A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination With Nivolumab and Ipilimumab Versus Nivolumab and Ipilimumab in Subjects With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Risk
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Sponsor: Exelixis

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CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 4 of 193 
 
PROTOCOL SYNOPSIS 
TITLE 
A Randomized, Double-Blind, Controlled Phase 3 Study of Cabozantinib in Combination with 
Nivolumab and Ipilimumab versus Nivolumab and Ipilimumab in Subjects with Previously 
Untreated Advanced or Metastatic Renal Cell Carcinoma of Intermediate or Poor Risk 
PROTOCOL NUMBER 
XL184-313 
CLINICAL PHASE 
Phase 3 
RATIONALE 
Multi-targeted tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) 
represent two systemic modalities that have been instrumental in the recent advancements of 
anticancer treatment over the past several years. Both classes of therapies have demonstrated 
broad clinical effects leading to new approved treatment options across multiple tumor types 
including genitourinary cancers. The success of these therapy types as single agents with distinct 
mechanisms of action has led to interest in evaluating combinations of TKIs with ICIs in search 
of further, possibly synergistic, anticancer clinical effects. 
Cabozantinib (XL184) is a potent inhibitor of multiple receptor tyrosine kinases (RTKs) known 
to play important roles in tumor cell proliferation and/or tumor neovascularization including the 
vascular endothelial growth factor receptor (VEGFR), MET, AXL, and RET. Inactivation of the 
von Hippel-Lindau (VHL) tumor suppressor protein in clear cell renal cell carcinoma (RCC) 
results in upregulation of VEGF, MET, and AXL. Increased expression of MET and AXL has 
been associated with poor prognosis in RCC (Gibney et al 2013, Zhou et al 2016, Ciamporcero et 
al 2015). In addition, targets of cabozantinib, including TYRO3, MER, and AXL (TAM family 
kinases), are implicated in promoting suppression of an antitumor immune response. Preclinical 
studies (Kwilas et al 2014, Song et al 2015, 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 which might present an 
opportunity for synergistic effects from combination treatment with ICIs independent of tumor 
programmed death receptor -1 ligand (PD-L1) expression.  
Cabozantinib (60 mg, tablets) has been compared with everolimus in patients with advanced RCC 
who had received prior therapy with at least one VEGFR-TKI in multicenter, randomized, open-
label, controlled Phase 3 study (METEOR; Choueiri et al 2015, Choueiri et al 2016). In this trial, 
658 subjects were randomized to receive cabozantinib (n = 330) or everolimus (n = 328). After a 
minimum follow-up of 11 months in the first 375 randomized subjects, the primary endpoint of 
PFS (by blinded independent radiology committee [BIRC]) was 7.4 months in the cabozantinib 
arm vs 3.8 months in the everolimus arm (hazard ratio [HR] 0.58 [95% confidence interval {CI} 
0.45, 0.75]; p-value < 0.001). Using Memorial Sloan Kettering Cancer Center (MSKCC) criteria, 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 5 of 193 
subgroup analyses of risk groups demonstrated a progression-free survival (PFS) benefit in 
subjects with favorable risk (HR 0.54 [95% CI 0.37, 0.79]), intermediate risk (HR 0.56 [95% CI 
0.37, 0.84]), and poor risk (HR 0.84 [95% CI 0.46, 1.53]). Objective response rate (ORR) per 
BIRC was 17% in the cabozantinib arm vs 3% in the everolimus arm (p-value < 0.001). An 
interim overall survival (OS) analysis at the time of this final PFS analysis demonstrated a trend 
toward longer OS (HR 0.67, p-value = 0.005, with p-value ≤ 0.0019 required for statistical 
significance). A subsequent OS analysis, performed after a median follow-up of approximately 19 
months in all 658 randomized subjects, demonstrated a significant improvement in OS, with 
median OS of 21.4 months in the cabozantinib arm and 16.5 months in the everolimus arm 
(HR 0.66 [95% CI 0.53, 0.83]; p-value = 0.00026). Subgroup analyses of OS according to each 
MSKCC risk group were consistent with the results for the overall population.  
Cabozantinib (60 mg, tablets) has also been compared with sunitinib in previously untreated 
advanced RCC patients in a randomized Phase 2 study (CABOSUN; Choueiri et al [Ann Oncol] 
2017, Choueiri et al [Eur J Cancer] 2018). In this trial, subjects were required to have either 
intermediate or poor risk disease according to International Metastatic RCC Database Consortium 
(IMDC) criteria and were randomized in a 1:1 ratio to receive either cabozantinib (n = 79) or 
sunitinib (n = 78). The primary endpoint in this trial was PFS. Compared with sunitinib, 
cabozantinib treatment significantly increased median PFS per BIRC (8.6 vs 5.3 months) and was 
associated with a 52% reduction in rate of progression or death (HR = 0.48; 95% CI 0.31, 0.74; 
two-sided p-value = 0.0008). The ORR per BIRC was 20% (95% CI 12.0, 30.8) for cabozantinib 
vs 9% (95% CI 3.7, 17.6) for sunitinib. Median OS was 26.6 months for cabozantinib vs 21.2 
months for sunitinib (HR = 0.80; 95% CI 0.53, 1.21) (Choueiri et al [Eur J Cancer] 2018). 
Cabozantinib treatment was associated with OS and PFS benefit in both intermediate and poor 
IMDC risk categories. 
Cabozantinib (60 mg, tablets) is approved in the US for the treatment of patients with advanced 
RCC and in the EU for the treatment of adult patients with advanced RCC after prior 
VEGF-targeted therapy or treatment-naïve adult patients with intermediate or poor risk RCC 
(Cabometyx™ US PI and EMA SmPC). Cabozantinib (60 mg, tablets) is also approved in the US 
and EU for the treatment of patients with hepatocellular carcinoma (HCC) who have been 
previously treated with sorafenib (Cabometyx US PI and EMA SmPC), based on the results of a 
randomized, double-blind, placebo-controlled, multicenter trial showing that treatment with 
cabozantinib was associated with statistically significant improvements in OS, PFS and ORR. 
Cabozantinib (140 mg, capsules) is also approved in the United States and in Europe, for the 
treatment of progressive, metastatic medullary thyroid cancer (MTC; Cometriq™ US PI and 
EMA SmPC). This was based on the results of a multicenter, randomized, double-blind, 
controlled Phase 3 study comparing cabozantinib (140 mg, capsules) with placebo in which 
cabozantinib demonstrated a statistically significant improvement of the primary endpoint of PFS 
(Elisei et al 2013). The capsule and tablet formulations are not bioequivalent or interchangeable. 
Nivolumab is a fully-human monoclonal immunoglobulin G4 (IgG4) kappa antibody specific for 
human programmed death-1 (PD-1) cell surface membrane receptor, a negative regulatory 
molecule expressed transiently following T-cell activation and on chronically stimulated T cells 
characterized by an “exhausted” phenotype. Through the inhibition of the interaction of PD-1 
with its ligands (PD-L1 and PD-L2), nivolumab has demonstrated the ability to generate 
increased anti-tumor immune responses and improvements in survival of cancer patients. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 6 of 193 
Single-agent nivolumab has been approved in multiple cancer types including patients with 
advanced RCC after prior antiangiogenic therapy in the US and in patients with advanced RCC 
after prior therapy in Europe (Opdivo™ US PI and EMA SmPC).  
Ipilimumab is a fully-human monoclonal IgG1kappa antibody that binds to the cytotoxic 
T-lymphocyte associated protein 4 (CTLA-4) antigen expressed on a subset of human T cells. 
The proposed mechanism of action for ipilimumab is interference of the interaction of CTLA-4 
with B7 molecules on antigen presenting cells, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA4/B7 interaction. Single-agent ipilimumab 
is approved in the US and Europe for the treatment of unresectable or metastatic melanoma 
(Yervoy™ US PI, EMA SmPC).  
In a randomized Phase 3 trial (CheckMate 214; Motzer et al 2018), 1096 subjects with previously 
untreated advanced RCC were randomized to receive nivolumab and ipilimumab (nivo+ipi; 
n=550) or sunitinib (n=546). The primary endpoints were OS, PFS per BIRC, and ORR per BIRC 
in the IMDC intermediate- and poor-risk subjects. At a median follow-up of 25.2 months, the 
18-month OS rate was 75% (95% CI 70, 78) with nivo+ipi vs 60% (95% CI 55, 65) with 
sunitinib; the median OS was not reached with nivo+ipi vs 26.0 months with sunitinib (HR = 0.63 
[95% CI 0.44, 0.89]; p-value < 0.001; by interpolation median OS for the nivo+ipi arm is 
estimated to be approximately 41 months). The median PFS by BIRC in the intermediate- and 
poor-risk population was 11.6 months vs 8.4 months (HR 0.82 [95% CI 0.64, 1.05]; 
p-value = 0.03). With extended follow-up in intermediate-risk or poor-risk patients, results for all 
three primary efficacy endpoints now show that nivolumab plus ipilimumab continues to be 
superior to sunitinib (Motzer et al 2019). The ORR in this population was 42% (9% complete 
response [CR]) for the nivo+ipi arm vs 27% (1% CR) for the sunitinib arm. The results from this 
study led to approval in the US and other regions of nivolumab in combination with ipilimumab 
for patients with intermediate or poor risk, previously untreated advanced RCC (Opdivo US 
PI/SmPC and Yervoy US PI/SmPC). Based on 4 years of follow-up, the median OS for the active 
arm (nivolumab plus ipilimumab) in intermediate or poor risk subjects was reported to be 
48.1 months (Albiges et al 2020), approximately 7 months longer than originally projected for the 
control arm in the XL184-313 study. 
Cabozantinib has been evaluated in combination with nivolumab (referred to as doublet) and in 
combination with nivolumab and ipilimumab (referred to as triplet) in an ongoing Phase 1 clinical 
trial in subjects with various pretreated advanced genitourinary cancers (Apolo et al [Ann Oncol] 
2016, Nadal et al 2017, Nadal et al 2018). In the dose escalation stage of the study, no dose 
limiting toxicities (DLTs) were reported for either the doublet or triplet combination. The 
recommended Phase 2 dose (RP2D) for the doublet was cabozantinib 40 mg orally once daily 
(qd) with nivolumab 3 mg/kg administered intravenously (IV) every 2 weeks (q2w) and the 
RP2D for the triplet was cabozantinib 40 mg qd with nivolumab 3 mg/kg IV q3w and ipilimumab 
1 mg/kg IV q3w (maximum 4 doses) followed by nivolumab 3mg/kg IV q2w. Data are available 
for a total of 78 subjects enrolled in this trial, including 14 subjects with RCC. The ORR for 
13 RCC subjects evaluable for response for either the doublet or triplet combination was 54% 
(7 responders of 13 subjects). The remainder of RCC subjects evaluable for response (6 of 13) 
had stable disease (SD) reported as their best response to date. The median PFS in these RCC 
subjects was 18.4 months (95% CI 6.4, 18.4) and the median OS was not reached. Most frequent 
treatment-related Grade 3 or 4 adverse events (AEs) across all genitourinary cancer indications 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 7 of 193 
and dose levels for the triplet therapy (n=29) included hypertension (10%), diarrhea (10%), 
fatigue (7%), anorexia (3%), mucositis (3%), proctitis (3%) and thromboembolic events (3%). 
Two cases of hepatitis (Grade 3 or 4) and one case of immune-related colitis (Grade 3 or 4) were 
reported for the triplet therapy. Grade 3 or 4 laboratory abnormalities reported in subjects treated 
with the triplet therapy across all explored dose levels included hypophosphatemia (n=6), 
increased lipase (n=4), decreased lymphocyte count (n=4), hypokalemia (n=3), alanine 
aminotransferase (ALT) increased (n=3), aspartate aminotransferase (AST) increased (n=3), 
hyponatremia (n=2), amylase increased (n=2), hypocalcemia (n=1), and decreased platelet counts 
(n=1). There were no Grade 5 AEs. Following the encouraging Phase 1 results of the combination 
of cabozantinib and nivolumab, a randomized Phase 3 trial (CheckMate 9ER, NCT03141177) has 
been initiated evaluating the efficacy of cabozantinib in combination with nivolumab versus 
sunitinib in previously untreated advanced or metastatic RCC.   
The recently reported results from the CheckMate 9ER study indicated that cabozantinib in 
combination with nivolumab improved PFS (HR 0.51 [95% CI 0.41, 0.64], P < 0.0001; median, 
16.6 vs 8.3 mo) and OS (HR 0.60 [98.89% CI 0.40, 0.89]; P = 0.0010; medians not reached) 
versus sunitinib (Choueiri et al 2020) in previously untreated advanced renal cell carcinoma. 
These results were consistent across all prespecified IMDC risk and PD-L1 subgroups. 
Furthermore, the ORR (95% CI) was significantly higher with cabozantinib in combination 
with nivolumab compared to sunitinib (55.7% [50.1-61.2] vs 27.1% [22.4-32.3]; P < 0.0001), and 
8.0% versus 4.6% of patients achieved complete response. Median duration of response was 
20.2 months for patients treated with cabozantinib in combination with nivolumab compared to 
11.5 months for patients treated with sunitinib. 
In the Phase 3 CheckMate 214 study, the combination of nivolumab with ipilimumab showed 
efficacy in previously untreated intermediate- and poor-risk RCC subjects (NCT02231749; 
Motzer et al 2018). However, there was only modest clinical benefit for this therapy in the 
subgroup of subjects with low PD-L1 (PD-L1 <1%) which accounts for approximately two thirds 
of this patient population. Patients with low PD-L1 may respond well to VEGF-targeted agents. 
Therefore, combination of nivolumab and ipilimumab with cabozantinib is attractive because of 
the potential for improved clinical outcomes for all subjects irrespective of PD-L1 expression 
(Apolo et al 2014). Further evaluation of cabozantinib in combination with nivolumab and 
ipilimumab in previously untreated RCC patients of intermediate- and poor-risk is warranted. 
The current Phase 3 study evaluates the safety and efficacy of cabozantinib in combination with 
nivolumab and ipilimumab versus nivolumab and ipilimumab in combination with placebo in 
previously untreated subjects with locally advanced or metastatic RCC of intermediate- or poor-
risk (as defined by IMDC criteria). Masking (blinding) oral study medication in the experimental 
and control arm will minimize the potential for bias and help ensure that both study arms are 
treated and assessed similarly throughout the trial.   

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 8 of 193 
OBJECTIVES and ENDPOINTS 
The objective of this study is to evaluate the efficacy and safety of cabozantinib in combination 
with nivolumab and ipilimumab versus nivolumab and ipilimumab in previously untreated 
subjects with intermediate- and poor-risk advanced or metastatic RCC.  
Primary efficacy endpoint: 
• 
Duration of PFS, per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1), by Blinded Independent Radiology Committee (BIRC)  
Secondary efficacy endpoint: 
• 
Duration of OS 
Additional endpoints: 
• 
ORR per RECIST 1.1 by BIRC 
• 
PFS and ORR per RECIST 1.1 by BIRC according to PD-L1 status 
• 
PFS and ORR per RECIST 1.1 as assessed by the Investigator 
• 
Duration of radiographic response as assessed by the Investigator and by BIRC   
• 
Safety through the evaluation of AEs, including immune-related AEs (irAEs), and other 
safety assessments.  
• 
Pharmacokinetics (PK) of cabozantinib given in combination with nivolumab and ipilimumab 
• 
Immunogenicity of nivolumab and ipilimumab given in combination with cabozantinib  
• 
Correlation of biomarker analyses with clinical outcomes 
• 
Health-related quality of life (HRQoL) as assessed by the EuroQol Health questionnaire 
instruments (EQ-5D-5L)   
• 
Health care resource utilization 
STUDY DESIGN 
This is a multicenter, randomized, double-blinded, controlled Phase 3 trial of cabozantinib in 
combination with nivolumab and ipilimumab versus nivolumab and ipilimumab in combination 
with matched placebo.  
Approximately 840 eligible subjects with intermediate- or poor-risk advanced or metastatic RCC 
by IMDC criteria will be randomized in a 1:1 ratio at approximately 180 sites. The study was 
originally designed to enroll 676 subjects; the sample size was increased to accommodate new, 
external data about the expected median OS in the control arm (see Section 9.5). 
Special accommodations during the global COVID-19 pandemic are described in Appendix K. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 9 of 193 
Pre-Treatment Period: Potential subjects will be screened to determine whether they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 28 days 
before randomization unless otherwise specified.   
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in a 
1:1 fashion to receive double-blinded study treatment as follows:  
Experimental arm:  
Cabozantinib (40 mg oral, once daily [qd]) + nivolumab (3 mg/kg infusion, once every 3 weeks 
[q3w]) x 4 doses + ipilimumab (1 mg/kg infusion, q3w) x 4 doses, 
followed by cabozantinib (40 mg oral qd) + nivolumab infusion (480 mg flat dose q4w). 
Nivolumab will be administered for a maximum of 2 years. 
Control arm:  
Cabozantinib-matched placebo (oral, qd) + nivolumab (3 mg/kg infusion, q3w) x 4 doses + 
ipilimumab (1 mg/kg infusion, q3w) x 4 doses, 
followed by cabozantinib-matched placebo (oral, qd) + nivolumab infusion (480 mg flat dose 
q4w). Nivolumab will be administered for a maximum of 2 years.  
Randomization will be stratified by the following factors established at screening: 
• 
IMDC prognostic score (1-2 risk factors [intermediate] vs 3-6 risk factors [poor]) 
• 
Region ([US or Canada or Europe or Australia or New Zealand] vs [Latin America or Asia]) 
The IMDC risk factors (Heng et al 2009) are the following:   
• 
Karnofsky performance status (KPS) < 80% 
• 
Less than 1 year from initial RCC diagnosis (including original localized disease if 
applicable) to systemic treatment  
• 
Hemoglobin < lower limit of normal (LLN) 
• 
Corrected calcium > 10 mg/dL 
• 
Absolute neutrophil count (ANC) > upper limit of normal (ULN) 
• 
Platelet count > ULN 
 
Subjects will receive study treatment (see Investigational Regimen below) 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 anti-cancer treatment, or any other 
reasons for treatment discontinuation listed in the protocol. 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 (Section 5.7.6.2).  
Crossover between treatment arms will not be allowed. 
Transition to Unblinded Treatment: The study may transition to unblinded treatment at the 
discretion of the Sponsor and upon any necessary discussions with regulatory authorities after 
analyses of PFS and OS have been performed. If the study is declared futile or the null hypothesis 
for the primary endpoint of PFS is not rejected (negative study), the study will be unblinded and 
investigators and subjects will be notified. If the null hypothesis for the primary endpoint of PFS 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 10 of 193 
is rejected (positive study), the study will not be unblinded until the null hypothesis for the 
secondary endpoint of OS is rejected or the final analysis of OS is performed.  
Once the study transitions to unblinded treatment, investigators and subjects will be notified of 
the randomized treatment assignment to allow for appropriate treatment decisions. Protocol 
procedures and assessments will continue without change. 
Post-Treatment Period: Subjects who discontinue from study treatment (including subjects in the 
Maintenance Phase [below]) will return to the site for two follow-up visits for safety assessments. 
The first Post-Treatment Follow-up Visit (FU-1) for safety evaluation 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 follow-up visit (FU-2) for safety evaluation will be conducted 
approximately 100 (±14) days after the date of the decision to permanently discontinue study 
treatment.  
Radiographic tumor assessments and health-related quality of life (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. Consequently, these 
assessments may be required in the Post-Treatment Period for some subjects.  
In addition, subjects are to be contacted every 12 weeks (± 14 days) after the 100-day FU-2 visit 
to assess survival status and document receipt of systemic non-protocol anti-cancer therapy 
(NPACT). This will continue until the subject expires or the Sponsor decides to discontinue 
collection of these data. Further, coinciding with each analysis of OS, sites will be required to 
determine the survival status for all subjects not known to be deceased as of the data cutoff date 
for the analysis. This will require additional subject contacts outside the 12-week schedule. Every 
effort must be made to collect this protocol-specific information unless consent for non-
interventional study assessments is withdrawn. Assessments of OS/NPACT are not required in 
the Maintenance Phase (below). 
Study Completion:  The study will be considered complete if any of the following criteria apply: 
• 
futility analysis of PFS: the trial has been declared futile by the Sponsor, or 
• 
primary analysis of PFS: null hypothesis is not rejected, or  
• 
primary analysis of PFS: null hypothesis is rejected for PFS and the null hypothesis is 
rejected for OS (or the final planned analysis for OS has been conducted) 
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, and after 
treatment assignment has been unblinded, the Sponsor may initiate a 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 have been completed. 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). 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 11 of 193 
In the Maintenance Phase, subjects on active study treatment will continue to receive study 
treatment until they meet the protocol-required criteria for treatment discontinuation. Subjects in 
the Maintenance Phase 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 as necessary. 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 AESIs [whether serious 
or not], and AEs leading to dose modifications or treatment discontinuation); and other reportable 
events (drug-induced liver injury [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 840 eligible subjects will be randomized 1:1 to receive cabozantinib in 
combination with nivolumab and ipilimumab or nivolumab and ipilimumab in combination with 
placebo (420 per arm). 
The study was originally designed to enroll 676 subjects; the sample size was increased to 
accommodate new, external data about the expected median OS in the control arm (see 
Section 9.5). 
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. Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or 
metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell component, including 
subjects who also have a sarcomatoid feature. 
2. Intermediate- or poor-risk RCC as defined by IMDC criteria (Section 3.4). 
3. Measurable disease per RECIST 1.1 as determined by the Investigator. Measurable disease 
must be outside the radiation field if radiation therapy was previously administered. 
4. Shipment of archival tumor tissue (unstained slides or paraffin block) to the study central 
laboratory prior to randomization. The tumor tissue can be obtained from any organ except 
brain or bone and must have been biopsied no more than 2 years prior to the date of informed 

 
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consent. Alternatively, a fresh tumor sample must be obtained and shipped to the study 
central laboratory prior to randomization if archival tumor tissue is unavailable or inadequate.  
5. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, 
unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Examples of 
exceptions are subjects with Grade 2 neuropathy or alopecia who are allowed for trial 
participation. 
6. Age eighteen years or meeting country definition of adult, whichever is older, on the day of 
consent. 
7. Karnofsky Performance Status (KPS) ≥ 70%.   
8. 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 GI/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection.   
b. Criterion intentionally left blank. 
c. Platelets ≥ 100,000/µL (≥ 100 GI/L) without transfusion within 2 weeks before screening 
laboratory sample collection.  
d. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) without transfusion within 1 week before screening 
laboratory sample collection and no clinical evidence of bleeding.  
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3  ULN.   
f. Total bilirubin ≤ 1.5  ULN (with the exception that total bilirubin for subjects with 
Gilbert’s disease ≤ 3  ULN). 
g. Serum creatinine ≤ 1.5  ULN or calculated creatinine clearance ≥ 40 mL/min (≥ 0.67 
mL/sec) using the Cockcroft-Gault equation (see Table 5-3 for Cockcroft-Gault formula). 
h. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine 
protein ≤ 1 g. 
9. Capable of understanding and complying with the protocol requirements and must have 
signed the informed consent document prior to any screening assessments except those 
procedures performed as standard of care within the screening window. 
10. Sexually active fertile subjects and their partners must agree to use highly effective methods 
of contraception (defined in Appendix D) during the course of the study and for 5 months for 
women, and 7 months for men, after the last dose of study treatment. A barrier contraceptive 
method (eg, condom) is also required. 
 
11. 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 are 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) 

 
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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. Prior systemic anticancer therapy for unresectable locally advanced or metastatic RCC 
including investigational agents. 
Note: One prior systemic adjuvant therapy is allowed for completely resected RCC and if 
recurrence occurred at least 6 months after the last dose of adjuvant therapy. 
Note: Adjuvant therapy with a PD-1 or PD-L1 inhibitor in combination with a CTLA-4 
inhibitor is not permitted. 
2. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 
4 weeks prior to randomization. Subjects with clinically relevant ongoing complications from 
prior radiation therapy are not eligible.  
3. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or radiosurgery and stable for at least 4 weeks prior to randomization after 
radiotherapy, or at least 4 weeks prior to randomization after major surgery (eg, removal or 
biopsy of brain metastasis). Subjects who are neurologically symptomatic as a result of their 
CNS disease, or are receiving systemic corticosteroid treatment (prednisone equivalent 
> 10 mg/day) at the planned time of randomization are not eligible.  
4. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).  
a. Allowed anticoagulants are: 
i. 
Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose 
low molecular weight heparins (LMWH)  
ii. 
Therapeutic doses of LMWH in subjects without known brain metastases who are on 
a stable dose of LMWH for at least 1 week before randomization without clinically 
significant hemorrhagic complications from the anticoagulation regimen or the tumor 
Note: Subjects who switch from an oral anticoagulant to LMWH are allowed if the oral 
anticoagulant was stopped ≥ 5 half-lives of the oral anticoagulant prior to planned 
randomization date. 
5. Administration of a live, attenuated vaccine within 30 days prior to randomization. The use of 
inactivated (killed) vaccines for the prevention of infectious disease is permitted. 

 
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6. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
a. Cardiovascular disorders: 
i. 
Congestive heart failure (CHF) class III or IV as defined by the New York Heart 
Association, unstable angina pectoris, serious cardiac arrhythmias (eg, ventricular 
flutter, ventricular fibrillation, Torsades de pointes).  
ii. 
Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg 
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. 
iii. 
Stroke, transient ischemic attack (TIA), myocardial infarction, or other symptomatic 
ischemic event or thromboembolic event (eg, deep venous thrombosis, pulmonary 
embolism [DVT/PE]) within 6 months before randomization.  
Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic 
and stable at screening and treated with LMWH for at least 1 week before 
randomization. 
Note: Non-symptomatic white matter disease in the brain is acceptable. 
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. 
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 pulmonary blood vessels. 
f. Other clinically significant disorders such as: 
i. 
Autoimmune disease that has been symptomatic or required treatment within the past 
two years from the date of randomization.  
 
Note: Patients with a history of Crohn’s disease or ulcerative colitis are always 
excluded. 
Note: Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 

 
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ii. 
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization.  
Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. Adrenal 
replacement steroid doses > 10 mg daily prednisone equivalent are permitted. 
Transient short-term use of systemic corticosteroids for allergic conditions (eg, 
contrast allergy) is also allowed. 
iii. 
Active infection requiring systemic treatment. Acute or chronic hepatitis B or C 
infection, known human immunodeficiency virus (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness, or known positive test for 
tuberculosis infection where there is clinical or radiographic evidence of active 
mycobacterial infection. 
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. 
Uncompensated/symptomatic hypothyroidism. 
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 or allogeneic stem cell transplant. 
xi. 
Known history of COVID-19 unless the subject has clinically recovered from the 
disease at least 30 days prior to randomization. 
7. Major surgery (eg, nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 4 
weeks prior to randomization. Minor surgeries within 10 days prior to randomization. 
Subjects must have complete wound healing from major or minor surgery before 
randomization. Subjects with clinically relevant ongoing complications from prior surgery are 
not eligible. 
8. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 14 days before randomization. Furthermore, subjects with a 
history of additional risk factors for torsades de pointes (eg, long QT syndrome) are also 
excluded. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs 
at intervals of approximately 3 min must be performed within 30 min after the initial ECG, 
and the average of these three consecutive results for QTcF will be used to 
determine eligibility.  
9. History of neuropsychiatric disorder likely to interfere with ability to comply with protocol 
requirements or give informed consent. 
10. Pregnant or breastfeeding females. 

 
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11. Inability to swallow tablets or unwillingness or inability to receive IV administration. 
12. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe infusion-related reactions to monoclonal antibodies. 
Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency 
or glucose-galactose malabsorption are also excluded. 
13. Any other active malignancy at time of randomization or diagnosis of another malignancy 
within 3 years prior to randomization that requires active treatment, except for locally curable 
cancers that have been apparently cured, such as basal or squamous cell skin cancer, 
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.  
 
ESTIMATED LENGTH OF SUBJECT PARTICIPATION 
It is estimated that subjects will participate for an average of approximately 12-18 months on 
study treatment. Subjects will be followed until death, withdrawal of consent, or Sponsor decision 
to no longer collect survival data. 
ESTIMATED STUDY DATES 
It is estimated that 21 months will be required to randomize 840 subjects. The number of events 
required for the primary analyses of PFS (249 events among the first 440 randomized subjects) is 
expected to be observed approximately 23 months after the first subject is randomized. The 
number of events required for the final analysis for the secondary endpoint of OS (433 events 
among 840 subjects) is expected to be observed approximately 69 months after the first subject is 
randomized. 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. The estimates for the timing of event-driven analyses do not include 
the additional months required for event ascertainment, data quality review, data analysis and 
interpretation.  
INVESTIGATIONAL REGIMEN DOSE / ROUTE / DURATION 
The first four doses of nivolumab will be administered once every 3 weeks (q3w) at 3 mg/kg over 
a period of 30 minutes, followed by ipilimumab at 1 mg/kg over a period of 30 minutes. After the 
first four doses are completed, no further ipilimumab will be given and nivolumab will be 
administered at a flat dose of 480 mg as an IV infusion over 30 min every 4 weeks (q4w). In this 
study, treatment with nivolumab will be given for a maximum of 2 years from the start of study 
treatment. 
Subjects will also take blinded oral study medication (2 tablets containing 20 mg each of 
cabozantinib or placebo equivalent) once daily (qd). The subject will be fasted (with the 
exception of water) for at least 2 hours before receiving cabozantinib/placebo. Upon completion 
of the 2-hour fast, the subject will receive the oral dose of cabozantinib/placebo with a minimum 
of 8 oz (240 mL) of water and then the subject will continue to fast for 1 hour. 
Two dose reduction levels of the oral study medication (cabozantinib or placebo equivalent) will 
be allowed (20 mg qd and 20 mg every other day [qod]). Dose reductions for nivolumab and 
ipilimumab will not be allowed and AEs will be managed by dose delays.   

 
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Subjects will continue study treatment as long as they continue to experience clinical benefit in 
the opinion of the Investigator or until unacceptable toxicity, the need for alternative systemic 
anticancer treatment, or other reasons for treatment discontinuation.  
Nivolumab, ipilimumab, and cabozantinib/matched placebo will be supplied by the Sponsor. 
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. 
Radiographic assessments per RECIST 1.1 by the Investigator will be used for treatment 
decisions. Overall survival will be assessed at scheduled visits and every 12 weeks (± 14 days) 
after the FU-2 visit. 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 
Chest / Abdomen / Pelvis (CAP): Computed tomography (CT) of CAP or CT chest and magnetic 
resonance imaging (MRI) abdomen/pelvis will be performed in all subjects at screening (prior to 
randomization). The first tumor assessment after randomization should be performed at W10D1 
(± 7 days). Subsequent tumor assessments should be performed every 8 weeks (± 7 days) through 
Week 50. Upon completion of 50 weeks of radiographic assessment, these assessments will be 
performed every 12 weeks (± 7 days). Additional imaging of potential disease sites should be 
performed whenever radiographic disease progression (PD) is suspected. 
Brain: MRI (or CT) of the brain will be performed in all subjects at screening. After 
randomization, MRI (or CT) scans of the brain are only required in subjects with known brain 
metastasis (or if clinically indicated) following the same post-baseline frequency as the imaging 
for CAP. MRI is the preferred method for brain. If CT of the brain is performed instead of MRI, 
ambiguous results must be confirmed by MRI unless MRI is contraindicated. (Note: in order to 
meet the eligibility requirements of the study, brain metastasis must have been treated and stable 
for at least 4 weeks before randomization after radiotherapy or major surgery [eg, removal or 
biopsy of brain metastasis].) 
Bone scans: Technetium bone scans (TBS) should be performed at screening for all subjects. 
After randomization, bone scans will be performed in subjects with known bone metastases and 
otherwise as clinically indicated per standard of care. Any soft tissue lesions associated with 
identified bone lesions must be imaged by CT/MRI and assessed in alignment with the CAP 
assessments. Bone scan findings alone cannot be used for the determination of progression or 
response and need to be corroborated by CT or MRI, which will be used as the basis for RECIST 
evaluations. 
Tumor assessments should continue on the protocol-defined schedule, relative to the date of 
randomization, regardless of whether study treatment is given, reduced, held or discontinued. The 
same imaging modalities used at screening will be used for subsequent tumor assessments after 
randomization. 
Radiographic response and PD 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 

 
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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. 
Radiographic tumor assessments are to continue until the following criteria are met: 
• 
For subjects who discontinue study treatment upon determination of Investigator-assessed 
radiographic PD per RECIST 1.1, tumor assessments may cease. 
• 
For subjects who discontinue study treatment before Investigator-assessed radiographic PD, 
tumor assessments are to continue per the protocol-defined schedule until Investigator-
assessed radiographic PD per RECIST 1.1.  
• 
For subjects who continue to receive study treatment after Investigator-assessed 
radiographic PD 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. 
 
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 promptly sent 
to the BIRC, which also will review prior radiation history data for the purpose of selection of 
target lesions. 
OVERALL SURVIVAL FOLLOW-UP ASSESSMENTS 
Overall survival (OS) will be assessed every 12 weeks (± 14 days) after the FU-2 visit, which 
occurs 100 (±14) days after the date of the decision to discontinue study treatment. Subjects will 
be followed until death or Sponsor decision to no longer collect these data. Receipt of systemic 
NPACT will also be collected during follow-up contacts. If a subject withdraws consent for non-
interventional study assessments, information regarding survival status may be obtained from 
public records such as government vital statistics or obituaries, as permitted by local regulations.  
SAFETY ASSESSMENTS 
Routine laboratory safety evaluations will be performed on the date of the first dose (W1D1) and 
every 3 weeks on nivolumab/ipilimumab dosing days (W4D1, W7D1, W10D1), and then every 
4 weeks thereafter (W14D1, W18D1, W22D1 etc). Additional laboratory assessments (serum 
chemistry, hematology and urinalysis only) will be performed at W3D1, W6D1, W9D1, and 
W12D1. Routine safety follow-up visits will be performed 30 (+14) days (FU-1 visit) after the 
date of the decision to permanently discontinue study treatment.  
Monitoring will continue for unrelated SAEs (Table 8-1) through the 100 (± 14) day (FU-2) visit 
after the date of decision to permanently discontinue study treatment. Related AEs leading to 
study treatment discontinuation, AESIs, and related SAEs will continue to be followed until 
resolution (event is fully resolved, ≤ Grade 2 severity, or is deemed stable/irreversible by the 
Investigator). Further details on AE follow up and data collection requirements are available in 
Appendix H. 

 
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Safety assessments will include physical examination, vital signs, performance status, 12-lead 
ECG, hematology, serum chemistry, coagulation tests, urine tests (including UPCR), 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, immune-
related AEs [irAEs]) will be assessed by the Investigator. Severity grade will be defined by the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 5 
(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. 
Special accommodations during the global COVID-19 pandemic are described in Appendix K. 
PHARMACOKINETIC ASSESSMENTS 
Blood samples will be obtained from all subjects in both study arms. Samples will be collected 
for plasma cabozantinib concentration measurement predose on Week 1, Day 1 (W1D1), W4D1, 
W7D1, W10D1, and W14D1. 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.  
Serum concentrations of nivolumab and ipilimumab will be measured. Samples will be collected 
for serum nivolumab and ipilimumab concentration measurement predose on W1D1, W4D1, 
W7D1, W10D1, W14D1, W26D1, and FU-1 and FU-2 visits. The results will be used to confirm 
exposure to nivolumab and ipilimumab.  
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 both study arms for immunogenicity 
assessment (anti-drug antibodies [ADA] for nivolumab and ipilimumab) predose on W1D1, 
W14D1, W26D1, and FU-1 and FU-2 visits. Samples will be analyzed for neutralizing ADA 
response to nivolumab and/or ipilimumab if ADA testing is positive. 
BIOMARKER ASSESSMENTS 
Peripheral blood and tumor tissue will be collected and may be assessed for exploratory 
biomarker analyses. Tumor tissue (fresh, or archival [ie, within 2 years prior to the date of 
informed consent]) will be obtained once consent is provided and shipped to central laboratory for 
analysis. PD-L1 expression by IHC of tumor will be determined.   
For assessment of PD-L1 expression, evaluation of at least 100 viable tumor cells is required. 
Positive staining is defined as ≥ 1% and negative staining is defined as < 1% of cells that exhibit 
circumferential and/or partial linear plasma membrane staining at any intensity. High cytoplasmic 
staining can interfere with membrane scoring and will define as “indeterminate”. Additionally, 
failure of PD-L1 staining due to suboptimal tissue sample integrity or assay failure will also be 
defined as “indeterminate”. 

 
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Peripheral blood samples will be obtained pre-dose and on days as specified in the Schedule of 
Assessments. Optional tumor biopsies may be collected approximately 6 weeks after the first 
dose of study treatment.  
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  
• 
T-cell infiltration and tumor gene expression (ie, mutational load assessment) in tumor 
specimens for association with clinical outcome 
• 
Circulating immune cells in peripheral blood (ie, lymphocyte subset analyses by flow 
cytometry) 
• 
Plasma biomarkers (ie, cytokines/chemokines, VEGF, metabolome) 
• 
Tumor whole-genome sequencing and gene expression analysis 
• 
Cell and/or pharmacogenomic analyses (ie circulating tumor DNA [ctDNA]) 
Collection of biomarker samples (with the exception of PD-L1 assessments) may be halted early 
or sampling frequency may be reduced at the discretion of the Sponsor. 
HEALTH-RELATED QUALITY OF LIFE (HRQOL) 
Subjects will be requested to complete the EuroQol Health questionnaire instruments EQ-5D-5L 
during screening and every 3 weeks after randomization until W10D1 and every 4 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 endpoint. Subjects are to complete the questionnaires 
prior to each clinic visit. HRQOL assessments will no longer be collected for subjects if the study 
transitions to the Maintenance Phase. 
HEALTH CARE RESOURCE UTILIZATION 
Health care resource utilization parameters will be collected from randomization through the 
FU-2 visit. 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 endpoint in this study is BIRC-determined PFS. Treatment with 
cabozantinib in combination with nivolumab and ipilimumab will be inferred to be superior to 
treatment with nivolumab and ipilimumab if the null hypothesis of no difference between arms in 
duration of PFS is rejected.  
In the primary analysis, PFS is defined as the time from randomization to the earlier of either 
radiographic PD per RECIST 1.1 as determined by the BIRC or death from any cause.  
The study is designed to provide adequate power for both PFS (primary endpoint) and OS 
(secondary endpoint). A larger sample size is needed to provide reasonable power to evaluate OS 

 
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than for PFS. Thus, to allow longer, more robust PFS follow up among a fewer number of 
subjects and to avoid biasing the events included in the PFS analysis towards shorter event times, 
the study will employ a “trial within a trial” design (Hessel et al 2016); the event-driven primary 
analysis of PFS will be conducted after at least 249 PFS events have been observed among the 
first 440 randomized patients, defined as the PFS Intent-to-Treat (PITT) population. This will 
provide the study with 90% power  to reject the null hypothesis of no difference in PFS using a 2-
sided log-rank test with a 5% level of significance assuming a true HR of 0.66. Assuming an 
exponential distribution of PFS, this corresponds with a 52% increase in median PFS from 11.6 
months to 17.6 months. In the current design, the minimum observed effect that would result in 
statistical significance for PFS is an HR of 0.78, a 28% improvement in median PFS from 11.6 to 
14.9 months. 
For the secondary endpoint of improving duration of OS, the trial was originally designed as 
follows: a total of 342 events among 676 randomized subjects (the ITT population) are required 
to provide 90% power to reject the null hypothesis of no difference in OS using the log-rank test 
at the 2-sided significance level of 5%, 3 planned interim analyses (see Section 9.6), and 
assuming a true HR of 0.70 . Assuming an exponential distribution for OS, this corresponds to a 
43% increase in median survival from 41 months to 58.6 months. Under this design the minimum 
observed effect that would result in statistical significance for OS is an HR of 0.80, a 25% 
improvement in median from 41 to 51.1 months; a minimum observed difference in medians of 
approximately 10 months. 
In response to new data supporting a median OS in the control arm of 48 months instead of the 
previously assumed 41 months (Albiges et al 2020), the study has been modified as follows: a 
total of 433 events among 840 randomized subjects (the ITT population) are required to provide 
90% power to reject the null hypothesis of no difference in OS using the log-rank test at a 2-sided 
significance level of 5%, 3 planned interim analyses (see Section 9.6), and assuming a true HR of 
0.73. Assuming an exponential distribution for OS, this corresponds to a 37% increase in median 
survival from 48 months to 65.8 months. Under this design the minimum observed effect that 
would result in statistical significance for OS is an HR of 0.824, a 21% improvement in median 
from 48 to 58.25 months; a minimum observed difference in medians of approximately 
10 months. 
This increase in sample size does not inflate Type 1 error because (a) it was done solely in 
response to new external data about the expected median OS of the control arm, and (b) the 
control arm median is a nuisance parameter with respect to the minimum observed difference in 
medians that results in rejection of the null hypothesis. This change ensures the trial retains the 
ability to reject the null hypothesis for OS if the observed difference in medians is approximately 
10 months. 
Inflation of Type 1 error associated with testing multiple endpoints (primary and secondary) will 
be controlled by applying a hierarchical testing procedure: OS will be tested only if the null 
hypothesis of no difference between arms in PFS is rejected. Three interim analyses of OS are 
planned and will include the entire ITT population available at the time of each analysis. The 
first, conducted at the time of the primary PFS analysis (if the null hypothesis for PFS is 
rejected), is anticipated to include 27% of the total deaths necessary for the primary analysis of 
OS (ie, 27% information fraction). This is intended primarily as an administrative analysis to 
provide a qualitative evaluation of OS at the time of the primary PFS analysis. Subsequent 

 
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interim analyses of OS are planned at the 50% and 75% information fractions. Inflation of Type 1 
error associated with these interim analyses will be controlled using a Lan-DeMets 
O’Brien-Fleming alpha-spending function.  
To help limit exposure to the experimental regimen should interim data suggest it is unlikely to 
demonstrate superior efficacy, a non-binding futility analyses of PFS per BIRC is planned to be 
performed at the 40% information fraction for PFS. Further details are provided in Section 9.6. 
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. Primary stratification analyses will 
be based on the stratification factors used for the randomization as recorded in the interactive 
response technologies (IRT) system.   
With an assumed constant accrual rate of 40 subjects per month, a 1:1 treatment allocation ratio, 
and 3 interim analyses of OS, a total of 840 subjects (420 per treatment arm) are required to 
observe the required number of events within the planned study duration: approximately 
21 months accrual; approximately 23 months after first subject randomized to observe the 
required PFS events among the first 440 subjects and approximately 69 months after first subject 
randomized to observe the required deaths for OS among 840 subjects. 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.  
The PITT population may be expanded by 25% from the first 440 to the first 550 randomized if a 
review of accumulating PFS events suggests that the 249 events required for the analysis will not 
be reached due to censoring caused by a higher than expected study drop-out or non-compliance 
stemming from the COVID-19 pandemic.  
Study Completion:  
The study will be considered complete if any of the following criteria apply: 
- 
futility analysis of PFS: the trial has been declared futile by the Sponsor, or  
- 
primary analysis of PFS: null hypothesis is not rejected, or  
- 
primary analysis of PFS: null hypothesis is rejected for PFS and the null hypothesis is 
rejected for OS (or the final planned analysis for OS has been conducted). 
 
 

 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.....................................................................................................4 
LIST OF ABBREVIATIONS ............................................................................................28 
1 
BACKGROUND ......................................................................................................32 
1.1 
Renal Cell Carcinoma ......................................................................................32 
1.2 
Cabozantinib ....................................................................................................33 
1.3 
Nivolumab........................................................................................................35 
1.4 
Ipilimumab .......................................................................................................35 
1.5 
Combination Therapy of Nivolumab and Ipilimumab .....................................36 
1.6 
Combination Therapy of Cabozantinib with Nivolumab or Cabozantinib with 
Nivolumab and Ipilimumab .............................................................................37 
1.7 
Rationale ..........................................................................................................40 
1.7.1 
Rationale for Evaluating Cabozantinib in Combination with 
Nivolumab and Ipilimumab in IMDC Intermediate- and Poor-Risk 
RCC......................................................................................................40 
1.7.2 
Rationale for Study Design ..................................................................41 
1.7.3 
Rationale for Study Treatment Dose Selection and Treatment Schedule42 
1.8 
Overall Risk Benefit Assessment .....................................................................43 
1.8.1 
Summary of Benefits and Risks ...........................................................45 
1.9 
Study Conduct ..................................................................................................45 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................45 
2.1 
Objectives ........................................................................................................45 
2.2 
Endpoints .........................................................................................................46 
3 
STUDY DESIGN......................................................................................................47 
3.1 
Study Sites .......................................................................................................47 
3.2 
Estimated Study Dates and Duration of Subject Participation ........................47 
3.3 
Overview of Study Design ...............................................................................47 
3.4 
Treatment Groups and Randomization ............................................................51 
3.5 
Study Blinding .................................................................................................52 
3.5.1 
Blinding of Study Treatments ..............................................................52 
3.5.2 
Unblinding Procedure for Individual Subjects ....................................52 
3.6 
Treatment Discontinuation and Study Withdrawals ........................................53 
3.6.1 
Treatment Discontinuation ...................................................................53 
3.6.2 
Study Withdrawal ................................................................................55 
3.6.3 
Study Completion ................................................................................55 
3.6.4 
End of Trial ..........................................................................................55 

 
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4 
STUDY POPULATION ...........................................................................................56 
4.1 
Target Population .............................................................................................56 
4.2 
Inclusion Criteria .............................................................................................56 
4.3 
Exclusion Criteria ............................................................................................57 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................61 
5.1 
Pre-Treatment Period .......................................................................................61 
5.2 
Treatment Period ..............................................................................................62 
5.3 
Transition to Unblinded Treatment ..................................................................63 
5.4 
Post-Treatment Period .....................................................................................63 
5.5 
Maintenance Phase/Treatment After Study Completion .................................64 
5.6 
Unscheduled Visits or Assessments .................................................................65 
5.7 
Procedure details ..............................................................................................66 
5.7.1 
Demographics, Baseline Characteristics, Medical and Cancer History66 
5.7.2 
Physical Examination...........................................................................67 
5.7.3 
Vital Signs ............................................................................................67 
5.7.4 
Electrocardiograms ..............................................................................67 
5.7.5 
Safety Laboratory Assessments ...........................................................68 
5.7.6 
Tumor Assessments .............................................................................71 
5.7.7 
Health-related Quality of Life Assessments ........................................74 
5.7.8 
Health Care Resource Utilization ........................................................75 
5.7.9 
Pharmacokinetic Assessments .............................................................75 
5.7.10 
Immunogenicity Assessments ..............................................................76 
5.7.11 
Biomarker Assessments .......................................................................76 
5.7.12 
Overall Survival ...................................................................................78 
5.8 
Protocol Deviations ..........................................................................................78 
6 
TREATMENTS ........................................................................................................78 
6.1 
Composition, Formulation, and Storage ..........................................................78 
6.1.1 
Study Treatment: Cabozantinib in Combination with Nivolumab and 
Ipilimumab or Nivolumab and Ipilimumab .........................................79 
6.2 
Study Treatment Schedule of Administration ..................................................80 
6.2.1 
Study Treatment Administration on Week 1 Day 1 (W1D1) ..............81 
6.2.2 
Cabozantinib/Placebo Administration outside the Clinic ....................82 
6.3 
Treatment After Study Completion .................................................................83 
6.4 
Compliance ......................................................................................................83 
6.5 
Study Treatment Accountability ......................................................................84 
6.6 
Safety Considerations ......................................................................................84 
6.6.1 
Management of Hepatocellular Toxicity Associated with 
Cabozantinib/Placebo and Nivolumab/Ipilimumab .............................85 

 
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6.6.2 
Management of AEs Associated with Cabozantinib/Placebo ..............88 
6.6.3 
Management of AEs Associated with Nivolumab and Ipilimumab ..102 
7 
CONCOMITANT MEDICATIONS AND THERAPIES ......................................111 
7.1 
Allowed Therapy ...........................................................................................111 
7.2 
Prohibited or Restricted Therapy ...................................................................113 
7.3 
Potential Drug Interactions ............................................................................114 
7.3.1 
Potential Drug Interactions with Cabozantinib ..................................114 
7.3.2 
Potential Drug Interactions with Nivolumab and Ipilimumab ...........116 
8 
SAFETY .................................................................................................................116 
8.1 
Adverse Events and Laboratory Abnormalities .............................................116 
8.1.1 
Adverse Events ..................................................................................116 
8.1.2 
Laboratory Abnormalities ..................................................................117 
8.2 
Serious Adverse Events .................................................................................118 
8.2.1 
Definitions..........................................................................................118 
8.2.2 
Regulatory Reporting .........................................................................120 
8.3 
Adverse Events of Special Interest ................................................................121 
8.3.1 
General Information on Immune-Related Adverse Events ................122 
8.4 
Follow-Up of Adverse Events .......................................................................123 
8.5 
Other Safety Considerations ..........................................................................124 
8.5.1 
Pregnancy ...........................................................................................124 
8.5.2 
Medication Errors/Overdose ..............................................................124 
9 
STATISTICAL CONSIDERATIONS....................................................................125 
9.1 
Analysis Populations ......................................................................................125 
9.1.1 
Intention-to-Treat Population.............................................................125 
9.1.2 
PFS Intention-to-Treat Population .....................................................125 
9.1.3 
Safety Population ...............................................................................125 
9.2 
Study Endpoints .............................................................................................125 
9.2.1 
Definitions..........................................................................................125 
9.2.2 
Primary Efficacy Endpoint ................................................................126 
9.2.3 
Secondary Efficacy Endpoint ............................................................127 
9.2.4 
Additional Endpoints .........................................................................127 
9.3 
Control of Type I Error ..................................................................................128 
9.4 
Safety Analyses ..............................................................................................128 
9.4.1 
Adverse Events ..................................................................................128 
9.4.2 
Laboratory Test Results .....................................................................129 
9.4.3 
Other Safety Endpoints ......................................................................129 
9.5 
Power and Sample Size ..................................................................................129 
9.6 
Interim Analyses ............................................................................................131 

 
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10 
OTHER ANALYSES .............................................................................................132 
10.1 
Pharmacokinetic Analyses .............................................................................132 
10.2 
Immunogenicity Analyses .............................................................................133 
10.3 
Biomarker Analyses .......................................................................................133 
11 
DATA QUALITY ASSURANCE ..........................................................................134 
12 
STUDY COMMITTEES ........................................................................................134 
12.1 
Executive Safety Committee (ESC) ...............................................................134 
12.2 
Independent Data Monitoring Committee (IDMC) .......................................134 
12.3 
Blinded Independent Radiology Committee (BIRC) .....................................135 
12.4 
Clinical Steering Committee (CSC) ...............................................................136 
13 
ETHICAL ASPECTS .............................................................................................136 
13.1 
Local Regulations ..........................................................................................136 
13.2 
Informed Consent...........................................................................................136 
13.3 
Institutional Review Board/ Ethics Committee .............................................137 
13.4 
Disposition of Subject Samples .....................................................................137 
14 
CONDITIONS FOR MODIFYING THE PROTOCOL.........................................137 
15 
CONDITIONS FOR TERMINATING THE STUDY ...........................................137 
16 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORD 
KEEPING ...............................................................................................................138 
16.1 
Investigator’s Files and Retention of Documents ..........................................138 
16.2 
Source Documents and Background Data .....................................................139 
16.3 
Audits and Inspections ...................................................................................139 
16.4 
Case Report Forms .........................................................................................139 
17 
MONITORING THE STUDY ................................................................................140 
18 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS .141 
19 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS..........141 
20 
COMPLIANCE WITH DATA PROTECTION LAWS .........................................142 
21 
REFERENCES .......................................................................................................143 
APPENDICES .................................................................................................................149 
 
 
 

 
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LIST OF TABLES 
 
Table 5-1:  
IMDC Prognostic Score ............................................................................ 66 
Table 5-2:  
Laboratory Panels ..................................................................................... 70 
Table 5-3:  
Estimation of the Creatinine Clearance by Cockcroft and Gault .............. 71 
Table 6-1:  
Cabozantinib Tablet Components and Composition ................................ 79 
Table 6-2:  
Placebo Tablet Components and Composition ......................................... 79 
Table 6-3:  
Suggested Management of Hepatotoxicity Associated with Study 
Treatment .................................................................................................. 87 
Table 6-4:  
Dose Reductions of Cabozantinib (Oral Dosing) ..................................... 90 
Table 6-5:  
Dose Modifications for Cabozantinib-Related AEs ................................. 90 
Table 6-6:  
Management of Diarrhea Associated with Cabozantinib ......................... 93 
Table 6-7: 
Management of Hypertension Associated with Cabozantinib .................. 95 
Table 6-8: 
Management of Hand-Foot Syndrome (PPE) Associated with 
Cabozantinib ............................................................................................. 97 
Table 6-9: 
Management of Proteinuria Associated with Cabozantinib ...................... 99 
Table 6-10: 
Adverse Event Criteria for Dose Delay, Resumption, and Discontinuation 
of Nivolumab and Ipilimumab ................................................................ 104 
Table 8-1:  
Adverse Events of Special Interest ......................................................... 122 
Table 9-1 
Summary of Endpoint Analysis .............................................................. 131 
 
LIST OF FIGURES 
 
Figure 3-1: 
XL184-313 Study Schema ........................................................................ 48 
 
LIST OF APPENDICES 
 
Appendix A: Schedule of Assessments ........................................................................ 149 
Appendix B: Maintenance Phase .................................................................................. 156 
Appendix C: Karnofsky Performance Status Criteria .................................................. 159 
Appendix D: Highly Effective Methods of Contraception ........................................... 160 
Appendix E: Management Algorithms ........................................................................ 164 
Appendix F: Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)..       
…………………………………………………………………………..172 
Appendix G: List of Strong Inducers and Inhibitors of CYP3A4 ................................ 181 
Appendix H: Collection, Follow-Up, and Documentation Requirements for AEs, AESIs, 
and SAEs ................................................................................................. 183 
Appendix I: EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version ....... 186 
Appendix J:  Child-Pugh Scoring System .................................................................... 189 
Appendix K: COVID-19 Instructions ........................................................................... 190 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
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 
BIRC 
blinded independent radiology committee 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CAP 
chest/abdomen/pelvis 
CAP 
chest/abdomen/pelvis 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTLA-4 
cytotoxic T-lymphocyte associated protein 4 
CYP 
cytochrome P450 
DICOM 
Digital Imaging and Communications in Medicine 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
EDC 
electronic data capture 
ESC 
Executive Safety Committee 
FACS 
fluorescence-activated cell sorting 

 
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Abbreviation or Term 
Definition 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
FU-1 
Post-Treatment Follow-up Visit #1 
FU-2 
Post-Treatment Follow-up Visit #2 
GCP 
Good Clinical Practice 
GGT 
-glutamyltranspeptidase 
GI 
gastrointestinal 
GLP  
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus  
HR 
hazard ratio 
HRQOL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICI 
immune checkpoint inhibitor  
IDMC 
Independent Data Monitoring Committee 
IgG1 
immunoglobulin G1 
IgG4 
immunoglobulin G4 
IHC 
immunohistochemistry  
IMDC 
International mRCC Database Consortium 
INR 
International Normalized Ratio 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
IRT 
interactive response technologies 
ITT 
intent-to-treat 
IV 
intravenous 
KPS 
Karnofsky performance status 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LMWH 
low molecular weight heparins  
MDSC 
myeloid-derived suppressor cell 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex 
MI 
myocardial infarction 
mRCC 
metastatic renal cell carcinoma 
MRI 
magnetic resonance imaging 

 
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Abbreviation or Term 
Definition 
MRP2 
multidrug resistance-associated protein 2 
MSKCC 
Memorial Sloan-Kettering Cancer Center  
MTC 
medullary thyroid cancer 
NCI 
National Cancer Institute 
NE 
not evaluable 
NPACT 
nonprotocol anticancer therapy 
NSCLC 
non–small-cell lung cancer 
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 receptor-1 ligand 
PE 
pulmonary embolism 
PFS 
progression-free survival 
PITT 
PFS Intent-to-Treat 
PK 
pharmacokinetic or pharmacokinetics 
PPE 
palmar-plantar erythrodysesthesia  
PPI 
proton pump inhibitor  
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
once daily 
qnw 
once every n weeks 
qod 
every other day 
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 
RP2D 
recommended Phase 2 dose 
RPLS 
reversible posterior leukoencephalopathy syndrome (preferred term: 
posterior reversible encephalopathy syndrome [PRES]) 
RSI 
reference safety information  
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SJS 
Suspected Stevens-Johnson syndrome 

 
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Abbreviation or Term 
Definition 
SNP 
single nucleotide polymorphism  
SoD 
sum of the diameters 
T4 
thyroxine 
TAM 
tumor-assisted macrophage  
TBS 
technetium bone scan 
TEN 
Toxic Epidermal Necrolysis 
TEAE 
treatment-emergent adverse event  
TIA 
transient ischemic attack  
TKI 
tyrosine kinase inhibitor 
Treg 
regulatory T-cell 
TSH 
thyroid-stimulating hormone  
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
VEGF(R) 
vascular endothelial growth factor (receptor) 
VHL 
von Hippel-Lindau 
W1D1 
Week 1 Day 1  
WBC 
white blood cell 
 
 
 

 
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1 
BACKGROUND 
1.1 
Renal Cell Carcinoma 
Renal cell carcinoma (RCC) is the eighth most common cancer in the world. RCC accounts for 
90% to 95% of malignant neoplasms arising from the kidney. Globally, over 330,000 cases of 
RCC are reported each year with over 100,000 deaths occurring as a result of progression of 
metastatic disease (Znaor et al 2015). In the United States, there are approximately 65,000 new 
cases each year and about 15,000 deaths from RCC annually (Siegel et al 2018). Recent 
advances in surgical and systemic therapies have significantly changed the management of RCC. 
However, the rate of RCC-related mortality has increased despite earlier detection of smaller 
kidney tumors (Sun et al 2011; Hollingsworth et al 2006). Over the last decade, an increased 
understanding of the biology of RCC has led to development of multiple agents that target 
specific growth pathways. The vascular endothelial growth factor (VEGF) and mammalian target 
of rapamycin (mTOR) pathways have been found to be important targets in RCC disease. 
Multiple drugs targeting these pathways have been approved, including cabozantinib which 
targets the VEGF pathway and other receptor tyrosine kinases (RTKs; Banumathy and 
Cairns 2010, Section 1.2). More recently treating cancer with immunotherapies has also 
expanded treatment options. Nivolumab, a programmed death receptor 1 (PD-1) antibody, is the 
only immune checkpoint inhibitor (ICI) indicated for the treatment of relapsed disease 
(Opdivo™ US PI). Recently, the results of the Checkmate-214 trial (Motzer et al 2018) led to 
approval in the US and other regions of nivolumab in combination with ipilimumab for patients 
with intermediate- or poor-risk, previously untreated advanced RCC (Section 1.5), which 
constitutes the control arm of this study. 
Several academic groups have identified variables associated with survival and created 
prognostic models in metastatic RCC (mRCC). These risk models are commonly used for 
choosing therapies or selecting patients for treatment in clinical trials. The International mRCC 
Database Consortium (IMDC) model stratifies patients into 3 prognostic groups, based on 6 
adverse prognostic factors, into favorable (0 factors), intermediate (1-2 factors), and poor risk 
(3-6 factors) groups (Heng et al 2009). Historically, agents for previously untreated patients with 
mRCC have been associated with median overall survival (OS) of 43.2 months in patients with 
favorable risk disease (which accounts for approximately 25% of all untreated mRCC), 
22.5 months in those with intermediate risk disease (which accounts for approximately 50% of 
all untreated mRCC) and only 7.8 months in those with poor risk disease according to IMDC 
criteria (Heng et al 2013).  

 
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1.2 
 Cabozantinib 
Cabozantinib (XL184) is a potent inhibitor of multiple RTKs known to play important roles in 
tumor cell proliferation and/or tumor neovascularization including the VEGF receptor (VEGFR), 
MET, AXL, and RET. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein in 
clear cell RCC results in upregulation of VEGF, MET, and AXL. Increased expression of MET 
and AXL has been associated with poor prognosis in RCC (Gibney et al 2013, Zhou et al 2016, 
Ciamporcero et al 2015). In addition, targets of cabozantinib, including TYRO3, MER, and AXL 
(TAM family kinases), are implicated in promoting suppression of an antitumor immune 
response. Preclinical studies (Kwilas et al 2014, Song et al 2015, 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, which might present an opportunity for synergistic effects from combination 
treatment with immune checkpoint inhibitors (ICIs) independent of tumor programmed death 
receptor-1 ligand (PD-L1) expression.  
Cabozantinib (60 mg, tablets) has been compared with everolimus in patients with advanced 
RCC who had received prior therapy with at least one VEGFR-tyrosine kinase inhibitor 
(VEGFR-TKI) in multicenter, randomized, open-label, controlled Phase 3 study (METEOR; 
Choueiri et al 2015, Choueiri et al 2016). In this trial, 658 subjects were randomized to receive 
cabozantinib (n = 330) or everolimus (n = 328). After a minimum follow-up of 11 months in the 
first 375 randomized subjects, the primary endpoint of progression-free survival (PFS) by 
blinded independent radiology committee (BIRC) was 7.4 months in the cabozantinib arm vs 
3.8 months in the everolimus arm (hazard ratio [HR] 0.58 [95% confidence interval {CI} 0.45, 
0.75]; p-value < 0.001). Objective response rate (ORR) per BIRC was 17% in the cabozantinib 
arm vs 3% in the everolimus arm (p-value < 0.001). An interim OS analysis at the time of this 
final PFS analysis demonstrated a trend toward longer OS (HR = 0.67, p-value = 0.005; p-value 
≤ 0.0019 required for statistical significance). A subsequent OS analysis, performed after a 
median follow-up of approximately 19 months in all 658 randomized subjects, demonstrated a 
significant improvement in OS, with median OS of 21.4 months in the cabozantinib arm and 
16.5 months in the everolimus arm (HR = 0.66 [95% CI 0.53, 0.83]; p-value = 0.00026). 
Subgroup analyses of PFS and OS based on a range of demographic and baseline characteristics 
were consistent with the results for the overall population. Grade 3-4 adverse reactions and 
laboratory abnormalities that occurred in ≥ 5% of cabozantinib-treated patients were 
hypertension, diarrhea, fatigue, palmar-plantar erythrodysesthesia (PPE), hyponatremia, 
hypophosphatemia, hypomagnesemia, lymphocytes decreased, anemia, hypokalemia, and 
-glutamyltranspeptidase (GGT) increased (Cabometyx™ US PI).  

 
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Cabozantinib (60 mg, tablets) has also been compared with sunitinib in previously untreated 
advanced RCC patients in a randomized Phase 2 study (CABOSUN; Choueiri et al [Ann Oncol] 
2017, Choueiri et al [Eur J Cancer] 2018). In this trial, subjects were required to have either 
intermediate or poor risk disease according to IMDC criteria and were randomized in 1:1 ratio to 
receive either cabozantinib (n = 79) or sunitinib (n = 78). The primary endpoint in this trial was 
PFS. Compared with sunitinib, cabozantinib treatment significantly increased median PFS per 
BIRC (8.6 vs 5.3 months) and was associated with a 52% reduction in rate of progression or 
death (adjusted HR = 0.48; 95% CI 0.31, 0.74; two-sided p-value = 0.0008). The ORR per BIRC 
was 20% (95% CI 12.0, 30.8) for cabozantinib vs 9% (95% CI 3.7, 17.6) for sunitinib. For the 
analysis of the secondary endpoint of OS, only available data through 13 January 2017 were 
used. Kaplan-Meier estimates for median duration of OS were 30.3 months in the cabozantinib 
arm vs 21.0 months in the sunitinib arm (adjusted HR = 0.74; 95% CI 0.47, 1.14). The median 
time of follow up for OS was 28.9 months. A subsequent analysis of OS with data through 
01 July 2017 was consistent with the prior results (adjusted HR = 0.80; 95% CI 0.53, 1.21; Choueiri 
et al [Eur J Cancer] 2018). The most frequent Grade 3-4 adverse reactions (≥5%) in 
cabozantinib-treated patients were hypertension, diarrhea, hyponatremia, hypophosphatemia, 
PPE, fatigue, alanine aminotransferase (ALT) increased, decreased appetite, stomatitis, pain, 
hypotension, and syncope. 
Cabozantinib (60 mg, tablets) is approved in the US for the treatment of patients with advanced 
RCC and in the EU for the treatment of adult patients with advanced RCC after prior 
VEGF-targeted therapy or treatment-naïve adult patients with intermediate or poor risk RCC 
(Cabometyx™ US PI and EMA SmPC). Cabozantinib (60 mg, tablets) is also approved in the 
US and EU for the treatment of patients with hepatocellular carcinoma (HCC) who have been 
previously treated with sorafenib (Cabometyx US PI and EMA SmPC), based on the results of a 
randomized, double-blind, placebo-controlled, multicenter trial showing that treatment with 
cabozantinib was associated with statistically significant improvements in OS, PFS and ORR. 
Cabozantinib (140 mg, capsules) is also approved in the US and in the EU, for the treatment of 
progressive, metastatic medullary thyroid cancer (MTC; Cometriq™ US PI and EMA SmPC). 
This was based on the results of a multicenter, randomized, double-blind, controlled Phase 3 
study comparing cabozantinib (140 mg, capsules) with placebo in which cabozantinib 
demonstrated a statistically significant improvement of the primary endpoint of PFS (Elisei et al 
2013). The capsule and tablet formulations are not bioequivalent or interchangeable. 

 
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1.3 
Nivolumab 
Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) kappa antibody that is 
specific for the human PD-1 cell surface membrane receptor, a negative regulatory molecule 
expressed transiently following T-cell activation and on chronically stimulated T cells 
characterized by an “exhausted” phenotype. Through the inhibition of the interaction of PD-1 
with its ligands (PD-L1 and PD L2), nivolumab has demonstrated the ability to generate 
increased anti-tumor immune responses and improvements in survival of cancer patients. 
Single-agent nivolumab has been approved in multiple cancer types including patients with 
advanced RCC after prior antiangiogenic therapy in the US and in patients with advanced RCC 
after prior therapy in Europe (Opdivo™ US PI and EMA SmPC). Approval was based on the 
clinical activity of nivolumab observed in a large Phase 3 trial conducted in 821 subjects with 
advanced RCC previously treated with 1 or 2 anti-angiogenic therapies who were randomized to 
receive nivolumab 3 mg/kg every 2 weeks (q2w) or everolimus 10 mg once-daily (qd) 
(CheckMate-025, NCT01668784; Motzer et al 2015). A planned interim analysis, after a 
minimum of follow-up of 14 months, demonstrated a statistically significant and clinically 
meaningful improvement in OS of nivolumab monotherapy vs everolimus (median OS, 
25.0 months vs 19.6 months, respectively; HR = 0.73 [98.5% CI 0.57, 0.93]; p-value = 0.002). 
ORR was 25% for nivolumab vs 5% for everolimus. In an assessment of OS by favorable-, 
intermediate-, and poor-risk IMDC groups, OS benefit for nivolumab over everolimus was 
observed across all subgroups (Escudier et al 2017). However, greater benefit was observed in 
the intermediate- (HR = 0.73; 95% CI 0.56, 0.95) and poor-risk subgroup (HR = 0.60; 
95% CI 0.42, 0.86) versus the favorable-risk subgroup (HR = 0.79; 95% CI 0.39, 1.58). The 
most common adverse reactions (reported in at least 20% of nivolumab-treated patients) were 
fatigue, cough, nausea, rash, dyspnea, diarrhea, constipation, decreased appetite, back pain, 
and arthralgia.  
1.4 
Ipilimumab 
Ipilimumab is a fully-human monoclonal IgG1 kappa antibody that binds to the cytotoxic 
T-lymphocyte associated protein 4 (CTLA-4) antigen expressed on a subset of human T cells. 
The proposed mechanism of action for ipilimumab is interference of the interaction of CTLA-4 
with B7 molecules on antigen presenting cells, with subsequent blockade of the inhibitory 
modulation of T-cell activation promoted by the CTLA4/B7 interaction. Single-agent 
ipilimumab is approved in the US and Europe for the treatment of unresectable or metastatic 
melanoma (Yervoy™ US PI and EMA SmPC).  

 
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Ipilimumab monotherapy for the treatment of mRCC refractory to or ineligible for interleukin-2 
was studied in Phase 2 clinical trial MDX010-11 (NCT00057889). Two sequential cohorts were 
studied, each with a loading dose of 3 mg/kg followed by 3 doses of either 1 mg/kg (group 3-1; 
n = 21) or 3 mg/kg (group 3-3; n = 40). Patients with stable disease (SD) or a partial response 
(PR) or complete response (CR) were allowed additional treatment. Many patients received more 
than the conventional 4 doses of ipilimumab. In Group 3-1 (n = 21), 1 patient (5%) had a PR 
(Yang et al 2007). In Group 3-3 (n = 40), 5 patients (12.5%) had a PR. Among 14 previously 
untreated patients in Group 3-3, 3 (21%) had a PR. The major toxicities were colitis (all Grade 3 
and 4; 14% in Group 3-1, 33% in Group 3-3) and hypophysitis (1 Grade 3/4, 1 Grade 1/2 in 
Group 3-3; none in Group 3-1). Most reported adverse events (AEs) were Grade 1/2 (57% in 
Group 3-1, 35% in Group 3-3) or Grade 3 (38% in Group 3-1, 48 % in Group 3-3). There were 6 
patients (15%) with Grade 4 AEs in Group 3-3. The most common treatment related AEs in 
Group 3-1 (total 81%) and Group 3-3 (total 93%) were diarrhea (38% and 40%, respectively) 
and fatigue (33% and 38%, respectively). Most AEs were manageable with appropriate 
treatment, including high dose corticosteroids and hormone replacement. 
1.5 
Combination Therapy of Nivolumab and Ipilimumab  
Nivolumab and ipilimumab have been evaluated in combination in previously untreated locally 
advanced or metastatic RCC subjects. In a Phase 1 study nivolumab and ipilimumab were 
evaluated in combination at various doses (CheckMate-016; Hammers et al 2017). In this trial 
approximately half of the enrolled subjects were previously untreated and most were favorable 
risk (~45%) or intermediate risk (~48%) per Memorial Sloan Kettering Cancer Center (MSKCC) 
criteria. The same ORR of 40.4% was reported for the combination of nivolumab 3 mg/kg + 
ipilimumab 1 mg/kg (N3I1) as well as for nivolumab 1 mg/kg + ipilimumab 3 mg/kg (N1I3). 
Median OS was not reached (95% CI 26.7 months, not evaluable [NE]) in the N3I1 arm and 
32.6 months (95% CI: 26.0 months, NE) in patients in the N1I3 arm. At 12 and 24 months, OS 
was 81% and 67% in the N3I1 arm and 85% and 70% in the N1I3 arm, respectively (Hammers et 
al 2017).  
In a randomized Phase 3 trial (CheckMate 214, Motzer et al 2018), 1096 subjects with 
previously untreated advanced RCC were randomized to receive nivolumab+ipilimumab 
(nivo+ipi; n=550) or sunitinib (n=546). The primary endpoints were OS, PFS per BIRC, and 
ORR per BIRC in the IMDC intermediate- and poor-risk subjects. At a median follow-up of 
25.2 months, the 18-month OS rate was 75% (95% CI 70, 78) with nivo+ipi vs 60% (95% CI 55, 
65) with sunitinib; the median OS was not reached with nivo+ipi vs 26.0 months with sunitinib 
(HR = 0.63 [95% CI 0.44, 0.89]; p-value < 0.001; by interpolation median OS for the nivo+ipi 

 
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arm is estimated to be approximately 41 months). The median PFS by BIRC in the intermediate- 
and poor-risk population was 11.6 months vs 8.4 months (HR 0.82 [95% CI 0.64, 1.05]; 
p-value = 0.03). With extended follow-up in intermediate-risk or poor-risk patients, results for all 
three primary efficacy endpoints now show that nivolumab plus ipilimumab continue to be 
superior to sunitinib (Motzer et al 2019). The ORR in this population was 42% (9% CR) for the 
nivo+ipi arm vs 27% (1% CR) for the sunitinib arm. Higher expression of PD-L1 (≥1%) was 
associated with greater magnitude of benefit in survival in the intermediate- and poor-risk 
population with an HR for OS of 0.45 (95% CI 0.29, 0.71; p-value < 0.001) for the PD-L1 
subgroup ≥ 1% vs 0.73 (95% CI 0.56, 0.96; p-value = 0.0249) for the PD-L1 < 1% subgroup. 
A similar trend was observed in terms of response rate with an ORR of 58% for nivo+ipi vs 22% 
for sunitinib in PD-L1 ≥ 1% and an ORR of 37% for nivo+ipi vs 26% for sunitinib in PD-L1 
<1%. There was no PFS benefit observed in the PD-L1 < 1% sub-group in the intermediate- and 
poor-risk patients. A statistically significant difference was observed for survival in the Intent-to-
Treat (ITT) population (secondary endpoint) with median OS not reached in the nivo+ipi arm vs 
32.9 months for the sunitinib arm (HR 0.68 [95% CI 0.49, 0.95]; p-value = 0.0003). Of note, 
there was no benefit in terms of response rate or PFS in the IMDC favorable risk population: 
sunitinib was superior to the combination of nivolumab and ipilimumab (ORR of 29% for 
nivo + ipi versus 52% for sunitinib; PFS of 15.3 months for nivo+ipi vs 23.1 months for 
sunitinib). The most common adverse reactions (reported in at least 20% of all nivo+ipi-treated 
patients) were fatigue, rash, diarrhea, musculoskeletal pain, pruritus, nausea, cough, pyrexia, 
arthralgia, and decreased appetite (Opdivo US PI). The results from this study led to approval in 
the US and other regions of nivolumab in combination with ipilimumab for patients with 
intermediate or poor risk, previously untreated advanced RCC (Opdivo US PI /SmPC and 
Yervoy US PI/SmPC). Based on 4 years of follow-up, the median OS for the active arm 
(nivolumab plus ipilimumab) in intermediate or poor risk subjects was reported to be 
48.1 months (Albiges et al 2020), approximately 7 months longer than originally projected for 
the control arm in the COSMIC-313 study. 
1.6 
Combination Therapy of Cabozantinib with Nivolumab or Cabozantinib with 
Nivolumab and Ipilimumab 
Preclinical studies (Kwilas et al 2014, Song et al 2015, Lu et al 2017) and clinical observations 
on circulating immune suppressive cells and immune effector cells in patients with urothelial 
cancer (UC; Apolo et al 2014) suggest that cabozantinib promotes an immune-permissive 
environment, which might present an opportunity for synergistic effects from combination 
treatment with ICIs. In vitro and in vivo experiments employing a murine colon carcinoma cell 
line (MC38-CEA) demonstrated that cabozantinib treatment altered immune modulation and 

 
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immune subset conditioning (Kwilas et al 2014). Specifically, treatment of tumor cells with 
cabozantinib in vitro led to increased tumor-cell expression of major histocompatibility complex 
(MHC) class 1 antigen and greater sensitivity of tumor cells to T-cell-mediated killing. In a 
mouse MC38-CEA tumor model, cabozantinib treatment led to increased peripheral CD8+ T-cell 
counts, decreased regulatory T-cells (Treg) and myeloid-derived suppressor cells (MDSCs), and 
decreased Treg suppressor activity. Furthermore, synergistic effects including increased CD8+ 
T cell infiltration and decreased infiltration by MDSCs and tumor-assisted macrophages (TAMs) 
were observed when a poxviral-based cancer vaccine was administered in addition to 
cabozantinib in the mouse tumor model. Further, robust synergistic effects of the combination of 
cabozantinib with antibodies against PD-1/PD-L1 and CTLA4 were demonstrated in a 
castration-resistant prostate cancer mouse model by suppression of MDSC-promoting cytokines 
(Lu et al 2017). 
The reductions in Treg cells following treatment with cabozantinib was also observed in subjects 
with advanced refractory urothelial cancer (UC; discussed below; Apolo et al 2014). In addition, 
in subjects with metastatic triple-negative breast cancer who received salvage therapy with 
cabozantinib, a persistent increase of circulating CD3+ cells and a persistent decrease of CD14+ 
monocytes were observed possibly reflecting activation of systemic antitumor immunity 
(Tolaney et al 2017). Together, the preclinical and clinical observations suggest that 
cabozantinib promotes an immunopermissive environment, which might present an opportunity 
for synergistic effects from combination treatment with PD-1 targeting ICIs independent of 
tumor PD-L1 expression.  
In an ongoing Phase 1 study, the combination of cabozantinib with nivolumab and ipilimumab is 
being evaluated in subjects with previously treated advanced genitourinary cancers, including 
UC and RCC (Apolo et al [Ann Oncol] 2016, Nadal et al 2017, Nadal et al 2018). The 
combination of cabozantinib with nivolumab is referred to as doublet and the combination of 
cabozantinib with nivolumab and ipilimumab is referred to as triplet. In the dose escalation stage 
of the study, no dose limiting toxicities (DLTs) were reported for either the doublet or triplet 
combination. The recommended Phase 2 dose (RP2D) for the doublet was cabozantinib 40 mg 
administered orally with nivolumab 3 mg/kg administered intravenously (IV) and the RP2D for 
the triplet was cabozantinib 40 mg qd with nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV 
(maximum 4 doses). Data are available for a total of 78 subjects enrolled in this trial, including 
14 subjects with RCC. The ORR for 13 RCC subjects evaluable for response for either the 
doublet or triplet combination was 54% (7 responders of 13 subjects). The remaining RCC 
subjects evaluable for response (6 of 13) had stable disease (SD) reported as their best response 

 
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to date. There was a pronounced effect on PFS and OS: median PFS in these RCC subjects was 
18.4 months (95% CI 6.4, 18.4) and the median OS was not reached. Most frequent treatment-
related Grade 3 or 4 AEs across all genitourinary cancer indications and dose levels for the triplet 
therapy (n=29) included hypertension (10%), diarrhea (10%), fatigue (7%), anorexia (3%), 
mucositis (3%), proctitis (3%) and thromboembolic events (3%). Two cases of hepatitis (Grade 3 
or 4) and one case of immune-related colitis (Grade 3 or 4) were reported for the triplet therapy. 
Grade 3 or 4 laboratory abnormalities reported in subjects treated with the triplet therapy across 
all explored dose levels included hypophosphatemia (n=6), increased lipase (n=4), decreased 
lymphocyte count (n=4), hypokalemia (n=3), ALT increased (n=3), aspartate aminotransferase 
(AST) increased (n=3), hyponatremia (n=2), amylase increased (n=2), hypocalcemia (n=1), and 
decreased platelet counts (n=1). There were no Grade 5 AEs. 
The ongoing randomized, open-label, Phase 3 CheckMate 9ER study (CA2099ER; 
NCT03141177) evaluated cabozantinib in combination with nivolumab versus sunitinib in 
subjects with previously untreated advanced or metastatic RCC of all IMDC risk categories. This 
study recently reported that cabozantinib in combination with nivolumab improved PFS (HR 
0.51 [95% CI 0.41, 0.64], P < 0.0001; median, 16.6 vs 8.3 mo) and OS (HR 0.60 [98.89% CI 
0.40, 0.89]; P = 0.0010; medians not reached) versus sunitinib in previously untreated advanced 
renal cell carcinoma (Choueiri et al 2020). These results were consistent across all prespecified 
IMDC risk and PD-L1 subgroups. Furthermore, the ORR (95% CI) was significantly higher 
with cabozantinib in combination with nivolumab compared to sunitinib (55.7% 
[50.1-61.2] vs 27.1% [22.4-32.3]; P < 0.0001), and 8.0% versus 4.6% of patients achieved 
complete response. Median duration of response was 20.2 months for patients treated with 
cabozantinib in combination with nivolumab compared to 11.5 months for patients treated with 
sunitinib.  
CheckMate 9ER initially included a cabozantinib/nivolumab/ipilimumab (‘triplet’) arm which 
stopped enrollment after nivolumab /ipilimumab demonstrated improved OS versus sunitinib in 
the Phase 3 CheckMate 214 study (NCT02231749; Motzer et al 2018). According to a 
preliminary report, 46 subjects were randomized to the triplet combination in the CheckMate 
9ER study. Of these 46 subjects, 36 (78%) had a Karnofsky performance status (KPS) score of 
90 to 100, and the IMDC prognostic score was favorable for 11 (24%), intermediate in 27 (59%), 
or poor in 8 (17%). Forty-four (96%) of these subjects actually received triplet treatment, and 36 
(82%) of those 44 were continuing to receive study treatment per data received on 10 July 
2018. Two (4.5%) of the 44 subjects had died [PD (1), other reason (1)]. Serious adverse events 
were reported in 10 (23%) of the 44 subjects, including the following system organ classes: 

 
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hepatobiliary (hepatitis [2], cholangitis [1], drug-induced liver injury [1], hepatotoxicity [1], 
immune-mediated hepatitis [1]), investigations (ALT increased [1], AST increased [1]), 
pneumocystis jirovecii  infection (1), pneumonia (1), rash (1), thrombocytopenia (1), myocardial 
infarction (1), and ischemic stroke (1). The most common AEs overall among these 44 subjects 
were fatigue (9) or asthenia (7), ALT increased (10), rash (10), nausea (8), decreased appetite 
(8), diarrhea (8), mucosal inflammation (8), hepatotoxicity (7), AST increased (7), 
palmar-plantar erythrodysaesthesia (7), cough (6), dysgeusia (6), and myalgia (6). AEs leading to 
treatment discontinuation were reported in 9 (20.5%) of the 44 subjects, including ALT 
increased (4), AST increased (3), amylase increased (1), blood alkaline phosphatase (ALP) 
increased (1), -glutamyltranspeptidase (GGT) increased (1), lipase increased (1), drug-induced 
liver injury (1), hepatitis (1), hepatotoxicity (1), diarrhoea (1), asthenia (1) and ischemic 
stroke (1).   
1.7 
Rationale 
1.7.1 
Rationale for Evaluating Cabozantinib in Combination with Nivolumab and 
Ipilimumab in IMDC Intermediate- and Poor-Risk RCC  
Cabozantinib approval in the US and in the EU includes the population of treatment-naïve 
advanced RCC patients of IMDC intermediate- or poor-risk. More recently, the nivolumab with 
ipilimumab combination also received approval in the US and in the EU for previously untreated 
advanced RCC patients of IMDC intermediate- or poor-risk. The combination of cabozantinib 
with nivolumab and ipilimumab (“triplet”) was initially evaluated against sunitinib in the 
CheckMate 9ER RCC study, but enrollment in this triplet combination was closed after the 
combination of nivolumab with ipilimumab was shown to be superior to sunitinib in the 
CheckMate 214 RCC study.  
In the Phase 3 CheckMate 214 study, the combination of nivolumab with ipilimumab showed 
efficacy in previously untreated intermediate- and poor-risk RCC subjects (NCT02231749; 
Motzer et al 2018). However, there was only modest clinical benefit for this therapy in the 
subgroup of subjects with low PD-L1 (PD-L1 < 1%), which accounts for approximately two 
thirds of the patient population. Patients with low PD-L1 may respond well to VEGF-targeted 
agents. Therefore, combination of nivolumab and ipilimumab with cabozantinib is attractive 
because of the potential for improved clinical outcomes for all subjects irrespective of PD-L1 
expression (Apolo et al 2014). Further evaluation of cabozantinib in combination with 
nivolumab and ipilimumab in previously untreated RCC patients of intermediate- and poor-risk 
is warranted.  

 
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The current Phase 3 study evaluates the efficacy and safety of cabozantinib in combination with 
nivolumab and ipilimumab versus nivolumab and ipilimumab in previously untreated subjects 
with locally advanced or metastatic RCC of intermediate- or poor-risk (as defined by 
IMDC criteria).  
1.7.2 
Rationale for Study Design 
This is a randomized, double-blind, controlled Phase 3 study of cabozantinib in combination 
with nivolumab and ipilimumab versus nivolumab and ipilimumab in previously untreated 
subjects with advanced or metastatic RCC of intermediate- or poor-risk (as defined by IMDC 
criteria). The primary endpoint is PFS evaluated by a blinded independent radiology committee 
(BIRC). PFS is an accepted regulatory and clinical endpoint for studies with cancer patients 
including advanced RCC: several agents including sunitinib, pazopanib, and cabozantinib were 
approved by regulatory agencies for previously untreated patients with advanced RCC based on 
an increase in PFS. While OS remains a “gold standard” for oncology trials, there are now 
multiple active therapies approved for previously treated patients. Subsequent treatment with 
these agents (which could include single-agent cabozantinib) could confound the effect on OS in 
previously untreated patients. Therefore, PFS remains an important indicator of clinical benefit 
in first-line mRCC and has been chosen as the primary endpoint for this trial with OS as the 
secondary endpoint. Masking (blinding) oral study medication in the experimental and control 
arms and use of a BIRC for assessment of radiographic endpoints will minimize the potential for 
bias and help ensure that both study arms are treated and assessed similarly throughout the trial. 
Crossover between treatment arms will not be allowed.  
In this study, subjects with favorable-risk disease are not being enrolled. Based on recent data for 
the combination of nivolumab and ipilimumab as described above in Section 1.5, clinical benefit 
was not demonstrated for the combination of nivolumab and ipilimumab relative to sunitinib in 
the IMDC favorable risk population (CheckMate-214, Motzer et al 2018).  
Region is included as a stratification factor to account for differences in standard-of-care 
therapies for advanced RCC. Ensuring balance by region should ensure reasonable similarity in 
new treatments upon progression, thereby strengthening the likelihood of an unbiased assessment 
of OS. 
PD-L1 is considered an immune-related biomarker that can be expressed on tumor cells and 
immune cells. Previous clinical studies have suggested that PD-L1 expression levels may have 
an impact on clinical outcomes of ICI therapy. In the Phase 3 study of nivolumab in combination 
with ipilimumab described above in Section 1.5 (CheckMate-214; Motzer et al 2018), higher 

 
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expression of PD-L1 (≥1%) was associated with greater magnitude of clinical benefit in the 
intermediate- and poor-risk population. Addition of cabozantinib may improve the outcome for 
patients with low PD-L1 expression (Apolo et al [Ann Oncol] 2016). Tumor PD-L1 status is not 
included as a stratification factor at randomization as it was deemed impractical to delay 
treatment for subjects with previously untreated advanced or metastatic RCC until the results of 
PD-L1 testing from the central laboratory were available before being able to enroll in the study 
if eligible.  
In order to comprehensively evaluate the clinical effect of the combination therapy of 
cabozantinib with nivolumab and ipilimumab, the current Phase 3 study includes analyses of 
health-related quality of life (HRQOL), health care resource utilization, pharmacokinetics, and 
biomarkers. 
1.7.3 
Rationale for Study Treatment Dose Selection and Treatment Schedule 
In this Phase 3 study, the cabozantinib dose will be 40 mg qd based on results from the ongoing 
Phase 1 study evaluating cabozantinib in combination with nivolumab as described in 
Section 1.6 (Apolo et al [Ann Oncol] 2016, Nadal et al 2017, Nadal et al 2018). The RP2D of 
nivolumab and ipilimumab (for triplet therapy) in this Phase 1 study was 3 mg/kg and 1 mg/kg, 
respectively (maximum of 4 doses of ipilimumab), followed by nivolumab 3 mg/kg 
monotherapy. Nivolumab 3 mg/kg administered q2w has been shown to be similar to a 240 mg 
flat dose q2w which has been approved based on clinical data and modeling and simulation 
approaches using population PK and exposure-response analyses of data from studies in multiple 
tumor types (melanoma, non-small-cell lung cancer [NSCLC], RCC, and UC where body weight 
normalized dosing (mg/kg) has been used. Recently, a flat dose of nivolumab at 480 mg given 
q4w was determined to be equivalent to the 240 mg dose q2w and was approved by the US FDA 
for most nivolumab indications including RCC (Opdivo™ US PI). Therefore, in accordance with 
the current US PI, nivolumab will be administered at a dosing regimen of 480 mg q4w after the 
first four doses of nivolumab and ipilimumab administered q3w.  
Previous clinical studies with ICIs suggest that there may be minimal benefit in extending 
treatment beyond a total of 2 years (Herbst et al 2016; Robert et al 2017; Spigel et al 2017). 
Therefore, in the current study, treatment with nivolumab will be given for a maximum of 
2 years from the start of study treatment. Subjects will be allowed to receive treatment with 
cabozantinib as long as they continue to experience clinical benefit in the opinion of the 
Investigator or until unacceptable toxicity, the need for subsequent systemic anti-cancer 

 
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treatment, or until any other reasons for treatment discontinuation listed in the protocol 
(Section 3.6). 
1.8 
Overall Risk Benefit Assessment  
Renal cell carcinoma (RCC) is the eighth most common cancer in the world. RCC accounts for 
90% to 95% of malignant neoplasms arising from the kidney. Over 330,000 cases of RCC are 
reported each year worldwide with over 100,000 deaths occurring as a result of progression of 
metastatic disease (Znaor et al 2015). There remains a need for additional therapies and the 
opportunity to improve outcomes for this patient population. 
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. 
Cabozantinib tablets (60 mg) are approved in the US for the treatment of patients with advanced 
RCC and in the EU for the treatment of adult patients with advanced RCC after prior VEGF-
targeted therapy or treatment-naïve adult patients with intermediate or poor risk RCC 
(Cabometyx™ US PI and EMA SmPC). Approval was based on improvement in PFS and OS 
compared with everolimus in Phase 3 Study XL184-308 in previously treated RCC patients 
(METEOR; Choueiri et al [N Engl J Med] 2015, Choueiri et al [Lancet Oncol] 2016) and in PFS 
compared with sunitinib in Phase 2 Study A031203 in treatment-naïve patients (CABOSUN; 
Choueiri et al [Ann Oncol] 2017, Choueiri et al [Eur J Cancer] 2018).  
Immunotherapies have also expanded treatment options in RCC: the combination of nivolumab 
(anti-PD-1 antibody) and ipilimumab (anti-CTLA4 antibody) is indicated for treatment-naïve 
RCC patients while single-agent nivolumab is the only ICI indicated for the treatment of 
advanced RCC after prior anti-angiogenic therapy (Opdivo US PI and SmPC; NCCN V3.2018). 
Recently, clinical data from a randomized Phase 3 trial (CheckMate 214, Motzer et al 2018) have 
led to the approval in the US and other regions of nivolumab in combination with ipilimumab for 
treatment of previously untreated patients with intermediate- and poor-risk per IMDC criteria.  
Preclinical studies (Kwilas et al 2014, Song et al 2015, Lu et al 2017) and clinical observations 
on circulating immune suppressive cells and immune effector cells in patients with UC 
(Apolo et al 2014) suggest that cabozantinib promotes an immune-permissive environment, 
which might present an opportunity for synergistic effects from combination treatment with ICIs 
independent of tumor PD-L1 expression. In an ongoing Phase 1 study, the combination of 
cabozantinib with nivolumab and ipilimumab is being evaluated in subjects with previously 
treated advanced genitourinary cancers including UC and RCC (Apolo et al [Ann Oncol] 2016, 
Nadal et al 2017, Nadal et al 2018). In the dose escalation stage of the study, no DLTs were 

 
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reported for the cabozantinib and nivolumab combination (doublet) or the cabozantinib and 
nivolumab + ipilimumab (triplet) combination. Data are available for a total of 78 subjects 
enrolled in this trial, including 14 subjects with RCC. The ORR for 13 RCC subjects evaluable 
for response for either the doublet or triplet combination was 54% (7 responders of 13 subjects). 
The remainder of RCC subjects evaluable for response (6 of 13) had SD reported as their best 
response to date. There was a pronounced effect on PFS and OS: median PFS in these RCC 
subjects was 18.4 months (95% CI 6.4, 18.4) and the median OS was not reached. The triplet 
regimen was found to be tolerable and the available safety profile in this study reflects the 
established profile of cabozantinib and nivolumab + ipilimumab. There were no Grade 5 AEs.  
Based on the encouraging clinical experience in the Phase 1 study, the current Phase 3 trial 
evaluates the safety and efficacy of cabozantinib in combination with nivolumab and ipilimumab 
versus nivolumab and ipilimumab in subjects with locally advanced or metastatic RCC of 
intermediate or poor risk (as defined by IMDC criteria). The selection of the intermediate- and 
poor-risk population for the current study is based on results from the CheckMate 214 study, 
which did not show a clinical benefit for the nivolumab + ipilimumab combination relative to 
sunitinib in the IMDC favorable-risk subgroup (Motzer et al 2018).  
The safety profile of each of the constituents of the triplet combination is well defined and the 
triplet combination has been studied in previous clinical trials. Dose management guidelines are 
included in the current study protocol for the most important risks (Section 6.6). 
Study inclusion/exclusion criteria were designed to prevent subjects at a heightened safety risk 
from entering the study. The protocol provides guidance to investigators for the management of 
important AEs that are associated with cabozantinib (Section 6.6.2) and nivolumab and 
ipilimumab (Section 6.6.3). A pattern of immune-related AEs (irAEs) has been defined, for 
which management algorithms have been developed (Appendix E): most high-grade events are 
manageable with the use of corticosteroids or hormone replacement therapies as instructed in 
these algorithms. 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 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 conducting studies in oncology. Additionally, the Sponsor’s Safety 
Committee will monitor the blinded safety of the study on a regular basis.  

 
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1.8.1 
Summary of Benefits and Risks 
Cabozantinib and the combination of nivolumab and ipilimumab have each demonstrated clinical 
activity in previously untreated intermediate- and poor-risk RCC patients, and cabozantinib in 
combination with nivolumab has demonstrated activity across all risk groups. In addition, 
preliminary clinical data suggest that cabozantinib in combination with nivolumab and 
ipilimumab exhibits clinical activity. Therefore, based on preclinical observations, the 
demonstrated clinical activity of nivolumab and ipilimumab and of cabozantinib in this patient 
population, and the known safety profiles of these agents, the potential benefits of evaluating 
these agents outweigh the potential risks. 
1.9 
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. 
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). 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objective of this study is to evaluate the efficacy and safety of the combination of 
cabozantinib with nivolumab and ipilimumab versus the combination of nivolumab and 
ipilimumab in previously untreated subjects with intermediate- and poor-risk advanced or 
metastatic RCC.  

 
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2.2 
Endpoints 
Primary Efficacy Endpoint: 
• Duration of PFS, per Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1), by Blinded Independent Radiology Committee (BIRC)  
Secondary Efficacy Endpoint: 
• Duration of OS 
Additional Endpoints: 
• ORR per RECIST 1.1 by BIRC 
• PFS and ORR per RECIST 1.1 by BIRC according to PD-L1 status 
• PFS and ORR per RECIST 1.1 as assessed by the Investigator 
• Duration of radiographic response as assessed by the Investigator and by BIRC   
• Safety through the evaluation of AEs, including irAEs, and other safety assessments.  
• Pharmacokinetics (PK) of cabozantinib given in combination with nivolumab and 
ipilimumab 
• Immunogenicity of nivolumab and ipilimumab given in combination with cabozantinib 
• Correlation of biomarker analyses with clinical outcomes 
• Health-related quality of life (HRQoL) as assessed by the EuroQol Health questionnaire 
instruments (EQ-5D-5L)   
• Health care resource utilization 

 
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3 
STUDY DESIGN 
3.1 
Study Sites 
This study will be conducted at approximately 180 sites. 
3.2 
Estimated Study Dates and Duration of Subject Participation 
It is estimated that 21 months will be required to randomize 840 subjects. The number of events 
required for the primary analysis of PFS (249 events among the first 440 subjects randomized) is 
expected to be observed approximately 23 months after the first subject is randomized. The 
number of events required for the final analysis for the secondary endpoint of OS (433 events 
among 840 subjects) is expected to be observed approximately 69 months after the first subject is 
randomized. 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. The estimates for the timing of event-driven analyses do not include 
the additional months required for event ascertainment, data quality review, data analysis and 
interpretation.  
It is estimated that subjects will participate for an average of 12-18 months on study treatment. 
Some study assessments continue periodically after study treatment is discontinued, and subjects 
will be followed until death, withdrawal of consent, or Sponsor decision to no longer collect 
these data. 
3.3 
Overview of Study Design 
This is a Phase 3 multicenter, randomized, double-blind, controlled trial of cabozantinib with 
nivolumab and ipilimumab vs nivolumab and ipilimumab in subjects with intermediate or poor 
risk advanced or metastatic RCC not previously treated with systemic therapy. The primary 
efficacy endpoint is BIRC-determined PFS. Cabozantinib-matched placebo will be given in 
combination with nivolumab and ipilimumab in the control arm to mask (blind) the study 
treatment. Approximately 840 eligible subjects will be randomized to receive study treatment as 
described in Figure 3-1 and Section 3.4.  
The study was originally designed to enroll 676 subjects; the sample size was increased to 
accommodate new, external data about the expected median overall survival in the control arm 
(see Section 9.5). 
The PITT population may be expanded by 25% from the first 440 to the first 550 randomized if a 
review of accumulating PFS events suggests that the 249 events required for the analysis will not 

 
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be reached due to censoring caused by a higher than expected study drop-out or non-compliance 
stemming from the COVID-19 pandemic.  
Special accommodations during the global COVID-19 pandemic are described in Appendix K. 
Figure 3-1: 
XL184-313 Study Schema 
 
IMDC, international metastatic renal cell carcinoma database consortium; IV, intravenous; PO, oral administration; qd, once 
daily; q3(4)w once every 3(4) weeks; RECIST, response evaluation criteria in solid tumors; RCC, renal cell carcinoma 
 
Each subject’s course of treatment will consist of the following periods: 
Pre-Treatment Period: Potential subjects will be screened to determine whether they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 28 days 
before randomization unless otherwise specified. 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in 
a 1:1 fashion to receive either cabozantinib in combination with nivolumab and ipilimumab or 
placebo in combination with nivolumab and ipilimumab. 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 or until unacceptable toxicity, the need for subsequent systemic 
anti-cancer treatment, or until any other reasons for treatment discontinuation listed in the 
protocol (Section 3.6). 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 
Advanced or metastatic 
RCC (N=840)  
•
Clear cell 
component 
•
Intermediate/ 
poor risk 
•
Measurable disease  
•
Previously 
untreated 
Stratification factors 
•
IMDC prognostic 
score 
•
Region 
Randomization 1:1 
Cabozantinib 40 mg PO qd 
Nivolumab 3 mg/kg IV q3w (4 doses) 
Ipilimumab 1 mg/kg IV q3w (4 doses) 
Then 
Cabozantinib 40 mg PO qd 
Nivolumab 480 mg flat dose IV q4w (up 
to 2 years) 
Matched placebo PO qd 
Nivolumab 3 mg/kg IV q3w (4 doses) 
Ipilimumab 1 mg/kg IV q3w (4 doses) 
Then 
Matched placebo PO qd 
Nivolumab 480 mg flat dose IV q4w (up 
to 2 years) 
Treat until 
RECIST 1.1-
defined 
progression or 
unacceptable 
toxicity.  
Subjects may 
be treated 
beyond 
progression at 
Investigator’s 
discretion 

 
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treatment and that the potential benefit of continuing study treatment outweighs potential risks 
(Section 5.7.6.2).  
Transition to Unblinded Treatment: The study may transition to unblinded treatment at the 
discretion of the Sponsor and upon any necessary discussions with regulatory authorities after 
analyses of PFS and OS have been performed. If the study is declared futile or the null 
hypothesis for the primary endpoint of PFS is not rejected (negative study), the study will be 
unblinded and investigators and subjects will be notified. If the null hypothesis for the primary 
endpoint of PFS is rejected (positive study), the study will not be unblinded until the null 
hypothesis for the secondary endpoint of OS is rejected or the final analysis of OS is performed.  
Once the study transitions to unblinded treatment, investigators and subjects will be notified of 
the randomized treatment assignment to allow for appropriate treatment decisions. Protocol 
procedures and assessments will continue without change. 
Post-Treatment Period: Subjects who discontinue from study treatment (including subjects in 
the Maintenance Phase [below]) will return to the site for two follow-up visits for safety 
assessments. The first Post-Treatment Follow-up Visit (FU-1) for safety is to occur 30 (+14) 
days after the date of the decision to permanently discontinue study treatment (defined as the 
later of the decision to permanently discontinue study treatment or the last dose of study 
treatment). A second follow-up visit (FU-2) will be conducted approximately 100 (±14) days 
after the date of the decision to permanently discontinue study treatment. 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. Consequently, these assessments may be required in the Post-Treatment 
Period for some subjects.  
In addition, subjects are to be contacted every 12 weeks (± 14 days) after the 100-day Post-
Treatment Follow-Up Visit (FU-2) to assess survival status and document receipt of systemic 
nonprotocol anti-cancer therapy (NPACT). This will continue until the subject expires or the 
Sponsor decides to discontinue collection of these data. Further, coinciding with each analysis of 
OS, sites will be required to determine the survival status for all subjects not known to be 
deceased as of the data cutoff date for the analysis. This will require additional subject contacts 
outside the 12-week schedule. Every effort must be made to collect this protocol-specific 
information unless consent for non-interventional study assessments is withdrawn. Assessments 
of OS/NPACT are not required in the Maintenance Phase (below). 

 
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Study Completion: The study will be considered complete if any of the following criteria apply: 
• futility analysis of PFS: the trial has been declared futile by the Sponsor, or 
• primary analysis of PFS: null hypothesis is not rejected, or  
• primary analysis of PFS: null hypothesis is rejected for PFS and the null hypothesis is 
rejected for OS (or the final planned analysis for OS has been conducted) 
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, and 
after treatment assignment has been unblinded, the Sponsor may initiate a 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 have been completed. 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 on active study treatment will continue to receive study 
treatment until they meet the protocol-required criteria for treatment discontinuation. Subjects in 
the Maintenance Phase 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 as necessary (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 AESIs [whether 
serious or not], and AEs leading to dose modifications or treatment discontinuation); and other 
reportable events (drug-induced liver injury [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. 

 
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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 1:1 ratio to the following treatment arms:  
• Experimental arm:   
Cabozantinib (40 mg oral, once daily [qd]) + nivolumab (3 mg/kg infusion, once every 
3 weeks [q3w]) x 4 doses + ipilimumab (1 mg/kg infusion, q3w) x 4 doses,  
followed by cabozantinib (40 mg oral qd) + nivolumab infusion (480 mg flat dose q4w). 
Nivolumab will be administered for a maximum of 2 years.   
• Control arm:  
Cabozantinib-matched placebo (oral, qd) + nivolumab (3 mg/kg infusion, q3w) x 4 doses + 
ipilimumab (1 mg/kg infusion, q3w) x 4 doses,  
followed by cabozantinib-matched placebo (oral, qd) + nivolumab infusion (480 mg flat dose 
q4w). Nivolumab will be administered for a maximum of 2 years. 
 
Details about treatment regimens are provided in Section 6. 
Randomization will be stratified by the following factors established at screening: 
• IMDC prognostic score (1-2 risk factors [intermediate] vs 3-6 risk factors [poor]) 
• Region ([US or Canada or Europe or Australia or New Zealand] vs [Latin America or 
Asia]) 
The IMDC risk factors are (Heng et al 2009): 
• Karnofsky performance status (KPS) < 80% 
• Less than 1 year from initial RCC diagnosis (including original localized disease if 
applicable) to systemic treatment  
• Hemoglobin < lower limit of normal (LLN) 
• Corrected calcium > 10 mg/dL 
• Absolute neutrophil count (ANC) > upper limit of normal (ULN) 
• Platelet count > ULN 

 
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The most recent evaluations used to establish eligibility must be used to determine the risk factor 
category for stratification. Results from the central laboratory should be used for these purposes 
whenever possible. Local laboratory results for stratification will be allowed in instances where a 
central laboratory result has not been obtained and would delay randomization approval, or for 
laboratory values that are required to be repeated closer to randomization. Results from local 
laboratory assessments used to determine the appropriate stratification values are to be 
documented in source materials and carefully reviewed by site personnel before entry into the 
IRT for randomization and sent to the local laboratory management vendor of the study.  
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. 
3.5 
Study Blinding 
3.5.1 
Blinding of Study Treatments 
The cabozantinib-matched placebo will be given in combination with nivolumab and ipilimumab 
in the control arm to blind (mask) study treatment. 
Study treatment assignment will be unknown to the subjects, investigators, study centers, 
Sponsor, and any contract research organization (CRO) affiliated with the study other than those 
authorized to access treatment assignment for regulatory safety reporting and submission 
processes (see Section 8.2.2), IRT administration, and drug supply management. 
Cabozantinib-matched placebo will be packaged and color-, size-, and shape-matched to be 
indistinguishable from cabozantinib (Section 6.1).  
3.5.2 
Unblinding Procedure for Individual Subjects 
Blinding of oral study treatment is critical to the integrity of this clinical study and therefore if a 
subject’s treatment assignment is disclosed to the study site the subject will have all study 
treatment discontinued. In the event of a medical emergency, the treating physician may decide 
that knowledge of the investigational product is critical to the subject’s management of that 
emergency. In this rare situation, the treating physician may access the treatment information for 
this subject through the IRT system. The blind should only be broken for the specific subject in 
question and, before breaking the blind of an individual subject’s study treatment, the 

 
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Investigator should have determined that the information will alter the subject’s immediate 
medical management. In the vast majority of cases, AEs may be properly managed without the 
need for unblinding (see Section 6.6). An unblinded notification including the subject ID, 
treatment arm, and date of unblinding will be provided to the Investigator.  
3.6 
Treatment Discontinuation and Study Withdrawals 
Details for handling treatment discontinuation and study withdrawal are discussed in 
Sections 3.6.1 and 3.6.2, respectively.  
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 for each individual component of study treatment (there may be more 
than one decision over time) must be recorded in source documents and transcribed to study case 
report forms (CRFs). 
3.6.1 
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 all 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 all 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.  
The following are possible reasons for discontinuation of all study treatment: 
• 
Subject no longer experiences clinical benefit as determined by the Investigator (eg, disease 
progression [PD] and/or clinical deterioration attributable to PD where either is unlikely to 
reverse with continued study treatment and/or supportive care).  
• 
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 discuss such circumstances with the Sponsor. 
• 
The investigator feels it is not in the best interest of the subject to continue on study.  

 
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• 
Subject participation in another clinical study using an investigational agent, investigational 
medical device, or other intervention. 
• 
Necessity for treatment with non-protocol systemic anti-cancer 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 K.) 
• 
Refusal of sexually active fertile subjects to use highly effective methods of contraception 
(defined in Appendix D).  
• 
Female subjects who become pregnant. 
• 
Request by the Sponsor 
• 
Unblinding of study treatment by the Investigator (prior to unblinding of study treatment for 
all subjects) 
• 
Subject request to discontinue all study treatments (with or without concurrent withdrawal of 
informed consent).  
• 
Significant noncompliance with the protocol schedule in the opinion of the Investigator or 
the Sponsor. 
• 
Subject is determined to have been randomized to receive placebo following study-wide 
unblinding 
In addition, specific criteria for discontinuation of cabozantinib are provided in Section 6.6.2 and 
for discontinuation of nivolumab/ipilimumab are provided in Section 6.6.3.2. The maximum 
treatment period for nivolumab/ipilimumab is specified in Section 3.4. 
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 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 

 
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follow-up, and documentation of subsequent anti-cancer treatment(s) unless consent for non-
interventional study assessments is also withdrawn. 
If a subject is discontinued from study treatment because of an AE (including AESI; Table 8-1) 
considered to be related to study treatment, the event must be followed until resolution or 
determination by the Investigator that the event has become stable or irreversible. 
3.6.2 
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. 
3.6.3 
Study Completion 
The study will be considered complete if any of the following criteria apply: 
- 
futility analysis of PFS: the trial has been declared futile by the Sponsor, or 
- 
primary analysis of PFS: null hypothesis is not rejected, or  
- 
primary analysis of PFS: null hypothesis is rejected for PFS and the null hypothesis is 
rejected for OS (or the final planned analysis for OS has been conducted). 
3.6.4 
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 previously untreated intermediate- and poor-risk advanced or 
metastatic RCC. 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. Histologically confirmed advanced (not amenable to curative surgery or radiation 
therapy) or metastatic (AJCC Stage IV) renal cell carcinoma with a clear-cell 
component, including subjects who also have a sarcomatoid feature. 
2. Intermediate- or poor-risk RCC as defined by IMDC criteria (Section 3.4) 
3. Measurable disease per RECIST 1.1 as determined by the Investigator. Measurable 
disease must be outside the radiation field if radiation therapy was previously 
administered. 
4. Shipment of archival tumor tissue (unstained slides or paraffin block) to the study 
central laboratory prior to randomization. The tumor tissue can be obtained from any 
organ except brain or bone and must have been biopsied no more than 2 years prior to 
the date of informed consent. Alternatively, a fresh tumor sample must be obtained 
and shipped to the study central laboratory prior to randomization if archival tumor 
tissue is unavailable or inadequate.  
5. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior 
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive 
therapy. Examples of exceptions are subjects with Grade 2 neuropathy or alopecia 
who are allowed for trial participation. 
6. Age eighteen years or meeting country definition of adult, whichever is older, on the 
day of consent. 
7. Karnofsky Performance Status (KPS) ≥70%.   
8. 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 GI/L) without granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory 
sample collection.   
b. Criterion intentionally left blank 
c. Platelets ≥ 100,000/µL (≥ 100 GI/L) without transfusion within 2 weeks 
before screening laboratory sample collection.  

 
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d. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) without transfusion within 1 week before 
screening laboratory sample collection and no clinical evidence of bleeding.  
e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3  
ULN.   
f. Total bilirubin ≤ 1.5  ULN (with the exception that total bilirubin for 
subjects with Gilbert’s disease ≤ 3  ULN). 
g. Serum creatinine ≤ 1.5  ULN or calculated creatinine clearance ≥ 40 mL/min 
(≥ 0.67 mL/sec) using the Cockcroft-Gault equation (see Table 5-3 for 
Cockcroft-Gault formula).  
h. Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 
24-h urine protein ≤ 1 g.  
9. Capable of understanding and complying with the protocol requirements and must 
have signed the informed consent document prior to any screening assessments 
except those procedures performed as standard of care within the screening window. 
10. Sexually active fertile subjects and their partners must agree to use highly effective 
methods of contraception (defined in Appendix D) during the course of the study and 
for 5 months for women, and 7 months for men, after the last dose of study treatment. 
A barrier contraceptive method (eg, condom) is also required. 
11. 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 are 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. Prior systemic anticancer therapy for unresectable locally advanced or metastatic 
RCC including investigational agents.  
Note: One prior systemic adjuvant therapy is allowed for completely resected RCC 
and if recurrence occurred at least 6 months after the last dose of adjuvant therapy. 
Note: Adjuvant therapy with a PD-1 or PD-L1 inhibitor in combination with a 
CTLA-4 inhibitor is not permitted. 
2. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy 
within 4 weeks prior to randomization. Subjects with clinically relevant ongoing 
complications from prior radiation therapy are not eligible.  
3. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or radiosurgery and stable for at least 4 weeks prior to 

 
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randomization after radiotherapy or at least 4 weeks prior to randomization after 
major surgery (eg, removal or biopsy of brain metastasis). Subjects who are 
neurologically symptomatic as a result of their CNS disease, or are receiving systemic 
corticosteroid treatment (prednisone equivalent > 10 mg/day) at the planned time of 
randomization are not eligible.  
4. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).  
a. Allowed anticoagulants are: 
i. 
Low-dose aspirin for cardioprotection (per local applicable guidelines) and 
low-dose low molecular weight heparins (LMWH)  
ii. 
Therapeutic doses of LMWH in subjects without known brain metastases who 
are on a stable dose of LMWH for at least 1 week before randomization 
without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor  
Note: Subjects who switch from an oral anticoagulant to LMWH are allowed if 
the oral anticoagulant was stopped ≥ 5 half-lives of the oral anticoagulant prior 
to planned randomization date.  
5. Administration of a live, attenuated vaccine within 30 days prior to randomization. 
The use of inactivated (killed) vaccines for the prevention of infectious disease is 
permitted. 
6. The subject has uncontrolled, significant intercurrent or recent illness including, but 
not limited to, the following conditions: 
a. Cardiovascular disorders: 
i. 
Congestive heart failure (CHF) class III or IV as defined by the New York 
Heart Association, unstable angina pectoris, serious cardiac arrhythmias 
(eg, ventricular flutter, ventricular fibrillation, Torsades de pointes).  
ii. 
Uncontrolled hypertension defined as sustained blood pressure (BP) 
> 150 mm Hg systolic or > 90 mm Hg diastolic despite optimal 
antihypertensive treatment. 
iii. 
Stroke, transient ischemic attack (TIA), myocardial infarction, or other 
symptomatic ischemic event or thromboembolic event (eg, deep venous 
thrombosis, pulmonary embolism [DVT/PE]) within 6 months before 
randomization.  
Note: Subjects with a diagnosis of DVT within 6 months are allowed if 
asymptomatic and stable at screening and treated with LMWH for at least 
1 week before randomization. 
Note: Non-symptomatic white matter disease in the brain is acceptable. 
b. Gastrointestinal (GI) disorders including those associated with a high risk of 
perforation or fistula formation: 

 
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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. 
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 pulmonary blood vessels. 
f. Other clinically significant disorders such as: 
i. 
Autoimmune disease that has been symptomatic or required treatment within 
the past two years from the date of randomization.  
 
Note: Patients with a history of Crohn’s disease or ulcerative colitis are 
always excluded 
Note: Subjects with type I diabetes mellitus, hypothyroidism only requiring 
hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) 
not requiring systemic treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll. 
ii. 
Any condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive 
medications within 14 days of randomization.  
Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. 
Adrenal replacement steroid doses > 10 mg daily prednisone equivalent are 
permitted. Transient short-term use of systemic corticosteroids for allergic 
conditions (eg, contrast allergy) is also allowed. 
iii. 
Active infection requiring systemic treatment. Acute or chronic hepatitis B or 
C infection, known human immunodeficiency virus (HIV) or acquired 
immunodeficiency syndrome (AIDS)-related illness, or known positive test 
for tuberculosis infection where there is clinical or radiographic evidence of 
active mycobacterial infection. 
iv. 
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced 
pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomograph (CT) scan  
v. 
Serious non-healing wound/ulcer/bone fracture.  
vi. 
Malabsorption syndrome. 
vii. 
Uncompensated/symptomatic hypothyroidism. 

 
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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 or allogeneic stem cell transplant. 
xi. 
Known history of COVID-19 unless the subject has clinically recovered from 
the disease at least 30 days prior to randomization. 
7. Major surgery (eg, nephrectomy, GI surgery, removal or biopsy of brain metastasis) 
within 4 weeks prior to randomization. Minor surgeries within 10 days prior to 
randomization. Subjects must have complete wound healing from major or minor 
surgery before randomization. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible. 
8. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 14 days before randomization. Furthermore, subjects 
with a history of additional risk factors for torsades de pointes (eg, long QT 
syndrome) are also excluded. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional 
ECGs at intervals of approximately 3 min must be performed within 30 min after the 
initial ECG, and the average of these three consecutive results for QTcF will be used 
to determine eligibility  
9. History of neuropsychiatric disorder likely to interfere with ability to comply with 
protocol requirements or give informed consent. 
10. Pregnant or breastfeeding females. 
11. Inability to swallow tablets or unwillingness or inability to receive IV administration. 
12. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations or history of severe infusion-related reactions to monoclonal antibodies. 
Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption are also excluded. 
13. Any other active malignancy at time of randomization or diagnosis of another 
malignancy within 3 years prior to randomization that requires active treatment, 
except for locally curable cancers that have been apparently cured, such as basal or 
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the 
prostate, cervix, or breast.  
  

 
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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 the date of 
randomization (which will be defined as W1D1 for subjects randomized who never receive study 
treatment). 
All assessments for safety and HRQOL assessments will be scheduled based on W1D1.  
Unscheduled visits for safety evaluations are allowed at any time and required in circumstances 
described herein. 
All assessments for efficacy (CT or magnetic resonance imaging [MRI], bone scans) and 
HRQOL will be scheduled based on the date of randomization.  
See Appendix A for the schedule of assessments. Special accommodations during the global 
COVID-19 pandemic are described in Appendix K. 
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 assign 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 5.7. Qualifying 
screening assessments must be performed within 28 days before randomization unless otherwise 
stated (eg, certain laboratory values must be obtained closer to randomization). Eligibility criteria 
based on laboratory values should be based on central laboratory results whenever possible with 
the exception of serum pregnancy test for females of childbearing potential and urinalysis, which 
will be performed at the local laboratory. Local laboratory results can be used in lieu of central 
laboratory results in instances when a central laboratory result has not been obtained in time and 
would delay randomization approval or for laboratory tests that are required to be repeated closer 

 
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to randomization. Study eligibility is based on a subject meeting all of the study inclusion criteria 
and none of the exclusion criteria at screening.  
Information to be collected on screen failures: 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 will be collected for all screen failures: 
• Informed consent information 
• Failed inclusion/exclusion criteria 
• Demographics 
• Serious adverse events (SAEs) 
5.2 
Treatment Period 
Subjects eligible after completing all screening evaluations will be randomly assigned in a 1:1 
fashion (Section 3.4) to receive either cabozantinib in combination with nivolumab and 
ipilimumab or cabozantinib-matched placebo in combination with nivolumab and ipilimumab 
(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 any reduction (cabozantinib/placebo only), 
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 
anti-cancer treatment, or until any other reasons for treatment discontinuation listed in the 
protocol (Section 3.6). 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 and that the potential benefit of continuing study treatment outweighs 
potential risks (Section 5.7.6.2). Crossover between treatment arms will not be allowed. 
Study completion is defined in Section 3.6.3. 

 
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Safety will be assessed on the date of the first dose (W1D1) and every 3 weeks (W4D1, W7D1, 
W10D1), and then every 4 weeks thereafter (W14D1, W18D1, W22D1 etc). Additional 
evaluations of hematology, serum chemistry, and urinalysis will be performed at W3D1, W6D1, 
W9D1, and W12D1. Safety follow-up visits will be performed 30 (+14) days (FU-1 visit) and 
approximately 100 (±14) days (FU-2 visit) after the date of the decision to permanently 
discontinue study treatment (see Section 5.4). All post-randomization safety laboratory tests may 
be assessed by local laboratories. 
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 5.7.6, and HRQOL 
assessments should be performed as described in Section 5.7.7. The schedule of assessments 
should be maintained regardless of whether study treatment is given, reduced, held 
or discontinued. 
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 
Transition to Unblinded Treatment 
The study may transition to unblinded treatment at the discretion of the Sponsor and upon any 
necessary discussions with regulatory authorities after analyses of PFS and OS have been 
performed. If the study is declared futile or the null hypothesis for the primary endpoint of PFS is 
not rejected (negative study), the study will be unblinded and investigators and subjects will be 
notified. If the null hypothesis for the primary endpoint of PFS is rejected (positive study), the 
study will not be unblinded until the null hypothesis for the secondary endpoint of OS is rejected 
or the final analysis of OS is performed.  
Once the study transitions to unblinded treatment, investigators and subjects will be notified of 
the randomized treatment assignment to allow for appropriate treatment decisions. Protocol 
procedures and assessments will continue without change. 
5.4 
Post-Treatment Period 
Subjects who discontinue from study treatment (including subjects in the Maintenance Phase 
[below]) will return to the site for two follow-up visits for safety assessments. The first follow-up 

 
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visit (FU-1 visit) will occur 30 (+14) days and the second follow-up visit (FU-2) will occur 100 
(±14 days) after the date of the decision to discontinue study treatment. Refer to Appendix A for 
a description of all assessments for the Post-Treatment Follow-Up Visits. Further details on AE 
follow up and data collection requirements are available in Appendix H. 
Adverse events are to be documented and/or followed as described in Section 8.3. 
Following treatment discontinuation each subject will continue to be followed for survival. The 
investigator (or designee) will make contact with the subject every 12 weeks (± 14 days) after the 
second follow-up visit (FU-2) until the subject expires, withdraws consent for such contacts, or 
the Sponsor decides to cease collecting these data for the study.  
At each contact, the Investigator (or designee) will determine whether 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 systemic 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 5.7.6. Consequently, these assessments may be required in 
the Post-Treatment Period for some subjects.  
5.5 
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 3.6.3). When sufficient data have been collected to 
adequately evaluate all study endpoints, and after treatment assignment has been unblinded, the 
Sponsor may initiate a 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 have been completed. The Sponsor is to notify the sites if or when the study will enter 

 
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the Maintenance Phase or if an alternative post-Study Completion option will be implemented 
(Section 6.3). 
In the Maintenance Phase, subjects on active study treatment will continue to receive study 
treatment until a criterion for protocol-defined discontinuation has been met (Section 3.6.1). 
Subjects in the Maintenance Phase 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 
as necessary. 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). 
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) 
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. 
5.6 
Unscheduled Visits or Assessments 
If the Investigator determines that a subject should be monitored more frequently or with 
additional laboratory parameters assessments than indicated by the protocol-defined visit 
schedule, unscheduled visits or assessments are permitted. The laboratory assessments should be 
done by the central laboratory; however, if the results are needed immediately (eg, for 
AE management), they may be done by the local laboratory and the results forwarded to the 
management vendor for handling of local laboratory data. In such instances, a sample for central 
laboratory analysis should also be collected. If study treatment is held, the study site should 
perform unscheduled visits weekly (or more frequently) as clinically indicated during the 

 
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intervening time between the last dose and the time drug is restarted to monitor subject safety 
and appropriateness for re-treatment. 
5.7 
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 case 
report forms (CRFs; see Section 16.4). 
5.7.1 
Demographics, Baseline Characteristics, Medical and Cancer History 
Demographics at screening will include age at informed consent, medical and cancer history, 
surgical history, radiation therapy history, and systemic anti-cancer treatment history including 
names of agents and administration dates. To ensure subject privacy, date of birth and subject 
initials will not be collected by the Sponsor. 
The study will enroll RCC subjects of intermediate- or poor-risk per IMDC criteria. The 
following IMDC risk factors (Heng et al 2009) should be scored per Table 5-1: 
• Karnofsky performance status < 80% 
• Less than 1 year from initial RCC diagnosis (including original localized disease if 
applicable) to systemic treatment  
• Hemoglobin < LLN 
• Corrected calcium > 10 mg/dL 
• Absolute neutrophil count > ULN 
• Platelet count > ULN 
The most-recent evaluations used to establish eligibility must be used to determine the risk factor 
category for stratification. Results from assessments used to determine the appropriate 
stratification values are to be documented in source materials and carefully reviewed by site 
personnel before entry into the IRT for randomization. 
Table 5-1:  
IMDC Prognostic Score 
Prognosis 
Number of risk factors 
Favorable 
0 
Intermediate 
1 or 2 
Poor 
3 or more 
Source: Heng et al 2009 

 
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5.7.2 
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 
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 KPS score of the subject will be assessed at screening and each scheduled safety assessment 
starting on W1D1. A table of KPS criteria is included in Appendix C for reference. 
Refer to Appendix A for the schedule of physical examination and KPS assessments. 
5.7.3 
Vital Signs 
Vital signs including approximately 5-minute sitting BP, pulse, respiration rate, and temperature 
will be assessed according to the schedule in Appendix A. 
On study treatment infusion days, vital signs should be assessed within 60 minutes prior to 
initiation of the infusion, and further vital sign assessment should be performed during and after 
the infusion as clinically indicated.  
5.7.4 
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 the corrected QT interval 
calculated by the Fridericia formula (QTcF). A QTcF ≤ 500 ms per ECG within 14 days before 
randomization is required to demonstrate eligibility for study treatment. If at any time a single 
ECG shows a QTcF with an absolute value > 500 ms or an increase in the QTcF of at least 60 ms 
from baseline, 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.  
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 

 
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study and will be deemed AEs. If values meet criteria defining them as serious, they must be 
reported as SAEs (Section 8.2). 
The Fridericia formula is depicted below for calculation of the QTcF value. 
 
QT = measured QT interval in milliseconds; RR = measured R to R interval (which can 
be derived from the heart rate as 60/heart rate) 
 
5.7.5 
Safety Laboratory Assessments 
Laboratory analytes that will be measured for this study are listed in Table 5-2. 
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). Laboratory values essential for eligibility determination should be obtained from the central 
laboratory whenever possible with the exception of serum pregnancy test for females of 
childbearing potential and urinalysis, which will be performed at the local laboratory. Local 
laboratory results can be used in lieu of central laboratory results in instances when a central 
laboratory result has not been obtained in time and would delay randomization approval and for 
laboratory tests that are required to be repeated closer to randomization or within 72 hours of 
checkpoint inhibitor infusion. 
The following is a list of criteria for conducting safety laboratory assessments: 
• Central laboratory assessment is required for pharmacokinetics (PK) and immunogenicity 
measurements; 
• Local laboratory assessment is required for:  
o 24-hour urine protein tests (if performed in addition to or in lieu of urine 
protein/creatinine ratio), with results forwarded to the local lab management 
vendor; 
o HIV testing, if mandated by local institution guidance; 
o Urinalysis, microscopic urine examination (if needed), serum/urine pregnancy 
(for females of childbearing potential). Results or status from these tests will be 

 
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recorded on CRFs but will not be submitted to the study local laboratory 
management vendor. 
o Labs required within 72 hours of infusions of nivolumab and ipilimumab, ie, 
hematology, serum chemistry and urinalysis, may be obtained through the local 
lab.  
Specific laboratory test information: 
• To confirm suitability for treatment, all laboratory tests (except for pregnancy test) must 
be performed within 14 days prior to administering the first dose of study treatment. 
Serum chemistry tests will include corrected calcium. 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, or if required by 
local institution guidance. 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. For all subsequent treatments, serum chemistry, hematology, and urinalysis 
laboratory samples must be collected within 72 hours and the results reviewed before any 
study treatment infusion is administered on study. 
• A serum pregnancy test (for females of childbearing potential) 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) is required for women under the age of 55 years to 
confirm menopause during the screening period.  
• Hepatitis B viral infection status is determined by assessment of hepatitis B surface 
antigen (HBsAg). 
• Hepatitis C viral infection status is guided by HCV antibody status; if positive, then a 
reflex test for HCV RNA determines eligibility. 
• Thyroid function assessment must comprise TSH and free T4 evaluations. Free T4 is 
required at screening and is required subsequently only if the TSH is out of range. 

 
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Table 5-2:  
Laboratory Panels 
Central or Local 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 (T4; required 
at screening; after screening 
only if TSH is outside normal 
range) 
 
Other parameters 
• Follicle stimulating hormone 
(FSH)a 
 
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 
• -glutamyltranspeptidase (GGT) 
• glucose  
• lactate dehydrogenase (LDH) 
• lipase  
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin (including conjugated 
and unconjungated fractions) 
• total protein 
Virology 
• hepatitis B surface antigen (HBsAg; 
screening) 
• hepatitis C virus antibody (HCV Ab; 
HCV RNA reflex testing if antibody 
positive [screening]) 
Urine Chemistry 
• Protein (spot urine; fully 
quantitative) 
• Creatinine (spot urine; fully 
quantitative) 
• Urine protein/creatinine 
ratio (UPCR; spot urine) 
  
Local Laboratory Only 
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 (if mandated locally 
[screening]) 
a For women under the age of 55 years to confirm menopause 

 
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Table 5-3:  
Estimation of the Creatinine Clearance by Cockcroft and Gault 
Serum creatinine in conventional units (mg/dL) 
• Males: (140 – age) x weight (kg)/(serum creatinine × 72) 
• Females: [(140 – age) x weight (kg)/(serum creatinine × 72)] × 0.85 
Serum creatinine in SI units (µmol/L) 
• Males: [(140 – age) x weight (kg)/(serum creatinine)] × 1.23 
• Females: [(140 – age) x 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 seriousness criteria, the event (with associated laboratory values) needs to be 
reported as an SAE (see Section 8.2).  
5.7.6 
Tumor Assessments 
5.7.6.1 
General 
Radiographic response and PD will be determined using RECIST version 1.1 (Appendix F). 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). The first tumor assessment 
after randomization should be performed at W10D1 (± 7 days). Subsequent tumor 
assessments should be performed every 8 weeks (± 7 days) through Week 50. Upon 
completion of 50 weeks on study, these assessments will be performed every 12 weeks (± 7 

 
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days). Additional imaging of potential disease sites should be performed whenever 
radiographic PD is suspected.  
2. Brain: MRI (or CT) of the brain will be performed in all subjects at screening. After 
randomization, MRI (or CT) scans of the brain are only required in subjects with known 
brain metastasis (or if clinically indicated) following the same post-baseline frequency as the 
imaging for CAP. MRI is the preferred method for brain. If CT of the brain is performed 
instead of MRI, ambiguous results must be confirmed by MRI unless MRI is contraindicated. 
(Note: in order to meet the eligibility requirements of the study, brain metastasis must have 
been treated and stable for at least 4 weeks before randomization after radiotherapy or major 
surgery [eg, removal or biopsy of brain metastasis].) 
3. Bone scans: Technetium bone scans (TBS) should be performed at screening for all subjects. 
After randomization, bone scans will be performed in subjects with known bone metastases 
and otherwise as clinically indicated per standard of care. Any soft tissue lesions associated 
with identified bone lesions must be imaged by CT/MRI and assessed in alignment with the 
CAP assessments. Bone scan findings alone cannot be used for the determination of 
progression or response and need to be corroborated by CT or MRI (which will be used as 
the basis for RECIST evaluations). 
The same imaging modalities used at screening are to be used for subsequent tumor assessments 
after randomization. If there is clinical concern regarding the administration of any contrast, then 
a non-contrast CAP imaging study is acceptable as a screening assessment if it clearly 
demonstrates measurable disease per RECIST 1.1 that can be followed without the need for 
contrast. If at a follow up imaging time point the use of contrast is prohibited (eg, due to acquired 
impaired renal function or contrast allergy) then the same modality should be used 
without contrast. 
Tumor assessments should continue on the protocol-defined schedule, relative to the date of 
randomization, regardless of whether study treatment is given, reduced, held or discontinued.  
Radiographic response and PD 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 progression determined by the 

 
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Investigator does not necessarily warrant discontinuation of tumor assessments or study 
treatment. 
Radiographic tumor assessments are to continue until the following criteria are met: 
• For subjects who discontinue study treatment upon determination of Investigator-
assessed radiographic PD per RECIST 1.1, tumor assessments may cease. 
• For subjects who discontinue study treatment before Investigator-assessed 
radiographic PD, tumor assessments are to continue per the protocol-defined schedule 
until Investigator-assessed radiographic PD per RECIST 1.1.  
• For subjects who continue to receive study treatment after Investigator-assessed 
radiographic PD 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. 
Refer to Appendix A for the schedule for these assessments. 
5.7.6.2 
Confirmation of Tumor Response and Tumor 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 after the initial PD criteria were met. This is to be performed no later than the next 
scheduled tumor assessment. After discussion with and agreement from the Sponsor, 
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 .  

 
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Reasons for treatment discontinuation are provided in Section 3.6. For subjects who continue 
treatment after documentation of radiographic progression, regularly scheduled imaging will 
continue until treatment discontinuation.  
5.7.6.3 
Blinded Independent Radiology Committee (BIRC) 
All radiological studies acquired at all scheduled time points and any additional (unscheduled) 
radiological images acquired for tumor lesion assessment 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). 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 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.   
The BIRC will evaluate prior radiation history for the purpose of valid identification of target 
lesions and will review all images per RECIST 1.1 in a central, blinded, and 
independent fashion. 
5.7.7 
Health-related Quality of Life Assessments 
Health-related quality of life (HRQOL) assessments will be performed using the EuroQol Health 
questionnaire instruments EQ-5D-5L. 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 rating scale (VAS) (Appendix 
I). The utility data generated from EQ-5D assessments are recommended for and commonly used 
in cost effectiveness analysis. The first assessment will be at Screening within 14 days prior to 
randomization. Assessment will be collected every 3 weeks after randomization until W10D1 
and every 4 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 endpoint. 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. 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 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 ascertain that their reporting not be influenced by such information 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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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.  
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.  
Completed questionnaires and any unsolicited comments written by the subject should be 
reviewed and assessed by the Investigator for responses that could indicate potential (S)AEs. 
This assessment should be documented in the study source records.  
Patient-reported outcomes cannot be provided by study personnel. 
HRQOL assessments will no longer be collected for subjects if the study transitions to the 
Maintenance Phase. 
5.7.8 
Health Care Resource Utilization 
Health care resource utilization parameters will be collected from randomization through the 
FU-2 visit. 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. 
5.7.9 
Pharmacokinetic Assessments 
Blood samples for PK assessment will be obtained from all subjects in both study arms. Samples 
will be collected for plasma cabozantinib concentration measurement pre-dose on W1D1, 
W4D1, W7D1, W10D1, and W14D1. 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. 
Serum concentrations of nivolumab and ipilimumab will be measured. Samples will be collected 
for serum nivolumab and ipilimumab concentration measurement predose on W1D1, W4D1, 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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W7D1, W10D1, W14D1, W26D1, FU-1 and FU-2 visits. The results would be used to confirm 
exposure to nivolumab and ipilimumab.  
Blood samples should be drawn from a site other than the infusion site (ie, contralateral arm) on 
days of infusion. If the infusion was interrupted, the interruption details will also be documented 
on the CRF. Further details of PK sample collection and processing will be provided to the site in 
the laboratory/procedure manual. 
Collection of PK samples may be halted early or sampling frequency may be reduced at the 
discretion of the Sponsor.    
5.7.10 
Immunogenicity Assessments 
Blood samples will be obtained from all subjects in both study arms for immunogenicity 
assessment (anti-drug antibodies [ADA] for nivolumab and ipilimumab) by validated 
immunoassays predose on W1D1, W14D1, W26D1, and FU-1 and FU-2 visits. Samples will be 
analyzed for neutralizing ADA response to nivolumab and/or ipilimumab if ADA testing is 
positive. 
5.7.11 
Biomarker Assessments 
Blood and tissue samples will be obtained once consent is provided and shipped to central 
laboratory for analysis. Refer to Appendix A for the schedule for these assessments and to 
“Exelixis Laboratory Manual for PD/Biomarker Samples” for specific details. 
Tumor tissue (most recent archival [ie, within 2 years prior to date of informed consent]) will be 
obtained during screening. PD-L1 expression (28-8 monoclonal antibody) by IHC of tumor 
material will be determined and results will be provided during the course of the study. If no 
archival tumor tissue is available, a fresh biopsy must be collected in order to be considered for 
study participation.   
For assessment of PD-L1 expression, evaluation of at least 100 viable tumor cells is required. 
Positive staining is defined as ≥ 1% and negative staining is defined as <1% of cells that exhibit 
circumferential and/or partial linear plasma membrane staining at any intensity. High 
cytoplasmic staining can interfere with membrane scoring and will define as “indeterminate”. 
Additionally, failure of PD-L1 staining due to suboptimal tissue sample integrity or assay failure 
will also be defined as “indeterminate”. 

 
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Protocol XL184-313 Protocol Amendment 3.0 
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An optional biopsy can be collected approximately 6 weeks post first dose of study treatment. 
Peripheral blood samples will be obtained pre-dose and on days as specified in the Schedule of 
Assessments.  
Exploratory analyses may include, but may not be limited to, the following: 
• 
PD-L1 and MET in tumor specimens for association with clinical outcomes  
• 
T-cell infiltration and tumor gene expression (ie, mutational load assessment) in tumor 
specimens and blood for association with clinical outcome 
• 
Circulating immune cells in peripheral blood (ie, lymphocyte subset analyses by flow 
cytometry) 
• 
Plasma biomarkers (ie, cytokines/chemokines, VEGF, metabolome) 
• 
Tumor whole-genome sequencing and gene expression analysis 
• 
Cell and/or pharmacogenomic analyses (ie circulating tumor DNA [ctDNA]) 
Collection of biomarker samples (with the exception of PD-L1 assessments) may be halted early 
or sampling frequency may be reduced at the discretion of the Sponsor. 
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 indications. 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), 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/ 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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tolerability, PK, and/ or pharmacodynamics (biomarker analyses) of cabozantinib and/or 
nivolumab/ipilimumab. 
The biomarker assessment samples may also be used for diagnostic assay development related to 
study treatment and for the discovery of biomarkers that may prove to be valuable surrogates for 
clinical response as well as to understand the underlying mechanisms of the disease.  
5.7.12 
Overall Survival 
Overall survival (OS) will continue to be assessed every 12 weeks (± 14 days) after the second 
post-treatment follow-up visit (FU-2), which occurs 100 (±14) days after discontinuation of 
study treatment. Subjects will be followed until death or Sponsor decision to no longer collect 
these data. Receipt of systemic NPACT will also be collected during follow-up contacts. If a 
subject withdraws consent for non-interventional study assessments, 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). 
5.8 
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 whether 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.   
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 K. 

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CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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6.1.1.3 
Combination Treatment: Nivolumab and Ipilimumab 
Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Nivolumab is an IgG4 kappa immunoglobulin that has a calculated 
molecular mass of 146 kDa. 
Nivolumab is a sterile, preservative-free, non-pyrogenic, clear to opalescent, colorless to 
pale-yellow liquid that may contain light (few) particles. Nivolumab injection for IV infusion is 
supplied as 100 mg/10 mL (10 mg/mL) single-dose vials. Each mL of nivolumab solution 
contains nivolumab (10 mg), mannitol (30 mg), pentetic acid (0.008 mg), polysorbate 80 
(0.2 mg), sodium chloride (2.92 mg), sodium citrate dihydrate (5.88 mg), and Water for 
Injection, USP. It may contain hydrochloric acid and/or sodium hydroxide to adjust pH to 6. 
Ipilimumab is a recombinant, human monoclonal antibody that binds to the CTLA-4 antigen. 
Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 
148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.  
Ipilimumab is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow 
solution for IV infusion, which may contain a small amount of visible translucent-to-white, 
amorphous ipilimumab particulates. Ipilimumab injection for IV infusion is supplied as 
200 mg/40 mL (5 mg/mL) single-dose vials. Each mL contains 5 mg of ipilimumab and the 
following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol 
(10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris 
hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7. 
Nivolumab and ipilimumab injections are to be administered as IV infusions through a 
0.2-micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified 
doses. These agents are not to be administered as an IV push or bolus injection. Please refer to 
the nivolumab and ipilimumab local prescribing information or the pharmacy manual for further 
details regarding storage, preparation and administration. Care must be taken to assure sterility of 
the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent. 
Nivolumab 100 mg/10 mL (10 mg/mL) and ipilimumab 200 mg/40 mL (5 mg/mL) injections for 
IV use will be provided by the Sponsor. 
6.2 
Study Treatment Schedule of Administration 
Two tablets of cabozantinib (20 mg each) or matched placebo once-daily (qd) will be 
administered orally.  

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Nivolumab will be administered at a dose of 3 mg/kg as an IV infusion once every 3 weeks 
(q3w) for the first four doses followed by the standard dosing regimen of 480 mg as an IV 
infusion once every 4 weeks (q4w) for no more than 2 years.  
Ipilimumab will be administered at a dose of 1 mg/kg as an IV infusion q3w for a maximum of 
up to four doses. Subjects will receive the combination regimen with the first infusion of 
nivolumab and ipilimumab given on the same day as the first dose of cabozantinib or placebo.  
The dose of nivolumab and ipilimumab will need to be adjusted based on the subject’s current 
body weight on study should a change of at least 10% compared with baseline be documented. 
Subjects will receive oral study treatment and (up to 2 years) nivolumab as long as they continue 
to experience clinical benefit as assessed by the Investigator or until unacceptable toxicity, the 
need for subsequent systemic anti-cancer treatment, or until any other reasons for treatment 
discontinuation listed in the protocol (Section 3.6).  
For guidance on dose modifications, interruptions, delays, or discontinuations due to AEs, refer 
to Section 6.6.2 for cabozantinib and Section 6.6.3 for nivolumab/ipilimumab.  
6.2.1 
Study Treatment Administration on Week 1 Day 1 (W1D1) 
Nivolumab and Ipilimumab: 
Doses of nivolumab (3 mg/kg) will always be administered IV at the clinic by infusion on Day 1 
of each 21-day cycles for the first 4 doses. Thereafter, doses (480 mg) will be administered on 
Day 1 of each 28-day cycle. In this study, treatment with nivolumab will be given for a 
maximum of 2 years from the start of study treatment. 
Doses of ipilimumab (1 mg/kg) will always be administered IV at the clinic by infusion on Day 1 
of each 21-day cycles for a maximum of four doses. Cycles may be longer if nivolumab or 
ipilimumab treatment is delayed due to toxicity or other reasons. 
When nivolumab and ipilimumab are to be administered on the same day, nivolumab is to be 
administered first. Nivolumab infusion (approximately 30 minutes) must be promptly followed 
by a saline flush to clear the line of nivolumab before starting the ipilimumab infusion. The 
second infusion will always be ipilimumab study drug (approximately 30 minutes infusion) and 
will start after the infusion line has been flushed and participant has been observed to ensure no 
infusion reaction has occurred. The time in between infusions is expected to be approximately 30 
minutes (from the end of the nivolumab infusion to the start of the ipilimumab infusion).  

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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On W1D1, nivolumab and ipilimumab are to be administered before the oral study treatment.  
The infusion of nivolumab and ipilimumab will be prepared according to the local prescribing 
information or the pharmacy manual. The IV administration of nivolumab and ipilimumab can 
only occur in a clinical setting with staff experienced in managing of infusion-related reactions 
and with access to emergency services.   
Subjects should be carefully monitored for infusion reactions during IV administration. If an 
acute infusion reaction is noted, participants should be managed according to Section 6.6.3.  
Cabozantinib/Placebo: 
The subject will be fasted (with the exception of water) for at least 2 hours before receiving 
cabozantinib/placebo. Upon completion of the 2-hour fast, the subject will receive the oral dose 
of cabozantinib/placebo with a minimum of 8 oz (240 mL) of water in the clinic.   
• After taking cabozantinib/placebo, the subject will continue to fast for a further 1 hour 
while under observation to monitor for potential AEs.  
• If the subject develops an infusion reaction, the administration of oral study treatment 
will be delayed or interrupted until the subject has recovered and the Investigator believes 
that it is safe to administer cabozantinib/placebo. 
For cabozantinib/placebo dosing on subsequent dosing days refer to Section 6.2.2. 
6.2.2 
Cabozantinib/Placebo Administration outside the Clinic 
The subject should take cabozantinib/placebo 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 should 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/placebo with a full glass of water (minimum of 8 oz or 240 mL) with no food 
intake for one hour post-dose. If the subject’s schedule requires taking cabozantinib/placebo 
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/placebo.  

 
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Protocol XL184-313 Protocol Amendment 3.0 
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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/placebo. 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.  
6.3 
Treatment After Study Completion 
After study completion (see Section 3.6.3), 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 nivolumab, ipilimumab, or cabozantinib is terminated for other 
reasons, including but not limited to lack of efficacy and/or not meeting the study 
objectives (eg, study is declared futile or the null hypothesis is not rejected for the 
primary endpoint of PFS);  
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). 

 
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Protocol XL184-313 Protocol Amendment 3.0 
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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. At completion of 
the study, to satisfy regulatory requirements regarding drug accountability, all unused study 
treatment will be reconciled and destroyed according to applicable state, federal, and local 
regulations. 
6.6 
Safety Considerations 
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 100 days for 
unrelated SAEs (Table 8-1) 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 8.3. Further details for follow-up and data 
collection requirements for AEs, SAEs, and AESIs are summarized in Appendix H. 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, nivolumab, and ipilimumab have class-specific 
safety profiles based on their mechanisms of action but may also cause AEs that overlap.  
- 
Examples of VEGFR-TKI associated AEs caused by cabozantinib are hypertension and 
hand-foot syndrome.  
- 
Examples of irAEs caused by nivolumab are pneumonitis, colitis, hepatitis, nephritis, 
skin reactions, encephalitis, and endocrinopathies.  
- 
Examples of irAEs caused by ipilimumab are hepatitis, endocrinopathies and 
hypophysitis.  
- 
Examples of overlapping AEs are diarrhea and elevations in liver function tests 
(transaminases, bilirubin; see Section 6.6.1).  

 
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Protocol XL184-313 Protocol Amendment 3.0 
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• 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 
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/placebo, nivolumab, or ipilimumab for AEs may occur at 
any time and independently at the discretion of the Investigator (for hepatocellular toxicity 
see below). If all study treatment is interrupted for more than 12 weeks, treatment should be 
discontinued unless approved by the Sponsor.   
• In the case of AEs of hepatocellular toxicity, the Investigator should follow the guidance 
provided in Section 6.6.1, which summarizes the dose modification guidance for BOTH 
cabozantinib/placebo treatment as well as nivolumab/ipilimumab treatment. 
• In the case of AEs of non-hepatocellular toxicity, the Investigator should follow the guidance 
on dose modifications of cabozantinib/placebo treatment in Section 6.6.2, and on dose 
modifications of nivolumab and ipilimumab in Section 6.6.3 with more detailed guidance in 
Appendix E. 
6.6.1 
Management of Hepatocellular Toxicity Associated with Cabozantinib/Placebo 
and Nivolumab/Ipilimumab 
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib, nivolumab, and ipilimumab. It is recommended that subjects with 
elevation of ALT, AST, and/or bilirubin have more frequent laboratory monitoring of these 
parameters. If possible, hepatotoxic concomitant medications should be discontinued in subjects 
who develop increased values of ALT, AST, or bilirubin, and other causes (eg, cancer-related, 
infection) should be evaluated.   

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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The following condition requires discontinuation of all study drugs:  
• Drug-related ALT or AST > 3 × ULN in combination with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with drug-induced liver injury (DILI).  
Table 6-3 provides suggested guidance on management of hepatotoxicity related to 
cabozantinib/placebo and nivolumab/ipilimumab. 
In the event cabozantinib/placebo is interrupted and nivolumab/ipilimumab delayed due to an  
increase of serum  ALTor AST> 3.0 x ULN or serum total bilirubin > ULN to 1.5 x ULN, 
nivolumab and (if fewer than 4 ipilimumab doses have been administered and no AE has 
occurred that led to discontinuation of ipilimumab alone) ipilimumab should be resumed upon 
return of liver function tests to baseline grade, at which time cabozantinib/placebo should be 
resumed with a dose reduction (from either  two tablets per day to one tablet per day, or one 
tablet per day to one tablet every other day, as appropriate).  
If no additional ipilimumab is to be administered, the dose of cabozantinib/placebo should be 
re-escalated from one tablet per day to two tablets per day no sooner than 10 days after 
resumption of blinded oral therapy. Alternatively, if the subject had been taking one tablet every 
other day, then the dose of cabozantinib/placebo may be re-escalated to one tablet every day and, 
if tolerated, then to two tablets per day no sooner than 14 days thereafter.   
Consult with the medical monitor to discuss further management should rechallenge be followed 
by any recurrence of increased liver function tests. 
Dose delays should not alter the timing of other study assessments, including but not limited to 
tumor imaging scheduled based on W1D1 (≤ 3 days after randomization).  
For additional information on dose modifications of nivolumab/ipilimumab treatment, refer to 
Section 6.6.3 and Appendix E. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Table 6-3:  
Suggested Management of Hepatotoxicity Associated with Study Treatment 
Severity of LFTa 
Elevations by 
Laboratory Value 
Dose Modification Guidanceb 
Management/Follow-up Guidance 
AST or ALT > ULN 
to 3.0 x ULN and/or 
total bili > ULN to 
1.5 x ULN, 
regardless of baseline 
value 
• Cabozantinib: 
− Continue cabozantinib per 
protocol 
• Nivolumab /Ipilimumab: 
− Continue therapy per protocol 
• Monitor LFTs per protocol. 
• Discontinue concomitant hepatotoxic 
medications, if possible. 
AST or ALT > 3.0 x 
ULN to ≤ 5 x ULN 
or total bili > 1.5 x 
ULN to ≤ 3 x ULN, 
regardless of baseline 
value 
• Cabozantinib:  
− Interrupt cabozantinib dosing. 
− If LFTs return to baseline grade, 
resume cabozantinib at a 
reduced dose. After completion 
of ipilimumab regimen, 
re-escalate cabozantinib dose as 
per protocol. If no additional 
ipilimumab doses are to be 
administered, the dose of 
cabozantinib may be 
re-escalated no sooner than 
10 days after re-initiation of 
cabozantinib.   
− See Section 6.6.1 for additional 
guidance. 
• Nivolumab /Ipilimumab:  
− Delay therapy per protocol.  
− If LFTs return to baseline grade, 
resume therapy per protocol. 
• Monitor LFTs twice weekly or more 
frequently as deemed clinically necessary.  
− If tapering off steroid therapy, monitor 
LFTs once weekly or more often per 
clinical judgmentc. 
− If LFTs return to baseline grade, resume 
with routine monitoring. 
• If LFT elevations persist > 3 days or 
worsen:  
− Administer 0.5-1 mg/kg/day 
methylprednisolone or oral equivalent. 
− When LFTs return to baseline grade or 
CTCAE Grade ≤1, taper steroids over at 
least 1 monthc. 
− Consider prophylactic antibiotics for 
opportunistic infections. 
AST or ALT 
> 5 x ULN or  
total bili > 3 x ULN, 
regardless of baseline 
value  
• Cabozantinib:  
− Discontinue cabozantinib if  
ALT or AST > 8 x ULN.  
− Otherwise interrupt 
cabozantinib dosing and resume 
at a reduced dose after LFTs 
return to baseline grade 
(Sponsor approval required) 
•  Nivolumab /Ipilimumab:  
− Delay dose or permanently 
discontinue. 
• 
Monitor LFTs twice weekly or 
more frequently as deemed 
clinically necessary.  
• 
During steroid taper, monitor LFTs 
once weekly or more often per 
clinical judgmentc. 
• 
For AST or ALT > 5 x ULN to 
≤ 20 x ULN, or total bilirubin > 3 x 
ULN to ≤ 10 x ULN: 
− 
 Administer 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent.  
• 
For AST or ALT > 20 x ULN, or 
total bilirubin > 10 x ULN: 
− 
Administer 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent.  

 
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Severity of LFTa 
Elevations by 
Laboratory Value 
Dose Modification Guidanceb 
Management/Follow-up Guidance 
* In most cases of AST or ALT 
> 5 x ULN, study treatment will 
be permanently discontinued. If 
the investigator determines a 
possible favorable benefit/risk 
ratio that warrants continuation 
of study treatment, a discussion 
between the investigator and the 
Medical Monitor/ designee must 
occur and approval from 
Medical Monitor prior to 
resuming therapy must be 
obtained. 
 
• 
Add prophylactic antibiotics for 
opportunistic infections. 
• 
Consult Gastroenterologist. 
• 
If LFT elevations do not improve 
in > 3 days, worsen or rebound: 
− 
Add mycophenolate mofetil 1g 
BID. 
− 
If no response within an 
additional 3-5 days, consider 
other immunosuppressants per 
local guidelines. 
• 
Dosing may resume when 
laboratory values return to 
baseline. 
• 
Taper steroids over at least 1 
monthc. 
ALT or AST 
> 3 × ULN AND 
total bilirubin 
> 2 × ULN AND no 
radiographic 
evidence of biliary 
obstruction 
• All study drugs must be 
discontinued. 
• 
Follow the above management/follow-up 
guidance by grade. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; bili, bilirubin; CTCAE, Common Terminology Criteria for 
Adverse Events; IV, intravenous; LFT, liver function tests; ULN, upper limit of normal 
a LFTs include AST, ALT and total bilirubin. 
b For brevity, the term “cabozantinib” refers to blinded oral study treatment of cabozantinib or cabozantinib-matched placebo. 
c Subjects on IV steroids may be switched to an equivalent dose of oral corticosteroids (eg, prednisone) at start of tapering or 
earlier, once sustained clinical improvement is observed. Lower bioavailability should be taken into account when switching 
to the equivalent dose of oral corticosteroids. 
 
6.6.2 
Management of AEs Associated with Cabozantinib/Placebo 
Throughout the remainder of Section 6 the term “cabozantinib” refers to blinded oral study 
treatment of cabozantinib or cabozantinib-matched placebo. Considerations for management of 
AEs associated with oral study medication are presented below. 
• The assigned dose for cabozantinib is 40 mg qd.  
• Two dose reduction levels of cabozantinib (20 mg qd and 20 mg every other day [qod]) are 
permitted (see Table 6-4).  

 
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• Dose modification criteria for treatment-related AEs of cabozantinib are shown in Table 6-5. 
Grade 1 and tolerable Grade 2 AEs are managed similarly; Grade 3 and intolerable Grade 2 
AEs are managed similarly.  
• Dose reinstitution and reescalation after dose interruptions and/or reductions:  
o If the subject recovers from his or her toxicities to CTCAE v5 ≤ Grade 1 or to the 
baseline value (or lower) and the AE was unrelated to oral study medication, then oral 
study medication may be restarted with no change in dose.  
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 related to oral study medication, then cabozantinib may 
be reinitiated but this must be at a reduced dose (see Table 6-4).  
o Subjects receiving a dose of 20 mg every other day (qod) 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 must discontinue cabozantinib/placebo upon discussion with the Sponsor. 
o Re-escalation to the previous dose may be allowed at the discretion of the Investigator 
but no sooner than 10 days beyond improvement of AEs that led to the dose reduction to 
Grade 1 (or baseline value), as long as AEs are deemed tolerable and easily managed by 
optimized supportive treatment. Dose reescalation is not allowed following a 
cabozantinib-related dose reduction for Grade 4 hematologic toxicities or Grade 4 AEs 
affecting major organs (eg, central nervous system [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,  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 6-4:  
Dose Reductions of Cabozantinib (Oral Dosing) 
First Dose Level Reduction 
Second Dose Level Reduction 
20 mg daily (qd) 
20 mg every other day (qod) 
Cabozantinib must be discontinued upon discussion with the Sponsor if a dose of 20-mg cabozantinib every other 
day (minimum dose) is not tolerated. 
 
Table 6-5:  
Dose Modifications for Cabozantinib-Related AEs 
CTCAE v5 Grade 
Recommended Guidelines for Management 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib at the 
current dose level if AE is manageable and tolerable. 
Grade 2 AEs that are tolerable 
and are easily managed 
 
Grade 2 AEs that 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 
value) 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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6.6.2.1 
Warnings, Precautions, and Management Guidelines for Adverse Events 
Associated with Cabozantinib Treatment 
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 Brochure. 
Other medically important but less frequent AEs include arterial thrombotic AEs (eg, TIA, and 
MI) and venous thrombotic AEs (eg, DVT and PE), severe hemorrhagic events, proteinuria, 
wound healing complications, GI perforation, abscesses including intra-abdominal and pelvic 
abscess, GI and non-GI fistula formation, osteonecrosis, and reversible posterior 
leukoencephalopathy syndrome (RPLS; preferred term: posterior reversible encephalopathy 
syndrome). 
Adverse events associated with laboratory test abnormalities that were experienced by ≥ 5% of 
cabozantinib-treated subjects 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, alkaline phosphatase (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 6-4). 
Cabozantinib should be discontinued for the following AEs: visceral perforation or fistula 
formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, 
hypertensive emergency, persistent uncontrolled hypertension despite optimal medical 
management, and RPLS. 

 
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6.6.2.1.1 Gastrointestinal Disorders 
Gastrointestinal (GI) 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. 
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 6-6. 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. 
Following improvement in diarrhea, dose re-escalation should follow the guidelines listed in 
Section 6.6.2.  

 
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Table 6-6:  
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 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 
counts and physical examination while on study. The risk of hemorrhage in cabozantinib-treated 
subjects with brain metastases has not been thoroughly analyzed. Subjects enrolled with treated 
and stable brain metastases should be monitored with a high index of suspicion if symptoms that 
could be due to a CNS hemorrhage occur. 
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 anti-cancer therapy. Deep vein thrombosis (DVT) and pulmonary 
embolism (PE) have been observed in clinical studies with cabozantinib, including fatal events. 
Subjects who develop a PE and/or DVT should have study treatment interrupted until therapeutic 
anticoagulation is established. Treatment with cabozantinib may be resumed in subjects with PE 
or DVT if it is determined that the event is uncomplicated and that the subject is deriving clinical 
benefit from cabozantinib treatment and that anticoagulation does not place them at a significant 
risk that outweighs the benefit of resuming treatment per discretion of the Investigator and 
according to individual protocols. 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, myocardial infarction) have been observed in studies with 
cabozantinib. Further treatment with cabozantinib should be discontinued in subjects who 
develop an acute myocardial infarction, cerebral infarction, or any other clinically significant 
arterial thromboembolic complication. 
6.6.2.1.5 Hypertension 
Table 6-7 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 

 
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readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement.  
Cabozantinib should be discontinued in subjects with hypertensive emergency. 
Table 6-7: 
Management of Hypertension 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 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose level or interrupt 
cabozantinib treatment per investigator discretion 
• 
Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP 
< 150 mm Hg systolic and < 100 mm Hg diastolic, 
cabozantinib treatment should be dose reduced further or 
interrupted 
• 
Cabozantinib treatment should be dose interrupted if upper 
limits of systolic BP (≥ 160 mm Hg) are sustained and not 
adequately manageable or if systolic BP is > 180 mm Hg or 
sustained diastolic BP > 110 mm Hg, or if subject is 
symptomatic 
• Re-start cabozantinib treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at 
< 150 mm Hg systolic and < 100 mm Hg diastolic 
Hypertensive emergencyb 
 
• 
Discontinue cabozantinib treatment 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 
mm Hg or diastolic BP > 100 mm Hg based on their clinical judgment and assessment of the individual subject. 
b Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending end-
organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, 
encephalopathy, kidney damage). 
 

 
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6.6.2.1.6 Stomatitis and Mucositis 
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk for complications before study treatment is initiated. Appropriate correction of 
local factors should be instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis. During treatment with cabozantinib, good oral hygiene and 
standard local treatments such as non-traumatic and non-irritating cleansing, and oral rinses 
(eg, with a weak solution of salt and baking soda) should be maintained. Lips should be kept 
moisturized with lip balm. The use of lipstick, lip-gloss, and Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as clinically indicated.  
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 (for 
tumor biopsies at least 10 days before the procedure). The decision to resume treatment with 
cabozantinib after surgery should be based on clinical judgment of adequate wound healing. 
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 6-8. 
Table 6-8: 
Management of Hand-Foot Syndrome (PPE) 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 levela. 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 cabozantinib 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. 
a Permitted dose levels are defined by individual protocols. 
 
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 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 6-9 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 6-9: 
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 
(> 226.2 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 the 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 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 factors include decreased 
immune status (eg, after myelosuppressive anti-cancer 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. Pharmacologic 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 (~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 the site’s ECG read, 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 the average increase is > 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 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
• Send ECGs to central ECG laboratory for independent read 
• 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: 

 
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• Symptoms are determined to be unrelated to the QT interval prolongation 
• The QTcF value > 500 ms or increase of > 60 ms above baseline is not confirmed by a 
cardiologist consultation. 
• 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 (confirmed by central ECG lab) 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 6-5 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. 
6.6.3 
Management of AEs Associated with Nivolumab and Ipilimumab  
The assigned dose for nivolumab is 3 mg/kg IV q3w for the first four doses followed by 
480 mg IV q4w.  
The assigned dose for ipilimumab is 1 mg/kg IV q3w for a maximum of up to four doses.  
Dose reductions are not allowed for nivolumab or ipilimumab. AEs associated with nivolumab 
and ipilimumab are managed with dose delays. 

 
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For more detailed guidance on management of non-hepatocellular AEs associated with 
nivolumab and ipilimumab please see Appendix E. For recommendations on management of 
hepatocellular toxicity and dose modifications of both cabozantinib/placebo treatment and 
nivolumab/ipilimumab treatment, see Section 6.6.1 
6.6.3.1 
Immune-related Adverse Events (irAEs) 
The immune-modulating properties of ICIs, such as the anti-PD-1 antibody nivolumab, and anti-
CTLA-4 antibody ipilimumab are able to undermine immunologic tolerance and generate a 
subset of AEs (called immune related AEs or irAEs) with an autoimmmune inflammatory 
pathomechanism. IrAEs may involve every 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 such as nivolumab are fatigue, fever, and chills. Organ-specific 
irAEs consist of pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, skin adverse 
reactions, encephalitis, myocarditis, and endocrinopathies (hypophysitis, adrenal insufficiency, 
hyperglycemia).  
Early recognition and management of irAEs associated with immuno-oncology agents may 
mitigate severe toxicity. Medical management of irAEs focuses on suppressing the immune 
response with non-steroidal and steroidal anti-inflammatory medication. Management algorithms 
have been developed and should be followed for subjects with suspected irAEs. Further 
information on management of nivolumab/ipilimumab-associated irAEs is provided in Section 
6.6.3.2 and Appendix E, and can also be found in the US PI. 
6.6.3.2 
Dose Modification Criteria for Nivolumab and Ipilimumab 
For dose modification criteria and management of AEs related to hepatotoxicity, refer to Table 
6-3. For other AEs categorized by SOC, refer to Table 6-10. Further criteria and guidance for 
dose delays, resumptions and discontinuations of nivolumab and ipilimumab are provided in 
Sections 6.6.3.2.1 and 6.6.3.2.2.

 
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Table 6-10: 
Adverse Event Criteria for Dose Delay, Resumption, and Discontinuation of Nivolumab and Ipilimumab  
Drug-Related AEs per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Gastrointestinal 
Colitis or Diarrhea 
Grade 2  
Delay dose. 
Dosing may resume when AE resolves to baseline.  
Grade 3  
Nivolumab monotherapy: Delay 
dose. 
Dosing may resume when AE resolves to baseline. 
 
When administered with 
ipilimumab: Permanently 
discontinue Ipilimumab. 
Nivolumab monotherapy may be resumed when AE 
resolves to baseline. If Grade 3 diarrhea or colitis 
recurs while on nivolumab monotherapy, 
permanently discontinue. 
Grade 4  
Permanently discontinue. 
 - 
Renal 
Serum Creatinine Increased 
Grade 2 or 3  
Delay dose. 
Dosing may resume when AE resolves to Grade ≤ 1  
or baseline value. 
Grade 4  
Permanently discontinue. 
 - 
Pulmonary 
Pneumonitis 
Grade 2  
Delay dose. 
Dosing may resume after pneumonitis has resolved 
to ≤ Grade 1. 
Grade 3 or 4  
Permanently discontinue. 
- 

 
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Drug-Related AEs per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Endocrinopathy 
• 
May resume treatment if drug-related endocrinopathies adequately controlled with only physiologic hormone replacement. 
Adrenal Insufficiency 
Grade 2 adrenal 
insufficiency 
Delay dose. 
Dosing may resume after adequately controlled with 
hormone replacement. 
Grade 3 or 4 adrenal 
insufficiency or adrenal 
crisis 
Delay dose or permanently 
discontinue. 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If adrenal insufficiency resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug. 
Hyperglycemia 
Hyperglycemia requiring 
initiation or change in daily 
management (Grade 2 or 3) 
Delay dose. 
Dosing may resume if hyperglycemia resolves to 
Grade ≤1 or baseline value, or is adequately 
controlled with glucose-controlling agents. 
Grade 4 
Delay dose or permanently 
discontinue. 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If hyperglycemia resolves, or is adequately 
controlled with glucose-controlling agents, 
participant may not require discontinuation of study 
drug. 
 Hypophysitis or Hypopituitarism  
Symptomatic Grade 1-3 that 
is also associated with 
corresponding abnormal lab 
and/or pituitary scan 
Delay dose.  
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement. 
Grade 4 
Delay dose or permanently 
discontinue. 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement, 
participant may not require discontinuation of study 
drug. 

 
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Drug-Related AEs per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Hyperthyroidism or  Hypothyroidism 
Grade 2 or 3 
Delay dose. 
Dosing may resume if endocrinopathy resolves to be 
asymptomatic, or is adequately controlled with only 
physiologic hormone replacement or other medical 
management. 
Grade 4 
Delay dose or permanently 
discontinue. 
Mandatory discussion with and approval from the 
Medical Monitor needed prior to resuming therapy. 
If endocrinopathy resolves or is adequately 
controlled with physiologic hormone replacement or 
other medical management, participant may not 
require discontinuation of study drug. 
Skin 
Rash 
Grade 2 rash covering 
> 30% body surface area or 
Grade 3 rash  
Delay dose.  
Dosing may resume when rash reduces to ≤ 10% 
body surface area.  
Suspected Stevens-Johnson 
syndrome (SJS), toxic 
epidermal necrolysis (TEN) 
or drug reaction with 
eosinophilia and systemic 
symptoms (DRESS) 
Delay dose. 
Dosing may resume if SJS, TEN, or DRESS is ruled 
out and rash reduces to ≤ 10% body surface area. 
Grade 4 rash or confirmed 
SJS, TEN, or DRESS 
Permanently discontinue. 
 - 
Neurological 
Guillain-Barre Syndrome (GBS) 
Any Grade 
Permanently discontinue. 
- 
Myasthenia Gravis (MG) 
Any Grade 
Permanently discontinue. 
- 
Encephalitis 
Any Grade encephalitis 
Delay dose.  
After workup for differential diagnosis, (ie, 
infection, tumor-related), if encephalitis is not drug 
related, then dosing may resume when AE resolves.  
Any Grade drug-related 
encephalitis  
Permanently discontinue. 
 - 

 
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Drug-Related AEs per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Myelitis 
Any Grade myelitis 
Delay dose. 
After workup for differential diagnosis, (ie, 
infection, tumor-related), if myelitis is not drug 
related, then dosing may resume when AE resolves.  
Any Grade drug-related 
myelitis 
Permanently discontinue. 
 - 
Neurological (other than GBS, MG, 
encephalitis, or myelitis) 
Grade 2 
Delay dose. 
Dosing may resume when AE resolves to baseline.  
Grade 3 or 4 
Permanently discontinue. 
 - 
Myocarditis 
Myocarditis 
Symptoms induced from 
mild to moderate activity or 
exertion 
Delay dose. 
Dosing may resume after myocarditis has resolved. 
 
Severe or life threatening, 
with symptoms at rest or 
with minimal activity or 
exertion, and/or where 
intervention indicated. 
Permanently discontinue. 
 - 
Other Clinical AE 
Pancreatitis:  
 
Amylase or Lipase increased  
Grade 3 with symptoms 
Delay dose. 
Note: Grade 3 increased amylase or lipase without 
signs or symptoms of pancreatitis does not require 
dose delay.  
Dosing may resume when patient becomes 
asymptomatic. 
Grade 4 
 
Permanently discontinue unless 
an alternative etiology (such as 
pancreatic metastases) fully 
explains the findings. 
 - 
Uveitis  
Grade 2 uveitis 
Delay dose. 
Dosing may resume if uveitis responds to topical 
therapy (eye drops) and after uveitis resolves to 
Grade ≤ 1 or baseline. If patient requires oral 
steroids for uveitis, then permanently discontinue 
study drug.  
Grade 3 or 4 uveitis 
Permanently discontinue. 
 - 

 
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Drug-Related AEs per CTCAE V5 
Severity  
Action Taken 
Clarifications, Exceptions, and Resume Criteria 
Other Drug-Related AE (not listed above) 
Grade 2 non-skin AE, except 
fatigue 
Delay dose. 
Dosing may resume when AE resolves to Grade ≤ 1 
or baseline value. 
Grade 3 AE - First 
occurrence lasting ≤ 7 days 
Delay dose. 
Dosing may resume when AE resolves to Grade ≤ 1 
or baseline value. 
Grade 3 AE - First 
occurrence lasting > 7 days 
Permanently discontinue. 
 - 
Recurrence of Grade 3 AE 
of any duration 
Permanently discontinue. 
 - 
Grade 4 or Life-threatening 
adverse reaction 
Permanently discontinue. 
 - 
Other Lab abnormalities  
Other drug-related lab abnormality (not 
listed above) 
Grade 3 
Delay dose. 
Exceptions: 
No delay required for Grade 3 lymphopenia. 
 
Permanent Discontinuation for Grade 3 
thrombocytopenia > 7 days or associated with 
bleeding.  
Grade 4 
Permanently discontinue. 
Exceptions: The following events do not require 
discontinuation of study drug:  
• Grade 4 neutropenia ≤ 7 days 
• Grade 4 lymphopenia or leukopenia 
• Grade 4 isolated electrolyte 
imbalances/abnormalities that are not associated 
with clinical sequelae and are responding to 
supplementation/appropriate management within 
72 hours of their onset 
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, hypertension, bronchospasm, or other allergic-like reactions.) 
Hypersensitivity reaction or infusion 
reaction 
Grade 3 or 4 
Permanently discontinue. 
Refer to Section 6.6.3.3 on treatment of 
nivolumab/ipilimumab-related infusion reactions.  
DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms; SJS, Suspected Stevens-Johnson syndrome; TEN, Toxic Epidermal Necrolysis 
 

 
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6.6.3.2.1 Dose Delay and Restart Criteria for Nivolumab and Ipilimumab 
Immuno-oncology agents, such as nivolumab and ipilimumab, are associated with AEs that 
differ in severity and duration from AEs caused by other therapeutic classes. Early recognition 
and management of AEs associated with immuno-oncology agents may mitigate severe toxicity.  
Delayed doses of nivolumab and ipilimumab should be administered as soon as the subject meets 
criteria to resume treatment. If a dose has been delayed, the subject should not wait until the next 
scheduled dosing date.  
In addition to criteria and guidelines in Table 6-10, subjects may resume treatment with these 
study drugs when the drug-related AE(s) resolve to Grade  1 or baseline value, with the 
following exceptions: 
• Systemic corticosteroids for control of infusion reactions or irAEs must have been tapered to 
a dose level ≤ 10 mg/day of prednisone equivalent before resuming treatment with 
nivolumab/ipilimumab. 
• If all study treatment is interrupted for > 12 weeks, the subject must be permanently 
discontinued from study treatment unless approved by the Sponsor.  
Refer to Appendix E for a complete list of criteria for resumption of nivolumab and ipilimumab 
treatment. 
6.6.3.2.2 Criteria for Discontinuation of Nivolumab and Ipilimumab  
If a subject meets criteria for discontinuation and the investigator is unable to determine whether 
the event is related to one or both checkpoint inhibitors, the subject should discontinue both 
nivolumab and ipilimumab with the exception of certain cases of liver function test elevation 
(See Section 6.6.1). 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 12 weeks, the 
Medical Monitor must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory studies should also 
continue as clinically indicated during such dosing delays. 
6.6.3.3 
Treatment of Nivolumab and Ipilimumab-Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such 
a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. 

 
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Regardless of whether the event is attributed to these study drugs, all Grade 3 or 4 infusion 
reactions should be reported within 24 hours to the study Sponsor Medical Monitor or designee 
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
CTCAE v5 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated): 
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional administrations of these study drugs. 
For Grade 2 symptoms: (moderate reaction; required therapy or infusion interruption but 
responds promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for  24 hours): 
Stop the study drug infusion, begin an IV infusion of normal saline, and treat the participant with 
diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg; 
remain at bedside and monitor participant until resolution of symptoms. Corticosteroid and/or 
bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, 
then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further 
complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion 
rate. Monitor participant closely. If symptoms recur, then no further study dug will be 
administered at that visit. 
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before study drug infusions. If necessary, 
corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used. 
For Grade 3 or 4 symptoms: (severe reaction; Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms 
following initial improvement; hospitalization indicated for other clinical sequelae (eg, renal 

 
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impairment, pulmonary infiltrates). Grade 4: Life-threatening; pressor or ventilatory support 
indicated): 
Immediately discontinue infusion of these study drugs. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 
slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 
100 mg IV (or equivalent), as needed. Participant should be monitored until the Investigator is 
comfortable that the symptoms will not recur. Nivolumab + ipilimumab will be permanently 
discontinued. Investigators should follow their institutional guidelines for the treatment of 
anaphylaxis. Remain at bedside and monitor participant until recovery of the symptoms. 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given be given (eg, oral 
antihistamine or corticosteroids). 
7 
CONCOMITANT MEDICATIONS AND THERAPIES 
7.1 
Allowed Therapy 
• Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• Adrenal replacement steroid doses at > 10 mg daily prednisone equivalent are permitted.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, ASCO or ESMO guidelines).  
• Bisphosphonates or RANK-L inhibitors can be used per standard of care if the benefit 
outweighs the risk per the Investigator’s discretion  
Note: osteonecrosis of the jaw (ONJ) 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. 

 
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• Inhaled, intranasal, intra-articular, and topical corticosteroids are allowed if minimal 
systemic absorption. Systemic corticosteroids are allowed for control of infusion reactions or 
irAEs and must be tapered to a dose level ≤ 10 mg/day of prednisone equivalent before next 
nivolumab/ipilimumab administration. Prophylactic steroid treatment for subjects with 
contrast allergies prior to tumor imaging is allowed. 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances:  
o Low dose low molecular weight heparins (LMWH) for prophylactic use are allowed if 
clinically indicated and the benefit outweighs the risk per the Investigator’s discretion.  
o Therapeutic doses of LMWH at the time of the first dose of study treatment are 
allowed if the subject has no evidence of brain metastasis, has been on a stable dose of 
LMWH for at least 1 week, and has had no complications from a thromboembolic 
event or the anticoagulation regimen.  
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 
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).  
o For restrictions on oral anticoagulants see Section 7.2. 
Potential drug interactions with cabozantinib are summarized in Section 7.3.1. The drug 
interaction potential of nivolumab is unknown as no formal PK drug-drug interaction studies 
have been conducted (nivolumab US prescribing information).  

 
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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. 
• 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), unless blinded oral study 
treatment has been permanently discontinued. 
• Any non-protocol systemic anti-cancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides, drugs specifically for the treatment of the cancer under investigation). 
• Immunosuppressive agents including immunosuppressive doses of systemic corticosteroids 
with exceptions as stated in Section 7.1 except when both nivolumab and ipilimumab have  
been permanently discontinued. 
• Live vaccines are prohibited  during treatment and until 100 days after the last doses of 
nivolumab and ipilimumab (eg, intranasal influenza, measles, mumps, rubella, oral polio, 
BCG, yellow fever, varicella, and TY21a typhoid vaccines). 
• The use of inactivated (killed) vaccines for the prevention of infectious disease is permitted. 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Local anti-cancer 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 known to prolong the QTc interval should be avoided in subjects 
who receive cabozantinib until they have permanently discontinued cabozantinib treatment 

 
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(refer to http://www.qtdrugs.org for a list of drugs which have the potential to prolong the 
QTc interval). 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s 
Wort) may significantly decrease cabozantinib concentrations and should be avoided 
(Appendix G). Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
significantly increase the exposure to cabozantinib.  
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations and should be 
avoided (Appendix G). Grapefruit, star fruit, and Seville oranges may also increase plasma 
concentrations of cabozantinib and should be avoided. 
Additional information on potential drug interactions with cabozantinib is provided in 
Section 7.3.1. 
The US prescribing information for nivolumab and ipilimumab notes that no formal PK 
drug-drug interaction studies have been conducted using these agents. 
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 to CYP2C8 (ie, CYP2C9, CYP2C19, CYP2D6, 
CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib 
concentrations (30 μM).  

 
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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 (Appendix G). Other drugs that induce CYP3A4 should be 
used with caution because these drugs have the potential to decrease exposure (AUC) to 
cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(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 (AUC) 
to cabozantinib (Appendix G). 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%, so 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 cabozantinib 
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 
cabozantinib Investigator Brochure. 
7.3.2 
Potential Drug Interactions with Nivolumab and Ipilimumab 
Cytochrome P450 enzymes, as well as conjugation/glucuronidation reactions, are not involved in 
the metabolism of nivolumab. No formal drug interaction studies for nivolumab and ipilimumab 
have been conducted (nivolumab and ipilimumab US prescribing information). 
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 

 
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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 through 30 days (100 days for SAEs and certain other events 
[Table 8-1]) 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 by the investigational site. Further details are provided 
in Appendix H. 
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 individual study drug by the Investigator will be 
based on the following two definitions: 
• Not Related: An event is assessed as not related to study drug 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 drug 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. 
8.1.2 
Laboratory Abnormalities 
All laboratory data required by this protocol and any other clinical investigations will be 
reviewed by the Investigator. Any abnormal value that leads to a change in subject management 
(eg, dose reduction, delay, or study drug discontinuation, 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. 

 
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8.2 
Serious Adverse Events  
8.2.1 
Definitions 
The SAE definition and reporting requirements are in accordance with the International 
Conference on Harmonization (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 
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 

 
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the Investigator to permanently discontinue study treatment or the date of the last dose of 
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 the initial consent and through 100 days after the date of the decision to 
permanently discontinue 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: 
• 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.  

 
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• While most hospitalizations necessitate reporting of an SAE, hospitalizations that do not 
require SAE reporting are 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 less 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 
Exelixis Drug Safety group (or designee) will process and evaluate all SAEs 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. 
Exelixis 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. 
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. 
As a general rule, the treatment blind will be broken by authorized Sponsor and/or CRO 
personnel prior to reporting an SAE that meets the criteria for expediting reporting to the 
Regulatory Authorities and to some central ECs. Other than those involved in the unblinding and 

 
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submission processes, the Investigator, Sponsor, and CRO staff will remain blinded to the 
treatment assignment. 
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 8-1).  
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 is provided in the protocol (Section 6.6.3) 
and can also be found in the local prescribing information for nivolumab and ipilimumab. 

 
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Table 8-1:  
Adverse Events of Special Interest  
Event 
• 
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 × ULN in combination with total bilirubin > 2 × ULN  
o 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
• 
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. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and hypophysitis 
• 
Hepatitis, including AST or ALT > 10 × ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia gravis, and 
meningoencephalitis 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, influenza-like 
illness, systemic inflammatory response syndrome, and systemic immune activation 
• 
Nephritis 
• 
Ocular toxicities (eg, uveitis, retinitis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
≥ Grade 2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; ULN, upper limit of 
normal. All events that meet the listed criteria should be reported regardless of Investigator attribution to study treatment. 
 
8.3.1 
General Information on Immune-Related Adverse Events 
The immune-modulating properties of immune checkpoint-inhibitors are able to undermine 
immunologic tolerance and generate a subset of AEs (called irAEs) with an autoimmmune 
inflammatory pathomechanism. Immune-related AEs may involve any organ or tissue (Michot et 
al 2016). Most irAEs occur within the first 12 weeks of exposure to ICIs but some 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 

 
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endocrinopathies (pituitary, thyroid, adrenal, testes). Diagnosis of endocrine dysfunction is 
challenging with relatively unspecific symptoms. The following additional laboratory testing of 
the endocrine axes may be helpful: prolactin (pituitary-hypothalamic function), FT4 and TSH 
(pituitary-thyroid function), luteinizing hormone (LH) and follicle-stimulating hormone (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 infiltration of periportal tissue and surrounding 
primary biliary ducts) and pneumonitis (acute interstitial pneumonia). Less frequent irAEs 
include neurologic syndromes (myasthenia gravis, Guillian-Barré syndrome, aseptic meningitis), 
ocular AEs (uveitis), renal AEs (interstitial nephritis), cardiac AEs (myocarditis), and pancreatic 
AEs (lipase increase). 
8.4 
Follow-Up of Adverse Events 
Nonserious AEs (see below for AESIs [Table 8-1]) 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 
by the Investigator to permanently discontinue study treatment or the date of the last dose of 
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 until 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 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 provided in Appendix H.  

 
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8.5 
Other Safety Considerations 
8.5.1 
Pregnancy 
Use of highly effective methods of contraception (Appendix D) is very important during the 
study and must continue for 5 months for women, and 7 months for men, 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. If a female partner of a male subject becomes pregnant 
during the study, the Sponsor will ask the pregnant female partner to consent 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 
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 up to 5 months from the 
last dose of nivolumab or up to 4 months from the last dose of cabozantinib. 
8.5.2 
Medication Errors/Overdose 
Medication error is defined as the administration of each 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 cabozantinib Investigator Brochure for 
additional management recommendations regarding overdoses of cabozantinib and to  
Appendix E regarding overdoses of nivolumab or ipilimumab. 

 
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9 
STATISTICAL CONSIDERATIONS 
Details of the planned analyses, including any modifications implemented prior to conducting 
analyses, will be provided in a separate Statistical Analysis Plan (SAP) that will be finalized 
before the primary endpoint analysis is performed. Any 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 the SAP. 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 following populations will be employed for statistical analyses. 
9.1.1 
Intention-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all subjects who are randomized, regardless 
of whether any study treatment or the correct study treatment is received.    
9.1.2 
PFS Intention-to-Treat Population 
The first 440 subjects that are randomized (based upon Greenwich Mean Time randomization 
date/time values) will be considered as the PFS Intent-to Treat (PITT) population.    
9.1.3 
Safety Population 
The Safety population will consist of all subjects who receive any amount of study treatment. 
Subjects who receive any amount of cabozantinib in error will be summarized in the 
experimental (cabozantinib plus nivolumab and ipilimumab) arm.  
9.2 
Study Endpoints 
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 the following events: 
PD as determined by the BIRC per RECIST 1.1 or death due to any cause. The definition of 
radiographic PD and censoring rules for the primary analysis are described in Section 9.2.2.1. 
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 date the subject was last known to be alive.  

 
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9.2.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is duration of PFS per RECIST 1.1 as determined by BIRC. 
9.2.2.1 
Primary Analysis: Progression-Free Survival 
The primary analysis of PFS is event-driven and will be conducted after at least 249 events have 
been observed in the PITT population (see Section 9.1.2). It is designed to include only 
progression events as determined by the BIRC per RECIST 1.1. Clinical deterioration or 
radiographic progression 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 surgical resection of target tumor lesion(s) 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 or surgery. 
• 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.  
• 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. 
Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided 0.05 level of significance. The stratification factors are those used to 
stratify the randomization (see Section 3.4).  
The median PFS and the associated 95% CI for each treatment arm will be estimated using the 
Kaplan-Meier method. The HR with 95% CIs will be estimated using a Cox regression model 
and will include the same stratification factors described above. 
In the primary analysis of PFS, if the p-value for the stratified log-rank test is statistically 
significant and the HR (λ cabozantinib + nivolumab/ipilimumab/ λ nivolumab/ipilimumab+placebo) 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 plus nivolumab/ipilimumab 
compared with the group receiving nivolumab/ipilimumab plus placebo. 
Analyses of PFS based upon investigator assessment will follow the same methods. 

 
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9.2.2.2 
Supportive Analyses 
Supportive (sensitivity) analyses will be conducted using all PFS events and subjects in the ITT 
population at the time of the primary PFS analysis in the PITT population. 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 will be conducted using Cox regression models and subgroup analyses 
performed employing Kaplan-Meier methods. 
9.2.3 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint for this study is duration of OS. Formal hypothesis testing is 
planned for this endpoint. 
9.2.3.1 
Overall Survival 
The primary analysis of OS is event-driven and will be conducted after at least 433 deaths have 
been observed in the ITT population (Section 9.1.1). 
Hypothesis testing between the two treatment arms will be performed using the stratified log-
rank test with a 2-sided 0.05 level of significance. The stratification factors are those used to 
stratify the randomization (see Section 3.4). 
The median duration of OS and the associated 95% CI for each treatment arm will be estimated 
using the Kaplan-Meier method. The HR with 95% CIs will be estimated using a Cox regression 
model and will include the same stratification factors described above. 
Three interim analyses of OS are planned. Details are provided in Section 9.6. 
At any analysis of OS (interim or final), if the p-value for the stratified log-rank test is 
statistically significant and the HR (λ cabozantinib + nivolumab/ipilimumab/ λ nivolumab/ipilimumab+placebo) 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 plus 
nivolumab/ipilimumab compared with the group receiving nivolumab/ipilimumab plus placebo.  
9.2.4 
Additional Endpoints  
Details of the planned analyses of these endpoints will be provided in the SAP: 

 
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• ORR per RECIST 1.1 by BIRC 
• PFS and ORR per RECIST 1.1 by BIRC according to PD-L1 status 
• PFS and ORR per RECIST 1.1 as assessed by the Investigator 
• Duration of radiographic response as assessed by the Investigator and by BIRC   
• Safety through the evaluation of AEs, including irAEs, and other safety assessments.  
• PK of cabozantinib given in combination with nivolumab and ipilimumab 
• Immunogenicity of nivolumab and ipilimumab given in combination with cabozantinib 
• Correlation of biomarker analyses with clinical outcomes 
• Health-related quality of life (HRQoL) as assessed by the EuroQol Health questionnaire 
instruments (EQ-5D-5L) 
• Health care resource utilization 
9.3 
Control of Type I Error 
Inflation of Type 1 error associated with testing multiple endpoints (primary and secondary) will 
be controlled by applying a hierarchical testing procedure: OS will be tested only if the null 
hypothesis of no difference between arms in PFS is rejected. 
Three interim analyses of OS are planned (see Section 9.6). Inflation of Type 1 error associated 
with interim analyses will be controlled using a Lan-DeMets O’Brien-Fleming alpha-spending 
function.  
All other statistical evaluations of efficacy will be considered exploratory. 
9.4 
Safety Analyses 
All safety analyses will be performed using the Safety population. No formal statistical 
comparisons between the two treatment arms are planned. 
9.4.1 
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 the 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 date of first dose of study treatment. Only TEAEs with an onset date prior to date of 
decision for treatment discontinuation (the later of the date of the decision of the Investigator to 
permanently discontinue study treatment or the date of the last dose of study treatment taken by 

 
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the subject) + 30 days (+ 100 days for SAEs and certain other AEs; Section 8.3) will be tabulated 
in summary tables. 
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. 
9.4.2 
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.  
9.4.3 
Other Safety Endpoints 
Changes or shifts from baseline in vital signs, performance status, and QTc interval will be 
summarized by treatment group. 
The number of subjects experiencing dose reduction (cabozantinib only), interruption, 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. 
9.5 
Power and Sample Size 
The study is designed to provide adequate power for both PFS and OS. A larger sample size is 
needed to provide reasonable power for OS than for PFS. As a result, if PFS is 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 fewer number of subjects this study employs a 
“trial within a trial design.” The primary analysis of PFS will be conducted after at least 249 PFS 
events have been observed among the first 440 randomized subjects, defined as the PFS 
Intent-to-Treat (PITT) population.  

 
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For PFS, a total of 249 events in the first 440 randomized subjects provides the study with 90% 
power for a 2-sided log-rank test with a 5% level of significance to detect a HR of 0.66. 
Assuming an exponential distribution of PFS, this corresponds with a 52% increase in median 
PFS from 11.6 months to 17.6 months. In the current design, the minimum observed effect that 
would result in statistical significance for PFS is a HR of 0.78, a 28% improvement in median 
from 11.6 to 14.9 months. Interim analysis of PFS is not planned.   
For OS, the study was originally designed as follows: a total of 342 deaths among 
676randomized subjects are required to provide 90% power to reject the null hypothesis of no 
difference in OS using the log-rank test, a 2-sided significance level of 5%, three planned interim 
analyses (see Section 9.6), and assuming  a true HR of 0.70. Assuming an exponential 
distribution for OS, this corresponds to a 43% improvement in median survival from 41 months 
to 58.6 months. Under this design, the minimum observed effect that would result in statistical 
significance for the final analysis of OS is an HR of 0.80, a 25% improvement in median from 41 
to 51.1 months; a minimum difference in observed medians of approximately 10 months. 
In response to new data supporting a median OS in the control arm of 48 months instead of the 
previously assumed 41 months (Albiges et al 2020), the study has been modified as follows: A 
total of 433 events among 840 randomized subjects (the ITT population) are required to provide 
90% power to reject the null hypothesis of no difference in OS using the log-rank test at a 
2-sided significance level of 5%, 3 planned interim analyses (see Section 9.6), and assuming a 
true HR of 0.73. Assuming an exponential distribution for OS, this corresponds to a 37% 
increase in median survival from 48 months to 65.8 months. Under this design the minimum 
observed effect that would result in statistical significance for OS is an HR of 0.824, a 21% 
improvement in median from 48 to 58.25 months; a minimum observed difference in medians of 
approximately 10 months. 
This increase in sample size does not inflate Type 1 error because (a) it was done solely in 
response to new external data about the expected median OS of the control arm, and (b) the 
control arm median is a nuisance parameter with respect to the minimum observed difference in 
medians that results in rejection of the null hypothesis. This change ensures the trial retains the 
ability to reject the null hypothesis for OS if the observed difference in medians is approximately 
10 months. 
With an assumed constant accrual rate of 40 subjects per month, a 1:1 treatment allocation ratio, 
and 3 interim analyses of OS, a total of 840 subjects (420 per treatment arm) is required to 
observe the required number of events within the planned study duration (approximately 

 
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21 months accrual; approximately 23 months after first subject randomized to observe the 
required PFS events among 440 subjects and approximately 69 months after first subject 
randomized to observe the required deaths for OS among 840 subjects). 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.The PITT population may be expanded by 25% from the first 440 to the first 550 
randomized if a review of accumulating PFS events suggests that the 249 events required for the 
analysis will not be reached due to censoring caused by a higher than expected study drop-out or 
non-compliance stemming from the COVID-19 pandemic.  
An overview of the endpoints and operating characteristics is shown in Table 9-1: 
 
Table 9-1 
Summary of Endpoint Analysis 
Accrual per month 
40 
Randomization allocation 
1:1 
Endpoint: 
PFS: Primary 
endpoint 
OS: Secondary 
endpoint 
 Power 
90% 
90% 
 Alpha allocated (2-sided) 
0.05 
0.05 
 # of interim analyses (approximate information fraction) 
1 (40%) 
Futility, non-binding 
(1-sided) 
3 (27%, 50%, 75%) 
Efficacy 
 Assumed median, control (months) 
11.6 
48 
 Assumed median, experimental (months) 
17.6 
65.8 
 Assumed HR 
0.66 
0.73 
 Number of events 
249 
433 
 N for analysis 
440 (PITT population) 
840 (ITT Population) 
 Time to enroll (months) 
11 
21 
 Time to trigger event (months) 
23 
69 
 Maximum HR to reject Ho (experimental median 
in months) 
0.78 (14.9)  
0.824 (58.25) 
Minimum difference in medians (months) to reject Ho 
(under standard assumptions) 
3.3 
10.25 
9.6 
Interim Analyses 
The number of events required to evaluate OS is based upon the most accurate 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. 

 
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Three interim analyses of OS are planned at approximately the 27%, 50% and 75% information 
fractions, employing a Lan-DeMets O’Brien-Fleming alpha-spending function. Details and 
boundaries for these interim and the final analysis are shown in the table below: 
 
1st Interim 
2nd Interim 
3rd Interim 
Final 
Approximate information fraction 
27% 
50% 
75% 
100% 
Approximate # of events 
117 
217 
325 
433 
Maximum HR to reject Ho 
0.464 
0.668 
0.77 
0.824 
Critical p-value to reject Ho 
0.0000324 
0.003 
0.018 
0.044 
Rejection of the null hypotheses for OS at the first interim analysis at about 27% information is 
not expected: it is designed primarily as an administrative analysis, will coincide with the 
primary analysis of PFS and will be performed only if the null hypothesis for PFS is rejected. 
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 OS will depend upon the 
actual information fraction at the time of the analyses.  
If null hypothesis of no differences in OS is rejected at a planned interim OS analysis in favor of 
the arm with cabozantinib plus nivolumab/ipilimumab, no subsequent testing of OS is planned. 
To help limit exposure to the experimental regimen should interim data suggest it is unlikely to 
demonstrate superior efficacy, a non-binding futility analyses of PFS is planned to be performed 
at the 40% information fraction (approximately 100 events) for PFS. The analysis will be based 
upon radiographic evaluations per the BIRC. Results will be reviewed by the IDMC and actions 
taken as described in Section 12.2. 
10 
OTHER ANALYSES 
10.1 
Pharmacokinetic Analyses 
The plasma concentration of cabozantinib will be analyzed by 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.  

 
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Serum concentrations of nivolumab and ipilimumab will also be measured and summarized 
by visit.  
10.2 
Immunogenicity Analyses 
Results of anti-drug antibody (ADA) testing (immunogenicity) 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, TMB) 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 
eCRFs 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 eCRF database (ie, electronic data capture 
[EDC] system). Study databases will be subject to electronic and manual quality assurance 
procedures. 
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 Sponsor’s 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 and will not be authors on publications resulting from 
the study. IDMC members will be selected for their expertise in oncology.   
This IDMC will convene regularly, including a safety assessment after a total of 30 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 
• Review the results of a futility analysis of PFS (as described in Section 9.6) and make a 
recommendation, described below. 

 
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Safety data will be provided at regular intervals to the IDMC in the form of unblinded 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. 
For the futility analysis (described in Section 9.6):  
• If the results of the futility analysis yield an observed HR for PFS per BIRC of < 1.059 
(and in the absence of significant safety concerns), the IDMC will recommend the trial 
continue. Note that the boundary of 1.059 is based on the 40% information fraction and 
may have to be recomputed based on the actual number of events observed. 
• If the results of the futility analysis yield an observed HR for PFS per BIRC of ≥ 1.059, 
the IDMC will refer the analysis results and a recommendation to a Sponsor Executive 
Committee (composed of individuals not involved in day-to-day trial conduct). The 
Executive Committee will review the analysis results and IDMC recommendation to 
make a decision about whether the trial will continue or be declared futile. 
• If the trial is declared futile, study actions may include, but are not limited to 
discontinuing enrollment and/or discontinuing study treatment for study subjects. 
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 
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 5.7.6.3). The BIRC will 
be comprised of board-certified radiologists who will determine radiographic response and 

 
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progression following randomization. Additional imaging results may be requested by the 
Sponsor for BIRC review. 
Additional details regarding BIRC member qualification, training, methods, procedures, and 
other issues relevant to committee operations will be described in the BIRC Charter. 
12.4 
Clinical Steering Committee (CSC) 
The Clinical Steering Committee consists of physicians who have an expertise in treating 
patients with RCC. The CSC will provide critical scientific guidance including, but not limited 
to, protocol design and implementation and interpretation of clinical study results.  
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 Code of 
Federal Regulations, 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 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 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 

 
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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. 
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. 
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). 
15 
CONDITIONS FOR TERMINATING THE STUDY 
The study will be considered complete if any of the following criteria apply: 
- 
futility analysis of PFS: the trial has been declared futile by the Sponsor, or 
- 
primary analysis of PFS: null hypothesis is not rejected, or  
- 
primary analysis of PFS: null hypothesis is rejected for PFS and the null hypothesis is 
rejected for OS (or the final planned analysis for OS has been conducted). 

 
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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. 
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; physician’s and nurse’s 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. 

 
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16.2 
Source Documents and Background Data 
Upon request, the Investigator will make available for review to 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. 
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 EDC screens or forms for studies that utilize EDC. 
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: 

 
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• 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”) 
• 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. 
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. 
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. 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 
Albiges L, Tannir NM, Burotto M, McDermott DF, Plimack ER, Barthélémy P, Porta C, et al. 
Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal 
cell carcinoma in CheckMate 214: 4-year follow-up and subgroup analysis of patients 
without nephrectomy. Ann Oncol. 2020;31 (Suppl 4):S559–S560. Abstract 711P. 
Apolo AB, Mortazavi A, Stein M, Pal SK, Davarpanah N, Parnes HL, et al. A phase I study of 
cabozantinib plus nivolumab (CaboNivo) in patients (pts) refractory metastatic 
urothelial carcinoma (mUC) and other genitourinary tumors. Ann Oncol. 
2016;27(suppl 6). Abstract 774PD. 
Apolo AB, Tomita Y, Lee M-J, Lee S, Frosch A, Steinberg SM, et al. Effect of cabozantinib on 
immunosuppressive subsets in metastatic urothelial carcinoma. J Clin Oncol. 
2014;32(suppl_15). Abstract 4501. 
Banumathy G, Cairns P. Signaling pathways in renal cell carcinoma. Cancer Biol Ther. 
2010;10(7):658-64. 
Choueiri TK, Powles T, Burotto M, Bourlon MT, Zurawski B, et al. Nivolumab + cabozantinib 
vs sunitinb in first-line treatment for advanced renal cell carcinoma: First results from 
the randomized Phase III CheckMate 9ER trial. Ann Oncol. 2020;31 
(Suppl 4):S1159. Abstract 6960_PR. 
Choueiri TK, Hessel C, Halabi S, Sanford B, Michaelson MD, Hahn O, et al. Cabozantinib 
versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate 
or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free 
survival by independent review and overall survival update. Eur J Cancer. 
2018;94:115-125. 
Choueiri TK, Hessel C, Halabi S, Sanford B, Hahn O, Michaelson MD, et al. Progression-free 
survival by independent review and updated overall survival results from Alliance 
A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy 
for patients with metastatic renal cell carcinoma. Ann Oncol. 2017;28(suppl_5). 
Abstract LBA38. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 144 of 193 
Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib 
versus everolimus in advanced renal cell carcinoma (METEOR): final results from a 
randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-27. 
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib 
versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015;373(19):1814-23. 
Ciamporcero E, Miles KM, Adelaiye R, Ramakrishnan S, Shen L, Ku S, Pizzimenti S, et al. 
Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma 
models. Mol Cancer Ther. 2015;14(1):101-10. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. US Department of 
Health and Human Services. National Institutes of Health. National Cancer Institute. 
Published: November 27, 2017 [cited 30 April 2018]. Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in 
progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-46. 
Escudier B, Sharma P, McDermott DF, George S, Hammers HJ, Srinivas S, et al. CheckMate 
025 randomized Phase 3 study: Outcomes by key baseline factors and prior therapy 
for nivolumab versus everolimus in advanced renal cell carcinoma. Eur Urol. 
2017;72(6):962-971.  
FDA. Guidance for industry: Clinical trial endpoints for the approval of cancer drugs and 
biologics. December 2018. 
Garcia-Tsao G, Sanyal AJ, Grace ND, Carey WD, et al. Prevention and management of 
gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol. 
2007;102(9):2086-102. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 145 of 193 
Gibney GT1, Aziz SA, Camp RL, Conrad P, Schwartz BE, Chen CR, et al. c-Met is a prognostic 
marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol. 
2013;24(2):343-9. 
Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and 
efficacy of nivolumab in combination with ipilimumab in metastatic renal cell 
carcinoma: The CheckMate 016 Study. J Clin Oncol. 2017;35(34):3851-3858. 
Herbst RS, Earon E, Kim D-W, Cho BC, Gadgeal S, Léna H et al. KEYNOTE-010: Durable 
clinical benefit in patients with previously treated, PD-L1-expressing NSCLC who 
completed pembrolizumab. J Thor Oncol 2016; 12(1_suppl). Abstract 0A03.07. 
Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et al. External 
validation and comparison with other models of the International Metastatic Renal-
Cell Carcinoma Database Consortium prognostic model: a population-based study. 
Lancet Oncol. 2013;14(2):141-8. 
Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for 
overall survival in patients with metastatic renal cell carcinoma treated with vascular 
endothelial growth factor-targeted agents: results from a large, multicenter study. 
J Clin Oncol. 2009;27(34):5794-9. 
Hessel C, Mangeshkar M, Motzer RJ, Escudier B, Powles TB, Schwab G, Choueiri TK. 
Evaluation of the novel “trial within a trial” design of METEOR, a randomized phase 
3 trial of cabozantinib versus everolimus in patients (pts) with advanced RCC. 
Ann Oncol. 2016;27(6):266-95. Abstract 8158. 
Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK. Rising incidence of small renal 
masses: a need to reassess treatment effect. J Natl Cancer Inst. 2006 Sep 
20;98(18):1331-4. 
Kwilas AR, Ardiani A, Donahue RN, Aftab DT, Hodge JW. Dual effects of a targeted small-
molecule inhibitor (cabozantinib) on immune-mediated killing of tumor cells and 
immune tumor microenvironment permissiveness when combined with a cancer 
vaccine. J Transl Med. 2014;12:294.  

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 146 of 193 
Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial 
immunotherapy for castration-resistant prostate cancer. Nature. 
2017;543(7647):728-32. 
Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-
related adverse events with immune checkpoint blockade: a comprehensive review. 
Eur J Cancer. 2016;54:139-48. 
Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, et al. 
Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal 
cell carcinoma: extended follow-up of efficacy and safety results from a randomised, 
controlled, phase 3 trial. Lancet Oncol. 2019;20(10):1370-1385. 
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. 
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. 
N Engl J Med. 2018;378(14):1277-90. 
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab 
versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015;373(19):1803-13.  
Nadal RM, Mortazavi A, Stein M, Pal SK, Davarpanah NN, Parnes HL et al. Results of phase I 
plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo 
plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) 
and other genitourinary (GU) malignancies. J Clin Oncol. 2018;36(suppl 6). Abstract 
515. 
Nadal R, Mortazavi A, Stein M, Pal SK, Davarpanah N, Parnes H, et al. Final results of a Phase I 
study of cabozantinib + nivolumab and cabozantinib + nivolumab + ipilimumab in 
patients with metastatic urothelial carcinoma and other genitourinary malignancies. 
Ann Oncol. 2017;28:(suppl 5):v295-v329. Abstract 8460. 
NCCN. National Comprehensive Cancer Network Guidelines. Kidney Cancer. Version 3.2018. 
February 6, 2018.  

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Robert C, Long G, Schachter J, Arance A, Grob J, Mortier L, et al. Long-term outcomes in 
patients with ipilimumab-naive advanced melanoma in the phase 3 KEYNOTE-006 
study who completed pembrolizumab treatment; Journal of Clinical Oncology 2017 
35:(15_suppl). Abstract 9504. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 
Song EK, Tai WM, Messersmith WA, Bagby S, Purkey A, Quackenbush KS, et al. Potent 
antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal 
cancer patient-derived tumor explant model. Int J Cancer. 2015;136(8):1967-75.  
Spigel DR, McLeod M, Hussein M, Waterhouse D, Einhorn L, Horn L, et al. Randomized results 
of fixed-duration (1-year) vs continuous nivolumab in patients with advanced non-
small cell lung cancer. Ann Oncol. 2017;28(Suppl_5). Abstract 12970. 
Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and 
predictive models in renal cell carcinoma: a contemporary review. Eur Urol. 
2011;60(4):644-61.  
Tolaney SM, Ziehr DR, Guo H, Ng MR, Barry WT, Higgins MJ, et al. Phase II and biomarker 
study of cabozantinib in metastatic triple-negative breast cancer patients. Oncologist. 
2017 Jan;22(1):25-32. 
Turnage RH, Badgwell B. Abdominal wall, umbilicus, peritoenum, mesentery, omentum and 
retroperitoneum. In: Townsend CM Jr, Beauchamp RD, Evers BM, Mattox KL, 
editors. Sabiston Textbook of Surgery. 19th ed. Philadelphia, PA: Saunders Elsevier; 
2012. p1102.  
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, double-
blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with 
disease-related anemia. J Clin Oncol. 2007;25(9):1027-32.  
Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-
CTLA4 antibody) causes regression of metastatic renal cell cancer associated with 
enteritis and hypophysitis. J Immunother. 2007;30(8):825-30. 
Znaor A, Lortet-Tieulent J, Laversanne M, Jemal A, Bray F. International variations and trends 
in renal cell carcinoma incidence and mortality. Eur Urol. 2015;67(3):519-30.  

 
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Zhou L, Liu XD, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and AXL overcomes 
resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 
2016;35(21):2687-97. 

 
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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 3 Day 1 [W3D1]), 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, bone scans) as well as EQ-5D-5L will be scheduled based on the date of 
randomization 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 time through 
W14D1 and within ± 5 days of the nominal visit day after W14D1, unless otherwise indicated. If study treatment is held or missed 
after W1D1, assessments should continue following the schedule described below. 
Unscheduled safety assessments, if required as defined in the protocol, are to be performed weekly (or more frequently as clinically 
indicated). See Section 5.5 for further details. 
Special accommodations during the global COVID-19 pandemic are described in Appendix K.

 
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Appendix A: Schedule of Assessments 
 
Pre-
randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 14 (± 5 days) 
First Post-
Treatment 
Follow-Up Visit 
(FU-1; 30+14 days 
after decision to 
discontinue study 
treatment)m 
Second Follow-Up 
Visit (FU-2; 
100±14 days after 
decision to 
discontinue study 
treatment)m 
W
3 
D 
1 
W
4 
D 
1 
W 
6 
D 
1 
W
7 
D 
1 
W 
9 
D 
1 
W
10
D
1 
W
12
D
1 
W
14
D
1 
Informed consent                    
(Section 5.1) 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical and 
cancer history (Section 5.7.1) 
≤ 28 days 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination + weight   
(Section 5.7.2) 
≤ 14 days           
(with height) 
X                      
(prior to first dose; 
symptom-directed) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
Vital signs                                      
(Section 5.7.3) 
≤ 14 days 
X                  
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
IMDC prognostic score 
(Section 3.4) 
≤ 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
Karnofsky performance status     
(Section 5.7.2) 
≤ 14 days 
X                  
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, etc) 
X 
 
12-lead ECG                                 
(Section 5.7.4)c  
≤ 14 days 
Xd              
(prior to first dose) 
 
 
 
X 
 
 
 
X 
Every 12 weeks 
(W26D1, W38D1, etc) 
X 
 
Hematologye (Section 5.7.5) 
≤14 days 
Xd              
(prior to first dose) 
X 
X 
X 
X 
X 
X 
X 
X 
Every 4 weeks 
(W18D1, W22D1, etc) 
X 
 
Serum chemistrye 
(Section 5.7.5) 
≤ 14 days 
Xd              
(prior to first dose) 
X 
X 
X 
X 
X 
X 
X 
X 
Every 4 weeks 
(W18D1, W22D1, etc) 
X 
 
 

 
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Appendix A: Schedule of Assessments (continued) 
 
Pre-
randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 14 (± 5 days) 
First Post-
Treatment 
Follow-Up Visit 
(FU-1; 30+14 
days after 
decision to 
discontinue study 
treatment)m 
Second Follow-Up 
Visit (FU-2; 
100±14 days after 
decision to 
discontinue study 
treatment)m 
W
3 
D 
1 
W
4 
D 
1 
W 
6 
D 
1 
W 
7 
D 
1 
W
9 
D 
1 
W 
10 
D
1 
W
12 
D 
1 
W 
14 
D 
1 
PT/INR and PTT 
(Section 5.7.5) 
≤ 14 days 
Xd             
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
Thyroid function test  
(Section 5.7.5) 
≤ 14 days 
 
 
X 
 
X 
 
X 
 
X 
Every 8 weeks 
(W22D1, W30D1, 
etc) 
X 
 
Follicle stimulating hormone f 
(Section 5.7.5) 
≤ 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis screeningg 
(Section 5.7.5) 
≤ 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing (if required by 
local regulations; Section 
5.7.5) 
≤ 14 days 
 
 
 
 
 
 
 
 
 
 
 
 
UPCR  
(Section 5.7.5).  
(In addition, 24-h urine protein 
by local lab at Investigator’s 
discretion.) 
≤ 14 days 
Xd             
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
Urinalysis by local labe 
(Section 5.7.5) 
≤ 14 days 
Xd             
(prior to first dose) 
X 
X 
X 
X 
X 
X 
X 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
Serum or urine pregnancy test 
by local labe (Section 5.7.5) 
≤ 7 days  
(serum) 
Xd             
(serum: prior to 
first dose) 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1, 
etc) 
X 
 
Tumor tissue (Section 5.7.11) 
Xh 
 
 
 
 
Xl 
 
 
 
 
 
 
 
 
 

 
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Appendix A: Schedule of Assessments (continued) 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 14 (± 5 days) 
First Post-
Treatment 
Follow-Up Visit 
(FU-1; 30+14 
days after 
decision to 
discontinue study 
treatment)m 
Second Follow-Up 
Visit (FU-2; 100±14 
days after decision 
to discontinue 
study treatment)m 
W
3 
D 
1 
W
4 
D 
1 
W 
6 
D 
1 
W 
7 
D 
1 
W 
9 
D 
1 
W
10
D
1 
W
12
D
1 
W
14
D
1 
Tumor assessment:  
CT/MRI  
Chest, Abdomen, Pelvis  
(Section 5.7.6) 
≤ 28 days 
CT of CAP or CT chest and MRI of abdomen/pelvis will be performed in all subjects at screening, at W10D1 (± 7 days), and every 8 weeks 
(± 7 days) after randomization through Week 50. After Week 50, these assessments will be performed every 12 weeks (± 7 days). 
 
Tumor assessments should continue on the protocol-defined schedule, relative to the date of randomization, regardless of whether study 
treatment is given, reduced, held or discontinued. The same imaging modalities used at screening will be used for subsequent tumor 
assessments after randomization. 
 
For subjects who discontinue study treatment before Investigator-assessed radiographic PD, tumor assessments are to continue per the 
protocol defined schedule until Investigator-assessed radiographic PD per RECIST 1.1. 
For subjects who continue to receive study treatment after investigator-assessed radiographic PD because of investigator-assessed clinical 
benefit that outweighs the potential risks, tumor assessments are to continue per the protocol defined schedule until study treatment is 
permanently discontinued.  
 
Tumor assessment:  
MRI/CT Brain                                    
(Section 5.7.6) 
≤ 28 days 
 
MRI (or CT) of the brain will be performed at screening in all subjects at screening. After randomization, MRI (or CT) scans of the brain 
are only required in subjects with known brain metastasis or if clinically indicated by signs and symptoms suggestive of new central 
nervous system (CNS) metastases. Assessments after randomization will be performed at the same frequency as imaging for CAP. MRI is 
the preferred method for brain. If CT of the brain is performed instead of MRI, ambiguous results must be confirmed by MRI unless MRI 
is contraindicated. 
 
Tumor assessments should continue on the protocol-defined schedule, relative to the date of randomization, regardless of whether study 
treatment is given, reduced, held or discontinued. The same imaging modalities used at screening will be used for subsequent tumor 
assessments after randomization. 
 
For subjects who discontinue study treatment before Investigator-assessed radiographic PD, tumor assessments are to continue per the 
protocol defined schedule until Investigator-assessed radiographic PD per RECIST 1.1. 
For subjects who continue to receive study treatment after investigator-assessed radiographic PD because of investigator-assessed clinical 
benefit that outweighs the potential risks, tumor assessments are to continue per the protocol defined schedule until study treatment is 
permanently discontinued. 
 
Tumor assessment:  
Bone scan  
Whole body  
 (Section 5.7.6) 
≤ 28 days 
Technetium bone scans should be performed at screening for all subjects. After randomization, bone scans will be performed in 
subjects with known bone metastases and otherwise as clinically indicated per standard of care. Any soft tissue lesions 
associated with identified bone lesions must be imaged by CT/MRI and assessed in alignment with the CAP assessments. Bone 
scan findings alone cannot be used for the determination of progression or response and need to be corroborated by CT or MRI 
(which will be used as the basis for RECIST evaluations). 
 
 

 
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Appendix A: Schedule of Assessments (continued) 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 14 (± 5 days) 
First Post-
Treatment 
Follow-Up Visit 
(FU-1; 30+14 days 
after decision to 
discontinue study 
treatment)m 
Second 
Follow-Up Visit 
(FU-2; 100±14 
days after 
decision to 
discontinue 
study 
treatment)m 
W 
3 
D 
1 
W
4
D
1 
W
6
D
1 
W
7
D
1 
W
9
D
1 
W
10
D
1 
W
12
D
1 
W
14
D
1 
HRQOL- EQ-5D-5Li               
(Section 5.7.7 ) 
≤ 14 days 
 
W4D1, W7D1, W10D1, W14D1 then every 4 weeks thereafter.  
 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 5.7.6. Consequently these 
assessments may be required in the Post Treatment Period for some subjects.  
Health Care Resource 
Utilization (Section 5.7.8) 
 
Hospital admissions, emergency room visits, intensive care unit admissions, surgeries, and transfusions from randomization through the 
FU-2 visit.   
Cabozantinib/placebo PK 
plasma samplesj,k                   
(Section 5.7.9) 
 
X                   
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
 
 
 
Nivolumab+ipilimumab PK 
serum samplesk                   
(Section 5.7.9) 
 
X                   
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
W26D1 
X 
X 
Immunogenicity blood samplek  
(Section 5.7.10) 
 
X                   
(prior to first dose) 
 
 
 
 
 
 
 
X 
W26D1 
X 
X 
Pharmacogenetic blood 
samplek  (Section 5.7.11) 
 
X                   
(prior to first dose) 
 
 
 
 
 
 
 
 
 
 
 
Immune cell profiling blood 
samplek (Section 5.7.11) 
 
 X                  
(prior to first dose)  
 
 
 
X 
 
 
 
X 
 
 
 
Plasma biomarker samplesk 
(Section 5.7.11) 
 
X                   
(prior to first dose) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Cell and/or pharmacogenomic 
blood samplek (Section 5.7.11) 
 
X 
(prior to first dose) 
 
 
 
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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Protocol XL184-313 Protocol Amendment 3.0 
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Appendix A: Schedule of Assessments (continued) 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
After Beginning of 
Week 14 (± 5 days) 
First Post-
Treatment 
Follow-Up Visit 
(FU-1; 30+14 days 
after decision to 
discontinue study 
treatment)m 
Second 
Follow-Up Visit 
(FU-2; 100±14 
days after 
decision to 
discontinue 
study 
treatment)m 
W 
3 
D 
1 
W
4
D
1 
W
6
D
1 
W
7
D
1 
W
9
D
1 
W
10
D
1 
W
12
D
1 
W
14
D
1 
Adverse events              
(Section 8) 
Document new or worsening AEs from informed consent for SAEs and from first dose for nonserious AEs. Continue monitoring through 30 days (100 days for 
unrelated SAEs [Table 8-1]) after the date of the decision to permanently discontinue study treatment. 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). 
 
Cabozantinib / Placebo dosing 
(Section 6.1.1.1 / 6.1.1.2)  
 
Cabozantinib or placebo tablets given on W1D1 after nivolumab/ipilimumab infusion.  
Taken once daily at home thereafter until study treatment is discontinued. 
 
 
Nivolumab dosing 
(Section 6.1.1.3; weight-based 
dose W1D1, W4D1, W7D1, 
W10D1, flat dose from 
W14D1 onwards) 
 
 
X 
 
X 
 
X 
 
X 
 
Nivolumab will be 
administered as an IV 
infusion at the clinic 
W14D1 and every 4 weeks 
until treatment is 
discontinued (to a 
maximum of 2 years). 
 
 
 
Ipilimumab dosing 
(Section 6.1.1.3; weight-based 
dose W1D1, W4D1, W7D1, 
W10D1) 
 
X 
 
X 
 
X 
 
X 
No further doses 
 
 
Dispense/return of oral study 
drug and compliance 
accounting (Section 6.5)n 
 
X 
 
X 
 
X 
 
X 
 
X 
Every 4 weeks 
(W18D1, W22D1 
etc) 
 
 
Additional systemic anti-
cancer treatment and survival 
status (Sections 5.7.12) 
 
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. 

 
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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 for females of child-bearing potential) 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, and urinalysis laboratory samples must be collected within 72 hours and the results be reviewed before any study treatment 
infusion administered on study. These assessments are not required prior to the first dose if there has been no change in subject’s clinical status since 
screening. Results (with the exception of routine urinalyses and pregnancy tests) must be provided to the local laboratory management vendor. See 
Section 5.7.5 and the Laboratory Manual for more detailed information on laboratory assessments.  
f For women under the age of 55 years, confirm menopause as needed. 
g Hepatitis B surface antigen and Hepatitis C antibody (with reflex testing of HCV RNA if antibody test is positive) to be assessed at screening. 
h Shipment of archival tumor tissue (unstained slides or paraffin block) to the study central laboratory prior to randomization. The tissue can be obtained/sampled 
from any organ except brain or bone and must be biopsied no more than 2 years prior to the date of informed consent. Alternatively, a fresh tumor sample must 
be obtained and shipped to the study central laboratory prior to randomization if archival tissue is unavailable or inadequate. 
i 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. 
j For each on-treatment visit, the PK sample should be collected approximately 8 or more hours after the previous dose of cabozantinib/placebo, and if 
cabozantinib/placebo will be administered on that day, should be collected prior to cabozantinib/placebo administration. The investigator will ask the subject 
for the date and time of the most recent prior dose of cabozantinib/placebo and this information will be recorded on the appropriate CRF page.  
k  Central laboratory assessements are required for these measurements. 
l An optional biopsy can be collected approximately 6 weeks after the first dose of study treatment. 
m Date of the decision to permanently discontinue study treatment by the subject is defined as the later of the decision to permanently discontinue study treatment 
or the last dose of study treatment. 
n 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. 
 
 

 
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Appendix B: Maintenance Phase  
When sufficient data have been collected to adequately evaluate all study endpoints, and after 
treatment assignment has been unblinded, the Sponsor may initiate a 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 for 
regulatory purposes. 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 active study treatment until a criterion 
for protocol-defined discontinuation has been met (Section 3.6.1). Subjects in the Maintenance 
Phase 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 as necessary. 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. 

 
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Study drug accountability is to continue as described in Section 6.5. 
 
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. 
 
 
 
 

 
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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 
Nivolumab infusion: Once every 4 weeks 
(maximum of 2 years of treatment in total);  
Cabozantinib (oral): Daily. 
Study treatment may continue until a 
criterion for discontinuation is met 
(Section 3.6.1).  
- 
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, medication 
errors with sequelae) 
Submit reports to Sponsor per Section 8.2 
Reporting of AEs (including 
AESIs): 
• 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: Karnofsky Performance Status Criteria 
ECOG Performance Status Scale (reference only) 
Karnofsky Performance Status Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (eg, light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

 
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Appendix D: Highly Effective Methods of Contraception 
In Inclusion Criterion #10 (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 until the end of relevant systemic exposure, defined as 5 months for women, and 
7 months for men, after the last dose of study treatment.   
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. 
Contraception guidance for female subjects of childbearing potential 
One of the highly effective methods of contraception listed below, in combination with one 
acceptable barrier method below, is required during study duration and until the end of relevant 
systemic exposure, defined as 5 months after the last dose of study treatment. Local laws and 
regulations may require use of alternative and/or additional contraception methods.  
Highly effective contraceptive methods that are user dependent: These methods have a failure 
rate of < 1% per year when used consistently and correctly. Typical use failure rates may differ 
from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
o Oral or injectable 
Highly effective contraceptive methods that are user independent: 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 

 
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• Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system 
• Intrauterine device 
• Bilateral tubal occlusion 
• Vasectomized partner 
o A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the female subject of childbearing potential 
and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used 
• Sexual abstinence 
o Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study drug. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
- 
It is not necessary to use any other method of contraception when complete 
abstinence is elected. 
- 
Female subjects of childbearing potential who choose complete abstinence must 
continue to have pregnancy tests per the protocol. Acceptable alternate methods 
of highly effective contraception must be discussed in the event that any of these 
subjects chooses to forego complete abstinence. 
 

 
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Acceptable barrier methods for use in combination with a highly effective method: 
• Male or female condom with or without spermicide 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
Unacceptable as a Sole Method of Contraception: 
• Male or female condom with or without spermicide. Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception of which inhibition of ovulation is not the 
primary mechanism of action 
• Periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) 
• Withdrawal (eg, coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method 
 

 
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Contraception guidance for male participants with partner(s) of childbearing potential  
Male subjects with female partners of childbearing potential are eligible if they agree to the 
following during the treatment and until the end of relevant systemic exposure, defined as 
7 months after the last dose of study treatment. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the Investigator. 
• Male subjects are required to use a condom during study duration and until end of 
relevant systemic exposure, defined as 7 months after the last dose of study treatment. 
• Female partners of male subjects in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the 
last dose of treatment in the male participant. 
Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the last dose of study treatment. Refrain from 
donating sperm for the duration of the study treatment and until 7 months after the last dose of 
study treatment. 
 
 
 
 

 
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Appendix E: Management Algorithms  
These general guidelines constitute guidance to the Investigator and may be supplemented 
by discussions with the Medical Monitor representing the Sponsor. The guidance applies to 
all immuno-oncology agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. 
The oral equivalent of the recommended IV doses may be considered for ambulatory 
patients with low-grade toxicity. The lower bioavailability of oral corticosteroids should be 
taken into account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 
For recommendations on dose modifications of BOTH cabozantinib/placebo treatment and 
nivolumab/ipilimumab treatment due to hepatocellular toxicity, see Section 6.6.1. 
 

 
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Appendix F: Response Evaluation Criteria in Solid Tumors Version 1.1 (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 timepoint 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. 
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 

 
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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 timepoint 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. 
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 

 
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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 
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. 

 
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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 may be evaluated for changes but will not be used to determine 
progressive disease 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 tumor has met criteria 
for response or stable disease in order to differentiate between response (or stable disease) and 
progressive disease.    
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. 
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. 
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. 

 
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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. 
 

 
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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. 
 
 
 

 
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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. 
 
 

 
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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, 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 isnot 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 later than 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. 
 

 
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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 later 
than 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. 
 
 

 
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Appendix G: 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/star fruit/Seville oranges 
Idelalisib 
Nefazodone 
Carbamazepine 
Efavirenz 
Enzalutamide 
Erythromycin 
Mitotane 
Modafinil 
Nevirapine 
Oxcarbazepine 
Phenytoin 
Rifampin 
St. John’s Wort 

 
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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 

 
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Appendix H: Collection, Follow-Up, and Documentation Requirements for AEs, AESIs, 
and SAEs 
All AEs that are not serious and not AESIs (AEs of special interest; see Table 8-1) that start or 
worsen after the first dose of study treatment through the 30-day post-treatment follow-up 
(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 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 (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 and 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 (as defined above), 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 (as defined 
above), 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.  

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 184 of 193 
A summary of the event surveillance (Table H-1) and follow-up requirements (Table H-2) are 
shown in the following page:

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Table H-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 
8-1) 
IC 
FU-2 
IC 
FU-2 
Related SAE 
IC 
FU-2 
IC 
ever 
AE, adverse event; AESI, adverse event of special interest (Table 8-1); 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 H-2: Requirements for Following up on Events Documented and Reported in Table H-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 8-1) 
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 8-1); 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 
 
 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 186 of 193 
Appendix I: EuroQoL Questionnaire EQ-5D-5L, USA (English) Sample Version 
Under each heading, please the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking   
 
 
 
❑ 
I have slight problems walking  
 
 
 
❑ 
I have moderate problems walking 
  
 
 
❑ 
I have severe problems walking 
  
 
 
❑ 
I am unable to walk 
 
 
 
 
 
❑ 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
❑ 
I have slight problems washing or dressing myself   
❑ 
I have moderate problems washing or dressing myself  
❑ 
I have severe problems washing or dressing myself   
❑ 
I am unable to wash or dress myself   
 
 
❑ 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
❑ 
I have slight problems doing my usual activities  
 
❑ 
I have moderate problems doing my usual activities  
❑ 
I have severe problems doing my usual activities  
 
❑ 
I am unable to do my usual activities  
 
 
❑ 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
❑ 
I have slight pain or discomfort  
 
 
 
❑ 
I have moderate pain or discomfort   
 
 
❑ 
I have severe pain or discomfort  
 
 
 
❑ 
I have extreme pain or discomfort  
 
 
 
❑ 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
❑ 
I am slightly anxious or depressed  
 
 
 
❑ 
I am moderately anxious or depressed  
 
 
❑ 
I am severely anxious or depressed   
 
 
❑ 
I am extremely anxious or depressed  
 
 
❑ 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 187 of 193 
• We would like to know how good or bad your health is  
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health      
 you can imagine 
The worst health    
 you can imagine 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 188 of 193 
TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below.  
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
Page 189 of 193 
Appendix J:  Child-Pugh Scoring System 
Modified Child-Pugh classification of severity of liver disease (Garcia-Tsao et al 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% 
 
 
 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Appendix K: COVID-19 Instructions 
This appendix describes contingencies and accommodations to address 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 patient 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 when randomized subjects 
may not physically access the site clinic, the accommodations outlined below may be permitted 
if allowed by local and other applicable regulations (Note: special accommodations are not 
permitted for screening assessments). 
Safety Assessments 
Safety assessments should still be performed within the protocol-defined windows with potential 
modification as outlined below.  
If a safety assessment visit cannot take place at the study site, laboratory tests (eg, bloodwork), 
ECGs, vital signs, and as appropriate, physical exams should be performed remotely (eg, with a 
local physician), if possible. Any remote laboratory assessments must be performed by 
laboratories accredited by the local jurisdiction or at the patient’s home with a qualified home 
visit health professional. It is expected that safety laboratory assessments be obtained at every 
protocol-specified visit and, at a minimum, are to include complete blood count, ALT, AST, total 
bilirubin, serum creatinine, electrolytes, and (as applicable) pregnancy tests.   
In addition, the Investigator or designee must regularly contact the subject (eg, by phone or video 
call) to ascertain the subject’s condition and occurrence of any symptom-based AEs per the 
relevant protocol-defined visit schedule. 
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 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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may be possible to continue with study treatment, but this must be discussed on a case-by-case 
basis with the Medical Monitor.  
If a safety assessment visit is delayed beyond the protocol-specified window, study treatment 
must be held until a safety follow-up visit can occur at the study site, at a local health care 
provider’s office, or remotely (eg, via telephone or videoconference). Study treatment can be 
resumed after a treatment hold if treatment criteria per protocol are met per the Investigator’s 
judgment. Delays in safety assessment visits outside the protocol-defined windows need to be 
reported as deviations. 
Tumor Assessments 
Tumor assessments should be continued as required per protocol at the imaging facility where 
screening scans have been performed or at a qualified local imaging facility. Imaging should be 
performed within or as close to the study visit window as possible for scheduled imaging time 
points. If missed or delayed tumor assessments cannot be avoided, study treatment can be 
continued if safety assessment visits are being conducted and there is no safety concern per 
Investigator’s judgment. Delays in tumor imaging or missed tumor imaging need to be reported 
as deviations. 
Treatment Visits 
Administration of study treatment should continue as required per protocol. The study Medical 
Monitor should be notified if a dose hold is planned beyond the allowed protocol-defined 
window. Delays in administration of study treatment outside the allowed protocol-defined 
window need to be reported as deviations. 
Note: If an interruption of all study treatment for greater than 12 weeks occurs, subjects 
are required to permanently discontinue study treatment unless permitted to continue by 
the Sponsor.  
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 a satellite site or another 
study site location but under the supervision of the subject’s study site Investigator, with the 
approval of the Sponsor and in accordance with all applicable regulations.   

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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Informed Consent 
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 (including consent for 
remote visits and delivery of oral treatment to subject’s home). If additional consent 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. 
Subjects Who Develop COVID-19 
Subjects who develop COVID-19 while on study may be allowed to continue study treatment if 
the Investigator determines that the risk-benefit ratio for the subject favors continued treatment, 
and the Sponsor approves the decision. 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 must assess whether the event should 
be reported as an SAE using their clinical judgment. The Investigator should further consider 
whether the diagnosis meets the criteria of being a significant medical event. 
Documentation of Data Impacted by COVID-19 
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. 
When recording data missing, impacted, or related to COVID-19 in the electronic CRFs, the 
conventions listed in the table 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. 

 
CONFIDENTIAL 
Protocol XL184-313 Protocol Amendment 3.0 
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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’. Refer to 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”. 
o 
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.” 
o 
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”. Also, 
“Reason for dose delay” should be entered as “Other”. Describe the reason in 
the “Specify” field, including the term “COVID-19” (if/when ‘Specify’ field is 
available). 
o 
For example – Other, Specify: “Subject unable to travel due to COVID-19 
restrictions.”