtained from all subjects in the experimental arm (cabozantinib + 
atezolizumab) for immunogenicity assessment predose on W1D1, W13D1, W25D1, and at the 
Post-Treatment Follow-up visits (ie, FU-1 and FU-2). Collection of immunogenicity samples may 
be halted early or sampling frequency may be reduced at the discretion of the Sponsor.  
BIOMARKER ASSESSMENTS 
Peripheral blood samples will be obtained as specified in the Appendix A. Archival tumor tissue 
(most recently obtained) will be provided, if available. If archival tissue and 
histological/cytological confirmation of disease are not available, a tumor biopsy may be 
collected during screening with subject consent. An optional tumor biopsy may be collected 
approximately 6 weeks after the first dose of study treatment; other time points may be acceptable 
provided the tumor sample is collected prior to progressive disease. Exploratory analyses may 
include, but may not be limited to, the following: 
• 
PD-L1 and MET and other relevant biomarkers in tumor specimens for association with 
clinical outcomes  
• 
Immune cell infiltration and mutational load assessment in tumor specimens for association 
with clinical outcome 
• 
Circulating immune cells in peripheral blood  
• 
Blood biomarkers (ie, cytokines/chemokines, VEGF) 
• 
Cell and/or plasma pharmacogenomics (eg, circulating tumor DNA [ctDNA]) 
Some biomarker samples may only be collected at selected sites (see the study laboratory manual 
for details). Collection of biomarker samples may be halted early or sampling frequency may be 
reduced at the discretion of the Sponsor. 
HEALTH-RELATED QUALITY OF LIFE  
Health-related quality of life assessments will be performed using the EuroQol Health 
questionnaire instrument EQ-5D-5L. Subjects will be requested to complete the assessment at 

 
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baseline (within 14 days prior to randomization) and every 6 weeks thereafter. Subjects will 
continue completing questionnaires regardless of whether study treatment is given, reduced, held, 
or discontinued until the date of the last tumor imaging assessment or the study meets its primary 
endpoints. Consequently these assessments may be required in the Post Treatment Period for 
some subjects. Subjects should complete the questionnaire on the day of the visit prior to seeing 
study site personnel. HRQOL assessments will no longer be collected for subjects who transition 
to the Crossover Phase or if the study transitions to the Maintenance Phase. 
HEALTHCARE RESOURCE UTILIZATION 
Healthcare resource utilization parameters will be collected from randomization through the 
100-Day Post-Treatment Follow-up Visit (FU-2). These include hospital admissions, emergency 
room visits, intensive care unit admissions, length of stay, surgeries, and transfusions. These data 
will not be collected in the Maintenance Phase. 
STATISTICAL METHODS 
The primary efficacy analyses in this study are the comparisons between the combination 
treatment and control arms for OS and PFS. These analyses will be performed for subjects 
enrolled in the global enrollment phase which will not include subjects enrolled in the Mainland 
China Extension Phase. Treatment with cabozantinib in combination with atezolizumab will be 
inferred to be superior to treatment with sorafenib if the null hypothesis of no difference between 
arms is rejected in favor of the experimental arm for either OS or PFS. Inflation of Type 1 error 
associated with multiple primary endpoints and the secondary efficacy endpoint of PFS between 
single-agent cabozantinib and sorafenib will be controlled by a closed testing procedure that 
employs a modified Bonferroni procedure, a gatekeeping technique, and the fallback method (see 
Section 9.5). The study-wise 2-sided alpha of 5% will be nominally divided between primary 
endpoints PFS (1%) and OS (4%), with the secondary PFS endpoint tested at the 1% level only if 
the primary PFS test is successful. If the null hypotheses are rejected for both the primary and 
secondary PFS endpoints, the 1% alpha for PFS will be reallocated to OS, allowing it to be tested 
at the 5% level. 
Duration of OS is defined as time from randomization to death due to any cause. Duration of PFS 
is defined as time from randomization to the earlier of either PD per RECIST 1.1 as determined 
by the BIRC or death from any cause.  
The primary analyses of OS and PFS will be event-driven and will be conducted independently 
after at least the number of events required for each analysis has been observed. 
PFS and OS will be summarized descriptively using the Kaplan-Meier method. Inferential 
comparisons between treatment arms will use the stratified log-rank test. The HR will be 
estimated using a stratified Cox proportional hazards model. Stratification will be based on the 
stratification factors used for the randomization as recorded in the Interactive Response 
Technology (IRT) system.  
The study is designed to provide adequate power for analyses of both primary endpoints of PFS 
and OS comparing the experimental arm with the control arm, and for the analysis of the 
secondary endpoint of PFS comparing the single-agent cabozantinib arm with the control arm. 
For the primary endpoints, a larger sample size is needed to provide reasonable power for OS 

 
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than is required to evaluate PFS. As a result, if PFS were to be evaluated in the entire study 
sample required for OS, the PFS events may be biased toward shorter progression times. Thus, to 
allow longer, more robust PFS follow up among a smaller number of subjects this study employs 
a “trial within a trial design” (Hessel et al 2016).  
The total sample size was planned to be 740 subjects randomized in a 2:1:1 fashion: 370 to the 
experimental combination arm (cabozantinib + atezolizumab), 185 to the control arm (sorafenib), 
and 185 to the single-agent cabozantinib arm. However, enrollment commenced under a 
randomization ratio of 6:3:1 per the original protocol design, and there was a dynamic transition 
in randomization allocation over time. As a result, the needed enrollment of 185 subjects in the 
single-agent cabozantinib arm was not expected to be reached at the planned total global 
enrollment phase sample size of 740 subjects. Therefore, to ensure complete enrollment in the 
single-agent cabozantinib arm, the total global enrollment phase was extended to accrue a total of 
approximately 840 subjects. 
For primary PFS, a total of 257 events in the first 372 subjects randomized in a 2:1 ratio in the 
experimental and control arms (n=248 and 124, respectively; defined as the PFS Intent-to-Treat 
[PITT] population) provide the study with 90% power for a 2-sided log-rank test with a 1% level 
of significance to detect a hypothesized true HR of 0.6. Assuming an exponential distribution for 
PFS, this corresponds with a 67% increase in median PFS from 3.6 months to 6.0 months. The 
minimum observed effect that would result in statistical significance for PFS is an HR of 0.71, a 
41% improvement in median from 3.6 to 5.1 months. Interim analysis of the primary PFS 
endpoint is not planned.  
For OS, a total of 368 deaths among all 555 subjects randomized in a 2:1 ratio in the experimental 
(n=370) and control arms (n=185) are required to provide 90% power to detect an HR of 0.69 
using the log-rank test and a 2-sided significance level of 4%. Assuming an exponential 
distribution for OS, this corresponds to a 45% increase in median survival from 12.3 months to 
17.8 months. The minimum observed effect that would result in statistical significance for the 
primary analysis of OS is an HR of 0.7942, a 26% improvement in median from 12.3 to 15.5 
months. 
Two interim analyses of OS are planned and will include all subjects in the ITT population 
available at the time of each analysis. These are planned at the 33% and 66% information 
fractions. The first interim analysis (IA1) will coincide with the primary analysis of PFS and will 
be performed only if the null hypothesis for primary PFS is rejected and is expected to occur at 
approximately the 33% information fraction. Should the timing of IA1 trend towards an 
information fraction much higher than expected (eg, due to faster-than-expected deaths or slower-
than-expected PFS events), the plan for the interim analyses of OS may be modified (see 
Section 9.8). Inflation of Type 1 error associated with these interim analyses will be controlled 
using Lan-DeMets O’Brien-Fleming (LD-OF) alpha-spending functions based upon a 4% total 
alpha allocation for OS.  
The secondary analysis of PFS for the single-agent cabozantinib arm vs the control (sorafenib 
arm) will be performed for subjects enrolled in the global enrollment phase which will not 
include subjects enrolled in the Mainland China Extension Phase. For this analysis, a total of 283 
events among all 370 subjects (185 per arm) in the single-agent cabozantinib and control arms 
provides the study with 85% power for a 2-sided log-rank test with a 1% level of significance to 
detect a hypothesized true HR of 0.65. Assuming an exponential distribution for PFS, this 

 
XL184-312 Protocol Amendment 5.0 
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corresponds with a 53% increase in median PFS from 3.6 months to 5.5 months. The minimum 
observed effect that would result in statistical significance for PFS is an HR of 0.735, a 36% 
improvement in median from 3.6 to 4.9 months.  
An interim analysis of secondary PFS is planned contemporaneously with the primary PFS 
analysis and will include all subjects in single-agent cabozantinib and control arms of the ITT 
population available at the time of the analysis. This is anticipated to be at 67% information 
fraction (to be performed only if the null hypothesis for PFS is rejected). Inflation of Type 1 error 
associated with these interim analyses will be controlled using Lan-DeMets O’Brien-Fleming 
(LD-OF) alpha-spending functions based upon a 1% total alpha allocation for secondary PFS. 
With a constant accrual rate of 30 subjects per month, it is anticipated that it will take 
approximately 18.4 months to observe the required primary PFS events (16.5 months of subject 
accrual) and approximately 38 months to observe the required deaths for OS (25 months of 
subject accrual) to evaluate the primary endpoints in the combination and control arms. Assuming 
the same accrual rate, it is anticipated that it will take approximately 25 months to observe the 
required secondary PFS events (25 months of subject accrual) to evaluate the secondary endpoint 
in the single-agent cabozantinib and control arms. The true intervals required to meet these 
milestones may be longer or shorter due to divergence from assumptions, including non-constant 
accrual rate due to the time required for all study sites to become active, or due to the impact of 
the global COVID-19 pandemic on subject enrollment and other aspects of study conduct. 
The sample size for the global study may be increased up to an additional 25% if a review of the 
accumulating data suggests that the COVID-19 pandemic has caused the rate of study dropout or 
non-compliance to increase to a degree that the ability to adequately evaluate study endpoints 
may be undermined. The Mainland China Extension Phase will not be expanded beyond 
148 subjects. 
China Subpopulation: The primary scope of the China subpopulation analysis is to allow 
evaluation of consistency in efficacy and safety with the global study population per NMPA 
guidance. Since the China subpopulation is not powered to demonstrate statistical significance in 
terms of efficacy, no formal hypothesis testing will be performed. All data summaries for the 
China subpopulation will be descriptive. The safety and efficacy data in the China subpopulation 
will be analyzed separately for the same endpoints using the same analysis methods as for the 
global population. The analyses for this subpopulation will be performed when the data are of 
sufficient maturity to allow evaluation of consistency in efficacy and safety. 
 
 

 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................25 
LIST OF ABBREVIATIONS ........................................................................................................32 
1. 
BACKGROUND ........................................................................................................36 
1.1. 
Hepatocellular Carcinoma ..........................................................................................36 
1.2. 
Cabozantinib ...............................................................................................................37 
1.3. 
Atezolizumab ..............................................................................................................39 
1.4. 
Combination of Cabozantinib and Atezolizumab .......................................................42 
1.5. 
Rationale .....................................................................................................................43 
1.5.1. 
Rationale for Evaluating Cabozantinib in Combination with Atezolizumab in 
Advanced HCC ...........................................................................................................43 
1.5.2. 
Rationale for Study Design .........................................................................................44 
1.5.3. 
Rationale for Study Treatment Dose Selection and Treatment Schedule ...................46 
1.6. 
Overall Risk Benefit Assessment ...............................................................................48 
1.6.1. 
Summary of Benefits and Risks .................................................................................49 
1.7. 
Study Conduct ............................................................................................................49 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................51 
2.1. 
Objectives ...................................................................................................................51 
2.2. 
Endpoints ....................................................................................................................52 
3. 
STUDY DESIGN .......................................................................................................53 
3.1. 
Study Sites ..................................................................................................................53 
3.2. 
Estimated Study Dates and Duration of Subject Participation ...................................53 
3.3. 
Overview of Study Design ..........................................................................................53 
3.4. 
Treatment Groups and Randomization .......................................................................58 
3.5. 
Treatment Discontinuation and Withdrawals .............................................................58 
3.5.1. 
Treatment Discontinuation .........................................................................................59 
3.5.2. 
Study Withdrawal .......................................................................................................60 
3.5.3. 
Study Completion .......................................................................................................61 
3.5.4. 
End of Trial .................................................................................................................61 
4. 
STUDY POPULATION .............................................................................................62 
4.1. 
Target Population ........................................................................................................62 
4.2. 
Inclusion Criteria ........................................................................................................62 

 
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4.3. 
Exclusion Criteria .......................................................................................................64 
5. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................69 
5.1. 
Pre-Treatment Period ..................................................................................................69 
5.2. 
Treatment Period ........................................................................................................70 
5.3. 
Crossover Phase ..........................................................................................................72 
5.4. 
Post-Treatment Period ................................................................................................73 
5.5. 
Mainland China Extension Phase ...............................................................................73 
5.6. 
Maintenance Phase/Treatment after Study Completion .............................................74 
5.7. 
Unscheduled Visits or Assessments ...........................................................................75 
5.8. 
Procedure details .........................................................................................................75 
5.8.1. 
Demographics, Medical and Cancer History ..............................................................75 
5.8.2. 
Physical Examination .................................................................................................75 
5.8.3. 
Vital Signs ..................................................................................................................76 
5.8.4. 
Electrocardiograms .....................................................................................................76 
5.8.5. 
Safety Laboratory Assessments ..................................................................................77 
5.8.6. 
Tumor Assessments ....................................................................................................81 
5.8.7. 
Tumor Marker Assessment .........................................................................................85 
5.8.8. 
Health-related Quality of Life Assessments ...............................................................85 
5.8.9. 
Healthcare Resource Utilization .................................................................................86 
5.8.10. 
Pharmacokinetic Assessments ....................................................................................86 
5.8.11. 
Immunogenicity Assessments ....................................................................................86 
5.8.12. 
Biomarker Assessments ..............................................................................................86 
5.8.13. 
Overall Survival ..........................................................................................................88 
5.9. 
Protocol Deviations ....................................................................................................88 
6. 
TREATMENTS ..........................................................................................................89 
6.1. 
Composition, Formulation, and Storage .....................................................................89 
6.1.1. 
Study Treatment ..........................................................................................................89 
6.1.2. 
Sorafenib .....................................................................................................................90 
6.2. 
Treatment Schedule of Administration .......................................................................90 
6.2.1. 
Experimental Arm: Cabozantinib in Combination with Atezolizumab .....................90 
6.2.2. 
Control Arm: Sorafenib ..............................................................................................91 
6.2.3. 
Single-Agent Cabozantinib Arm: Cabozantinib .........................................................91 
6.2.4. 
Study Drug Administration on Week 1 Day 1 (W1D1) .............................................91 

 
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6.2.5. 
Cabozantinib Administration outside the Clinic .........................................................93 
6.2.6. 
Sorafenib Administration outside the clinic ...............................................................93 
6.3. 
Treatment after Study Completion .............................................................................94 
6.4. 
Compliance .................................................................................................................94 
6.5. 
Study Treatment Accountability .................................................................................94 
6.6. 
Safety Considerations .................................................................................................95 
6.6.1. 
Management of AEs with Dose Reductions and/or Dose Interruptions .....................95 
6.6.2. 
Warnings, Precautions, Guidelines for Management of Adverse Events .................102 
7. 
CONCOMITANT MEDICATIONS AND THERAPIES ........................................143 
7.1. 
Allowed Therapy ......................................................................................................143 
7.2. 
Prohibited or Restricted Therapy ..............................................................................144 
7.3. 
Potential Drug Interactions .......................................................................................146 
7.3.1. 
Potential Drug Interactions with Cabozantinib .........................................................146 
7.3.2. 
Potential Drug Interactions with Atezolizumab .......................................................148 
7.3.3. 
Potential Drug Interactions with Sorafenib ..............................................................148 
8. 
SAFETY ...................................................................................................................149 
8.1. 
Adverse Events and Laboratory Abnormalities ........................................................149 
8.1.1. 
Adverse Events .........................................................................................................149 
8.1.2. 
Laboratory Abnormalities .........................................................................................150 
8.2. 
Serious Adverse Events ............................................................................................150 
8.2.1. 
Definitions ................................................................................................................150 
8.2.2. 
Regulatory Reporting ................................................................................................152 
8.3. 
Adverse Events of Special Interest ...........................................................................153 
8.3.1. 
General Information on Immune-Related Adverse Events ......................................155 
8.4. 
Follow-Up of Adverse Events ..................................................................................155 
8.5. 
Other Safety Considerations .....................................................................................156 
8.5.1. 
Pregnancy .................................................................................................................156 
8.5.2. 
Medication Errors/Overdose .....................................................................................157 
9. 
STATISTICAL CONSIDERATIONS .....................................................................158 
9.1. 
Analysis Populations ................................................................................................158 
9.1.1. 
Intention-to-Treat Population ...................................................................................158 
9.1.2. 
Safety Population ......................................................................................................159 
9.2. 
Primary Efficacy Endpoints ......................................................................................159 

 
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9.2.1. 
Definitions ................................................................................................................159 
9.2.2. 
Primary Analysis ......................................................................................................160 
9.3. 
Secondary Efficacy Endpoint ...................................................................................162 
9.3.1. 
Progression Free Survival (PFS) per BIRC between Single-Agent 
Cabozantinib and Control Arms ...............................................................................162 
9.4. 
Additional Endpoints ................................................................................................162 
9.5. 
Control of Type I Error .............................................................................................163 
9.6. 
Safety Analyses ........................................................................................................164 
9.6.1. 
Adverse Events .........................................................................................................164 
9.6.2. 
Laboratory Test Results ............................................................................................165 
9.6.3. 
Other Safety Endpoints .............................................................................................165 
9.7. 
Power and Sample Size ............................................................................................165 
9.8. 
Interim Analyses .......................................................................................................168 
9.9. 
Analysis Methodology for China Subpopulation .....................................................170 
10. 
OTHER ANALYSES ...............................................................................................171 
10.1. 
Pharmacokinetic Analyses ........................................................................................171 
10.2. 
Immunogenicity Analyses ........................................................................................171 
10.3. 
Biomarker Analyses ..................................................................................................171 
11. 
DATA QUALITY ASSURANCE ............................................................................172 
12. 
STUDY COMMITTEES ..........................................................................................173 
12.1. 
Executive Safety Committee (ESC) .........................................................................173 
12.2. 
Independent Data Monitoring Committee (IDMC) ..................................................173 
12.3. 
Clinical Steering Committee (CSC) .........................................................................174 
12.4. 
Blinded Independent Radiology Committee (BIRC) ...............................................174 
13. 
ETHICAL ASPECTS ...............................................................................................175 
13.1. 
Local Regulations .....................................................................................................175 
13.2. 
Informed Consent .....................................................................................................175 
13.3. 
Institutional Review Board/ Ethics Committee ........................................................176 
13.4. 
Disposition of Subject Samples ................................................................................176 
14. 
CONDITIONS FOR MODIFYING THE PROTOCOL ..........................................177 
15. 
CONDITIONS FOR TERMINATING THE STUDY .............................................178 
16. 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORD 
KEEPING .................................................................................................................179 

 
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16.1. 
Investigator’s Files and Retention of Documents .....................................................179 
16.2. 
Source Documents and Background Data ................................................................179 
16.3. 
Audits and Inspections ..............................................................................................180 
16.4. 
Case Report Forms ...................................................................................................180 
17. 
MONITORING THE STUDY .................................................................................182 
18. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS ................................................................................................................183 
19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ...........184 
20. 
COMPLIANCE WITH DATA PROTECTION LAWS ...........................................185 
21. 
REFERENCES .........................................................................................................186 
APPENDICES .............................................................................................................................194 
 
 
 

 
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LIST OF TABLES 
Table 1: 
Summary of Safety Events in the Dose-Escalation Stage of Study XL184-
021 through 21 August 2018 ......................................................................................47 
Table 2: 
Laboratory Panels .......................................................................................................80 
Table 3: 
Estimation of the Creatinine Clearance by Cockcroft and Gault ...............................81 
Table 4: 
Criteria for Discontinuing Radiographic Assessments ...............................................83 
Table 5: 
Cabozantinib Tablet Components and Composition ..................................................89 
Table 6: 
Atezolizumab Infusion Requirements and Guidance .................................................92 
Table 7: 
Dose Levels of Cabozantinib (Oral Dosing) ..............................................................98 
Table 8: 
Dose Modifications for Cabozantinib-Related AEs ...................................................99 
Table 9: 
Dose Interruptions of Atezolizumab .........................................................................100 
Table 10: Dose Modifications for Atezolizumab-Associated Adverse Events ........................100 
Table 11: Management of Diarrhea Associated with Cabozantinib .........................................105 
Table 12: Management of Hypertensiona Associated with Cabozantinib ................................107 
Table 13: Management of Palmar-plantar Erythrodysesthesia Associated with 
Cabozantinib .............................................................................................................109 
Table 14: Management of Proteinuria Associated with Cabozantinib .....................................111 
Table 15: Management Guidelines for Immune-Related Pulmonary Events, Including 
Pneumonitis ..............................................................................................................118 
Table 16: Management Guidelines for Immune-Related Diarrhea or Colitis ...........................119 
Table 17: Management Guidelines for Endocrine Events ........................................................120 
Table 18: Atezolizumab Management Guidance of Immune-Related Dermatologic 
Events .......................................................................................................................123 
Table 19: Atezolizumab Management Guidance of Immune-Related Ocular Events ..............125 
Table 20: Management Guidelines for Immune-Related Meningoencephalitis .......................126 
Table 21: Management Guidelines for Immune-Related Neurologic Disorders ......................127 
Table 22: Management Guidelines for Immune-Mediated Myelitis ........................................128 
Table 23: Management Guidelines for Pancreatic Events, Including Pancreatitis ...................128 
Table 24: Management Guidelines for Immune-Related Nephritis ..........................................130 
Table 25: Management Guidelines for Immune-Related Cardiac Events ................................132 
Table 26: Management Guidelines for Immune-Related Myositis ...........................................132 
Table 27: Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosisor Macrophage Activation Syndrome .....................................135 
Table 28: Management Guidelines for Hepatic Events Associated with Atezolizumab ..........138 

 
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Table 29: Management Guidelines for Hepatic Events Associated with Cabozantinib ...........139 
Table 30: Management of Hepatic Encephalopathy Associated with Study Treatment ..........141 
Table 31: Adverse Events of Special Interest ...........................................................................154 
Table 32: Analysis Populations for the Global Enrollment Phase ............................................158 
Table 33: Summary of Endpoint Operating Characteristics .....................................................167 
 
LIST OF FIGURES 
 
Figure 1: 
XL184-312 Study Schema ..........................................................................................54 
 
LIST OF APPENDICES 
 
Appendix A: Schedule of Assessments .....................................................................................194 
Appendix B: Maintenance Phase ..............................................................................................201 
Appendix C: Performance Status Criteria .................................................................................204 
Appendix D: Preexisting Autoimmune Diseases and Immune Deficiencies ............................205 
Appendix E: Response Evaluation Criteria in Solid Tumors Version 1.1 (also known as 
RECIST 1.1) .............................................................................................................206 
Appendix F: List of Strong Inducers and Inhibitors of CYP3A4 .............................................215 
Appendix G: Infusion-Related Reaction and Cytokine Release Syndrome Guidelines ...........216 
Appendix H: Methods of Contraception ...................................................................................219 
Appendix I: Barcelona Clinic Liver Cancer (BCLC) Staging and Treatment Strategy ............220 
Appendix J: Child-Pugh Scoring System ..................................................................................221 
Appendix K: Collection, Follow-Up, and Documentation Requirements for AEs, 
AESIs, and SAEs ......................................................................................................222 
Appendix L:  EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version ...............224 
Appendix M:  COVID-19 Instructions......................................................................................226 
 
 
 
 

 
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LIST OF ABBREVIATIONS  
AASLD 
American Association for the Study of Liver Diseases 
AE 
adverse event 
AESI 
adverse event of special interest 
ACTH 
adrenocorticotropic hormone 
AFP 
alpha-fetoprotein  
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration-vs-time curve 
BCAAs 
branched-chain amino acids  
BCLC 
Barcelona Clinic Liver Criteria 
bid 
twice daily 
BIRC 
Blinded Independent Radiology Committee 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CAP 
chest/abdomen/pelvis 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CSC 
Clinical Steering Committee 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA  
CYP 
cytochrome P450 
DICOM 
Digital Imaging and Communications in Medicine  
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DVT 
deep vein thrombosis  

 
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EASL 
European Association for the Study of the Liver 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EMA SmPC 
European Medicines Agency Summary of Product Characteristics  
ESC 
Executive Safety Committee 
ES-SCLC 
extensive-stage small cell lung cancer  
FACS 
fluorescence-activated cell sorting 
FDG 
fluorodeoxyglucose 
FSH 
follicle stimulating hormone 
FT4 
free thyroxine  
FU-1 
first Post-Treatment Follow-up visit (30 [+14] days after decision to discontinue 
study treatment) 
FU-2 
second Post-Treatment Follow-up visit (100 [± 14] days after decision to discontinue 
study treatment) 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyltranspeptidase 
GI 
Gastrointestinal 
GLP  
Good Laboratory Practice 
HbA1c 
Hemoglobin A1c 
HBV 
hepatitis B virus  
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HE 
hepatic encephalopathy 
HGF 
hepatocyte growth factor 
HLH 
hemophagocytic lymphohistiocytosis 
HR 
hazard ratio 
HRQOL 
health-related quality of life 
HIV 
human immunodeficiency virus  
IA1 
first interim analysis 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICI 
immune checkpoint inhibitor 
IDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
IHC 
immunohistochemistry  
INR 
International Normalized Ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 

 
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IRF 
independent radiology facility 
IRR 
infusion-related reaction  
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IV 
intravenous or intravenously 
LD-OF 
Lan-DeMets O’Brien-Fleming  
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LH 
luteinizing hormone 
LMWH 
low molecular weight heparins  
LOLA 
L-ornithine L-aspartate 
MAS 
macrophage activation syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MRP2 
multidrug resistance-associated protein 2 
MTC 
medullary thyroid cancer 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
NPACT 
nonprotocol anticancer therapy 
ONJ 
osteonecrosis of the jaw 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed death receptor 1 
PD-L1 
programmed death ligand 1 
PEI 
percutaneous ethanol injection  
PFS 
progression-free survival 
PITT 
PFS Intent-to-Treat 
PK 
pharmacokinetic or pharmacokinetics 
PPE 
palmar-plantar erythrodysesthesia  
PPI 
proton pump inhibitor  
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome  
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
once daily 
qnw 
once every n weeks 
qod 
every other day 

 
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QTcF 
Corrected QT interval calculated by the Fridericia formula  
RCC 
renal cell carcinoma 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RFA 
radiofrequency ablation 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RSI 
reference safety information  
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SNP 
single nucleotide polymorphism  
TACE 
transarterial chemoembolization  
TARE 
transarterial radioembolization 
TEAE 
treatment-emergent adverse event  
TIA 
transient ischemic attack  
TKI 
tyrosine kinase inhibitor 
TNBC 
triple negative breast cancer 
Treg 
regulatory T-cell 
TSH 
thyroid-stimulating hormone  
TTP 
time to progression  
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
US PI 
US prescribing information  
VAS 
visual analog scale  
VEGFR 
vascular endothelial growth factor receptor  
W#D# 
Week # Day #  
WBC 
white blood cell 
 
 
 

 
XL184-312 Protocol Amendment 5.0 
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1. 
BACKGROUND 
1.1. 
Hepatocellular Carcinoma 
Liver cancer is the second most frequent cause of cancer deaths worldwide (Ferlay et al 2015). 
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, accounting 
for approximately 90% of cases. In 2015, 854,000 new liver cancer cases were reported 
worldwide and 810,000 deaths occurred (Global Burden of Disease Liver Cancer 2017; EASL 
2018). The estimated incidence and mortality rates of liver cancer in the USA in 2016 were 
approximately 42,000 and 30,000 cases, respectively (American Cancer Society 2018); incidence 
and mortality in the EU in 2012 were 52,000 and 48,000 cases, respectively (Ferlay et al 2013).  
Surgical resection and transplantation are potential curative treatment modalities for HCC. 
Ablative therapies (eg, radiofrequency ablation [RFA], microwave ablation [MWA], and 
percutaneous ethanol injection [PEI]) are being used for early stage unresectable HCC. 
Transarterial chemoembolization (TACE) is used generally for intermediate stage disease. The 
current standard of care for the systemic treatment of advanced unresectable HCC is sorafenib, 
which is a small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR) and 
other protein kinases. In a randomized placebo-controlled Phase 3 study (SHARP), sorafenib 
improved the primary endpoint of overall survival (OS) in subjects with Child-Pugh A advanced 
HCC who had not received prior systemic therapy (Llovet et al 2008). Median OS was 10.7 
months in the sorafenib arm and 7.9 months in the placebo arm (hazard ratio [HR] 0.69; 95% 
confidence interval [CI] 0.55, 0.87; p-value < 0.001). A similar HR was observed (with a shorter 
duration of OS than in the SHARP trial) in a corresponding placebo-controlled Phase 3 trial 
conducted in an Asian-Pacific population in which infection with hepatitis B virus (HBV) was 
the main cause of HCC: median OS was 6.5 months vs 4.2 months (HR 0.68; 95% CI: 0.50, 
0.93; p-value = 0.014) (Cheng et al 2009). The VEGFR-targeting tyrosine kinase inhibitor (TKI) 
lenvatinib was shown to be non-inferior to sorafenib in subjects with advanced HCC who had 
not received prior systemic therapy (Kudo et al 2018) leading to US and EU approval in this 
population. In that study, median OS for lenvatinib was 13.6 months compared with 12.3 months 
for sorafenib (HR 0.92; 95% CI 0.79, 1.06). 
Recently, immune checkpoint inhibitors (ICIs) that modulate the regulatory effects of 
programmed death receptor 1 (PD-1) with programmed death ligand 1 (PD-L1) have 
demonstrated activity in the treatment of HCC. The monoclonal antibody PD-1 inhibitor 
nivolumab was granted accelerated approval for the treatment of patients with HCC following 
prior sorafenib, regardless of PD-L1 status based on an objective response rate (ORR) 

 
XL184-312 Protocol Amendment 5.0 
Page 37 of 229 
determined by blinded central review of 18.2% (n=154); 3.2% of subject achieved a complete 
response (CR). Another anti-PD-1 antibody, pembrolizumab, demonstrated encouraging ORR of 
17% in sorafenib-pretreated HCC subjects in a single-arm Phase 2 study (Zhu et al [Lancet 
Oncol] 2018) and was also granted accelerated approval in the US for the treatment of patients 
with HCC previously treated with sorafenib. 
1.2. 
Cabozantinib 
Cabozantinib (XL184) is an inhibitor of multiple receptor tyrosine kinases (RTKs) known to 
play important roles in tumor cell proliferation and/or tumor neovascularization including MET, 
VEGFR, AXL, and RET.  
The RTK MET and its cognate ligand hepatocyte growth factor (HGF) play an important role in 
tumor pathobiology, including tumor growth, survival, neo-angiogenesis, invasion, and 
dissemination (Gherardi et al 2012). MET pathway activation and dysregulation have been 
implicated in multiple cancers, including HCC. Although its prevalence is not well characterized 
and may be influenced by source of tissue or methodology, MET has been found to be 
overexpressed in HCC compared with non-tumor liver tissue, with higher MET expression 
linked to poorer prognosis (Kaposi-Novak et al 2006, Kiss et al 1997, Ueki et al 1997). 
Moreover, small-molecule inhibitors of MET have been shown to exhibit efficacy in preclinical 
models of HCC (You et al 2011, Huynh et al 2012) and in early-phase clinical studies (Santoro et 
al 2013). The VEGFRs and ligands are central mediators of tumor neo-angiogenesis and 
lymphangiogenesis (Carmeliet et al 2011). High tumor microvessel density appears predictive of 
poor disease-free survival after HCC resection, and tumor vascular invasion is a well-established 
negative prognostic factor (Tanaka et al 1989, Greten et al 2009). Resistance to VEGF-targeted 
therapies may arise from the up-regulation of alternative pro-angiogenic and pro-invasive 
signaling pathways, including the MET pathway (Rimassa et al 2016, Rimassa et al 2018). 
Consistent with this, combined inhibition of VEGFR and MET results in efficacy enhanced over 
that achieved via inhibition of either pathway alone in tumor models (Aftab and McDonald 2011, 
Sennino et al [Cancer Discov] 2012, Sennino and McDonald [Nat Rev Cancer] 2012, You et al 
2011).  
In addition, other targets of cabozantinib are implicated in promoting tumor immune suppression 
including TYRO3, MER, and AXL (TAM family kinases). Preclinical studies (Kwilas et al 
2014, Lu et al 2017) and clinical observations on circulating immune suppressive cells and 
immune effector cells in cancer patients (Apolo et al 2014) suggest that cabozantinib promotes 
an immune-permissive environment that might present an opportunity for synergistic effects 
from combined treatment with ICIs.  

 
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Cabozantinib capsules (140 mg) are approved in the US for the treatment of patients with 
progressive, metastatic medullary thyroid cancer (MTC) and in the European Union for the 
treatment of patients with progressive, unresectable locally advanced or metastatic MTC 
(Cometriq™ US PI, EMA SmPC). Cabozantinib tablets (60 mg) are approved in the US, Europe, 
and other regions for advanced renal cell carcinoma (RCC; different patient populations 
depending on region; Cabometyx™ US prescribing information [US PI], European Medicines 
Agency Summary of Product Characteristics [EMA SmPC]). Based on the results from the 
studies described below, cabozantinib tablets (60 mg) have also been approved in the US and EU 
for the treatment of hepatocellular carcinoma (HCC) in patients who have previously been 
treated with sorafenib (Cabometyx US PI and EMA SmPC). 
The clinical activity and safety of cabozantinib (60 mg, tablets) in HCC has been demonstrated 
in a randomized placebo-controlled Phase 3 study (CELESTIAL) in subjects with advanced 
HCC who had received prior therapy with sorafenib (subjects were required to have progressed 
during or following prior systemic therapy and up to 2 prior lines of systemic therapy were 
allowed; Abou-Alfa et al 2018). A total of 773 subjects were enrolled. The primary endpoint of 
the study was OS. Up to three analyses of OS were planned: two interim analyses and a final 
analysis to occur when 311, 466 and 621 deaths (50%, 75% and 100%, respectively, of the total 
required number of events) had been observed. At the second pre-planned interim analysis, the 
prespecified event-driven primary efficacy endpoint analysis of the 707 subjects enrolled at the 
data cutoff (470 cabozantinib, 237 placebo), demonstrated a statistically significant improvement 
in OS for subjects in the cabozantinib arm compared with placebo (Intent-to-Treat [ITT] 
population): the HR, adjusted for stratification factors, was 0.76 (95% CI 0.63, 0.92; stratified 
log-rank p-value = 0.0049; critical p-value to reject the null hypothesis of equal OS = 0.021). 
The Kaplan-Meier estimates for median duration of OS were 10.2 months in the cabozantinib 
arm vs 8.0 months in the placebo arm, an estimated 2.2-month difference in the medians. The 
landmark estimate of the proportion of subjects event-free at 12 months was 46% in the 
cabozantinib arm compared with 34% in the placebo arm. The secondary endpoint analysis of 
PFS as determined by the investigator per Response Evaluation Criteria in Solid Tumors version 
1.1 (RECIST 1.1) yielded a median duration of PFS of 5.2 months in the cabozantinib arm and 
1.9 months in the placebo arm. The HR, adjusted for stratification factors, was 0.44 (95% CI 
0.36, 0.52, stratified log-rank p-value < 0.0001). Investigator-determined ORR per RECIST 1.1 
was 4% and 0.4% for subjects in the cabozantinib and placebo arms, respectively (unstratified 
Fisher exact test p-value = 0.0059); all were partial responses (PRs). In addition, there was a high 
rate of stable disease (SD) in the cabozantinib arm relative to placebo (60% vs 33%). 
Conversely, more subjects in the placebo arm had progressive disease (PD) as best overall 

 
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response (21% cabozantinib vs 55% placebo). In the cabozantinib arm of this HCC study, 99% 
of subjects experienced an adverse event (AE) regardless of causality, and 92% of subjects in the 
placebo arm had an AE. Adverse events reported for ≥ 20% of subjects in the cabozantinib arm 
by decreasing frequency were diarrhea, decreased appetite, palmar-plantar erythrodysesthesia 
(PPE), fatigue, nausea, hypertension, vomiting, aspartate aminotransferase (AST) increased, and 
asthenia. Grade 3 or 4 AEs regardless of causality were reported for 68% of subjects in the 
cabozantinib arm and 36% in the placebo arm. Grade 3 or 4 AEs reported for ≥ 5% of subjects in 
the cabozantinib arm by decreasing frequency were PPE, hypertension, AST increased, fatigue, 
diarrhea, asthenia, and decreased appetite. The higher incidence of Grade 3 or 4 AEs in the 
cabozantinib arm compared with the placebo arm was mainly due to the higher incidences of 
PPE (cabozantinib 17%, placebo 0%) and hypertension (16%, 1.7%) of those grades. The results 
of this study were the basis for regulatory applications to the US FDA and EMA for treatment of 
patients with advanced HCC who have received prior therapy. 
Earlier clinical evaluation of cabozantinib in HCC was conducted in a Phase 2 study that 
included both previously-treated and treatment-naïve subjects with advanced HCC (n=41; Kelley 
et al 2017). Progression-free survival from first dose throughout the study was estimated for all 
HCC subjects using a piecewise method; median PFS was 5.2 months. Tumor regression 
appeared independent of prior sorafenib exposure. 
1.3. 
Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody which potently and 
selectively inhibits binding of PD-L1 on tumor cells and tumor infiltrating immune cells in the 
tumor microenvironment (McDermott et al 2016). Through this interaction, atezolizumab 
interrupts the negative regulatory effects of PD-L1 on T-cell proliferation and function that result 
from PD-L1 binding to PD-1 and B7.1 (CD80) expressed on T lymphocytes and other immune 
cells. The result is an increase in the susceptibility of tumor cells to T-cell-mediated immune 
response, an effect that has been demonstrated in clinical activity across several tumor types. 
Atezolizumab injection, for intravenous (IV) use (1200 mg q3w), has been approved in the 
United States, the European Union, and other regions for the treatment of patients with advanced 
urothelial carcinoma (UC) after prior platinum containing chemotherapy or in a subset patients 
who are considered cisplatin-ineligible (different patient populations are indicated depending on 
region; Rosenberg et al 2016, Balar et al 2017). Atezolizumab is also approved for patients with 
locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy 
(Fehrenbacher et al 2016; Tecentriq™ US PI and EMA SmPC). Recently, atezolizumab was also 
granted accelerated approval in the US for treatment in combination with paclitaxel protein-

 
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bound for adult patients with unresectable locally advanced or metastatic triple negative breast 
cancer (TNBC) whose tumors express PD-L1 (Schmid et al 2018) and was also approved for 
first-line treatment in combination with carboplatin and etoposide in adult patients with 
extensive-stage small cell lung cancer (ES-SCLC; Horn et al 2018, Tecentriq US PI). Regulatory 
approvals of atezolizumab are either based on prolongation of OS or PFS, increased response 
rate, or durable responses. Treatment with atezolizumab is generally well-tolerated but can be 
associated with immune-related adverse events (irAEs).  
In a Phase 1b study of atezolizumab (1200 mg q3w) in combination with the anti-VEGF 
targeting antibody bevacizumab by the data cutoff of 26 July 2018, 103 subjects with advanced 
HCC naïve to systemic therapy had been enrolled (NCT02715531; Pishvaian et al 2018) and 
were evaluable for safety; 73 of these subjects were evaluable for efficacy with a minimum 
follow-up period of 16 weeks. Among the efficacy-evaluable subjects, the median survival 
follow-up was 7.2 months. The ORR by independent radiology facility (IRF) was 27% (with 
4 CRs) per RECIST 1.1 and was 34% (with 8 CRs) per mRECIST; ORR by Investigator per 
RECIST 1.1 was 32% with 1 CR. Confirmed responses were reported across the patient 
population regardless of HCC etiology, geographic region, baseline alpha-fetoprotein (AFP) 
levels, or extrahepatic spread of tumor. The investigator-assessed median PFS was 14.9 months 
(range: 0.5 to 23.9+ months) with a 6-month PFS rate of 65%; the IRF-assessed median PFS per 
RECIST 1.1 was 7.5 months (range: 0.4 to 23.9+ months). The median estimates for duration of 
response (DOR) and OS were not yet reached at the data cutoff. In the safety population (n=103), 
the most common (≥ 20% incidence) AEs were decreased appetite (28%), fatigue (20%), rash 
(20%), and pyrexia (20%). Treatment-related Grade 3 or 4 AEs were reported in 28 subjects 
(27%), most commonly hypertension (10 subjects [10%]). Five (5) Grade 5 AEs were observed, 
2 of which were assessed as treatment related (one sepsis, one pneumonitis). Adverse events of 
special interest (AESIs) of any grade for atezolizumab were reported for 54% of subjects, and 
AESIs of any grade for bevacizumab were reported for 47% of subjects. Immune-related AESIs 
for atezolizumab of ≥ Grade 3 requiring corticosteroid treatment included pneumonitis (2 
subjects), autoimmune encephalitis, drug-induced liver injury (DILI), colitis, AST increased, 
γ-glutamyltranspeptidase (GGT) increased, diabetes mellitus, and pancreatitis (1 subject each). A 
total of 19 subjects (18%) experienced treatment-related SAEs. The combination was considered 
well tolerated with no new safety signals beyond the established safety profiles of the individual 
agents. The high response rate observed suggested that the combination of atezolizumab with 
bevacizumab has synergistic activity in advanced HCC. Following these encouraging data, a 
Phase 3 study of atezolizumab in combination with bevacizumab compared with sorafenib in 
patients with untreated locally advanced or metastatic HCC has been initiated (NCT03434379). 

 
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These results improved upon the preliminary single-agent data with atezolizumab in subjects 
with treatment-naïve advanced HCC, in which few objective responses were observed (data 
provided by Roche):  
• A Phase 1a study evaluating the safety, PK, and preliminary evidence of biologic activity of 
atezolizumab administered as a single agent included 15 subjects with advanced HCC; 
5 subjects had not received prior systemic therapy (NCT01375842). For the 15 subjects with 
HCC, the median duration of treatment was 2 months (range: 0.7-6.3 months) at the time of 
data cutoff. There were no confirmed objective responses observed in the HCC subjects. The 
most commonly reported AEs (≥ 20%) in the HCC subjects (n=15) were fatigue and AST 
increased (40.0% each), diarrhea and nausea (33.3% each), ALT increased, 
thrombocytopenia, and decreased appetite (26.7% each), and pyrexia, anaemia, 
hypomagnesaemia, headache, and pruritus (20.0% each). Treatment-related ≥ Grade 3 AEs 
were AST increased (20.0%), ALT increased, blood ALP increased, blood bilirubin 
increased, and hepatocellular injury (6.7% each). Treatment-related SAEs occurred in 
3 subjects and all were single occurrences (hepatocellular injury, device-related infection, 
and blood bilirubin increased).  
• A second Phase 1 study evaluated the PK, safety, and preliminary anti-tumor activity of 
atezolizumab monotherapy in Chinese subjects with solid tumors (NCT02825940). Twenty-
one subjects with HCC were enrolled; 7 subjects had not received prior systemic therapy. Of 
the 7 previously-untreated HCC subjects, 2 subjects had a confirmed objective response. The 
two confirmed responses were still ongoing at the time of the clinical cutoff date (duration of 
responses: 6.90+ and 5.55+ months; + denotes a censored observation). Median PFS was 
1.5 months (95% CI: 1.4, not estimable) and median OS was 14.6 months (95% CI: 4.9, 
14.6) for the previously untreated HCC subjects. The most commonly reported AEs (≥ 20%) 
in the HCC subjects were AST increased and blood bilirubin increased (47.6% each), ALT 
increased (42.9%), pyrexia and decreased appetite (28.6% each), blood ALP increased and 
fatigue (23.8% each). Treatment-related ≥ Grade 3 AEs were blood bilirubin increased, 
hypokalemia and hyponatremia, lymphocyte count increased (2 subjects), pyrexia, diplopia, 
anemia, febrile infection, and hypoglycemia. Treatment-related SAEs occurred in 5 subjects 
and included one subject each with Grade 3 hepatic function abnormal, Grade 3 ALT 
increased, Grade 2 AST increased, Grade 4 lipase increased, and one subject with Grade 4 
hepatic failure and Grade 2 ascites. 
Similarly, the response rate of single-agent bevacizumab had been previously reported as 13% 
(6 of 46 subjects; Siegel et al 2008), suggesting the high response rate observed with the 

 
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combination of atezolizumab and bevacizumab of the combination of atezolizumab and 
bevacizumab was not solely a result of either agent alone and resulted from synergistic activity 
between the two agents in advanced HCC. 
1.4. 
Combination of Cabozantinib and Atezolizumab 
Currently, atezolizumab is being evaluated in combination with cabozantinib (40 mg and 60 mg 
once daily orally) with atezolizumab (1200 mg intravenously [IV] q3w) in multiple tumor 
cohorts in multi-tumor cohort Phase 1b trial XL184-021 (NCT03170960). In the dose escalation 
stage of the study, there were no dose-limiting toxicities (DLTs) or SAEs at either dose level of 
cabozantinib evaluated. Through 21 August 2018, all the subjects in the dose escalation stage 
(n=12) were still receiving study treatment, with the median follow-up of 33.4 weeks of 
treatment (range: 26-50 weeks). The majority of AEs were of Grade 1 or 2 including irAEs. 
Grade 3 AEs included five events of hypertension, two events each of diarrhea and 
hypophosphatemia, and one event each of pulmonary embolism, hyperglycemia, GGT increased, 
AST increased, ALT increased, lymphocyte count decreased, lipase increased, muscular 
weakness, nephritis, and myositis (verbatim term). No Grade 4 or 5 AEs were reported. Among 
10 evaluable subjects with clear cell RCC enrolled in the dose escalation stage, the investigator-
assessed confirmed ORR was 70% with 1 CR and 6 PRs. Although both dose levels of 60 mg 
and 40 mg cabozantinib were considered tolerable without DLTs, 40 mg cabozantinib once daily 
(qd) in combination with the standard dose level of 1200 mg atezolizumab was considered the 
preferred dose level from a benefit/risk evaluation perspective due to its favorable safety profile 
over a prolonged time on study treatment with minimal dose reductions and encouraging 
preliminary efficacy. Subsequent to the decision to further evaluate the 40 mg cabozantinib dose 
in combination with atezolizumab, the Expansion Stage of the XL184-021 was initiated. As of 
05 February 2019, 157 additional subjects had been enrolled in the expansion cohorts evaluating 
cabozantinib (40 mg, qd) + atezolizumab (1200 mg IV q3w). At the time of the cutoff, no 
subjects had been enrolled in the HCC cohort, which was added in a recent protocol amendment.  
Through 29 January 2019, safety data were evaluable for 141 expansion stage subjects. At that 
time, the subject with the greatest treatment duration in the expansion stage had been receiving 
study treatment for approximately 11 months. The most frequently reported AEs (≥ 20% 
incidence) of any grade regardless of causality were fatigue (30%), diarrhea (28%), decreased 
appetite (24%), AST increased (22%), ALT increased (21%), and dysgeusia (21%). Grade 4 AEs 
irrespective of causality were reported for 10 subjects and comprised: AST increased, GGT 
increased, neutropenia, thrombocytopenia, CK increased, sodium decreased, hyperlipasemia, 
intestinal perforation, renal failure chronic, sepsis. Grade 5 AEs were reported for 9 subjects and 

 
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comprised: dehydration, transitional cell carcinoma (2 subjects with UC), disease progression 
(3 subjects), general physical health deterioration, hepatic failure, and intestinal obstruction. The 
Grade 5 event of dehydration was assessed as related to study treatment and occurred in a 
90 year-old male with castration-resistant prostate cancer; the subject had significant 
co-morbidities prior to enrollment, including protein energy malnutrition with cachexia, ascites 
and edema. 
1.5. 
Rationale 
1.5.1. 
Rationale for Evaluating Cabozantinib in Combination with Atezolizumab in 
Advanced HCC 
Targeting the VEGF-signaling pathway with small molecule TKIs has improved the clinical 
outcome of patients with advanced HCC; however, the OS benefit has been modest with a 
median OS between 10.7 and 13.6 months (Llovet et al 2008; Kudo et al 2018). More recently 
immune checkpoint therapies that inhibit the interaction between PD-1 and PD-L1 have shown 
encouraging clinical activity in VEGFR-TKI pretreated and VEGFR-TKI naïve subjects with 
advanced HCC (El-Khoueiry et al 2017). HCC is thought to be a good candidate for 
immunotherapies since liver carcinogenesis is closely linked to impaired anticancer immunity. 
For example, chronic liver inflammation in subjects with chronic liver disease leads to 
upregulation of the immune checkpoint PD-1/PD-L1, activation of immune suppressive cells 
such as regulatory T-cells (Tregs), and secretion of immunosuppressive cytokines, promoting 
immunotolerance and emergence and progression of HCC (Jenne and Kubes 2013; Xu et al 
2006; Kassel et al 2009; Matsuzaki et al 2007). Besides the encouraging clinical data of 
single-agent ICIs in HCC there is a strong rationale to combine PD-1/PD-L1 targeting agents 
with multi-tyrosine kinase inhibitors such as cabozantinib or other VEGF-targeting drugs due to 
their potential synergistic effects in creating an immunopermissive environment (Khan and 
Kerbel 2018). Recent data from an ongoing Phase 1b trial evaluating an ICI (pembrolizumab) in 
combination with a VEGFR-TKI (lenvatinib) has shown that this combination is tolerable with 
encouraging antitumor activity (Ikeda et al 2018) with a response rate of 27% (confirmed 
responses) based on assessment of 26 subjects and a median PFS of 9.69 months. Similarly, a 
combination of atezolizumab with the VEGF targeting agent bevacizumab has demonstrated 
very encouraging preliminary clinical activity in subjects with advanced HCC with a response 
rate of 27% and a median PFS of 7.5 months based on independent radiological assessment per 
RECIST 1.1 of 73 subjects (Pishvaian et al 2018). Moreover, the combination of cabozantinib 
with atezolizumab has shown very encouraging clinical activity and tolerability in subjects with 
advanced cancer in a Phase 1b multi-tumor cohort study (refer to Section 1.4). Based on all of 
the above, further evaluation of cabozantinib in combination atezolizumab is warranted and has 

 
XL184-312 Protocol Amendment 5.0 
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the potential to improve the clinical outcome of subjects with advanced HCC due to synergistic 
activities of the two agents.  
1.5.2. 
Rationale for Study Design 
This study is a randomized, controlled Phase 3 study of cabozantinib in combination with 
atezolizumab versus sorafenib in subjects with advanced HCC who have not received previous 
systemic anticancer therapy. The multiple primary endpoints are PFS by Blinded Independent 
Radiology Committee (BIRC) and OS. 
Historically, OS has been used as a primary endpoint in clinical trials for HCC, a disease that 
long had very few treatment options, even after the approval of sorafenib. In the past two years, 
several agents have been approved for post-sorafenib therapy (eg, nivolumab in the United States 
and regorafenib worldwide), and lenvatinib has demonstrated non-inferiority to sorafenib for 
previously untreated patients leading to US and EU approval in that population, providing 
another potential treatment option. Regorafenib improved overall survival after progression on 
sorafenib in subjects with prior sorafenib tolerance in the RESORCE trial (Bruix et al 2017), 
leading to approval in this population. Recently, ramucirumab has demonstrated improved OS 
and PFS versus placebo in patients with elevated (≥ 400 ng/mL) baseline AFP following 
sorafenib treatment as the first biomarker-selected treatment in HCC (Zhu et al [J Clin Oncol] 
2018). Nivolumab was the first checkpoint inhibitor approved by FDA in advanced HCC based 
upon promising ORR in the non-randomized Checkmate-040 trial (El-Khoueiry et al 2017). In 
addition, FDA granted accelerated approval for pembrolizumab in sorafenib-pretreated advanced 
HCC based on promising ORR (17%) in the non-randomized KEYNOTE-224 study (Zhu et al 
[Lancet Oncol] 2018). 
Given the multiple treatment options currently available and the changing treatment landscape in 
advanced HCC, subsequent anticancer therapy may confound the effect on OS in treatment-naïve 
subjects. Further, in the double-blinded, placebo-controlled Phase 3 study of cabozantinib in 
previously-treated HCC, a statistically significant improvement in both OS and PFS (per 
investigator assessment) for cabozantinib was demonstrated (refer to Section 1.2). Based on 
these data, cabozantinib (60 mg tablets) has been approved in the US and EU for treatment of 
patients with HCC who were previously treated with sorafenib. These approvals introduce the 
potential for off-study crossover for the subjects randomized to the sorafenib arm in the proposed 
study in the regions where cabozantinib is commercially available.  

 
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Also, a meta-analysis conducted using data from 10 studies with a total of 20 treatment arms and 
6689 subjects suggests that either time to progression (TTP) or PFS could serve as a surrogate 
marker for OS in the clinical trials of advanced HCC (Lee et al 2016).  
Therefore, PFS may provide an important indicator of clinical benefit in first line subjects and 
has been chosen as a multiple primary endpoint for this trial. For the purpose of evaluating 
radiographic study endpoints, a BIRC will be used to minimize bias in this open-label study. 
Given the importance of OS as an endpoint in HCC, OS will also be a multiple primary endpoint 
and will be analyzed whether or not the PFS analysis is positive. In order to avoid confounding 
the analysis of OS, crossover between treatment arms within the study will not be allowed until 
all endpoints of the study are available and shown to sufficiently support the safety and efficacy 
of the combination of cabozantinib + atezolizumab.  
In recent years regulatory agencies have issued guidance for evaluating combination therapies 
requiring nonclinical and clinical evidence that supports the need for both components of the 
treatment regimen. In light of this guidance, direct discussions with regulatory agencies, and the 
limited amount of clinical data available for the administration of cabozantinib in the first-line 
HCC setting, a third treatment arm (approximately 185 subjects) will be enrolled in which 
subjects receive single-agent cabozantinib in order to determine its contribution to the overall 
safety and efficacy of the combination with atezolizumab in this patient population. Given the 
statistically significant improvement in OS and PFS demonstrated with single-agent cabozantinib 
in a previously treated HCC population and subsequent regulatory approval for cabozantinib to 
treat those patients, early observations of clinical activity in a previously untreated HCC 
population, and the demonstration of efficacy of other VEGFR-TKIs (eg, sorafenib, lenvatinib) 
in a previously untreated HCC population, exploration of cabozantinib (at the recommended 
single-agent dose of 60 mg) in a previously untreated HCC population is justified. A formal 
planned analysis of PFS for the single-agent cabozantinib arm vs the control arm (sorafenib) as a 
secondary endpoint will evaluate the relative efficacy of those two agents and will provide the 
basis for establishing the contribution of cabozantinib to combination therapy administered in the 
experimental arm. 
In order to evaluate the full clinical benefits of the combination therapy of cabozantinib with 
atezolizumab, the current Phase 3 study includes analyses of health-related quality of life 
(HRQOL), healthcare resource utilization, pharmacokinetics (PK), and biomarkers. 
 

 
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It is planned to include up to 148 subjects from mainland China in this study to assess safety and 
efficacy in the China subpopulation. In the event enrollment in mainland China is incomplete by 
the time the global enrollment phase has been completed, a Mainland China Extension Phase 
will be implemented to complete enrollment and facilitate subpopulation analyses as needed. The 
global population will include all subjects enrolled during the global enrollment phase (including 
subjects enrolled at sites in mainland China during that phase), and the China subpopulation will 
include all subjects enrolled at sites in China (ie, during both the global enrollment phase and the 
Mainland China Extension Phase). 
1.5.3. 
Rationale for Study Treatment Dose Selection and Treatment Schedule 
In accordance with the standard approved dose, atezolizumab 1200 mg will be administered as 
an IV infusion over 60 min (± 15 min) every 3 weeks (± 2 days) on Day 1 of each 21-day cycle 
(Tecentriq US PI, SmPC). 
The approved tablet dose level for the single-agent treatment of advanced RCC is 60 mg and was 
also the dose used for the evaluation of cabozantinib as a single agent in the Phase 3 
CELESTIAL study in previously treated HCC, which supported the recent approvals of that dose 
for the treatment of HCC following previous treatment with sorafenib in the US and EU. Dose 
reductions to 40 mg and 20 mg are utilized to manage AEs. In the Phase 3 CELESTIAL study in 
HCC, the average daily dose was 35.8 mg/day, taking into account dose modifications.  
In the Dose-Escalation Stage of the Phase 1b study XL184-021 evaluating the combination of 
cabozantinib with atezolizumab, cabozantinib was administered orally daily at dose levels of 
40 and 60 mg in escalation cohorts (NCT03170960). A total of 12 subjects with advanced RCC 
were enrolled, six subjects at each cabozantinib dose level (40 mg and 60 mg). After reviewing 
safety data at both dose levels, the Cohort Review Committee determined that cabozantinib 
40 mg qd orally in combination with 1200 mg atezolizumab q3w IV would be the recommended 
dose for further evaluation in the Expansion Stage of the study in multiple tumor types; the 
Expansion Stage is currently ongoing. The 40-mg dose was also determined to be the 
recommended dose for cabozantinib in the clinical evaluation of the combination of cabozantinib 
with nivolumab, another antibody inhibitor of the PD-1/PD-L1 pathway (Apolo et al 2016).  
A safety summary with a data cutoff date of 21 August 2018 of the XL184-021 Dose-Escalation 
Stage showed that all 12 enrolled subjects were still active. The median duration of follow-up at 
that time was 33.4 weeks (range: 26-50 weeks). The majority of all-causality AEs at both dose 
levels (cabozantinib 40 and 60 mg) were of Grade 1 and 2 in severity and there were no Grade 4 
or 5 events. Grade 3 AEs at the cabozantinib 40 mg dose level included hypertension (n=3), 

 
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hypophosphatemia (n=1), pulmonary embolism (n=1), hyperglycemia (n=1), GGT increased 
(irAE, n=1), muscular weakness (n=1), and myositis (verbatim term, irAE, n=1). Grade 3 AEs at 
the cabozantinib 60 mg dose level included hypertension (n=2), diarrhea (n=2), AST increased 
(irAE, n=1), ALT increased (irAE, n=1), hypophosphatemia (n=1), lipase increased (irAE, n=1), 
lymphocyte count decreased (n=1), and nephritis (n=1). All AEs were manageable by dose 
modifications including dose reductions and dose delays as well as supportive care. Both 
assigned dose levels of cabozantinib (40 mg and 60 mg) were well tolerated over extended 
dosing periods with no DLTs during the Dose-Escalation Stage, and confirmed responses were 
observed. However, there was a higher rate of dose reductions (cabozantinib) and dose delays 
(atezolizumab) in subjects enrolled at the cabozantinib 60 mg dose level, suggesting that the 
longer term tolerability of the combination was improved at the cabozantinib 40 mg dose level. 
The overall safety profile of each study treatment component remained consistent with previous 
reports. A safety overview for the two dose level cohorts explored in the Dose-Escalation Stage 
is shown in Table 1. 
Table 1: 
Summary of Safety Events in the Dose-Escalation Stage of Study XL184-021 
through 21 August 2018 
Event 
Cabozantinib 40 mg + 
Atezolizumab 1200 mg 
(N=6) 
Cabozantinib 60 mg + 
Atezolizumab 1200 mg 
(N=6) 
DLT 
0 
0 
SAE 
0 
0 
Grade 3 AE 
5 (83%) 
6 (100%) 
Grade 3 Immune-related AE (irAE) 
1 (17%) 
2 (33%) 
AE leading to cabozantinib dose reduction 
3 (50%) 
6 (100%) 
AE leading to atezolizumab dose delay 
1 (17%) 
4 (67%) 
AE, adverse event; SAE, serious adverse event. 
As of 11 February 2019, 11 of the 12 subjects continue on study treatment. The first subject 
enrolled in the Dose Escalation Stage discontinued in January 2019, after 15+ months on study 
treatment. 
Subsequent to the decision to further evaluate the 40 mg cabozantinib dose in combination with 
atezolizumab, the expansion stage of the XL184-021 was initiated. As of 05 February 2019, 
157 additional subjects had been enrolled in the expansion cohorts evaluating cabozantinib 
(40 mg, qd) + atezolizumab (1200 mg IV q3w); information on the 141 subjects evaluable for 
safety as of 29 January 2019 is provided in Section 1.4. 

 
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1.6. 
Overall Risk Benefit Assessment  
Liver cancer is the second most frequent cause of cancer deaths worldwide (Ferlay et al 2015). 
Hepatocellular carcinoma is the most common form of primary liver cancer, accounting for 
approximately 90% of cases. In 2015, 854,000 new liver cancer cases were reported worldwide 
and 810,000 deaths occurred (Global Burden of Disease Liver Cancer 2017; EASL 2018). The 
estimated incidence and mortality rates of liver cancer in the USA in 2016 were approximately 
42,000 and 30,000 cases, respectively (American Cancer Society 2018 ); incidence and mortality 
in the EU in 2012 were 52,000 and 48,000 cases, respectively (Ferlay et al 2013).  
Cabozantinib is a potent inhibitor of multiple RTKs known to play important roles in tumor cell 
proliferation and/or tumor neovascularization including MET, VEGFR, AXL, and RET. 
Recently, a randomized placebo-controlled Phase 3 study (CELESTIAL) of cabozantinib 
(60 mg, tablets) in subjects with advanced HCC who had received prior therapy with sorafenib 
has been conducted. The study met its primary endpoint of improving survival of subjects treated 
with cabozantinib, and the safety and tolerability of cabozantinib in that population was 
established in the study (Abou-Alfa et al 2018). The results of this study (see Section 1.2) lead to 
the approval in the US FDA and EU for treatment of patients with advanced HCC who have 
received prior sorafenib. Early evaluation of cabozantinib in previously treated and untreated 
HCC subjects showed clinical activity regardless of prior therapy. 
Recently, immunotherapies have expanded treatment options for subjects with advanced HCC. 
For example, nivolumab, a PD-1 targeting ICI received accelerated approval in the United States 
based on response rate and response duration for the treatment of subjects with advanced HCC 
who have been previously treated with sorafenib (Opdivo US PI; NCCN V3.2018). A Phase 3 
trial evaluating nivolumab in treatment-naïve advanced HCC is ongoing (NCT02576509). 
Similarly, pembrolizumab, another PD-1 inhibitor, has received accelerated approval for the 
treatment of HCC patients who have received prior sorafenib, and is being further evaluated in 
combination with lenvatinib in a previously untreated population. In addition, based on very 
encouraging early clinical stage study results, atezolizumab is also being evaluated in a Phase 3 
trial in combination with bevacizumab compared with sorafenib in subjects with untreated 
locally advanced or metastatic HCC (NCT03434379). 
The combination dosing regimen of cabozantinib and atezolizumab for the current study is based 
on the dose finding results in the ongoing Phase 1b combination study (NCT03170960) and is 
expected to mitigate potential overlapping AEs and improve long-term tolerability of the 
regimen. The dose in the single-agent cabozantinib arm has demonstrated improved OS and PFS 
in RCC and previously treated HCC. 

 
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In this study subjects will be allowed to receive treatment as long as they continue to experience 
clinical benefit in the opinion of the investigator (see Section 5.8.6.3) or until unacceptable 
toxicity, the need for subsequent systemic anticancer treatment, or until any other reasons for 
treatment discontinuation listed in the protocol (Section 3.5). 
Study inclusion/exclusion criteria were designed to prevent subjects at a heightened safety risk 
from entering the study (Section 4.2 and Section 4.3). The protocol provides guidance to 
investigators for the management of important AEs that are associated with cabozantinib, 
atezolizumab, and sorafenib (Section 6.6.2). Frequent safety assessments including laboratory 
assessments allow identification and early intervention of potential AEs due to study treatment. 
An Independent Data Monitoring Committee (IDMC) will monitor the safety of the study on a 
regular basis. The committee will operate independently from the Sponsor and the clinical 
investigators. To minimize the potential introduction of bias, these individuals will not have any 
direct contact with the study site personnel or subjects. IDMC members will be selected for their 
expertise in conducting studies in oncology. Additionally, the Sponsor’s safety committee will 
monitor the safety of the study on a regular basis.  
1.6.1. 
Summary of Benefits and Risks 
Cabozantinib and atezolizumab have demonstrated clinical activity as single agents and in 
combination with other drugs in various tumor types including HCC. In addition, in the ongoing 
Phase 1b study the combination of cabozantinib with atezolizumab has been well tolerated and 
demonstrated encouraging clinical activity indicating possible synergistic effects of both agents 
in subjects with advanced cancer. The safety profile of each agent is well defined, and dose 
modification guidelines have been established and used in previous clinical studies to effectively 
manage side effects. The combination therapy of atezolizumab and cabozantinib provides a new 
treatment opportunity with a manageable safety profile for subjects with advanced HCC who 
normally have a 5-year survival of less than 10%. The clinical activity of the combination is 
expected to be superior to treatment with either agent alone.  
1.7. 
Study Conduct 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonisation (ICH) Guidelines and also consistent with the most 
recent accepted version of the Declaration of Helsinki. In addition, all applicable local laws and 
regulatory requirements relevant to the use of new therapeutic agents in the countries involved 
will be adhered to. 

 
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The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) must approve the protocol, any amendments, 
and the subject informed consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to participation 
in this clinical trial. The rights, safety, and well-being of participating subjects are the most 
important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel for whom sanctions have been invoked or there has been scientific misconduct or 
fraud (eg, loss of medical licensure, debarment, etc). 

 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of this study is to evaluate the efficacy of cabozantinib in combination 
with atezolizumab versus sorafenib in subjects with advanced HCC who have not received 
previous systemic anticancer therapy. A secondary objective is to evaluate the single-agent 
activity of cabozantinib compared with sorafenib in this patient population. 

 
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2.2. 
Endpoints 
Primary Efficacy Endpoints: 
• Duration of PFS per RECIST 1.1, by BIRC for the experimental arm (cabozantinib + 
atezolizumab) vs the control arm (sorafenib) 
• Duration of OS for the experimental arm (cabozantinib + atezolizumab) vs the control 
arm (sorafenib) 
Secondary Efficacy Endpoints: 
• PFS per RECIST 1.1 by BIRC for the single-agent cabozantinib arm vs the control arm 
(sorafenib) 
Additional Endpoints: 
• ORR, TTP, and DOR per RECIST 1.1 by BIRC and Investigator  
• Evaluation of radiographic response per modified RECIST (mRECIST) 
• Safety through the evaluation of AEs, including irAEs and other AESIs  
• Characterization of the PK of cabozantinib in subjects with previously untreated HCC  
• Immunogenicity of atezolizumab given in combination with cabozantinib 
• Change in serum AFP from baseline 
• Correlation of biomarker analyses with clinical outcomes 
• Health-related quality of life (HRQOL) as assessed by the EuroQol Health questionnaire 
instrument (EQ-5D-5L) 
• Healthcare resource utilization 

 
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3. 
STUDY DESIGN 
3.1. 
Study Sites 
This study will be conducted at approximately 250 global clinical sites. 
3.2. 
Estimated Study Dates and Duration of Subject Participation 
It is estimated that it will take approximately 25 months to randomize 740 subjects in the ITT 
population for the primary and secondary analyses at approximately 250 global sites. The 
number of events required for the final analysis of one of the endpoints of PFS (257 events 
among the first 372 subjects randomized to the cabozantinib + atezolizumab combination and 
sorafenib arms) is expected to be observed approximately 18 months after the first subject is 
randomized. The number of events required for the final analysis of OS (368 events among the 
555 subjects randomized to the cabozantinib + atezolizumab combination and sorafenib arms) is 
expected to be observed approximately 38 months after the first subject is randomized.  
After completion of the global enrollment phase, additional subjects (up to 148) may be enrolled 
in a Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. It is estimated that randomization of the subjects in mainland China during the 
global enrollment phase and Mainland China Extension Phase will require at least 21 months. 
The true intervals required to meet the milestones above may be longer or shorter due to 
divergence from assumptions, including non-constant accrual rate due to the time required for all 
study sites to become active, or due to the impact of the global COVID-19 pandemic on subject 
enrollment and other aspects of study conduct.  
It is estimated that subjects will participate for an average of 6 months on study treatment. Some 
study assessments continue periodically after study treatment is discontinued, and subjects will 
be followed until death, withdrawal of consent for non-interventional study assessments, or 
Sponsor decision to no longer collect these data. 
3.3. 
Overview of Study Design 
This is a multicenter, randomized, open-label, controlled Phase 3 trial of cabozantinib in 
combination with atezolizumab versus sorafenib in subjects with advanced HCC who have not 
received previous systemic anticancer therapy. PFS and OS are multiple primary efficacy 
endpoints. Additionally there will be a third arm to evaluate the single-agent safety and activity 
of cabozantinib. Approximately 740 eligible subjects with advanced HCC were planned to be 
randomized in a 2:1:1 ratio at approximately 250 sites in this trial to receive study treatment in 

 
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the global enrollment phase of the study as described in Section 3.3. However, enrollment 
commenced under a randomization ratio of 6:3:1 per the original protocol design, and there was 
a dynamic transition in randomization allocation over time. As a result, the needed enrollment of 
185 subjects in the single-agent cabozantinib arm was not expected to be reached at the planned 
total global enrollment phase sample size of 740 subjects. Therefore, to ensure complete 
enrollment in the single-agent cabozantinib arm, the total global enrollment phase was extended 
to accrue a total of approximately 840 subjects. 
After completion of the global enrollment phase, additional subjects (up to 148) may be enrolled 
in a Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. The global population will include all subjects enrolled during the global 
enrollment phase (including subjects enrolled at sites in mainland China during that phase), and 
the China subpopulation will include all subjects enrolled at sites in China (ie, during both the 
global enrollment phase and the Mainland China Extension Phase). 
The sample size for the global study may be increased up to an additional 25% if a review of the 
accumulating data suggests that the COVID-19 pandemic has caused the rate of study dropout or 
non-compliance to increase to a degree that the ability to adequately evaluate study endpoints 
may be undermined. The Mainland China Extension Phase will not be expanded beyond 148 
subjects. 
Special accommodations during the global COVID-19 pandemic are described in Appendix M. 
Figure 1: 
XL184-312 Study Schema 
 

 
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The trial consists of the following phases:  
Pre-Treatment Period: Potential subjects will be screened to determine if they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 28 days 
before randomization unless otherwise specified.  
Guidance for diagnosis of HCC in cirrhotic patients by imaging is provided in Section 5.8.6.1. 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in 
a 2:1:1 manner to receive study treatment as follows:  
Experimental arm (at least 370 subjects):  
Cabozantinib (40 mg oral, qd) +  
Atezolizumab (1200 mg infusion, q3w) 
Control arm (at least 185 subjects):  
Sorafenib (400 mg, twice a day [bid]) 
Single-Agent Cabozantinib Arm (approximately 185 subjects):  
Cabozantinib (60 mg qd)  
Details about the investigational regimens are provided in Section 6. 
Subjects will receive study treatment as long as they continue to experience clinical benefit in the 
opinion of the Investigator (see Section 5.8.6.3) or until there is unacceptable toxicity, the need 
for subsequent systemic anticancer treatment, or any other reasons for the treatment 
discontinuation listed in the protocol (Section 3.5). Subjects are allowed to discontinue one 
component of the experimental arm (cabozantinib and atezolizumab) but continue to receive the 
other. Crossover from the control or single-agent cabozantinib arms to experimental therapy will 
not be allowed unless study transitions to a Crossover Phase. 
Crossover Phase: The study may transition to a Crossover Phase if the analysis of the primary 
endpoint of OS for the global ITT population (ie, not including subjects enrolled in the Mainland 
China Extension Phase) shows statistically significant and clinically meaningful evidence of 
improvement.  
The Crossover Phase will only be implemented upon decision by the Sponsor and following any 
required discussion with regulatory authorities following review of the data. Crossover may be 
implemented independently and at different points in time for study sites and subjects in 

 
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mainland China compared to other sites and subjects in the global study. If the decision is made 
to enter the Crossover Phase, study sites will have 8 weeks to determine eligibility and begin 
administration of crossover treatment (cabozantinib + atezolizumab combination) to eligible 
subjects randomized to the control arm (sorafenib) or the single-agent cabozantinib arm; 
subsequently no further crossover will be allowed.  
The study is expected to have completed enrollment in the global enrollment phase at the time of 
transitioning to the Crossover Phase for subjects who enrolled in that phase, but accrual of 
subjects in the Mainland China Extension Phase may still be ongoing at that point. In the 
Crossover Phase safety and efficacy assessments will continue as scheduled; PK, biomarker, 
HRQOL, and healthcare resource utilization assessments will be discontinued. 
Post-Treatment Period: A first Post-Treatment Follow-up visit (FU-1) for safety evaluation 
(including subjects in the Maintenance Phase [below]) is to occur 30 (+14) days after the date of 
the decision to permanently discontinue study treatment (defined as the later of the date of the 
decision to permanently discontinue study treatment or the date of the last dose of study 
treatment). A second Post-Treatment Follow-up visit (FU-2) for safety evaluation will be 
conducted approximately 100 days (±14 days) after the date of the decision to permanently 
discontinue study treatment. Further details for follow-up and data collection requirements for 
AEs, SAEs, and AESIs are summarized in Appendix K.  
Radiographic tumor assessments and HRQOL assessments are to continue, regardless of whether 
study treatment is given, reduced, held or discontinued until a protocol-defined criterion for 
ending radiographic assessments is met (see Section 5.8.6.3). Consequently these assessments 
may be required in the Post-Treatment Follow-up Period for some subjects.  
In addition, subjects are to be contacted every 12 weeks (± 14 days) after FU-2 to assess survival 
status and document receipt of subsequent anticancer therapy. This follow-up will continue until 
the subject expires or the Sponsor decides to discontinue collection of these data; however, these 
assessments are not required in the Maintenance Phase (below). Every effort must be made to 
perform these evaluations unless consent is withdrawn. 
Mainland China Extension Phase: After completion of the global enrollment phase, additional 
subjects (up to 148) may be enrolled in a Mainland China Extension Phase at sites in mainland 
China for evaluation in a China subpopulation. The Pre-Treatment, Treatment, and Post-
Treatment Periods of the study will be conducted in the same manner in the Mainland China 
Extension Phase as for subjects who were enrolled in the global enrollment phase. 

 
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Study Completion: The study will be considered complete if the null hypothesis is rejected for 
the primary endpoint of OS (experimental vs control arm) in either of the two planned interim 
analyses or if the final planned analysis for OS has been conducted (irrespective of the results) 
and any required supportive analyses for China are completed. 
Maintenance Phase/Treatment After Study Completion: The purpose of the Maintenance 
Phase is to continue to provide long-term access to study drug(s) to subjects who are deriving 
clinical benefit even after the study objectives have been completed (Study Completion, see 
above). When sufficient data have been collected to adequately evaluate all study endpoints, 
subjects who continue study treatment may enter the study Maintenance Phase. Upon initiation 
of the Maintenance Phase, the Sponsor considers the safety and efficacy profile of the 
experimental treatment regimen within this study to have been sufficiently established and data 
analyses required for regulatory purposes to have been completed. If a Crossover Phase has been 
implemented, the Maintenance Phase may not begin before the Week 9 Day 1 (W9D1) visit has 
elapsed in the Crossover Phase for the last subject randomized to sorafenib or single-agent 
cabozantinib who crossed over to receive cabozantinib + atezolizumab. The Sponsor is to notify 
the sites if or when the study will enter the Maintenance Phase or if an alternative post-Study 
Completion option will be implemented (Section 6.3).  
In the Maintenance Phase, subjects will continue to receive study treatment until they meet the 
protocol-required criteria for treatment discontinuation. Subjects are to undergo periodic safety 
assessments (including local laboratory tests) and tumor assessments. The nature and frequency 
of these assessments during the Maintenance phase are to be performed per institutional standard 
of care and guidance from the sponsor (see Appendix B). It is the Investigator’s responsibility to 
ensure that subject visits occur frequently enough and adequate assessments are performed to 
ensure subject safety.  
In order to continue to collect important safety information for subjects enrolled in the study 
during the Maintenance Phase, reporting of SAEs; certain AEs (including irAEs and other AESIs 
[whether serious or not], and AEs leading to dose modifications or treatment discontinuation); 
and other reportable events (pregnancy and medication errors with sequelae) is to continue per 
protocol requirements specific to the Maintenance Phase. 
The study clinical database will be closed upon initiation of the Maintenance Phase. Important 
safety information (noted above) collected in the Maintenance Phase will be captured in the 
safety database. Only data collected prior to implementation of Maintenance Phase will be 
reported in a clinical study report. 

 
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End of Trial: End of trial is defined as the last scheduled visit or scheduled procedure for the 
last subject (including Maintenance Phase assessments). 
3.4. 
Treatment Groups and Randomization  
After obtaining informed consent, the site representative will use the designated web-based 
interactive response technology (IRT) system to register a subject. The IRT will assign a unique 
subject number. When a subject has been deemed eligible at the study site, the site representative 
will use the IRT to randomize and enroll the subject into the study.  
Eligible subjects will be randomly assigned in a 2:1:1 ratio to the following treatment arms:  
• Experimental arm: Cabozantinib (40 mg oral, qd) + atezolizumab (1200 mg infusion, q3w) 
• Control arm: Sorafenib (400 mg, bid) 
• Single-agent cabozantinib arm: Cabozantinib (60 mg oral, qd) 
Details about treatment regimens are provided in Section 6. 
Randomization will be stratified by the following factors established at screening: 
• Disease etiology (HBV [with or without hepatitis C virus {HCV}], HCV [without HBV], or 
Other) 
• Region (Asia, Other) 
• Presence of extrahepatic disease and/or macrovascular invasion (Yes, No) 
Randomization should occur as close as possible to the planned start of treatment (ie, within 
3 days). Subjects are defined as enrolled in the study if randomized. Changes to stratification 
values entered in the IRT will not be performed after randomization. Randomization will not be 
voided except under very rare circumstances and with Sponsor approval. Subjects who sign 
consent, are assigned a subject identifier, and are screened (to any degree, including rescreening) 
but never randomized are deemed permanent screen failures.  
If initiated, subjects recruited in the Mainland China Extension Phase will be randomized 
according to the same 2:1:1 scheme as subjects in the global enrollment phase. 
3.5. 
Treatment Discontinuation and Withdrawals 
Details for handling treatment discontinuation and study withdrawal are discussed in 
Sections 3.5.1 and 3.5.2, respectively.  

 
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If a subject requests to discontinue study treatment and/or withdraws study consent, the 
Investigator must establish the specific nature of the subject’s request. 
The subject’s decisions (there may be more than one over time) must be recorded in source 
documents and transcribed to study case report forms (CRFs). 
3.5.1. 
Treatment Discontinuation 
Subjects will receive study treatment until treatment discontinuation for any of the reasons listed 
below. Subjects may discontinue study treatment and assessments or withdraw their consent to 
participate in the study at any time without prejudice. If a subject discontinues study treatment, 
the reason will be documented in source documents and all study treatment will be stopped. The 
Investigator may also discontinue a subject from study treatment if in his or her clinical 
judgment it is in the best interest of the subject or if the subject cannot comply with the protocol. 
In addition, the investigator will also discontinue a subject from study treatment upon the 
Sponsor’s request or if the Sponsor chooses to terminate the study.  
Furthermore, any of the following conditions require withdrawal of the subject from study 
treatment: 
• Unacceptable side effects the Investigator feels may be due to study treatment. Continuation 
of one component of the combination study treatment while discontinuing the other will be 
allowed. The Investigator is encouraged to consult with the Sponsor before discontinuing 
subjects from study treatment.  
• Subject participation in another clinical study using an investigational agent, investigational 
medical device, or other intervention. 
• Necessity for treatment with nonprotocol systemic anticancer therapy.  
• Necessity for interrupting all study treatment for greater than 12 weeks for study-treatment 
related AEs unless approved by the Sponsor. (Note: temporary interruptions of study 
treatment for greater than 12 weeks due to the effects of COVID-19 and unrelated to AEs are 
described in Appendix M) 
• Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use highly effective methods of contraception (Appendix H).  
• Female subjects who become pregnant. 
• Request by the Sponsor. 
• Significant noncompliance with the protocol schedule in the opinion of the Investigator or 
the Sponsor. 

 
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To ensure timely Sponsor notification of study treatment discontinuations, site personnel are to 
promptly record treatment discontinuations in the study IRT. The reason for study treatment 
discontinuation must be recorded in source documents and case report forms (CRFs). 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 the minimum a registered letter requesting contact 
with the clinic should be sent to the subject (or the subject’s legal guardian). 
For subjects who discontinue study treatment, every effort must be made to undertake protocol-
specified follow-up procedures including end-of-treatment assessments, survival follow-up, and 
documentation of subsequent anticancer treatment(s) unless consent for noninterventional study 
treatments is also withdrawn. If a subject is discontinued from study treatment because of an AE 
(including AESI; Table 31) considered to be related to study treatment and the event is ongoing 
30 days after the last dose of study treatment, the event must be followed until resolution or 
determination by the investigator that the event has become stable or irreversible. 
Specific criteria for discontinuation of cabozantinib are provided in Section 6.6.2.1, for 
discontinuation of atezolizumab are provided in Section 6.6.2.2, and for sorafenib are provided 
in Section 6.6.2.3. 
3.5.2. 
Study Withdrawal 
Upon discontinuation of study treatment, at any time without prejudice, subjects may:  
• Continue study interventions (eg, examination, blood and tissue sampling radiographic 
assessments, questionnaires) and non-interventional study assessments (eg, medical record 
review, survival contacts), or 
• Withdraw their consent for study interventions but continue non-interventional study 
assessments, or  
• Withdraw their consent for both study interventions and non-interventional study 
assessments.  
Reasons for study withdrawal will be recorded in the source documents and CRFs. As 
applicable, no further study procedures or assessments will be performed or study data collected. 
For subjects who withdraw consent, determination of survival status from public records such as 
government vital statistics or obituaries will be performed as allowed by local regulations. 
Subjects who withdraw from the study will not be replaced. 

 
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3.5.3. 
Study Completion 
The study will be considered complete if the null hypothesis is rejected for the primary endpoint 
of OS (experimental vs control arm) in either of the two planned interim analyses or if the final 
planned analysis for OS has been conducted (irrespective of the results), all other planned formal 
inference tests have been performed (eg, for secondary efficacy endpoints), and any required 
supportive analyses for China are completed. 
3.5.4. 
End of Trial 
End of trial is defined as the last scheduled visit or scheduled procedure for the last subject 
(including Maintenance Phase assessments). 

 
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4. 
STUDY POPULATION 
4.1. 
Target Population 
This study will enroll subjects with treatment-naïve advanced HCC. Eligibility criteria for this 
study have been carefully considered to ensure the safety of the study subjects and to safeguard 
the integrity of the study results. It is imperative that subjects fully meet all inclusion criteria and 
none of the exclusion criteria. The Sponsor will not grant waivers to study eligibility criteria. 
4.2. 
Inclusion Criteria 
1. Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic 
patients by multiphase imaging using CT or MRI per the American Association for the Study 
of Liver Diseases (AASLD) (Marrero et al 2018) or European Association for the Study of 
the Liver (EASL 2018) guidelines.  
Note: Sites must receive Sponsor accreditation for imaging-based diagnosis of HCC prior to 
implementing this methodology. In addition, subjects who do not meet the AASLD or EASL 
guidelines for imaging diagnosis of HCC or who do not have cirrhosis must have histological 
or cytological diagnosis of HCC. 
2. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, 
surgery, ablation therapy) or locoregional therapy (eg, TACE). 
3. The subject is receiving antiviral therapy per local standard of care if the subject has active 
HBV infection (defined by HBsAg positive); the subject must have HBV DNA < 500 IU/mL.  
4. Measurable disease per RECIST 1.1 as determined by the Investigator.  
5. Barcelona Clinic Liver Cancer (BCLC) stage Category B or C (Appendix I). 
6. Child-Pugh Score of A (Appendix J). 
7. Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events 
(CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically 
nonsignificant and/or stable on supportive therapy as determined by the Investigator.  
8. Age eighteen years or older on the day of consent. 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  

 
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10. Adequate organ and marrow function, based upon meeting all of the following laboratory 
criteria within 14 days prior to randomization: 
a. Absolute neutrophil count (ANC) ≥ 1500/µL (≥ 1.5 × 109/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection.  
b. White blood cell (WBC) count ≥ 2000/µL (≥ 2.0 × 109/L). 
c. Platelets ≥ 60,000/µL (≥ 60 × 109/L) without transfusion within 2 weeks before screening 
laboratory sample collection.  
d. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion within 2 weeks before screening 
laboratory sample collection.  
e. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization (if HbA1c results 
are unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL) 
f. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 5 × upper limit 
of normal (ULN).  
g. Total bilirubin ≤ 2 mg/dL (≤ 34.2 µmol/L). 
h. Serum albumin ≥ 2.8 g/dL (≥ 28 g/L). 
i. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min 
(≥ 0.67 mL/sec) using the Cockcroft-Gault equation (see Table 3). 
j. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h protein 
≤ 1 g. 
11. Capable of understanding and complying with the protocol requirements and must have 
signed the informed consent document prior to any screening assessment except those 
procedures performed as standard of care within the screening window. 
12. Sexually active fertile subjects and their partners must agree to use highly effective methods 
of contraception that alone or in combination result in a failure rate of less than 1% per year 
when used consistently and correctly (see Appendix H) during the course of the study and for 
5 months after the last dose of study treatment. A barrier method (eg, condom) is also 
required. 

 
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13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects 
are considered to be of childbearing potential unless one of the following criteria is met: 
documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea 
in a woman > 45 years-of-age in the absence of other biological or physiological causes. In 
addition, females < 55 years-of-age must have a serum follicle stimulating hormone (FSH) 
level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of 
medical records, medical examination, or medical history interview by study site staff.  
4.3. 
Exclusion Criteria 
 
1. Known fibrolamellar carcinoma, sarcomatoid HCC or mixed hepatocellular 
cholangiocarcinoma. 
2. Prior systemic anticancer therapy for advanced HCC including but not limited to 
chemotherapy, small molecule kinase inhibitors, and ICIs. Subjects who have received local 
intratumoral or arterial chemotherapy are eligible.  
3. Documented hepatic encephalopathy (HE) within 6 months before randomization (see 
Section 6.6.2.4 for a case definition of HE). 
4. Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) 
within 6 months before randomization. 
5. Subjects who have received any local anticancer therapy including surgery, PEI, RFA, 
MWA, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) 
within 28 days prior to randomization 
6. Radiation therapy for bone metastasis within 2 weeks, any other external beam radiation 
therapy within 8 weeks prior to randomization. Subjects with clinically relevant ongoing 
complications from prior radiation therapy are not eligible. 
7. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 8 weeks prior to 
randomization. Subjects who are neurologically symptomatic or are receiving systemic 
corticosteroid treatment at the planned time of randomization are not eligible.  

 
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8. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and 
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed 
anticoagulants:  
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low 
molecular weight heparins (LMWH)  
9. Administration of a live, attenuated vaccine within 30 days prior to randomization. 
10. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT) or 
triphasic liver magnetic resonance imaging (MRI) because of allergy or other 
contraindication to both CT and MRI contrast agents. 
11. The subject has uncontrolled, significant intercurrent or recent (within the last 3 months 
before randomization [unless otherwise specified below]) illness including, but not limited 
to, the following conditions: 
a. Cardiovascular and cardiac disorders: 
i. 
Congestive heart failure (CHF) class III or IV as defined by the New York Heart 
Association, unstable angina pectoris, serious cardiac arrhythmias.  
ii. 
Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg 
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. 
iii. 
Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or 
other ischemic event or thromboembolic event (eg, DVT, pulmonary embolism) 
within 6 months before randomization. 
iv. 
History of risk factors for torsades de pointes (eg, long QT syndrome).  
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, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction.  

 
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ii. 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months prior to randomization. Complete healing of an intra-abdominal 
abscess must be confirmed prior to randomization. 
iii. 
Gastric or esophageal varices that are untreated or incompletely treated 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 before randomization are 
eligible. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) 
of red blood, or other history of significant bleeding (eg, pulmonary hemorrhage) within 
3 months before randomization.  
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation. 
e. Lesions invading major blood vessel, including, but not limited to: inferior vena cava, 
pulmonary artery, or aorta. Subjects with lesions invading the intrahepatic vasculature, 
including portal vein, hepatic vein, and hepatic artery, are eligible.  
f. Other clinically significant disorders such as: 
i. 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, 
antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix D for a more 
comprehensive list of autoimmune diseases and immune deficiencies). Subjects with 
the following conditions are eligible for the study: 
• A history of autoimmune-related hypothyroidism and on thyroid replacement 
hormone  
• Controlled Type 1 diabetes mellitus and on an insulin regimen 
• Asthma that requires intermittent use of bronchodilators 
• Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only provided all of following are true: 

 
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o Rash covers < 10% of body surface area 
o Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
o No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high potency or oral corticosteroids within the 
previous 12 months  
ii. 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days 
before randomization.  
Note: Inhaled, intranasal, intra-articular, and topical corticosteroids and 
mineralocorticoids are permitted.  
Transient use of systemic corticosteroids for allergic conditions such as contrast 
allergy is allowed. 
iii. 
Active infection requiring systemic treatment, known history of infection with human 
immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS)-related illness, or a known positive test for tuberculosis due to tuberculosis 
infection. Subjects with active hepatitis B virus infection controlled with antiviral 
therapy are eligible (see Inclusion Criterion 3). Subjects with active, uncontrolled 
hepatitis C virus infection are eligible provided liver function meets eligibility criteria 
and are receiving management of the disease per local institutional practice (note: 
antiviral treatment for HCV is allowed with Sponsor approval). Subjects with history 
of COVID-19 must have recovered from the disease at least 30 days prior to 
randomization. 
iv. 
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening 
chest CT scan  
v. 
Serious non-healing wound/ulcer/bone fracture.  
vi. 
Malabsorption syndrome. 

 
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vii. 
Symptoms of thyroid dysfunction with thyroid function test corroboration (Note: 
asymptomatic subjects with an isolated abnormal free thyroxine [FT4] are eligible). 
viii. 
Moderate to severe hepatic impairment (Child-Pugh B or C [Appendix J]). 
ix. 
Requirement for hemodialysis or peritoneal dialysis. 
x. 
History of solid organ transplant including liver transplant, or allogeneic stem cell 
transplant. 
12. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before 
randomization. Minor surgeries within 10 days before randomization. Subjects must have 
complete wound healing from major surgery or minor surgery before randomization. 
Subjects with clinically relevant ongoing complications from prior surgery are not eligible. 
13. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per 
electrocardiogram (ECG) within 14 days before randomization. 
Note: If a single ECG shows a QTcF with an absolute value > 480 ms, two additional ECGs 
at intervals of approximately 3 min must be performed within 30 min after the initial ECG, 
and the average of these three consecutive results for QTcF will be used to determine 
eligibility  
14. History of psychiatric illness likely to interfere with ability to comply with protocol 
requirements or give informed consent. 
15. Pregnant or breastfeeding females. 
16. Inability to swallow tablets. 
17. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe hypersensitivity to monoclonal antibodies. Subjects with 
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption are also excluded. 
18. Any other active malignancy at time of randomization or diagnosis of another malignancy 
within 2 years before randomization that requires active treatment, except for superficial skin 
cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.  
 

 
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5. 
STUDY ASSESSMENTS AND PROCEDURES 
This protocol generally presents scheduled timelines for study procedures by abbreviated 
references to week (W) and day (D) (eg, W1D1, W3D1 etc.) relative to the date of the first dose 
of study treatment (defined as W1D1). Study W1D1 should occur within 3 days of 
randomization (W1D1 will be defined as the date of randomization for subjects who never 
receive study treatment). 
All assessments for safety, efficacy (CT or MRI), and HRQOL assessments will be scheduled 
based on W1D1. Special accommodations during the global COVID-19 pandemic are described 
in Appendix M. 
Unscheduled visits for safety evaluations are allowed at any time, and required in circumstances 
described herein. 
See Appendix A for the schedule of assessments. 
5.1. 
Pre-Treatment Period 
Informed consent must be obtained prior to initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for research. However, evaluations 
performed as part of routine care prior to informed consent can be utilized as screening 
evaluations if permitted by the site’s IRB/EC policies. Informed consent may be obtained greater 
than 28 days before randomization. At informed consent a study site representative will use the 
web-based IRT to register subjects. The IRT will assigned a unique subject identifier; subject 
identifiers are not to be re-assigned if a subject is determined to be ineligible, and subjects are to 
maintain their original identifier if re-screening is required or if the subject experiences a change 
in study site or investigator. 
To determine subject eligibility as stipulated in Section 4, subjects will undergo required 
screening evaluations as outlined in Appendix A and described in Section 5.8.  
Guidance for diagnosis of HCC in cirrhotic patients by imaging is provided in Section 5.8.6.1. 
Qualifying screening assessments must be performed within 28 days before randomization 
unless otherwise stated (eg, certain lab values must be obtained closer to randomization). 
Eligibility criteria based on laboratory values should be based on central laboratory results. 
Exceptions for using local laboratory test results for eligibility determination include serum 

 
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pregnancy test (for females of child-bearing potential), urinalysis, repeat lab tests to confirm 
central lab test results, and laboratory tests which cannot be obtained from the central lab in time 
before the planned randomization date. Study eligibility is based on a subject meeting all of the 
study inclusion criteria and none of the exclusion criteria at screening. 
A subject who signs informed consent but fails to satisfy all eligibility criteria for any reason will 
be considered a screen failure. Data on the following information will be collected for all screen 
failures: 
• Informed consent information 
• Failed inclusion/exclusion criteria 
• Demographics 
• SAEs 
5.2. 
Treatment Period 
Subjects eligible after completing all screening evaluations will be randomly assigned in a 2:1:1 
fashion to receive cabozantinib in combination with atezolizumab or sorafenib or cabozantinib 
alone (Section 6.1.1). Subjects should receive their first dose of study treatment within 3 days 
after randomization.  
While the subject is receiving study treatment the subject’s clinical status is to be evaluated by an 
investigator at each clinic visit to confirm that the subject is suitable for continuing study 
treatment and to make timely decisions regarding the reduction, interruption, or restarting of 
study treatment. Clinical laboratory results from samples obtained during clinic visits and tumor 
assessments from imaging visits are to be reviewed by an investigator.  
Subjects will receive study treatment as long as they continue to experience clinical benefit in the 
opinion of the Investigator or until unacceptable toxicity, the need for subsequent systemic 
anticancer treatment, or until any other reasons for treatment discontinuation listed in the 
protocol (Section 3.5.1). Treatment with study treatment may continue after radiographic 
progression per RECIST 1.1 as long as the Investigator believes that the subject is still receiving 
clinical benefit from study treatment (see Section 5.8.6.3), that the potential benefit of continuing 
study treatment outweighs potential risks, and no other therapies are considered by the 
Investigator to be more appropriate. Subjects on the experimental arm (cabozantinib + 
atezolizumab) are allowed to discontinue one component of the study treatment but continue to 
receive the other. Escalation of cabozantinib from 40 mg qd to 60 mg qd in the experimental arm 
is allowed after Sponsor approval for subjects who are tolerating the 40 mg cabozantinib dose 

 
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level well and have been treated on this dose level for at least 4 weeks. In general, subjects who 
develop clinically relevant adverse events (eg, Grade 3 or 4 AEs) are not allowed to dose 
escalate cabozantinib from 40 qd to 60 mg qd. Crossover between treatment arms will not be 
allowed unless study transitions to the Crossover Phase. 
Study completion is defined in Section 3.5.3. 
Required safety assessments are to be performed on a schedule based on the date of the first dose 
(W1D1) and every 3 weeks (± 3 days) (ie, W4D1, W7D1, W10D1, etc). For subjects in the 
combination arm, required safety assessments may occur outside the protocol-defined windows 
due to safety-driven delays in atezolizumab administration and will not be considered protocol 
deviations as long as required safety assessments are performed at least every 3 weeks 
(± 3 days). See the CRF completion guidelines for instructions on how to enter study data in such 
circumstances. The following are the reminders: 
• Doses of atezolizumab must not be given less than 19 days apart (see Section 6.2.4). 
• Specific laboratory tests are required to be performed and evaluated within 72 hours prior to 
each administration of atezolizumab (see Section 5.8.5). 
• The tumor assessment and HRQOL schedules are to be maintained relative to the date of first 
dose of study treatment (or randomization date for subjects never treated) irrespective of the 
dates of safety assessments. 
• PK and biomarker sample collection schedules are per schedule of assessments (Appendix A 
and Appendix B). 
Safety follow-up visits will be performed 30 (+14) days (FU-1) and approximately 100 days 
(± 14 days) (FU-2) after the date of the decision to permanently discontinue study treatment (see 
Section 8.4).  
If study treatment is held due to AEs, investigators should perform additional safety assessments 
weekly (or more frequently as clinically indicated). 
Radiographic tumor assessments should be performed as described in Section 5.8.6, and HRQOL 
assessments should be performed as described in Section 5.8.8. The schedule of assessments 
should be maintained regardless of whether study treatment is given, reduced, held or 
discontinued until a criterion for discontinuation of radiographic assessments is met (see 
Section 5.8.6.2). 

 
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In accordance with the ITT principle, HRQOL, radiographic tumor assessments, and survival 
follow-up are to be performed per protocol even for subjects randomized who never receive 
study treatment. For such subjects, W1D1 is defined as the date of randomization.  
5.3. 
Crossover Phase 
The study may transition to a Crossover Phase if the analysis of the primary endpoint of OS for 
the global ITT population (ie, not including subjects enrolled in the Mainland China Extension 
Phase) shows statistically significant and clinically meaningful evidence of improvement in 
favor of the experimental arm.  
The Crossover Phase will only be implemented upon decision by the Sponsor and following any 
required discussion with regulatory authorities following review of the data. Crossover may be 
implemented independently and at different points in time for study sites and subjects in 
mainland China compared to other sites and subjects in the global study. If the decision is made 
to enter the Crossover Phase, study sites will have 8 weeks to determine eligibility and begin 
administration of crossover treatment (cabozantinib + atezolizumab combination) to eligible 
subjects randomized to the control arm (sorafenib) or the single-agent cabozantinib arm; 
subsequently no further crossover will be allowed.  
• Subjects randomized to the sorafenib control arm or single-agent cabozantinib arm will have 
the option to crossover to receive the cabozantinib + atezolizumab combination if they meet 
predefined eligibility criteria.  
• Subjects randomized to the cabozantinib + atezolizumab experimental arm who are still 
receiving study treatment and subjects randomized to the sorafenib control arm or 
single-agent cabozantinib arm who are still receiving study treatment and do not crossover to 
the experimental arm may continue on originally assigned study treatment until a criterion 
for protocol-defined discontinuation has been met.  
• Subjects randomized to the cabozantinib + atezolizumab experimental arm who are in the 
post treatment period and subjects randomized to the sorafenib control arm or single-agent 
cabozantinib arm who do not crossover to cabozantinib + atezolizumab and are in the 
post-treatment period will continue with post treatment assessments. 
The study is expected to have completed enrollment in the global enrollment phase at the time of 
transitioning to the Crossover Phase for subjects who enrolled in that phase, but accrual of 
subjects in the Mainland China Extension Phase may still be ongoing at that point. In the 
Crossover Phase safety assessments and efficacy assessments will continue as scheduled; PK, 
biomarker, HRQOL, and healthcare resource utilization assessments will be discontinued. 

 
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5.4. 
Post-Treatment Period 
A first Post-Treatment Follow-up visit (FU-1) for safety evaluation (including subjects in the 
Maintenance Phase [below]) is to occur 30 (+14) days after the date of the decision to 
permanently discontinue study treatment (defined as the later of the date of the decision to 
permanently discontinue study treatment or the date of the last dose of study treatment). A 
second Post-Treatment Follow-up visit (FU-2) for safety evaluation will be conducted 
approximately 100 days (±14 days) after the date of the decision to permanently discontinue 
study treatment. Refer to Appendix A for a description of all assessments for the Post Treatment 
Follow-Up Visits. Further details for follow-up and data collection requirements for AEs, SAEs, 
and AESIs are summarized in Appendix K.  
Adverse events are to be documented and/or followed as described in Section 8.4. 
Following treatment discontinuation each subject will continue to be followed for survival and 
receipt of subsequent anticancer therapy. The investigator (or designee) will make contact with 
the subject at least as frequently as every 12 weeks (± 14 days) after FU-2 until the subject 
expires, withdraws consent for such contacts, or the Sponsor decides to discontinue collection of 
these data for the study.  
At each contact, the investigator (or designee) will determine if the subject died, and if so, record 
the date and cause of death as best can be determined. All efforts must be undertaken by the 
study sites to determine the date of death (or date subject last known alive at the time of a data 
cutoff). This may include, but not necessarily be limited to telephone contacts, communication at 
study visits, registered letters, and reviews of local obituaries and government death records. 
Receipt of subsequent nonprotocol anticancer therapy (NPACT) will also be collected during the 
Post-Treatment Period. If a subject is lost to follow-up, multiple attempts to contact the study 
subject or designee must be documented in the subject records. 
HRQOL outcomes and radiographic tumor assessments will be collected regardless of whether 
study treatment is given, reduced, held, or discontinued until the date of the last tumor imaging 
assessment as described in Section 5.8.6.3. Consequently these assessments may be required in 
the Post-Treatment Period for some subjects. 
5.5. 
Mainland China Extension Phase 
After completion of the global enrollment phase, additional subjects (up to 148) may be enrolled 
in a Mainland China Extension Phase at sites in mainland China for evaluation in a China 
subpopulation. The Pre-Treatment Period (Section 5.1), Treatment Period (Section 5.2), and 

 
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Post-Treatment Period (Section 5.4) of the study will be conducted in the same manner in the 
Mainland China Extension Phase as for subjects who were enrolled in the global enrollment 
phase. 
5.6. 
Maintenance Phase/Treatment after Study Completion 
The purpose of the Maintenance Phase is to continue to provide long-term access to study 
drug(s) to subjects who are deriving clinical benefit even after the study objectives have been 
completed (Study Completion, see Section 3.5.3). When sufficient data have been collected to 
adequately evaluate all study endpoints, subjects who continue study treatment may enter the 
study Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor considers the 
safety and efficacy profile of the experimental treatment regimen within this study to have been 
sufficiently established and data analysis required for regulatory purposes to have been 
completed. If a Crossover Phase has been implemented, the Maintenance Phase may not begin 
before the Week 9 Day 1 (W9D1) visit has elapsed in the Crossover Phase for the last subject 
randomized to sorafenib or single-agent cabozantinib who crossed over to receive cabozantinib + 
atezolizumab. The Sponsor is to notify the sites if or when the study will enter the Maintenance 
Phase or if an alternative post-Study Completion option will be implemented (Section 6.3). 
In the Maintenance Phase, subjects will continue to receive study treatment until a criterion for 
protocol-defined discontinuation has been met (Section 3.5.1). Subjects are to undergo periodic 
safety assessments (including local laboratory tests) and tumor assessments (Appendix B). The 
nature and frequency of these assessments are to be performed per institutional standard of care 
and guidance from the Sponsor. It is the Investigator’s responsibility to ensure that subject visits 
occur frequently enough and adequate assessments are performed to ensure subject safety.  
In order to continue to collect important safety information on subjects still enrolled in the study, 
reporting of SAEs, AESIs, and other reportable events (DILI, pregnancy, and medication errors 
with sequelae) is to continue per protocol (Section 8.2.2). 
Further, the following AEs, whether serious or not, are to be reported using the same process as 
for reporting SAEs described in the protocol Section 8.2 (though SAE reporting timeline 
requirements do not apply to non-serious events reported in these categories): 
• Adverse events of special interest (AESIs) 
• Adverse events, whether serious or not, leading to study treatment discontinuation 
• Adverse events, whether serious or not, leading to study treatment dose modification (ie, 
causing study treatment to be interrupted, delayed, or reduced) 

 
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Study drug accountability is to continue as described in Section 6.5. 
Only data collected prior to implementation of Maintenance Phase will be reported in a clinical 
study report. 
5.7. 
Unscheduled Visits or Assessments 
If the Investigator determines that a subject should be monitored more frequently or with 
additional laboratory assessments than indicated by the protocol-defined visit schedule, 
unscheduled visits or assessments are permitted. The laboratory assessments should be done by 
the central lab; however, if the results are needed immediately (eg, for AE management), they 
may be done by the local lab and the results forwarded to the management vendor for handling 
of local laboratory data. If study treatment is held, the study site should perform unscheduled 
visits or telephone calls weekly (or more frequently) as clinically indicated during the 
intervening time between the last dose and the time drug is restarted to monitor subject safety 
and appropriateness for re-treatment with study treatment. 
5.8. 
Procedure details 
This section describes evaluations to be performed and items to be recorded or available on 
source documents. Data from some required evaluations may not be collected on study CRFs 
(see Section 16.4). 
5.8.1. 
Demographics, Medical and Cancer History 
Demographics at screening will include age at informed consent, medical and cancer history, 
surgical history, radiation therapy history, and other local anticancer treatment history including 
names of procedures, agents and administration dates. To ensure subject privacy, date of birth 
and subject initials will not be collected by the Sponsor. 
5.8.2. 
Physical Examination 
Physical examinations will include height (screening visit only), weight, performance status, and 
an assessment of the following systems: skin, head, eyes, ears, nose, throat, respiratory system, 
cardiovascular system, GI system, neurological condition, blood and lymphatic systems, and the 
musculoskeletal system. Symptom-directed physical examination will be conducted on W1D1 
before first dose of study treatment and after randomization. Any ongoing/intercurrent condition 

 
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prior to first dose must be recorded as medical history. Significant new findings that begin or 
worsen after first dose must be recorded as AEs.  
The ECOG performance status of the subject will be assessed during screening and at each 
scheduled safety assessment starting on W1D1. A table of performance status criteria is included 
in Appendix C for reference. 
Refer to Appendix A for the schedule of physical examination and performance status 
assessments. 
5.8.3. 
Vital Signs 
Vital signs including 5-minute sitting BP, pulse, respiratory rate, and temperature will be 
assessed at screening, at all scheduled safety visits, and at all unscheduled visits if possible. On 
atezolizumab infusion days, vital signs should be assessed within 60 min prior to initiation of the 
infusion, and further vital sign assessment should be performed during and after the infusion as 
clinically indicated.  
Refer to Appendix A for the schedule of these assessments. 
5.8.4. 
Electrocardiograms 
At screening and during the study, single ECG assessments will be performed with standard 
12-lead ECG equipment according to standard procedures to determine QTcF. A QTcF ≤ 480 ms 
per single ECG within 14 days before randomization is required to demonstrate eligibility for 
study treatment. If at any time after the first dose of treatment the single ECG shows a QTcF 
with an absolute value > 500 ms or an increase from baseline of > 60 ms, two additional ECGs at 
intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the 
average of these three consecutive results for QTcF will be used as the value assessed (see 
Section 6.6.2.1.15).  
ECGs will be performed at the time points indicated in Appendix A. 
Guidelines for management of corrected QT prolongation associated with cabozantinib and 
sorafenib are provided in Sections 6.6.2.1.15 and 6.6.2.3, respectively. 
Abnormalities in the ECG that lead to a change in subject management (eg, dose reduced or 
interrupted, treatment discontinued, requirement for additional medication or monitoring) or 
result in clinical signs and symptoms are considered clinically significant for the purposes of this 
study and will be deemed AEs. If values meet criteria defining them as serious, they must be 
reported as SAEs (Section 8.2). 

 
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The Fridericia formula is depicted below for calculation of the corrected QT interval (QTcF). 
 
QT = measured QT interval in milliseconds; RR = measured R to R interval (which can 
be derived from the heart rate as 60/heart rate) 
 
5.8.5. 
Safety Laboratory Assessments 
Laboratory analytes that will be measured for this study are listed in Table 2. The schedule for 
laboratory assessments is provided in Appendix A. Laboratory tests to establish eligibility must 
be done within 14 days before randomization unless otherwise stated (Appendix A). 
Central laboratory assessments: Hematology, serum chemistry, coagulation, UPCR including 
components, hepatitis, and thyroid function tests are to be performed by a central laboratory, 
including laboratory assessments obtained at unscheduled visits whenever possible. All central 
safety laboratory results will be provided to the Investigator.  
Eligibility criteria based on laboratory values should be based on central laboratory results. 
Exceptions for using local laboratory test results for eligibility determination include serum 
pregnancy test, urinalysis, certain laboratory values that are required to be repeated closer to 
randomization, and laboratory tests which cannot be obtained from the central lab in time before 
the planned randomization date (see Appendix A). 
Local laboratory assessments: Routine (dipstick) analysis, microscopic urine examination, and 
serum/urine pregnancy tests (for females of child-bearing potential) are to be done by local 
laboratory. Results or status from these tests will be recorded on CRFs and will not be submitted 
to the study local laboratory management vendor. 
24-hour urine protein tests, at any scheduled or unscheduled visit, are to be done by local 
laboratory and the lab results forwarded to the study local laboratory management vendor. 
After randomization, local laboratory analyses may be employed if the results are required by the 
Investigator in a rapid timeframe (eg, needed for making rapid treatment decision or monitoring 
for AEs, SAEs).  

 
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Guidance on central vs local clinical laboratory analyses for post-randomization safety 
laboratory samples: 
• If possible, the serum chemistry, hematology, coagulation, and thyroid function tests are to 
be done via central laboratory, but may be done locally if central laboratory testing is not 
feasible in a timely manner. 
o Serum chemistry, hematology, and coagulation tests (specific parameters listed in 
Table 2) must be performed, and results must be reviewed within 72 hours prior 
to atezolizumab administration. 
o If the subject has symptoms indicative of a thyroid function disorder, thyroid 
function test results are to be reviewed prior to administering atezolizumab. 
Urinalysis is to be done locally. Local test results are to be submitted to the local laboratory 
management vendor as described in Table 2. 
o Urinalysis must be performed, and results must be reviewed within 72 hours prior 
to atezolizumab administration. 
All local laboratory results must be forwarded to the study local laboratory management vendor 
if performed in lieu of the central laboratory assessment at any scheduled or unscheduled visit.  
Other specific laboratory test information: 
• To confirm suitability for treatment after randomization, 12-lead ECG and all laboratory tests 
(except for pregnancy test) must be performed within 14 days prior to administering the first 
dose of study treatment. These assessments do not need to be performed on W1D1 unless the 
subjects’ clinical status has changed (eg, onset of new symptoms indicative of clinical 
deterioration) since the most recent assessment performed to establish eligibility and 
suitability for study treatment. If any of these tests are performed on W1D1, the results must 
be available to and reviewed by the investigator prior to any treatment being administered.  
• A serum pregnancy test must be repeated before dosing on W1D1 unless a pregnancy 
evaluation was done during screening within 7 days prior to W1D1. 
• Follicle stimulating hormone (FSH). For women under the age of 55 years to confirm 
menopause as needed during the screening period.  
• Hepatitis B surface antigen and core antibody (with reflex testing of hepatitis B DNA if either 
antigen or core antibody is positive; hepatitis B DNA testing is mandatory in mainland 
China), and Hepatitis C antibody (with reflex testing of HCV RNA if antibody test is positive) 
will be assessed at screening by central laboratory. If central laboratory results are not 

 
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available at the time of randomization, local laboratory results may be used with Sponsor 
approval.  
• HIV test will be performed at screening if required by local regulation. Results from this test 
do not need to be forwarded to the study local laboratory management vendor. 
• In addition to the safety laboratory assessments, tumor marker (AFP) will be assessed by the 
central lab at screening, predose on W1D1, and after first dose of study treatment as described 
in the schedule of assessments (Appendix A). These assessments will not be used to determine 
PD in this study. 
 
 

 
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Table 2: 
Laboratory Panels 
Central Laboratory 
If performed by local laboratory submit results to study local laboratory management vendor 
Hematology 
• White blood cell (WBC) count 
with differential (ANC, 
basophils, eosinophils, 
lymphocytes, monocytes) 
• hematocrit 
• platelet count 
• red blood cell count 
• hemoglobin 
 
Coagulation 
• prothrombin time 
(PT)/International Normalized 
Ratio (INR)  
• partial thromboplastin time 
(PTT) 
 
Thyroid function 
• thyroid-stimulating hormone 
(TSH) 
• Free thyroxine (FT4; required 
at screening; after screening 
only if TSH is outside normal 
range) 
 
Other parameters 
• Follicle Stimulating Hormone 
(FSH)a 
• Alpha-fetoprotein (AFP) 
 
Serum Chemistry 
• albumin 
• total alkaline phosphatase (ALP) 
• amylase 
• alanine amino transferase (ALT) 
• aspartate amino transferase (AST) 
• blood urea nitrogen (BUN) 
• corrected calcium  
• bicarbonate 
• chloride 
• creatinine 
• γ-glutamyltranspeptidase (GGT) 
• glucose  
• lactate dehydrogenase (LDH) 
• lipase  
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin (including unconjugated 
and conjugated fractions)  
• total protein 
 
Urine Chemistry 
• Protein (spot urine; fully 
quantitative) 
• Creatinine (spot urine; fully 
quantitative) 
• Urine protein/creatinine ratio 
(UPCR; spot urine) 
 
Virology 
• Hepatitis B surface antigen, 
Hepatitis B core antibody, 
(with reflex testing of 
hepatitis B DNA if either 
antigen or core antibody is 
positive [hepatitis B DNA 
mandatory in mainland 
China]) 
• Hepatitis C antibody (with 
reflex testing of HCV RNA 
if antibody test is positive) 
 
Local Laboratory 
Submit only 24-hour urine protein test results to study local laboratory management vendor 
Urinalysis 
(Dipstick or Routine per 
Institutional Standard) 
• pH 
• specific gravity 
• ketones 
• protein 
• glucose 
• nitrite 
• urobilinogen  
• leukocyte esterase 
• blood 
Microscopic Urine Examination 
• Perform at the discretion of the 
investigator based on results or routine 
urinalysis or as clinically indicated 
 
Urine Chemistry 
• 24-hour urine protein: perform at the 
discretion of the investigator based on 
increases in UPCR from routine 
assessments 
Pregnancy Blood Test (prior 
to first dose) 
• β-human chorionic 
gonadotropin (β-HCG) 
 
Pregnancy Urine or Blood 
Test (after first dose of study 
treatment) 
• β-human chorionic 
gonadotropin (β-HCG) 
 
Virology 
• HIV test (if mandated by 
local regulation) 
a For women under the age of 55 years to confirm menopause as needed. 

 
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Table 3: 
Estimation of the Creatinine Clearance by Cockcroft and Gault 
Based on serum creatinine in conventional units (mg/dL) 
• Males: (140 – age) × weight (kg)/(serum creatinine × 72) 
• Females: [(140 – age) × weight (kg)/(serum creatinine × 72)] × 0.85 
Based on serum creatinine in SI units (µmol/L) 
• Males: [(140 – age) × weight (kg)/(serum creatinine)] × 1.23 
• Females: [(140 – age) × weight (kg)/(serum creatinine)] × 1.04 
Abnormalities in any clinical laboratory test (including tests not required per protocol) that lead 
to a change in subject management (eg, dose interrupted or reduced, treatment discontinued, 
requirement for additional medication or monitoring) are considered clinically significant for the 
purposes of this study and should be reported as AEs. If laboratory values constitute part of an 
event that meets criteria defining it as serious, the event (with associated laboratory values) 
needs to be reported as an SAE (see Section 8.2).  
5.8.6. 
Tumor Assessments 
5.8.6.1. 
Diagnosis of HCC in Cirrhotic Patients by Imaging for Study Eligibility 
Clinical diagnosis of HCC by multiphase imaging using CT or MRI in subjects with cirrhosis 
according to AASLD or EASL HCC guidelines is acceptable for study eligibility. Diagnostic 
imaging hallmarks of HCC include arterial phase enhancement, tumor size, washout, enhancing 
capsule, and threshold growth. If the subject does not have cirrhosis or these imaging criteria 
cannot be assessed or are not met, histological or cytological diagnosis of HCC is required for 
study participation. Ultrasound, angiography, fluorodeoxyglucose (FDG)-positron emission 
tomography (PET), or AFP cannot be used for clinical diagnosis of HCC. Accreditation for HCC 
diagnostic imaging, as described in the amended study imaging manual, is required before a site 
can enroll subjects diagnosed with HCC via imaging alone. Diagnostic scans may be used for 
screening if they meet the criteria described in Section 5.8.6.2. For detailed guidance regarding 
diagnosis of HCC by imaging refer to the amended study imaging manual. 

 
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5.8.6.2. 
Routine Tumor Assessment 
Radiographic response and disease progression will be determined using RECIST version 1.1 
(Appendix E). For the purpose of determination of the radiographic study endpoints, central 
review of radiographic images will be conducted by a BIRC. All radiographic tumor assessments 
will be promptly sent to the BIRC, which also will review prior radiation history data for the 
purpose of selection of target lesions. Sites will be provided with instructions for how images 
should be collected and submitted to the BIRC. Study staff shall ensure that no images contain 
personal data as defined by applicable local, regional, and international laws and regulations. 
Radiographic tumor assessments will include the following:  
1. Chest / Abdomen / Pelvis (CAP): CT of CAP or CT chest and MRI abdomen/pelvis will be 
performed in all subjects at screening (prior to randomization). Tumor assessments after 
randomization should be performed every 6 weeks (± 7 days) through Week 49. After Week 
49, these assessments will be performed every 12 weeks (± 7 days). CT/MRI of the CAP 
should include a noncontrast study of at least the liver followed by contrast with triphasic CT 
imaging of the liver or liver MRI with gadolinium enhanced imaging including triphasic 
liver.  
2. Other sites: All other known or suspected sites of disease, including in the brain or bone, are 
to be imaged by CT/MRI at screening (prior to randomization). Any lesions identified, 
including bone lesions with a soft tissue component, are to be followed at subsequent tumor 
assessments as described for CAP above using the same modality as at screening. New 
suspected lesion sites identified after randomization, including suspected sites of bone or 
brain lesions, should be assessed by CT/MRI. MRI is the preferred method for brain lesion 
assessment. If CT of the brain is performed instead of MRI, ambiguous results must be 
confirmed by MRI. (Note: in order to meet the eligibility requirements of the study, brain 
metastasis must have been treated and stable for at least 8 weeks before randomization. 
Subjects without documented brain metastasis during the screening assessment are not 
required to undergo post-randomization brain imaging unless clinically indicated.)  
If there is clinical concern regarding the administration of any contrast agent, then tumor 
assessments for the liver should be performed by MRI with non-contrast CT of the chest. If at a 
follow up imaging time point the use of contrast is prohibited (eg, due to acquired impaired renal 
function) then the same modality should be used without contrast. 

 
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Tumor assessments should continue on the protocol-defined schedule regardless of whether 
study treatment is given, reduced, held or discontinued until a criterion for ending radiographic 
assessments is met. The same imaging modalities used at screening will be used for subsequent 
tumor assessments after randomization. Radiographic tumor assessments are to continue until the 
later of Investigator-determined radiographic progression per RECIST 1.1 or study treatment is 
permanently discontinued. Further guidance for continuation or termination of tumor 
assessments based on subject status is provided in Table 4.  
Table 4: 
Criteria for Discontinuing Radiographic Assessments 
Subject Status 
Action with Radiographic Assessments 
Study Treatment 
Permanently 
Discontinued? 
Investigator-Assessed 
rPD per RECIST 1.1 
Reached or Initiation of 
Systemic NPACT? 
No 
No 
Continue assessments 
No 
Yesa 
Continue assessments (ie, Investigator deems the 
clinical benefit of continued study drug treatment 
outweighs the potential risks) 
Yes 
No 
Continue assessments 
Yes 
Yes 
Discontinue assessments 
NPACT, non-protocol anticancer therapy; rPD, radiographic progressive disease; RECIST 1.1, Response 
Evaluation Criteria for Solid Tumors version 1.1. 
a Investigator-assessed rPD only. Receipt of NPACT is a requirement for study treatment discontinuation (see 
Section 3.5.1). 
 
Investigators are encouraged, if any doubt or ambiguities exist about radiographic progression, to 
continue study treatment if the subject is tolerating it acceptably, repeat radiographic tumor 
imaging at the next scheduled time point, and delay determination of progression until the 
findings indicating radiographic progression are unequivocal. Radiographic progression 
determined by the Investigator does not necessarily warrant discontinuation of tumor 
assessments or study treatment. 
Refer to Appendix A for the schedule for these assessments. 

 
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5.8.6.3. 
Confirmation of Tumor Response/Progression and Treatment beyond 
Progression 
For subjects with an overall response of PR or CR per RECIST 1.1 by investigator at a given 
time point, a repeat assessment is to be performed no fewer than 4 weeks after the criteria for 
response are first met. This may be performed at the next scheduled tumor assessment. 
In order to identify potential delayed immune-mediated tumor response, subjects with an overall 
response of PD per RECIST 1.1 who continue with study treatment because of evidence of 
clinical benefit as assessed by the Investigator should have tumor measurement outcomes 
confirmed by the Investigator after the initial Investigator-assessed PD criteria were met. This is 
to be performed no later than the next scheduled tumor assessment. Continuation of study 
treatment after confirmatory tumor imaging for PD is allowed for subjects who meet all the 
following criteria: 
• Clinical benefit per Investigator judgment 
• ECOG performance status of 0 or 1 
• Absence of unmanageable treatment-related AEs 
• Tumor status does not require urgent alternative medical interventions (eg, central nervous 
system [CNS] metastases) 
Subjects who are eligible to continue with study treatment must provide written informed 
consent. 
Reasons for treatment discontinuation are provided in Section 3.5.1. For subjects who continue 
treatment after the documentation of radiographic PD, regularly scheduled imaging will continue 
until treatment discontinuation.  
5.8.6.4. 
Blinded Independent Radiology Committee  
All radiological studies acquired at all scheduled time points and any additional (unscheduled) 
radiological images acquired to evaluate for potential metastatic disease must be sent to the 
BIRC preferably in original Digital Imaging and Communications in Medicine (DICOM) format 
(as detailed in the Site-specific Imaging Core Manual). The BIRC will evaluate prior radiation 
history for the purpose of valid identification of target lesions and all images in a central and 
independent fashion as further described in Section 12.4. Electronic transfer of scan files (via 
FTP, HTTP, or similar means) is preferred, although transfer on physical media (such as DVDs 
or CDs) is acceptable. For digital media, each disk should contain one time point for one subject. 
The site is expected to maintain a copy of digital data for the retention period applicable to the 

 
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protocol, GCPs, and federal, international and/or state legal and medical requirements. The 
Sponsor and or designee will retain the media for the life of the study.  
5.8.7. 
Tumor Marker Assessment 
Tumor marker samples (AFP) will be collected at screening, predose on W1D1, and after first 
dose of study treatment as described in the schedule of assessments (Appendix A). The tumor 
marker assessments will not be used to determine PD in this study. The samples will be analyzed 
by a central laboratory.  
5.8.8. 
Health-related Quality of Life Assessments 
Health-related QOL assessments will be performed using the EuroQol Health questionnaire 
instruments EQ-5D-5L (Appendix L). This is a standardized instrument for use as a measure of 
self-reported general health status. The EQ-5D-5L comprises 5 dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety) and a visual analog scale (VAS). The utility data 
generated from EQ-5D-5L are recommended for and commonly used in cost effectiveness 
analysis. The first assessment will be performed within 14 days prior to randomization. 
Assessment will be collected every 6 weeks after W1D1 (eg, W7D1, W13D1, etc). For 
randomized subjects who never receive study treatment, W1D1 is defined as the date of 
randomization. Subjects will continue completing questionnaires regardless of whether study 
treatment is given, reduced, held, or discontinued until the date of the last tumor imaging 
assessment or the study meets its primary endpoints. Consequently these assessments may be 
required in the Post-Treatment Period for some subjects (Appendix A). 
Subjects are to complete the questionnaires prior to each clinic visit or, if completed on the day 
of the visit, before seeing the study site personnel. If a clinic visit is not possible subjects should 
complete the questionnaires as per schedule and return it to the site either during the next visit or 
should send it to the site by fax or postal mail. Ideally, study subjects should not receive any 
information about their most recent medical results prior to completing the questionnaires in 
order to ensure that their reporting is not influenced by such information when completing the 
questionnaires. At clinic visits, questionnaires should be carefully reviewed by the study staff at 
the site for completeness.  
Subjects who are not compliant with completing the questionnaires should be reminded by the 
Investigator that these reports are an essential part of the study and timely completion is required.  
Every effort should be made by the study site to retrieve all HRQOL questionnaires including the 
assessment following radiographic progression or discontinuation of study treatment, and to keep 
them at the site as source documentation.  

 
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Translated copies of the EQ-5D-5L questionnaires, if required, and instructions for filling them 
out will be provided to each study site in a separate study manual. HRQOL assessments will no 
longer be collected for subjects who transition to the Crossover Phase or if the study transitions 
to the Maintenance Phase. 
5.8.9. 
Healthcare Resource Utilization 
Healthcare resource utilization parameters will be collected from randomization through the 
100-Day Post-Treatment Follow-up Visit (FU-2). These include hospital admissions, emergency 
room visits, intensive care unit admissions, length of stay, surgeries, and transfusions. These data 
will not be collected in the Maintenance Phase. 
5.8.10. 
Pharmacokinetic Assessments 
Blood samples will be obtained from all subjects in the experimental arm (cabozantinib + 
atezolizumab) and the single-agent cabozantinib arm (60 mg) for cabozantinib PK. Samples will 
be collected for plasma cabozantinib concentration measurement predose on W1D1, W4D1, 
W7D1, W10D1, and W13D1. The results will be used to confirm exposure to cabozantinib and 
to further characterize the population PK and exposure-response relationships for cabozantinib in 
this population. 
Blood samples will be obtained from all subjects in the experimental arm for atezolizumab PK. 
Serum samples will be collected predose on W1D1, W4D1, W7D1, W10D1, W13D1, and at the 
Post-Treatment Follow-up visits (FU-1 and FU-2). The results may be used to confirm exposure 
to atezolizumab.  
Collection of PK samples may be halted early or sampling frequency may be reduced at the 
discretion of the Sponsor.  
5.8.11. 
Immunogenicity Assessments 
Blood samples will be obtained from all subjects in the experimental arm (cabozantinib + 
atezolizumab) for immunogenicity assessment predose on W1D1, W13D1, W25D1, and at the 
Post-Treatment Follow-up visits (FU-1 and FU-2). Collection of immunogenicity samples may 
be halted early, or sampling frequency may be reduced at the discretion of the Sponsor. 
5.8.12. 
Biomarker Assessments 
Peripheral blood samples will be obtained as specified in Appendix A. Archival tumor tissue 
(most recently obtained) will be provided, if available. If archival tissue and 
histological/cytological confirmation of disease are not available, a tumor biopsy may be collected 
during screening with subject consent. An optional tumor biopsy may be collected approximately 

 
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6 weeks after the first dose of study treatment; other time points may be acceptable provided the 
tumor sample is collected prior to progressive disease. Treatment with cabozantinib or sorafenib 
must be interrupted for at least 5 days before optional tumor biopsies are performed and may not 
be reinitiated until complete wound healing has occurred (at least 10 days). Exploratory analyses 
may include, but may not be limited to, the following: 
• PD-L1, MET, and other relevant biomarkers in tumor specimens for association with clinical 
outcomes  
• Immune cell infiltration and mutational load assessment in tumor specimens for association 
with clinical outcome 
• Circulating immune cells in peripheral blood  
• Blood biomarkers (ie, cytokines/chemokines, VEGF) 
• Cell and/or plasma pharmacogenomics (eg, circulating tumor DNA [ctDNA]) 
Collection of biomarker samples may be halted early or sampling frequency may be reduced at 
the discretion of the Sponsor. Some biomarker samples may only be collected at selected sites 
(see the study laboratory manual for details). 
The required blood samples will be used to study plasma, serum, and cellular biomarkers. The 
most recent archival/fresh tumor biopsy and optional on-treatment tumor tissue samples will be 
used to evaluate changes in biomarker expression and genetic/genomic alterations. The analyses 
will help identify biomarkers that are predictive of response to the study drugs, and may help 
improve understanding of tumor development, tumor microenvironment, and effects on peripheral 
immune activity for the study indication. Analyses may include, but may not be limited to, 
sequencing of DNA and/or RNA from tissue and/or blood (plasma) to look for genetic/genomic 
alterations (eg, mutations, copy number variation, mutational burden), immunohistochemistry 
(IHC) assessment of biomarker levels in tissue (eg, MET, PD-L1), and immune cell profiling by 
fluorescence-activated cell sorting (FACS) analyses. Immune cell profiling by FACS may be 
conducted at selected sites. These studies may use conventional as well as novel technology or 
methodology. The goal is to correlate modulation of these putative biomarkers to clinical 
outcome as a consequence of study treatment.  
In addition, pharmacogenetic analyses involving single nucleotide polymorphism (SNP) 
genotyping may be performed in order to correlate variations in subject genotype with the safety/ 
tolerability, PK, and/or pharmacodynamics (biomarker analyses) of cabozantinib and/or 
atezolizumab. 

 
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The biomarker assessment samples may also be used for diagnostic assay development related to 
study drug and for the discovery of biomarkers that may prove to be valuable surrogates for 
clinical response and to understanding the underlying mechanisms of the disease.  
5.8.13. 
Overall Survival 
Overall survival will be assessed every 12 weeks (± 14 days) after the FU-2, which occurs 
100 days (±14 days) after discontinuation of study treatment. Subjects will be followed until 
death, withdrawal of consent for non-interventional study assessments, or Sponsor decision to no 
longer collect these data. Receipt of subsequent NPACT will also be collected during follow-up 
contacts. If a subject withdraws consent to participate in the study, information regarding 
survival status may be obtained from public records such as government vital statistics or 
obituaries, as permitted by local regulations. These assessments are not required for subjects who 
discontinue study treatment in the Maintenance Phase (such subjects are to be followed per 
standard of care). 
5.9. 
Protocol Deviations 
A protocol deviation is defined as any change, divergence, or departure from the requirements or 
procedures of this protocol or from ICH GCP. Efforts should be made to limit deviations. The 
Investigator is responsible for promptly reporting protocol deviations as applicable to their 
IRB/EC and/or to the Sponsor per IRB/EC policy. The Sponsor will determine the effect of the 
protocol deviation on the scientific soundness of the clinical study and subject safety, and 
determine if additional reports or actions are required. For important or repeated protocol 
deviations, additional action may include site re-training, hold or closure of enrollment, and/or 
site termination. 

 
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6. 
TREATMENTS 
6.1. 
Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the appropriate prescribing 
information for that country (if applicable) or the pharmacy manual and inventoried in 
accordance with applicable state and federal regulations. Special accommodations during the 
global COVID-19 pandemic are described in Appendix M. 
6.1.1. 
Study Treatment 
6.1.1.1. 
Cabozantinib (XL184) Tablets 
The Sponsor will provide each investigator with adequate supplies of cabozantinib, which will be 
supplied as 60-mg and 20-mg yellow film-coated tablets. The 60-mg tablets are oval and the 
20-mg tablets are round. Doses of 40 mg will comprise two 20-mg tablets. The components of 
the tablets are listed in Table 5.  
Table 5: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib Drug Substance (
 drug load as 
free base) 
Active Ingredient 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
Lactose Anhydrous (60M) 
Filler 
Hydroxypropyl Cellulose (EXF) 
Binder 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
Colloidal Silicon Dioxide 
Glidant 
Magnesium Stearate 
Lubricant 
 Film Coating which includes 
HPMC 2910/hypromellose 6 cp, titanium dioxide, 
triacetin, and iron oxide yellow 
Film Coating 
All study medication will be stored at controlled room temperature and inventoried according to 
applicable regulations. Further information on storage and handling will be provided in the 
pharmacy manual. 
6.1.1.2. 
Atezolizumab  
Atezolizumab is an Fc-engineered, humanized, monoclonal antibody (non-glycosylated IgG1 
kappa immunoglobulin) produced in Chinese hamster ovary cells with a calculated molecular 
mass of 145 kDa.  
CCI
CCI
CCI

 
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The Sponsor will provide each investigator with adequate supplies of atezolizumab, which will 
be supplied as a 1200 mg/20 mL (60 mg/mL) colorless to slightly yellow solution in single-dose 
vials. Atezolizumab solution contains the following inactive ingredients: glacial acetic acid, 
L-histidine, sucrose, and polysorbate 20. Refer to the package insert (or the local label) and the 
pharmacy manual for additional information and instructions for preparing atezolizumab for 
infusion. Commercially sourced solution used as diluent (0.9% NaCl) should be obtained by 
investigative sites according to local regulations. 
6.1.2. 
Sorafenib  
Sorafenib is a kinase inhibitor indicated for the treatment of HCC. The sponsor will provide each 
investigator with adequate supplies of commercially obtained sorafenib. Sorafenib tablets 
contain the following inactive ingredients: croscarmellose sodium, microcrystalline cellulose, 
hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide 
and ferric oxide red. Refer to the most current local prescribing information appropriate to the 
respective site location. 
6.2. 
Treatment Schedule of Administration 
6.2.1. 
Experimental Arm: Cabozantinib in Combination with Atezolizumab 
Cabozantinib at a dose of 40 mg (2 × 20 mg tablets) will be administered orally, once daily. 
Atezolizumab will be administered at a standard dosing regimen of 1200 mg as an IV infusion 
once every 3 weeks.  
Subjects will receive study treatment with cabozantinib and atezolizumab as long as they 
continue to experience clinical benefit as assessed by the investigator or until unacceptable 
toxicity, the need for subsequent systemic anticancer treatment, or until any other reasons for 
treatment discontinuation listed in the protocol (Section 3.5.1). Subjects are allowed to 
discontinue one component of the study treatment but continue to receive the other; investigators 
are encouraged to consult with the Sponsor before doing so.  
Escalation of cabozantinib from 40 mg qd to 60 mg qd is allowed after Sponsor approval for 
subjects who are tolerating the 40 mg cabozantinib dose level well and have been treated on this 
dose level for at least 4 weeks. In general, subjects who develop clinically relevant adverse 
events (eg, Grade 3 or 4 AEs) are not allowed to dose escalate cabozantinib from 40 qd to 60 mg 
qd. 
For guidance on dose modifications, interruptions, delays, or discontinuations due to AEs, refer 
to Sections 6.6.1 and 6.6.2.  

 
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6.2.2. 
Control Arm: Sorafenib 
The recommended dose of sorafenib in adults is 400 mg (two tablets of 200 mg) twice daily 
(equivalent to a total daily dose of 800 mg). For detailed guidance, refer to the most current local 
prescribing information appropriate to the respective site location. 
6.2.3. 
Single-Agent Cabozantinib Arm: Cabozantinib 
The dose of cabozantinib on the single-agent cabozantinib arm is 60 mg orally, once daily. 
Subjects will receive study treatment with cabozantinib as long as they continue to experience 
clinical benefit as assessed by the investigator (see Section 5.8.6.3) or until unacceptable 
toxicity, the need for subsequent systemic anticancer treatment, or until any other reasons for 
treatment discontinuation listed in the protocol (Section 3.5.1). For guidance on dose 
modifications, interruptions, delays, re-escalation after dose reductions, or discontinuations due 
to AEs, refer to the Section 6.6.1. 
6.2.4. 
Study Drug Administration on Week 1 Day 1 (W1D1) 
The first dose of study treatment should occur as soon as possible after randomization. The date 
of the first dose of study treatment is defined as W1D1. The first doses of all study treatments are 
to be administered at the clinic.  
Cabozantinib: 
For subjects receiving cabozantinib (experimental arm and single-agent cabozantinib arm), 
subjects will fast (with the exception of water) for at least 2 hours before receiving cabozantinib. 
Upon completion of the 2-hour fast, the subject will receive the oral dose of cabozantinib with a 
minimum of 8 oz (240 mL) of water in the clinic and then the subject will continue to fast for 
1 hour while under observation at the clinic. For subjects on the experimental arm (cabozantinib 
and atezolizumab), atezolizumab is to be administered first. For cabozantinib dosing on 
subsequent dosing days refer to Section 6.2.5. 
Atezolizumab: 
Doses of atezolizumab will be administered intravenously at the clinic by infusion every 3 weeks 
(± 2 days).  
The infusion of atezolizumab (1200 mg fixed dose) will be prepared according to local 
prescribing information or the pharmacy manual. The IV administration of atezolizumab can 
only occur in a clinical setting with staff experienced in managing of infusion-related reactions 
(IRRs) and with access to emergency services. The initial IV infusion of atezolizumab will be 
given over 60 min (± 15 min) without premedication for potential IRRs or CRS. Subsequent IV 
infusions may be given over 30 min (± 10 min) if the initial infusion is tolerated. Premedication 

 
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for IRRs or CRS is allowed after the initial infusion. No bolus or IV push of atezolizumab is 
allowed. Dose delays will be allowed for toxicities suspected to be due to atezolizumab 
administration. Atezolizumab infusion requirements and guidance are summarized in Table 6. 
Table 6: 
Atezolizumab Infusion Requirements and Guidance 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted. 
• 
Vital signs (blood pressure, pulse, respiratory rate, 
and temperature) should be recorded within 60 min 
prior to the infusion. 
• 
Atezolizumab should be infused over 60 (± 15) min. 
• 
If clinically indicated, vital signs should be recorded 
during the infusion at 15, 30, 45, and 60 min (± 5 min 
for all time points) during the infusion and at 
30 (± 10) min after the infusion. 
• 
Subjects should be informed about the possibility of 
delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such 
symptoms. 
• 
If the subject experienced an IRR or CRS with any 
previous infusion, premedication with 
antihistamines, antipyretics, and/or analgesics may 
be administered for subsequent doses at the 
discretion of the investigator. 
• 
Vital signs should be recorded within 60 min prior 
to the infusion. 
• 
Atezolizumab should be infused over 
30 (± 10) min if the previous infusion was tolerated 
without an IRR or CRS, or 60 (± 15) min if the 
subject experienced an IRR or CRS with the 
previous infusion. 
• 
If the subject experienced an IRR or CRS with the 
previous infusion or if clinically indicated, vital 
signs should be recorded during the infusion and at 
30 (± 5) min after the infusion. 
CRS, cytokine release syndrome; IRR, infusion-related reaction. 
After the IV administration of the first dose of atezolizumab in the clinic, the subject will wait 
for at least 1 hour before taking cabozantinib. If the subject develops an infusion reaction or 
CRS, the oral administration of cabozantinib will be delayed or interrupted until the subject has 
recovered and the Investigator believes that it is safe to administer cabozantinib. For 
management of IRRs or CRS refer to Appendix G. 
If the first dose of atezolizumab cannot be given for any reason, no oral treatment with 
cabozantinib is to be initiated.  
Sorafenib:  
On the first day subjects are to fast (with the exception of water) for at least 2 hours before 
receiving sorafenib. After the 2-hour fast, the subject are to take the 400 mg oral dose of 
sorafenib with a glass of water in the clinic with no food intake for one more hour post-dose 
while under observation at the clinic to monitor for potential AEs. Subsequent doses will be self-
administered at home (Section 6.2.6). Any unused study treatment must be returned to the study 
site for drug accountability and disposal.  

 
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Refer to the current sorafenib label appropriate to the respective site location for additional 
details regarding recent major label changes, indication and usage, dosage and administration, 
dose modifications, contraindications, warnings and precautions, adverse reactions, drug 
interactions, and use in specific populations. 
6.2.5. 
Cabozantinib Administration outside the Clinic 
The subject should take cabozantinib outside the clinic at approximately the same time every 
day, preferentially before going to bed, and should adhere to the fasting requirements described 
in this section.  
Subjects are to fast (with the exception of water) for at least 2 hours after eating the evening meal 
before taking their dose. After the 2-hour fast and before going to bed, subjects are to take 
cabozantinib with a full glass of water (minimum of 8 oz or 240 mL) with no food intake for one 
more hour post-dose. If the subject’s schedule requires taking cabozantinib during the day, the 
subject is to be instructed to follow the same fasting recommendations.  
Tablets should not be crushed or chewed. Grapefruit and Seville oranges (and products made 
from them) should be avoided while being treated with cabozantinib.  
Subjects are to be instructed to not make up vomited doses and to maintain the planned dosing 
schedule. Subjects are not to 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 are 
not to 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.  
6.2.6. 
Sorafenib Administration outside the clinic 
Sorafenib should be taken orally twice daily at the same time each day. Sorafenib should be 
taken either without food or with a low-fat or moderate fat meal. If a subject intends to have a 
high fat meal, sorafenib should be taken at least 1 hour before or 2 hours after the meal. 
Sorafenib tablets should be swallowed whole with a glass of water. Subjects should be instructed 
that if a dose of sorafenib is missed, the next dose should be taken at the regularly scheduled 
time, and the subject should not double the dose. Refer to the current sorafenib label appropriate 
to the respective site location for additional details regarding dosage and administration. 

 
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6.3. 
Treatment after Study Completion 
After study completion (see Section 3.5.3), subjects who continue to demonstrate clinical benefit 
may be eligible to receive Exelixis-supplied study treatment for the maximum treatment duration 
specified in Section 6.2 during the Maintenance Phase. Alternatively, study treatment may be 
provided via a rollover study requiring approval by responsible health authority and ethics 
committee or through another mechanism at the discretion of Exelixis.  
Exelixis reserves the right to terminate access to Exelixis-supplied study treatment if any of the 
following occur:  
a) The study is terminated due to safety concerns.  
b) The development of atezolizumab or cabozantinib is terminated for other reasons, 
including but not limited to lack of efficacy and/or not meeting the study objectives (eg, 
the null hypothesis is not rejected for the primary endpoint of OS). 
c) The participant can obtain medication from a government-sponsored or private health 
program.  
In all cases Exelixis will follow local regulations. Exelixis will work with study investigators to 
act in the best interest of subjects. 
6.4. 
Compliance 
Subject compliance with outpatient study treatment will be assessed by the site using drug 
dispensing and return records, infusion logs, progress notes about dose reductions/interruptions, 
and subject interview. These data will not be directly recorded in the CRF; rather, the CRF will 
capture infusion details and, for oral study treatment, intervals of constant dose and reasons for 
changes in dose level (eg, a new record completed each time dose level changes, including 
periods where no dose was taken, and the reason for a dose level change). 
6.5. 
Study Treatment Accountability 
The Investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding when and how 
much study treatment is dispensed and used by each subject in the study. Reasons for deviation 
from the expected dispensing regimen must also be recorded. Drug accountability will be 
performed periodically by the Sponsor or designee at interim monitoring visits. To satisfy 
regulatory requirements, at the time of site closure all unused study treatment will undergo final 
reconciliation and be destroyed according to applicable state, federal, and local regulations. 

 
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6.6. 
Safety Considerations 
6.6.1. 
Management of AEs with Dose Reductions and/or Dose Interruptions 
Subjects will be monitored for SAEs from the time of signing informed consent and for 
nonserious AEs from first dose of study treatment. Monitoring continues through 30 days 
(100 days for AESIs [Table 31] regardless of seriousness and for unrelated SAEs) after the date 
of the decision to permanently discontinue all study treatment (defined as the later of the date of 
the decision to discontinue all study treatment or the date of the last dose of any study treatment). 
Longer monitoring periods are required for related SAEs and certain other events as described in 
Section 8.4. Further details for follow-up and data collection requirements for AEs, SAEs, and 
AESIs are summarized in Appendix K. Subjects will be instructed to notify their physician 
immediately for any occurring AE. Causality assessment of AEs should include at minimum 
confounding factors such as disease and concomitant medications. Adverse event severity will be 
graded by the Investigator according to CTCAE v5.  
The following should be taken into consideration in decisions regarding management for 
treatment-related side effects: 
• Cabozantinib and atezolizumab have class-specific safety profiles based on their mechanism 
of action but may also cause AEs that overlap. For management of AEs in the experimental 
arm which can be clearly attributed to either cabozantinib or atezolizumab, independent dose 
modification for either agent is allowed.  
o Examples of VEGFR-TKI associated AEs caused by cabozantinib are 
hypertension and hand-foot syndrome.  
o Examples of AESIs caused by atezolizumab are pneumonitis and 
endocrinopathies.  
For AEs without clear attribution to either study treatment, management of toxicity should 
include dose modifications of both agents per the discretion of the Investigator. Examples of 
overlapping AEs are diarrhea and transaminase increases. 
• As a general approach all AEs should be managed with supportive care including both 
pharmacological and non-pharmacological treatments according to consensus management 
guidelines at the earliest signs of toxicity considered related to study treatment.  
• Study treatment may be continued for mild AEs if appropriate supportive care has been 
initiated to ameliorate symptoms. Should this be ineffective and toxicities become 

 
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unacceptable, dose modifications of study treatment should be considered to prevent 
worsening of toxicity. Moderate to severe AEs usually require dose modifications including 
dose reductions and/or interruptions. 
• Dose interruptions of cabozantinib or atezolizumab for AEs may occur at any time and 
independently at the discretion of the Investigator. If both study treatments in the 
experimental arm or sorafenib in the comparator arm are interrupted for more than 12 weeks, 
treatment should be discontinued unless approved by the Sponsor. Dose interruptions of 
sorafenib for AEs may also occur at any time at the discretion of the Investigator. 
• Subjects on the experimental arm (cabozantinib + atezolizumab) will be allowed to 
discontinue one component of the study treatment but continue to receive the other; the 
Investigator is encouraged to discuss such circumstances with the Sponsor. 
Cabozantinib: 
• The assigned dose for cabozantinib in the experimental combination arm is 40 mg qd. 
Escalation of cabozantinib from 40 mg qd to 60 mg qd is allowed after Sponsor approval for 
subjects who are tolerating the 40 mg cabozantinib dose level well and have been treated on 
this dose level for at least 4 weeks. In general, subjects who develop clinically relevant 
adverse events (eg, Grade 3 or 4 AEs) are not allowed to dose escalate cabozantinib from 
40 mg qd to 60 mg qd. The assigned dose for cabozantinib in the single-agent cabozantinib 
arm is 60 mg qd.  
• Two dose reduction levels of cabozantinib (20 mg daily, and 20 mg every other day [qod]) 
are permitted on the experimental combination arm (see Table 7). 
Note: Subjects who have their dose escalated to 60 mg on the experimental arm would be 
permitted to reduce dose back to 40 mg before further reduction to lower dose levels. 
• Two dose reduction levels of cabozantinib (40 mg daily, 20 mg daily) are permitted on the 
single-agent cabozantinib arm (see Table 7).  
• Dose modification criteria for treatment-related AEs of cabozantinib are shown in Table 8. 
• Dose reinstitution and reescalation after dose interruptions and/or reductions:  
o If the subject recovers from his or her toxicities to ≤ Grade 1 per CTCAE v5 or to the 
baseline value (or lower) and the AE was unrelated to cabozantinib, then cabozantinib 
may be restarted with no change in dose.  

 
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o If the subject recovers from his or her toxicities to ≤ Grade 1 or to the baseline value (or 
lower) and the AE was deemed possibly related to cabozantinib, then cabozantinib may 
be restarted at a reduced dose (see Table 8). Subjects who initiated treatment with 
cabozantinib at 40 mg and experience a possibly related AE of Grade 1 or 2 severity may 
be restarted with no dose change after recovery of the toxicities to ≤ Grade 1 or to the 
baseline value (or lower) if appropriate supportive care can prevent or minimize the risk 
of the AE. 
o Subjects receiving a dose of 20 mg qod on the experimental combination arm (20 mg qd 
on the single-agent cabozantinib arm) who have cabozantinib interrupted may be 
restarted at the same dose if deemed safe at the discretion of the Investigator. Subjects 
unable to tolerate a dose of 20 mg qod (20 mg qd on the single-agent cabozantinib arm) 
must discontinue cabozantinib. 
o Reescalation to the previous dose may be allowed at the discretion of the Investigator for 
AEs which have resolved or recovered to Grade 1 (or baseline value) and deemed 
tolerable and easily managed by optimized supportive treatment. Dose reescalation is not 
allowed following a cabozantinib-related dose reduction for Grade 4 AEs affecting major 
organs (eg, CNS, cardiac, hepatic, renal, pulmonary, GI). 
• Guidelines for the management of specific AEs of cabozantinib such as GI disorders, non-GI 
fistula formation, hemorrhage, thromboembolic events, hypertension, stomatitis and 
mucositis, skin disorders, osteonecrosis, proteinuria, nervous system disorders, hepatocellular 
toxicity, infections and infestations, blood system disorders, fatigue, weight loss, QTc 
prolongation, electrolyte disorders, endocrine disorders, and respiratory disorders are 
provided in Section 6.6.2.1. 

 
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Table 7: 
Dose Levels of Cabozantinib (Oral Dosing) 
Assigned Starting 
Dose 
First Dose Level 
Reduction 
Second Dose Level 
Reduction 
Third Dose Level 
Reduction 
40 mg daily (qd)a 
(Experimental arm) 
20 mg daily (qd) 
20 mg every other day 
(qod)b  
No dose reduction 
permitted 
60 mg daily (qd) 
(Single-agent 
cabozantinib arm) 
40 mg daily (qd) 
20 mg daily (qd)c 
No dose reduction 
permitted 
a Subjects who have their dose escalated to 60 mg on the experimental arm would be permitted to reduce dose 
back to 40 mg before further reduction to lower dose levels. 
b Cabozantinib will be discontinued on the experimental if a dose of 20-mg cabozantinib every other day is not 
tolerated.  
c Cabozantinib will be discontinued on the single-agent cabozantinib arm if a qd dose of 20 mg cabozantinib is 
not tolerated  
 
 

 
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Table 8: 
Dose Modifications for Cabozantinib-Related AEs 
CTCAE v5 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib at 
the current dose level if AE is manageable and tolerable. 
Grade 2 AEs which are tolerable and 
are easily managed 
 
Grade 2 AEs which are intolerable 
and cannot be adequately managed  
Continue cabozantinib at the current dose level with 
supportive care. 
 
Cabozantinib should be dose reduced or interrupted. 
Note: It is recommended that dose interruptions be as brief as 
possible.  
Grade 3 AEs (except clinically 
non-relevant laboratory abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction of cabozantinib and 
optimal medical care.  
Note: It is recommended that dose interruptions be as brief as 
possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory abnormalities) 
Cabozantinib must be interrupted immediately.  
In general, cabozantinib should be discontinued 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 of 
cabozantinib following recovery to Grade 1 (or 
baseline) and optimal medical care  
Sponsor must be contacted to discuss treatment continuation 
upon resolution of AEs.  
AE, adverse event. 
Note: Cabozantinib dose modification criteria for specific medical conditions are provided in Section 6.6.2.1.  

 
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Atezolizumab: 
• The assigned dose for atezolizumab is 1200 mg IV every 3 weeks. Infusion will occur every 
three weeks (± 2 days). 
• Dose delays are allowed for atezolizumab (see Table 9), but dose reductions are not allowed.  
• Dose modification criteria for irAEs and other AESIs and for guidance on reinstituting 
atezolizumab are shown in Table 10. 
• If corticosteroids are initiated for treatment of irAEs, they must be tapered over ≥ 1 month to 
≤ 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
• Guidelines for the management of IRRs and CRS, irAEs for atezolizumab (ie, pneumonitis, 
hepatitis, diarrhea/colitis, myocarditis, endocrinopathies including hypophysitis, and 
infection) and other AESIs are provided in Section 6.6.2.2. 
Table 9: 
Dose Interruptions of Atezolizumab 
Assigned dose 
Dose Interruptions 
1200-mg atezolizumab IV q3w 
At any time to manage unacceptable AESIs 
AESI, adverse events of special interest; q3w, once every 3 weeks;  
 
Table 10: 
Dose Modifications for Atezolizumab-Associated Adverse Events 
CTCAE v5 Grade 
Recommended Management 
Grade 1 immune-mediated myelitis* 
Grade 1 pericarditis** 
Grade 2 myocarditis 
Grade 1a - 2 pneumonitis 
Grade 2 nephritis 
Transaminases (ALT or AST):  
• 
Increases to between > 3 × ULN and ≤ 10 × ULN 
(from baseline values ≤ ULN), or  
• 
Increases to between > 5 × ULN and ≤ 10 × ULN 
(from baseline values between > ULN and 
≤ 3 × ULN), or 
• 
Increases to between > 8 × ULN and ≤ 10 × ULN 
(from baseline values between > 3 × ULN and 
≤ 5 × ULN) 
Delay treatment with atezolizumab 
Treatment may be resumed in subjects 
following recovery to Grade 0-1 
* Continue atezolizumab unless symptoms 
worsen or do not improve. 
** Withhold treatment with atezolizumab and 
conduct a detailed cardiac evaluation to 
determine the etiology and manage 
accordingly. 

 
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CTCAE v5 Grade 
Recommended Management 
Grade 2 immune-mediated neuropathy (any cranial 
nerve disorder, including facial paresis, should be 
managed as per Grade 2 guidelines)*** 
Grade 2 or 3 diarrhea or colitis 
Grade 2 or 3 myositis 
Symptomatic adrenal insufficiency, hypothyroidism, 
or hyperthyroidism; Grade 2 or 3 hypophysitis; or 
Grade 3 or 4 hyperglycemia  
Grade 2 ocular inflammatory toxicity 
Grade 2 or 3 pancreatitis or Grade 3 or 4 increases in 
amylase or lipase levels  
Grade 3 or 4 infection 
Grade 2 infusion-related reactions or cytokine release 
syndrome 
Grade 3 rash 
Suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis (any grade) 
Other Grade 2 or 3 atezolizumab-associated AEs 
Delay treatment with atezolizumab 
Treatment may be resumed in subjects 
following recovery to Grade 0-1. 
*** For general immune-related neuropathy, 
if the event resolves to Grade 1 or better, 
resume atezolizumab. For facial paresis, if 
event resolves fully, resume atezolizumab; if 
event does not resolve fully while 
withholding atezolizumab, permanently 
discontinue atezolizumab. 
 
Grade 2 - 4 immune-mediated myelitis 
Grade 3 or 4 immune-mediated neuropathy, including 
facial paresis 
Grade 2 - 4 myocarditis 
Grade 4 myositis and/or recurrent Grade 3 myositis 
Grade 3 or 4 pneumonitis 
Grade 3 or 4 nephritis  
AST or ALT > 10 × ULN or total bilirubin > 3 × ULN 
Grade 4 diarrhea or colitis 
Grade 4 hypophysitis and/or recurrent hypophysitis 
Myasthenic syndrome/myasthenia gravis, Guillain-
Barré or meningoencephalitis (all grades) 
Grade 3 or 4 ocular inflammatory toxicity 
Grade 4, or recurrent Grade 2 or 3, immune-mediated 
pancreatitis 
Permanently discontinue atezolizumab  

 
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CTCAE v5 Grade 
Recommended Management 
Grade 3 or 4 infusion-related reactions or cytokine 
release syndrome 
Grade 4 rash 
Confirmed Stevens-Johnson syndrome or toxic 
epidermal necrolysis (any grade) 
Other Grade 4 or recurrent Grade 3 atezolizumab-
associated AEs 
Permanently discontinue atezolizumab  
AE, adverse event; AESI, adverse events of special interest; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; irAE, immune-related adverse event; ULN, upper limit of normal. 
Note: Additional information for atezolizumab dose modification criteria and treatment recommendations for 
irAEs, infusion reactions, and other AESIs are provided in Section 6.6.2.2.  
a Consider interrupting atezolizumab for Grade 1 pneumonitis. 
b Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-mediated event. The decision to re-challenge patients with atezolizumab should be based on 
investigator's assessment of benefit−risk and documented by the investigator. The Medical Monitor is available to 
advise as needed. 
 
Sorafenib:  
• The assigned dose for sorafenib is 400 mg twice daily.  
• When dose reduction is necessary, the sorafenib dose may be reduced to 400 mg once daily 
(qd). If additional dose reduction is required, sorafenib may be reduced to a single 400 mg 
dose every other day (qod). 
For additional details on management guidance of AEs refer to the most current sorafenib 
prescribing information appropriate to the respective site location. 
6.6.2. 
Warnings, Precautions, Guidelines for Management of Adverse Events 
Management of severe or intolerable adverse reactions may require temporary dose reductions 
and/or interruptions for cabozantinib and sorafenib, and/or dose delays of atezolizumab therapy.  
6.6.2.1. 
Cabozantinib 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, nausea, decreased appetite, vomiting, 
weight decreased, PPE, constipation, hypertension, dysgeusia, dysphonia, and asthenia. For a full 
description of the safety profile of cabozantinib, refer to the Cabozantinib Investigator’s 
Brochure. 

 
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Other medically important but less frequent AEs including arterial thrombotic AEs (eg, TIA and 
MI) and venous thrombotic AEs (eg, deep vein thrombosis [DVT] and pulmonary embolism), 
severe hemorrhagic events, proteinuria, wound healing complications, GI perforation, abscesses 
including intra-abdominal and pelvic abscesses, GI and non-GI fistula formation, osteonecrosis, 
and reversible posterior leukoencephalopathy syndrome (RPLS; also known by the preferred 
term posterior reversible encephalopathy syndrome [PRES]). 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects treated 
with cabozantinib in descending order of frequency were anemia, AST increased, ALT 
increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, 
hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, 
hyponatremia, ALP increased, leukopenia, and hyperglycemia. 
Adverse events may occur within the first few weeks in the course of treatment with 
cabozantinib, as cabozantinib is expected to reach steady state exposure at approximately 
2 weeks following first dose. Events that generally have an early onset include hypocalcemia, 
hypokalemia, thrombocytopenia, hypertension, PPE, abdominal pain, mucosal inflammation, 
constipation, diarrhea, and vomiting. Adverse events should be managed with supportive care at 
the earliest signs of toxicity. Dose reductions and treatment interruptions should be considered. 
Dose reductions are recommended for events that, if persistent, could become serious or 
intolerable (Table 8). 
Cabozantinib should be permanently discontinued for the following AEs, regardless of whether 
these events are deemed related to cabozantinib: visceral perforation or fistula formation, serious 
and life-threatening rhabdomyolysis, severe hemorrhage, serious arterial thromboembolic events, 
nephrotic syndrome, hypertension with life-threatening consequences, persistent uncontrolled 
hypertension despite optimal medical management, and RPLS. 
6.6.2.1.1. Gastrointestinal Disorders 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After starting 
treatment with cabozantinib, subjects should be monitored for early signs of GI perforation such 
as abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for 
developing GI perforation or fistula (Turnage and Badgwell 2012) are present. Discontinue 
cabozantinib and initiate appropriate management in subjects who have been diagnosed with GI 
perforation or fistula. 

 
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Diarrhea: Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. Guidelines for the 
evaluation and management of diarrhea are shown in Table 11. Administration of 
antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one antidiarrheal 
agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, 
cabozantinib should be temporarily interrupted or dose reduced. When the diarrhea is controlled, 
retreatment with cabozantinib may be acceptable per investigator decision. In addition, general 
supportive measures should be implemented such as continuous oral isotonic hydration, 
correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-
containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever diarrhea 
has occurred during treatment with cabozantinib. Infections of the perianal region should be 
treated per local guidelines. 

 
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Table 11: 
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (eg, loperamide 4 mg followed 
by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide per 
day]) 
• 
Dietary modifications (eg, small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add solid 
foods and discontinue or decrease antidiarrheal treatment after 12 h 
diarrhea-free interval 
o 
Diarrhea not resolving: Continue/resume antidiarrheal treatment  
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend clinic 
• 
Rule out infection (eg, stool sample for culture) 
o 
Administer antibiotics as needed (eg, if fever or Grade 3-4 
neutropenia persists > 24 h) 
• 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or 
to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower grade diarrhea consider hospitalization 
and IV hydration 
• 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider 
restarting study treatment at reduced dose 
o 
Diarrhea not resolving: Start and or continue antidiarrheal treatment 
(eg, loperamide 4 mg followed by 2 mg after each episode of 
diarrhea [maximum: 16 mg loperamide per day]). Consider starting 
second line antidiarrheal or referral to gastroenterologist 
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment 
or prophylaxis of nausea and vomiting, along with supportive care. Dehydration and electrolyte 
abnormalities may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. Antiemetic medications should be assessed for 
potential drug interactions (refer to Section 7.3.1 for further details). 
6.6.2.1.2. Non-Gastrointestinal Fistula 
Complications from radiation therapy especially of the thoracic cavity including mediastinum 
have been identified as a possible predisposing risk factor for non-GI fistula formation in 
subjects undergoing treatment with VEGF pathway inhibitors. 

 
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Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with a non-GI fistula. 
6.6.2.1.3. Hemorrhage 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be monitored for bleeding events with serial complete blood count 
(CBCs) and physical examination while on study. The risk of hemorrhage in cabozantinib-
treated subjects with brain metastases has not been thoroughly analyzed. Subjects enrolled with 
treated and stable brain metastases should be monitored with a high index of suspicion if 
symptoms that could be due to a CNS hemorrhage occur. 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 2.5 mL of red blood). 
6.6.2.1.4. Thromboembolic events  
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in 
clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary 
embolism and/or DVT should have study treatment interrupted until therapeutic anticoagulation 
is established. Treatment with cabozantinib may be resumed in subjects with pulmonary 
embolism or DVT if it is determined that the event is uncomplicated and that the subject is 
deriving clinical benefit from cabozantinib treatment and that anticoagulation does not place 
them at a significant risk that outweighs the benefit of resuming treatment per discretion of the 
Investigator. Low molecular weight heparins are the preferred management for thrombotic 
events; oral anticoagulants (eg, warfarin or other coumarin-related agents, direct thrombin or 
direct FXa inhibitors, or antiplatelet agents, or chronic use of aspirin above low dose levels for 
cardioprotection per local applicable guidelines) are not allowed. 
Arterial thrombotic events (eg, TIA, MI) have been observed in studies with cabozantinib. 
Further treatment with cabozantinib should be discontinued in subjects who develop an acute MI, 
cerebral infarction, or any other clinically significant arterial thromboembolic complication. 
6.6.2.1.5. Hypertension 
Table 12 provides treatment guidelines for hypertension deemed related to cabozantinib. Blood 
pressure should be monitored in a constant position visit to visit, either sitting or supine in a 
relaxed setting. Decisions to reduce or interrupt the dose of study treatment must be based on BP 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement.  

 
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Cabozantinib should be discontinued in subjects with hypertension with life threatening 
consequences (eg, malignant hypertension, transient or permanent neurologic deficit, 
hypertensive crisis) or when urgent intervention is indicated. 
Table 12: 
Management of Hypertensiona Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
> 150 mm Hg (systolic) a and < 160 mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm Hg 
 
• 
Optimize antihypertensive medications by adding new or 
additional antihypertensive medications and/or increase 
dose of existing medications. 
• 
Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does 
not result in BP < 150 mm Hg systolic and < 100 mm Hg 
diastolic. 
• 
If subject is symptomatic interrupt cabozantinib treatment 
and restart only if symptoms have resolved and BP is 
< 150 mm Hg systolic and < 90 mm Hg diastolic. 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose level or interrupt 
cabozantinib treatment per investigator discretion. 
Treatment should be interrupted if upper limits of systolic 
BP (≥ 160 mm Hg) are sustained and not adequately 
manageable or if systolic BP is > 180 mm Hg or sustained 
diastolic BP > 110 mm Hg, or if subject is symptomatic. 
• 
Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP 
< 150 mm Hg systolic and < 100 mm Hg diastolic, 
cabozantinib treatment should be dose reduced further or 
interrupted. 
• Re-start cabozantinib treatment at reduced dose and 
re-escalate only if BP falls to and is sustained at 
< 150 mm Hg systolic and < 100 mm Hg diastolic. 
Hypertension with life-threatening 
consequences (eg, malignant hypertension, 
transient or permanent neurologic deficit, 
hypertensive crisis); urgent intervention 
indicated 
• 
Discontinue cabozantinib treatment. 
• 
Initiate appropriate medical management. 
BP, blood pressure; MI, myocardial infarction. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP > 150 or 
diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
 

 
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6.6.2.1.6. Stomatitis and Mucositis 
Preventive measures for stomatitis and mucositis may include a comprehensive oral examination 
to identify and treat any potential risk for complications before study treatment is initiated. 
Appropriate correction of local factors should be instituted as indicated, such as modification of 
ill-fitting dentures and appropriate care of gingivitis. During treatment with cabozantinib, good 
oral hygiene and standard local treatments such as non-traumatic and non-irritating cleansing, 
and oral rinses (eg, with a weak solution of salt and baking soda) should be maintained. Lips 
should be kept moisturized with lip balm. The use of lipstick, lip-gloss, and Vaseline should be 
avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as clinically indicated.  
6.6.2.1.7. Skin and Subcutaneous Tissue Disorders 
Wound healing and surgery: Cabozantinib has the potential to cause wound healing 
complications and wound dehiscence which may even occur long after a wound has been 
considered healed. Therefore, surgical and traumatic wounds must not only be completely healed 
prior to starting cabozantinib treatment but must also be monitored for wound dehiscence, wound 
infection and other signs of impaired wound healing while the subject is being treated with 
cabozantinib. If dehiscence occurs, cabozantinib treatment should not be restarted until complete 
healing has taken place.  
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery and at 
least 5 days before an optional tumor biopsy. The decision to resume treatment with cabozantinib 
after surgery should be based on clinical judgment of adequate wound healing; subjects should 
be allowed to heal for at least 10 days after optional tumor biopsies. 
Palmar-plantar erythrodysesthesia (PPE; also known as hand-foot syndrome), skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and 
papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported 
with cabozantinib. All subjects on study should be advised on prophylactic measures including 
the use of emollients, removal of calluses, avoidance of exposure of hands and feet to hot water 
leading to vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of 
cotton gloves and socks to prevent injury and keep the palms and soles dry. 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and 
swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may 
also be affected. Adequate interventions are required to prevent worsening of skin symptoms 

 
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such as blisters, desquamations, ulcerations, or necrosis of affected areas. Analgesics may be 
required for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment recommendations in response to PPE are summarized in Table 13. 
Table 13: 
Management of Palmar-plantar Erythrodysesthesia Associated with 
Cabozantinib 
CTCAE v5 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if PPE is clinically 
insignificant and tolerable. Otherwise, cabozantinib 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 worsens at any time or does not 
improve after 2 weeks, proceed to the intervention guidelines for Grade 2. 
Grade 2  
Cabozantinib treatment may be continued if PPE is tolerated. Cabozantinib 
should be dose reduced or interrupted if PPE is intolerable. Continue urea 20% 
cream twice daily AND high potency steroid cream (eg, clobetasol 0.05%) once 
daily and add analgesics (eg, NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPE worsens or affects 
self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with high potency steroid cream (eg, 
clobetasol 0.05%) twice daily AND analgesics. Resume study drug at a reduced 
dose if PPE recovers to Grade ≤ 1. Discontinue subject from study treatment if 
PPE does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPE, palmar 
plantar erythrodysesthesia. 
 
6.6.2.1.8. Osteonecrosis 
Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors 
include use of bisphosphonates and denosumab, chemotherapy and anti-angiogenic drugs, use of 
corticosteroids, local radiotherapy, and dental or orofacial surgery procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, 
tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain 
or slow healing of the mouth or jaw after dental surgery may also be manifestations of 
osteonecrosis. 
Advise subjects regarding oral hygiene practice and to quickly report symptoms to the 
Investigator. Caution should be used in subjects receiving bisphosphonates. 

 
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Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be interrupted for at least 4 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a 
protracted time. 
6.6.2.1.9. Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring 
UPCR. Table 14 provides treatment guidelines for proteinuria deemed related to cabozantinib.  
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria 
> 3.5 grams per day in combination with low blood protein levels, high cholesterol levels, high 
triglyceride levels, and edema).  

 
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Table 14: 
Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
 
• 
Consider confirming with a 24-h protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. 
Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose interruption unless 
otherwise approved by sponsor. 
• 
If UPCR > 2 mg/mg, repeat UPCR monitoring within 7 days and once per 
week. If UPCR < 2 mg/mg on 2 consecutive readings, UPCR monitoring 
can revert to protocol-specific times. (Second reading is confirmatory and 
can be done within 1 week of first reading.)  
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR monitoring within 
7 days and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR monitoring, continue to interrupt 
cabozantinib treatment and check UPCR every 7 days. If UPCR decreases 
to < 2 mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of UPCR until it remains < 2 mg/mg on two consecutive 
measurements. If UPCR monitoring is determined to be stable (< 20% 
change) for 1 month then continue with UPCR monitoring per protocol or 
as clinically indicated. 
Nephrotic syndrome 
• 
Discontinue cabozantinib treatment 
UPCR, urine protein/creatinine ratio. 
 
6.6.2.1.10. Nervous System Disorders 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on 
nonclinical Good Laboratory Practice (GLP)-compliant toxicology studies. Dysphonia, 
dysgeusia, headache, dizziness, confusional state, convulsion, depression, memory impairment, 
hypoesthesia, peripheral neuropathy, insomnia, ataxia, and encephalopathy have been observed 
in clinical studies with cabozantinib. The development of any new or progressive, unexplained 
neurological symptoms should be assessed for underlying causes. 

 
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RPLS (also known as PRES) has been reported. RPLS should be considered in any subject 
presenting with seizures, headache, visual disturbances, confusion or altered mental function. 
Cabozantinib treatment should be discontinued in subjects with RPLS. 
6.6.2.1.11. Infections and Infestations 
Infections are commonly observed in cancer subjects. Predisposing risk factor include a 
decreased immune status (eg, after myelosuppressive anticancer therapies, splenectomy), 
destructive growth of the underlying malignancy including bone marrow infiltration with 
suppression of normal hematopoiesis, as well as the presence of IV devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until adequate healing has taken place. 
6.6.2.1.12. Blood and Lymphatic System Disorders 
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Subjects with hematologic toxicities may require additional 
or more frequent laboratory tests according to institutional guidelines. 
Dose reductions or dose interruptions for hematological toxicities are not mandated but can be 
applied as clinically indicated. Supportive care for thrombocytopenia or anemia, such as 
transfusions, may be managed according to institutional guidelines. The use of colony-
stimulating growth factors should be considered. Febrile neutropenia or evidence of infection 
associated with neutropenia must be assessed immediately and treated appropriately and in a 
timely manner according to institutional guidelines. 
6.6.2.1.13. Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression 
and/or anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be 
ruled out and treated according to standard of care. Pharmacological management should be 
considered after disease specific morbidities have been excluded when not prohibited.  
6.6.2.1.14. Weight Loss 
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacological therapy should be considered for appetite enhancement 
when not prohibited by a particular protocol. 

 
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6.6.2.1.15. Corrected QT Prolongation 
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a 
placebo-controlled study in subjects with MTC. A mean increase in QTcF of 10-15 ms was 
observed after 4 weeks after initiating cabozantinib treatment. A concentration-QTc relationship 
could not be definitively established. Changes in cardiac wave form morphology or new rhythms 
were not observed. No cabozantinib-treated subjects in this study had a QTcF > 500 ms. Review 
of the larger safety database (approximately 5000 subjects exposed to cabozantinib in clinical 
trials and in post-marketing experience) confirmed the absence of safety concerns associated 
with QT prolongation. There were no events of torsades de pointes reported. 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an increase 
of > 60 ms above baseline per ECG evaluation at the site, two additional ECGs must be 
performed with intervals not less than 3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or an increase of > 60 ms above baseline, 
the following actions must be taken: 
• Interrupt cabozantinib treatment 
• Immediately notify the Sponsor 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension) or those with a significant ventricular arrhythmia on ECG for a thorough 
cardiology evaluation and management 
• Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as 
clinically indicated 
• Send copies of ECGs to central ECG laboratory for independent read 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms and the average increase is 
≤ 60 ms above baseline or a consulting cardiologist or appropriate expert determines that the 
frequency of ECGs may revert to the schedule in the protocol. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Cabozantinib treatment may be restarted but only at a 
reduced dose level if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation 

 
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• The QTcF value > 500 ms or increase of > 60 ms above baseline is not confirmed 
Cabozantinib treatment has been interrupted through a minimum of 1 week following the 
return of the QTcF to ≤ 500 ms and ≤ 60 ms above baseline. 
• Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
Cabozantinib treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced dose 
6.6.2.1.16. Electrolyte Disorders 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with cabozantinib, and serum electrolyte 
levels should be monitored frequently while receiving cabozantinib. Clinically relevant 
electrolyte disorders should be managed according to the dose modification guidelines as 
outlined in Table 8 or as clinically indicated. Standard clinical practice guidelines should be used 
for management of electrolyte disorders and may include oral or IV replacement.  
6.6.2.1.17. Endocrine Disorders 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed with 
cabozantinib treatment. Currently available data are insufficient to determine the mechanism of 
thyroid function test alterations and its clinical relevance. Management of thyroid dysfunction 
(eg, symptomatic hypothyroidism) should follow accepted clinical practice guidelines.

 
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6.6.2.2. 
Atezolizumab 
The most common AEs reported in ≥ 20% of subjects treated with atezolizumab include fatigue, 
decreased appetite, nausea, urinary tract infection, pyrexia, and constipation (Tecentriq USPI).  
Subjects treated with atezolizumab may also develop IRRs or CRS as well as irAEs such as 
myocarditis, pericardial disorders, pneumonitis, hepatitis, colitis, nephritis, endocrinopathies 
(hypophysitis, thyroid disorders, adrenal insufficiency, Type 1 diabetes), skin disorders, severe 
cutaneous adverse reactions, ocular events, neurological toxicity (myasthenic 
syndrome/myasthenia gravis, Guillain-Barré syndrome, meningoencephalitis, facial paresis, or 
myelitis), pancreatitis, myositis, and embryo-fetal toxicity. Management guidance for 
atezolizumab-associated AEs is provided in Sections 6.6.2.2.1 through 6.6.2.2.15. 
For details on warnings & precautions, possible AEs and management guidance of AEs, and use 
in special patient populations refer to the local prescribing information of atezolizumab and the 
atezolizumab Investigator’s Brochure. In addition, Investigators may be informed separately of 
any new urgent safety concerns that may arise through direct communication from the Sponsor 
(eg, Dear Investigator Letters). 
The following are general recommendations for management of any other adverse events that 
may occur and are not specifically listed in the following subsections.  
• 
Subjects and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible 
immune-related adverse events prior to initiating therapy and throughout treatment and 
survival follow-up. There should be a high level of suspicion that new symptoms are 
treatment related. 
• 
In general, atezolizumab therapy should be continued with close monitoring for Grade 1 
toxicities, with the exception of some neurologic toxicities. 
• 
Consider holding atezolizumab for most Grade 2 toxicities and resume when symptoms 
and/or laboratory values resolve to Grade 1 or better.  Corticosteroids (initial dose of 
0.5-1 mg/kg/day of prednisone or equivalent) may be administered. 
• 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as a 
Grade 3 event.   
• 
Hold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day prednisone or equivalent).  Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before atezolizumab 
can be resumed.  If symptoms do not improve within 48 to 72 hours of high-dose 
corticosteroid use, other immunosuppressants may be offered for some toxicities. 
• 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by hormone 
replacement therapy. 

 
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• 
The investigator should consider the benefit-risk balance for a given subject prior to 
further administration of atezolizumab.  Resumption of atezolizumab may be considered 
in subjects who are deriving benefit and have fully recovered from the immune-related 
event.  The decision to re-challenge subjects with atezolizumab should be based on the 
investigator’s assessment of the benefits and risks and documented by the investigator.  
The Medical Monitor is available to advise as needed. 
6.6.2.2.1. Infusion-Related Reactions and Cytokine Release Syndrome 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab. These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al 2019). CRS has been 
well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager 
antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 
(Rotz et al 2017; Adashek and Feldman 2019), including atezolizumab. 
No premedication is indicated for the first administration of atezolizumab. However, subjects 
who experience an IRR or CRS with atezolizumab may receive premedication with 
antihistamines, antipyretics, and/or analgesics (eg, acetaminophen) for subsequent infusions. 
Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its 
potential for causing agranulocytosis. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in Appendix G. 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
IL-6, IL-10, IL-2, and IFN-γ (Merad and Martin 2020).  If a patient develops suspected CRS 
during the study, a differential diagnosis should include COVID-19, which should be confirmed 
or refuted through assessment of exposure history, appropriate laboratory testing, and clinical or 
radiologic evaluations per investigator judgment.  If a diagnosis of COVID-19 is confirmed, the 
disease should be managed as per local or institutional guidelines. 

 
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For subjects who develop COVID-19 while on study, the Investigator is to evaluate the overall 
risk-benefit ratio for the subject to determine whether holding study treatment(s) is in the best 
interest of the subject.  
6.6.2.2.2. Immune-Related Pulmonary Events 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, fatigue, 
hypoxia, pneumonitis, and pulmonary infiltrates. Subjects should be assessed for pulmonary 
signs and symptoms throughout the study and will also have CT scans of the chest performed at 
every tumor assessment.  
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies, 
such as pneumonia or other infections, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. COVID-19 
evaluation should be performed per institutional guidelines where relevant. Management 
guidelines for pulmonary events are provided in Table 15. 

 
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Table 15: 
Management Guidelines for Immune-Related Pulmonary Events, Including 
Pneumonitis 
Severity of Event  
Management 
Grade 1  
• 
Continue atezolizumab and monitor closely. 
• 
Re-evaluate on serial imaging. 
• 
Consider subject referral to pulmonary specialist. 
• 
For Grade 1 pneumonitis, consider withholding atezolizumab. 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer subject to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL with or without transbronchial biopsy. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
Resume atezolizumab if event resolves to Grade 1 or better. b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not 
resolve to Grade 1 or better while withholding atezolizumab. c,d 
• 
For recurrent events or events with no improvement after 48-72 hours of 
corticosteroids, treat as a Grade 3 or 4 event 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor. c 
• 
Oral or IV broad-spectrum antibiotics should be administered in parallel to the 
immunosuppressive treatment. 
• 
Bronchoscopy or BAL with or without transbronchial biopsy is recommended. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
BAL, bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on  the 
investigator’s benefit−risk assessment and in alignment with the protocol requirements for duration of treatment and 
documented by the Investigator a. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on the investigator’s benefit-
risk assessment and documented by the investigator. The Medical Monitor is available to advise as needed. 
d In case of pneumonitis, atezolizumab should not be resumed after permanent discontinuation. 
 
6.6.2.2.3. Immune-Related Colitis or Diarrhea 
Immune-related colitis has been associated with the administration of atezolizumab. 
Management guidelines for diarrhea or colitis are provided in Table 16. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of systemic 

 
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inflammation or acute-phase reactants (eg, increased c-reactive protein, platelet count, or 
bandemia): perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis.  
Table 16: 
Management Guidelines for Immune-Related Diarrhea or Colitis 
Severity of 
Event 
Management 
Grade 1 
• 
Continue atezolizumab 
• 
Initiate symptomatic treatment 
• 
Endoscopy is recommended if symptoms persist for > 7 days 
• 
Monitor closely 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Initiate symptomatic treatment 
• 
If strong clinical suspicion for immune-related colitis, start empiric IV steroids while 
waiting for definitive diagnosis 
• 
Subject referral to GI specialist is recommended 
• 
For recurrent events or events that persist > 5 days, initiate treatment with 1−2 mg/kg/day 
oral prednisone or equivalent. If the event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
Resume atezolizumab if event resolves to Grade 1 or better a,b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not resolve to 
Grade 1 or better while withholding atezolizumab c 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to GI specialist for evaluation and confirmatory biopsy 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. If event does not 
improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• 
Resume atezolizumab if event resolves to Grade 1 or better b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does not resolve to 
Grade 1 or better while withholding atezolizumab c 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor. c 
• 
Refer subject to GI specialist for evaluation and confirmatory biopsy. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 

 
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GI, gastrointestinal; IV, intravenous 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on the 
assessment of benefit-risk by the investigator and in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 
6.6.2.2.4. Immune-related Endocrinopathies 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Management guidelines for endocrine events 
are provided in Table 17. 
Monitor for signs and symptoms of hypophysitis. Subjects with unexplained symptoms such as 
headache, fatigue, myalgias, impotence, mental status changes, or constipation should be 
investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies. The subject 
should be referred to an endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating 
hormone and free triiodothyronine and FT4 levels should be measured to determine whether 
thyroid abnormalities are present. Pituitary hormone levels and function tests (eg, TSH, growth 
hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and MRI of the brain 
(with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.  
Table 17: 
Management Guidelines for Endocrine Events 
Event 
Management 
Hypophysitis (pan-
hypopituitarism)  
Grade 2-3 
• 
Withhold atezolizumab for up to 12 weeks after event onset b 
• 
Refer subject to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
Initiate hormone replacement therapy if clinically indicated. 
• 
If event resolves to Grade 1 or better, resume atezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact the 
Sponsor.c 
• 
For recurrent hypophysitis, treat as a Grade 4 event. 

 
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Event 
Management 
Hypophysitis (pan-
hypopituitarism)  
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor.c 
• 
Refer subject to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement.a 
• 
Initiate hormone replacement therapy if clinically indicated. 
Grade 1 hypothyroidism 
• 
Continue atezolizumab 
• 
Initiate treatment with thyroid replacement hormone 
• 
Monitor TSH closely 
Grade 2 hypothyroidism 
• 
Consider withholding atezolizumab 
• 
Initiate treatment with thyroid replacement hormone 
• 
Monitor TSH closely 
• 
Consider subject referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
Grade 3 and 4 
hypothryoidism 
• 
Withhold atezolizumab 
• 
Initiate treatment with thyroid replacement hormone 
• 
Monitor TSH closely 
• 
Refer to an endocrinologist 
• 
Admit patient to the hospital for developing myxedema (bradycardia, 
hypothermia, and altered mental status) 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
• 
Permanently discontinue atezolizumab and contact the Sponsor for life 
threatening immune-related hypothyroidismc 
Grade 1 hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• 
Continue atezolizumab 
• 
Monitor TSH every 4 weeks 
• 
Consider subject referral to endocrinologist 
TSH < 0.1 mU/L: 
• 
Follow guidelines for Grade 2 hyperthyroidism 
• 
Consider subject referral to endocrinologist 
Grade 2 hyperthyroidism 
• 
Consider withholding atezolizumab 
• 
Initiate treatment with anti-thyroid drug such as methimazole or carbimazole 
as needed 
• 
Consider subject referral to endocrinologist 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 

 
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Event 
Management 
Grade 3 and 4 
hyperthyroidism 
• 
Withhold atezolizumab 
• 
Initiate treatment with anti-thyroid drugs such as methimazole or 
carbimazole as needed 
• 
Refer to endocrinologist 
• 
Resume atezolizumab when symptoms are controlled and thyroid function is 
improving 
• 
Permanently discontinue atezolizumab and contact the Sponsor for life 
threatening immune-related hyperthyroidismc 
Symptomatic adrenal 
insufficiency 
Grade 2−4  
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to endocrinologist 
• 
Perform appropriate imaging 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
Resume atezolizumab if event resolves to Grade 1 or better and subject is 
stable on replacement therapyb  
• 
Permanently discontinue atezolizumab and contact the Sponsor if event does 
not resolve to Grade 1 or better or subject is not stable on replacement 
therapy while withholding atezolizumabc 
Hyperglycemia 
Grade 1 or 2  
• 
Continue atezolizumab 
• 
Investigate for diabetes. If subject has Type 1 diabetes, treat as Grade 3 
event. If subject does not have Type 1 diabetes, treat as per institutional 
guidelines. 
• 
Monitor for glucose control 
Hyperglycemia 
 Grade 3 or 4 
• 
Withhold atezolizumab. 
• 
Initiate treatment with insulin. 
• 
Evaluate for diabetic ketoacidosis and manage as per institutional 
guidelines. 
• 
Monitor for glucose control. 
• 
Resume atezolizumab when symptoms resolve and glucose levels are stable. 
IV, intravenous; MRI, magnetic resonance imaging; TSH, thyroid-stimulating hormone.  
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on 
assessment of benefit-risk by the investigator and  in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 

 
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6.6.2.2.5. Immune-Related Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab. The majority of cases of rash 
reported with the use of atezolizumab were mild in severity and self-limiting, with or without 
pruritus. Although uncommon, cases of severe cutaneous adverse reactions such as Stevens-
Johnson syndrome and toxic epidermal necrolysis have been reported with atezolizumab. A 
dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should be 
considered unless contraindicated. Management guidelines for dermatologic events are provided 
in Table 18. 
Table 18: 
Atezolizumab Management Guidance of Immune-Related Dermatologic 
Events 
Severity of Event 
Management of Skin Disorder 
Grade 1 
• 
Continue atezolizumab. 
• 
Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (eg, antihistamines). 
Grade 2 
• 
Continue atezolizumab. 
• 
Consider subject referral to dermatologist for evaluation and, if indicated, 
biopsy. 
• 
Initiate treatment with topical corticosteroids. 
• 
Consider treatment with higher-potency topical corticosteroids if event does 
not improve 
• 
If unresponsive to topical corticosteroids, consider oral prednisone 
0.5 mg/kg/day. 
Grade 3 
• 
Delay atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to dermatologist for evaluation and, if indicated, biopsy. 
• 
Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 1− 2 mg/kg/day if event does not improve within 48− 72 hours. 
• 
Resume atezolizumab if event resolves to Grade 1 or better.b 
• 
Permanently discontinue atezolizumab and contact Sponsor if event does 
not resolve to Grade 1 or better while withholding atezolizumab.c 
Grade 4 
• 
Permanently discontinue atezolizumab and contact Sponsor.c 

 
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Severity of Event 
Management of Skin Disorder 
Stevens-Johnson syndrome 
or toxic epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• 
Withhold atezolizumab for suspected Stevens-Johnson syndrome or toxic 
epidermal necrolysis. 
• 
Confirm diagnosis by referring subject to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if indicated, 
biopsy. 
• 
Follow the applicable treatment and management guidelines above. 
• 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, 
permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and  in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 
 
6.6.2.2.6. Immune-Related Ocular Events 
Treatment-emergent ocular events have been associated with atezolizumab. An ophthalmologist 
should evaluate visual complaints (eg, uveitis, retinal events). Management guidelines for ocular 
events are provided in Table 19. 

 
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Table 19: 
Atezolizumab Management Guidance of Immune-Related Ocular Events 
Severity of Event 
Management of Ocular Event 
Grade 1 
• 
Continue atezolizumab. 
• 
Subject referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• 
If symptoms persist, treat as a Grade 2 event. 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset.a 
• 
Subject referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• 
Resume atezolizumab if event resolves to Grade 1 or better.b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event 
does not resolve to Grade 1 or better while withholding atezolizumab.c 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor.c 
• 
Refer subject to ophthalmologist. 
• 
Initiate treatment with 1− 2 mg/kg/day oral prednisone or equivalent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab shoud be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 
 
6.6.2.2.7. Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any subject 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, or altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.  
All subjects being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 

 
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safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
Subjects with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 20. 
Table 20: 
Management Guidelines for Immune-Related Meningoencephalitis 
Severity of Event 
Management 
All grades 
• 
Permanently discontinue atezolizumab and contact the Sponsor a 
• 
Refer subject to neurologist 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or equivalent 
and convert to 1−2 mg/kg/day oral prednisone or equivalent upon improvement 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month 
IV, intravenous. 
a Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 
 
6.6.2.2.8. Immune-Related Motor and Sensory Neuropathy 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies. Management guidelines for neurologic disorders are provided in 
Table 21, with specific guidelines for myelitis provided in Table 22. 

 
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Table 21: 
Management Guidelines for Immune-Related Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy 
Grade 1 
• 
Continue atezolizumab 
• 
Investigate etiology 
• 
Any cranial nerve disorder (including facial paresis) should be managed as per 
Grade 2 management guidelines below. 
Immune-related 
neuropathy, including 
facial paresis,  
Grade 2  
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Investigate etiology and refer subject to neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
For general immune-related neuropathy: 
- Resume atezolizumab if event resolves to Grade 1 or betterb 
- Permanently discontinue atezolizumab and contact the Sponsor if event does not 
resolve to Grade 1 or better while withholding atezolizumab c 
• 
For facial paresis: 
- If event resolves fully, resume atezolizumab b 
- If event does not resolve fully while withholding atezolizumab, permanently 
discontinue atezolizumab and contact the Sponsor. c 
Immune-related 
neuropathy, including 
facial paresis, Grade 3 
or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor c  
• 
Refer subject to neurologist 
• 
Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome, 
any grade 
• 
Permanently discontinue atezolizumab and contact the Sponsor c 
• 
Refer subject to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of 1−2 mg/kg/day oral or IV prednisone or equivalent. 
IV, intravenous. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on 
assessment of benefit-risk by the investigator and in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 

 
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Table 22: 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab and contact the Sponsor.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
6.6.2.2.9. Immune-Related Pancreatitis 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis. Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests. 
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 23. 
Table 23: 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
Event 
Management 
Amylase and/or lipase elevation, 
Grade 1 
• 
Continue atezolizumab 
• 
Monitor amylase and lipase prior to dosing 
Amylase and/or lipase elevation, 
Grade 2 
Amylase and/or lipase > 1.5−2.0 × ULN: 
• 
Continue atezolizumab 
• 
Monitor amylase and lipase weekly 
• 
For prolonged elevation (eg, > 3 weeks), consider treatment with 
10 mg/day oral prednisone or equivalent 
Asymptomatic with amylase and/or lipase > 2.0 - 5.0 × ULN: 
Treat as Grade 3 event 
Amylase and/or lipase elevation, 
Grade 3 or 4  
• 
Withhold atezolizumab for up to 12 weeks after event onset.a  
• 
Refer subject to GI specialist 
• 
Monitor amylase and lipase every other day 
• 
If no improvement, consider treatment with 1−2 mg/kg/day oral 
prednisone or equivalent 
• 
Resume atezolizumab if event resolves to Grade 1 or betterb 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event 
does not resolve to Grade 1 or better while withholding atezolizumab c 

 
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Event 
Management 
• 
For recurrent events, permanently discontinue atezolizumab and contact 
the Sponsorc 
Immune-related pancreatitis, 
Grade 2 or 3 
 
• 
Withhold atezolizumab for up to 12 weeks after event onset a 
• 
Refer subject to GI specialist 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement 
• 
Resume atezolizumab if event resolves to Grade 1 or better b 
• 
Permanently discontinue atezolizumab and contact the Sponsor if event 
does not resolve to Grade 1 or better while withholding atezolizumab c 
• 
For recurrent events, permanently discontinue atezolizumab and contact 
the Sponsorc  
Immune-related pancreatitis, 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor c 
• 
Refer subject to GI specialist. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥ 1 month. 
GI, gastrointestinal; IV, intravenous; ULN, upper limit of normal. 
a Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced to 
≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator and  in alignment with the protocol requirements for duration of treatment and 
documented by the investigator. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as needed. 
 
6.6.2.2.10. Immune-Related Nephritis 
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function. Renal function, including serum creatinine, should 
be monitored throughout study treatment. Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs). Refer the 
patient to a renal specialist if clinically indicated. A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment.  

 
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Atezolizumab should be withheld for moderate (Grade 2) immune-related nephritis and 
permanently discontinued for severe nephritis (Grade 3 or 4). Refer subjects to a renal specialist 
and consider renal biopsy and supportive measures as indicated. Corticosteroids and/or 
additional immunosuppressive agents should be administered as clinically indicated. Refer to the 
current atezolizumab Investigator’s Brochure for further guidance on the management of 
immune-related nephritis. 
Subjects with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 24. 
Table 24: 
Management Guidelines for Immune-Related Nephritis 
Event 
Management 
Renal event, Grade 1  
• 
Continue atezolizumab.  
• 
Monitor kidney function closely, including creatinine and urine protein, until 
values resolve to within normal limits or to baseline values.  
Renal event, Grade 2  
• 
Withhold atezolizumab for up to 12 weeks after event onset. a  
• 
Refer patient to renal specialist.  
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.  
• 
If event resolves to Grade 1 or better, resume atezolizumab. b  
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact Medical Monitor. c 
Renal event, Grade 3 or 4  
• 
Permanently discontinue atezolizumab and contact Medical Monitor.  
• 
Refer patient to renal specialist and consider renal biopsy.  
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.  
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.  
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month.  
a Atezolizumab may be withheld for a longer period of time (ie, > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be based on an assessment of benefit-risk by the Investigator and in alignment with the protocol requirements for 
duration of treatment and documented by the investigator. The Medical Monitor is available to advise as needed.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral prednisone 
before atezolizumab can be resumed.  
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by the Investigator.  The Medical Monitor is available to advise as needed. 
 

 
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6.6.2.2.11. Immune-Related Cardiac Events 
Immune-Related Myocarditis 
Immune-related myocarditis has been associated with the administration of atezolizumab.  
Immune-related myocarditis should be suspected in any subject presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (eg, B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis and should be managed accordingly. Immune-related myocarditis needs to be 
distinguished from myocarditis resulting from infection (commonly viral, eg, in a subject who 
reports a recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 25. 
Immune-Mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis (see section on myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any patient 
presenting with chest pain associated with dyspnea or hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related 
(post myocardial infarction or iatrogenic), and autoimmune disorders, and should be managed 
accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by performing an 
ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
Table 25. Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a detailed 
cardiac evaluation to determine the etiology and manage accordingly. 

 
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Table 25: 
Management Guidelines for Immune-Related Cardiac Events 
Event 
Management 
Immune-related myocarditis, 
Grades 2-4 
 
Immune-related pericardial 
disorders, Grades 2-4 
• 
Permanently discontinue atezolizumab and contact the Sponsor.a 
• 
Refer subject to cardiologist 
• 
Initiate treatment as per institutional guidelines and consider antiarrhythmic 
drugs, temporary pacemaker, ECMO, or VAD as appropriate. 
• 
Initiate treatment with 1-2 mg/kg/day IV methylprednisolone or equivalent and 
convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a ECMO, extracorporeal membrane oxygenation; IV, intravenous; VAD, ventricular assist device. 
Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from 
the immune-related event. The decision to rechallenge with atezolizumab should be based on investigator’s 
assessment of benefit-risk, and documented by the investigator. The Medical Monitor is available to advise as 
needed. 
6.6.2.2.12. Immune-Related Myositis 
Myositis has been associated with the administration of atezolizumab. Myositis or inflammatory 
myopathies are a group of disorders sharing the common feature of inflammatory muscle injury; 
dermatomyositis and polymyositis are amongst the most common disorders. Initial diagnosis is 
based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), biochemical 
(serum creatinine-kinase increase), and imaging (electromyography/MRI) features and is 
confirmed with a muscle biopsy.  
Subjects with possible myositis should be referred to a rheumatologist or neurologist. Subjects 
with possible myositis should be monitored for signs of myocarditis. 
Subjects with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines presented in Table 26. 
Table 26: 
Management Guidelines for Immune-Related Myositis 
Event 
Management 
Immune-related myositis, 
Grade 1 
• 
Continue atezolizumab 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 

 
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Event 
Management 
Immune-related myositis, 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset a and contact 
Sponsor. 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines  
• 
Consider treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• 
If corticosteroids are initiated and event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive agent 
• 
If event resolves to Grade 1 or better, resume atezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
Immune-related myositis, 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onseta and contact the 
Sponsor 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines 
• 
Respiratory support may be required in more severe cases 
• 
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely compromised (eg, 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab.b 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Sponsor. Permanently 
discontinue atezolizumab and contact Medical Monitor.  c 
• 
For recurrent events, treat as a Grade 4 event. Permanently discontinue 
atezolizumab and contact the Sponsor. 
Immune-related myositis, 
Grade 4 
• 
Permanently discontinue atezolizumab and contact the Sponsor.c 
• 
Refer subject to rheumatologist or neurologist 
• 
Initiate treatment as per institutional guidelines.  
• 
Respiratory support may be required in more severe cases 
• 
Initiate treatment with corticosteroid equivalent to 1-2 mg/kg/day IV 
methylprednisolone or higher dose bolus if subject is severely compromised (eg, 
cardiac or respiratory symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 

 
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Event 
Management 
IV, intravenous 
a Atezolizumab may be withheld for a period of time (ie, > 12 weeks after event onset) to allow for corticosteroids (if initiated) 
to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time must be based 
on an assessment of benefit-risk by the Investigator and  in alignment with the protocol requirements for duration of treatment 
and documented by the investigator. The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent before 
atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab  should be based on Investigator’s assessment of 
benefit-risk, and documented by the Investigator. The Medical Monitor is available to advise as needed. 
6.6.2.2.13. Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.  
Subjects with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014). A subject should be classified as having HLH if five of the following eight 
criteria are met: 
• Fever ≥ 38.5°C 
• Splenomegaly 
• Peripheral blood cytopenia consisting of at least two of the following: 
− Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
− Platelet count < 100 × 109/L (100,000/µL) 
− ANC < 1.0 × 109/L (1000/µL) 
• Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(150 mg/dL) 
• Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• Low or absent natural killer cell activity 
• Ferritin > 500 mg/L (500 ng/mL) 
• Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations 
above age-adjusted laboratory-specific norms 
 

 
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Subjects with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al (2016). A febrile subject should be classified as 
having MAS if the following criteria are met: 
• Ferritin > 684 mg/L (684 ng/mL) 
• At least two of the following: 
− Platelet count ≤ 181 × 109/L (181,000/µL) 
− AST ≥ 48 U/L 
− Triglycerides > 1.761 mmol/L (156 mg/dL) 
− Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Subjects with suspected HLH or MAS should be treated according to the guidelines in Table 27. 
Table 27: 
Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosisor Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH or MAS 
• 
Permanently discontinue atezolizumab and contact Medical Monitor. 
• 
Consider patient referral to hematologist. 
• 
Initiate supportive care, including intensive care monitoring if indicated per 
institutional guidelines. 
• 
Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• 
If event does not respond to treatment within 24 hours, contact Sponsor and 
initiate treatment as appropriate according to published guidelines (La Rosée 
2015; Schram and Berliner 2015; La Rosée et al 2019). 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
HLH, hemophagocytic lymphohistiocytosis; IV, intravenous; MAS, macrophage activation syndrome 
6.6.2.2.14. Other Atezolizumab-Associated Immune-Related Adverse Events 
The following general management guidance should be applied for any other 
atezolizumab-associated irAEs: 
• Grade 2 or 3: delay atezolizumab dosing up to 12 weeks until irAE recovers to Grade 0-1 and 
corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day 
• Grade 4 or recurrent Grade 3: permanently discontinue atezolizumab 

 
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6.6.2.2.15. Embryo-Fetal Toxicity 
Based on its mechanism of action, atezolizumab can cause fetal harm when administered to a 
pregnant woman. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway 
can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal 
death. If atezolizumab is used during pregnancy, or if the subject becomes pregnant while taking 
atezolizumab, advise the subject of the potential risk to a fetus. Advise females of reproductive 
potential to use effective contraception during treatment with atezolizumab and for at least 
5 months after the last dose. 
6.6.2.3. 
Sorafenib 
The most common adverse reactions (≥ 20%) for sorafenib are diarrhea, fatigue, infection, 
alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, GI and 
abdominal pains, hypertension, and hemorrhage. 
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption of sorafenib therapy.  
Temporary interruption of sorafenib is recommended in subjects undergoing major surgical 
procedures. Temporary interruption or permanent discontinuation of sorafenib may be required 
for the following: 
• Cardiac ischemia or infarction 
• Hemorrhage requiring medical intervention 
• Severe or persistent hypertension despite adequate anti-hypertensive therapy 
• GI perforation  
• QTc prolongation 
o If at any time on study there is an increase in QTcF to an absolute value > 500 ms or 
> 60 ms above the baseline value, two additional ECGs must be performed with 
intervals not less than 3 min apart within 30 min after the initial ECG. If the average 
QTcF from the three ECGs is > 500 ms or > 60 ms above baseline, the following 
actions must be taken:  
 Discontinue treatment  
 Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, 
orthostatic hypotension) or those with a significant ventricular arrhythmia on 
ECG for a thorough cardiology evaluation and management 

 
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 Send copies of ECGs to central ECG laboratory for independent read 
• Severe DILI 
For additional details on warnings, precautions, possible AEs and management guidance of AEs 
refer to the most current local prescribing information appropriate to the respective study site 
location. 
6.6.2.4. 
Management of Hepatobiliary Adverse Events 
As this study will be evaluating subjects with advanced HCC, hepatobiliary AEs are expected to 
occur relatively frequently.  
Elevations of aminotransferases and bilirubin have been observed during treatment with some 
anticancer therapies including cabozantinib, atezolizumab, and sorafenib. Modifications of study 
treatment may be appropriate to address these events, and management guidance for these agents 
in response to increases in aminotransferases and bilirubin is provided in this section. 
General Guidance for Aminotransferase and Bilirubin Abnormalities 
Patients with advanced liver cancer may have elevations of aminotransferases (ALT and AST) or 
bilirubin due to their disease. As such, subjects on this study may enroll with elevations of 
AST/ALT up to 5 × ULN at baseline. It is recommended that subjects with elevations of ALT, 
AST, and/or bilirubin have more frequent laboratory monitoring of these parameters.  
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. If possible, hepatotoxic concomitant medications should be discontinued in subjects who 
develop increased values of ALT, AST, or bilirubin.For patients with elevated LFTs, concurrent 
medication, viral hepatitis, and toxic or neoplastic etiologies should be considered and addressed, 
as appropriate.  
Subjects with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have liver function tests (LFTs) performed immediately and reviewed before 
administration of the next dose of study drug. 

 
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Guidance for Management of Hepatotoxicity 
Guidance is provided on management of hepatotoxicity related to atezolizumab in Table 28 and 
to cabozantinib in Table 29.  
Table 28: 
Management Guidelines for Hepatic Events Associated with Atezolizumab 
Severity of Event 
Management 
If AST/ALT is within normal limits at 
baseline and increases to > 3 × ULN to 
≤ 10 × ULN 
or  
If AST/ALT is > ULN to ≤ 3 × ULN at 
baseline and increases to > 5 × ULN to 
≤ 10 × ULN 
or 
If AST/ALT is > 3 × ULN to ≤ 5 × ULN 
at baseline and increases to > 8 × ULN to 
≤ 10 × ULN 
 All events: 
• 
Monitor LFTs more frequently until return to baseline values.  
• 
Withhold atezolizumab for up to 12 weeks after event onset.a 
• 
For events of > 5 days’ duration, consider initiating treatment 
with 1-2 mg/kg/day prednisone or equivalent. 
• 
If event resolves to baseline or to Grade 1 or better, resume 
atezolizumab.b 
• 
If event does not resolve to baseline or to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact the Sponsor.c 
If AST or ALT increases to > 10 × ULN  
or 
total bilirubin increases to > 3 × ULN 
• 
Permanently discontinue atezolizumab and contact the Sponsor.c 
• 
Consider subject referral to GI specialist for evaluation and liver 
biopsy to establish etiology of hepatic injury.  
• 
Initiate treatment with 1-2 mg/kg/day prednisone or equivalent. 
• 
If event does not improve within 48 h after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to baseline, taper corticosteroids over ≥ 1 
month. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal; LFT, liver function test; ULN, upper 
limit of normal. 
a Atezolizumab may be withheld for a longer period of time (ie, > 12 weeks after event onset) to allow for corticosteroids (if 
initiated) to be reduced to ≤ 10 mg/day oral prednisone or equivalent. The acceptable length of the extended period of time 
must be based on the investigator’s benefit-risk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to advise as needed. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to ≤ 10 mg/day oral prednisone or equivalent 
before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in subjects who are deriving benefit and have fully recovered from the 
immune-related event. The decision to rechallenge subjects with atezolizumab should be based on the investigator’s benefit-
risk assessment and documented by the investigator. The Medical Monitor is available to advise as needed. 
 

 
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Table 29: 
Management Guidelines for Hepatic Events Associated with Cabozantinib 
Severity of Event 
Management  
If ALT/AST is ≤ 3.0 × ULN at 
baseline and increases to 
≥ 5.0 × ULN  
• 
Interrupt cabozantinib 
• 
Monitor LFTs more frequently until return to baseline values 
• 
If event resolves to baseline, or values stabilize at clinically acceptable 
levels, cabozantinib may be resumed at a reduced dose  
• 
Discontinue cabozantinib if hepatic dysfunction is not reversible despite 
temporary interruption of cabozantinib or drug-related ALT or AST 
> 3 × ULN in combination with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with DILI 
If ALT/AST is > 3.0 × ULN 
to ≤ 5.0 × ULN at baseline 
and doubles compared with 
the baseline values 
OR  
If ALT/AST is > 3.0 × ULN 
to ≤ 5.0 × ULN at baseline 
and increases are less than 
double but are accompanied 
by progressive elevations of 
total bilirubin and/or 
elevations of coagulation tests 
(eg, INR). 
• 
Interrupt cabozantinib 
• 
Monitor LFTs more frequently until return to baseline values. 
• 
If event resolves to baseline, or values stabilize at clinically acceptable 
levels, cabozantinib may be resumed at a reduced dose 
• 
Discontinue cabozantinib if hepatic dysfunction is not reversible despite 
temporary interruption of cabozantinib or drug-related ALT or AST 
> 3 × ULN in combination with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with DILI 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; INR, international 
normalized ratio; LFT, liver function test; ULN, upper limit of normal. 
 
Hepatic Encephalopathy 
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency. Hepatic 
encephalopathy is not uncommon in HCC patients and can be due to acute liver failure, portal 
systemic shunting and cirrhosis (Wong et al 2011, Willson et al 2013).  
The clinical manifestations of HE include a wide spectrum of neurological or psychiatric 
abnormalities ranging from subclinical alterations to coma (Vilstrup et al 2014). As HE 
progresses, personality changes, such as apathy, irritability, and dis-inhibition may be observed. 
In the most severe form of HE, affected individuals may develop marked confusion or 
disorientation, amnesia, greatly dulled or reduced consciousness (stupor), or loss of 
consciousness (coma). 

 
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In the Sponsor-conducted CELESTIAL XL184-309 study, there was a higher incidence of 
hepatic encephalopathy and encephalopathy in the cabozantinib arm as compared to the placebo 
arm, and the median time to onset in the cabozantinib arm was 5.9 weeks. Cabozantinib has been 
associated with diarrhoea, vomiting, decreased appetite, and electrolyte abnormalities. In HCC 
patients with compromised livers, these non-hepatic effects may be precipitating factors for the 
development of hepatic encephalopathy. Additionally, a higher relative proportion of patients 
with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with 
cabozantinib treatment. Furthermore, no cases of hepatic encephalopathy were reported in the 
RCC studies (METEOR and CABOSUN). 
There is no specific test used to diagnose HE. The diagnosis of HE is usually based on a 
combination of medical history, symptoms, and a clinical exam. Blood tests (eg, ammonia 
levels) can identify abnormalities associated with liver, kidney, and other conditions that may 
contribute to HE. High blood-ammonia levels alone are not confirmatory or prognostic. 
However, if a subject’s ammonia is normal, HE is less likely.  
Patients with liver insufficiency and altered mental status should be evaluated for alternative 
causes of brain dysfunction, including irAEs. Rare cases (0.4% of patients) of 
meningoencephalitis have been observed in patients who received atezolizumab monotherapy 
(see the atezolizumab IB for more information). Additionally, the existence of precipitating 
factors for HE (diarrhea, vomiting, decreased appetite, infections, electrolyte abnormalities, 
gastrointestinal [GI] bleeding, diuretic overdose, and constipation) may aid in the diagnosis 
(Vilstrup et al 2014).  
Adverse events of encephalopathy as graded per CTCAE v5.0 are shown below:  
• Grade 1: Mild symptoms  
• Grade 2: Moderate symptoms; limiting instrumental activities of daily living 
• Grade 3: Severe symptoms; limiting self-care activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death 
Management of Hepatic Encephalopathy 
In patients with HE, the first step in management is to identify and treat the precipitating factors 
for HE including, but not limited to, diarrhea, vomiting, decreased appetite, electrolyte 
abnormalities, infections, GI bleeding, diuretic overdose, and constipation. 
The following treatments are recommended (Vilstrup et al 2014): 

 
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• For symptomatic patients, consider treating with lactulose.  
• After the initial episode, lactulose is recommended for prevention of recurrent episodes of 
HE. 
• After the second episode, rifaximin is recommended as an add-on to lactulose for prevention 
of recurrent episodes of HE.  
• Intravenous (IV) L-ornithine L-aspartate (LOLA) and branched-chain amino acids (BCAAs) 
can be used as an alternative or additional agent to treat patients nonresponsive to 
conventional therapy. 
• Neomycin and metronidazole are alternative choices for treatment.  
For patients with higher grades (≥ Grade 3) HE, consider hospitalization. Patients who are at risk 
or unable to protect their airway need more intensive monitoring and are ideally managed in an 
intensive care setting. Please refer to Vilstrup et al 2014 for further information. Detailed 
guidelines for the management of HE are provided in Table 30. 
Table 30: 
Management of Hepatic Encephalopathy Associated with Study Treatment 
Hepatic Encephalopathy  
CTCAE v5.0 Grade 
Recommended Guidelines for Management and Dose Modification 
Grade 1 
Identify and treat any precipitating factor. 
If symptomatic, consider treatment for AEs. 
Continue study treatment if asymptomatic and an AE is manageable and tolerable. 
Grade 2  
 
Consider treatment for AEs. 
Continue study treatment if an AE is manageable and tolerable or interrupt study 
treatment for grade 2 AEs that are intolerable or cannot be adequately managed. 
If an irAE is suspected, consider initiating steroid treatment.  
Grade 3  
Consider hospitalization. 
If an irAE is suspected, consider initiating steroid treatment. 
Interrupt study treatment; Sponsor must be contacted to discuss treatment 
continuation upon resolution of AEs. 
Study treatment may resume if the toxicity can be easily managed with a dose 
reduction and optimal medical care. 
Grade 4  
Discontinue study treatment. 
Consider hospitalization. 
If an irAE is suspected, consider initiating steroid treatment. 
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; HE, hepatic encephalopathy; irAE, immune-
related adverse event. 
 

 
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Hepatic Failure 
Hepatic failure is a disorder characterized by liver dysfunction. Hepatic failure can be severe and 
life-threatening. Hepatic failure may develop rapidly over days or weeks (acute) or gradually 
over months or years (chronic). Hepatic failure can also develop in the setting of HCC when the 
functional reserve of the hepatocytes has declined. Clinical findings potentially indicating 
hepatic failure include, but are not limited to: jaundice, portal hypertension, ascites, HE, GI 
bleeding, and kidney failure. Laboratory findings include abnormal plasma levels of ammonia, 
bilirubin, lactic dehydrogenase, alkaline phosphatase, aminotransferase, and/or prolongation of 
prothrombin time (ie, International Normalized Ratio [INR]).  
Acute hepatic failure should be treated urgently as symptoms can worsen quickly. Subjects with 
acute hepatic failure may need to be treated in an intensive care setting.  
Adverse events of hepatic failure are graded per CTCAE v5.0 as below:  
• Grade 3: Asterixis; mild encephalopathy; DILI; limiting self-care (activities of daily living) 
• Grade 4: Life-threatening consequences; moderate to severe encephalopathy; coma  
• Grade 5: Death 
For management of hepatic failure related encephalopathy and aminotransferase and bilirubin 
abnormalities (including DILI), refer to the guidance described above in this section. For Grade 4 
events of hepatic failure, discontinue study treatment and treat symptoms accordingly. 
 

 
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7. 
CONCOMITANT MEDICATIONS AND THERAPIES 
7.1. 
Allowed Therapy 
• Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, ASCO or ESMO guidelines).  
• Bisphosphonates can be used per standard of care if the benefit outweighs the risk per the 
Investigator’s discretion (Section 6.6.2.1.8). 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates. Oral 
examinations are recommended at screening to determine eligibility and periodically during 
the study. In addition, subjects should be advised regarding oral hygiene practice and to 
quickly report symptoms to the Investigator. Frequent monitoring for potentially overlapping 
toxicities with study treatment is recommended.  
• Transfusions and hormone replacement should be utilized as indicated by standard clinical 
practice. 
• Inhaled, intranasal, intra-articular, or topical corticosteroids are allowed if minimal systemic 
absorption. Systemic corticosteroids are allowed for control of infusion reactions or irAEs 
and must be tapered over ≥ 1 month to a dose level ≤ 10 mg/day of prednisone equivalent 
before next atezolizumab administration. Prophylactic steroid treatment for subjects with 
contrast allergies prior to tumor imaging is allowed, and short term treatment with systemic 
corticosteroids for acute medical conditions (eg, exacerbation of chronic obstructive 
pulmonary disease [COPD]) is allowed if clinically indicated. 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances:  
o Low dose LMWH for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of LMWH after first dose of study treatment are allowed if clinically 
indicated (eg, for the treatment of DVT), and the benefit outweighs the risk per the 

 
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investigator’s discretion. For management of thromboembolic complications while on 
study, refer to Section 6.6.2.1.4.  
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (eg, due to kidney dysfunction, platelet 
decrease).  
o For restrictions on oral anticoagulants see Section 7.2. 
• Considerations for use of COVID-19 vaccine: At this time, there are limited data available 
for the use of COVID-19 vaccines in specific subsets of individuals such as the 
immunocompromised and cancer patients, including those receiving anticancer therapies 
such as cabozantinib, atezolizumab, and sorafenib. The decision to proceed with vaccination 
for subjects enrolled in this clinical study rests with the treating physician and the subject and 
should be taken after consideration of all safety precautions provided by the manufacturers of 
the vaccines and local health authorities. Please note, immunizations with live, attenuated 
COVID-19 vaccines or any experimental vaccines are not allowed. Exelixis will monitor all 
available information and provide additional guidance as appropriate. 
Potential drug interactions with cabozantinib, atezolizumab, and sorafenib are summarized in 
Section 7.3.1, Section 7.3.2, and Section 7.3.3, respectively.  
7.2. 
Prohibited or Restricted Therapy 
The following therapies are prohibited until study treatment has been permanently discontinued: 
• Any investigational agent or investigational medical device. 
• Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related agents, 
direct thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or chronic 
use of aspirin above low dose levels for cardioprotection per local applicable guidelines). 
• Any nonprotocol systemic anticancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer under 
investigation). 

 
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• Concomitant use of denosumab with atezolizumab is prohibited due to a potential for 
increased risk of infections. 
• Immunosuppressive agents including immunosuppressive doses of systemic corticosteroids 
with exceptions as stated in Section 7.1. 
• Metamizole (dipyrone) because of its potential for causing agranulocytosis. 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Local anticancer treatment including palliative radiation, ablation, embolization, or surgery 
with impact on tumor lesions should not be performed until radiographic progression per 
RECIST 1.1 has been established. If clinically unavoidable the investigator should consult 
the Sponsor prior to the procedure for safety guidance.  
• Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin (Wright et al 2007). 
• Concomitant medications that are known to prolong the QTc interval should be avoided in 
subjects until they have permanently discontinued cabozantinib or sorafenib treatment (refer 
to http://www.qtdrugs.org for a list of drugs which have the potential to prolong the QTc 
interval). 
• Live vaccines are prohibited while on study and until 5 months after last atezolizumab dose 
(eg, intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guérin, 
yellow fever, varicella, and TY21a typhoid vaccines). The use of inactivated (killed) 
vaccines for the prevention of infectious disease requires Sponsor approval with the 
exception of an inactivated influenza vaccine, which can be given without Sponsor approval. 
• Chronic co-administration of cabozantinib or sorafenib with strong inducers of the CYP3A4 
family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease concentrations of these study drugs and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  

 
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• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib or sorafenib, as 
this could significantly increase the exposure to these study drugs.  
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase concentrations of study drug and should be 
avoided. Grapefruit, star fruit, and Seville oranges may also increase plasma concentrations 
of these study drugs and should be avoided. 
Additional information on potential drug interactions with cabozantinib, atezolizumab, and 
sorafenib are summarized in Section 7.3.1, Section 7.3.2, and Section 7.3.3, respectively.  
7.3. 
Potential Drug Interactions 
7.3.1. 
Potential Drug Interactions with Cabozantinib 
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) show that 
clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect 
on the area under the plasma concentration-vs-time curve (AUC) of co-administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit 
CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 
isozymes that have lower [I]/Ki values compared with CYP2C8 (ie, CYP2C9, CYP2C19, 
CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
CYP enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations 
(30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with 
caution because these drugs have the potential to decrease exposure (ie, AUC) to cabozantinib. 

 
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Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations. Grapefruit, star fruit 
and Seville oranges may also increase plasma concentrations of cabozantinib and should be 
avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that inhibit CYP3A4 
should be used with caution because these drugs have the potential to increase exposure 
(ie, AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme inhibition potential is recommended.  
Please refer to the drug interaction tables at the following website for lists of substrates, inducers, 
and inhibitors of selected CYP450 isozyme pathways: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm).  
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib and/or 
a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic 
effect).

 
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Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting 
recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be a 
substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein 
transport activity. Therefore, cabozantinib may have the potential to increase plasma 
concentrations of co-administered substrates of P-glycoprotein (eg, fexofenadine, aliskiren, 
ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, 
saxagliptin, sitagliptin, talinolol, tolvaptan). In addition, cabozantinib was shown to be a 
substrate of drug transporter multidrug resistance-associated protein 2 (MRP2) in an in vitro 
assay. Administration of MRP2 inhibitors may result in increases in cabozantinib plasma 
concentrations. Therefore, concomitant use of MRP2 inhibitors (eg, cyclosporine, efavirenz, 
emtricitabine) should be approached with caution. Additional details related to these overall 
conclusions can be found in the investigator brochure. 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of 
gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
Investigator’s Brochure. 
7.3.2. 
Potential Drug Interactions with Atezolizumab 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not involved in 
the metabolism of atezolizumab. No drug interaction studies for atezolizumab have been 
conducted. There are no known interactions with other medicinal products or other form of 
interactions. For additional details refer to the local prescribing information and the atezolizumab 
Investigator’s Brochure.  
7.3.3. 
Potential Drug Interactions with Sorafenib 
Concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, 
phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), should be avoided when possible, 
because these drugs can decrease the systemic exposure to sorafenib. Bleeding and INR 
elevations have been reported in patients receiving both warfarin and sorafenib; subjects in the 
sorafenib comparator arm taking concomitant warfarin should be monitored for changes in PT 
and INR and for clinical bleeding episodes. For additional details refer to the local prescribing 
information appropriate to the local site location.  
 

 
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8. 
SAFETY 
8.1. 
Adverse Events and Laboratory Abnormalities 
8.1.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been enrolled in a clinical study and who may have been administered an investigational product, 
regardless of whether or not the event is assessed as related to the study treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, regardless 
of whether or not the event is assessed as related to the investigational product. This requirement 
includes specific events or symptoms associated with cancer progression or general clinical 
deterioration to ensure potential toxicities are not overlooked. Radiographic progression without 
associated clinical sequelae is not considered an AE; terms such as ‘disease progression’ should 
be avoided. Pre-existing medical conditions that worsen during a study will be recorded as AEs. 
Abnormal laboratory values, ECG findings, or vital signs are to be recorded as AEs if they meet 
the criteria described in Section 8.1.2. 
All untoward events that occur after informed consent through 30 days (100 days for SAEs and 
AESIs) after the date of the decision to permanently discontinue study treatment (defined as the 
later of the date of the decision to discontinue all study treatment or the date of the last dose of 
any study treatment) are to be recorded in the source documents by the investigational site.  
At each scheduled and unscheduled visit, AEs are to be identified and assessed based upon study 
procedures, routine and symptom-directed clinical investigations, and subject query/report. 
Assessment of the relationship of the AEs to study treatment by the investigator will be based on 
the following two definitions: 
• Not Related: An event is assessed as not related to study treatment if it is attributable to 
another cause and/or there is no evidence to support a causal relationship. 
• Related: An event is assessed as related to study treatment when there is a reasonable 
possibility that study treatment caused the event. Reasonable possibility means there is 
evidence to suggest a causal relationship between study treatment and the event. This event is 
called a suspected adverse reaction. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a drug. 

 
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8.1.2. 
Laboratory Abnormalities 
All laboratory data required by this protocol and any other clinical investigations will be 
reviewed. Any abnormal value that leads to a change in subject management (eg, dose reduction 
or delay or requirement for additional medication or monitoring) or that is considered to be of 
clinical significance by the Investigator will be reported as an AE or SAE as appropriate, unless 
this value is consistent with the subject’s present disease state or is consistent with values 
obtained prior to entry into the study. 
8.2. 
Serious Adverse Events  
8.2.1. 
Definitions 
The SAE definition and reporting requirements are in accordance with the ICH Guideline for 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death. 
• Is immediately life-threatening (ie, in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death). 
• Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
• Results in significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may not be immediately life-threatening, result in death, or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it jeopardizes the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
As soon as an investigator becomes aware of an AE that meets the criteria for an SAE, the 
investigator will document the SAE to the extent that information is available. 
SAEs, regardless of causal relationship, must be reported to the Sponsor or designee within 
24 hours of the investigator’s knowledge of the event by submitting the completed SAE report 

 
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form and any other pertinent SAE information as indicated on the SAE Reporting form (or in the 
SAE Reporting form Completion Guidelines) and confirming the report was received. Forms for 
reporting SAEs and contact information will be provided to the study sites. 
SAEs that must be recorded on an SAE Reporting form include the following: 
• All SAEs that occur after informed consent and through 100 days after the date of the 
decision to permanently discontinue study treatment (ie, the later of the date of the decision 
of the investigator to permanently discontinue study treatment or the date of the last dose of 
any study treatment taken by the subject) or the date the subject is deemed to be a screen 
failure. 
• Any SAEs assessed as related to study treatment or study procedures, even if the SAE occurs 
more than 100 days after the date of the decision to permanently discontinue study treatment. 
Note: If the subject does not meet the eligibility criteria during screening, then SAEs only need 
to be reported from the time the subject signs the informed consent until the day when the 
subject has been determined to not be eligible for study participation. 
SAEs that occur after consent through 100 days after the date of the decision to permanently 
discontinue of study treatment must also be recorded on the CRF page.  
The minimum information required for SAE reporting includes identity of Investigator, site 
number, subject number, and an event description. Other important information requiring timely 
reporting are the SAE term(s), the reason why the event is considered to be serious (ie, the 
seriousness criteria), and the Investigator’s assessment of the relationship of the event to study 
treatment. Additional SAE information including medications or other therapeutic measures used 
to treat the event, action taken with the study treatment because of the event, and the 
outcome/resolution of the event will be recorded on the SAE form. 
In all cases, the Investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the Investigator 
may be required to provide supplementary information as requested by the Sponsor’s Drug 
Safety personnel or designee. 
When reporting SAEs, the following additional points will be noted: 

 
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• When the diagnosis of an SAE is known or suspected, the Investigator will report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and 
symptoms may then be described in the event description.  
• Death will not be reported as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. Terms of “Unexplained Death” or “Death from unknown 
origin” may be used when the cause is unknown. In these circumstances the cause of death 
must be investigated and the diagnosis amended when the etiology has been identified. If an 
autopsy was performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
• Elective or previously scheduled surgeries or procedures for preexisting conditions that 
have not worsened after initiation of treatment (eg, a previously scheduled ventral hernia 
repair). SAEs must, however, be reported for any surgical or procedural complication 
resulting in prolongation of the hospitalization. 
• Prespecified study hospitalizations for observation. 
• Events that result in hospital stays of fewer than 24 hours and that do not require 
admission (eg, an emergency room visit for hematuria that results in a diagnosis of 
cystitis and discharge to home on oral antibiotics). 
• SAEs must be reported for any surgical or procedural complication resulting in prolongation 
of the hospitalization.  
8.2.2. 
Regulatory Reporting 
The Sponsor’s Drug Safety group (or designee) will process and evaluate all SAEs and AESIs as 
the reports are received. For each SAE received, the Sponsor will make a determination as to 
whether the criteria for expedited reporting to relevant regulatory authorities have been met. 
The Sponsor’s Drug Safety group (or designee) will assess the expectedness of each SAE to the 
study treatment using the current reference safety information (RSI) for each study drug. 
The Sponsor or its designee is responsible for reporting relevant SAEs to the relevant regulatory 
authorities, and participating investigators, in accordance with FDA regulations (21 Code of 
Federal Regulations [CFR] 312.32), ICH guidelines, European Clinical Trials Directive 
(Directive 2001/20/EC), and/or local regulatory requirements. 

 
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Reporting of SAEs by the Investigator to his or her IRB/ECs will be done in accordance with the 
standard operating procedures and policies of the IRB/EC. Adequate documentation must be 
maintained showing that the IRB/EC was properly notified. 
8.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) consist of immune-mediated AEs associated with 
ICIs, cases of potential DILI, and suspected transmission of an infectious agent by the study 
treatment (Table 31).  
AESIs will be reported to the Sponsor or designee using the SAE reporting form irrespective of 
whether the event is serious or nonserious; all AESIs must be reported within 24 hours using the 
SAE process as described in Section 8.2.  
Guidance for management of immune-mediated AEs associated is provided in Section 6.6.2.2 
and can also be found in the local prescribing information and Investigator’s Brochure for 
atezolizumab. 
 

 
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Table 31: 
Adverse Events of Special Interest  
Category 
Event 
DILI 
• 
Cases of potential DILI that include an elevated ALT or AST in combination with either an 
elevated bilirubin or clinical jaundice, as defined by Hy's Law and based on the following 
observations: 
o 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
o 
Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical 
jaundice 
Other 
• 
Suspected transmission of an infectious agent by the study treatment, as defined below 
 
o 
Any organism, virus, or infectious particle (eg, prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product. This term applies only when a contamination of study treatment is suspected. 
irAE 
• 
Pneumonitis 
irAE 
• 
Colitis 
irAE 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and 
hypophysitis 
irAE 
• 
Hepatitis, including AST or ALT > 10 × ULN 
irAE 
• 
Systemic lupus erythematosus 
irAE 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, 
meningoencephalitis, myelitis, and facial paresis 
irAE 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
influenza-like illness, hemophagocytic lymphohistiocytosis, and macrophage activation 
syndrome 
irAE 
• 
Nephritis 
irAE 
• 
Ocular toxicities (eg, uveitis, retinitis) 
irAE 
• 
Myositis 
irAE 
• 
Myopathies, including rhabdomyolysis 
irAE 
• 
≥ Grade 2 cardiac disorders 
irAE 
• 
Vasculitis 
irAE 
• 
Severe cutaneous reactions (eg, Stevens-Johnson syndrome, bullous dermatitis, toxic epidermal 
necrolysis) 

 
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ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; irAE, immune-related 
adverse event; ULN, upper limit of normal. 
 
8.3.1. 
General Information on Immune-Related Adverse Events 
The immune-modulating properties of checkpoint-inhibitors, such as the anti-PD-L1 antibody 
atezolizumab, are able to unbalance immunologic tolerance and generate a subset of AEs (called 
irAEs) with an autoimmune inflammatory pathomechanism. Immune-related adverse events may 
involve any organ or tissue (Michot et al 2016). Most irAEs occur within the first 12 weeks of 
exposure to ICIs but some of them may appear with a delayed onset. Diagnosis of irAEs should 
be based on exposure to an ICI and a reasonable immune-based mechanism of the observed AE. 
Whenever possible, histologic examination or other immune-based diagnostic evaluations should 
be used to support the diagnosis. Other etiologic causes including AEs from tumor progression 
should be ruled out. 
The spectrum of irAEs is wide and can be general or organ-specific. Examples of general irAEs 
in subjects treated with ICIs are fatigue, fever, and chills. Organ-specific irAEs consist of 
dermatitis (rash, pruritus, vitiligo, oral mucositis, and gingivitis), enterocolitis (diarrhea with 
abdominal pain and clinical or radiological evidence of colonic inflammation), and 
endocrinopathies (pituitary, thyroid, adrenal, testes). Diagnosis of endocrine dysfunction is 
challenging with relatively unspecific symptoms. Additional laboratory testing of the endocrine 
axes may be helpful: prolactin (pituitary-hypothalamic function), FT4 and TSH (pituitary-thyroid 
function), luteinizing hormone (LH) and FSH (pituitary-gonadal function), adrenocorticotropic 
hormone (ACTH) and cortisol (pituitary-adrenal function).  
Additional organ-specific irAEs include hepatitis (AST/ALT increases, hepatomegaly, periportal 
edema, periportal lymphadenopathy, lymphocyte infiltrates periportal and surrounding primary 
biliary ducts) and pneumonitis (acute interstitial pneumonia). Less frequent irAEs include 
neurologic disorders (myasthenia gravis, Guillain-Barré syndrome, aseptic meningitis, myelitis, 
facial paresis), ocular AEs (uveitis), renal AEs (interstitial nephritis), cardiac AEs (myocarditis), 
muscular AEs (myositis), skin-related AEs (Stevens-Johnson syndrome, toxic epidermal 
necrolysis), and pancreatic AEs (lipase increase). 
8.4. 
Follow-Up of Adverse Events 
Non-serious AEs (see below for AESIs [Table 31]) are to be recorded in the CRF until 30 days 
after the date of the decision to discontinue study treatment (the later of the date of the decision 

 
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by the investigator to permanently discontinue study treatment or the date of the last dose of any 
study treatment taken by the subject). The status of unrelated SAEs that are ongoing after the 
date of the decision to discontinue study treatment will be documented as of the 100-day FU-2 
visit. 
All AESIs (regardless of seriousness) and all related SAEs that are ongoing 100 days after the 
date of the decision to discontinue study treatment (the later of the date of the decision by the 
investigator to permanently discontinue study treatment or the date of the last dose of any study 
treatment taken by the subject), and AEs assessed as related that led to study treatment 
discontinuation that are ongoing 100 days after the date of the decision to discontinue study 
treatment, are to be followed until either: 
• the AE has resolved  
• the AE has improved to Grade 2 or lower  
• The Investigator determines that the event has become stable or irreversible. 
Further details on follow-up procedures are summarized in Appendix K. 
8.5. 
Other Safety Considerations 
8.5.1. 
Pregnancy 
Use of highly effective methods of contraception is very important during the study and for 
5 months after the last dose of study treatment. If a subject becomes pregnant during the study, 
she will be taken off study treatment. She will be followed through the end of her pregnancy and 
the infant should have follow up for at least 6 months after birth. Furthermore, male subjects 
must refrain from donating sperm and are required to use condoms in order to avoid transmission 
of study treatment in semen for the duration of study treatment and through 5 months after their 
last dose of study treatment. If a female partner of a male subject becomes pregnant during the 
study, the Sponsor will ask the pregnant female partner to be followed through the end of her 
pregnancy and for the infant to be followed for at least 6 months after birth. Both male and 
female subjects should seek advice and consider fertility preservation before receiving study 
treatment. 
The Investigator must inform the Sponsor of the pregnancy. Forms for reporting pregnancies will 
be provided to the study sites upon request. The outcome of a pregnancy (for a subject or for the 
partner of a subject) and the medical condition of any resultant offspring must be reported to the 
Sponsor or designee. Any birth defect or congenital anomaly must be reported as an SAE and 

 
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any other untoward events occurring during the pregnancy must be reported as AEs or SAEs, as 
appropriate. 
Females should not breastfeed while receiving study treatment and for the following periods 
after discontinuing study treatment: 
• Cabozantinib + atezolizumab: at least 5 months from the last dose of atezolizumab or 
4 months from the last dose of cabozantinib, whichever is later 
• Sorafenib: at least 2 weeks after the last dose of sorafenib 
• Single-agent cabozantinib: at least 4 months from the last dose of cabozantinib 
8.5.2. 
Medication Errors/Overdose 
Medication error is defined as the administration of study drug medication outside or above the 
established dosing regimens per the specific protocol.  
Any study medication overdose, misuse, abuse, or study medication error (excluding missed 
doses) that results in an AE or SAE requires reporting to the Sponsor or designee according to 
the guidance for AE and SAE reporting (Sections 8.1 and 8.2, respectively). 
In case of overdose, the Sponsor medical monitor or designee should be contacted promptly to 
discuss how to proceed. Any AEs that occur as a result of an overdose have to be treated 
according to clinical standard practice.  
Please refer to the Investigator’s Brochure for additional management recommendations for an 
overdose of cabozantinib. 
 

 
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9. 
STATISTICAL CONSIDERATIONS 
Details of the planned analyses, including sensitivity analyses or other strategies if needed to 
assess and address consequences of the COVID-19 pandemic on trial conduct and study data, 
will be provided in a separate Statistical Analysis Plan (SAP) that will be finalized before the last 
subject is randomized. The statistical principles applied in the design and planned analyses of 
this study are consistent with ICH E9 and FDA Guidance for Industry: Clinical Trial Endpoints 
for the Approval of Cancer Drugs and Biologics (2018). 
9.1. 
Analysis Populations 
The planned analysis populations to be employed for statistical analyses of data collected from 
subjects randomized during the global enrollment phase are briefly summarized in Table 32. 
These populations will include subjects in China randomized during the global enrollment phase. 
Subjects randomized during the Mainland China Extension Phase are excluded from these 
analyses; they will be included in separate analyses (see Section 9.9). Further information on 
these populations is provided in the sections below. 
Table 32: 
Analysis Populations for the Global Enrollment Phase 
Analysis  
Population  
Subjects 
Primary PFS 
PITT 
First 372 subjects randomized to 
experimental or control arm (may be 
expanded to include the first 410 
randomized subjects) 
Primary OS 
ITT 
ITT subjects randomized to experimental 
or control arm  
Secondary PFS 
ITT 
ITT subjects in control and single-agent 
cabozantinib arm  
Additional efficacy analyses 
ITT 
All randomized subjects  
Safety analyses 
Safety 
All subjects who received any study 
treatment 
ITT, Intent-to-Treat; OS, overall survival; PFS, progression-free survival; PITT, PFS Intent-to-Treat. 
 
9.1.1. 
Intention-to-Treat Population 
The ITT population will consist of all subjects who are randomized to any of the three study 
treatment arms (the experimental arm [cabozantinib plus atezolizumab], the single-agent 

 
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cabozantinib arm, or the control arm [sorafenib]) during the global enrollment phase, regardless 
of whether any study treatment or the correct study treatment is received. This population will be 
used for the primary OS analysis to compare the combination arm with the control arm 
(sorafenib), and also for the secondary PFS analysis to compare the single-agent cabozantinib 
arm with the control arm (sorafenib). Subjects randomized during the Mainland China Extension 
Phase are excluded from this population; they will be included in separate analyses (see Section 
9.9). 
9.1.1.1. 
PFS Intention-to-Treat Population 
The first 372 subjects that are randomized (based upon Greenwich Mean Time randomization 
date/time values) to the experimental (cabozantinib and atezolizumab, n=248) arm and control 
(sorafenib, n=124) arm will be considered as the PFS Intent-to Treat (PITT) population. The 
population may be extended to the first 410 subjects randomized to the two groups if a review of 
accumulating events suggests that the number of events required will not be reached (due to 
censoring) among the first 372 subjects originally planned. This population will be used for the 
primary PFS analysis to compare these arms. 
9.1.2. 
Safety Population 
The Safety population will consist of all subjects who randomized during the global enrollment 
phase and receive any amount of study treatment. Analyses based on Safety population will be 
performed according to the actual treatment received for the length of the study. Data handling 
rules for subjects in the experimental/control arm who received incorrect study treatment will be 
described in the SAP. Subjects randomized during the Mainland China Extension Phase are 
excluded from this population; they will be included in separate analyses (see Section 9.9). 
9.2. 
Primary Efficacy Endpoints 
The two primary efficacy endpoints are duration of PFS and OS. Subjects randomized to the 
experimental (cabozantinib and atezolizumab) arm and control (sorafenib) arm during the global 
enrollment phase will be considered for these analyses. Subjects randomized during the 
Mainland China Extension Phase will not be included in these analyses; they will be included in 
separate analyses (see Section 9.9). 
9.2.1. 
Definitions 
9.2.1.1. 
Duration of Progression-Free Survival 
Duration of PFS is defined as the time from randomization to the earlier of either radiographic 
PD per RECIST 1.1 or death due to any cause. The definition of disease progression and 
censoring rules for the primary analysis are described in Section 9.2.2. 

 
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9.2.1.2. 
Duration of Overall Survival 
Duration of OS is defined as the time from date of randomization to date of death due to any 
cause. For subjects who are alive at the time of data cutoff or are permanently lost to follow-up, 
duration of OS will be right censored at the earlier of the following: date the subject withdrew 
consent from all follow-up, data cutoff date, or the date the subject was last known to be alive.  
9.2.2. 
Primary Analysis 
9.2.2.1. 
 Progression-Free Survival 
The primary analysis of PFS is event-driven and will be conducted after at least 257 events have 
been observed in the PITT population (see Section 9.1.1.1). It is designed to include progression 
events as determined by the BIRC per RECIST 1.1. Clinical deterioration determined by the 
investigator will not be considered progression events.  
General censoring rules for the primary analysis of PFS are described below: 
• Subjects who receive systemic NPACT or nonprotocol radiation therapy (other than to bone) 
or surgery to resect target lesions before experiencing an event will be right censored at the 
date of the last tumor assessment prior to the date of initiation of subsequent therapy/surgery. 
If there is no such tumor assessment post randomization, the subject will be right censored on 
the date of randomization. 
• Subjects who have not experienced an event (and are not otherwise censored) at the time of 
data cutoff will be right censored on the date of their last tumor assessment post 
randomization that is on or prior to the data cutoff. If there is no such tumor assessment post 
randomization, the subject will be right censored on the date of randomization. 
• Subjects who miss 2 or more scheduled tumor assessments followed by an event will be right 
censored on the date of their most-recent tumor assessment prior to the missing assessments. 
If there is no such tumor assessment post randomization, the subject will be right censored on 
the date of randomization. 
Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided 0.01 level of significance. The stratification factors will be the same 
as those used to stratify the randomization (see Section 3.3). 
The median duration of PFS and the associated 95% and 99% CIs for each treatment arm will be 
estimated using the Kaplan-Meier method. The HR with 95% and 99% CIs will be estimated 
using a Cox regression model and will include the same stratification factors described above. 

 
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In the primary analysis of PFS, if the p-value for the stratified log-rank test is statistically 
significant and the HR (λ cabozantinib + atezolizumab/ λ sorafenib) is < 1, the null hypothesis of no 
difference between the two treatment arms in PFS will be rejected and it will be inferred that 
PFS is superior in the group receiving cabozantinib + atezolizumab compared with the group 
receiving sorafenib. 
9.2.2.2. 
Overall Survival  
The primary analysis of OS is event-driven and will be conducted after at least 368 deaths have 
been observed in the ITT population (Section 9.1.1) for the experimental and control arms. 
Hypothesis testing between the two treatment arms will be performed using the stratified log-
rank test with a 2-sided α level of significance (the α level will be defined per Section 9.5). The 
stratification factors will be the same as those used to stratify the randomization. 
The median duration of OS and the associated 95% and 1-α % CI for each treatment arm will be 
estimated using the Kaplan-Meier method. The HR with 95% and 1-α % CIs will be estimated 
using a Cox regression model and will include the same stratification factors described above. 
Details of interim analyses of OS are provided in Section 9.8. 
At any analysis of OS (interim or primary), if the p-value for the stratified log-rank test is 
statistically significant and the HR (λ cabozantinib + atezolizumab/ λ sorafenib) is < 1, the null hypothesis of 
no difference in OS between the two treatment arms will be rejected and it will be inferred that 
OS is superior in the group receiving cabozantinib + atezolizumab compared with the group 
receiving sorafenib. 
9.2.2.3. 
Supportive Analyses 
Supportive (sensitivity) analyses will be conducted using all PFS events and subjects in the ITT 
population (Section 9.1.1) for the experimental and control arms at the time of the primary PFS 
analysis in the PITT population (see Section 9.1.1.1). Additional sensitivity analyses of PFS will 
be defined in the SAP using alternative event definitions and censoring schemes to account for 
partial or completely missing assessments, address bias due to tumor assessment timing, and to 
evaluate the impact of potentially informative censoring. These analyses will be performed using 
the same statistical methods described for the primary analysis.  
Exploratory analyses of the effect of baseline characteristics, stratification factors, and other 
variables on PFS and OS will be conducted using Cox regression models and subgroup analyses 
performed employing Kaplan-Meier methods. 

 
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9.3. 
Secondary Efficacy Endpoint 
Formal hypothesis testing is planned for the secondary efficacy endpoint of PFS per BIRC for 
the single-agent cabozantinib arm vs the control arm (sorafenib). 
9.3.1. 
Progression Free Survival (PFS) per BIRC between Single-Agent Cabozantinib 
and Control Arms 
The analysis of PFS as a secondary endpoint is event-driven and will be conducted after at least 
283 events have been observed in the ITT population (see Section 9.1.1) for the single-agent 
cabozantinib and control arms. It is designed to include progression events as determined by the 
BIRC per RECIST 1.1. General censoring rules as described in Section 9.2.2.1 will be applied.  
Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test at the 2-sided α level (the α level will be defined per Section 9.5) in the ITT 
population, provided the null hypothesis for either PFS or OS is rejected in favor of the 
experimental arm (cabozantinib + atezolizumab) as described in Section 9.5. The stratification 
factors will be the same as those used to stratify the randomization (see Section 3.3). 
The median duration of PFS and the associated 95% and 99% CIs for each treatment arm will be 
estimated using the Kaplan-Meier method. The HR with 95% and 99% CIs will be estimated 
using a Cox regression model and will include the same stratification factors described above. 
In the secondary analysis of PFS, if the p-value for the stratified log-rank test is statistically 
significant and the HR (λ cabozantinib / λ sorafenib) is < 1, the null hypothesis of no difference between 
the two treatment arms in PFS will be rejected and it will be inferred that PFS is superior in the 
group receiving single-agent cabozantinib compared with the group receiving sorafenib. 
One interim analysis of secondary PFS is planned at approximately 67% information fraction. 
Details are provided in Section 9.8. 
9.4. 
Additional Endpoints  
Details of the planned analyses of these endpoints will be provided in the SAP: 
• ORR, TTP, and DOR per RECIST 1.1 by BIRC and Investigator  
• Evaluation of radiographic response per modified RECIST (mRECIST) 
• Safety through the evaluation of AEs, including irAEs and other AESIs  
• Characterization of the PK of cabozantinib in subjects with previously untreated HCC  
• Immunogenicity of atezolizumab given in combination with cabozantinib 
• Change in serum AFP from baseline 

 
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• Correlation of biomarker analyses with clinical outcomes 
• Health-related quality of life (HRQOL) as assessed by the EuroQol Health questionnaire 
instrument (EQ-5D-5L) 
• Healthcare resource utilization 
9.5. 
Control of Type I Error 
Inflation of Type 1 error associated with testing of multiple primary endpoints and a secondary 
efficacy endpoint (PFS between single-agent cabozantinib and control) will be controlled by a 
modified Bonferroni procedure, a gatekeeping technique, and the fallback method (FDA 2017). 
Initially, the study-wise 2-sided alpha of 5% will be unequally allocated between primary 
endpoints PFS (1%) and OS (4%). The secondary PFS endpoint will be tested at the 1% level 
only if the primary PFS test is successful. If the null hypotheses are rejected for both the primary 
and secondary PFS endpoints, the 1% alpha for PFS will be reallocated to OS, allowing it to be 
tested at the 5% level. 
Two interim analyses of OS are planned at the 33% and 66% information fractions (the first 
interim will coincide with the primary analysis of PFS and will be performed only if the null 
hypothesis for PFS is rejected and is expected to occur at approximately the 33% information 
fraction). One interim analysis is planned for secondary PFS endpoint contemporaneous with the 
primary PFS analysis with anticipated information fraction of 67%. Type 1 error associated with 
interim analyses will be controlled using Lan-DeMets O’Brien-Fleming (LD-OF) alpha-spending 
functions based upon a 4% total alpha allocation for OS and 1% for secondary PFS.  
The testing and alpha reallocation are elucidated below. 
First, test primary PFS at the 1% level. Then: 
1. If primary PFS is significant: 
a. Re-allocate its 1% alpha to secondary PFS per the fallback method. 
b. Conduct interim analysis of OS at 33% per LD-OF with 4% total alpha 
c. Conduct interim analysis of secondary PFS endpoint at 67% per LD-OF with 1% 
alpha. 
i. If interim analysis of secondary PFS is significant: 
• Re-allocate its 1% alpha to OS  
• Conduct interim analysis of OS at 66% per LD-OF with 5% alpha 
• No further inferential testing of secondary PFS will be performed. 

 
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ii. If interim analysis of secondary PFS is not significant: 
• The final analysis of secondary PFS will be conducted at an alpha of 
0.0096. 
• The alpha of subsequent OS analyses will be dependent on the timing 
and result of the final secondary PFS analysis. 
o The second interim analysis and the final for OS will be 
conducted per LD-OF with 4% alpha, if the second interim 
analysis occurs prior to the final analysis for secondary PFS, 
or, if it occurs after the final secondary PFS analysis where the 
final secondary PFS fails to reject its null hypothesis.  
o  The subsequent OS analyses will be conducted per LD-OF 
with 4.96% alpha if it occurs after the rejection of the null 
hypothesis for secondary PFS.  
d. Conduct interim and final analyses of OS with appropriate alpha as determined above 
2. If primary PFS is not significant:  
a. Secondary PFS analysis cannot be conducted 
b. Conduct interim and final analyses of OS per LD-OF with 4% total alpha 
i. If OS is not significant at final analysis, procedure ends 
All other statistical evaluations of efficacy will be considered exploratory. 
9.6. 
Safety Analyses 
All safety analyses will be performed using the Safety population (see Section 9.1.2). No formal 
statistical comparisons between these two treatment arms are planned. 
9.6.1. 
Adverse Events 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). The Investigator will classify the severity of 
AEs using CTCAE v5 and will judge each event to be “not related” or “related” to study 
treatment. 
A treatment emergent adverse event (TEAE) is defined as any event that begins or worsens on or 
after the date of first dose of study treatment. Only TEAEs with an onset date prior to date of 
decision for treatment discontinuation (defined as the later of the date of the decision to 
permanently discontinue study treatment or the date of the last dose of study treatment) 
+ 30 days (+ 100 days for SAEs and certain other AEs; Section 8.3) will be tabulated in 
summary tables. 

 
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The frequency and percentage of subjects with TEAEs will be tabulated for overall incidence by 
system organ class and/or preferred term by treatment arm. Related TEAEs, serious TEAEs, 
related serious TEAEs, high-grade TEAEs, Grade 5 TEAEs, and TEAEs resulting in study 
treatment discontinuation will be similarly summarized. Summaries by worst reported severity 
for each event within a subject will also be provided.  
At each level of summarization, a subject will be counted only once for each AE preferred term 
he/she experiences within that level (ie, multiple episodes of events with the same preferred 
terms will be counted only once). 
All reported subject deaths will be summarized by treatment group, cause of death, and 
relationship to study treatment. 
9.6.2. 
Laboratory Test Results 
Laboratory test results will be summarized by treatment group to evaluate worst post-baseline 
CTCAE grade and shifts or changes from baseline.  
9.6.3. 
Other Safety Endpoints 
Changes or shifts from baseline in vital signs, ECOG performance status, and QTc interval will 
be summarized by treatment group. 
The number of subjects experiencing dose reduction, interruption/delay, and/or discontinuation 
due to an AE will be provided. 
Concomitant medications will be standardized using the World Health Organization drug 
dictionary and summarized by class and preferred term.  
9.7. 
Power and Sample Size 
The study is designed to provide adequate power for analyses of both primary endpoints of PFS 
and OS comparing the experimental arm (cabozantinib + atezolizumab) with the control arm 
(sorafenib), and for the analysis of the secondary endpoint of PFS comparing single-agent 
cabozantinib with control arm. For the primary endpoints, a larger sample size is needed to 
provide reasonable power for OS than is required to evaluate PFS. As a result, if PFS were to be 
evaluated in the entire study sample, the PFS events may be biased toward shorter progression 
times. Thus, to allow longer, more robust PFS follow up among a smaller number of subjects, 
this study employs a “trial within a trial design” (Hessel et al 2016).  
The total sample size was planned to be 740 subjects randomized in a 2:1:1 fashion: 370 to the 
experimental combination arm (cabozantinib + atezolizumab), 185 to the control arm (sorafenib), 

 
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and 185 to the single-agent cabozantinib arm. However, enrollment commenced under a 
randomization ratio of 6:3:1 per the original protocol design, and there was a dynamic transition 
in randomization allocation over time. As a result, the needed enrollment of 185 subjects in the 
single-agent cabozantinib arm was not expected to be reached at the planned total global 
enrollment phase sample size of 740 subjects. Therefore, to ensure complete enrollment in the 
single-agent cabozantinib arm, the total global enrollment phase was extended to accrue a total 
of approximately 840 subjects. 
For primary PFS, a total of 257 events in the first 372 subjects randomized in a 2:1 ratio in the 
experimental and control arms (n=248 and 124, respectively; the PITT population) provide the 
study with 90% power for a 2-sided log-rank test with a 1% level of significance to detect a 
hypothesized true HR of 0.6. Assuming an exponential distribution of PFS, this corresponds with 
a 67% increase in median PFS from 3.6 months to 6.0 months. The minimum observed effect 
that would result in statistical significance for PFS is an HR of 0.71, a 41% improvement in 
median from 3.6 to 5.1 months. Interim analysis of the primary PFS endpoint is not planned. 
For OS, a total of 368 deaths among all 555 subjects randomized in a 2:1 ratio in the 
experimental (n=370) and control arms (n=185) are required to provide 90% power to detect an 
HR of 0.69 using the log-rank test and a 2-sided significance level of 4%. Assuming an 
exponential distribution for OS, this corresponds to a 45% increase in median survival from 
12.3 months to 17.8 months. The minimum observed effect that would result in statistical 
significance for the primary analysis of OS is an HR of 0.7942, a 26% improvement in median 
from 12.3 to 15.5 months. 
For the secondary endpoint of PFS for the single-agent cabozantinib arm vs the control arm 
(sorafenib), a total of 283 events among all 370 subjects (185 per arm) in the single-agent 
cabozantinib and control arms provides the study with 85% power for a 2-sided log-rank test 
with a 1% level of significance to detect a hypothesized true HR of 0.65. Assuming an 
exponential distribution for PFS, this corresponds with a 53% increase in median PFS from 3.6 
months to 5.5 months. The minimum observed effect that would result in statistical significance 
for PFS is an HR of 0.735, a 36% improvement in median from 3.6 to 4.9 months. 
With an average accrual rate of 30 subjects per month it is estimated that it will take 
approximately 18.4 months to observe the required primary PFS events (16.5 months of subject 
accrual) and approximately 38 months to observe the required deaths for OS (25 months of 
subject accrual) to evaluate the primary endpoints in the combination and control arms. 
Assuming the same accrual rate, it is anticipated that it will take approximately 25 months to 

 
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observe the required secondary PFS events (25 months of subject accrual) to evaluate the 
secondary endpoint in the single-agent cabozantinib and control arms. The true intervals required 
to meet these milestones may be longer or shorter due to divergence from assumptions, including 
non-constant accrual rate due to the time required for all study sites to become active, or due to 
the impact of the global COVID-19 pandemic on subject enrollment and other aspects of study 
conduct. The sample size for the global study may be increased up to an additional 25%  if a 
review of the accumulating data suggests that the COVID-19 pandemic has caused the rate of 
study dropout or non-compliance to increase to a degree that the ability to adequately evaluate 
study endpoints may be undermined. The Mainland China Extension Phase will not be expanded 
beyond 148 subjects. 
An overview of the primary and secondary endpoints and operating characteristics is shown in 
Table 33: 
Table 33: 
Summary of Endpoint Operating Characteristics 
Accrual per month 
30 subjects 
Randomization allocation 
2:1 within Experimental and Control 
Arms 
1:1 within Single-Agent 
Cabozantinib and Control 
Arms 
Endpoint: 
PFS: Primary 
endpoint 
OS: Primary 
endpoint 
PFS: 
Secondary endpoint 
 Power 
90% 
90% 
85% 
 Alpha allocated (2-sided) 
0.01 
0.04 
0.01 
 # of interim analyses (approximate 
information fraction) 
0 (NA) 
2 (33%, 66%)a 
1 (67%) 
 Assumed median, control (months) 
3.6 
12.3 
3.6 
 Assumed median, experimental (months) 
6.0 
17.8 
5.5 
 Assumed HR 
0.60 
0.69 
0.65 
 Number of events 
257 
368 
283 
 N for analysis 
 Population 
 n1 vs n2 
372 
PITT Population 
248 vs 124 
555 
ITT Population 
370 vs 185 
370 
ITT Population 
185 vs 185 
 Time to enroll (months) 
16.5 
25 
25 
 Time to trigger event (months) 
18.4 
38 
25 
a Should the timing of the first interim analysis trend towards an information fraction much higher than expected (eg, due to 
faster-than-expected deaths or slower-than-expected PFS events), the plan for the interim analyses of OS may be modified (see 
Section 9.8). 
China Subpopulation Sample Size: Up to 148 subjects from mainland China are planned to be 
enrolled (in the global and Mainland China Extension phases) in the study to meet a target of 
approximately 20% of the total sample size in the global enrollment (N=740). This population 
size is expected to be sufficient to allow evaluation of consistency in efficacy and safety in the 
China subpopulation compared with the global study per NMPA guidance. Analyses for the 
China subpopulation are described in Section 9.9. 

 
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9.8. 
Interim Analyses 
The number of events required to evaluate OS is based upon assumptions currently available and 
provides high power to detect the smallest clinically meaningful difference in OS under these 
assumptions. However, as there is uncertainty in the assumptions, interim analyses provide an 
opportunity to stop the trial early if the treatment benefit of the experimental arm is larger than 
expected, potentially allowing the new regimen to become available sooner to this patient 
population. 
Two interim analyses of OS are planned at approximately the 33% and 66% information 
fractions based on a total alpha of 4%. However, if the null hypotheses are rejected for both the 
primary and secondary PFS endpoints, the 1% alpha for PFS will be reallocated to OS per the 
fallback method. As a consequence, the final OS analysis will employ critical values from the 
spending function at the 5% level. The alpha level of the interim analysis at 66% will be 
dependent on the timing of the interim analysis and the results of secondary PFS interim and 
final analyses. The second interim analysis of OS at 66% information fraction can be conducted 
at the overall 5% alpha level only if it occurs after the null hypothesis for the secondary PFS is 
rejected at the interim analysis. 

 
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Details and boundaries for these interim and the final analyses are shown in the table below: 
Critical Values for Testing OS  
OS alpha 
total 
4.0% 
4.96% 
5.0%a 
OS analysis 
information 
fraction 
Critical 
p-value 
HR to reject 
Critical 
p-value 
HR to reject 
Critical  
p-value 
HR to reject 
33%b 
≤ 0.00011 
≤ 0.478 
NAc 
NAc 
≤ 0.0021 
≤ 0.482 
66%d 
≤ 0.00867 
≤ 0.701 
≤ 0.01196 
≤ 0.705 
≤ 0.0120 
≤ 0.705 
100% 
≤ 0.03728 
≤ 0.794 
≤ 0.04588 
≤ 0.797 
≤ 0.0463 
≤ 0.797 
HR, hazard ratio; NA, not applicable; OS, overall survival. 
a Analyses of OS will be conducted at 5% alpha level only if the null hypotheses for both the primary and 
secondary PFS endpoints are rejected prior to testing OS. 
b OS will not be tested at the 33% information fraction unless the null hypothesis for PFS has been rejected. 
c The interim analysis at 33% information fraction will be conducted at 4% alpha level.  
d The interim analysis at 66% information fraction will be conducted at 4% alpha level if it occurs prior to the 
secondary PFS analysis. It will be conducted at 4.96% alpha level if it happens after the null hypothesis for 
secondary PFS is rejected at the time of final analysis. It will be conducted at 5% alpha level only if the null 
hypothesis for secondary PFS is rejected at the interim analysis. 
Rejection of the null hypotheses for OS at the first interim analysis at about 33% information is 
not expected: it is designed primarily as an administrative analysis, expected to coincide with the 
primary analysis of PFS, and will be performed only if the null hypothesis for PFS is rejected. 
Should the timing of the first interim analysis (IA1) of OS  trend towards an information fraction 
much higher than expected (eg, due to faster-than-expected deaths or slower-than-expected PFS 
events), the interim analyses of OS will be conducted as follows: 
 
OS IA1 IF 
Proceed as 
Rationale 
< 50% 
perform IA1 and IA2 as planned 
above 
similar conditions to original plan 
50 to < 66% 
• perform IA1 at time of primary 
PFS, irrespective of whether PFS 
null hypothesis is rejected or not 
• Conduct IA2 at 80% IF (instead of 
66%) 
• Higher than expected information 
for OS negates administrative 
nature of the analysis. 
• Preserves two interim analyses as 
planned with reasonable intervals 
between them 
≥ 66% 
perform a single interim analysis at 
66% IF, irrespective of timing or 
results of primary PFS analysis. 
Information fraction meets or 
exceeds that of planned analysis at 
66% 
IA1, first interim analysis; IA2, second interim analysis; IF, information fraction; OS, overall survival 

 
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An interim analysis of secondary PFS is planned contemporaneously with the primary PFS 
analysis and will be conducted only if the null hypothesis for primary PFS is rejected. It is 
anticipated to be at approximately 67% information fraction based on a total alpha of 1%. At this 
fraction, the critical p-value is 0.0096, and the maximum HR to reject the null hypothesis 
is 0.626. 
Due to logistical considerations in event ascertainment and operational planning and conduct, the 
actual analyses may include more or fewer events than the target information fractions. The 
actual critical values employed at the interim and final analyses of secondary PFS and OS will 
depend upon the actual information fraction at the time of the analyses. Descriptive supportive 
analyses will be provided at the planned information fraction at the time of the analyses.      
If a null hypothesis is rejected for a given endpoint at interim analysis (secondary PFS or OS), no 
subsequent testing of that endpoint will be performed. 
Interim analysis of primary PFS and futility analyses of PFS or OS are not planned. 
9.9. 
Analysis Methodology for China Subpopulation 
The primary scope of the China subpopulation analysis is to allow evaluation of consistency in 
efficacy and safety with the global study population per NMPA guidance. Since the China 
subpopulation is not powered to demonstrate statistical significance in terms of efficacy, no 
formal hypothesis testing will be performed. All data summaries for the China subpopulation (to 
include all subjects from China from the global and Mainland China Extension phases) will be 
descriptive. The safety and efficacy data in the China subpopulation will be analyzed separately 
for the same endpoints using the same analysis methods as for the global population. The 
analyses for this subpopulation will be performed when the data are of sufficient maturity to 
allow evaluation of consistency in efficacy and safety.  
Details of the planned summaries will be provided in a separate SAP for the China subpopulation 
that will be finalized before the last subject is randomized in the China. 
 

 
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10. 
OTHER ANALYSES 
10.1. 
Pharmacokinetic Analyses 
The plasma concentration of cabozantinib will be analyzed by the designated laboratory using a 
validated bioanalytical method. Descriptive statistics (eg, number, mean and/or median, standard 
deviation, and coefficient of variation) will be used to summarize the concentration-time data per 
visit. Where appropriate, these data may be combined with data from other studies as part of a 
meta-analysis (ie, population PK analysis). The effect of cabozantinib exposure on biomarkers, 
clinical safety parameters (eg, selected AEs), or clinical response may also be explored.  
Serum concentrations of atezolizumab will also be measured and summarized. Descriptive 
statistics (eg, number, mean and/or median, standard deviation, and coefficient of variation) will 
be used to summarize the concentration-time data per visit.  
10.2. 
Immunogenicity Analyses 
Results of anti-drug antibody (ADA) testing (ie, immunogenicity testing) will be summarized 
overall as the number of subjects with ADA at any time point. The association between human 
ADA incidence, PK, and efficacy and/or safety outcomes may be explored. 
10.3. 
Biomarker Analyses 
Analyses may include MET and PD-L1 expression and other analyses (eg, tumor mutational 
burden) with clinical response.  
 

 
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11. 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be assured by verification and cross-check of the CRFs 
against the Investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug-dispensing log by the investigator. Authorized study site personnel will 
enter data directly into a computerized CRF database (ie, electronic data capture [EDC] system). 
Study databases will be subject to electronic and manual quality assurance procedures. 
 

 
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12. 
STUDY COMMITTEES 
12.1. 
Executive Safety Committee (ESC) 
The Sponsor’s Executive Safety Committee (ESC) provides safety oversight over periodic and 
ongoing reviews on product safety data and blinded study data (through a Safety Management 
Team). The ESC provides the company position and actions for all safety aspects of the 
company’s product to protect patient safety and public health. The ESC is managed and chaired 
by the Head of Drug Safety, and includes the following other members: Chief Medical Officer, 
Head of Clinical Development, Head of Regulatory Affairs and qualified representatives of other 
functional groups as appropriate. 
12.2. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be established to monitor the safety of the study on a regular basis. The 
committee will operate independently from the Sponsor and the clinical investigators. To 
minimize the potential introduction of bias, these individuals will not have any direct contact 
with the study site personnel or subjects. IDMC members will be selected for their expertise in 
oncology.  
This IDMC will convene regularly, including a safety assessment after a total of 50 subjects have 
been randomized and followed for at least 6 weeks. The primary responsibilities of the IDMC are 
to: 
• Review the accumulating safety data on a regular and an ad hoc basis 
• Make recommendations to the Sponsor regarding the continued conduct of the study based 
upon their evaluation of safety and efficacy data 
Safety data will be provided at regular intervals to the IDMC in the form of summary reports or 
data listings. To allow the evaluation of safety in the context of potential benefit, OS data 
(including Kaplan-Meier curves) may be reviewed by the IDMC at the time of safety summary 
reviews. The IDMC will have access to subjects’ individual treatment assignments. 
General stopping rules are as follows: 
• The IDMC members will use their expertise, experience and judgment to evaluate the safety 
data from the trial and recommend to Exelixis whether the trial should continue, be modified, 
or be stopped early for safety concerns. No formal rules for making these recommendations 
based upon safety data are planned. 

 
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The IDMC will communicate major safety concerns and recommendations regarding study 
modification or termination to the Sponsor’s senior management. 
Details of the composition, role, operational considerations, and stopping guidelines will be 
provided in a separate IDMC charter. 
12.3. 
Clinical Steering Committee (CSC) 
The Clinical Steering Committee of the study consists of physicians who have an expertise in 
treating patients with HCC. The CSC will provide critical scientific guidance including, but not 
limited to, protocol design and implementation and interpretation of clinical study results.  
12.4. 
Blinded Independent Radiology Committee (BIRC) 
A BIRC will be established to evaluate tumor scans and prior radiation history data of trial 
subjects in a central, blinded, and independent fashion (see also Section 5.8.6.4). The BIRC will 
be comprised of board-certified radiologists who will determine radiographic response and 
progression following randomization. Additional imaging results may be requested by the 
Sponsor for BIRC review. 
Primary analyses of radiographic study endpoints will be based upon BIRC assessments. 
Additional details regarding BIRC member qualification, training, methods, procedures, and 
other issues relevant to committee operations will be described in the BIRC Charter. 

 
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13. 
ETHICAL ASPECTS 
13.1. 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (January 1997) and remain consistent with the most recent 
version of the Declaration of Helsinki. The Investigator will ensure that the conduct of the study 
complies with the basic principles of GCP as outlined in the current version of 21 CFR, 
subpart D, Part 312, “Responsibilities of Sponsors and Investigators” Part 50, “Protection of 
Human Subjects” and Part 56, “Institutional Review Boards.” 
13.2. 
Informed Consent 
Sample ICFs will be supplied to each site. The Sponsor or its designee must review any proposed 
deviations from the sample ICF. The final IRB/EC-approved document must be provided to the 
Sponsor for regulatory purposes. 
It is the responsibility of the Investigator, or a person designated by the Investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness must be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
the ICF will be provided in a certified translation of the subject’s language. 
The CRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by study monitors at any time. If new safety information results in 
significant changes in the risk/benefit assessment, the consent form will be reviewed and updated 
as necessary. All subjects (including those already being treated) will be informed of the new 
information, will be given a copy of the revised form, and must give their consent to continue in 
the study. 
If a subject requests to discontinue study treatment and/or withdraws study consent, the 
Investigator must establish the specific nature of the subject’s request, as described in 
Section 3.5.2.  

 
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13.3. 
Institutional Review Board/ Ethics Committee  
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The Investigator will 
send a letter or certificate of IRB/ EC approval to the Sponsor (or designee) before subject 
enrollment and whenever subsequent modifications to the protocol are made. 
13.4. 
Disposition of Subject Samples 
Protocol-defined analyses are anticipated to result in depletion of all or almost all research 
samples. If a subject requests destruction of their tissue and blood samples, the Sponsor will 
make every attempt to destroy the samples. The Sponsor will notify the Investigator in writing 
that samples have been destroyed, if requested by the subject. 

 
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14. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
If deemed necessary, protocol modifications will be prepared, reviewed, and approved by the 
Sponsor representatives. 
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements, and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (eg, change in monitor or change of telephone number). 

 
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15. 
CONDITIONS FOR TERMINATING THE STUDY 
The Sponsor reserves the right to terminate the study, and Investigators reserve the right to 
terminate their participation in the study, at any time. Should this be necessary, the Sponsor and 
the Investigator will arrange the procedures on an individual study basis after review and 
consultation. In terminating the study, the Sponsor and the Investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interests. 

 
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16. 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND 
RECORD KEEPING 
16.1. 
Investigator’s Files and Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) the Investigator’s study file and 
(2) subjects’ clinical source documents. 
The Investigator’s study file will contain the protocol and protocol amendments, CRFs, query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence. 
Subjects’ clinical source documents to record key efficacy and safety parameters independent of 
the CRFs include the subjects’ hospital/ clinic records; physicians’ and nurses’ notes; the 
appointment book; original laboratory, ECG, electroencephalogram, x-ray, pathology and special 
assessment reports; signed ICFs; consultant letters; and subject screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for the maximum period 
required by applicable regulations and guidelines, institution procedures, or for the period 
specified by the Sponsor or designee, whichever is longer. After that period, the documents may 
be destroyed subject to local regulations with prior written permission from the Sponsor. If the 
Investigator wants to assign the study records to another party or move them to another location, 
the Sponsor must be notified in advance. 
If the Investigator cannot guarantee the archiving requirements at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
Investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
16.2. 
Source Documents and Background Data 
Upon request, the Investigator will make available for review by the Sponsor any required 
background data from the study documentation or clinic records. In case of special problems or 
governmental queries or requests for audit inspections, it is also necessary to have access to the 
complete study records, provided that subject confidentiality is protected. 

 
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16.3. 
Audits and Inspections 
The Investigator should understand that source documents for this study must be made available, 
after appropriate notification, to qualified personnel from the Sponsor’s Quality Assurance Unit 
(or designee) or to health authority inspectors. The verification of the CRF data must be by direct 
inspection of source documents. 
16.4. 
Case Report Forms  
The term “case report form” (CRF) includes electronic data capture screens or forms for studies 
that utilize electronic data capture. For enrolled subjects, all and only data for the procedures and 
assessments specified in this protocol and required by the CRFs are to be submitted on the 
appropriate CRF (unless source data are transmitted to the Sponsor or a designee electronically, 
eg, central laboratory data). Data from some procedures required by the protocol, such as 
physical examinations, will be recorded only on the source documents and will not be 
transcribed to CRFs. Additional procedures and assessments may be performed as part of the 
Investigator’s institution or medical practice standard of care. Data from assessments associated 
with the follow-up of AEs are to be recorded on unscheduled CRF pages. Otherwise, data for 
unscheduled or additional assessments are to remain in the subject’s medical record and are not 
to be recorded on CRFs unless specifically requested. 
The CRF casebook must be completed and signed by the Investigator or authorized delegate 
from the study staff. This also applies to records for those subjects who fail to complete the 
study. If a subject stops dosing or terminates from the study, the dates and reasons must be noted 
on the CRF. 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the Sponsor in the CRF and in all required reports. 
The Sponsor’s data management personnel (or designees) may, in specific circumstances, 
modify study data – without changing the meaning of the data – to ensure the dataset complies 
with conventions required for successful data extract, thesaurus coding, or uniform reporting and 
does not cause these processes to fail. Examples of these administrative changes include: 
• Substitution of non-standard ASCII characters (codes 128-255) or deletion of carriage returns 
(code 13) that are incompatible with the SAS XPT file format (eg, accented letters replaced 
with non-accented ones; e for é) 
• Splitting multiple verbatim AE terms into multiple records (eg, “nausea and vomiting” to 
separate records for “nausea” and “vomiting”) 

 
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• Reformatting failed eligibility criteria numbers for uniformity or specificity (eg, changing 
“2 a” to “2A”; or “2” to “2A” based on corroborating evidence from the clinical database) 
• Changing cause of death from “unknown” to “unknown cause of death” to facilitate coding 
in the MedDRA thesaurus 
Such changes follow a pre-defined documented process and can be clearly identified in the 
database audit trial. By participating in this study, investigators agree that such administrative 
changes are permissible without their specific prior approval. A list of all specific changes made 
can be provided to investigators upon request at any time. 

 
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17. 
MONITORING THE STUDY 
The responsible Sponsor monitor (or designee) will contact and visit the Investigator regularly 
and will be allowed on request to inspect the various records of the trial (CRFs and other 
pertinent data), provided that subject confidentiality is maintained in accordance with local 
requirements. 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout the 
study to verify both adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor is to have access to laboratory test reports and 
other subject records needed to verify the entries on the CRF. The Investigator (or designee) 
must agree to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 

 
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18. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The Investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents submitted to the Sponsor 
or designees, subjects are to be identified by identification codes and not by their names. The 
Investigator should keep a subject enrollment log showing codes, names, and addresses. The 
Investigator must maintain documents not for submission to the Sponsor or designees 
(eg, subjects’ written consent forms) in strict confidence. 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to the Sponsor and its partners or designees for review. 

 
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19. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings. The Investigator 
agrees to submit all manuscripts or abstracts to the Sponsor for review at least 30 days before 
submission. This allows the Sponsor to protect proprietary information and to provide comments 
based on information from other studies that may not yet be available to the Investigator. 
In the event that the Sponsor coordinates a publication or presentation of study results from all 
study sites, the participation of the investigator(s) or other representatives of the study site(s) as 
named author(s) shall be determined in accordance with Sponsor policy. Authorship will be 
assigned in accordance with contribution to design, execution, and interpretation and analysis of 
the study. 
The Sponsor may, at its sole option, provide funding to support the development, submission, 
and/or presentation of publications for scientific/medical journals or conferences. For 
publications coordinated by the Sponsor, the Sponsor may also provide funding to support travel 
and conference registration for the presenting author to attend the conference for the sole purpose 
of presenting the publication. 

 
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20. 
COMPLIANCE WITH DATA PROTECTION LAWS 
The conduct of this study and the processing of any personal data collected from each subject (or 
from a subject’s healthcare professional or other relevant third-party sources) by the Sponsor, the 
site and the Investigator for use in the study will fully adhere to the requirements set out in 
applicable data protection and medical privacy laws or regulations, including, without limitation, 
the General Data Protection Regulation ([EU] 2016/679) and any national implementing laws, 
regulations and secondary legislation, as amended or updated from time to time. The Sponsor 
shall ensure that at all times it has an appropriate legal basis for processing personal data under 
applicable data protection law (which may include consent from the subject or another lawful 
basis). 

 
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21. 
REFERENCES 
Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib 
in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 
2018;379(1):54-63.  
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti-programmed death-1 
antibody: raising awareness among community oncologist. J Oncol Practice 
2019;15:502-4. 
Aftab DT, McDonald DM. MET and VEGF: synergistic targets in castration-resistant prostate 
cancer. Clin Transl Oncol. 2011;13(10):703-9. 
American Cancer Society. Key Statistics about Liver Cancer. 
https://www.cancer.org/cancer/liver-cancer/about/what-is-key-statistics.html. 
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APPENDICES 
Appendix A: Schedule of Assessments  
The schedule of required assessments is presented in this appendix. Following randomization, 
assessments for safety and patient reported outcomes are to occur corresponding with study 
weeks (eg, Week 5 Day 1 [W5D1]) which are fixed from Week 1 Day 1 (W1D1) defined as the 
date of the first dose of study treatment. W1D1 should occur within 3 days after randomization. 
All assessments for radiographic endpoints (CT, MRI) as well as HRQOL (ie, EQ-5D-5L) will 
be scheduled based on W1D1 and are to be performed even for subjects randomized but never 
treated. For such subjects, W1D1 is defined as the date of randomization.  
In the absence of toxicity, all scheduled safety visits should occur within ± 3 days of the nominal 
visit day, unless otherwise indicated. For subjects in the combination arm, required safety 
assessments may occur outside the protocol defined windows due to safety-driven delays in 
atezolizumab administration and will not be considered protocol deviations as long as required 
safety assessments are performed at least every 3 weeks (± 3 days). See the CRF completion 
guidelines for instructions on how to enter study data in such circumstances.  
If study treatment is held or missed after W1D1, assessments should continue following the 
schedule described below. 
Unscheduled safety assessments or phone calls, if required as defined in the protocol, are to be 
performed weekly (or more frequently) as clinically indicated. See Section 5.7 for further details. 
Special accommodations during the global COVID-19 pandemic are described in Appendix M.

 
XL184-312 Protocol Amendment 5.0 
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Appendix A: Schedule of Assessments 
Assessment: 
Pre-randomization 
Post-randomization 
Screeninga 
(before 
randomization) 
W1D1  
(Should occur 
≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 13 (± 3 
days) 
First Post-
Treatment 
Follow-Up 
Visit (FU-1; 
30+14 days 
after decision 
to discontinue 
study 
treatment) 
Second Post-Treatment 
Follow Up Visit (FU-2; 100±14 
days after decision to 
discontinue study treatment) 
W4D
1 
W7D1 
W10D
1 
W13
D1 
Informed consent                 
(Section 5.1) 
Xb 
 
 
 
 
 
 
 
 
Demographics, medical and 
cancer history (Section 5.8.1) 
≤ 28 days 
X 
 
 
 
 
 
 
 
Physical examination + 
weight           (Section 
5.8.2)k 
≤ 14 days             
(with height) 
X                   
(prior to first 
dose; symptom-
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
Vital signs                                        
(Section 5.8.3)k 
≤ 14 days 
X                
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
Serum AFP 
(Section 5.8.7)k 
≤ 14 days 
X                
(prior to first 
dose) 
X 
X 
X 
X 
 
X 
X 
ECOG performance status          
(Section 5.8.2)k 
≤ 14 days 
X                
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
12-lead ECG                                 
(Section 5.8.4)c,k  
≤ 14 days 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 12 weeks 
(W25D1, W37D1, 
etc) 
X 
 
Hematology                                
by central labe,k (Section 
5.8.5) 
≤14 days 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
Chemistry                                   
by central labe,k (Section 
5.8.5) 
≤ 14 days 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
PT/INR and PTT                        
by central lab (Section 
5.8.5)e,k                                  
≤ 14 days 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 

 
XL184-312 Protocol Amendment 5.0 
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Assessment: 
Pre-randomization 
Post-randomization 
Screeninga 
(before 
randomization) 
W1D1  
(Should occur 
≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 13 (± 3 
days) 
First Post-
Treatment 
Follow-Up 
Visit (FU-1; 
30+14 days 
after decision 
to discontinue 
study 
treatment) 
Second Post-Treatment 
Follow Up Visit (FU-2; 100±14 
days after decision to 
discontinue study treatment) 
W4D
1 
W7D1 
W10D
1 
W13
D1 
Urinalysis                                    
by local labe,k (Section 5.8.5) 
≤ 14 days 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
Urine chemistry incl. UPCR       
by central lab (Section 5.8.5)k 
≤ 14 days 
(local labs allowed if 
needed to meet 
planned 
randomization date) 
Xd            
(prior to first 
dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
24 hour urine by local lab 
(Section 5.8.5)k 
 
Perform at the discretion of the Investigator based on  increases in UPCR from routine assessments 
Serum or urine pregnancy test    
by local lab (Section 5.8.5)k 
≤ 7 days  
(serum) 
Xd            
(serum: prior to 
first dose) 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1, 
etc) 
X 
 
Thyroid function test                  
by central lab (Section 
5.8.5)e,k 
≤ 14 days 
Xd            
(prior to first 
dose) 
X 
X 
 
X 
Every 6 weeks 
(W19D1, W25D1, 
etc) 
X 
 
Follicle stimulating hormone 
by central labf,k 
(Section 5.8.5) 
≤ 14 days 
 
 
 
 
 
 
 
 
Tumor tissue                                  
(Section 5.8.12) 
Xg 
 
An optional biopsy can be collected approximately 6 weeks 
after the first dose of study treatment; other time points may 
be acceptable provided the tumor sample is collected prior to 
progressive disease. Treatment with cabozantinib or sorafenib 
must be interrupted for at least 5 days before optional tumor 
biopsies are performed and may not be reinitiated until 
complete wound healing has occurred (at least 10 days). 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Assessment: 
Pre-randomization 
Post-randomization 
Screeninga 
(before 
randomization) 
W1D1  
(Should occur 
≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 13 (± 3 
days) 
First Post-
Treatment 
Follow-Up 
Visit (FU-1; 
30+14 days 
after decision 
to discontinue 
study 
treatment) 
Second Post-Treatment 
Follow Up Visit (FU-2; 100±14 
days after decision to 
discontinue study treatment) 
W4D
1 
W7D1 
W10D
1 
W13
D1 
 Diagnosis of HCC by 
imagingj 
(optional at radiology-
accredited sites)  
(Section 5.8.6.1) 
≤ 28 days 
 
 
 
 
 
 
 
 
Tumor assessment:  
CT/MRI  
Chest, Abdomen, Pelvis  
(Section 5.8.6) 
≤ 28 days 
CT of CAP or CT chest and MRI of abdomen/pelvis will be performed in all subjects at screening and then every 6 weeks (± 7 days) after 
randomization through Week 49. After Week 49, these assessments will be performed every 12 weeks (± 7 days). 
 
Tumor assessments should continue on the protocol-defined schedule regardless of whether study treatment is given, reduced, held or 
discontinued until a criterion for ending radiographic assessment is met (Section 5.8.6). The same imaging modality will be used for 
subsequent tumor assessments after randomization. 
 
For subjects who discontinue study treatment before Investigator-determined radiographic disease progression, tumor assessments are to 
continue per the protocol defined schedule until Investigator-assessed radiographic disease progression per RECIST 1.1. 
For subjects who continue to receive study treatment after Investigator-assessed radiographic disease progression because of Investigator-
assessed clinical benefit which outweighs the potential risks, tumor assessments are to continue per the protocol defined schedule until 
study treatment is permanently discontinued. 
Tumor assessment:  
MRI/CT  
Other Sites                                        
(Section 5.8.6) 
≤ 28 days 
 
All other known or suspected sites of disease, including in the brain or bone, are to be imaged by CT/MRI at screening (prior to 
randomization). Any lesions identified, including bone lesions with a soft tissue component, are to be followed at subsequent tumor 
assessments as described for CAP above using the same modality as at screening. New suspected lesion sites identified after 
randomization, including suspected sites of bone or brain lesions, should be assessed by CT/MRI. MRI is the preferred method for brain 
lesion assessment. If CT of the brain is performed instead of MRI, ambiguous results must be confirmed by MRI.  
 
Tumor assessments should continue on the protocol-defined schedule regardless of whether study treatment is given, reduced, held or 
discontinued until a criterion for ending radiographic assessment is met (Section 5.8.6). 
 
For subjects who discontinue study treatment before investigator-determined radiographic disease progression, tumor assessments are to 
continue per the protocol defined schedule until investigator-assessed radiographic disease progression per RECIST 1.1. 
For subjects who continue to receive study treatment after investigator-determined radiographic disease progression because of 
investigator-assessed clinical benefit which outweighs the potential risks, tumor assessments are to continue per the protocol defined 
schedule until study treatment is permanently discontinued. 

 
XL184-312 Protocol Amendment 5.0 
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Assessment: 
Pre-randomization 
Post-randomization 
Screeninga 
(before 
randomization) 
W1D1  
(Should occur 
≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 13 (± 3 
days) 
First Post-
Treatment 
Follow-Up 
Visit (FU-1; 
30+14 days 
after decision 
to discontinue 
study 
treatment) 
Second Post-Treatment 
Follow Up Visit (FU-2; 100±14 
days after decision to 
discontinue study treatment) 
W4D
1 
W7D1 
W10D
1 
W13
D1 
HRQOL-EQ-5D-5Lh               
(Section 5.8.8) 
≤ 14 days 
 
Every 6 weeks after W1D1 (eg, W7D1, W13D1, etc).  These assessments are to be performed regardless of whether 
study treatment is given, reduced, held or discontinued until the date of the last tumor imaging assessment as 
described in Section 5.8.6. Consequently these assessments may be required in the Post Treatment Period for some 
subjects. 
Cabozantinib 
PK plasma samplesi                   
(Section 5.8.10) 
 
X                
(prior to first 
dose) 
X 
predos
e 
X 
predose 
X 
predose 
X 
predo
se 
 
 
 
Atezolizumab 
 PK serum samples                   
(Section 5.8.10) 
 
X                
(prior to first 
dose) 
X 
predos
e 
X 
predose 
X 
predose 
X 
predo
se 
 
X 
X 
Immunogenicity blood sample  
(Section 5.8.11) 
 
X                
(prior to first 
dose) 
 
 
 
X 
W25D1 
X 
X 
Pharmacogenetic blood 
sample  (Section 5.8.12) 
 
X                
(prior to first 
dose) 
 
 
 
 
 
 
 
Immune cell profiling blood 
sample (Section 5.8.12) 
 
 X               
(prior to first 
dose)  
 
X 
 
X 
 
 
 
Cell and/or plasma 
pharmacogenomic samples 
(Section 5.8.12) 
 
X                
(prior to first 
dose) 
X 
X 
X 
X 
 
X 
 
Plasma biomarker samples 
(Section 5.8.12) 
 
X                
(prior to first 
dose) 
X 
X 
X 
X 
 
X 
 
Concomitant medication 
(Section 7) 
Document concomitant medication taken from 28 days before randomization through 30 days after the date of the decision to discontinue study treatment 

 
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Assessment: 
Pre-randomization 
Post-randomization 
Screeninga 
(before 
randomization) 
W1D1  
(Should occur 
≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 13 (± 3 
days) 
First Post-
Treatment 
Follow-Up 
Visit (FU-1; 
30+14 days 
after decision 
to discontinue 
study 
treatment) 
Second Post-Treatment 
Follow Up Visit (FU-2; 100±14 
days after decision to 
discontinue study treatment) 
W4D
1 
W7D1 
W10D
1 
W13
D1 
Adverse events                
(Section 8) 
Document new or worsening AEs from first dose (SAEs from informed consent) through 30 days (100 days for SAEs and AESIs) after the date of the decision to 
permanently discontinue study treatment. Related SAEs should be documented at any time. AE information will be collected at study visits and may also be 
collected at any time over the phone or by spontaneous subject report. On W1D1 AEs will be documented pre- and post-dose. Related AEs leading to study 
treatment discontinuation, AESIs (regardless of causality), and related SAEs are to be followed until resolution, ≤ Grade 2 severity, or determination by the 
investigator that the event is stable or irreversible (see Section 8.3). 
Healthcare Resource 
Utilization (Section 5.8.9) 
 
Collection of hospital admissions, emergency room visits, intensive care unit admissions, length of stay, surgeries, and transfusions from 
randomization through the 100-Day Post-Treatment Follow-up Visit (FU-2).   
Cabozantinib dosing 
(Sections 6.2.1, 6.2.3, 6.2.4, 
and 6.2.5)  
 
Experimental Arm: Cabozantinib tablets given on W1D1 after atezolizumab infusion.  
Taken once daily at home thereafter until study treatment is discontinued. 
Single-Agent Cabozantinib Arm: Cabozantinib tablets given in the clinic on W1D1. Taken once daily 
at home thereafter until study treatment is discontinued. 
 
Sorafenib dosing  
(Sections 6.2.2, 6.2.4, and 
6.2.6) 
 
Control Arm: First sorafenib dose (tablets) given on W1D1 in the clinic. 
Taken twice daily at home thereafter until study treatment discontinued 
 
Atezolizumab dosing 
(Section 6.1.1.2) 
 
Doses of atezolizumab will be administered intravenously at the clinic by infusion 
every 3 weeks (± 2 days). Atezolizumab dosing days may not necessarily align 
with safety assessment visits. 
 
 
Dispense/return of oral study 
drug and compliance 
accounting  
(Sections 6.4 and 6.5) l 
 
X 
X 
X 
X 
X 
Every 3 weeks 
(W16D1, W19D1 
etc) 
 
 
Additional anticancer 
treatment and survival status      
(Section 5.8.13) 
 
All treated subjects will be contacted at each post-treatment visit, including FU-1, FU-2, and every 12 weeks (± 14 days) after FU-2 visit 
until death. Any subjects who are randomized but not treated will be contacted every 12 weeks post-randomization until death 
a Results of screening assessments must be reviewed before randomization to confirm that the subject meets the eligibility criteria. 
b Informed consent may be obtained greater than 28 days prior to randomization, but must be provided before any study-specific procedures are performed; however 
evaluations performed as part of routine care prior to informed consent can be utilized as screening evaluations if permitted by the site’s IRB/EC policies. 
c Additional ECGs should be performed if clinically indicated. 
d This assessment is intended to confirm suitability for treatment after randomization. If this assessment has been performed during screening within 14 days (7 days for 
pregnancy test) prior to first dose (W1D1), this assessment does not need to be performed on W1D1 unless the subject’s clinical status has changed (eg, onset of new 
symptoms indicative of clinical deterioration). If the assessment is performed on W1D1, the results must be available to and reviewed by the investigator prior to any 
treatment being administered.  
e Serum chemistry, hematology, coagulation, and urinalysis laboratory samples must be collected, and results must be reviewed within 72 hours before any atezolizumab 
infusion administered on study. If the subject has symptoms indicative of a thyroid function disorder, thyroid function test results are to be reviewed prior to 

 
XL184-312 Protocol Amendment 5.0 
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administering atezolizumab. See Section 5.8.5 and the Laboratory Manual for more detailed information on laboratory assessments and when local assessments may be 
performed in lieu of central assessments for serum chemistry, hematology, coagulation, and thyroid function prior to atezolizumab administration.  
f For women under the age of 55 years to confirm menopause as needed. 
g Archival tumor tissue (most recently obtained) will be provided, if available. If archival tissue and histological/cytological confirmation of disease are not available, a 
tumor biopsy may be collected during screening with subject consent  
h HRQOL forms should be administered and collected prior to any other study-related activities for scheduled visits. Questionnaires should be completed prior to the 
clinic visit or if completed on the day of the visit prior to seeing the study site personnel. 
i For each on-treatment visit, the PK sample should be collected approximately 8 or more hours after the previous dose of cabozantinib, and if cabozantinib will be 
administered on that day, should be collected prior to cabozantinib administration. The investigator will ask the subject for the date and time of the most recent prior 
dose of cabozantinib and this information will be recorded on the appropriate CRF page.  
j Clinical diagnosis of HCC by multiphase imaging using CT or MRI in subjects with cirrhosis for eligibility may be performed at the sites accredited by the Sponsor. 
Diagnostic scans may be used for screening if they meet the criteria described in Section 5.8.6.2. Refer to the guidance on diagnosis of HCC in cirrhotic patients by 
imaging in Section 5.8.6.1. 
k For subjects in the combination arm, required safety assessments may occur outside the protocol defined windows due to safety-driven delays in atezolizumab 
administration and will not be considered protocol deviations as long as required safety assessments are performed at least every 3 weeks (± 3 days). See the CRF 
completion guidelines for instructions on how to enter study data in such circumstances 
l In exceptional circumstances (eg, COVID-19 pandemic), alternative methods of distribution of oral treatment to subjects may be considered in accordance with the 
study site’s local policies and all applicable regulations. 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix B: Maintenance Phase  
When sufficient data have been collected to adequately evaluate all study endpoints, and upon 
site notification by the Sponsor, subjects remaining on study treatment will enter the study 
Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor considers the safety 
and efficacy profile of the experimental treatment regimen (ie, cabozantinib + atezolizumab) 
within this study to have been sufficiently established for regulatory purposes. 
In the Maintenance Phase subjects will continue to receive study treatment until a criterion for 
protocol-defined discontinuation has been met (Section 3.5.1). Subjects are to undergo periodic 
safety assessments (including local laboratory tests) and tumor assessments; the nature and 
frequency of these assessments are to be performed per institutional standard of care and 
guidance from the Sponsor. It is the Investigator’s responsibility to ensure that subject visits 
occur frequently enough and adequate assessments are performed to ensure subject safety. 
In order to continue to collect important safety information on subjects still enrolled in the study, 
reporting of SAEs, AESIs, and other reportable events (pregnancy, DILI and medication errors 
with sequelae) is to continue per protocol (Section 8.2). 
Further, the following events (whether serious or not) are to be reported using the same process 
as for reporting SAEs described in protocol Section 8.2 (though SAE reporting timeline 
requirements do not apply to non-serious events reported in these categories): 
• Adverse events of special interest (AESIs) 
• Adverse events, whether serious or not, leading to study treatment discontinuation 
• Adverse events, whether serious or not, leading to study treatment dose modification (ie, 
causing study treatment to be interrupted, delayed, or reduced) 
Subjects who discontinue study treatment in the Maintenance Phase, or who had previously 
discontinued study treatment but had not yet completed the Post-Treatment Follow-Up Visits (ie, 
FU-1 and FU-2) at the time the transition to the Maintenance Phase, will undergo the final safety 
assessment at the Post-Treatment Follow-up Visits. Upon initiation of the Maintenance Phase, no 
further follow up is required for any subject who has completed the FU-1 and FU-2 Visits. 
Study drug accountability is to continue as described in Section 6.5. 
 

 
XL184-312 Protocol Amendment 5.0 
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See the Maintenance Phase Schedule of Assessments below. To receive study treatment supplies 
it may be necessary for subjects to visit the study site more frequently than clinic visits for safety 
and tumor evaluations performed per standard of care. 
Site monitoring visits will occur at a reduced frequency but must be frequent enough to ensure 
adherence to GCP, protocol compliance, adequate subject safety follow-up, study drug 
accountability, and reporting of SAEs and other reportable events. 
During the Maintenance Phase no data are to be entered into CRFs. Study central laboratory 
samples are not to be obtained. Local laboratory results are not to be submitted to the study local 
laboratory management vendor, radiographic images to the study central imaging vendor, or 
ECGs to the study central ECG vendor. 

 
XL184-312 Protocol Amendment 5.0 
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Appendix B: Schedule of Assessments: Maintenance Phase 
 
Assessment 
Study Period / Visit 
While Subject is Receiving Study 
Treatment 
(Until Treatment is Permanently 
Discontinued) 
Post-
Treatment 
Follow-Up 
Visits (ie, 
FU-1 and 
FU-2) 
Study drug accountability 
Every time study drug is dispensed 
a 
Study treatment 
Atezolizumab: Once every 3 weeks; 
Cabozantinib: Daily OR 
Sorafenib: Daily. 
Study treatment may continue until a criterion 
for discontinuation is met (Section 3.5).  
- 
Safety evaluation: 
Clinical examination and local 
laboratory assessments per SOC 
Frequency per standard of care 
a 
Reporting of SAEs, AESIs, and 
other reportable events (DILI, 
pregnancy, and medication errors 
with sequelae) 
Submit reports to Sponsor per Section 8.2 
Reporting of AEs: 
• leading to study treatment 
discontinuation 
• leading to study treatment dose 
modification (ie, causing study 
treatment to be withheld or 
reduced) 
Submit reports to Sponsor per the same process 
as for reporting SAEs per Section 8.2 
 
SAE reporting timeline requirements do not apply to non-
serious events reported in these categories 
Tumor assessments: 
Imaging methods per SOC 
Frequency per standard of care 
- 
AE, adverse event; DILI, drug-induced liver injury; FU-1, 30-Day Post-Treatment Follow-up Visit; FU-2, 100-Day 
Post-Treatment Follow-up Visit; SAE, serious adverse event; SOC = standard of care 
No data will be entered into electronic case report forms. Do not submit local laboratory results to the study local 
laboratory management vendor, radiographic images to the study central imaging vendor, or ECGs to the study central 
ECG vendor. 
a Subjects should return all unused study medication and undergo a safety evaluation per standard of care. 

 
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Appendix C: Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able 
to carry out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
 
 
 

 
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Appendix D: Preexisting Autoimmune Diseases and Immune Deficiencies 
Subjects should be carefully questioned regarding their history of acquired or congenital immune 
deficiencies or autoimmune disease. Subjects with any history of immune deficiencies or 
autoimmune disease listed in the table below are excluded from participating in the study. 
Possible exceptions to this exclusion could include: 
• Subjects with a medical history of such entities as atopic disease or childhood arthralgias 
where the clinical suspicion of autoimmune disease is low  
• Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone, controlled Type 1 diabetes mellitus and on an insulin regimen, or 
asthma that requires intermittent use of bronchodilators 
• Subjects with transient autoimmune manifestations of an acute infectious disease that 
resolved upon treatment of the infectious agent (eg, acute Lyme arthritis)  
Caution should be used when considering atezolizumab for subjects who have previously 
experienced a severe or life−threatening skin adverse reaction or pericardial disorder while 
receiving another immunostimulatory anti-cancer agent. 
Contact the Sponsor regarding any uncertainty over autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
Acute disseminated 
encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody 
syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myelitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic 
purpura 
Behçet disease 
Bullous pemphigoid 
Chronic fatigue syndrome 
Chronic inflammatory 
demyelinating polyneuropathy 
Churg-Strauss syndrome 
Dermatomyositis 
Diabetes mellitus type 1 
Dysautonomia 
Epidermolysis bullosa acquisita 
Gestational pemphigoid 
Giant cell arteritis 
Goodpasture syndrome 
Graves disease 
Guillain-Barré syndrome 
Hashimoto disease 
IgA nephropathy 
Inflammatory bowel disease 
Interstitial cystitis 
Kawasaki disease 
Lambert-Eaton myasthenia 
syndrome 
Lupus erythematosus 
Lyme disease - chronic 
Meniere syndrome 
Mooren ulcer 
Morphea 
Multiple sclerosis 
Myasthenia gravis 
Neuromyotonia 
Opsoclonus myoclonus syndrome 
Optic neuritis 
Ord thyroiditis 
Pemphigus 
Pernicious anemia 
Polyarteritis nodosa 
Polyarthritis 
Polyglandular autoimmune 
syndrome 
Primary biliary cholangitis 
Psoriasis 
Reiter syndrome 
Rheumatoid arthritis 
Sarcoidosis 
Scleroderma 
Sjögren’s syndrome 
Stiff-Person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vitiligo 
Vogt-Koyanagi-Harada disease 
Wegener granulomatosis 

 
XL184-312 Protocol Amendment 5.0 
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Crohn disease  
 
Appendix E: Response Evaluation Criteria in Solid Tumors Version 1.1 (also known as 
RECIST 1.1) 
Adapted from Eisenhauer et al 2009 
Definitions 
Baseline: Baseline is defined as the most recent assessment performed prior to randomization. 
Baseline assessments must be performed within the period defined in the protocol eligibility 
criteria.  
Measurable lesions: Except for lymph nodes as described below, measurable lesions are defined 
as those that can be accurately measured in at least 1 dimension (longest diameter to be recorded) 
as ≥ 10 mm with CT scan (if CT scans have slice thickness greater than 5 mm the minimum size 
for a measurable lesion is twice the slice thickness).  
• 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 recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but 
not for lesions in the lungs. The minimum size for measurability is the same as for CT 
(10 mm) as long as the scans are performed with slice thickness of 5 mm and no gap. If MRI 
is performed with thicker slices, the size of a measurable lesion at baseline should be twice 
the slice thickness. In the event there are interslice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Nonmeasurable lesions: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered 
nonmeasurable. Lymph nodes that have a short axis < 10 mm are considered nonpathological 
and are not be recorded or followed. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/ pulmonitis, and abdominal masses (not 
followed by CT or MRI), are considered as nonmeasurable. Following a time point response of 
CR, non-target lymph node lesions and new lymph node lesions must be measured to determine 
if they are or become pathologic in size. 

 
XL184-312 Protocol Amendment 5.0 
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Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline. Target lesions are to be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
that can be measured reproducibly should be selected. Target lesions will be measured at each 
assessment (longest axis for nonnodal lesions, shortest axis for measurable malignant nodal 
lesions). 
Nontarget lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥ 10 to <15 mm short axis) and all measurable lesions 
over and above the 5 target lesions are to be identified as non-target lesions and recorded at 
baseline. Measurements of these lesions are generally not required, but the presence, absence, or 
in rare cases unequivocal progression of each is to be recorded throughout follow-up. Lymph 
nodes that have a short axis < 10mm are considered non-pathological and are not to be recorded 
or followed. Following a time point response of CR, non-target lymph node lesions and new 
lymph node lesions must be measured to determine if they are or become pathologic in size.  
To be considered progression of non-target lesions in the presence of measurable disease, 
unequivocal progression is defined as substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of the therapy.  
Special Consideration 
Lesions by clinical examination will not be used for response in this study. 
Cystic lesions 
• Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same subject, these are preferred for selection as target lesions. 

 
XL184-312 Protocol Amendment 5.0 
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Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Lesions with prior local treatment 
• Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are not considered measurable.  
 
Imaging Methods 
The same method of assessment and the same technique used to characterize each identified and 
reported lesions at baseline should be used during each follow-up assessment. All measurements 
should be taken and recorded in metric notation using a ruler or calipers. Imaging based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but assessed by clinical examination (referring to biopsy-proven visible 
lesion(s) on the chest). 
Chest x-ray: Chest x-ray will not be used for response assessment in this study. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion is twice the slice thickness. MRI is 
also acceptable in certain situations (eg, for body scan) except for lung.  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 

 
XL184-312 Protocol Amendment 5.0 
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image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
Positron emission tomography will not be used for response assessment in this study. 
Ultrasound: Ultrasound will not be used for response assessment in this study. 
Bone scans may be used to assess the presence or disappearance of the bone component of bone 
lesions. CT or MRI scan will be used to confirm results of bone scans. Preferred method for 
confirmation is MRI.  
Tumor Markers: Tumor markers (eg, AFP) may be evaluated for changes in response to 
treatment but will not be used to determine PD in this study. 
Cytology, Histology: The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumour has met criteria 
for response or SD in order to differentiate between response (or stable disease) and PD.  
Time Point Assessments 
The frequency and schedule of tumor assessments is defined in the protocol. The schedule is to 
be maintained regardless of whether study treatment is reduced, interrupted, delayed, or 
discontinued until a protocol-defined criterion for ending radiographic assessments is met (see 
Section 5.7.6.2). 
At baseline, tumors and lymph nodes are classified and documented as target or nontarget lesions 
per the definitions provided above. It is possible to record multiple nontarget lesions involving 
the same organ as a single item (eg, ‘multiple liver metastases’). At all postbaseline (follow-up) 
evaluations the baseline classification (target, nontarget) is to be maintained and lesions are to be 
documented and described in a consistent fashion over time (eg, recorded in the same order on 
source documents). 
At each assessment, a sum of the diameters (longest for nonnodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and included in source documents. The baseline 
sum of the diameters (SoD) will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. The lowest SoD (nadir) since (and 
including) the baseline value will be used as reference for evaluating progression. 

 
XL184-312 Protocol Amendment 5.0 
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After baseline, target lesions should have the actual size documented, if possible, even if the 
lesions become very small. If in the opinion of the radiologist the lesion has likely disappeared, 0 
mm should be recorded. If the lesion is present but too small to measure, an indicator for ‘too 
small to measure’ should be included in source documents. 
For target lesions, measurements should be taken and recorded in metric notation.  
Nontarget lesions are to be assessed qualitatively (present, resolved, or unequivocal progression) 
and new lesions, if any, are to be documented separately. 
At each evaluation, progression status is to be determined based upon the time point status for 
target lesions, nontarget lesions, and new lesions. 
Finding of new lesions should not be attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor. Necrosis of pre-
existing lesions as part of a response to treatment should be excluded before defining a ‘new’ 
cystic lesion. A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion. If a new lesion is equivocal because of its small 
size, repeat scans need to confirm there is definitely a new lesion, and progression should be 
declared using the date of the initial scan. 
Time point progression cannot be based solely on bone scan findings. Bone scans are to be used 
to direct corroborative imaging with CT/MRI if necessary. These CT/MRI findings will be used 
for the determination of progression. 
 

 
XL184-312 Protocol Amendment 5.0 
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TIME POINT RESPONSE CRITERIA 
 
Target Lesion Time Point Response (TPR) 
Complete Response   
(CR) 
Disappearance of all target lesions. All pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm. 
Partial Response 
(PR) 
At least a 30% decrease in SoD of target lesions, taking as a reference the 
baseline SoD. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Progressive Disease     
(PD) 
At least a 20% increase in the SoD of target lesions, taking as a reference 
the smallest (nadir) SoD since (and including) baseline. In addition to the 
relative increase of 20%, the SoD must also demonstrate an absolute 
increase of at least 5 mm.  
Not Applicable (NA) 
No target lesion identified at baseline. 
Unable to Evaluate     
(UE) 
One or more target lesions are not imaged and the remainder of the SoD 
compared with the nadir SoD does not meet the criterion for PD. 
SoD, baseline sum of diameters (longest for non-nodal lesions; short axis for nodal lesions). 
If the target lesion for a subject meet the criteria for both PR and PD at a given time point, the target lesion 
response is PD. 
If the nadir of SoD is 0 (ie, the subject had a prior target lesion CR), the reappearance of any prior target 
lesion to any degree constitutes PD. 
 
 
Non-Target Lesion Time Point Response (TPR) 
Complete Response    
(CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Non-CR / Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease      
(PD) 
Unequivocal progression of non-target lesions. Unequivocal progression 
should normally not trump target lesion status. It must be representative 
of overall disease status change, not a single lesion increase. 
Not Applicable (NA) 
No non-target lesions identified at screening. 
Unable to Evaluate     
(UE) 
One or more non-target lesions are not imaged and the remaining non-
target lesions do not meet the criterion for PD. 
 
 
 

 
XL184-312 Protocol Amendment 5.0 
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New Lesion Time Point Response (TPR) 
Yes 
Lesion present at follow-up visit either for the very first time or re-
appearing (ie, lesion was present at baseline, disappeared at a follow-up 
visit and re-appeared later). Note: The appearance of one or more new 
lesions on CT or MRI scan is considered progression if these findings 
are unequivocally not due to a change in the imaging technique or 
modality. On bone scan, new lesions are not sufficient to qualify as PD. 
Confirmation should be obtained by performing CT or MRI of the area 
of concern to confirm results of bone scan. Preferred method for 
confirmation is MRI. 
No 
No new lesions present at follow-up. 
Unable to Evaluate     
(UE) 
Subject not assessed or incompletely assessed for new lesions. 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Evaluation of Overall Time Point Response 
Target Lesion TPR 
Non-target lesion TPR 
New lesion TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
 Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Any except PD 
No 
UE 
PD 
Any 
No or Yes 
PD 
Any 
PD 
No or Yes 
PD 
Any 
Any 
Yes 
PD** 
NA 
CR 
No 
CR* 
NA 
Non-CR/Non-PD 
No 
Non-CR/non-PD 
NA 
UE 
No 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; TPR, time point 
response; UE, unable to evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, 
NA, or UE. 
The overall response at a given time point does not depend upon the overall response assigned at any prior 
or subsequent time point (ie, confirmation requirement are not considered when assigning time point 
responses). 
* Subjects with an overall response of CR or PR must have a follow-up tumor assessment performed no 
less than 4 weeks after the criteria for response are first met (this may be performed at the next scheduled 
tumor assessment). However, the presence, absence, or status at this follow-up assessment is not considered 
when assigning a time point response at prior time points. 
** If a lesion disappears and reappears at a subsequent time point it should continue to be measured. 
However, the subject’s response at the point in time when the lesion reappears will depend upon the status 
of his/her other lesions. For example, if the subject’s tumor had reached a CR status and the lesion 
reappeared, then the subject would be considered PD at the time of reappearance. In contrast, if the tumor 
status was a PR or SD and one lesion which had disappeared then reappears, its maximal diameter should 
be added to the sum of the remaining lesions for a calculated response. 
Furthermore, in order to identify potential delayed immune-mediated tumor response, subjects with an 
overall response of PD per RECIST 1.1 who continue with study treatment because of evidence of clinical 
benefit as assessed by the investigator should have a follow-up tumor assessment no less than 4 weeks after 
the initial PD criteria were met. This may be performed at the next scheduled tumor assessment. However, 
the presence, absence, or status at this follow up assessment is not considered when assigning a time point 
response at prior time points. 
 

 
XL184-312 Protocol Amendment 5.0 
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Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. For subjects with an overall response of PR or CR at a given time point, a follow-up 
tumor assessment must be performed no less than 4 weeks after the criteria for response are first 
met. This may be performed at the next scheduled tumor assessment.  
In order to identify potential delayed immune-mediated tumor response, subjects with an overall 
response of PD per RECIST 1.1 who continue with study treatment because of evidence of 
clinical benefit as assessed by the investigator should have a follow-up tumor assessment no less 
than 4 weeks after the initial PD criteria were met. This may be performed at the next scheduled 
tumor assessment. 
However, the presence, absence, or status at these follow-up assessments is not considered when 
assigning a time point response at prior time points.  
Best Overall Response 
Best overall response, incorporating confirmation requirements, will be derived during statistical 
analysis from the series of time point responses and need not be considered when assigning 
response at each time point. 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix F: List of Strong Inducers and Inhibitors of CYP3A4 
Cabozantinib is a CYP3A4 substrate (Section 7.3.1 Potential drug interactions with 
cabozantinib). 
Chronic co-administration of cabozantinib with drugs known to be strong inducers of the 
CYP3A4 family may decrease cabozantinib concentrations and therefore should be avoided 
during treatment with cabozantinib. St. John’s Wort (Hypericum perforatum) is also known to be 
an inducer of CYP3A4 and should be avoided. 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family may increase 
cabozantinib concentrations and should be avoided during treatment with cabozantinib. 
Grapefruit, star fruit and Seville oranges may also increase plasma concentrations of 
cabozantinib and should be avoided during treatment with cabozantinib. 
 
Strong Inhibitors of CYP3A4 
Strong Inducers of CYPA4 
Antivirals 
Boceprevir 
Cobicistat 
Conivaptan 
Danoprevir 
Dasabuvir 
Elvitegravir 
Indinavir  
Lopinavir  
Nelfinavir 
Ombitasvir  
Paritaprevir 
Ritonavir  
Saquinavir 
Telaprevir  
Tipranavir  
Anti-Fungals 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Antibiotics 
Clarithromycin 
Telithromycin 
Troleandomycin 
Conivaptan 
Diltiazem 
Grapefruit juice 
Idelalisib 
Nefazodone 
Carbamazepine 
Efavirenz 
Enzalutamide 
Erythromycin 
Mitotane 
Modafinil 
Nevirapine 
Oxcarbazepine 
Phenytoin 
Rifampin 
St. John’s Wort 
This table is not all-inclusive. Please refer to the FDA website for the most updated lists of 
substrates, inducers, and inhibitors of selected CYP450 isozyme pathways: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix G: Infusion-Related Reaction and Cytokine Release Syndrome Guidelines 
Event 
Management Guideline 
Grade 1:a 
Feverb with or without constitutional symptoms 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then 
restart infusion at half the rate being given at the time of 
event onset. 
• If the infusion is tolerated at the reduced rate for 30 
minutes, the infusion rate may be increased to the original 
rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment,c including maintenance 
of IV fluids for hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in 
patients with significant symptoms and/or comorbidities, 
consider managing as per Grade 2. 
• For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics, and monitor closely for IRRs and/or CRS. 
Grade 2:a 
Feverb with hypotension not requiring 
vasopressors 
and/or 
Hypoxia requiring low-flow oxygend by nasal 
cannula or blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then 
restart infusion at half the rate being given at the time of 
event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment.c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely 
(in the ICU, if appropriate). Administer IV fluids as 
clinically indicated, and manage constitutional symptoms 
and organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic 
CRS (eg, sepsis). If no improvement within 24 hours, 
initiate workup and assess for signs and symptoms of HLH 
or MAS. 
• Consider IV corticosteroids (eg, methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.e 
• Consider hospitalization until complete resolution of 
symptoms. If no improvement within 24 hours, manage as 
per Grade 3, that is, hospitalize patient (monitoring in the 
ICU is recommended), permanently discontinue 
atezolizumab, and contact Sponsor. 
• If symptoms resolve to Grade 1 or better for 3 consecutive 
days, the next dose of atezolizumab may be administered. 
For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs and/or CRS. 
• If symptoms do not resolve to Grade 1 or better for 
3 consecutive days, contact Sponsor. 

 
XL184-312 Protocol Amendment 5.0 
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Grade 3:a 
Feverb with hypotension requiring a vasopressor 
(with or without vasopressin) 
and/or 
Hypoxia requiring high-flow oxygend by nasal 
cannula, face mask, non-rebreather mask, or 
Venturi mask  
• Permanently discontinue atezolizumab and contact Sponsor.f 
• Administer symptomatic treatment.c 
• For hypotension, administer IV fluid bolus and vasopressor 
as needed. 
• Monitor cardiopulmonary and other organ function closely; 
monitoring in the ICU is recommended. Administer IV fluids 
as clinically indicated, and manage constitutional symptoms 
and organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS 
(eg, sepsis). If no improvement within 24 hours, initiate 
workup and assess for signs and symptoms of HLH or MAS. 
• Administer IV corticosteroids (eg, methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.e 
• Hospitalize patient until complete resolution of symptoms. If 
no improvement within 24 hours, manage as per Grade 4, that 
is, admit patient to ICU and initiate hemodynamic 
monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to 
anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator and in 
consultation with the Sponsor.  
Grade 4:a 
Feverb with hypotension requiring multiple 
vasopressors (excluding vasopressin) 
and/or 
Hypoxia requiring oxygen by positive pressure 
(eg, CPAP, BiPAP, intubation and mechanical 
ventilation) 
• Permanently discontinue atezolizumab and contact 
Sponsor.f 
• Administer symptomatic treatment.c 
• Admit patient to ICU and initiate hemodynamic 
monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed. Monitor other organ function 
closely. Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic 
CRS (eg, sepsis). If no improvement within 24 hours, 
initiate workup and assess for signs and symptoms of HLH 
or MAS. 
• Administer IV corticosteroids (eg, methylprednisolone 
2 mg/kg/day or dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.e For patients who are 
refractory to anti-cytokine therapy, experimental 
treatmentsg may be considered at the discretion of the 
investigator and in consultation with the Sponsor. 
• Hospitalize patient until complete resolution of symptoms. 
ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bi-level positive airway pressure; 
CAR, chimeric antigen receptor; CPAP, continuous positive airway pressure; CRS, cytokine-release syndrome; 
CTCAE, Common Terminology Criteria for Adverse Events; eCRF, electronic Case Report Form; HLH , 
hemophagocytic lymphohistiocytosis; ICU, intensive care unit; IRR, infusion-related reaction; MAS, macrophage 
activation syndrome; NCCN, National Cancer Comprehensive Network; NCI, National Cancer Institute. 
Note: The management guidelines have been adapted from NCCN guidelines for management of CAR T-cell-
related toxicities (Version 2.2019). 
a Grading system for management guidelines is based on ASTCT consensus grading for CRS. NCI CTCAE 
(version 5.0) should be used when reporting severity of IRRs, CRS, or organ toxicities associated with CRS on 
the Adverse Event eCRF. Organ toxicities associated with CRS should not influence overall CRS grading. 
b Fever is defined as temperature ≥ 38°C not attributable to any other cause. In patients who develop CRS and 
then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when 

 
XL184-312 Protocol Amendment 5.0 
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subsequently determining event severity (grade). In this case, the grade is driven by the presence of 
hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or 
oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional 
practice. 
d Low flow is defined as oxygen delivered at ≤ 6 L/min, and high flow is defined as oxygen delivered at 
> 6 L/min. 
e There are case reports where anti-cytokine therapy has been used for treatment of CRS with immune 
checkpoint inhibitors (Rotz et al 2017; Adashek and Feldman 2019), but data are limited, and the role of such 
treatment in the setting of antibody-associated CRS has not been established. 
f Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the event. The decision to rechallenge with atezolizumab should be based on investigator’s assessment of 
benefit-risk, and documented by both the investigator. The Medical Monitor is available to advise as needed. 
For subsequent infusions, administer oral premedication with antihistamines, anti-pyretics, and/or analgesics, 
and monitor closely for IRRs and/or CRS. Premedication with corticosteroids and extending the infusion time 
may also be considered after assessing the benefit-risk ratio. 
g Refer to Riegler et al (2019) for information on experimental treatments for CRS. 
 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix H: Methods of Contraception 
In Inclusion Criterion 12 (Study Synopsis and Protocol Section 4.2): 
Sexually active fertile subjects and their partners must agree to use highly effective methods of 
contraception that alone or in combination result in a failure rate of less than 1% per year when 
used consistently and correctly during the course of the study and for 5 months after the last dose 
of study treatment. Such methods include: 
• Placement of an intrauterine device (IUD) 
• Placement of an intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to 
the preferred and usual lifestyle of the subject) 
• Combined (estrogen- and progestogen-containing) hormonal contraception*: 
o Oral 
o Intravaginal 
o Dermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation*: 
o Oral 
o Injectable  
o Implantable  
 
∗ 
The effect of cabozantinib on the PK of contraceptive steroids has not been investigated. Because oral 
contraceptives might possibly not be considered as “effective methods of contraception,” they should be used 
together with another method. 
 
Furthermore, male subjects must refrain from donating sperm and are required to use condoms in 
order to avoid transmission of study treatment in semen for the duration of study treatment and 
through 5 months after their last dose of study treatment. 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix I: Barcelona Clinic Liver Cancer (BCLC) Staging and Treatment Strategy 
Source: Forner et al 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix J: Child-Pugh Scoring System 
Modified Child-Pugh classification of severity of liver disease (Garcia-Tsao 2007) according to 
the degree of ascites, total bilirubin and albumin, prothrombin time, and degree of 
encephalopathy. Each measure is scored 1-3, with 3 indicating greatest severity: 
 
Points assigned 
Parameter 
1 
2 
3 
Ascites 
none 
mild/moderate 
(diuretic-responsive) 
tense (diuretic-
refractory) 
Total bilirubin, mg/dL 
< 2 
2-3 
> 3 
Albumin, g/dL 
> 3.5 
2.8-3.5 
< 2.8 
Prothrombin time 
 
 
 
Seconds over control 
1–3 
4–6 
> 6 
or 
 
 
 
INR 
< 1.7 
1.7-2.3 
> 2.3 
Encephalopathy 
none 
Grade 1-2 
(or precipitant-
induced) 
Grade 3-4 
(chronic) 
Child-Pugh score (A, B, or C) based on total score from the above point assignments: 
Grade 
Points 
1-year survival 
2-year survival 
A: well-compensated disease 
5–6 
100% 
85% 
B: significant functional compromise 
7–9 
80% 
60% 
C: decompensated disease 
10–15 
45% 
35% 
 
 
 

 
XL184-312 Protocol Amendment 5.0 
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Appendix K: Collection, Follow-Up, and Documentation Requirements for AEs, AESIs, 
and SAEs 
All adverse events (AEs) that are not serious and not AESIs (AEs of special interest; Table 31) 
that start or worsen after the first dose of study treatment through the 30-day post-treatment 
follow-up visit (FU-1) visit are to be entered into the electronic CRF data capture system (EDC). 
Such events continuing at the FU-1 visit are to be documented as “ongoing” in the EDC and do 
not require further documentation for study purposes. These events do not require a Drug Safety 
SAE Form to be completed. 
Additional requirements apply to the following events: 
• All serious adverse events (SAEs) that are judged by the investigator to be not related to 
study treatment that start or worsen after the subject’s initial informed consent through the 
100-day post-treatment follow-up visit (FU-2) visit are to have a Drug Safety SAE Form 
completed. Such events continuing at the FU-2 visit are to be documented as “ongoing” in 
the EDC and do not require further documentation for study purposes. 
• All AEs leading to study treatment discontinuation that are judged by the Investigator to be 
related to study treatment that are continuing at the FU-2 visit are to be followed by the 
Investigator until resolution, defined as: fully resolved or ≤ Grade 2 severity or the event is 
deemed stable/irreversible by the Investigator. In the EDC, only documentation of the status 
of “ongoing” at the FU-2 visit is required. If serious, the requirements for related SAEs 
apply. 
• All AESIs (regardless of seriousness) that start or worsen after the subject’s initial informed 
consent through the FU-2 visit are to have a Drug Safety SAE Form completed and be 
entered into the EDC. Such events continuing at the FU-2 visit are to be followed until 
resolution, with evidence of resolution provided on updates to the Drug Safety SAE Form. In 
the EDC, only documentation of the status of “ongoing” at the FU-2 visit is required. 
• All SAEs that are judged by the investigator to be related to study treatment that start or 
worsen at any time after the subject’s initial informed consent are to have a Drug Safety SAE 
Form completed. Such events that occur prior to the FU-2 visit are to be entered into the 
EDC. Such events continuing at the FU-2 visit are to be followed until resolution, with 
evidence of resolution provided on updates to the Drug Safety SAE Form. In the EDC, only 
documentation of the status of “ongoing” at the FU-2 visit is required. 
Summaries of the event surveillance (Table K-1) and follow-up requirements (Table K-2) are 
shown in the following page. 

 
XL184-312 Protocol Amendment 5.0 
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Table K-1: 
Requirements for Documenting the Incidence of AEs, SAEs and AESIs: 
Event type 
Event surveillance period (inclusive): 
EDC CRFa 
Drug Safety SAE Form 
Period 
start 
Period 
stop 
Period 
start 
Period 
stop 
AE: nonserious, non-AESI 
first dose 
FU-1 
NA 
NA 
SAE: not related 
IC 
FU-2 
IC 
FU-2 
Related AE leading to study treatment discontinuation  
first dose 
EOT date 
NA (if nonserious) 
NA (if nonserious) 
AESI: nonserious (AESIs: irAEs, potential DILI, Other; 
Table 31) 
IC 
FU-2 
IC 
FU-2 
Related SAE 
IC 
FU-2 
IC 
ever 
AE, adverse event; AESI, adverse event of special interest (Table 31); EDC, electronic CRF data capture system; CRF, case report form; DILI, drug-induced liver injury; 
EOT date, end of treatment date (later of the date of decision to discontinue study treatment or date of last dose); FU-1, follow-up visit 30 days after EOT date; FU-2, follow-up 
visit 100 days after EOT date; IC, informed consent; irAE, immune-related AE; NA, not applicable; SAE, serious AE. 
a 
See CRF completion guidelines for instructions regarding the appropriate page(s) to be completed 
Table K-2: 
Requirements for Following up on Events Documented and Reported as Defined in Table L-1 
Event type 
Event follow-up requirements 
If ongoing at… 
…follow until… 
…and document following on: 
Source documents 
EDC CRF 
Drug Safety 
SAE Form 
AE: nonserious, non-AESI 
FU-1 
NA 
status at FU-1 
status at FU-1 
NA 
SAE: not related, non-AESI 
FU-2 
NA 
status at FU-2 
status at FU-2 
status at FU-2 
Related AE leading to study treatment discontinuation  
FU-2 
Resolutionb 
evidence of 
resolution 
status at FU-2 
NA (if nonserious) 
AESI: regardless of seriousness (AESIs: irAEs, potential DILI, 
Other; Table 31) 
FU-2 
Resolutionb 
evidence of 
resolution 
status at FU-2 
evidence of resolution 
Related SAE 
FU-2 
Resolutionb 
evidence of 
resolution 
status at FU-2 
evidence of resolution 
AE, adverse event; AESI, adverse event of special interest (Table 31); EDC, electronic CRF data capture system; CRF, case report form; DILI, drug-induced liver injury; 
EOT date, end of treatment date (later of the date of decision to discontinue study treatment or date of last dose); FU-1, follow-up visit 30 days after EOT date; FU-2, follow-up 
visit 100 days after EOT date; IC, informed consent; irAE, immune-related AE; NA, not applicable; SAE, serious AE. 
a 
See CRF completion guidelines for instructions regarding the appropriate page(s) to be completed 
b 
Defined as: AE is fully resolved or ≤ Grade 2 severity or the event is deemed stable/irreversible by the Investigator 

 
XL184-312 Protocol Amendment 5.0 
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Appendix L:  EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version 
Under each heading, please choose the ONE box that best describes your health TODAY. 
CCI

 
CCI

 
XL184-312 Protocol Amendment 5.0 
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Appendix M:  COVID-19 Instructions 
This appendix describes contingencies and accommodations for sites and subjects impacted by 
the COVID-19 pandemic. In response to the evolving circumstances of the pandemic, the 
Sponsor will provide ongoing guidance to Investigators on study conduct to ensure subject safety 
and maintain the scientific integrity of the study. Investigators must also maintain awareness of 
and respond to instructions and guidelines from their local regulatory authorities during the 
pandemic. These will be temporary measures and are applicable only during the pandemic, and 
as necessary to abide by local public health requirements. These measures will be repealed back 
to the measures described in the full study protocol as soon as the situation (governmental rules, 
benefit/risk assessment for the trial) allows. 
Under the exceptional circumstances of the COVID-19 pandemic where randomized subjects are 
not able or willing to physically access the site clinic, the following accommodations may be 
permitted if allowed by local and other applicable regulations (Note: special accommodations are 
not permitted for screening assessments): 
• Safety assessments should still be performed unless the Investigator and Sponsor agree that 
specific assessments may be missed as long as this occurs in accordance with all applicable 
local regulations.  However, at a minimum, the Investigator or designee must regularly 
contact the subject (eg, by phone) to ascertain the subject’s condition and occurrence of any 
symptom-based AEs per the relevant protocol-defined visit schedule. If available, results of 
any remote assessments performed by a non-study local oncologist or primary care physician 
must be sent to the Investigator for review and documentation. If components of the safety 
assessment cannot be collected or the timing of safety assessments needs to be adjusted, it 
may be possible to continue with study treatment but this will have to be discussed on a case-
by-case basis with the Medical Monitor. Any remote laboratory assessments must be 
performed by laboratories accredited by the local jurisdiction. 
• Tumor assessments may be performed at another radiology facility rather than at the study 
site (this option is not available in Germany). Such facilities should perform tumor 
assessments in accordance with the protocol, but alternative image acquisition protocols (eg, 
single post-contrast vs triple phase) may be accepted if the preferred modality is not 
available. The treatment modality (eg, CT scan or MRI) should be the same as that utilized  
since the start of study entry in order to avoid discrepancies in imaging interpretation. 
Imaging should be performed within or as close to the study visit window for scheduled 
imaging time points as possible. The study site must collect tumor images generated off site 

 
XL184-312 Protocol Amendment 5.0 
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in a timely fashion for review and documentation by the Investigator and submission to the 
BIRC. 
• Alternative methods of distribution of oral treatment to subjects may be considered in 
accordance with the study site’s local policies and all applicable regulations. Confirmation of 
drug receipt will be obtained by sites. 
• Intravenous study treatment should generally only be administered at the study site, but 
circumstances may arise where the subject may receive infusions in another location under 
the supervision of the Investigator, with the approval of the Sponsor, and in accordance with 
all applicable regulations. 
If logistical challenges in providing study treatment or performing study-related assessments 
result in temporary interruption of all study treatment for greater than 12 weeks, subjects are 
required to permanently discontinue study treatment unless permitted to continue by the Sponsor. 
If it becomes necessary to employ any of the accommodations described in this appendix of 
COVID-19 Instructions, Investigators are to document each incident in source records as 
COVID-related. To comply with emerging regulatory guidance that such accommodations be 
reported and their impact on the study assessed, these will be collected by the Sponsor (or 
designee) as protocol-deviations. However, no corrective action will generally be expected if this 
appendix is followed. 
Subjects are to be informed of changes to standard procedures resulting from effects of the 
COVID-19 pandemic, and if necessary subject consent is to be acquired. If additional consent is 
necessary during the course of the study but cannot be immediately obtained from the subject in 
writing, the Investigator is to describe to the subject the additional information requiring consent, 
obtain verbal consent from the subject, document such consent in the subject file, and follow up 
with written consent the next time a subject returns to the site. This does not apply to initial 
consent to enter the study; in this case, written consent is still required. 
For subjects who develop COVID-19 while on study, the Investigator is to evaluate the overall 
risk-benefit ratio for the subject to determine whether holding study treatment(s) is in the best 
interest of the subject.  
Any cases of confirmed or suspected COVID-19 infections should follow the general AE 
reporting  requirements defined in the protocol. For any confirmed or suspected COVID-19 
cases, the Investigator is responsible for assessing if the event should be reported as a SAE using 

 
XL184-312 Protocol Amendment 5.0 
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their clinical judgment. The investigator should further consider if the diagnosis meets the 
criteria of being a significant medical event. 
When recording data missing, impacted, or related to COVID-19 in the electronic CRFs, the 
conventions below are to be employed. Also refer to updated CRF Completion Guidelines and 
site communication memos for additional instructions for how to document data missing or 
impacted by COVID-19. 
Case Report Form 
Instructions 
Adverse Event CRF 
• 
Record COVID-19 diagnoses as “COVID-19” 
• 
Record suspected cases as “suspected COVID-19” 
• 
If death is the outcome of such an event, the CTCAE grade should be 
assigned as ‘5’. 
See the CRF instructions for how to enter fatal events that started at a 
lower grade 
End of Study Treatment 
CRFs 
• 
Investigators are to use their best judgment to identify the primary 
reason for study treatment discontinuation. 
• 
If study treatment ended primarily due to a logistical issue associated 
with the COVID-19 pandemic and was unrelated to cancer 
progression or any AE: 
o Indicate “Other” as the reason for treatment discontinuation 
and describe the reason in the Specify field, including the 
term “COVID-19”. 
For example – Other, Specify: “Subject unable to travel due 
to COVID-19 restrictions ” 
• 
If study treatment ended primarily due to an AE caused by COVID-
19 or suspected COVID-19: 
o Indicate “AE/SAE unrelated to progression of disease under 
study”  
o Record the AE on the Adverse Event CRF as described 
above with Action Taken = “Treatment Discontinued” 
End of Radiographic 
Follow-Up CRF 
• 
If radiographic assessments ended primarily due to a logistical issue 
or AE caused by COVID-19 or suspected COVID-19: 
o Indicate “Other” as the reason for discontinuation and 
describe the reason in the Specify field, including the term 
“COVID-19.” 
For example – Other, Specify:  “Subject unable to travel due 
to COVID-19 restrictions ” or “Subject discontinued due to 
hospitalization for suspected COVID-19.” In the latter 
example, also record the AE on the Adverse Event CRF as 
“suspected COVID-19” 
Study Treatment CRFs 
• 
If study treatment was held or delayed solely due to a logistical issue 
associated with the COVID-19 pandemic: 
o For oral study treatment CRFs: Indicate “Other” as the 
reason the dosing interval ended and describe the reason in 
the Specify field, including the term “COVID-19”. 
o For IV dosing CRFs:  Enter “Yes” for “Dose delayed from 
prior infusion” and “Reason for dose delay” should be 

 
XL184-312 Protocol Amendment 5.0 
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Case Report Form 
Instructions 
entered as “Other” and describe the reason in the Specify 
field, including the term “COVID-19” (if/when ‘Specify’ 
field is available) 
For example – Other, Specify: “Subject unable to travel due 
to COVID-19 restrictions”