A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects With Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed After Prior Vascular Endothelial Growth Factor Receptor (VEGFR) -Targeted Therapy
Phase: PHASE3
Conditions: Differentiated Thyroid Cancer
Sponsor: Exelixis

CONFIDENTIAL 
This document (and all copies thereof) is the property of Exelixis, Inc. and contains valuable trade secrets and 
confidential information, including proprietary technical and business information (hereinafter "Confidential 
Information"). By accepting this document, you agree that the Confidential Information contained herein will not be 
disclosed to others without prior written authorization from Exelixis, Inc. and shall only be used for the purposes 
intended by the document. 
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of 
Cabozantinib (XL184) in Subjects with Radioiodine-Refractory 
Differentiated Thyroid Cancer Who Have Progressed after Prior 
VEGFR-Targeted Therapy 
 
 
PROTOCOL NUMBER: 
XL184–311 
STUDY TREATMENT: 
Cabozantinib vs Placebo 
IND NUMBER: 
113,446 
EudraCT NUMBER: 
2018-001771-21 
SPONSOR: 
Address as of 30 April 2018: 
Exelixis, Inc. 
210 E. Grand Ave. 
South San Francisco, CA 94080 
New address as of 11 June 2018: 
Exelixis, Inc. 
1851 Harbor Bay Pkwy. 
Alameda, CA 94502 
MEDICAL MONITOR: 
Soham Puvvada, MD, MBA 
 
DATE FINAL: 
30 April 2018 
 
 
 

 
 
Protocol XL184-311 
Page 3 of 165 
 
 
 
PROTOCOL ACCEPTANCE FORM 
PROTOCOL TITLE:  
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study of Cabozantinib (XL184) in 
Subjects with Radioiodine-Refractory Differentiated 
Thyroid Cancer Who Have Progressed after Prior 
VEGFR-Targeted Therapy 
PROTOCOL NUMBER: 
XL184–311 
STUDY TREATMENT: 
Cabozantinib vs Placebo 
IND NUMBER: 
113,446 
EudraCT NUMBER: 
2018-001771-21 
SPONSOR: 
Address as of 30 April 2018: 
Exelixis, Inc. 
210 E. Grand Ave. 
South San Francisco, CA 94080 
New address as of 11 June 2018: 
Exelixis, Inc. 
1851 Harbor Bay Pkwy. 
Alameda, CA 94502 
MEDICAL MONITOR: 
Soham Puvvada, MD, MBA 
DATE FINAL: 
30 April 2018 
 
 
 
By my signature below, I hereby state that I have read, and agree to abide by, the instructions, 
conditions, and restrictions of the protocol or protocol amendment referenced above. 
________________________________________________________________ 
Name of Investigator (print) 
 
________________________________________________________________ 
Name of Investigator (signature) 
 
 
Date 

 
 
Protocol XL184-311 
Page 4 of 165 
 
PROTOCOL SYNOPSIS 
TITLE 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib (XL184) in Subjects 
with Radioiodine-Refractory Differentiated Thyroid Cancer Who Have Progressed after Prior 
VEGFR-Targeted Therapy 
RATIONALE  
Thyroid cancer is the most common endocrine neoplasm with an estimate of more than 56,000 
newly diagnosed cases in the United States and 298,000 cases worldwide  in 2017 (WHO 2012; 
SEER Cancer Statistics 2017). Differentiated thyroid cancer (DTC) accounts for more than 
90% of all newly diagnosed thyroid cancers and is classified histologically as papillary thyroid 
carcinoma (PTC) and follicular thyroid carcinoma (FTC). Hürthle cell carcinoma (HTC) is a 
variant of FTC. Thyroid cancer is about 2.5 times more common in women than in men, and its 
incidence has almost tripled from the mid-1990s through 2014 (Roman et al 2017; Howlader et al 
2017).  
Surgical resection by either total thyroidectomy or unilateral lobectomy, with or without lymph 
node removal, is the main treatment for DTC and can be curative (Cooper et al 2009, 
NCCN 2017). However, a considerable number of DTC patients either have inoperable locally 
advanced disease or have residual or recurrent disease after surgery. Patients with a high risk of 
disease recurrence, incompletely resected cancer, or distant metastases may receive adjuvant 
therapy with radioactive iodine (RAI). Patients who develop RAI-refractory DTC have a very 
poor prognosis with an estimated median survival time of 2.5-3.5 years (Busaidy and 
Cabanillas 2012; Durante et al 2006, Schlumberger et al 2014). 
Recent treatment advancements for patients with RAI-refractory DTC include tyrosine kinase 
inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR), which 
inhibits tumor angiogenesis and causes hypoxia in malignant tissue. Sorafenib (Nexavar™) and 
lenvatinib (Lenvima™) inhibit multiple receptor tyrosine kinases (RTKs) including VEGFR and 
are approved in the United States and the European Union for patients with locally recurrent or 
metastatic, progressive DTC that is RAI-refractory. The approval of sorafenib is based on a 
randomized, placebo-controlled Phase 3 study, which enrolled patients with locally advanced or 
metastatic RAI-refractory DTC. Prior therapy with a VEGFR-TKI or chemotherapy was not 
allowed. Sorafenib significantly improved the primary endpoint of PFS compared with 
placebo (median 11 vs 5.8 months; HR = 0.59; p-value < 0.0001) and also improved 
ORR (12% vs 0.5%; p-value < 0.0001). Similarly, an OS benefit could not be demonstrated due 
to crossover to active treatment after progression (Brose et al 2014). The approval of lenvatinib is 
also based on a randomized, placebo-controlled Phase 3 study which enrolled patients with 
RAI-refractory DTC. The majority of patients had not received prior VEGFR-TKI therapy. 
Lenvatinib significantly improved the primary endpoint of progression-free survival (PFS) 
compared with placebo (median 18 vs 3.6 months; hazard ratio [HR] = 0.21; p-value < 0.001) as 
well as objective response rate (ORR; 65% vs 1.5%; p-value < 0.001). However, there was no 
overall survival (OS) benefit in the intent-to-treat (ITT) population, possibly due to 

 
 
Protocol XL184-311 
Page 5 of 165 
post-progression crossover to active treatment (Schlumberger et al 2015). Although initial therapy 
with VEGFR-targeting TKIs provides clinical benefits by improving PFS and ORR, the majority 
of RAI-refractory DTC patients will acquire resistance to therapy and develop disease 
progression. For DTC patients who develop resistance to VEGFR-TKI therapy, options are very 
limited and more effective therapies are needed. 
A better understanding of the molecular pathogenesis and mechanisms of thyroid cancer has 
shown great promise for the development of more effective treatment strategies (Xing 2013). 
MET and VEGF signaling have been implicated in tumor neo-angiogenesis, invasion, and 
dissemination, while dysregulation of MET and VEGF pathway components has been associated 
with poor prognosis in multiple tumor types (Carmeliet and Jain 2011, Trusolino et al 2010, 
Aftab and McDonald 2011). Resistance to VEGF-targeted therapies may arise from the 
upregulation of alternative pro-angiogenic and pro-invasive signaling pathways, including the 
MET pathway (Shojaei et al 2010, Zhou et al 2016, Sennino et al 2012, Ciamporcero et al 2015). 
Combined inhibition of VEGFR and MET represents a treatment opportunity which may enhance 
the efficacy over that achieved via inhibition of either pathway alone and overcome resistance 
(Sennino and McDonald 2012). The RET proto-oncogene encodes an RTK that is involved in 
tumor cell survival and proliferation (Drosten 2004). Sporadic PTCs can have chromosomal 
translocations involving the RET proto-oncogene (RET-PTC fusions). These rearrangements lead 
to constitutive activation of RET kinase and downstream signaling of the MAPK pathway. Thus, 
targeting the RET RTK activity represents a treatment opportunity in PTC (Pierotti 1996, 
Prescott 2015). 
Cabozantinib is an orally bioavailable small molecule TKI that potently inhibits VEGFR, MET, 
AXL, and RET, as well as a number of other RTKs that have also been implicated in tumor 
pathobiology, including KIT and FLT3. Cabozantinib suppresses MET and VEGFR2 signaling, 
rapidly inducing apoptosis of endothelial and tumor cells, resulting in tumor regression in a 
variety of xenograft models. Cabozantinib capsules (140 mg) are approved in the United States 
for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and in 
the European Union for the treatment of patients with progressive, unresectable locally advanced 
or metastatic MTC (Cometriq™ US PI and EMA SmPC). Cabozantinib tablets (60 mg) are 
approved in the United States, Europe, and other regions for advanced RCC (different patient 
populations depending on region; Cabometyx™ US PI and EMA SmPC). 
Encouraging preliminary clinical experience of cabozantinib in patients with RAI-refractory DTC 
has been demonstrated in three clinical trials. In a single-arm Phase 1 study (XL184-008), 
15 subjects with advanced, metastatic DTC were enrolled (Cabanillas 2014). This study also 
served as a drug-drug interaction study in subjects with advanced malignancies to support the 
initial regulatory submission of cabozantinib for the indication of progressive, metastatic MTC. 
Most patients in the RAI-refractory DTC cohort had received prior VEGFR-targeted therapy. The 
initial dose in this study was 140 mg cabozantinib (capsule formulation) per day. Subjects in the 
RAI-refractory DTC cohort received a median average daily dose of 62 mg cabozantinib per day. 
The ORR for DTC subjects in this study was 53%, and 40% of DTC subjects achieved stable 
disease as best response. Tumor regression appeared to be independent of prior VEGFR-targeted 
therapy. Duration of response ranged from 2.0 to 14.5+ months. Median PFS and OS were not 
reached (median follow-up was 12 months and 26 months, respectively). The safety profile of 
cabozantinib in this study was similar to that of other VEGFR-targeted therapies in DTC subjects.  

 
 
Protocol XL184-311 
Page 6 of 165 
In a Phase 2, single-arm Investigator-sponsored study (NCT01811212), 25 subjects with 
RAI-refractory DTC were enrolled that had progressed after one or two prior VEGFR-targeted 
therapies (Cabanillas 2017). The initial dose in this study was 60 mg cabozantinib (tablet 
formulation) per day. The ORR was 40%, and 52% of subjects had stable disease as best 
response. Median duration of response was 11 months. The median PFS was 13 months 
(95% confidence interval [CI]: 11, 35), and the median OS was 35 months (95% CI: 18, not 
reached). Dose reductions to 40 mg occurred in 56% of subjects, and further reductions to 20 mg 
occurred in 32% of subjects. The safety profile of cabozantinib in this study was similar to that of 
other VEGFR-targeted therapies in DTC.  
In addition, a single-arm Phase 2 study is currently evaluating cabozantinib at a dose of 60 mg qd 
in subjects with RAI-refractory DTC as first-line systemic anticancer therapy (NCT02041260). 
Thirty-five subjects with DTC were enrolled. The ORR was 54%, and 43% of subjects had stable 
disease as best response. Median PFS had not been reached as of 06 February 2018 
(Brose et al 2018).  
In summary, cabozantinib inhibits targets that are relevant in the tumor biology of DTC including 
VEGFRs, MET, and RET. In Phase 1 and Phase 2 studies cabozantinib has shown encouraging 
clinical activity in subjects with RAI-refractory DTC and therefore may be a promising treatment 
option for patients who have progressed after prior VEGFR-targeting TKIs. This Phase 3, 
multicenter, randomized, double-blind, placebo-controlled study evaluates the efficacy and safety 
of cabozantinib in subjects with RAI-refractory DTC who have progressed during or after prior 
VEGFR-targeted therapy. Subjects will receive 60 mg qd cabozantinib orally which has been 
shown to be effective and tolerable in this subject population. 
OBJECTIVES AND ENDPOINTS 
The objective of this study is to evaluate the effect of cabozantinib compared with placebo on 
PFS and ORR in subjects with RAI-refractory DTC who have progressed after prior 
VEGFR-targeted therapy.  
Primary endpoints: 
• 
Progression-free survival (PFS) per Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC) 
• 
Objective response rate (ORR) per RECIST 1.1 by BIRC 

 
 
Protocol XL184-311 
Page 7 of 165 
Additional endpoints: 
• 
Overall survival (OS) 
• 
Duration of objective tumor response 
• 
Safety and tolerability  
• 
Pharmacokinetics (PK) of cabozantinib 
• 
Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), 
and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or 
clinical outcome assessments may be performed 
• 
Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 
global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L) 
• 
Health care resource utilization 
STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of cabozantinib. 
Best supportive care (BSC) will be provided for subjects on both treatment arms. PFS and ORR 
(the co-primary efficacy endpoints) will be evaluated by BIRC. Approximately 300 eligible 
subjects will be randomized in a 2:1 ratio to receive either cabozantinib or placebo.  
Subjects’ trial participation will consist of the following periods: 
Pretreatment Period: Potential subjects will be screened to determine if they meet the required 
eligibility criteria. Qualifying screening assessments must be performed within 28 days before 
randomization unless otherwise specified. 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in a 
2:1 ratio to the following treatment arms:  
• 
Cabozantinib arm: Oral cabozantinib (60 mg) daily (qd)  
• 
Placebo arm: Oral cabozantinib-matched placebo qd  
Randomization will be stratified by: 
- 
Receipt of prior Lenvatinib (yes vs no) 
- 
Age at informed consent (≤ 65 years  vs > 65 years) 
Subjects on both arms will be treated with BSC. This excludes nonprotocol anticancer 
therapy (NPACT). 

 
 
Protocol XL184-311 
Page 8 of 165 
Crossover Phase: As subjects in the study population have limited treatment options, and to 
minimize the potential for differential dropout among subjects randomized to placebo with 
respect to the PFS endpoint as assessed by BIRC, the study will allow eligible subjects 
randomized to placebo to crossover to receive cabozantinib upon experiencing radiographic 
disease progression (PD) per RECIST 1.1 that is confirmed by the BIRC. To facilitate this: 
• 
A real-time dual-reader adjudicated BIRC review of radiographic images per RECIST 1.1 
will be employed to document objective radiographic PD contemporaneously with subject 
study participation. 
• 
At the time of investigator-determined radiographic progression per RECIST 1.1, 
investigators may request from the Sponsor medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD. 
• 
For subjects with BIRC-confirmed radiographic PD: 
• 
Upon authorization from the Sponsor medical monitor (or designee), investigators may 
unblind individual subjects via the Interactive Response Technology (IRT) system. 
• 
Unblinded subjects randomized to placebo have the following options: 
• 
Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B. 
• 
Such subjects who are ineligible or opt not to crossover to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• 
Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per Appendix A. 
• 
Subjects without radiographic progression per BIRC will not be unblinded and are to 
continue to receive blinded study treatment and undergo study assessments according to the 
schedule in Appendix A. 
End of Study Treatment: Subjects will receive blinded study treatment or unblinded treatment 
with cabozantinib as long as they continue to experience clinical benefit in the opinion of the 
investigator or until there is unacceptable toxicity or the need for nonprotocol systemic anticancer 
treatment. Treatment may continue after radiographic progression 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 risk.  
Post-Treatment Period: The final safety assessment will occur at the post-treatment follow-up 
visit 30 (+14) days after the date of the decision to discontinue study treatment unless a 
Grade 3/4 AE or a serious AE (SAE) is determined to be ongoing (the event would be followed 
until resolution). 
Radiographic tumor assessments and HRQOL (EQ-5D-5L) assessments will continue on the 
protocol-defined schedule (Appendix A) relative to the date of randomization regardless of 
whether study treatment is given, reduced, interrupted, or discontinued, including for subjects 

 
 
Protocol XL184-311 
Page 9 of 165 
randomized to placebo who cross over to receive cabozantinib (Appendix B). Consequently these 
assessments may be required in the Post-Treatment Period, including after the final safety 
assessment, for some subjects. 
In addition, subjects will be contacted approximately every 12 weeks after the Post-Treatment 
Follow-Up Visit to assess survival status and to document receipt of NPACT and subsequent 
progression status. Every effort must be made to collect these protocol-specific evaluations unless 
consent for non-interventional study assessments is withdrawn.  
Study Completion by Country or by Site: At the time the Maintenance Phase is initiated, the 
study will be considered complete at sites and in countries where all subjects have completed 
post-treatment safety follow-up.  
Maintenance Phase: After the primary efficacy endpoints have been analyzed and upon 
determination by the Sponsor that sufficient data have been collected to adequately evaluate all 
study endpoints to establish, for regulatory purposes, the safety and efficacy profile of the 
experimental drug within this study, the study will begin to transition to the Maintenance Phase.  
As a transitional step prior to initiation of the Maintenance Phase, all blinded study subjects will 
be unblinded, and study sites will be notified of their randomized treatment assignments.  
• 
Unblinded subjects randomized to placebo have the following options: 
o Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B.  
o Such subjects who are ineligible or opt not to cross over to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• 
Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per Appendix A. 
After the date the entire study is unblinded, study sites will have 8 weeks to determine eligibility 
and begin administration of crossover cabozantinib treatment to eligible subjects randomized to 
placebo; subsequently no further crossover will be allowed. 
Once the Week 9 Day 1 (W9D1) visit has elapsed in the Crossover Phase for the last placebo 
subject who crossed over to receive cabozantinib, and upon site notification by the Sponsor, the 
transition period will end, and the study will enter the study Maintenance Phase. 
In the Maintenance Phase, subjects are to be followed as described in Appendix C. Subjects 
remaining on study treatment will continue to receive it until a criterion for protocol-defined 
discontinuation has been met. Subjects are to undergo periodic safety assessments (including 
local laboratory tests) and tumor assessments; the nature and frequency of these assessments are 
to be performed per standard of care. It is the Investigator’s responsibility to ensure that subject 
visits occur frequently enough and adequate assessments are performed to ensure subject safety. 
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 Visit at 

 
 
Protocol XL184-311 
Page 10 of 165 
the time the transition to the Maintenance Phase, will undergo the final safety assessment at the 
post-treatment follow-up visit. Upon initiation of the Maintenance Phase, no further follow-up is 
required for any subject who has completed the Post-Treatment Follow-Up Visit. 
The study clinical database will be closed upon initiation of the Maintenance Phase. Only data 
collected prior to implementation of Maintenance Phase will be reported in a clinical study report. 
NUMBER OF SUBJECTS 
Approximately 300 eligible subjects will be randomized into the study at approximately 
150 global sites.  
TARGET POPULATION  
Eligibility criteria for all subjects are below. Waivers to these criteria will not be granted by the 
Sponsor. 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed diagnosis of DTC, including the following subtypes 
(Note: results of a previous biopsy will be accepted): 
a. Papillary thyroid carcinoma (PTC) including histological variants of PTC such as 
follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, 
Warthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of 
papillary carcinoma, poorly differentiated 
b. Follicular thyroid carcinoma (FTC) including histological variants of FTC such as 
Hürthle cell, clear cell, insular, and poorly differentiated 
2. Measurable disease according to RECIST 1.1 on computed tomography/magnetic resonance 
imaging (CT/MRI) performed within 28 days prior to randomization 
3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131 
for DTC 
4. Must have been previously treated with at least one of the following VEGFR-targeting TKI 
agents for DTC: lenvatinib or sorafenib.  
(Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited 
to) lenvatinib and sorafenib.) 
5. Must have experienced documented radiographic progression per RECIST 1.1 per 
Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the 
next anticancer therapy (which may be treatment in this study) 
6. Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events 
Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are 
clinically nonsignificant and/or stable on supportive therapy 
7. Age ≥ 16 years old on the day of consent  
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1  

 
 
Protocol XL184-311 
Page 11 of 165 
9. Adequate organ and marrow function based upon meeting all of the following laboratory 
criteria within 10 days before randomization:  
a. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without receipt of granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection 
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks 
before screening laboratory sample collection 
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before 
screening laboratory sample collection 
d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline 
phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN if the subject has 
documented bone metastases 
e. Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert’s 
disease ≤ 3 × ULN 
f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula) 
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) 
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff of 
the reference range or less than 0.50 mIU/L (< 0.50 μIU/mL), whichever is lower, within 28 
days before randomization. 
(Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be 
targeted.) 
11. Capable of understanding and complying with the protocol requirements and signed informed 
consent (or informed assent and parental/guardian consent for subjects < 18 years of age)  
12. Sexually active fertile subjects and their partners must agree to use highly effective methods 
of contraception that alone or in combination result in a failure rate of less than 1% per year 
when used consistently and correctly during the course of the study and for 4 months after the 
last dose of study treatment. For females, such methods include combined hormonal 
contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable 
hormonal contraception), placement of an intrauterine device, or placement of an intrauterine 
hormone-releasing system. Males must agree to use a barrier method (eg, condom) unless 
they have had a vasectomy. 

 
 
Protocol XL184-311 
Page 12 of 165 
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects 
are considered to be of childbearing potential unless one of the following criteria is met: 
permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or 
documented postmenopausal status (defined as 12 months of amenorrhea in a woman over 
45 years-of-age in the absence of other biological or physiological causes. In addition, 
females under 55 years-of-age must have a serum follicle stimulating hormone (FSH) 
level > 40 mIU/mL to confirm menopause). Note: Documentation may include review of 
medical records, medical examination, or medical history interview by study site staff.  
Exclusion Criteria 
1. Prior treatment with any of the following: 
a. Cabozantinib 
b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)   
c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib, 
pazopanib, axitinib, vandetanib) 
d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent) 
e. More than 1 systemic chemotherapy regimen (given as single agent or in combination 
with another chemotherapy agent) 
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before 
randomization 
3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic 
chemotherapy within 4 weeks before randomization 
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy 
within 4 weeks before randomization. Subjects with clinically relevant ongoing complications 
from prior radiation therapy that have not completely resolved are not eligible (eg, radiation 
esophagitis or other inflammation of the viscera). 
5. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before 
randomization. Eligible subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of randomization.  
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and 
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed 
anticoagulants:  
• 
Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low 
molecular weight heparins (LMWH) 
• 
Anticoagulation with therapeutic doses of LMWH in subjects without known brain 
metastases who are on a stable dose of LMWH for at least 6 weeks before randomization 
and who have had no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor 

 
 
Protocol XL184-311 
Page 13 of 165 
7. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
a. Cardiovascular disorders: 
i. 
Congestive heart failure class 3 or 4 as defined by the New York Heart Association, 
unstable angina pectoris, serious cardiac arrhythmias 
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic 
or > 100 mm Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other 
ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], 
pulmonary embolism) within 6 months before randomization. Subjects with a more 
recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with 
LMWH for at least 6 weeks before randomization. 
b. Gastrointestinal disorders (eg, malabsorption syndrome or gastric outlet obstruction) 
including those associated with a high risk of perforation or fistula formulation: 
i. 
Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel 
disease, ulcerative colitis, 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 before randomization 
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to 
randomization  
c. Clinically significant hematemesis or hemoptysis of  > 0.5 teaspoon (> 2.5 mL) of red 
blood or history of other significant bleeding 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: 
• 
Active infection requiring systemic treatment, infection with human 
immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or 
chronic hepatitis B or C infection  
• 
Serious non-healing wound/ulcer/bone fracture 
• 
Malabsorption syndrome  
• 
Moderate to severe hepatic impairment (Child-Pugh B or C) 
• 
Requirement for hemodialysis or peritoneal dialysis 
• 
Uncontrolled diabetes mellitus 
• 
History of solid organ transplantation 

 
 
Protocol XL184-311 
Page 14 of 165 
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before 
randomization. Complete wound healing from major surgery must have occurred 4 weeks 
before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 
10 days before randomization. Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible. 
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days 
before randomization   
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 3 consecutive results for QTcF will be used to determine eligibility.  
10. Pregnant or lactating females 
11. Inability to swallow tablets  
12. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations 
13. Diagnosis of another malignancy within 3 years before randomization, except for superficial 
skin cancers, or localized, low grade tumors deemed cured and not treated with systemic 
therapy 
ESTIMATED STUDY DATES AND LENGTH OF SUBJECT PARTICIPATION 
It is estimated that 15 months will be required to randomize approximately 300 subjects (200 in 
the cabozantinib arm, 100 in the placebo arm). The number of events required for the primary 
analysis of PFS is expected to be observed approximately 20 months after the first subject is 
randomized.  
It is estimated that subjects will receive study treatment for an average of 9 months. Subjects will 
be followed until death, withdrawal of consent from the study, or Sponsor decision to no longer 
collect these data.  
INVESTIGATIONAL REGIMEN DOSE/ ROUTE/ DURATION 
Subjects will take study medication (tablets containing 60-mg or 20-mg cabozantinib or placebo 
equivalent) once daily orally. 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 nonprotocol systemic anticancer, or other reasons for treatment discontinuation.  
The assigned (and highest allowed) dose is 60 mg qd. Two dose reduction levels of the oral study 
medication (cabozantinib or placebo equivalent) will be allowed (40 mg qd and 20 mg qd).  
COMPARATOR DRUG 
Placebo tablets that match cabozantinib tablets will be used as the comparator. 

 
 
Protocol XL184-311 
Page 15 of 165 
TUMOR ASSESSMENTS 
Radiographic response and disease progression will be determined using RECIST 1.1.  
Chest / Abdomen / Pelvis / Neck (CAPN): CT (or MRI) of CAPN will be performed in all 
subjects at screening and every 8 weeks (± 7 days) after randomization during the first 12 months 
on study. Upon subject completion of 12 months on study, these assessments will be performed 
every 12 weeks (± 14 days). If MRI of the abdomen and pelvis is performed at screening, then a 
CT of the chest and neck must be performed as well. Additional imaging of potential disease sites 
is to be performed whenever radiographic disease progression 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 following the same post-baseline frequency as the imaging for CAPN. MRI is the 
preferred imaging method for brain. If CT of the brain is performed instead of MRI, ambiguous 
results must be confirmed by MRI. (Note: In order to meet the eligibility requirements of the 
study, brain metastasis must have been treated and stable for at least 4 weeks before 
randomization. Subjects without documented brain metastasis during the screening assessment 
are not required to undergo post-randomization brain imaging unless clinically indicated.) 
Bone scans: Technetium bone scans will be performed at screening in all subjects and after 
randomization only in subjects with known bone metastasis every 24 weeks (± 14 days). 
Technetium bone scans are also to be performed for clinical symptoms indicative of new bone 
metastases. Bone scan findings alone cannot be used for the determination of progression or 
response per RECIST version 1.1 and need to be corroborated by CT or MRI. 
Tumor assessments are to continue on the protocol-defined schedule (Appendix A) relative to the 
date of randomization regardless of whether study treatment is given, reduced, held, or 
discontinued, including for subjects randomized to placebo who cross over to receive 
cabozantinib (Appendix B). The same imaging modalities used at screening will be used for 
subsequent tumor assessments after randomization. 
Investigators should, if any doubt or ambiguities exist about radiographic progression, have 
subjects continue study treatment if the subject is tolerating it acceptably, repeat radiographic 
tumor imaging at the next scheduled time point, and delay determination of progression until the 
findings indicating radiographic progression are unequivocal. 
Radiographic tumor assessments are to continue until the later of investigator-assessed 
radiographic disease progression per RECIST 1.1 that is confirmed per real-time BIRC review or 
the date of the decision to permanently discontinue study treatment; however, radiographic tumor 
assessments may cease at the time of first systemic nonprotocol anticancer therapy, if given 
before these milestones occur. Bone scan evaluations will end on the date of last CT/MRI scan. If 
the bone scan schedule does not coincide with the last CT/MRI scan, no additional bone scan is 
needed after the last CT/MRI scan has been performed. 
For the purpose of evaluating radiographic study endpoints and to minimize the potential for 
differential dropout in the placebo arm, a BIRC will be used in a real-time dual-reader 
adjudicated fashion. 

 
 
Protocol XL184-311 
Page 16 of 165 
To facilitate the real-time BIRC review, all radiographic tumor assessments are to be sent to the 
BIRC promptly after acquisition. Prior radiation history data will be sent to the BIRC for the 
purpose of selecting target lesions. BIRC evaluations of each radiographic time point are to be 
completed promptly after receipt of a complete set of images that meet quality requirements 
defined in the study imaging manual. 
At the time of investigator-determined radiographic progression per RECIST 1.1, investigators 
may request from the Sponsor’s medical monitor (or designee) confirmation of BIRC-determined 
radiographic PD. Only confirmation that BIRC-determined radiographic progression has been 
documented (or not) will be provided to the investigator. The BIRC readers will not be notified of 
these requests from the investigator, nor will the BIRC readers be informed of the nature of the 
investigator evaluation. Further details are provided in the study imaging charter. 
Crossover Phase: Subjects randomized to placebo who cross over to receive cabozantinib will 
have baseline re-established and will re-start the tumor assessment schedule. The new baseline is 
to be based upon the most recent set of scans performed prior to unblinding for crossover. If these 
scans were performed > 8 weeks prior to the first crossover dose, new scans are required to 
establish the crossover baseline. Radiographic studies performed after unblinding for crossover 
will not be submitted to the BIRC. After crossover, radiographic tumor assessments are to 
continue until the later of: (a) investigator-assessed radiographic disease progression per RECIST 
1.1 (relative to the new baseline), or (b) the date of the decision to permanently discontinue study 
treatment. However, radiographic tumor assessments may cease at the time of first systemic 
NPACT, if given before these milestones occur. Bone scan evaluations will end on the date of last 
CT/MRI scan. If the bone scan schedule does not coincide with the last CT/MRI scan, no 
additional bone scan is needed after the last CT/MRI scan has been performed (Appendix B). 
If the study transitions to the Maintenance Phase, tumor assessments will be done per standard of 
care if allowed per local regulations and will not be submitted to the BIRC. 
SAFETY ASSESSMENTS 
Adverse event (AE) seriousness, severity grade, and relationship to study treatment will be 
assessed by the Investigator. Severity grade will be defined by the National Cancer Institute 
(NCI) CTCAE v5. The Executive Safety Committee (ESC) and an Independent Data Monitoring 
Committee (IDMC) will be established to monitor the safety of the study on a regular basis. The 
membership and decision process of the IDMC are independent of the Sponsor and the study 
clinical Investigators.  
Subjects will undergo clinic visits every 2 weeks through Week 9 Day 1, and every 4 weeks 
thereafter. A post-treatment follow-up visit will be performed 30 (+14) days after the date of the 
decision to discontinue study treatment. Clinical safety assessments include physical examination, 
ECOG PS score, vital signs, 12-lead ECG, hematology, serum chemistries, coagulation panel, 
urinalysis, UPCR, and thyroid function panel. Subjects will be queried on AEs experienced 
during the study through 30 days after the decision to discontinue study treatment.  
In the Maintenance Phase safety assessments will be performed per standard of care if allowed 
per local regulations. 

 
 
Protocol XL184-311 
Page 17 of 165 
OVERALL SURVIVAL FOLLOW-UP ASSESSMENTS 
Subjects will be contacted approximately every 12 weeks after the post-treatment follow-up visit 
to assess survival status and to document receipt of NPACT and subsequent progression status 
unless consent to participate in non-interventional study assessments is withdrawn or the Sponsor 
deems sufficient efficacy data have been collected for the study.  
If the study transitions to the Maintenance Phase, OS and NPACT information will no longer be 
collected. 
PHARMACOKINETICS (PK) 
Blood samples will be taken from all subjects in both blinded treatment arms at W3D1, W5D1, 
and W9D1. Collection of PK samples may be halted early or sampling frequency may be 
modified at the discretion of the Sponsor.  
PK assessments will no longer be collected for subjects who transition to the Crossover Phase or 
if the study transitions to the Maintenance Phase. 
BIOMARKERS 
Available tumor tissue (from the most recently collected sample prior to subject participation in 
the study) will be obtained during screening or at enrollment for exploratory analysis to 
potentially evaluate biomarkers such as MET or RET and other pathway components (eg, RAS, 
BRAF), modulators associated with the mechanism of action of cabozantinib. 
Blood samples to evaluate plasma and/or serum biomarkers and circulating DNA (ctDNA) may 
be collected prior to first dose (W1D1) and postdose at specified time points. 
At selected sites, blood samples may be collected for the enumeration of circulating tumor cells 
(CTCs) prior to first dose (W1D1) and postdose at specified time points. Molecular markers 
potentially related to DTC and/or study treatment mechanism(s) of action may also be assessed in 
these CTC samples. 
A blood sample will be collected pre-dose on the day of first dose (W1D1) for genotyping/single 
nucleotide polymorphism/copy number variation analysis to correlate genetic variation with PK, 
safety, tolerability of and response to study treatment.  
Detailed instructions for sample processing, storage, and shipment will be provided in the 
translational medicine laboratory manual. 
Collection of these samples may be halted early or sampling frequency may be reduced at the 
discretion of the Sponsor. Biomarker analyses may not be performed at the time of the primary 
endpoint analyses and may extend beyond the end of the study. 
No pharmacodynamic or biomarker samples will be collected for subjects who transition to the 
Crossover Phase or if the study transitions to the Maintenance Phase.  
Note: Serum Tg levels will be analyzed as part of the routine clinical laboratory assessments. 
Results of serum Tg analyses will not be shared with investigators to avoid bias in the study. 

 
 
Protocol XL184-311 
Page 18 of 165 
HEALTH-RELATED QUALITY OF LIFE (HRQOL) 
Subjects will be requested to complete the EQ-5D-5L assessment at baseline (W1D1; prior to first 
dose) and every 4 weeks through Week 25, then every 8 weeks until the later of 8 weeks after 
radiographic progression per RECIST 1.1 as determined by the Investigator and confirmed by 
BIRC or the date of the decision to permanently discontinue study treatment. Assessments will 
continue on this schedule irrespective of whether study treatment is given, reduced, interrupted, 
or discontinued. Subjects should complete the questionnaire on the day of the visit prior to seeing 
study site personnel. 
HRQOL assessments will no longer be collected for subjects who transition to the Crossover 
Phase or if the study transitions to the Maintenance Phase. 
HEALTH CARE RESOURCE UTILIZATION 
Health care resource utilization parameters will be collected for each SAE reported during the 
study. These comprise start and stop dates or length of stay of emergency room visits, hospital 
admissions, and intensive care unit admissions. 
Health care resource utilization assessments will be discontinued if the study transitions to the 
Maintenance Phase. 
STATISTICAL METHODS 
The primary efficacy analyses for this study will compare the results in subjects randomized to 
receive cabozantinib to those in the placebo arm for co-primary endpoints PFS and ORR. 
Treatment with cabozantinib will be inferred to be superior to treatment with placebo if the null 
hypothesis of no difference between arms is rejected for either PFS or ORR.  
PFS is defined as time from randomization to the earlier of either radiographic PD per 
RECIST 1.1 as determined by the BIRC or death from any cause. ORR is defined as the 
proportion of subjects with the best overall response of complete response (CR) or partial 
response (PR) per RECIST 1.1 as determined by the BIRC that is confirmed at a follow-up 
assessment ≥ 28 days later.  
PFS will be summarized descriptively using the Kaplan-Meier method. The Inferential method 
for comparing the treatment arms will be the stratified log-rank test. The hazard ratio (HR) will 
be estimated using a stratified Cox proportional hazards model.  
ORR will be summarized descriptively, and inference testing conducted with the stratified 
Cochran–Mantel–Haenszel test. 
Stratification factors will be the same as those that were used in the IRT system for the 
randomization. 
The study is designed to provide adequate power for both PFS and ORR. It is estimated that 
100 subjects would be adequate to evaluate the co-primary endpoint of ORR alone and 
300 subjects will be needed to evaluate the co-primary endpoint of PFS. Thus, to allow an earlier 
evaluation of ORR, this study employs a “trial within a trial design” (Hessel et al 2016). The 
primary analysis of ORR will be limited to the first 100 subjects randomized to the study and 
defined as the ORR Intent-to-Treat (OITT) population. Analysis of ORR is expected to occur 

 
 
Protocol XL184-311 
Page 19 of 165 
6 months after the last subject is enrolled in the OITT population. Interim analysis of ORR is not 
planned.  
For ORR, 100 subjects provide a 2-sided 0.01 test of difference in proportion with > 90% power 
to reject the null hypothesis of no difference in ORR, assuming a true ORR of 2% in the placebo 
arm and 35% in the cabozantinib arm (a 33 percentage point difference), a pooled variance 
estimate, and a 2:1 allocation ratio. 
The study will proceed to full enrollment of 300 subjects irrespective of the results of the ORR 
analysis in the OITT population. 
The primary PFS analysis will include all randomized subjects (ITT population). Supportive 
analyses of ORR will be conducted in the ITT population at the time of the primary PFS analysis. 
The primary analysis of PFS is event-driven and will be conducted after at least 193 events have 
been observed. A total of 193 events among 300 randomized subjects provide the study with 
90% power for a 2-sided log-rank test with a 4% level of significance to detect an HR of 0.61. 
Assuming an exponential distribution of PFS, this corresponds to an increase in median PFS of 
64%, from 5.5 months to 9 months.  
A single interim analysis of PFS is planned at the time of the primary ORR analysis. 
Approximately 43% of the planned total PFS events are expected to have been observed in the 
ITT population at that time. Rejection of the null hypothesis for PFS at this interim analysis is not 
expected; it is intended to allow evaluation of PFS at the time of the primary analysis of ORR. 
Inflation of Type 1 error arising from repeated analyses of PFS will be controlled by a 
Lan-DeMets O’Brien Fleming alpha spending function, using the actual information fraction at 
the time of the interim analysis. 
Inflation of Type 1 error associated with two co-primary endpoints is controlled by a modified 
Bonferroni procedure, performing a 2-sided test of ORR at the 1% level and of PFS at the 
4% level. Additionally, the fallback method for alpha allocation (FDA 2017) will be implemented 
as follows: 
• 
If the null hypothesis is rejected for ORR its alpha allocation of 1% will be passed to PFS 
which will then be tested at the 5% level. 
• 
If the null hypothesis is not rejected for ORR, then PFS will be tested at its original alpha 
allocation of 4%. 
• 
As an interim analysis will be performed for the second co-primary endpoint of PFS, the 
alpha spending function used to determine the critical values for rejection will be based upon 
a total alpha of either 5% or 4% conditioned upon whether or not the null is rejected for ORR, 
respectively (see following examples). 

 
 
Protocol XL184-311 
Page 20 of 165 
Under this design, and with the application of the fallback method (see Section 9.9), the minimum 
observed effects that would result in statistical significance for PFS are as follows: 
• 
If Ho is rejected for ORR and PFS is tested at the 5% level under the fallback method the 
minimum observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0013 
0.474 
5.5 
11.6 
Final 
100% 
0.0496 
0.742 
5.5 
7.4 
• 
If Ho is not rejected for ORR and PFS is tested at the original 4% allocation the minimum 
observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0008 
0.469 
5.5 
11.7 
Final 
100% 
0.0397 
0.738 
5.5 
7.5 
Assuming a constant accrual rate of 20 subjects per month and using a 2:1 treatment allocation 
ratio, a total of 300 subjects (200 in the cabozantinib arm, 100 in the placebo arm) are required to 
observe the required number of PFS events within the planned study duration (15 months accrual; 
approximately 20 months to observe the required 193 events for PFS). 
The final analysis of OS will be performed at the time of the primary PFS analysis. Inferential 
measures will be presented for descriptive purposes. At the time of the analysis of ORR, if the 
null hypothesis for ORR is rejected an administrative interim analysis of OS will be performed 
with the primary purpose of evaluating the potential for detriment to survival with cabozantinib 
treatment. 
Data from the Crossover Phase will be summarized or listed separately and will not be included 
as part of the primary evaluation of either arm. 
All sample sizes and event milestones were computed using Cytel Software EAST 5.0.  
Sponsor personnel will remain blinded until the earlier of successful rejection of the null 
hypothesis for ORR or the time of the primary PFS analysis. Unblinded full-study data will not be 
released to or shared with the operational study teams at the Contract Research Organization, 
investigators, or study subjects until after the analysis of the PFS endpoint. 
 
 

 
 
Protocol XL184-311 
Page 21 of 165 
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................4 
TABLE OF CONTENTS ...................................................................................................21 
LIST OF TABLES .............................................................................................................25 
LIST OF ABBREVIATIONS ............................................................................................27 
1 
BACKGROUND ......................................................................................................30 
1.1 
Thyroid Cancer ................................................................................................30 
1.2 
Molecular Pathology of Thyroid Cancer .........................................................31 
1.3 
Treatment of Differentiated Thyroid Cancer ...................................................32 
1.4 
Cabozantinib ....................................................................................................34 
1.4.1 
Cabozantinib in Thyroid Cancer ..........................................................34 
1.5 
Rationale ..........................................................................................................40 
1.5.1 
Rationale for Study Design ..................................................................41 
1.5.2 
Rationale for Including Adolescent Subjects .......................................41 
1.5.3 
Rationale for Cabozantinib Dose Selection .........................................42 
1.5.4 
Rationale for Placebo ...........................................................................42 
1.5.5 
Rationale for Crossover Phase .............................................................43 
1.6 
Overall Risk Benefit Assessment.....................................................................43 
1.6.1 
Summary of Benefits and Risks ...........................................................44 
1.7 
Study Conduct ..................................................................................................45 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................46 
2.1 
Objectives ........................................................................................................46 
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 .................................................................................................51 
3.5.1 
Blinding of Study Treatments ..............................................................51 
3.5.2 
Unblinding Procedure for Individual Subjects ....................................52 
3.6 
Discontinuation and Withdrawal .....................................................................53 
3.6.1 
Treatment Discontinuation...................................................................53 
3.6.2 
Study Withdrawal ................................................................................55 

 
 
Protocol XL184-311 
Page 22 of 165 
4 
STUDY POPULATION ...........................................................................................56 
4.1 
Target Population .............................................................................................56 
4.2 
Inclusion Criteria .............................................................................................56 
4.3 
Exclusion Criteria ............................................................................................58 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................61 
5.1 
Pretreatment Period ..........................................................................................61 
5.2 
Treatment Period ..............................................................................................62 
5.3 
Crossover Phase ...............................................................................................64 
5.4 
Post-Treatment Period .....................................................................................65 
5.4.1 
Post-Treatment Follow-Up Visit..........................................................65 
5.4.2 
Extended Follow-up .............................................................................65 
5.5 
Maintenance Phase...........................................................................................66 
5.6 
Unscheduled Visits ..........................................................................................68 
5.7 
Instructions for Specific Procedures ................................................................68 
5.7.1 
Demographics, Medical, and Cancer History ......................................68 
5.7.2 
Physical Examination...........................................................................68 
5.7.3 
Vital Signs ............................................................................................69 
5.7.4 
Electrocardiograms ..............................................................................69 
5.7.5 
Laboratory Assessments ......................................................................70 
5.7.6 
Tumor assessment ................................................................................73 
5.7.7 
Health-Related Quality of Life (HRQOL) Assessments .....................76 
5.7.8 
Health Care Resource Utilization ........................................................77 
5.7.9 
Pharmacokinetics (PK) ........................................................................77 
5.7.10 
Pharmacogenetic and Biomarker Analyses .........................................78 
5.7.11 
Overall Survival ...................................................................................79 
6 
TREATMENTS AND PROCEDURES ...................................................................80 
6.1 
Study Treatment Dosing ..................................................................................80 
6.1.1 
Study Treatment Administration on Week 1 Day 1 (W1D1) ..............80 
6.1.2 
Subsequent Dose Administration .........................................................80 
6.2 
Study Medications ...........................................................................................81 
6.2.1 
Composition, Formulation, and Storage ..............................................81 
6.2.2 
Cabozantinib (XL184) .........................................................................81 
6.2.3 
Placebo .................................................................................................82 
6.3 
Compliance ......................................................................................................82 
6.4 
Study Treatment Accountability ......................................................................82 
6.5 
Study Drug Dose Modifications ......................................................................83 
6.5.1 
Reductions and Interruptions ...............................................................83 
6.5.2 
Dose Reinstitution and Re-escalation ..................................................85 

 
 
Protocol XL184-311 
Page 23 of 165 
6.6 
Best Supportive Care .......................................................................................85 
6.7 
Warnings, Precautions, and Guidelines for Management of Potential 
Cabozantinib Adverse Events ..........................................................................85 
6.7.1 
General .................................................................................................85 
6.7.2 
Gastrointestinal Disorders ....................................................................86 
6.7.3 
Non-Gastrointestinal Fistula ................................................................88 
6.7.4 
Hemorrhage..........................................................................................89 
6.7.5 
Thromboembolic Events ......................................................................89 
6.7.6 
Hypertension ........................................................................................89 
6.7.7 
Stomatitis and Mucositis ......................................................................90 
6.7.8 
Skin Disorders ......................................................................................91 
6.7.9 
Osteonecrosis .......................................................................................92 
6.7.10 
Proteinuria ............................................................................................93 
6.7.11 
Nervous System Disorders ...................................................................94 
6.7.12 
Hepatocellular Toxicity .......................................................................94 
6.7.13 
Infections and Infestations ...................................................................95 
6.7.14 
Blood and Lymphatic System Disorders .............................................95 
6.7.15 
Fatigue..................................................................................................95 
6.7.16 
Weight Loss .........................................................................................96 
6.7.17 
Corrected QT Prolongation ..................................................................96 
6.7.18 
Electrolyte Disorders ...........................................................................98 
7 
CONCOMITANT MEDICATIONS AND THERAPIES ........................................99 
7.1.1 
Allowed Therapies ...............................................................................99 
7.1.2 
Prohibited or Restricted Therapies .....................................................100 
8 
SAFETY .................................................................................................................104 
8.1 
Adverse Events and Laboratory Abnormalities .............................................104 
8.1.1 
Laboratory Data .................................................................................104 
8.2 
Serious Adverse Events .................................................................................105 
8.2.1 
Definitions..........................................................................................105 
8.2.2 
Regulatory Reporting .........................................................................107 
8.3 
Follow-up of Adverse Events ........................................................................108 
8.4 
Other Safety Considerations ..........................................................................108 
8.4.1 
Pregnancy ...........................................................................................108 
8.4.2 
Medication Errors ..............................................................................108 
9 
STATISTICAL CONSIDERATIONS....................................................................110 
9.1 
Analysis Populations ......................................................................................110 
9.1.1 
Intent-to-Treat (ITT) Population ........................................................110 

 
 
Protocol XL184-311 
Page 24 of 165 
9.1.2 
Overall Response Rate Intent-to-Treat (OITT) Population ...............110 
9.1.3 
Safety Population ...............................................................................110 
9.2 
Primary Efficacy Endpoints ...........................................................................110 
9.2.1 
Definitions..........................................................................................110 
9.2.2 
Primary Analysis ................................................................................111 
9.2.3 
Supportive Analyses ..........................................................................112 
9.3 
Overall Survival .............................................................................................113 
9.4 
Health-Related Quality of Life ......................................................................113 
9.5 
Pharmacokinetic Analysis ..............................................................................113 
9.6 
Safety Analyses ..............................................................................................114 
9.6.1 
Adverse Events ..................................................................................114 
9.6.2 
Laboratory Test Results .....................................................................114 
9.6.3 
Other Safety Endpoints ......................................................................114 
9.7 
Additional Endpoints .....................................................................................115 
9.8 
Interim Analyses ............................................................................................115 
9.9 
Control of Type I Error ..................................................................................115 
9.10 
Power and Sample Size ..................................................................................116 
9.11 
Crossover Phase .............................................................................................117 
9.12 
Maintenance Phase.........................................................................................117 
10 
DATA QUALITY ASSURANCE ..........................................................................118 
11 
STUDY COMMITTEES ........................................................................................118 
11.1 
Executive Safety Committee ..........................................................................118 
11.2 
Independent Data Monitoring Committee .....................................................118 
11.3 
Blinded Independent Radiology Committee ..................................................119 
12 
ETHICAL ASPECTS .............................................................................................119 
12.1 
Local Regulations ..........................................................................................119 
12.2 
Informed Consent...........................................................................................120 
12.2.1 
Informed Consent for the Crossover Phase .......................................121 
12.3 
Institutional Review Board/Ethics Committee ..............................................121 
12.4 
Disposition of Subject Samples .....................................................................121 

 
 
Protocol XL184-311 
Page 25 of 165 
13 
CONDITIONS FOR MODIFYING THE PROTOCOL.........................................121 
14 
CONDITIONS FOR TERMINATING THE STUDY OR LIMITING DATA 
COLLECTION .......................................................................................................122 
15 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORDING 
KEEPING ...............................................................................................................122 
15.1 
Investigator’s Files and Retention of Documents ..........................................122 
15.2 
Source Documents and Background Data .....................................................123 
15.3 
Audits and Inspections ...................................................................................123 
15.4 
Case Report Forms .........................................................................................123 
16 
MONITORING THE STUDY ................................................................................124 
17 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS .125 
18 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS..........125 
19 
REFERENCES .......................................................................................................126 
20 
APPENDICES ........................................................................................................132 
 
Appendix A: Schedule of Assessments ........................................................................ 133 
Appendix B: Crossover Phase - Eligibility Criteria and Schedule of Assessments ..... 138 
Appendix C: Maintenance Phase.................................................................................. 146 
Appendix D: Medically Accepted Methods of Contraception ..................................... 149 
Appendix E: Potential Drug Interactions with Cabozantinib ....................................... 153 
Appendix F: ECOG Performance Scale ....................................................................... 154 
Appendix G: Guidelines for Best Supportive Care ...................................................... 155 
Appendix H: Response Evaluation Criteria in Solid Tumors Version 1.1 ................... 156 
Appendix I: 
EuroQol questionnaire EQ-5D-5L, USA (English) Sample Version ..... 164 
 
LIST OF TABLES 
Table 1-1: 
Study NCT01811212: Objective Response Rate, Progression-Free 
Survival, and Overall Survival (N=25) ..................................................... 36 
Table 1-2: 
Study NCT01811212: Summary of Adverse Events and Selected 
Laboratory Abnormalities (N=25) ............................................................ 37 
Table 5-1: 
Laboratory Panels ..................................................................................... 72 
Table 5-2: 
Estimation of the Creatinine Clearance by Cockcroft and Gault .............. 73 
Table 6-1: 
Cabozantinib Tablet Components and Composition ................................ 81 
Table 6-2: 
Placebo Tablet Components and Composition ......................................... 82 

 
 
Protocol XL184-311 
Page 26 of 165 
Table 6-3: 
General Dose Modification Criteria .......................................................... 84 
Table 6-4: 
Dose Reductions ....................................................................................... 84 
Table 6-5:  
Management of Diarrhea Associated with Cabozantinib ......................... 88 
Table 6-6: 
Management of Hypertension Associated with Cabozantinib .................. 90 
Table 6-7: 
Management of Hand-Foot Syndrome (PPE) Associated with 
Cabozantinib ............................................................................................. 92 
Table 6-8: 
Management of Proteinuria Associated with Cabozantinib ...................... 93 
Table 6-9: 
Management of Hepatotoxicity Associated with Cabozantinib................ 94 
Table 20-1: Schedule of Assessments Crossover Phase ................................................. 143 
Table 20-2: Schedule of Assessments: Maintenance Phase ........................................... 148 
 

 
 
Protocol XL184-311 
Page 27 of 165 
LIST OF ABBREVIATIONS 
Abbreviation or 
Term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BIRC 
blinded independent radiology committee 
BP 
blood pressure 
BSC 
best supportive care 
CAPN 
chest, abdomen, pelvis, neck 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating DNA 
CYP 
cytochrome P450 
DICOM 
Digital Imaging and Communications in Medicine 
DOR 
duration of response 
DTC 
differentiated thyroid cancer 
DVT 
deep vein thrombosis 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EDC 
electronic data-capture 
EMA SmPC 
European Medicines Agency Summary of Product Characteristics 
ESC 
Executive Safety Committee 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
FTC 
follicular thyroid carcinoma 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
HCC 
hepatocellular carcinoma 
HR 
hazard ratio 
HRQOL 
health-related quality of life 

 
 
Protocol XL184-311 
Page 28 of 165 
Abbreviation or 
Term 
Definition 
HTC 
Hürthle cell carcinoma 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISS 
investigator-sponsored study 
ITT 
intent to treat  
LDH 
lactate dehydrogenase 
LMWH 
low molecular weight heparin 
LT4 
levothyroxine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAPK 
MAP kinase pathway 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
NCCN 
National Comprehensive Cancer Network 
NPACT 
nonprotocol anticancer therapy 
OITT 
Objective response rate intent-to-treat population 
ONJ 
osteonecrosis of the jaw 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PPE 
palmar-plantar erythrodysesthesia  
PPI 
proton pump inhibitor 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PS 
performance status 
PTC 
papillary thyroid carcinoma 
qd 
once daily 
QTcF 
corrected QT interval by Fridericia 
RAI 
radioactive iodine 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RSI 
reference safety information 
RPLS 
reversible posterior leukoencephalopathy (also known as posterior 

 
 
Protocol XL184-311 
Page 29 of 165 
Abbreviation or 
Term 
Definition 
reversible encephalopathy syndrome) 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SoD 
sum of the diameters 
TEAE 
treatment-emergent adverse event 
Tg 
thyroglobulin 
TIA 
transient ischemic attack 
TKI 
tyrosine kinase inhibitor 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UPCR 
urine protein:creatinine ratio 
US PI  
United States Prescribing Information 
VEGF(R) 
vascular endothelial growth factor (receptor) 
WHO 
World Health Organization 
XL184 
Exelixis code name for investigational product cabozantinib 

 
 
Protocol XL184-311 
Page 30 of 165 
1 
BACKGROUND  
1.1 
Thyroid Cancer 
Thyroid cancer is the most common endocrine neoplasm with an estimate of more than 56,000 
newly diagnosed cases in the United States and 298,000 cases worldwide in 2017 (WHO 2012; 
SEER Cancer Statistics 2017). It is about 2.5 times more common in women than in men, and 
the incidence has almost tripled from the mid-1990s through 2014 (Roman et al 2017; 
Howlader et al 2017). Thyroid cancer can occur at any age, but most tumors are diagnosed 
between the third and sixth decade of life. The majority of thyroid cancers are epithelial tumors 
that originate from thyroid follicular cells and can be classified on the basis of histology into 
differentiated thyroid cancers (DTC) including papillary thyroid carcinoma (PTC) and follicular 
thyroid carcinoma (FTC), and undifferentiated, anaplastic thyroid carcinoma (Sherman 2003, 
DeLellis et al 2004, Lloyd et al 2017). Medullary thyroid carcinoma (MTC) is a neuroendocrine 
tumor which originates from para-follicular C-cells in the thyroid.  
Differentiated thyroid cancer accounts for more than 90% of all newly diagnosed thyroid 
cancers. Papillary thyroid carcinoma is the most common type of thyroid cancer, accounts for 
about 80%, and is characterized by its papillary growth pattern of follicular cells with distinct 
nuclei. Several microscopic variants of PTC have been identified including clear cell, columnar 
cell, cribriform-morular, diffuse sclerosing, follicular, macrofollicular, microcarcinoma, solid, 
tall cell, and Warthin-like. Follicular thyroid carcinoma is the second most common thyroid 
cancer and accounts for about 5-15% of DTC cases. Follicular thyroid carcinomas are solitary 
encapsulated tumors with invasion of follicular cells into the tumor capsule and/or vascular 
system. Hürthle cell carcinoma (HTC), also named oxyphilic or oncocytic cell carcinoma, is 
considered a variant of FTC. At initial diagnosis of DTC, about 10% of patients have local tumor 
invasion into surrounding tissues and/or distant metastases. Common sites of distant metastases 
are lung and bone, but other soft tissues and the central nervous system (CNS) can also be 
involved. The main predicators of outcome for patients with distant metastases are age, location 
of metastases, and uptake of radioactive iodine. In most cases the cause of thyroid cancer is 
unknown. Risk factors for thyroid cancer include a diet low in iodine and environmental 
radiation exposure (Pellegriti et al 2013). Inherited conditions such as familial adenomatous 
polyposis and Cowden’s disease have also been linked to thyroid cancers due to certain germline 
mutations, as well as a family history of the disease (Guilmette and Nose 2018).  
 

 
 
Protocol XL184-311 
Page 31 of 165 
1.2 
Molecular Pathology of Thyroid Cancer 
A better understanding of the molecular pathogenesis and mechanisms of thyroid cancer has 
shown great promise for the development of more effective treatment strategies (Xing 2013). 
These include inhibition of angiogenesis and disruption of aberrant intracellular signaling 
pathways involved in tumorigenesis.  
MET and vascular endothelial growth factor (VEGF) signaling have been implicated in tumor 
neo-angiogenesis, invasion, and dissemination, while dysregulation of MET and VEGF pathway 
components has been associated with poor prognosis in multiple tumor types (Carmeliet and 
Jain 2011, Trusolino et al 2010, Aftab and McDonald 2011). Increased levels of VEGF have 
been documented in recurrent thyroid cancer following surgery and in patients with metastatic 
disease (Zhou et al 2012; Klubo-Gwiezdzinska et al 2007). The angiogenic activity observed in 
DTC led to the development of anti-VEGF targeted therapies. Resistance to VEGF-targeted 
therapies may arise from the upregulation of alternative pro-angiogenic and pro-invasive 
signaling pathways, including the MET pathway (Shojaei et al 2010, Zhou et al 2016, 
Sennino et al 2012, Ciamporcero et al 2015). Combined inhibition of the VEGF receptor 
(VEGFR) and MET represents a treatment opportunity which may enhance the efficacy over that 
achieved via inhibition of either pathway alone and overcome resistance (Sennino and 
McDonald 2012). 
The MAP kinase pathway (MAPK) and the PI3K-AKT signaling pathways are the most common 
disrupted or upregulated pathways in the tumorigenesis of thyroid cancer. Activation of the 
MAPK pathway can result from BRAF and RAS mutations or RET and ALK rearrangements. 
RET is a proto-oncogene which encodes a receptor tyrosine kinase (RTK) that is involved in 
tumor cell survival and proliferation (Drosten 2004). Mutations that activate RET kinase activity 
are frequently found in patients with MTC (Elisei 2008, Moura 2009). About 10-20% of sporadic 
PTCs have chromosomal translocations involving the RET proto-oncogene (RET-PTC fusions). 
The prevalence of RET-PTCs fusions is higher after radiation exposure (50-80%) and in young 
adults with PTC (Ciampi 2007). The most prevalent RET rearrangements are RET/PTC1 
(CCD6-RET) representing approximately 60-70%, RET/PTC3 (NCOA4-RET) representing 
approximately 20-30%, and RET/PTC2 (PRKAR1A-RET) representing 5% (Nikiforov 2011, 
Bongarzone et al 1998, Tallini et al 1998). These rearrangements lead to constitutive activation 
of RET kinase and downstream signaling of the MAPK pathway. Targeting the RET RTK 
activity represents a treatment opportunity in MTC and PTC (Pierotti 1996, Prescott 2015). 

 
 
Protocol XL184-311 
Page 32 of 165 
Presence of BRAF mutation (V600E) is associated with a more aggressive form of cancer and is 
highly prevalent in radioactive iodine-refractory PTC (Xing et al 2005). The PI3K-AKT 
signaling pathway is activated in a smaller fraction of patients with PTC and FTC and leads to 
increased cell proliferation (Ringel et al Cancer Res 2001). 
1.3 
Treatment of Differentiated Thyroid Cancer 
Surgical resection by either total thyroidectomy or unilateral lobectomy, with or without lymph 
node removal, is the main treatment for DTC. Patients with a high risk of disease recurrence, or 
incompletely resected cancer, or distant metastases, may receive adjuvant radioactive iodine 
(RAI). After thyroidectomy life-long thyroid hormone replacement with levothyroxine (LT4) is 
indicated. LT4 replacement therapy lowers thyroid-stimulating hormone (TSH) levels by a 
negative feedback through the hypothalamic-pituitary axis and helps to prevent the growth of 
remaining thyroid cancer cells (Cooper et al 2009, National Comprehensive Cancer Network 
[NCCN] 2017). Patients who develop RAI-refractory DTC have a very poor prognosis with an 
estimated median survival time of 2.5-3.5 years (Busaidy and Cabanillas 2012; Durante et 
al 2006, Schlumberger et al 2014). Chemotherapy-based salvage therapy is a less preferred 
treatment modality in RAI-refractory DTC because of its modest activity and unfavorable 
toxicity profile. Recent treatment advancements for patients with RAI-refractory DTC include 
tyrosine kinase inhibitors (TKIs) targeting the VEGFR which inhibits tumor angiogenesis and 
causes hypoxia in malignant tissue. VEGFR signaling plays a critical role in progressive DTC 
which are highly vascularized tumors (Keefe et al 2010). Sorafenib (Nexavar™) and lenvatinib 
(Lenvima™) inhibit multiple RTKs including VEGFRs and are approved in the United States 
and the European Union for patients with locally recurrent or metastatic, progressive DTC that is 
RAI-refractory.  
Approval of sorafenib is based on an international, randomized (1:1), placebo-controlled, Phase 
3 study which enrolled 417 patients (207 sorafenib arm, 210 placebo arm) with RAI-refractory 
DTC (Brose et al, Lancet 2014). Patients received 400 mg sorafenib or matching placebo given 
orally twice-daily and were required to have measurable disease for eligibility. Prior receipt of 
targeted therapy or chemotherapy was not allowed. Median age was 63 years; male and female 
gender was equally represented. The majority of patients had ECOG PS of 0 or 1 (> 95%). The 
most frequent histologies were PTC (57%), FTC (25%), and poorly differentiated DTC (10%). 
The most common metastatic disease sites were lung (86%), lymph node (51%), and 
bone (27%). Sorafenib significantly improved the primary endpoint of PFS compared with 
placebo (median 11 vs 5.8 months; HR = 0.59; p-value < 0.0001) and also significantly 
improved ORR (12% vs 0.5%; p-value < 0.0001). An OS benefit was not observed in the ITT 

 
 
Protocol XL184-311 
Page 33 of 165 
population possibly due to crossover to active treatment after progression. The median duration 
of treatment was 10.6 months among patients who received sorafenib and 6.5 months among 
patients who received placebo. Dose reductions occurred in 64% of patients in the sorafenib 
group vs 9.1% in the placebo group, resulting in a mean sorafenib dose of 651 mg per day. 
Adverse events occurred in 98.6% of patients in the sorafenib group vs 87.6% in the placebo 
group. The most frequent AEs of Grade 3 or 4 in the sorafenib group versus placebo group were 
hand-foot skin reaction (20.3% vs 0%), hypertension (9.7% vs 2.4%), fatigue (5.8% vs 1.4%), 
diarrhea (5.8% vs 1%), and weight loss (5.8% vs 1%). Treatment discontinuation due to an AE 
occurred in 18.8% of sorafenib treated patients. 
Approval of lenvatinib is based on an international, randomized (2:1), double-blind, 
placebo-controlled, Phase 3 study which enrolled 392 patients (261 lenvatinib arm, 131 placebo 
arm) with RAI-refractory DTC (Schlumberger et al NEJM 2015). Patients received 24 mg 
lenvatinib or matching placebo once daily and were required to have measurable disease for 
eligibility. Up to one prior treatment regimen with a TKI was allowed. Median age was 63 years; 
males and females were equally represented. The majority of patients had Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) of 0 or 1 (> 95%) and ~75% were treatment 
naïve and had not received a prior TKI therapy. The most common histology was PTC (~50%), 
followed by FTC (~19%), HTC (~18%), and poorly differentiated DTC (~13%). The most 
common metastatic disease sites were lung (~90%) and bone (~38%). Lenvatinib significantly 
improved the primary endpoint of progression-free survival (PFS) compared with placebo 
(median 18 vs 3.6 months; hazard ratio [HR] = 0.21; p-value < 0.001) and also significantly 
improved the objective response rate (ORR; 65% [4 complete responses {CRs} and 165 partial 
responses {PRs}] vs 1.5%; p-value < 0.001). There was no overall survival (OS) benefit in the 
intent-to-treat (ITT) population possibly due to post-progression crossover to active treatment. 
The median duration of treatment was 13.8 months among patients who received lenvatinib and 
3.9 months among patients who received placebo. Dose reductions occurred in 67.8% in the 
lenvatinib group vs 4.6% in the placebo group, resulting in a mean lenvatinib dose of 17.2 mg 
per day. Treatment-related adverse events (AEs) occurred in 97.3% of patients in the lenvatinib 
group vs 59.5% in the placebo group. The most frequent AEs of Grade 3 or higher in the 
lenvatinib arm versus placebo arm were hypertension (41.8% vs 2.3%), proteinuria (10% vs 0%), 
decreased weight (9.6% vs 0%), fatigue or asthenia (9.2% vs 2.3%), diarrhea (8% vs 0%), and 
decreased appetite (5.4% vs 0%). Treatment discontinuation due to an AE occurred in 14.2% of 
lenvatinib treated patients. 

 
 
Protocol XL184-311 
Page 34 of 165 
Although initial therapy with VEGFR-targeting TKIs provides clinical benefits by improving 
PFS and ORR, the majority of DTC patients will acquire resistance to therapy and develop 
progressive disease (PD). For DTC patients who develop resistance to TKI therapy, options are 
very limited and more effective therapies are needed. 
1.4 
Cabozantinib 
Cabozantinib is an orally bioavailable small molecule TKI that potently inhibits VEGFRs, MET, 
AXL, and RET, as well as a number of other RTKs that have also been implicated in tumor 
pathobiology, including KIT and FLT3. Cabozantinib suppresses MET and VEGFR signaling, 
rapidly inducing apoptosis of endothelial and tumor cells, resulting in tumor regression in a 
variety of tumor models. Cabozantinib capsules (140 mg) are approved in the US for the 
treatment of patients with progressive, metastatic MTC and in the European Union for the 
treatment of patients with progressive, unresectable locally advanced or metastatic MTC 
(Cometriq™ US prescribing information [US PI], European Medicines Agency Summary of 
Product Characteristics [EMA SmPC]). Cabozantinib tablets (60 mg) are approved in the US, 
Europe, and other regions for advanced renal cell carcinoma (RCC; different patient populations 
depending on region; Cabometyx™ US PI, EMA SmPC).  
1.4.1 
Cabozantinib in Thyroid Cancer 
Clinical experience of cabozantinib in thyroid cancer is available in subjects with RAI-refractory 
DTC and advanced MTC following prior VEGFR-targeted therapy. 
1.4.1.1 
Phase 1 Study XL184-008 
Study XL184-008 was a Phase 1, single-arm drug-drug interaction study that included a cohort 
of 15 subjects with RAI-refractory DTC that was metastatic or unresectable (Cabanillas 2014). 
After the primary analysis of pharmacokinetics (PK; drug-drug interaction), subjects continued 
on treatment and were evaluated for efficacy and safety. All subjects received open-label 
cabozantinib at an initial dose of 140 mg qd. Key eligibility criteria for the RAI-refractory DTC 
cohort included histologically confirmed metastatic or surgically unresectable disease, at least 
one measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0, 
platelets ≥ 100,000/mm3, hemoglobin ≥ 8 g/dL, and ECOG PS ≤ 2. Tumor assessments were 
performed using computed tomography/magnetic resonance imaging (CT/MRI) at baseline, at 
Day 64, and every 8 weeks thereafter until documented PD per RECIST or initiation of 
nonprotocol anticancer therapy (NPACT).  

 
 
Protocol XL184-311 
Page 35 of 165 
The RAI-refractory DTC cohort enrolled 15 subjects, including 7 subjects (47%) with PTC, 
5 subjects (33%) with FTC, and 3 subjects (20%) with HTC. The median age of these subjects 
was 53 years, and most subjects were female (9 females, 6 males). The majority of subjects 
(73%) had received prior VEGFR-targeted therapy for the disease. 
Of the 14 subjects evaluable for tumor response, 8 subjects (53%) had a confirmed PR, and 
6 subjects (40%) had stable disease (SD). Tumor regression appeared independent of prior 
VEGFR-targeted therapy: 5 of 11 subjects who had received at least 1 prior VEGFR-targeted 
therapy achieved PR, and all 3 subjects who had received no prior VEGFR-targeted therapy also 
achieved PR. The disease control rate (CR + PR + SD) at Week 17 was 80%. Among the eight 
subjects with an objective response, including those with censored data, duration of 
response (DOR) ranged from 61 to 442 days; the median DOR was not reached. The median PFS 
and OS were not reached (median follow-up was 12 months and 26 months, respectively).  
The 15 subjects with RAI-refractory DTC treated with cabozantinib in Study XL184-008 
received an initial dose of 140 mg qd (capsule formulation). Nearly all subjects (93%) required at 
least 1 dose reduction during the study. The median average daily dose was 62 mg, and the 
median relative dose intensity was 45%. The most frequently reported AEs during the study were 
consistent with those in subjects with other tumor types who received single-agent cabozantinib 
and included aspartate aminotransferase (AST) increased (100%), diarrhea (87%), nausea (80%), 
fatigue (80%), decreased appetite (80%), alanine aminotransferase (ALT) increased (73%), 
lactate dehydrogenase (LDH) increased (73%), and hypocalcemia (60%). The most frequent 
Grade 3 or higher AEs included hyponatremia (27%), lipase increased (20%), diarrhea (20%), 
hypertension (13%), decreased appetite (13%), and weight deceased (13%). 
1.4.1.2 
Phase 2 Investigator-Sponsored Studies 
1.4.1.2.1 Study NCT01811212 
NCT01811212, a Phase 2, single-arm Investigator-sponsored study (ISS) evaluated cabozantinib 
in 25 subjects with RAI-refractory DTC that had progressed after prior VEGFR-targeted therapy 
(Cabanillas 2017). Twenty-one (21) subjects (84%) had received one prior VEGFR-targeted 
therapy and 4 subjects (16%) had received two. Most patients had aggressive histology 
(28% poorly differentiated thyroid cancer, 20% HTC, 16% FTC) and distant metastases 
(84% bone, 36% liver, 20% brain) at study entry. All subjects received open-label cabozantinib 
at an initial dose of 60 mg qd (tablet formulation). Of the 23 subjects evaluable for tumor 
response, 10 subjects (40%) had a confirmed PR, and 13 subjects (52%) had SD; objective 
responses were observed across all histologic types and in subjects who had brain metastases at 

 
 
Protocol XL184-311 
Page 36 of 165 
study entry. Ten (10) of 21 subjects who had received only 1 prior VEGFR-targeted therapy 
achieved a response. The median PFS was 12.7 months (95% confidence interval [CI]: 
10.9, 34.7), and the median OS was 34.7 months (95% CI: 18.3, not reached). Table 1-1 provides 
a summary of key efficacy outcomes. 
Table 1-1: 
Study NCT01811212: Objective Response Rate, Progression-Free Survival, 
and Overall Survival (N=25) 
Overall Response Rate 
 
Best overall response, n (%) 
 
Confirmed partial response 
10 (40) 
Stable diseasea 
13 (52) 
Non-evaluableb 
2 (8) 
Response by number of prior VEGFR-targeted therapies, n/N (%) 
 
1 prior VEGFR-targeted  therapy 
10/21 (48) 
2 prior VEGFR-targeted  therapies 
0/4c (0) 
Progression-Free Survival 
 
Median progression-free survival, months (95% CI) 
12.7 (10.9, 34.7) 
Landmark estimates (% of subjects event-free) 
 
12 months 
55 (38, 79) 
24 months 
25 (13, 50) 
Overall Survival 
 
Median overall survival, months (95% CI) 
34.7 (18.3, not reached) 
Landmark estimates (% of subjects event-free) 
 
12 months 
80 (65, 97) 
24 months 
66 (49, 88) 
CI, confidence interval; VEGFR, vascular endothelial growth factor receptor. 
a Two subjects had unconfirmed partial responses. 
b Two subjects were not evaluable due to lack of imaging studies. One subject had clinical progression, and the 
other subject discontinued due to adverse event. 
c Variable degree of tumor reduction was observed in 3 evaluable patients (6%, 19%, 30%). 
Cabozantinib treatment in Study NCT01811212 was well-tolerated: 7 subjects (28%) received 
only 60 mg qd, 4 subjects (16%) dose-escalated to 80 mg qd, 6 subjects (24%) dose-reduced to 
40 mg qd, and 8 subjects (32%) dose-reduced to 20 mg qd. Of the 275 cycles (each cycle was 
28 days) of cabozantinib administered to the 25 subjects, 16% of the cycles were administered at 
80 mg qd, 38% at 60 mg qd, 25% at 40 mg qd, and 21% at 20 mg qd. The safety profile was 

 
 
Protocol XL184-311 
Page 37 of 165 
similar to that of other VEGFR-targeted therapies in DTC subjects, with manageable AEs during 
treatment. Table 1-2 provides a summary of AEs reported in ≥ 10% of subjects, including 
laboratory AEs that were deemed possibly, probably, or definitely associated with cabozantinib. 
The most frequent Grade 3 AEs (≥ 5%) were fatigue (12%), weight loss (12%), diarrhea, and 
palmar-plantar erythrodysesthesia (PPE; each 8%). In addition, an increase in TSH level 
(1.1-8.6 mIU/L) was observed in 6 subjects (at baseline all subjects were on LT4 for postsurgical 
hypothyroidism, and 24 had suppressed TSH). The most frequent Grade 3 laboratory 
abnormalities were hypophosphatemia (16%), lipase or amylase increased (12%), 
neutropenia (12%), and hypokalemia (8%). 
Table 1-2: 
Study NCT01811212: Summary of Adverse Events and Selected Laboratory 
Abnormalities (N=25) 
Adverse Event or Laboratory 
Abnormality 
Grade 1 
n (%) 
Grade 2 
n (%) 
Grade 3 
n (%) 
General Disorders 
 
 
 
Fatigue 
11 (44) 
5 (20) 
3 (12) 
Anorexia 
12 (48) 
4 (16) 
0 
Weight loss 
9 (36) 
3 (12) 
3 (12) 
Pain 
6 (24) 
2 (8) 
0 
Gastrointestinal Disorders 
 
 
 
Dysgeusia 
8 (32) 
4 (16) 
0 
Oral mucositis 
11 (44) 
3 (12) 
0 
Dry mouth 
6 (24) 
1 (4) 
0 
Nausea 
13 (52) 
3 (12) 
0 
Vomiting 
5 (20) 
2 (8) 
0 
Diarrhea 
9 (36) 
7 (28) 
2 (8) 
Other gastrointestinal disorders 
9 (36) 
1 (4) 
0 
Dermatologic 
 
 
 
Palmar-planter erythrodysesthesia 
8 (32) 
9 (36) 
2 (8) 
Rash 
4 (16) 
0 
0 
Other dermatologic disorder 
6 (24) 
4 (16) 
0 

 
 
Protocol XL184-311 
Page 38 of 165 
Adverse Event or Laboratory 
Abnormality 
Grade 1 
n (%) 
Grade 2 
n (%) 
Grade 3 
n (%) 
Vascular 
 
 
 
Hypertension 
6 (24) 
5 (20) 
1 (4) 
Proteinuria 
7 (28) 
1 (4) 
0 
Bleedinga 
4 (16) 
1 (4) 
1 (4) 
Other 
 
 
 
Headache 
5 (20) 
1 (4) 
0 
Other musculoskeletal 
3 (12) 
0 
0 
Voice alteration 
8 (32) 
2 (8) 
0 
Chemistry Abnormalities 
 
 
 
Liver transaminase elevation 
19 (76) 
0 
1 (4) 
Hypomagnesemia 
11 (44) 
2 (8) 
1 (4) 
Lipase or amylase elevation 
3 (12) 
1 (4) 
3 (12) 
Hypocalcemia 
7 (28) 
4 (16) 
1 (4) 
Hypophosphatemia 
3 (12) 
2 (8) 
4 (16) 
Hypokalemia 
4 (16) 
0 
2 (8) 
Alkaline phosphatase elevation 
4 (16) 
0 
0 
Hematology Abnormalities 
 
 
 
Anemia 
6 (24) 
3 (12) 
0 
Thrombocytopenia 
8 (32) 
0 
0 
Leukopenia 
5 (20) 
2 (8) 
0 
Neutropenia 
1 (4) 
0 
3 (12) 
a Grade 1: epistaxis (n=2), hematuria (n=1), and rectal bleeding (n=1); Grade 2: intracranial bleeding (n=1, 
associated with a new diagnosis of brain metastasis); Grade 3: retroperitoneal hematoma (n=1). 
1.4.1.2.2 Study NCT02041260 
NCT02041260, a Phase 2, single-arm ISS is currently evaluating cabozantinib at a dose of 60 mg 
qd (tablet formulation) in subjects with RAI-refractory DTC who have not received prior 
systemic anticancer therapy, including receptor TKIs. Preliminary results of this study were 
presented at the Multidisciplinary Head and Neck Cancers Symposium in February 2018 
(Brose et al 2018). 
Eligibility criteria for the study included: metastatic RAI-refractory thyroid cancer, treatment 
naïve to VEGFR inhibitor, life expectancy > 3 months, and an ECOG PS of 0-2. Cabozantinib 

 
 
Protocol XL184-311 
Page 39 of 165 
therapy was initiated at 60 mg qd. The primary endpoint of the study was overall response per 
RECIST 1.1, and secondary endpoints were PFS, clinical benefit rate, time-to-progression, DOR, 
and safety.  
Thirty five subjects (49% male) enrolled in the study, and the median age was 65 years 
(range: 45, 84 years). Of the subjects included in the study, 23 (66%) had papillary histology, 
3 (9%) had follicular (Hürthle cell) histology, and 9 (26%) had poorly differentiated histology. 
The median time on study treatment was 35 weeks (range: 3, 198 weeks), and among those 
evaluable for tumor response (n=34), a PR was achieved in 19 patients (54%), and SD in 
15 patients (43%). Nine subjects (26%) experienced SD for greater than 6 months. 
Seventeen subjects had a best target lesion reduction of ≥ 30%, and the disease control rate 
(CR+PR+SD > 6 months) was 80%. As of 06 February 2018, 16 subjects still remained on 
treatment. Although median PFS has not been reached (6 subjects have experienced PD so far), 
PFS at 6 months and 12 months were 88% and 65%, respectively.  
The most frequent treatment-related AEs reported were hyperglycemia (28 subjects [80%]), 
diarrhea (27 subjects [77%]), malaise/fatigue (26 subjects [74%]), and weight 
loss (25 subjects [71%]). Grade ≥ 3 AEs occurring in more than 1 subject were 
hypertension (5 subjects [14%]), increased lipase (3 subjects [9%]), pulmonary 
embolism (2 subjects [6%]), and hyponatremia (2 subjects [6%]). 
1.4.1.3 
Phase 3 Study XL184-301 
A Phase 3, randomized, double-blind, placebo-controlled study (EXAM) was conducted in 
subjects with radiographically documented progression MTC. A total of 330 subjects were 
randomized in a 2:1 ratio to receive either cabozantinib (140 mg, capsule formulation) or placebo 
respectively. A significant increase in PFS per independent radiology review committee (primary 
endpoint) was seen in the cabozantinib arm compared with placebo (median of 11.2 vs 4.0 
months; HR = 0.28; 95 CIs: 0.19, 0.40). For the secondary endpoint of ORR per independent 
radiology review committee, confirmed PRs occurred in 28% of cabozantinib-treated subjects 
and no placebo-treated subjects; responses were durable (median duration 14.6 months). The 
final analysis of the secondary endpoint of OS included 218 deaths and showed a non-significant 
trend for improved duration of OS in the cabozantinib arm compared with the placebo arm 
(medians of 26.6 vs 21.1 months, respectively; HR = 0.85; 95% CI: 0.64, 1.12; p = 0.2409). 
Because MTC is a relatively rare disease, the study was not designed to be large enough to 
provide high power to detect the minimum clinically significant difference in the secondary 
endpoint of OS.  

 
 
Protocol XL184-311 
Page 40 of 165 
In all subjects, the median duration of cabozantinib treatment was 10.8 months, and the 
75th percentile for duration of treatment was 24.8 months. The maximum duration of treatment 
was 59.4 months at the data cutoff of the final OS analysis. A first dose reduction to 40 mg 
occurred in 82% of cabozantinib-treated subjects, and a second dose reduction to 20 mg occurred 
in 46% of cabozantinib-treated subjects. The safety population included a total of 214 subjects 
who received cabozantinib. The most frequent AEs (≥ 30%) were diarrhea (70.1%), weight 
decreased (57.9%), PPE (52.8%), decreased appetite (49.1%), nausea (46.7%), fatigue (42.5%), 
dysgeusia (35.0%), hair color changes (34.1%), and hypertension (32.7%). The most frequent 
Grade 3/4 AEs (≥ 5%) in cabozantinib-treated subjects were diarrhea (21.5%), PPE (12.6%), 
hypocalcemia (10.7%), lipase increased (10.7%), fatigue (9.8%), weight decreased (9.8%), 
hypertension (8.9%), decreased appetite (7.0%), asthenia (6.5%), hypokalemia (5.6%), and ALT 
increased (5.1%). 
Study XL184-301 led to regulatory approval of cabozantinib (as Cometriq capsules) for the 
treatment of progressive, metastatic MTC in the US and Europe. While dose reductions from 
140 mg to 100 mg and 60 mg of cabozantinib did not appear to negatively affect efficacy, it is 
unknown if a lower starting dose of cabozantinib can maintain efficacy while improving 
tolerability. Therefore, Study XL184-401 (EXAMINER) has been initiated as a 
post-authorization measure to compare the efficacy and safety of oral cabozantinib at 60 mg 
(tablet formulation) versus 140 mg (capsule formulation) using a non-inferiority trial design with 
a primary endpoint of PFS. The study is currently enrolling. 
1.5 
Rationale 
Encouraging preliminary clinical activity of cabozantinib in patients with RAI-refractory DTC 
has been demonstrated in three clinical trials. In addition, cabozantinib is approved in the United 
States for the treatment of patients with progressive, metastatic MTC and in the European Union 
for the treatment of patients with progressive, unresectable locally advanced or metastatic MTC. 
Based on the current clinical experience with cabozantinib in differentiated thyroid carcinoma 
and the mechanism of action by inhibition of MET, VEGFR, and RET which play a critical role 
in angiogenesis, tumor proliferation and metastases, evaluating cabozantinib in subjects with 
DTC therapy appears to be promising. Thus, Study XL184-311 has been designed to further 
establish the clinical efficacy and safety of cabozantinib administered orally in subjects with 
RAI-refractory DTC who have progressed after prior VEGFR-targeted therapy. 

 
 
Protocol XL184-311 
Page 41 of 165 
1.5.1 
Rationale for Study Design 
There are no approved therapies for the treatment of RAI-refractory DTC after progression 
following VEGFR-targeted therapy. Current NCCN guidelines provide a category 2A 
recommendation for cabozantinib in treatment of progressive and/or persistent disease when 
clinical trials are not available (NCCN 2017). 
This is a randomized, double-blind, placebo-controlled, Phase 3 study of cabozantinib for the 
treatment of RAI-refractory DTC in subjects who have progressed following VEGFR-targeted 
therapy. Placebo has been chosen as the comparator in this study due to the lack of available 
treatments in this population. The 2:1 randomization was selected to limit exposure of subjects to 
placebo. All subjects will receive best supportive care (BSC) in addition to the randomized study 
treatment (Appendix G).  
PFS and ORR are the primary efficacy endpoints, with OS as an additional endpoint. PFS has 
been used as an endpoint in other DTC clinical trials, and ORR often correlates with PFS (for 
discussion of other DTC clinical trials, see Section 1.3). As subjects in the study population have 
limited treatment options, and to minimize the potential for differential dropout among subjects 
randomized to placebo with respect to the PFS endpoint as assessed by blinded independent 
radiology committee (BIRC), the study will allow subjects randomized to placebo to crossover to 
receive cabozantinib upon experiencing BIRC-confirmed radiographic PD (see Section 5.3 and 
Appendix B). 
In addition, the standardized measure of health status EQ-5D-5L, developed by the EuroQol 
group, will be used in order to provide a generic measure of health (Herdman 2011). The 
questionnaire will be completed by the subjects. The objective will be to assess the time to 
deterioration of these outcomes to support the primary endpoints. 
1.5.2 
Rationale for Including Adolescent Subjects  
Although thyroid cancer in children and adolescents is a rare disease, the incidence is increasing 
by an annual incidence of 1.1% per year. The highest incidence occurs in children from 
15-19 years. Compared with adults, DTC in children presents at more advanced stages and has a 
higher recurrence rate. The prevalence of distant metastasis in children is more common 
compared with adults (ie, lung metastases 20% vs 2%, respectively; Rivkees et al 2011). 
Children with DTC usually respond well to RAI therapy. However, in the rare event of 
RAI-refractory DTC in children and adolescents, experience with alternative treatment options is 

 
 
Protocol XL184-311 
Page 42 of 165 
limited (Verburg et al 2017). This study allows subjects ≥ 16 years of age to participate in order 
to address an unmet medical need. 
1.5.3 
Rationale for Cabozantinib Dose Selection  
The initial dose in this study will be 60 mg cabozantinib (tablet formulation) orally once 
daily (qd) or placebo matched control. This dose level and formulation has demonstrated 
tolerability, safety, and efficacy in subjects with advanced RCC who are treatment naïve as well 
as following prior VEGFR-targeted therapy (Cabometyx™ US PI) and in subjects with advanced 
hepatocellular carcinoma (HCC) who had previously received sorafenib (Ghassan et al 2018). 
Cabozantinib 60 mg qd orally has also been used as initial dose in ISSs in DTC (refer to the 
above sections). Preliminary efficacy in DTC was observed at the initial dose level of 60 mg as 
well the dose reduction levels of 40 mg and 20 mg (Cabanillas et al, JCO 2017). In the Phase 3 
study XL184-301 (EXAM) in MTC with an initial dose of 140 mg (capsule formulation) of 
cabozantinib the most common final dose level was 60 mg. Additionally, in a Phase 1 dose 
escalation study in Japanese subjects (Study XL184-014) with advanced or metastatic solid 
tumors, two formulations of cabozantinib were evaluated (capsule and tablet). The maximum 
tolerated dose for the capsule formulation was determined to be 60 mg qd, and there was only 
1 of 6 subjects who experienced dose-limiting toxicities at the 60 mg qd dose with the tablet 
formulation, which was used as the recommended Phase 2 dose. Thus, the proposed initial dose 
for this Phase 3 study of cabozantinib is 60 mg qd in the tablet formulation. 
1.5.4 
Rationale for Placebo 
Randomized, double-blind studies with a placebo control have been used in prior DTC studies 
using VEGFR TKIs as the experimental arm (Schlumberger et al 2015; Brose et al 2014). This 
design allows for evaluation of the natural history of advanced DTC in placebo-treated subjects 
of the comparator arm as well as the true effects of the tested agent in the experimental arm. In 
this study, the lack of available treatment options in patients with DTC who had received prior 
VEGFR-TKI therapy supports the use of a randomized, double-blind study design with a placebo 
arm. A 2:1 randomization schedule will be employed to minimize the number of subjects 
randomized to placebo. All subjects will receive BSC in addition to the randomized study 
treatment. For subjects randomized to the placebo arm, crossover to receive cabozantinib will be 
allowed after radiographic progression has been confirmed by the BIRC. 
 

 
 
Protocol XL184-311 
Page 43 of 165 
1.5.5 
Rationale for Crossover Phase  
There are currently no approved therapies for treatment of RAI-refractory DTC after progression 
following prior VEGFR-targeted therapy. As subjects in the study population have limited 
treatment options, and to minimize the potential for differential dropout among subjects 
randomized to placebo with respect to the PFS endpoint as assessed by BIRC, the study will 
allow subjects randomized to placebo to crossover to receive cabozantinib upon experiencing 
BIRC-confirmed radiographic PD.  
The eligibility criteria for crossover are intended to ensure that the subjects who crossover to 
receive cabozantinib do not have predisposing risks for treatment with cabozantinib. 
1.6 
Overall Risk Benefit Assessment  
Thyroid cancer is the most common endocrine neoplasm with an estimate of more than 
56,000 newly diagnosed cases in the United States and 298,000 cases worldwide in 2017 
(WHO 2012; SEER Cancer Statistics 2017). DTC accounts for more than 90% of all newly 
diagnosed thyroid cancers. Surgical resection by either total thyroidectomy or unilateral 
lobectomy, with or without lymph node removal, is the main treatment for DTC. Patients with a 
high risk of disease recurrence, incompletely resected cancer, or distant metastases may receive 
adjuvant RAI. Patients who develop RAI-refractory DTC have a very poor prognosis and require 
further treatment. Small molecule TKIs targeting VEGFR, which is highly expressed in DTC 
tumors, and other receptors involved in tumor growth have been approved for the initial 
treatment of locally recurrent or metastatic, progressive DTC that is RAI-refractory. Although 
initial therapy with VEGFR-targeting TKIs provides clinical benefits by improving PFS and 
ORR, the majority of DTC patients will acquire resistance to therapy and develop PD. There are 
no proven treatment options for these patients. 
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. 
Antitumor activity has been observed in multiple tumor indications (Schöffski et al 2017, 
Choueiri et al 2018). Cabozantinib is approved as Cometriq (140 mg cabozantinib capsules) in 
the US and the EU for the treatment of progressive, metastatic MTC. Cabometyx (60 mg 
cabozantinib tablets) is approved in the US, Europe, and other regions for advanced RCC 
(different patient populations depending on region). Cabometyx is currently under review in the 

 
 
Protocol XL184-311 
Page 44 of 165 
EU based on statistically improved PFS compared with sunitinib in treatment-naïve RCC. A 
placebo-controlled study of cabozantinib in previously-treated HCC has demonstrated an 
improvement in duration of OS for cabozantinib. Regulatory applications in the US and EU were 
submitted on March 2018. 
Encouraging preliminary clinical activity of cabozantinib in patients with RAI-refractory DTC 
has been demonstrated in three clinical trials (Section 1.4.1). Based on the current clinical 
experience with cabozantinib in thyroid carcinoma and the mechanism of action by inhibition of 
MET, VEGFR, and RET, as described above, evaluating cabozantinib in subjects with DTC 
appears to be promising. Thus, Study XL184-311 has been designed to further establish the 
clinical efficacy and safety of cabozantinib administered orally in subjects with RAI-refractory 
DTC who have progressed after prior VEGFR-targeted therapy.  
Study eligibility criteria were designed to prevent subjects at a safety risk from entering the 
study. The protocol allows for study treatment dose reductions (Section 6.5.1) in order to manage 
potential drug-related toxicities adequately. Section 6.7 of the protocol provides guidance to 
investigators for the management of important AEs in this clinical trial. Further guidance 
regarding other AEs is presented in the cabozantinib Investigator’s Brochure. Frequent safety 
assessments including laboratory assessments allow for 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 IDMC 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.  
1.6.1 
Summary of Benefits and Risks 
Preliminary clinical data suggest that cabozantinib exhibits substantial activity against 
RAI-refractory DTC. The safety profile of cabozantinib is well defined, and dose management 
guidelines have been instituted for the most important risks. 

 
 
Protocol XL184-311 
Page 45 of 165 
1.7 
Study Conduct 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonisation (ICH) Guidelines and also consistent with the most 
recent accepted version of the Declaration of Helsinki. In addition, all applicable local laws and 
regulatory requirements relevant to the use of new therapeutic agents in the countries involved 
will be adhered to. 
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; for every subject < 18 years of age, freely given written informed assent and 
informed consent from a parent or guardian must be obtained 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). 

 
 
Protocol XL184-311 
Page 46 of 165 
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objective of this study is to evaluate the effect of cabozantinib compared with placebo on 
PFS and ORR in subjects with RAI-refractory DTC who have progressed after prior 
VEGFR-targeted therapy.  
2.2 
Endpoints 
Primary endpoints: 
• PFS per RECIST 1.1 by BIRC 
• ORR per RECIST 1.1 by BIRC 
Additional endpoints: 
• Overall survival (OS) 
• Duration of objective tumor response 
• Safety and tolerability  
• Pharmacokinetics (PK) of cabozantinib 
• Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), 
and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or 
clinical outcome assessments may be performed  
• Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 
global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L) 
• Health care resource utilization 

 
 
Protocol XL184-311 
Page 47 of 165 
3 
STUDY DESIGN 
3.1 
Study Sites 
This study will be conducted at approximately 150 global clinical sites. 
3.2 
Estimated Study Dates and Duration of Subject Participation 
It is estimated that it will take 15 months to randomize approximately 300 subjects (ITT 
population) at approximately 150 global sites. The number of events required for the primary 
analysis of PFS by BIRC is expected to be observed approximately 20 months after the first 
subject is randomized. The co-primary endpoint ORR by BIRC will be assessed among the first 
100 randomized subjects (ORR Intent-to-Treat [OITT] population) and the primary analysis is 
expected to be conducted approximately 6 months after the last subject of the OITT population 
has been randomized.  
It is estimated that subjects will receive study treatment for an average of 9 months. Subjects will 
be followed until death, withdrawal of consent from the study (Section 3.6.2), or Sponsor 
decision to no longer collect these data. 
3.3 
Overview of Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial of cabozantinib 
in subjects with RAI-refractory DTC who have progressed after prior VEGFR-targeted therapy. 
Best supportive care will be provided for subjects on both treatment arms. Progression-free 
survival and ORR are the primary efficacy endpoints. Approximately 300 eligible subjects will 
be randomized in a 2:1 ratio to receive either cabozantinib or placebo as described in Section 3.4.  
Each subject’s trial participation will consist of the following periods: 
Pretreatment Period: Potential subjects will be screened to determine if they meet the required 
eligibility criteria. Qualifying screening assessments must be performed within 28 days before 
randomization unless otherwise specified (Appendix A). Eligibility criteria based on laboratory 
values should use the central laboratory result (for exceptions, refer to Section 5.7.5). 

 
 
Protocol XL184-311 
Page 48 of 165 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in 
a 2:1 ratio to receive cabozantinib or placebo (Section 3.4).  
Crossover Phase: Subjects randomized to the placebo arm have the opportunity to crossover to 
receive cabozantinib upon experiencing radiographic PD per RECIST 1.1 per investigator that is 
confirmed by the BIRC. To facilitate this: 
• A real-time dual-reader adjudicated BIRC review of radiographic images per RECIST 1.1 
will be employed to document objective radiographic progression contemporaneously with 
subject study participation. 
• At the time of investigator-determined radiographic progression per RECIST 1.1, 
investigators may request from the Sponsor’s medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD. 
• For subjects with BIRC-confirmed radiographic progression: 
• Upon authorization from Sponsor’s medical monitor (or designee), investigators may 
unblind individual subjects via the Interactive Response Technology (IRT) system. 
• Unblinded subjects randomized to placebo have the following options: 
• Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B. 
• Such subjects who are ineligible or opt not to crossover to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per Appendix A. 
• Subjects without radiographic progression per BIRC will not be unblinded and are to 
continue to receive blinded study treatment and undergo study assessments according to the 
schedule in Appendix A. Safety assessments will continue, efficacy assessments will be per 
standard of care if allowed per local regulation; PK, biomarker, and health-related quality of 
life (HRQOL) will be discontinued. 

 
 
Protocol XL184-311 
Page 49 of 165 
End of Study Treatment: Subjects will receive blinded study treatment or unblinded treatment 
with cabozantinib as long as they continue to experience clinical benefit in the opinion of the 
investigator or until there is unacceptable toxicity or the need for nonprotocol systemic 
anticancer treatment. Treatment may continue after radiographic PD per RECIST 1.1 as 
determined by the investigator in the absence of nonprotocol systemic anticancer treatment 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 risk. 
Post-Treatment Period: A post-treatment follow-up visit will occur 30 (+14) days after the date 
of the decision to discontinue study treatment.  
Radiographic tumor assessments and HRQOL assessments are to continue on the 
protocol-defined schedule relative to the date of randomization regardless of whether study 
treatment is given, reduced, held, or discontinued, including for subjects randomized to placebo 
who cross over to receive cabozantinib (Appendix B). Consequently these assessments may be 
required in the Post-Treatment Period, including after the final safety assessment, for some 
subjects. In addition, subjects are to be contacted every 12 weeks (± 7 days) after the 
Post-Treatment Follow-Up Visits to assess survival status and document receipt of NPACT and 
subsequent progression status. This will continue until the subject expires or the Sponsor decides 
to discontinue collection of these data in the study. Every effort must be made to collect these 
protocol-specific evaluations unless consent to participate in the study is withdrawn.  
Study Completion by Country or by Site: At the time the Maintenance Phase is initiated, the 
study will be considered complete at sites and in countries where all subjects have completed 
post-treatment safety follow-up. 
Maintenance Phase: After the primary efficacy endpoints have been analyzed and upon 
determination by the Sponsor that sufficient data have been collected to adequately evaluate all 
study endpoints to establish, for regulatory purposes, the safety and efficacy profile of the 
experimental drug within this study, the study will begin to transition to the Maintenance Phase. 

 
 
Protocol XL184-311 
Page 50 of 165 
As a transitional step prior to initiation of the Maintenance Phase, all blinded study subjects will 
be unblinded and study sites will be notified of their randomized treatment assignments.  
• Unblinded subjects randomized to placebo have the following options: 
o Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B.  
o Such subjects who are ineligible or opt not to cross over to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per in Appendix A. 
After the date the entire study is unblinded, study sites will have 8 weeks to determine eligibility 
and begin administration of crossover cabozantinib treatment to eligible subjects randomized to 
placebo; subsequently no further crossover will be allowed. 
Once the W9D1 visit has elapsed in the Crossover Phase for the last placebo subject who crossed 
over to receive cabozantinib, and upon site notification by the Sponsor, the transition period will 
end, and the study will enter the study Maintenance Phase.  
In the Maintenance Phase, subjects are to be followed as described in Appendix C. Subjects 
remaining on study treatment will continue to receive it until a criterion for protocol-defined 
discontinuation has been met. Subjects are to undergo periodic safety assessments (including 
local laboratory tests) and tumor assessments; the nature and frequency of these assessments are 
to be performed per standard of care. It is the Investigator’s responsibility to ensure that subject 
visits occur frequently enough and adequate assessments are performed to ensure subject safety. 
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 Visit at 
the time the transition to the Maintenance Phase, will undergo the final safety assessment at the 
post-treatment follow-up visit. Upon initiation of the Maintenance Phase, no further follow-up is 
required for any subject who has completed the Post-Treatment Follow-Up Visit.  

 
 
Protocol XL184-311 
Page 51 of 165 
The study clinical database will be closed upon initiation of the Maintenance Phase. Only data 
collected prior to implementation of Maintenance Phase will be reported in a clinical study 
report. 
3.4 
Treatment Groups and Randomization 
When an individual subject has been deemed eligible at the study site, the site representative will 
use the designated IRT system to enroll the subject into the study. Eligible subjects will be 
randomly assigned in a 2:1 ratio to the following treatment arms:  
• Cabozantinib arm: Oral cabozantinib (60 mg) qd  
• Placebo arm: Oral cabozantinib-matched placebo qd  
Details about treatment regimens are provided in Section 6. 
Randomization will be stratified by the following factors: 
• Receipt of prior Lenvatinib (yes vs no) 
• Age at informed consent (≤ 65 years vs > 65 years) 
Randomization should occur as close as possible prior to the planned start of treatment (ie, 
within 24 hours prior if practicable but no more than 3 days). Subjects are defined as enrolled in 
the study if randomized. Changes to stratification values entered in the IRT system will not be 
performed after randomization. Randomization “roll backs” will not be allowed except under 
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 
This is a randomized, double-blind, placebo-controlled study of cabozantinib in subjects with 
RAI-refractory DTC after prior VEGFR-TKI therapy. Cabozantinib-matched placebo will be 
given in the control arm to blind (mask) study treatment. 
Until individual subjects or the study has been unblinded (Section 3.3), study treatment 
assignment will be unknown to the subjects, investigators, study centers, Sponsor, and any 
Contract Research Organization 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 system administration, and drug supply management. 

 
 
Protocol XL184-311 
Page 52 of 165 
Cabozantinib-matched placebo will be packaged and color-, size-, and shape-matched to be 
indistinguishable from cabozantinib (Section 6.1).  
Study treatment assignment will be unblinded and information provided to the Investigators upon 
request for subjects with radiographic PD per RECIST 1.1 confirmed by the BIRC (see 
Section 3.5.2) or when the study is unblinded. 
3.5.2 
Unblinding Procedure for Individual Subjects 
3.5.2.1 
Unblinding an Individual Subject for Safety Purposes 
In the event of a medical emergency while a subject’s treatment assignment remains blinded, the 
treating physician may decide that knowledge of the investigational product is critical to the 
subject’s management. 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. Before breaking the blind of an individual subject’s study treatment 
the investigator should have determined that the information will alter the subject’s immediate 
management; the investigator should consult the Sponsor’s medical monitor prior to unblinding 
any subject. In the vast majority of cases AEs may be properly managed without the need for 
unblinding (see Section  6.5). An unblinded notification including the subject ID, treatment arm, 
and date of unblinding will be provided to the investigator and to the chair of the IDMC. A 
blinded notification that includes only the subject ID and the date of unblinding will be provided 
to the responsible medical monitor and the Sponsor’s Drug Safety Department Physician. 
Blinding of study treatment prior to efficacy endpoint ascertainment is critical to the integrity of 
this clinical trial, and therefore if a subject’s treatment assignment is disclosed to the study site 
via this process the subject will have study treatment discontinued. 
3.5.2.2 
Unblinding an Individual Subject for Potential Crossover Treatment with 
Cabozantinib 
As subjects in the study population have limited treatment options, and to minimize the potential 
for differential dropout among subjects randomized to placebo with respect to the PFS endpoint 
as assessed by BIRC, the study will allow subjects randomized to placebo to crossover to receive 
cabozantinib upon experiencing PD per RECIST 1.1 that is confirmed by the BIRC. To facilitate 
this, at the time of investigator-determined radiographic progression per RECIST 1.1, 
investigators may request from the Sponsor medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD. For subjects with BIRC-confirmed radiographic PD, upon 
authorization from the Sponsor medical monitor (or designee), investigators may unblind 
individual subjects via the IRT system to learn their treatment assignment. If the subject was 

 
 
Protocol XL184-311 
Page 53 of 165 
originally randomized to the placebo arm, investigators may evaluate eligibility for crossover to 
receive cabozantinib (see Section 5.3 and Appendix B). 
3.6 
Discontinuation and Withdrawal 
Details for handling treatment discontinuation and study withdrawal are discussed in 
Sections 3.6.1 and 3.6.2.  
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: 
• Discontinue study treatment only; other study interventions (including radiographic and 
laboratory evaluations) and non-interventional study assessments (including subject/relative 
contact and medical records review) may continue 
• Discontinue study treatment and withdraw consent for other study interventions; 
non-interventional study assessments (including subject/relative contact and medical records 
review) may continue (where permitted by local regulations) 
• Discontinue study treatment and withdraw of consent for all study interventions and 
non-interventional study assessments. 
The subject’s decisions (there may be more than one over time) must be recorded in source 
documents and transcribed to study case report forms (CRFs). 
3.6.1 
Treatment Discontinuation 
Subjects will receive study treatment until treatment discontinuation for any of the reasons listed 
below. Subjects may discontinue study treatment at any time without prejudice. If a subject 
discontinues study treatment, the reason will be documented in source documents. However, the 
subject will continue to be followed for safety as described in Section 5.4.1 and survival as 
described in Section 5.4.2; for subjects who discontinue study treatment prior to radiographic 
PD, tumor assessments and HRQOL assessments should continue per the protocol-defined 
schedule (Section 5.4.2). For subjects who discontinue study treatment, every effort must be 
made to continue protocol-specified evaluations and follow-up (Appendix A; Appendix B) 
unless the subject also withdraws consent to participate in other study interventions and/or 
non-interventional study assessments (see Sections 3.6.2 and 12.2). Subjects who request to 
discontinue study interventions may consent to allow non-interventional study assessments (eg, 
medical record review and survival contacts) where permitted by local regulations. Otherwise, all 
subjects will be followed until death or until a decision by the Sponsor is made to stop collection 
of these data. 

 
 
Protocol XL184-311 
Page 54 of 165 
The following are possible reasons for discontinuation from study treatment: 
• Subject no longer experiences clinical benefit as determined by the investigator (ie, 
radiographic PD; clinical deterioration attributable to PD and unlikely to reverse with 
continued study treatment and/or supportive care). Note: If study treatment is withdrawn for 
this reason, the date of this decision is to be recorded and every effort should be made to 
continue safety evaluations and collection of nonprotocol treatment information and 
follow-up information for survival.  
• Unacceptable side effects the investigator feels may be due to study treatment 
• The investigator feels it is not in the best interest of the subject to continue on study  
• Participation in another clinical study using an investigational agent or investigational 
medical device 
• Necessity for treatment with nonprotocol systemic anticancer therapy  
• Necessity for withholding study treatment for greater than 8 weeks for AEs, unless 
continuation of treatment is approved by the Sponsor 
• Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
• Pregnancy of a female subject  
• Request by the Sponsor  
• Subject request to discontinue study treatment  
• Unblinding of study treatment by the Investigator (prior to crossover) 
• Significant noncompliance with the protocol schedule in the opinion of the investigator or the 
Sponsor 
The Sponsor should be notified of all discontinuations of study treatment as soon as possible. If a 
subject fails to return for the protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at a minimum, a registered letter should be 
sent to the subject (or the subject’s legal guardian) requesting contact with the study site.  
For subjects who withdraw or are withdrawn from study treatment, every effort must be made to 
continue protocol-specified evaluations and procedures through the post-treatment follow-up and 
extended follow-up visits unless consent for study procedures and/or evaluations is also 
withdrawn. All subjects will be followed until death, unless consent to do so is specifically 
withdrawn by the subject or until a decision by the Sponsor is made to stop collection of these 
data. 

 
 
Protocol XL184-311 
Page 55 of 165 
3.6.2 
Study Withdrawal 
Subjects may withdraw their consent for study interventions (eg, exams, blood and tissue 
sampling radiographic assessments, questionnaires) and/or to participate in non-interventional 
study assessments (eg, medical record review, survival contacts) at any time without prejudice. If 
so, the reason for study consent withdrawal will be recorded in the source documents and CRFs 
(see Section 12.2). As applicable, no further study procedures or assessments will be performed 
or study data collected for this subject, other than the determination of survival status from 
public records such as government vital statistics or obituaries as allowed by local regulations. 
Subjects who withdraw will not be replaced.  
 

 
 
Protocol XL184-311 
Page 56 of 165 
4 
STUDY POPULATION 
4.1 
Target Population 
This study will enroll subjects with RAI-refractory DTC who have progressed after prior 
VEGFR-targeted therapy. 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. 
Study eligibility criteria for all subjects are below (eligibility criteria for subjects in the placebo 
arm who opt to crossover to receive cabozantinib are in Appendix B): 
4.2 
Inclusion Criteria 
1. Histologically or cytologically confirmed diagnosis of DTC, including the following 
subtypes (Note: results of a previous biopsy will be accepted): 
a. PTC including histological variants of PTC such as follicular variant, tall cell, columnar 
cell, cribriform-morular, solid, oxyphil, Warthin-like, trabecular, tumor with nodular 
fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated 
b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and 
poorly differentiated  
2. Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to 
randomization 
3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131 
for DTC  
4. Must have been previously treated with at least one of the following VEGFR-targeting TKI 
agents for DTC: lenvatinib or sorafenib. 
(Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited 
to) lenvatinib and sorafenib.) 
5. Must have experienced documented radiographic progression per RECIST 1.1 per 
Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the 
next anticancer therapy (which may be treatment in this study) 
6. Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events 
Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are 
clinically nonsignificant and/or stable on supportive therapy 
7. Age ≥ 16 years old on the day of consent  
8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1  

 
 
Protocol XL184-311 
Page 57 of 165 
9. Adequate organ and marrow function, based upon meeting all of the following laboratory 
criteria within 10 days before randomization:  
a. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without receipt of granulocyte 
colony-stimulating factor support within 2 weeks before screening laboratory sample 
collection 
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks 
before screening laboratory sample collection 
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before 
screening laboratory sample collection 
d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × upper 
limit of normal (ULN). ALP ≤ 5 × ULN if the subject has documented bone metastases 
e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease ≤ 3 × ULN 
f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula). 
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) 
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff 
of the reference range or less than 0.50 mIU/L (< 0.50 μIU/mL), whichever is lower, within 
28 days before randomization. 
(Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be 
targeted.) 
11. Capable of understanding and complying with the protocol requirements and signed 
informed consent (or informed assent and parental/guardian consent for subjects < 18 years 
of age) 
12. Sexually active fertile subjects and their partners must agree to use highly effective methods 
of contraception that alone or in combination result in a failure rate of less than 1% per year 
when used consistently and correctly during the course of the study and for 4 months after 
the last dose of study treatment. For females, such methods include combined hormonal 
contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable 
hormonal contraception), placement of an intrauterine device, or placement of an 
intrauterine hormone-releasing system. Males must agree to use a barrier method (eg, 
condom) unless they have had a vasectomy. 

 
 
Protocol XL184-311 
Page 58 of 165 
13. Female subjects of childbearing potential must not be pregnant at screening. Female subjects 
are considered to be of childbearing potential unless one of the following criteria is met: 
permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 
or documented postmenopausal status (defined as 12 months of amenorrhea in a woman 
over 45 years-of-age in the absence of other biological or physiological causes. In addition, 
females under 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 treatment with any of the following: 
a. Cabozantinib 
b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)   
c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib, 
pazopanib, axitinib, vandetanib) 
d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent) 
e. More than 1 systemic chemotherapy regimen (given as single agent or in combination 
with another chemotherapy agent) 
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before 
randomization 
3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic 
chemotherapy within 4 weeks before randomization 
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation 
therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing 
complications from prior radiation therapy that have not completely resolved are not eligible 
(eg, radiation esophagitis or other inflammation of the viscera). 
5. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before 
randomization. Eligible subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of randomization.  

 
 
Protocol XL184-311 
Page 59 of 165 
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and 
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following 
allowed anticoagulants:  
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose 
low molecular weight heparins (LMWH) 
• Anticoagulation with therapeutic doses of LMWH in subjects without known brain 
metastases who are on a stable dose of LMWH for at least 6 weeks before 
randomization and who have had no clinically significant hemorrhagic complications 
from the anticoagulation regimen or the tumor 
7. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
a. Cardiovascular disorders: 
i. Congestive heart failure class 3 or 4 as defined by the New York Heart Association, 
unstable angina pectoris, serious cardiac arrhythmias 
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg 
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or 
other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], 
pulmonary embolism) within 6 months before randomization. Subjects with a more 
recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with 
LMWH for at least 6 weeks before randomization. 
b. Gastrointestinal disorders (GI; eg, malabsorption syndrome or gastric outlet obstruction) 
including those associated with a high risk of perforation or fistula formulation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel 
disease, ulcerative colitis, 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 before randomization 
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to 
randomization  
c. Clinically significant hematemesis or hemoptysis of  > 0.5 teaspoon (> 2.5 mL) of red 
blood or history of other significant bleeding within 3 months before randomization 
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation 
e. Lesions invading major pulmonary blood vessels 

 
 
Protocol XL184-311 
Page 60 of 165 
f. Other clinically significant disorders such as: 
• Active infection requiring systemic treatment, infection with human 
immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or 
chronic hepatitis B or C infection  
• Serious non-healing wound/ulcer/bone fracture 
• Malabsorption syndrome  
• Moderate to severe hepatic impairment (Child-Pugh B or C) 
• Requirement for hemodialysis or peritoneal dialysis 
• Uncontrolled diabetes mellitus 
• History of solid organ transplantation 
8. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before 
randomization. Complete wound healing from major surgery must have occurred 4 weeks 
before randomization and from minor surgery (eg, simple excision, tooth extraction) at least 
10 days before randomization. Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible. 
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days 
before randomization   
Note: If a single electrocardiogram (ECG) shows a QTcF with an absolute value > 500 ms, 
two additional ECGs at intervals of approximately 3 min must be performed within 30 min 
after the initial ECG, and the average of these 3 consecutive results for QTcF will be used 
to determine eligibility.  
10. Pregnant or lactating females 
11. Inability to swallow tablets  
12. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations 
13. Diagnosis of another malignancy within 3 years before randomization, except for superficial 
skin cancers, or localized, low grade tumors deemed cured and not treated with systemic 
therapy 
 
 

 
 
Protocol XL184-311 
Page 61 of 165 
5 
STUDY ASSESSMENTS AND PROCEDURES 
Study treatment will be administered orally on a continuous daily basis. This document generally 
presents scheduled times for study procedures by 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 after randomization. 
All assessments for safety and HRQOL assessments will be scheduled based on W1D1. 
All assessments for efficacy (CT or MRI, bone scans) will be scheduled based on the date of 
randomization.  
Unscheduled visits for safety evaluation are allowed at any time and required under 
circumstances described herein (Section 5.6). 
See Appendix A for the schedule of study procedures; Appendix B for assessments during the 
Crossover Phase, Appendix C for the Maintenance Phase. 
5.1 
Pretreatment 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. The investigator must ensure that the subject is consented 
based on the most recently IRB/EC-approved version of the ICF. At informed consent, subjects 
will be assigned a 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. 
Subjects will undergo screening assessments to determine eligibility and have baseline 
evaluations as outlined in Appendix A, including medical history, prior cancer treatment, tumor 
morphology, physical examination and vital signs, 12-lead ECG, clinical laboratory assessments, 
pregnancy test, and disease assessment. Biopsy will be required for those subjects that have not 
had previous histological or cytological diagnosis of DTC. Biopsy can be performed more than 
28 days prior to randomization. Healing from biopsy must be complete at least 10 days prior to 
randomization. 

 
 
Protocol XL184-311 
Page 62 of 165 
Study eligibility is based on a subject meeting all of the study inclusion criteria and none of the 
exclusion criteria at screening. Qualifying screening assessments, with the exception of tumor 
biopsy, must be performed within 28 days before randomization (or within 7 days before 
randomization for pregnancy test, 14 days before randomization for physical examination and 
12-lead ECG, and 10 days before randomization for laboratory tests and other selected 
assessments [see Appendix A]).  
5.2 
Treatment Period 
Subjects eligible after completing all screening evaluations will be randomly assigned in a 2:1 
fashion to receive cabozantinib or matched placebo (Sections 3.4 and 6).  
Study W1D1 is defined as the first day of blinded study treatment—either cabozantinib or 
matched placebo (see Section 6.1.1). (For subjects who are randomized but not treated, W1D1 is 
defined as day of randomization.) 
Subjects should receive their first dose of study treatment within 3 days after randomization. See 
Appendix A for requirement for repeat assessments needed before first dose to confirm 
suitability for study treatment (Appendix B for subjects in the placebo arm for the Crossover 
Phase). 
Please refer to Appendix A (Appendix B for Crossover Phase) and Section 5.7.5 for handling of 
all samples for laboratory assessments.  
While the subject is receiving study treatment, the subject’s clinical status is to be evaluated by 
the treating physician at each clinic visit to confirm that the subject is suitable for continuing 
study treatment. Clinical laboratory results from samples obtained during clinic visits and tumor 
assessments from imaging visits are to be reviewed promptly by the treating physician for the 
same purpose.  
Subjects randomized to placebo have the opportunity to crossover to receive cabozantinib upon 
experiencing investigator-determined radiographic PD that is BIRC-confirmed, if eligible (see 
Section 5.4.2 and Appendix B).  
Subjects will receive blinded study treatment or unblinded treatment with cabozantinib as long as 
they continue to experience clinical benefit in the opinion of the investigator until the earlier of 
unacceptable toxicity, the need for nonprotocol systemic anticancer therapy, or until any of the 
other reasons for treatment discontinuation described in Section 3.6.1. Study treatment may 

 
 
Protocol XL184-311 
Page 63 of 165 
continue to be administered after radiographic PD per RECIST 1.1 has been determined, 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 risk.  
Clinic visits for safety evaluations will occur prior to dosing on W1D1 and at minimum every 
2 weeks (± 3 days) after treatment is initiated through W9D1 and then every 4 weeks (± 5 days) 
thereafter independent of any dose interruptions. The final safety assessment will occur at the 
post-treatment follow-up visit 30 (+14) days after the date of the decision to discontinue 
treatment unless a Grade 3/4 AE or an SAE is determined to be ongoing (the event would be 
followed until resolution; see Section 8.3).  
If study treatment is interrupted, investigators should perform additional safety assessments 
weekly or more frequently as clinically indicated. Results of safety assessments should be 
reviewed as soon as they become available in order to make timely decisions regarding the 
continuation, interruption, or restarting of study treatment.  
Radiographic tumor assessments (Section 5.7.6) and HRQOL assessments (Section 5.7.7) should 
be performed according to the schedule in Appendix A (Appendix B for the Crossover Phase, 
Appendix C for the Maintenance Phase [HRQOL will no longer be collected for subjects who 
transition to the Crossover Phase or if the study transitions to the Maintenance Phase]). Health 
care resource utilization assessments (Section 5.7.8) will be discontinued if the study transitions 
to the Maintenance Phase. 
In accordance with the ITT principle, radiographic tumor assessments, HRQOL, and survival 
follow-up are to be performed per protocol even for subjects randomized but who never receive 
study treatment. For such subjects, W1D1 is defined as the date of randomization. 
Blood samples for pharmacogenetic, plasma biomarker, and potential CTC analysis 
(Section 5.7.10) will be collected according to the schedule in Appendix A. (These assessments 
will be discontinued for the Crossover Phase or Maintenance Phase.) 
In addition, tumor tissue (from the most recently collected sample prior to subject enrollment in 
the study) will be obtained (Section 5.7.10) during screening or at enrollment for exploratory 
analysis of biomarkers such as RET or MET and potentially other pathway components (eg, 
RAS, BRAF) or modulators associated with the mechanism of action of cabozantinib and/or 
DTC.  

 
 
Protocol XL184-311 
Page 64 of 165 
Pharmacokinetic blood samples for determination of plasma concentrations of cabozantinib 
(Section 5.7.9) will be performed according to the schedule in Appendix A.  
All PK, pharmacodynamic/biomarker, and pharmacogenetic assessments will be discontinued for 
the Crossover Phase or Maintenance Phase. 
The schedule for assessments should be maintained independent of any dose interruptions. 
5.3 
Crossover Phase 
As subjects in the study population have limited treatment options, and to minimize the potential 
for differential dropout among subjects randomized to placebo with respect to the PFS endpoint 
as assessed by BIRC, the study will allow subjects randomized to placebo to crossover to receive 
cabozantinib upon experiencing investigator-determined radiographic PD that is confirmed by 
the BIRC. To facilitate this: 
• A real-time dual-reader adjudicated BIRC review of radiographic images per RECIST 1.1 
will be employed to document objective radiographic progression contemporaneously with 
subject study participation. 
• At the time of investigator-determined radiographic progression per RECIST 1.1, 
investigators may request from the Sponsor’s medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD. 
• For subjects with BIRC-confirmed radiographic progression: 
• Upon authorization from Sponsor’s medical monitor (or designee), investigators may 
unblind individual subjects via the IRT system. 
• Unblinded subjects randomized to placebo have the following options: 
• Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B. 
• Such subjects who are ineligible or opt not to crossover to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per Appendix A. 

 
 
Protocol XL184-311 
Page 65 of 165 
• Subjects without radiographic progression per BIRC will not be unblinded and are to 
continue to receive blinded study treatment and undergo study assessments according to the 
schedule in Appendix A. 
In the Crossover Phase safety assessments will continue per protocol, radiographic tumor 
assessments will be per standard of care; PK, biomarker, and HRQOL will be discontinued. 
See Appendix B for more details. 
5.4 
Post-Treatment Period 
5.4.1 
Post-Treatment Follow-Up Visit 
Subjects who discontinue from study treatment will return to the site 30 (+14) days after the date 
of the decision to discontinue study treatment. During the Post-Treatment Follow-Up Visit, 
safety assessments will be performed. Please refer to Appendix A for a description of all the 
assessments at this visit. (Assessments in the Post-Treatment period for subjects who discontinue 
study treatment in the Crossover Phase are provided in Appendix B.) 
Adverse events are to be documented and/or followed as described in Section 8.3. 
5.4.2 
Extended Follow-up 
Following treatment discontinuation for whatever reason, subjects will continue to be followed 
either via clinic visit or telephone contact approximately every 12 weeks (± 7 days) for the 
following information unless the subject withdraws consent for non-interventional study 
assessments: 
• Survival status of the subject or date of death and primary cause of death 
• Receipt of NPACTs: drug or procedure name and start/stop dates 
• Information on subsequent progression following systemic NPACT (eg, date of subsequent 
radiographic progression or last known radiographic assessment) 
Radiographic disease assessments and EQ-5D-5L are to continue in the Extended Follow-Up 
period as necessary per the schedule for these assessments in Appendix A, unless the subject 
withdraws from study interventions. 
Subjects will be followed until death or until the Sponsor’s decision to no longer collect these 
data.  

 
 
Protocol XL184-311 
Page 66 of 165 
At each contact, the investigator (or designee) will determine if the subject died, and if so, record 
the date and cause of death. 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 cut-off). 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 (where allowed by local 
regulations). If subject is lost to follow-up, multiple attempts to contact must be made and 
documented in the subject records.  
5.5 
Maintenance Phase 
After the primary efficacy endpoints have been analyzed and upon determination by the Sponsor 
that sufficient data have been collected to adequately evaluate all study endpoints to establish, 
for regulatory purposes, the safety and efficacy profile of the experimental drug within this 
study, the study will begin to transition to the Maintenance Phase.  
As a transitional step prior to initiation of the Maintenance Phase, all blinded study subjects will 
be unblinded and study sites will be notified of their randomized treatment assignments.  
• Unblinded subjects randomized to placebo have the following options: 
o Such subjects may be provided by the Investigator the opportunity, if eligible (see 
Appendix B), to enter the Crossover Phase to receive cabozantinib and undergo study 
assessments per Appendix B.  
o Such subjects who are ineligible or opt not to cross over to receive cabozantinib are to 
have study treatment discontinued and proceed with post-treatment assessments as 
described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the 
investigator believes the subject is still deriving clinical benefit. Study assessments are to 
continue per in Appendix A. 
After the date the entire study is unblinded, study sites will have 8 weeks to determine eligibility 
and begin administration of crossover cabozantinib treatment to eligible subjects randomized to 
placebo; subsequently no further crossover will be allowed. 
Once the W9D1 visit has elapsed in the Crossover Phase for the last placebo subject who crossed 
over to receive cabozantinib, and upon site notification by the Sponsor, the transition period will 
end, and the study will enter the study Maintenance Phase. 

 
 
Protocol XL184-311 
Page 67 of 165 
Subjects remaining on study treatment will continue to receive it until a criterion for 
protocol-defined discontinuation has been met (Section 3.6.1). Subjects are to undergo periodic 
safety assessments (including local laboratory tests) and tumor assessments; the nature and 
frequency of these assessments are to be performed per standard of care, as allowed by local 
regulations. It is the Investigator’s responsibility to ensure that subject visits occur frequently 
enough and adequate assessments are performed to ensure subject safety. 
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 Visit at 
the time the transition to the Maintenance Phase, will undergo the final safety assessment at the 
post-treatment follow-up visit. Upon initiation of the Maintenance Phase, no further follow-up is 
required for any subject who has completed the Post-Treatment Follow-Up Visit. 
In order to continue to capture important safety information on subjects still enrolled in the 
study, reporting of SAEs and other reportable events (pregnancy 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 8.1.1 (though SAE reporting timeline 
requirements do not apply to non-serious events reported in these categories): 
• Adverse Events (serious or not) leading to cabozantinib treatment discontinuation 
• Adverse Events (serious or not) leading to cabozantinib dose modification (ie, causing 
cabozantinib to be withheld or reduced) 
Other non-serious AEs will not be collected by the Sponsor as they are unlikely to meaningfully 
change the safety profile established in earlier phases of this study. 
Study drug accountability is to continue as described in Section 6.4. 
See Maintenance Phase Schedule of Assessments (Appendix C). 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 to ensure adherence to GCP, protocol 
compliance, adequate subject safety follow-up, study drug accountability, and reporting of SAEs 
and other reportable events. 

 
 
Protocol XL184-311 
Page 68 of 165 
During the Maintenance Phase no data are to be entered into electronic CRFs; the study clinical 
database will be closed upon initiation of the Maintenance Phase. Study central laboratory 
samples are not to be obtained. 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 imaging vendor. 
5.6 
Unscheduled Visits 
If the investigator determines that a subject should be monitored more frequently or with 
additional imaging and/or laboratory parameter assessments than indicated by the 
protocol-defined visit schedule these unscheduled visits or assessments are permitted. The 
laboratory assessments should be done by the central laboratory; however, if the results are 
needed immediately, 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. Any imaging studies performed to assess tumor 
status will be collected for BIRC review. 
If study treatment is interrupted, during the intervening time between the last dose and the time 
drug is restarted the study site should perform unscheduled visits weekly or more frequently as 
clinically indicated to monitor subject safety and appropriateness for retreatment with study 
treatment. 
5.7 
Instructions for Specific Procedures 
This section describes evaluations to be performed and items to be recorded or available on 
source documents. Data from some required evaluations may not be collected on study CRFs 
(see Section 15.4). 
5.7.1 
Demographics, Medical, and Cancer History 
Demographics, medical, and cancer history at screening will include age at informed consent, 
medical and cancer history, surgical history, radiation therapy history, and systemic anticancer 
treatment history including names of agents, administration dates and progression date on or 
after RAI therapy and VEGFR-targeting TKI. To ensure subject privacy, date of birth and 
subject initials will not be collected by the Sponsor. 
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 

 
 
Protocol XL184-311 
Page 69 of 165 
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 should be recorded in source documents and on CRFs.  
The ECOG PS of the subject will be assessed at each scheduled safety assessment starting on 
W1D1. A table is included in Appendix F for reference. 
Refer to Appendix A for the schedule of physical examination and performance status 
assessments. 
5.7.3 
Vital Signs 
Vital signs include 5-minute sitting BP, pulse, respiratory rate, and temperature will be assessed 
at screening, at all regularly scheduled visits, and at all unscheduled visits if possible. 
Refer to Appendix A for the schedule of these assessments. 
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 QTcF. A QTcF ≤ 500 ms 
per single ECG within 14 days before randomization is required to demonstrate eligibility for 
study treatment. If at any time the 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 as the 
value assessed. 
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 
study and will be deemed AEs. If values meet criteria defining them as serious, they must be 
reported as SAEs (Section 8.2). 

 
 
Protocol XL184-311 
Page 70 of 165 
The Fridericia formula is depicted below for calculation of the corrected QT interval (QTcF). 
 
QT = measured QT interval in milliseconds; RR = measured R to R interval (which can 
be derived from the heart rate as 60/heart rate) 
 
5.7.5 
Laboratory Assessments 
Laboratory analytes that will be measured for this study are listed in Table 5-1. The schedule for 
laboratory assessments is provided in Appendix A. Laboratory tests to establish eligibility must 
be done within 10 days before randomization unless otherwise stated. 
Central laboratory assessments: Hematology, serum chemistry, coagulation, UPCR including 
components, and thyroid function tests are to be performed by a central laboratory, including 
labs obtained at unscheduled visits whenever possible. All central laboratory results will be 
provided to the Investigator.  
Eligibility criteria based on laboratory values should be based on central laboratory results. 
Exceptions for using local laboratory test results for eligibility determination include serum/urine 
pregnancy test, urinalysis, and repeat lab tests to confirm central lab test results, and lab tests 
which cannot be obtained by the central lab in time before the planned randomization date.  
Local laboratory assessments: Routine (dipstick) analysis, microscopic urine examination, and 
serum/urine pregnancy tests are to be done by local laboratory. Results or status from these tests 
will be recorded on CRFs and will not be submitted to the study local laboratory management 
vendor. 
24-hour urine protein tests, at any scheduled or unscheduled visit, are to be done by local 
laboratory and the lab results forwarded to the study local laboratory management vendor. 
After randomization local laboratory assessments may be obtained in lieu of the central 
laboratory assessments if the results are required by the Investigator in a rapid timeframe (eg, 
needed for making rapid treatment decision or monitoring for AEs, SAEs).  
All local laboratory results must be forwarded to the study local laboratory management vendor 
if performed in lieu of the central laboratory assessment at any scheduled or unscheduled visit.  

 
 
Protocol XL184-311 
Page 71 of 165 
Specific laboratory test information: 
• To confirm suitability for study treatment after randomization: 
o 12-lead ECG must be repeated unless it was performed during screening within 14 days 
prior to administering the first dose of study treatment. 
o All laboratory tests (except for pregnancy test) must be repeated unless screening 
evaluations were performed within 10 days prior to administering the first dose of study 
treatment. 
o ECG and laboratory 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.  
o A pregnancy test must be repeated before dosing on the date of first dose of study 
treatment (W1D1) unless a pregnancy evaluation was done during screening within 
7 days prior to W1D1. 
o 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. 
• Throughout the study, fasted glucose will be monitored. On days when the blood sample is 
drawn, subjects should fast overnight (no caloric intake for at least 8 hours, consumption of 
water is allowed).  
• Follicle stimulating hormone (FSH). For women under the age of 55 years to confirm 
menopause as needed during the screening period. 

 
 
Protocol XL184-311 
Page 72 of 165 
Table 5-1: 
Laboratory Panels 
Central Laboratory 
If performed by local laboratory in lieu of central lab assessment, submit results to study local laboratory 
management vendor 
Hematology 
Serum chemistry 
Urine chemistry 
• White blood cell count (WBC) with 
differential (neutrophils [absolute 
neutrophil count; ANC], basophils, 
eosinophils, lymphocytes, monocytes) 
• hematocrit 
• platelet count 
• red blood cell count 
• hemoglobin 
 
 
Coagulation 
• Prothrombin time/international 
normalized ratio (PT/INR) 
• Partial thromboplastin time (PTT) 
 
 
Other Parameters 
• Thyroglobulin in serum (Tg) 
• Follicle Stimulating Hormone (FSH)b 
  
• albumin 
• total alkaline phosphatase 
• amylase 
• alanine aminotransferase (ALT) 
• aspartate aminotransferase (AST) 
• blood urea nitrogen (BUN) 
• calcium (corrected)  
• bicarbonate 
• chloride 
• creatinine 
• γ-glutamyltranspeptidase (GGT) 
• glucose 
• lactate dehydrogenase (LDH) 
• lipase  
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin (conjugated and 
unconjungated if total bilirubin 
elevated) 
• total protein  
• Protein (spot urine; fully 
quantitative) 
• Creatinine (fully 
quantitative)  
• Urine protein/creatinine 
ratio (UPCR; spot urine) a  
Thyroid function 
• Thyroid stimulating 
hormone (TSH), free T4 
(fT4), free T3 (fT3) 
Local Laboratory 
Submit only 24-hour urine protein test results to study local laboratory management vendor 
Urinalysis (Dipstick or Routine) 
Microscopic Urine Examination 
Pregnancy test at screening 
• pH 
• specific gravity 
• ketones 
• protein 
• glucose 
• nitrite 
• urobilinogen 
• leukocyte esterase 
• blood 
 
• Perform at the discretion of the 
investigator based on results or 
routine urinalysis or as clinically 
indicated 
 
 
24-Hour Urine Collection 
• 24-hour urine proteina 
• β-human chorionic 
gonadotropin (β-HCG) in 
serum 
 
 
Pregnancy after first dose of 
study treatment 
• β-human chorionic 
gonadotropin (β-HCG) in 
serum or urine 
 
a When UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result (see 
Table 6-8)  
b For women under the age of 55 years to confirm menopause as needed. 
 

 
 
Protocol XL184-311 
Page 73 of 165 
Table 5-2: 
Estimation of the Creatinine Clearance by Cockcroft and Gault 
Serum creatinine in conventional units (mg/dL) 
• 
Males: (140 – age) × weight (kg)/(serum creatinine × 72) 
• 
Females: [(140 – age) × weight (kg)/(serum creatinine × 72)] × 0.85 
Serum creatinine in SI units (µmol/L) 
• 
Males: [(140 – age) × weight (kg)/(serum creatinine)] × 1.23 
• 
Females: [(140 – age) × weight (kg)/(serum creatinine)] × 1.04 
Abnormalities in any clinical laboratory test (including tests not required per protocol) that leads 
to a change in subject management (eg, dose interrupted or reduced, treatment discontinued, 
requirement for additional medication or monitoring) are considered clinically significant for the 
purposes of this study and should be reported as AEs. If laboratory values constitute part of an 
event that meets criteria defining it as serious, the event (with associated laboratory values) 
needs to be reported as an SAE (see Section 8.2). In cases of discordance on AE grading between 
duplicate local and central labs, the lab abnormality with the higher grade should be referenced 
for AE reporting purposes. 
5.7.6 
Tumor assessment 
5.7.6.1 
General 
Radiographic response and radiographic PD will be determined using RECIST version 1.1. For 
the purpose of determining the study endpoints of PFS, response rates, and DOR, central review 
of radiographic images will be conducted by a BIRC. All radiographic tumor assessments (both 
scheduled and unscheduled) will be sent to the BIRC, which also will review prior radiation 
history data for the purpose of selection of target lesions. 
All CT/MRI (chest/abdomen/pelvis/neck [CAPN], brain) and technetium bone scan imaging 
studies are recommended to be performed using the study-specified imaging protocol (refer to 
the most recent version of the imaging manual). To ensure image consistency, the same imaging 
modalities and acquisition protocols used at screening should be used for subsequent tumor 
assessments. All imaging must be acquired and transmitted for central review in original Digital 
Imaging and Communications in Medicine (DICOM) format (not a secondary capture). 
Low-dose non-contrast CT images from combined positron emission tomography/computed 
tomography (PET/CT) imaging cannot be used for tumor evaluations in this study. 

 
 
Protocol XL184-311 
Page 74 of 165 
Radiographic tumor assessments will include the following:  
1. Chest / Abdomen / Pelvis / Neck (CAPN): CT (or MRI) of CAPN will be performed in all 
subjects at screening and every 8 weeks (± 7 days) after randomization during the first 
12 months on study. Upon subject completion of 12 months on study, these assessments will 
be performed every 12 weeks (± 14 days). If MRI of the abdomen and pelvis is performed at 
screening, then a CT of the chest and neck must be performed as well. Additional imaging of 
potential disease sites is to 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 following the same post-baseline frequency as the imaging for CAPN. MRI 
is the preferred imaging method for brain. If CT of the brain is performed instead of MRI, 
ambiguous results must be confirmed by MRI. (Note: In order to meet the eligibility 
requirements of the study, brain metastasis must have been treated and stable for at least 
4 weeks before randomization. Subjects without documented brain metastasis during the 
screening assessment are not required to undergo post-randomization brain imaging unless 
clinically indicated.) 
3. Bone scans: Technetium bone scans will be performed at screening in all subjects and after 
randomization only in subjects with known bone metastasis every 24 weeks (± 14 days). 
Technetium bone scans are also to be performed for clinical symptoms indicative of new 
bone metastases. Bone scan findings alone cannot be used for the determination of 
progression or response per RECIST version 1.1 and need to be corroborated by CT or MRI. 
Tumor assessments are to continue on the protocol-defined schedule (Appendix A) relative to the 
date of randomization regardless of whether study treatment is given, reduced, held, or 
discontinued, including for subjects randomized to placebo who cross over to receive 
cabozantinib (Appendix B). The same imaging modalities used at screening will be used for 
subsequent tumor assessments after randomization. 
Investigators should, if any doubt or ambiguities exist about radiographic progression, have 
subjects 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. 
 

 
 
Protocol XL184-311 
Page 75 of 165 
Radiographic tumor assessments are to continue until the later of investigator-assessed 
radiographic disease progression per RECIST 1.1 that is confirmed per real-time BIRC review or 
the date of the decision to permanently discontinue study treatment; however, radiographic 
tumor assessments may cease at the time of first systemic NPACT, if given before these 
milestones occur. Bone scan evaluations will end on the date of last CT/MRI scan. If the bone 
scan schedule does not coincide with the last CT/MRI scan, no additional bone scan is needed 
after the last CT/MRI scan has been performed. 
5.7.6.2 
Crossover Phase  
Subjects randomized to placebo who cross over to receive cabozantinib will have baseline 
re-established and will re-start the tumor assessment schedule. The new baseline is to be based 
upon the most recent set of scans performed prior to unblinding for crossover. If these scans 
were performed > 8 weeks prior to first crossover dose, new scans are required to establish the 
crossover baseline. Radiographic studies performed after unblinding for crossover will not be 
submitted to the BIRC. After crossover, radiographic tumor assessments are to continue until the 
later of: (a) investigator-assessed radiographic disease progression per RECIST 1.1 (relative to 
the new baseline), or (b) the date of the decision to permanently discontinue study treatment. 
However, radiographic tumor assessments may cease at the time of first systemic NPACT, if 
given before these milestones occur. Bone scan evaluations will end on the date of last CT/MRI 
scan. If the bone scan schedule does not coincide with the last CT/MRI scan, no additional bone 
scan is needed after the last CT/MRI scan has been performed (Appendix B). 
5.7.6.3 
Confirmation of Tumor Response   
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. 
5.7.6.4 
Confirmation of Tumor Progression by BIRC 
At the time of investigator-determined radiographic progression per RECIST 1.1, investigators 
may request from the Sponsor’s medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD.  
5.7.6.5 
Blinded Independent Radiology Committee  
For the purpose of evaluating the radiographic study endpoints and to minimize the potential for 
differential dropout in the placebo arm, a BIRC will be employed in a real-time dual-reader 
adjudicated fashion. 

 
 
Protocol XL184-311 
Page 76 of 165 
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 in original 
DICOM format (as detailed in the Site-specific Imaging Core Manual) promptly after 
acquisition. Electronic transfer of scan files (via FTP, HTTP, or similar means) is required. For 
this study paper or film will be unacceptable, as will transfer of physical media files. 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. 
Prior radiation history will be sent to the BIRC for the purpose of valid identification of target 
lesions. The BIRC will review all images per RECIST 1.1 in a central, blinded, and independent 
fashion. 
BIRC evaluations of each radiographic time point are to be completed promptly after receipt of a 
complete set of images that meet quality requirements defined in the study imaging manual. 
At the time of investigator-determined radiographic progression per RECIST 1.1, investigators 
may request from the Sponsor’s medical monitor (or designee) confirmation of 
BIRC-determined radiographic PD. Only confirmation that BIRC-determined radiographic 
progression has been documented (or not) will be provided to the investigator. The BIRC readers 
will not be notified of these requests from the investigator, nor will the BIRC readers be 
informed of the nature of the investigator evaluation. 
Further details are provided in the study imaging charter. 
5.7.7 
Health-Related Quality of Life (HRQOL) Assessments 
The standardized measure of health status EQ-5D-5L, developed by the EuroQol group, will be 
used in order to provide a generic measure of health (Herdman 2011). EQ-5D-5L has two pages 
(Appendix I): a descriptive page with five dimensions which assesses changes in mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression, and global health in patients. 
Each dimension can be reported on 5 levels (no problems, slight problems, moderate problems, 
severe problems, and extreme problems). The second page has a 0-100 visual analogue scale 
which records the respondent’s self-rated health between 100 (‘the best health you can imagine’) 
and 0 (‘the worst health you can imagine’) and serves as a quantitative measure of health by the 
individual respondents.  

 
 
Protocol XL184-311 
Page 77 of 165 
The questionnaire will be completed by the subject. Assessments are to continue according to the 
schedule in Appendix A, irrespective of whether study treatment is given, reduced, interrupted, 
or discontinued. 
Subjects should complete the questionnaire on the day of the visit prior to seeing study site 
personnel. Subjects should not receive any information on their most recent medical results prior 
to completing the questionnaires in order to not influence their reporting. At clinic visits, 
completed questionnaires should be carefully reviewed for completeness by study site personnel. 
If a clinic visit is not possible, subjects should complete the questionnaire per schedule and 
return it to the site. Every effort should be made by the site to retrieve all completed 
questionnaires including the assessment following radiographic progression or discontinuation of 
study treatment.  
Translated copies of the EQ-5D-5L questionnaire and instructions for filling them out will be 
provided to each study site in a separate study manual. The EQ-5D-5L questionnaire may be 
omitted in patients who speak a language for which there is not an approved translation of this 
tool. 
HRQOL assessments will be discontinued for subjects who transition to the Crossover Phase or 
if the study transitions to the Maintenance Phase. 
5.7.8 
Health Care Resource Utilization 
Health care resource utilization parameters will be collected for each SAE reported during the 
study. These comprise start and stop dates or length of stay of emergency room visits, hospital 
admissions, and intensive care unit admissions.  
Health care resource utilization assessments will be discontinued if the study transitions to the 
Maintenance Phase. 
5.7.9 
Pharmacokinetics (PK) 
Pharmacokinetic sample collection is required in all subjects unless otherwise approved by the 
Sponsor.  
The concentration of cabozantinib will be measured in PK samples according to the schedule in 
Appendix A. Subjects will be asked to record the time of the dose taken the night before PK 
samples are collected.  

 
 
Protocol XL184-311 
Page 78 of 165 
The scheduled PK sample should be taken whether or not study treatment is administered on that 
day. Each PK sample should be collected approximately 8 or more hours after the previous dose 
of study treatment and if study treatment will be administered on that day, prior to study 
treatment administration. The investigator will ask the subject for the date and time of the most 
recent prior dose of study treatment and this information will be recorded in the source 
documents and transcribed onto the appropriate CRF page. Collection of these blood samples 
may be halted early or sampling frequency may be reduced at the discretion of the Sponsor. 
Cabozantinib plasma concentrations will be measured using a validated bioanalytical method. 
The concentration of cabozantinib in these samples will be used to confirm exposure to 
cabozantinib and to further characterize the PK of cabozantinib in this population in combination 
with data from other studies (eg, the population PK models). These concentration data may also 
be used to explore the relationship of exposure and clinical safety parameters (eg, selected AEs) 
or clinical response.  
Detailed instructions for sample preparation will be provided in a separate manual.  
PK assessments will be discontinued for subjects who transition to the Crossover Phase or if the 
study transitions to the Maintenance Phase. 
5.7.10 
Pharmacogenetic and Biomarker Analyses 
A pharmacogenetic blood sample will be collected pre-dose Week 1 Day 1 for 
genotyping/single nucleotide polymorphism/copy number variation analysis to correlate genetic 
variation with PK, safety, tolerability of and response to study treatment. This sample may also 
be used to facilitate tumor biomarker analyses or for assay development. 
Blood samples will be collected to evaluate plasma and/or serum biomarkers. These may include 
target receptors and ligands (eg, VEGF-A, HGF, soluble VEGFR2, and MET) and other markers 
related to cabozantinib mechanism of action and/or DTC. Blood samples may also be collected 
to evaluate ctDNA. CTCs may be analyzed in blood samples collected at selected sites. Tumor 
tissue from the most recently collected sample prior to subject enrollment in the study will be 
obtained during screening or at enrollment for exploratory biomarker analysis to evaluate the 
expression levels or mutational status of target kinases such as MET or RET and potentially 
other pathway components or modulators associated with the mechanism of action of 
cabozantinib, or related to DTC. 

 
 
Protocol XL184-311 
Page 79 of 165 
All pharmacodynamic/biomarker blood and tumor samples for these studies will be collected 
according to the schedule in Appendix A. 
The specific requirements for tumor samples, detailed instructions on blood sample processing, 
and the handling and shipment of all samples are provided in the translational medicine 
laboratory manual. Collection of these samples may be halted early or sampling frequency may 
be reduced at the discretion of the Sponsor. Biomarker analyses may not be performed at the 
time of the primary endpoint analyses and may extend beyond the end of the study. 
No biomarker assessments will be collected for subjects who transition to the Crossover Phase or 
if the study or if the study transitions to the Maintenance Phase. 
5.7.11 
Overall Survival 
Overall survival will be assessed every 12 weeks (± 7 days) after the post-treatment follow-up 
visit, which occurs 30 days (+14 days) after discontinuation of study treatment. Subjects will be 
followed until death or Sponsor decision to no longer collect these data. Receipt of NPACT and 
subsequent progression status 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). 

 
 
Protocol XL184-311 
Page 80 of 165 
6 
TREATMENTS AND PROCEDURES 
6.1 
Study Treatment Dosing  
The start of study treatment dosing should occur as soon after randomization as practical, ie, 
within 24 hours if possible but no more than 3 days after. Subjects will take the tablet(s) once 
daily at bedtime except for Week 1 Day 1: the first dose of study treatment will be administered 
in the clinic so that each subject can be observed for initial tolerability (see Section 6.1.1). 
Subsequent doses will be self-administered at home. Any unused study treatment must be 
returned to the study site for drug accountability and disposal.  
The assigned (and highest allowed) dose is 60 mg qd cabozantinib (or matched placebo), which 
should be maintained in the absence of treatment-emergent toxicity. Guidelines for these 
potential dose alterations are discussed in Section 6.5.  
Subjects are to be instructed not to eat grapefruit, Seville oranges, or products made with these 
fruits (including juice, jams, or candies) while on study treatment. See Section 7.1.2 for other 
potential drug interactions.  
Subjects randomized to placebo will have the opportunity to crossover to receive cabozantinib 
upon experiencing BIRC-confirmed radiographic PD, if eligible (Appendix B). 
6.1.1 
Study Treatment Administration on Week 1 Day 1 (W1D1) 
On the first day of treatment the subject should fast (with the exception of water) for at least 
2 hours before receiving study treatment. Required study examinations and blood draws should 
be done during this time prior to any study treatment administration. Upon completion of the 
2-hour fast the subject should take the tablets with a minimum of 8 oz (240 mL) of water in the 
clinic and then continue to fast for 1 hour while under observation.  
6.1.2 
Subsequent Dose Administration 
Subjects should fast (with the exception of water) for at least 2 hours after eating the evening 
meal before taking their dose of study treatment. After the 2-hour fast and before going to bed, 
subjects are to take the tablets with a minimum of 8 oz (240 mL) water with no more food intake 
for at least 1 hour postdose. If the subject’s schedule requires taking study treatment during the 
day, the subject should be instructed to follow the same fasting recommendations.  
Subjects should be instructed to not make up vomited doses or missed doses and to maintain the 
planned dosing schedule. Subjects should not make up for missed doses if more than 12 hours 
have elapsed after the time the subject would usually take study treatment. 

 
 
Protocol XL184-311 
Page 81 of 165 
Dose reductions and interruptions due to intolerance are outlined in Section 6.5.1. 
Subjects will receive blinded study treatment or unblinded treatment with cabozantinib as long as 
they continue to experience clinical benefit in the opinion of the investigator or until the earlier 
of unacceptable toxicity, the need for nonprotocol systemic anticancer therapy or until any of the 
other reasons for treatment discontinuation described in Section 3.6.  
Treatment may continue after radiographic PD per RECIST 1.1 has been determined 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 risk.  
6.2 
Study Medications 
6.2.1 
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. 
6.2.2 
Cabozantinib (XL184) 
The Sponsor will provide adequate supplies of cabozantinib, which will be supplied as 60-mg 
and 20-mg yellow film-coated tablets. The 60-mg tablets are oval and the 20-mg tablets are 
round. The components of the tablets are listed in Table 6-1. 
Table 6-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib Drug Substance (25% drug load as free base) 
Active Ingredient 
31.68 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose Anhydrous (60M) 
Filler 
19.42 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.00 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
6.00 
Colloidal Silicon Dioxide 
Glidant 
0.30 
Magnesium Stearate 
Lubricant 
0.75 
Opadry® Yellow Film Coating which includes HPMC 
2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide yellow 
Film Coating 
4.00 
All study medication will be stored at controlled room temperature and inventoried according to 
applicable regulations. Further information on storage and handling will be provided in the 
pharmacy manual. 

 
 
Protocol XL184-311 
Page 82 of 165 
6.2.3 
Placebo 
Subjects randomized to the placebo arm will receive cabozantinib-matched placebo which will 
be indistinguishable in shape, size, color, and packaging from the active cabozantinib tablets. 
The composition of the placebo tablets are listed in Table 6-2. Dosing instructions are identical 
to that for the cabozantinib arm. 
Table 6-2: 
Placebo Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
99.5 
Magnesium Stearate 
Lubricant 
0.5 
Opadry Yellow Film Coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide yellow 
Film Coating 
4.0 
6.3 
Compliance  
Subject compliance with outpatient study treatment regimens will be assessed by the site using 
drug dispensing and return records, progress notes about dose reductions/holds and subject 
interview. These data will not be directly recorded in the electronic CRF; rather, the CRF will 
capture intervals of constant dose and reasons for changes in dose level (eg, a new record 
completed each time a dose level changes, including periods where no dose was taken, and the 
reason for a dose level change). 
6.4 
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. At completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all unused study treatment will be 
reconciled and destroyed according to applicable regulations.  

 
 
Protocol XL184-311 
Page 83 of 165 
6.5 
Study Drug Dose Modifications 
6.5.1 
Reductions and Interruptions  
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruptions): 
• 
As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity. Should this be ineffective, dose reductions or interruptions should be considered to 
prevent worsening of toxicity. 
• 
General dose modification criteria for study treatment are shown in Table 6-3. Doses may be 
modified at any time on study treatment.  
• 
The assigned dose for study treatment is 60 mg qd. Two dose reductions will be permitted 
(Table 6-4): 
o 60 mg qd to 40 mg qd (first level dose reduction) 
o 40 mg qd to 20 mg qd (second level dose reduction) 
• 
Dose modifications may also occur in the setting of lower grade toxicity than defined in 
Table 6-3, if the investigator feels it is in the interest of a subject’s safety. 
• 
Dose interruptions of study treatment for any reason are allowed for up to 8 weeks. 
Restarting treatment after interruptions longer than 8 weeks may be allowed with approval of 
the Sponsor. 
• 
All treatment modifications should be entered into CRFs within 72 hours. 
Guidelines for the management of specific AEs such as GI disorders, non-GI fistula, 
hemorrhagic events, thromboembolic events, hypertension, stomatitis and mucositis, skin 
disorders, osteonecrosis, proteinuria, nervous system disorders, hepatocellular toxicity, infections 
and infestations, blood and lymphatic system disorders, fatigue, weight loss, QTc prolongation, 
electrolyte disorders, and endocrine disorders are provided in Section 6.7.  

 
 
Protocol XL184-311 
Page 84 of 165 
Table 6-3: 
General Dose Modification Criteria 
Toxicity Criteria  
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue study treatment at 
the current dose level if AE is manageable and tolerable. 
Grade 2 AEs which are tolerable and are 
easily managed 
 
Grade 2 AEs which are intolerable and 
cannot be adequately managed 
Continue study treatment at the current dose level with 
supportive care. 
 
Study treatment 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) 
Study treatment should be interrupted unless the toxicity can 
be easily managed with a dose reduction of study treatment 
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) 
Study treatment must be interrupted immediately.  
In general, study treatment 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 
study treatment following recovery to Grade 1 (or 
baseline) and optimal medical care  
Sponsor must be contacted to discuss treatment continuation 
upon resolution of AEs. 
AE, adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 6.7. For 
retreatment criteria of study treatment after a dose hold see Section 6.5.2. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to study treatment or had an 
unclear relationship to study treatment. 
Table 6-4: 
Dose Reductions 
Assigned dose  
First Dose Level Reduction 
Second Dose Level Reduction 
60 mg of study treatment oral qd 
40 mg of study treatment oral qd 
20 mg of study treatment oral qd 
qd, once daily 
Study treatment must be discontinued if a qd dose of 20 mg cabozantinib/matched placebo (minimum dose) is not 
tolerated. 

 
 
Protocol XL184-311 
Page 85 of 165 
For subjects unblinded for the potential to crossover (see Section 5.3), study treatment will be 
unblinded, and dose modifications will occur in an unblinded fashion. 
6.5.2 
Dose Reinstitution and Re-escalation 
After study treatment has been interrupted, if the subject recovers from his or her AEs to 
CTCAE v5 Grade  ≤ 1 or to the baseline value (or lower) and the AE was unrelated to study 
treatment, then study treatment may be restarted with no change in dose.  
If the subject recovers from his or her AEs to Grade ≤ 1 or to the baseline value (or lower) and 
the toxicity was deemed possibly related to study treatment, then study treatment may be 
restarted at a reduced dose (see Table 6-4 for the schedule of dose reductions). Subjects receiving 
a daily dose of 20 mg may be restarted at the same dose if deemed safe at the discretion of the 
investigator. Subjects unable to tolerate a daily dose of 20 mg will discontinue study treatment. 
Re-escalation to the previous dose (but not higher than 60 mg qd) may be allowed at the 
discretion of the investigator for AEs which have resolved or recovered to Grade 1 (or baseline 
value) and are deemed tolerable and easily managed by optimized supportive treatment. Dose 
re-escalation is not allowed for a dose reduction triggered by Grade 4 AEs affecting major 
organs (eg, CNS, cardiac, hepatic, renal). 
6.6 
Best Supportive Care  
To ensure that available BSC is provided as needed to all subjects entered into the trial, subjects 
will be seen and evaluated every 2 weeks up to Week 9 and then every 4 weeks thereafter as 
outlined in Section 5.2. Interval history and indicated physical examinations and laboratory tests 
will be monitored regularly and equally for all subjects, permitting prompt recognition of 
abnormalities. Treatment with BSC will be instituted promptly, as clinically appropriate, for all 
subjects with symptoms or complications. 
General guidelines for other aspects of BSC are found in Appendix G.  
6.7 
Warnings, Precautions, and Guidelines for Management of Potential 
Cabozantinib Adverse Events 
6.7.1 
General 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, weight 
decreased, PPE, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and 

 
 
Protocol XL184-311 
Page 86 of 165 
dyspnea. For a full description of the safety profile of cabozantinib, refer to the Cabozantinib 
Investigator’s Brochure. 
Other medically important but less frequent AEs including arterial thrombotic AEs (eg, TIA, and 
MI) and venous thrombotic AEs (eg, deep vein thrombosis [DVT] and pulmonary embolism), 
severe hemorrhagic events, proteinuria, wound healing complications, GI perforation, abscesses 
including intra-abdominal and pelvic abscess, GI and non-GI fistula formation, osteonecrosis, 
and reversible posterior leukoencephalopathy syndrome (RPLS; also known as posterior 
reversible encephalopathy syndrome [PRES]). 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects treated 
with cabozantinib in descending order of frequency were anemia, AST increased, ALT 
increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, 
hypophosphatemia, LDH increased, lipase increased, neutropenia, hyponatremia, ALP increased, 
leukopenia, and hyperglycemia. 
Adverse events may occur within the first few weeks in the course of treatment, 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). 
Study treatment 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.  
6.7.2 
Gastrointestinal Disorders  
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After starting 
treatment, 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 2016) are present. Discontinue study treatment and 
initiate appropriate management in subjects who have been diagnosed with GI perforation or 
fistula. 

 
 
Protocol XL184-311 
Page 87 of 165 
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 6-5. 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, 
study treatment should be temporarily interrupted or dose reduced. When the diarrhea is 
controlled, retreatment with study treatment 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. Infections of the perianal region should be treated per local 
guidelines. 

 
 
Protocol XL184-311 
Page 88 of 165 
Table 6-5:  
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 intravenously, 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 interaction (refer to Section 7.1.2.1 for further details).  
6.7.3 
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. 
Discontinue study treatment and initiate appropriate management in subjects who have been 
diagnosed with a non-GI fistula. 

 
 
Protocol XL184-311 
Page 89 of 165 
6.7.4 
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. 
Study treatment should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 2.5 mL of red blood). 
6.7.5 
Thromboembolic Events 
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in 
clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary 
embolism and/or DVT should have study treatment interrupted until therapeutic anticoagulation 
is established. Treatment may be resumed in subjects with pulmonary embolism or DVT if it is 
determined that the event is uncomplicated, the subject is deriving clinical benefit from study 
treatment, and 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) are not allowed. 
Arterial thrombotic events (eg, TIA, MI) have been observed in studies with cabozantinib. 
Further treatment should be discontinued in subjects who develop an acute MI, cerebral 
infarction, or any other clinically significant arterial thromboembolic complication. 
6.7.6 
Hypertension 
Table 6-6 provides treatment guidelines for hypertension deemed related to cabozantinib. Blood 
pressure should be monitored in a constant position visit to visit, either sitting or supine in a 
relaxed setting. Decisions to reduce or interrupt the dose of study treatment must be based on BP 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement.  
Study treatment should be discontinued in subjects with hypertensive emergency. 

 
 
Protocol XL184-311 
Page 90 of 165 
Table 6-6: 
Management of Hypertension Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 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 study treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does not 
result in BP < 150 mm Hg systolic or < 100 mm Hg diastolic 
• If subject is symptomatic interrupt study treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce study treatment by one dose levelb or interrupt study 
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 or 
< 100 mm Hg diastolic, study treatment should be dose reduced 
further or interrupted 
• 
Study treatment should be dose interrupted if upper limits of 
systolic BP (≥ 160 mm Hg) are sustained and not adequately 
manageable or if systolic BP is > 180 mm Hg or diastolic BP 
> 110 mm Hg, or if subject is symptomatic 
• Re-start study treatment at the most tolerable dose and re-escalate 
only if BP falls to and is sustained at < 150 mm Hg systolic and 
< 100 mm Hg diastolic 
Hypertensive emergencyc 
• 
Discontinue study treatment 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 or 
diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols. 
c Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending end-organ 
damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, 
kidney damage). 
6.7.7 
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, 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. 

 
 
Protocol XL184-311 
Page 91 of 165 
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.  
6.7.8 
Skin 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 study 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 study 
treatment. If dehiscence occurs, study treatment should not be restarted until complete healing 
has taken place.  
Study treatment should be stopped at least 28 days prior to scheduled surgery. The decision to 
resume study treatment after surgery should be based on clinical judgment of adequate wound 
healing. 
Palmar-plantar erythrodysesthesia (also known as hand-foot syndrome), skin rash (including 
blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular 
rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported with 
cabozantinib. All subjects on study should be advised on prophylactic measures including the use 
of emollients, removal of calluses, avoidance of exposure of hands and feet to hot water leading 
to vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of cotton 
gloves and socks to prevent injury and keep the palms and soles dry. 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and 
swollen areas on the palms and soles. The lateral sides of the fingers or periungual zones may 
also be affected. Adequate interventions are required to prevent worsening of skin symptoms 
such as blisters, desquamations, ulcerations, or necrosis of affected areas. Analgesics may be 
required for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment recommendations in response to PPE are summarized in Table 6-7. 

 
 
Protocol XL184-311 
Page 92 of 165 
Table 6-7: 
Management of Hand-Foot Syndrome (PPE) Associated with Cabozantinib 
CTCAE v5 Grade  
Action To Be Taken  
Grade 1 
Study treatment may be continued at the current dose if PPE is clinically insignificant and 
tolerable. Otherwise, study treatment should be reduced to the next lower dose level.a 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  
Study treatment may be continued if PPE is tolerated. Study treatment should be dose 
reduced or interrupted if PPE is intolerable. Continue urea 20% cream twice daily AND 
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 study treatment until severity decreases to Grade 1 or 0. Continue treatment of 
skin reaction with high potency steroid cream (eg, clobetasol 0.05%) twice daily AND 
analgesics. Resume study treatment 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. 
6.7.9 
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. 
Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
study treatment 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. 

 
 
Protocol XL184-311 
Page 93 of 165 
6.7.10 
Proteinuria 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring 
UPCR. Table 6-8 provides treatment guidelines for proteinuria deemed related to study 
treatment.  
Study treatment 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). 
Table 6-8: 
Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria  
(UPCR) 
Action To Be Taken 
≤ 1 mg/mg  
(≤ 113.1 mg/mmol) 
• No change in study treatment or monitoring 
 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 mg/mmol) 
 
• Consider confirming with a 24-hour protein assessment within 7 days 
• No change in study treatment required if UPCR ≤ 2 mg/mg or urine protein 
≤ 2 g/24 hours on 24-hour urine collection. 
• Dose reduce or interrupt study treatment if UPCR > 2 mg/mg on repeat UPCR 
testing or urine protein > 2 g/24 hours on 24-hour urine collection. Continue 
study treatment on a reduced dose if UPCR decreases to < 2 mg/mg. Consider 
holding study treatment if UPCR remains > 2 mg/mg despite a dose reduction 
until UPCR decreases to < 2 mg/mg. Restart study treatment at a reduced dose 
after a dose hold unless otherwise approved by sponsor. 
• Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 
2 consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of first 
reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is 
determined to be stable (< 20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
 
 
• Hold study treatment pending repeat UPCR within 7 days and/or 24-hour 
urine protein.  
• If ≥ 3.5 on repeat UPCR, continue to hold study treatment and check UPCR 
every 7 days. If UPCR decreases to < 2 mg/mg, restart study treatment at a 
reduced dose, and monitoring of urine protein/creatinine should continue 
weekly until the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg 
and < 2 mg/mg for 1 month or is determined to be stable (< 20% change) for 
1 month, check urine protein/creatinine per protocol or as clinically indicated. 
Nephrotic syndrome 
• Discontinue study treatment 
UPCR, urine protein creatinine ratio. 

 
 
Protocol XL184-311 
Page 94 of 165 
6.7.11 
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. 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, 
headache, visual disturbances, confusion or altered mental function. Study treatment should be 
discontinued in subjects with RPLS. 
6.7.12 
Hepatocellular Toxicity 
Evaluations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib. 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) should be evaluated. 
Table 6-9: 
Management of Hepatotoxicity Associated with Cabozantinib 
Severity of ALT, AST, total bilirubin 
Elevations by CTCAE 
Treatment Dose Modification 
Grade 1 
• Dose adjustment is usually not required. 
• Consider discontinuing concomitant hepatotoxic medications 
and add supportive care as indicated.  
Grade 2 
• Interrupt study treatment if lasting longer than 1 week. 
• Restart study treatment after lab abnormalities have resolved to 
at least CTCAE Grade ≤ 1 or baseline. 
Grade ≥ 3          
• Interrupt study treatment and consider more frequent 
monitoring of ALT, AST, and bilirubin. 
• Restart study treatment at a reduced dose after lab 
abnormalities have resolved to at least CTCAE Grade ≤ 1 or 
baseline. 
• Discontinue if lab abnormalities cannot be reversed despite 
interruption of study treatment. 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events 

 
 
Protocol XL184-311 
Page 95 of 165 
The following conditions require discontinuation of study treatment unless these laboratory 
abnormalities have recovered to Grade 1 or baseline level after an interruption and the sponsor 
has approved reinstitution of study treatment:  
• Drug-related ALT or AST > 8 × ULN. 
• Drug-related ALT or AST > 3 × ULN in combination with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with drug-induced liver injury.  
Elevations of aminotransferases when hepatic metastases are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than a doubling) 
and if there are no progressive elevations in serum bilirubin concentration or coagulation factors.  
6.7.13 
Infections and Infestations 
Infections are commonly observed in cancer subjects. Predisposing risk factor include a 
decreased immune status (eg, after myelosuppressive anticancer therapies, splenectomy), 
destructive growth of the underlying malignancy including bone marrow infiltration with 
suppression of normal hematopoiesis, as well as the presence of intravenous devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Study treatment should be interrupted until adequate healing has taken place. 
6.7.14 
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.  
6.7.15 
Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression 
and/or anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be 

 
 
Protocol XL184-311 
Page 96 of 165 
ruled out and treated according to standard of care. Pharmacological management should be 
considered after disease specific morbidities have been excluded when not prohibited.  
6.7.16 
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. 
6.7.17 
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 (> 15,000 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, 2 additional 
ECGs must be performed with intervals not less than 3 min apart within 30 min after the initial 
ECG. 

 
 
Protocol XL184-311 
Page 97 of 165 
If the average QTcF from the three ECGs is > 500 ms, the following actions must be taken: 
• Interrupt study treatment 
• Immediately notify the Sponsor and submit ECGs to the Sponsor for independent review. 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, 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) 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced dose level 
if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation 
• The QTcF value > 500 ms is not confirmed  
• Study treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 ms. 
• QT prolongation can be unequivocally associated with an event other than study treatment 
administration and is treatable/has been resolved  
• Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
Study treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced dose 

 
 
Protocol XL184-311 
Page 98 of 165 
6.7.18 
Electrolyte Disorders 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with cabozantinib. In some cases these 
have been Grade 3 or 4 and/or serious. Serum electrolyte levels should be monitored frequently 
while receiving study treatment. Deficits should be corrected when an electrolyte abnormality is 
noted in order to avoid worsening. Correction of electrolyte abnormalities should be 
accompanied by increasing frequency of monitoring. Clinically relevant electrolyte disorders 
should be managed according to the dose modification guidelines as outlined in Table 6-3 or as 
clinically indicated. Standard clinical practice guidelines should be used for management of 
electrolyte disorders and may include oral or intravenous replacement.  

 
 
Protocol XL184-311 
Page 99 of 165 
7 
CONCOMITANT MEDICATIONS AND THERAPIES 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before randomization through 30 days after the date of the decision to 
permanently discontinue study treatment are to be recorded in source documents and the CRF.  
7.1.1 
Allowed Therapies 
• Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (eg, ASCO or ESMO guidelines).  
• Bisphosphonates or denosumab can be used to control bone loss or hypercalcemia if the 
benefit outweighs the risk per the investigator’s discretion (Section 6.7.9). 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates or 
denosumab. 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 (including TSH-suppressive thyroid hormone 
therapy) should be utilized as indicated by standard clinical practice. 

 
 
Protocol XL184-311 
Page 100 of 165 
• 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 6 weeks, 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 6.7.5.  
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 7.1.2. 
Potential drug interactions with cabozantinib are summarized in Section 7.1.2.1 and are 
discussed in more detail in the Investigator’s Brochure.  
7.1.2 
Prohibited or Restricted Therapies 
The following therapies are prohibited until study treatment has been permanently discontinued: 
• Any investigational agent or investigational medical device. 
• Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related agents, 
direct thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or chronic 
use of aspirin above low dose levels for cardioprotection per local applicable guidelines). 
• Any nonprotocol systemic anticancer treatment (eg, chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of DTC). 

 
 
Protocol XL184-311 
Page 101 of 165 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Local anticancer treatment including palliative radiation, ablation, embolization, or surgery 
with impact on tumor lesions should not be performed until radiographic progression per 
RECIST 1.1 has been established. If clinically unavoidable the investigator should consult 
the Sponsor prior to the procedure for safety guidance.  
• Erythropoietic stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin (Wright et al 2007). 
• Concomitant medications that are known to prolong the QTc interval should be avoided in 
subjects who receive cabozantinib until they have permanently discontinued cabozantinib 
treatment (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. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended. See Appendix E for further details. 
• 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. Grapefruit, star fruit, and Seville oranges may also increase plasma concentrations 
of cabozantinib and should be avoided. See Appendix E for further details. 
Additional information on potential drug interactions with cabozantinib is provided in 
Section 7.1.2.1.  

 
 
Protocol XL184-311 
Page 102 of 165 
7.1.2.1 
Potential Drug Interactions with Cabozantinib  
Cytochrome P450 (CYP): 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 AUC of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, 
cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not 
anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared 
with CYP2C8 (ie, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data 
indicate that cabozantinib is unlikely to induce CYP enzymes, except for possible induction of 
CYP1A1 at high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 
77% reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in 
healthy volunteers. Co-administration of cabozantinib with strong inducers of the CYP3A4 
family (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib concentrations. The 
chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 
should be used with caution because these drugs have the potential to decrease exposure (AUC) 
to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
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.  
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 and 
Seville oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 
inhibitors and other drugs that inhibit CYP3A4 should be avoided because these drugs have the 

 
 
Protocol XL184-311 
Page 103 of 165 
potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme inhibition potential is recommended.  
For lists of inducers and inhibitors of selected CYP450 isozyme pathways, refer to Appendix E. 
Protein Binding: Cabozantinib is highly bound (approximately 99.9%) 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). Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound 
(eg, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because 
warfarin is a highly protein bound drug with a low therapeutic index, administration of oral 
anticoagulants is not allowed in subjects receiving cabozantinib due to the potential for a protein 
binding displacement interaction. 
Other Interactions: As food increases exposure levels of cabozantinib, fasting recommendations 
should be followed (Section 6.1). 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. Additional details related to these overall conclusions can be found in the 
investigator brochure. 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no 
clinically-relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, 
concomitant use of gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) 
is not contraindicated in subjects administered cabozantinib. (Note: Cimetidine should be 
avoided because of its potential to interfere with CYP3A4 mediated metabolism of 
cabozantinib). 
Drugs that prolong QTc interval: Drugs known to prolong QTc interval should be avoided. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure.  
 

 
 
Protocol XL184-311 
Page 104 of 165 
8 
SAFETY 
8.1 
Adverse Events and Laboratory Abnormalities 
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 definition 
also includes events associated with medication errors and uses of the investigational product 
outside of what is in the protocol, including misuse and abuse. Preexisting medical conditions 
that worsen during a study should 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 8.3. 
All untoward events that occur after informed consent through 30 days after the date of the 
decision to discontinue study treatment are to be recorded by the investigational site. At each 
scheduled and unscheduled visit, AEs are to be identified and assessed based upon study 
procedures, routine and symptom-directed clinical investigations, and subject query/report.  
Assessment of the relationship of the AE to the study treatment by the investigator will be based 
on the following two definitions: 
• Not Related: An event is assessed as not related to study treatment if it is attributable to 
another cause and/or if there is no evidence to support a causal relationship. 
• Related: An event is assessed as related to study treatment when there is a reasonable 
possibility that the study treatment caused the event. Reasonable possibility means there is 
evidence to suggest a causal relationship between the drug 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. 
8.1.1 
Laboratory Data 
All laboratory data obtained during the course of the study, comprising both central laboratory 
assessments required by this protocol and any other clinical investigations, should be reviewed 
by the investigator. Clinically significant laboratory abnormalities should be reported as AEs by 
the Investigator. In general, laboratory abnormalities that lead to a change in subject 

 
 
Protocol XL184-311 
Page 105 of 165 
management (eg, dose withheld or reduced, treatment discontinued; requirement for additional 
medication or monitoring) are considered to be clinically significant.  
8.2 
Serious Adverse Events 
The SAE definition and reporting requirements are in accordance with the ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2A. 
8.2.1 
Definitions 
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 a persistent or 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 should document the SAE to the extent that information is available. 
These SAEs, regardless of causal relationship, must be reported to the Sponsor or designee 
immediately (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. Significant follow-up information (as defined in the SAE Reporting form Completion 
Guidelines) must also be reported immediately (within 24 hours of the investigator’s awareness 
of the new information).  

 
 
Protocol XL184-311 
Page 106 of 165 
Serious AEs that must be recorded on an SAE Reporting form include the following: 
• All SAEs that occur after informed consent and through 30 days after the date of the decision 
to discontinue study treatment (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 30 days after the date of the decision to discontinue study treatment. 
Serious AEs that occur after the initiation of study treatment through 30 days after the date of the 
decision to discontinue study treatment must also be recorded on the AE CRF page. 
The minimum information required for SAE reporting includes identity of investigator, site 
number, subject number, an event description, 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 Exelixis Drug Safety 
personnel or designee. 
When reporting SAEs, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the investigator should 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 should 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 etiology identified. If an 
autopsy was performed, the autopsy report should be provided.  

 
 
Protocol XL184-311 
Page 107 of 165 
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
o 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. 
o Pre-specified study hospitalizations for observation. 
o Events that result in hospital stays of fewer than 24 hours and that do not require 
admission (eg, an emergency room visit for hematuria that results in a diagnosis of 
cystitis and discharge to home on oral antibiotics). 
• SAEs must be reported for any surgical or procedural complication resulting in prolongation 
of the hospitalization.  
8.2.2 
Regulatory Reporting 
The Sponsor’s Drug Safety group (or designee) will process and evaluate all SAEs as the reports 
are received. For each SAE received, the Sponsor will make a determination as to whether the 
criteria for expedited reporting to relevant regulatory authorities have been met. 
The Sponsor’s Drug Safety group (or designee) will assess the expectedness of each SAE to the 
study treatment using the current reference safety information (RSI) for each study treatment. 
The Sponsor or its designee is responsible for reporting relevant SAEs to the relevant regulatory 
authorities, and participating investigators, in accordance with Food and Drug Administration 
(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. 

 
 
Protocol XL184-311 
Page 108 of 165 
8.3 
Follow-up of Adverse Events 
All SAEs that are ongoing 30 days after the date of the decision to discontinue study treatment, 
and AEs assessed Grade 3 or 4 that led to study treatment discontinuation that are ongoing 
30 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. 
This requirement also applies to related SAEs that occur > 30 days after the date of the decision 
to discontinue study treatment. 
The status of all other AEs that are ongoing 30 days after the date of the decision to discontinue 
study treatment will be documented as of the Post-Treatment Follow-Up Visit. 
8.4 
Other Safety Considerations 
8.4.1 
Pregnancy 
Use of medically accepted methods of contraception is very important during the study and for 
4 months post-study treatment. If a subject becomes pregnant during the study, she will be taken 
off study treatment. She will be followed through the end of her pregnancy and the infant should 
have a follow-up at least 6 months after birth. If a female partner of a male subject becomes 
pregnant during the study, the pregnant female partner will be asked to consent to be followed 
through the end of her pregnancy and the infant should have a follow-up for at least 6 months 
after birth. 
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 
Exelixis 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. 
8.4.2 
Medication Errors 
Medication error is defined as the administration of study treatment medication outside or above 
the established dosing regimens per the specific protocol. Any overdose or medication error 
(excluding missing doses) that results in an AE or SAE requires reporting within 24 hours to the 
Sponsor or designee. Forms for reporting medication errors will be provided to the study sites. 

 
 
Protocol XL184-311 
Page 109 of 165 
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.  
In the event of overdose, renal and metabolic clinical laboratory parameters should be monitored 
at least weekly or as deemed clinically appropriate to assess any possible changing trends. In the 
case of any laboratory abnormalities resulting from an overdose, laboratory parameters should be 
continued to be monitored until any abnormalities return to baseline levels. Supportive measures 
should be undertaken as clinically indicated, with particular attention to fluid and electrolyte 
status, electrocardiographic changes, and hydration. Study treatment should be held until it is 
determined that it is safe to restart. 
Please refer to the Investigator’s Brochure for additional management recommendations for an 
overdose of study treatment. 

 
 
Protocol XL184-311 
Page 110 of 165 
9 
STATISTICAL CONSIDERATIONS 
Details of the planned analyses will be provided in a separate Statistical Analysis Plan (SAP) that 
will be finalized before the first efficacy endpoint analysis is conducted. The statistical principles 
applied in the design and planned analyses of this study are consistent with ICH E9, FDA 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drug and Biologics 
(2007), and FDA Guidance for Industry: Multiple Endpoints in Clinical Trials (draft, 2017).  
9.1 
Analysis Populations 
The following populations will be employed for statistical analyses. 
9.1.1 
Intent-to-Treat (ITT) Population 
The 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 
Overall Response Rate Intent-to-Treat (OITT) Population 
The OITT population will consist of the first 100 subjects who are randomized, regardless of 
whether any study treatment or the correct study treatment is received. 
9.1.3 
Safety Population 
The Safety population will consist of all subjects who receive any amount of treatment. Subjects 
who receive both treatments in error will be summarized in the cabozantinib arm.  
9.2 
Primary Efficacy Endpoints 
The co-primary efficacy endpoints are duration of PFS and ORR per BIRC per RECIST 1.1. 
Sponsor personnel will remain blinded until the earlier of successful rejection of the null 
hypothesis for ORR or the time of the primary PFS analysis. Unblinded full-study data will not 
be released to or shared with the operational study teams at the Contract Research Organization, 
investigators, or study subjects until after the analysis of the PFS endpoint. 
9.2.1 
Definitions 
Duration of PFS is defined as the time from randomization to the earlier of the following events: 
radiographic PD per RECIST 1.1 as determined by the BIRC or death due to any cause. The 
definition of PD and censoring rules for the primary analysis are described in Section 9.2.2.2.  
The ORR is defined as the proportion of subjects with a best overall response of confirmed CR 
or confirmed PR per BIRC per RECIST 1.1. The confirmation is to occur at least 28 days after 
the response of CR/PR was observed. 

 
 
Protocol XL184-311 
Page 111 of 165 
9.2.2 
Primary Analysis 
9.2.2.1 
Objective Response Rate (ORR) 
The ORR is defined as the proportion of subjects with a best overall response of confirmed 
complete response (CR) or confirmed PR per RECIST 1.1. per BIRC, The  primary analysis of 
ORR will be in the OITT population. 
Hypothesis testing will be performed using the Fisher’s exact test at the 2-sided α=0.01 level of 
significance. 
Point estimates of ORR, the difference in ORR between the two treatment arms, and associated 
CIs will be provided. The 99% CIs will be calculated using exact methods except for the 
difference in ORR between the two treatment arms which will use asymptotic confidence limits. 
If the p-value for the two-sided Fisher’s exact test is less than 0.01 and the point estimate for 
ORR in the cabozantinib arm is higher than that in the placebo arm, the null hypothesis of no 
difference in ORR will be rejected and it will be inferred that ORR is superior in the 
cabozantinib arm compared with the placebo arm. 
If sufficient responses are observed, additional supportive analyses will be conducted using 
appropriate methods to adjust for stratification factors. 
The study will proceed to full enrollment of 300 subjects irrespective of the results of the ORR 
analysis in the OITT population. 
9.2.2.2 
Progression-Free Survival (PFS) 
The primary analysis of the co-primary endpoint of PFS will be performed among subjects in the 
ITT population. It is designed to include radiographic progression events as determined by the 
BIRC per RECIST 1.1 and deaths due to any cause. Clinical deterioration or radiographic 
progression determined by the investigator will not be considered progression events in the 
primary analysis of PFS. 

 
 
Protocol XL184-311 
Page 112 of 165 
General censoring rules for the primary analysis of PFS are described below: 
• Subjects who receive systemic NPACT or nonprotocol radiation therapy (other than to bone) 
or surgery to resect target lesions before experiencing an event will be right censored at the 
date of the last tumor assessment prior to the date of initiation of subsequent therapy/surgery. 
If there is no such tumor assessment post randomization, the subject will be right censored on 
the date of randomization. 
• Subjects who have not experienced an event (and are not otherwise censored) at the time of 
data cutoff will be right censored on the date of their last tumor assessment post 
randomization that is on or prior to the data cutoff. If there is no such tumor assessment post 
randomization, the subject will be right censored on the date of randomization. 
• Subjects who miss two or more scheduled tumor assessments followed by an event will be 
right censored on the date of their most-recent tumor assessment prior to the missing 
assessments. If there is no such tumor assessment post randomization, the subject will be 
right censored on the date of randomization. 
 
The analysis of PFS is event-based and will be conducted after at least 193 events (progression 
per RECIST 1.1 per BIRC or death) have been observed in the ITT population (see 
Section 9.10). 
Hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided, 0.04 or 0.05 level of significance (see Section 9.9). The stratification 
factors are those used to stratify the randomization (see Section 3.4). 
The median duration of PFS and the associated 95% CI for each treatment arm will be estimated 
using the Kaplan-Meier method. The stratified HR and its 96% or 95% CI will be estimated 
using a Cox proportional-hazard model with treatment group as the independent variable. The 
stratification factors will be the same as those used to stratify the randomization. 
In the primary analysis of PFS, if the p-value for the stratified log-rank test is statistically 
significant and the HR (λ cabozantinib/ λ placebo) is < 1, the null hypothesis of no difference in 
PFS will be rejected and it will be inferred that PFS is superior in the cabozantinib arm compared 
with the placebo arm. 
9.2.3 
Supportive Analyses  
Additional supportive (sensitivity) analyses of PFS will be defined in the SAP using alternative 
event definitions and censoring schemes to account for partial or completely missing 

 
 
Protocol XL184-311 
Page 113 of 165 
assessments, address bias due to tumor assessment timing, evaluate the impact of potentially 
informative censoring, and address potential discrepancies between the documentation of 
progression per the BIRC and per the investigator. These analyses will be performed using the 
same statistical methods described for the primary analysis (see Section 9.2.2.2).  
Exploratory analyses of the effect of baseline characteristics, stratification factors, and other 
variables will be conducted using Cox proportional-hazard models and subgroup analyses 
performed employing Kaplan-Meier methods.  
9.3 
Overall Survival  
The final analysis of OS will be conducted at the time of the primary analysis of PFS. All deaths 
occurring as of that time will be considered for the analysis.  
The analysis will include median duration of OS and the associated 95% CI for each treatment 
arm estimated using the Kaplan-Meier method. The stratified HR and its 95% CI will be 
estimated using a Cox proportional-hazard model with treatment group as the independent 
variable. The stratification factors will be the same as those used to stratify the randomization. 
Log-rank p-values will be calculated and will be presented for descriptive purposes; formal 
inferences will not be drawn. 
At the time of the analysis of ORR, if the null hypothesis for ORR is rejected an administrative 
interim analysis of OS will be performed with the primary purpose of evaluating the potential for 
detriment to survival with cabozantinib treatment. 
9.4 
Health-Related Quality of Life 
EQ-5D-5L will be used to evaluate HRQOL (Section 5.7.7). EQ-5D-5L includes six questions: 
mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health score.  
Details of the planned analyses for these data will be provided in the SAP. 
9.5 
Pharmacokinetic Analysis 
Descriptive statistics (eg, number, mean and/or median, standard deviation, and coefficient of 
variation) will be used to summarize the concentration-time data for each study visit. Where 
appropriate, these data may be combined with data from other studies as part of a meta-analysis 
such as Population PK analysis and will be reported separately. The influence of exposure on 
biomarker changes, clinical safety parameters (eg, selected AEs), or clinical response may also 
be explored; these analyses will be reported separately,  

 
 
Protocol XL184-311 
Page 114 of 165 
9.6 
Safety Analyses 
All safety analyses will be performed using the Safety population. No formal statistical 
comparisons between the two treatment arms are planned. 
9.6.1 
Adverse Events 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary. 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.  
The frequency and percentage of subjects with TEAEs will be tabulated for overall incidence by 
system organ class and preferred term by treatment arm. Related TEAEs, serious TEAEs, related 
serious TEAEs, TEAEs resulting in study treatment discontinuation and TEAEs resulting in 
study treatment modification (either dose reduction or dose delay) will be similarly summarized. 
TEAEs and related TEAEs will also be summarized for worst reported severity within each 
subject.  
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 arm, cause of death, and 
relationship to study treatment. 
9.6.2 
Laboratory Test Results 
Selected laboratory test results will be summarized by treatment arm to evaluate worst 
post-baseline CTCAE grade and shifts or changes from baseline.  
9.6.3 
Other Safety Endpoints 
Changes or shifts from baseline in vital signs, ECOG PS, and QTc interval will be summarized 
by treatment arm. 
The number of subjects experiencing dose reduction, delay, and/or discontinuation due to an AE 
will be provided. 

 
 
Protocol XL184-311 
Page 115 of 165 
Concomitant medications will be standardized using the World Health Organization (WHO) 
drug dictionary and summarized by class and preferred term. 
9.7 
Additional Endpoints  
Details of the planned analyses of these endpoints will be provided in the SAP: 
• Duration of objective tumor response 
• Relationship of baseline and postbaseline changes in biomarkers, serum Tg, and CTCs 
and/or ctDNA with treatment and/or clinical outcome assessments may be performed  
• Health care resource utilization 
9.8 
Interim Analyses 
A single interim analysis of PFS is planned at the time of the primary ORR analysis. 
Approximately 43% of the planned total PFS events are expected to have been observed at that 
time. Rejection of the null hypothesis for PFS at the interim analysis is not expected; it is 
intended to allow evaluation of PFS at the time of the primary analysis of ORR. Inflation of 
Type 1 error arising from repeated analyses of PFS will be controlled by a Lan-DeMets O’Brien 
Fleming alpha spending function, using the actual information fraction at the interim analysis. 
9.9 
Control of Type I Error 
The multiplicity issue resulting from analysis of two co-primary endpoints (PFS and ORR) will 
be addressed by applying a modified Bonferroni procedure (dividing the alpha between the 
co-primary endpoints). 
ORR will be tested at the 2-sided 1% α level and PFS will be tested at the 2-sided 4% (α) 
significance level.  

 
 
Protocol XL184-311 
Page 116 of 165 
Additionally, the fallback method for alpha allocation (FDA 2017) will be implemented as 
follows: 
• If the null hypothesis is rejected for ORR its alpha allocation of 1% will be passed to PFS 
which will then be tested at the 5% level. 
• If the null hypothesis is not rejected for ORR, then PFS will be tested at its original alpha 
allocation of 4%. 
• As an interim analysis will be performed for the second co-primary endpoint of PFS, the 
alpha spending function used to determine the critical values for rejection will be based upon 
a total alpha of either 5% or 4% conditioned upon whether the null is rejected for ORR or 
not, respectively (see Section 9.8). 
The primary objectives of the study will be declared as met if at least one hypothesis is rejected 
at its respective α level. All other statistical evaluations of efficacy will be considered 
exploratory. 
9.10 
Power and Sample Size 
The study is designed to provide adequate power for both co-primary endpoints of ORR and 
PFS. It is estimated that 100 subjects would be adequate to evaluate the co-primary endpoint of 
ORR alone, and 300 subjects will be needed to evaluate the co-primary endpoint of PFS. Thus, 
to allow an earlier evaluation of ORR, this study employs a “trial within a trial design” 
(Hessel et al 2016). The primary analysis of ORR will be limited to the first 100 subjects 
randomized to the study and defined as the OITT population. Analysis of ORR is expected to 
occur 6 months after the last subject is enrolled in this population.  
For ORR, 100 subjects provide a 2-sided 0.01 test of difference in proportions with > 90% power 
to reject the null hypothesis of no difference in ORR, assuming a true ORR of 2% in the placebo 
arm and 35% in the cabozantinib arm (a 33 percentage point difference), a pooled variance 
estimate, and a 2:1 allocation ratio.  

 
 
Protocol XL184-311 
Page 117 of 165 
For the primary endpoint of PFS, assuming exponential distribution, proportional hazards, and a 
2:1 treatment allocation ratio (cabozantinib:placebo), 193 events are required to provide 
90% power to detect an HR of 0.61 using the log-rank test and a 2-sided significance level of 
0.04. This corresponds to a 36% reduction in the risk of progression or death, or a 
64% improvement in median PFS from 5.5 months to 9.0 months. Under this design, and with 
the application of the fallback method (see Section 9.9) the minimum observed effects that 
would result in statistical significance for PFS are: 
• If Ho is rejected for ORR and PFS is tested at the 5% level under the fallback method, the 
minimum observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0013 
0.474 
5.5 
11.6 
Final 
100% 
0.0496 
0.742 
5.5 
7.4 
• If Ho is not rejected for ORR and PFS is tested at the original 4% allocation, the minimum 
observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0008 
0.469 
5.5 
11.7 
Final 
100% 
0.0397 
0.738 
5.5 
7.5 
With a constant accrual rate of 20 subjects per month and using a 2:1 treatment allocation ratio, a 
total of 300 subjects (200 in the cabozantinib arm, 100 in the placebo arm) are required to 
observe the required number of PFS events within the planned study duration (15 months 
accrual; approximately 20 months to observe the required events). 
Power and sample size estimates were estimated using EAST v5 by Cytel Software. 
9.11 
Crossover Phase 
Data from the Crossover Phase will be summarized or listed separately and will not be included 
as part of the primary evaluation of either arm. 
9.12 
Maintenance Phase 
Data for subjects who enter the Maintenance Phase will not be entered in the clinical database. 
Data from the safety database will be summarized or listed separately. 
 

 
 
Protocol XL184-311 
Page 118 of 165 
10 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be assured by verification and crosscheck of the CRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug-dispensing log by the investigator. Authorized study site personnel will 
transcribe source data into CRFs in an electronic data-capture (EDC) computer database. Study 
databases will be subject to electronic and manual quality assurance procedures. 
11 
STUDY COMMITTEES 
11.1 
Executive Safety Committee 
The Sponsor’s Executive Safety Committee (ESC) is established to ensure a quarterly review of 
product safety data. The ESC is managed by the Head of Benefit-Risk Management and includes 
the following members: Head of Drug Safety, Chief Medical Officer, Senior Drug Development 
Physician, and qualified representatives of other functional groups as appropriate. It is the 
responsibility of this Committee to review all available safety data (AE and SAEs) from ongoing 
Exelixis clinical trials and other sources (including post-marketing safety surveillance) in order 
to assess and monitor evolving safety trends, evaluate potential changes to clinical trial protocols 
based on safety analysis, and, ultimately, to safeguard subject safety. The ESC will review 
blinded (pooled) data from this study. Additional ad hoc meetings will convene as required to 
address specific safety concerns.  
11.2 
Independent Data Monitoring Committee 
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 study clinical investigators. To 
minimize the potential introduction of bias, these individuals will not have any direct contact 
with the study site personnel or subjects. IDMC members will be selected for their expertise in 
oncology and/or biostatistics.  
This IDMC will convene periodically (at a minimum twice yearly) and the start date will depend 
on subject accrual rates. The primary responsibilities of the IDMC are to: 
• Review the accumulating safety data on a regular and an ad hoc basis 
• Evaluate the results of the planned analysis of ORR and contemporaneous interim analysis of 
PFS 
• Make recommendations to the Sponsor regarding the continued conduct of the study based 
upon their evaluation of safety data. 

 
 
Protocol XL184-311 
Page 119 of 165 
Safety data will be provided at regular intervals to the IDMC in the form of unblinded summary 
reports or data listings. The IDMC will have access to subjects’ individual treatment 
assignments. Unblinded safety and efficacy summaries will be produced for the IDMC by an 
independent statistical center designated by the Sponsor. 
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. 
• Evaluate the results of the interim analysis of PFS per the alpha spending function. 
• Stopping early for futility is not planned. 
The IDMC will communicate major safety concerns and recommendations regarding study 
modification or termination to Exelixis senior management. 
Details of the composition, role, operational considerations, and stopping guidelines will be 
provided in a separate IDMC charter. 
11.3 
Blinded Independent Radiology Committee 
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 5.7.6.5). The BIRC will 
be comprised of board-certified radiologists who will determine radiographic response and 
progression following randomization. Additional imaging results may be requested by the 
Sponsor for BIRC review. 
Primary analyses of radiographic study endpoints will be based upon BIRC assessments. 
Additional details regarding BIRC member qualification, training, methods, procedures, and 
other issues relevant to committee operations will be described in the BIRC Charter. 
12 
ETHICAL ASPECTS 
12.1 
Local Regulations 
The study must fully adhere to the principles outlined in GCP ICH E6 Tripartite Guideline 
(January 1997) and remain consistent with the most recent accepted version of the Declaration of 
Helsinki. The investigator will ensure that the conduct of the study complies with the basic 
principles of GCP as outlined in the current version of 21 CFR, subpart D, Part 312, 

 
 
Protocol XL184-311 
Page 120 of 165 
“Responsibilities of Sponsors and Investigators,” Part 50, “Protection of Human Subjects,” and 
Part 56, “Institutional Review Boards.”  
12.2 
Informed Consent 
Sample ICFs will be supplied to each site. The Sponsor or its designee must review any proposed 
deviations from the sample ICFs. The final IRB/EC-approved documents must be provided to the 
Sponsor for regulatory purposes. 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness must be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
the ICF will be provided in a certified translation of the subject’s language. 
In the case where the subject is < 18 years of age, the investigator, or person designated by the 
investigator, is responsible for obtaining written informed assent from each participating subject 
and written informed consent from each subject’s parent or guardian after adequate explanation 
of the aims methods, anticipated benefits, and potential hazards of the study. The parent/guardian 
must be present during the entire informed consent discussion. Copies of the informed assent 
form and the ICF for the parent/guardian must be provided to the subject and parent/guardian. 
The CRF for this study contains a section for transcribing documentation of informed subject 
consent, and this must be completed appropriately. Signed ICFs must remain in each subject’s 
study file and must be available for verification by study monitors at any time. If new safety 
information results in significant changes in the risk/benefit assessment, the consent form will be 
reviewed and updated as necessary. All subjects (including those already being treated) will be 
informed of the new information, will be given a copy of the revised form, and must give their 
consent to continue in the study. 
If a subject requests to discontinue study treatment and/or withdraws study consent, the 
Investigator must establish the specific nature of the subject’s request, as described in 
Section 3.6. Subjects’ decisions (individual subjects may make more than one over time) must be 
recorded in source documents and transcribed to study CRFs. 

 
 
Protocol XL184-311 
Page 121 of 165 
12.2.1 
Informed Consent for the Crossover Phase 
In addition to the main study ICF, informed consent for the Crossover Phase must be obtained on 
a separate ICF for subjects randomized to the placebo arm who experienced BIRC-confirmed 
radiographic progression and choose to enter the Crossover Phase of the study. It is the 
responsibility of the investigator, or a person designated by the investigator, to obtain written 
informed consent from each subject (or the subject’s legally authorized representative) 
participating in the Crossover Phase after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. Informed consent for the Crossover Phase must be 
obtained through the same process established for the main study (which includes obtaining 
informed assent from subjects < 18 years of age and informed consent from parents/guardians; 
Section 12.2) 
12.3 
Institutional Review Board/Ethics Committee 
This study is being conducted under a United States Investigational New Drug application and 
other regulatory applications, as applicable. 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 the current 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. 
12.4 
Disposition of Subject Samples 
Protocol-defined analyses are anticipated to result in depletion of all or almost all of the research 
samples. If a subject requests destruction of their tissue and blood samples, the Sponsor will 
destroy the samples. The Sponsor will notify the Investigator in writing that the samples have 
been destroyed. 
13 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications may be made and will be prepared, reviewed, and approved by the 
Sponsor. 
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 changes that involve only logistical or administrative 
aspects of the trial (eg, change in monitor, change of telephone number). 

 
 
Protocol XL184-311 
Page 122 of 165 
14 
CONDITIONS FOR TERMINATING THE STUDY OR LIMITING DATA 
COLLECTION 
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. 
15 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORDING 
KEEPING 
15.1 
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  (some may be predefined by the project to record key data 
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 informed consent forms; 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, 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 requirement 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 

 
 
Protocol XL184-311 
Page 123 of 165 
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. 
15.2 
Source Documents and Background Data 
Upon request, the investigator will supply the Sponsor with any required background data from 
the study documentation or clinic records. This is particularly important when errors in data 
transcription are suspected. 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. 
15.3 
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. 
15.4 
Case Report Forms 
The term “case report form” 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. 

 
 
Protocol XL184-311 
Page 124 of 165 
The Sponsor’s data management personnel (or designees) may, in specific circumstances, 
modify study data – without changing the meaning of the data – to ensure the dataset complies 
with conventions required for successful data extract, thesaurus coding, or uniform reporting and 
does not cause these processes to fail. Examples of these administrative changes include: 
• Substitution of non-standard ASCII characters (codes 128-255) or deletion of carriage returns 
(code 13) that are incompatible with the SAS XPT file format (eg, accented letters replaced 
with non-accented ones; e for é) 
• Splitting multiple verbatim AE terms into multiple records (eg, “nausea and vomiting” to 
separate records for “nausea” and “vomiting”) 
• 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 trail. 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. 
16 
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.  

 
 
Protocol XL184-311 
Page 125 of 165 
17 
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, subject data are to be pseudonymised: subjects are to be identified only by arbitrary 
identification codes (the study subject ID assigned by the IRT system) and not by their names, 
initials, birth dates, or other personal identifiers. The investigator should keep a subject 
enrollment log showing codes, names, and addresses. This information will be maintained solely 
at the study site. 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. 
18 
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. 

 
 
Protocol XL184-311 
Page 126 of 165 
19 
REFERENCES 
Aftab DT, McDonald DM. MET and VEGF: Synergistic targets in castration-resistant prostate 
cancer. Clin Transl Oncol 2011;13:703–709.  
Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA. RET/ NTRK1 
rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation 
with clinicopathological features. Clin Cancer Res. 1998;4(1): 223–228.  
Brose MS, Shenoy S, Bhat N, Harlacker AK, Yurtal RK, Posey ZA, et al. A Phase 2 Trial of 
Cabozantinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid 
Carcinoma in the First-Line Setting. Presented at: The Multidisciplinary Head and 
Neck Cancers Symposium 2018; Scottsdale, AZ. 
Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, et al. DECISION investigators. Sorafenib in 
radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid 
cancer: a randomised, double-blind, phase 3 trial. Lancet 2014 Jul 26;384(9940):319-
28. 
Busaidy NL, Cabanillas ME. DTC: management of patients with radioiodine nonresponsive 
disease. J Thyroid Res 2012;2012:618985. 
Cabanillas, M, Brose M, Holland J, et al. A phase I study of cabozantinib (XL184) in patients 
with differentiated thyroid cancer. Thyroid 2014;24(10):1508-1514. 
Cabanillas ME, de Souza JA, Geyer S, et al. Cabozantinib as salvage therapy for patients with 
tyrosine kinase inhibitor – refractory differentiated thyroid cancer: results of a 
multicenter phase 2 international thyroid oncology group trial. J Clin Oncol 
2017;35(29):3315-3321. 
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 
2011;473(7347):298–307.  
Choueiri TK, Hessel C, Halabi S, Sanford BL, 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 Canc. 2018;94:115-
125 

 
 
Protocol XL184-311 
Page 127 of 165 
Ciampi R, Nikiforov YE. RET/PTC rearrangements & BRAF mutations in thyroid 
tumorigenesis. Endocrinology. 2007; 148:936–941. 
Ciamporcero E, Miles KM, Adelaiye R, Ramakrishnan S, Shen L, et al. Combination strategy 
targeting VEGF and HGF/c-met in human renal cell carcinoma models. Mol Cancer 
Ther. 2015 Jan;14(1):101-10. 
Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association 
management guidelines for patients with thyroid nodules and differentiated thyroid 
cancer. Thyroid. 2009; 19:1167–1214.  
DeLellis RA, Lloyd RV, Heitz PU, Eng C. World Health Organization Classification of 
Tumours. Pathology and Genetics of Tumours of Endocrine Organs. Lyon: IARC 
Press; 2004. 
Drosten M, Hilken G, Böckmann M, Rödicker F, Mise N, et al. Role of MEN2A-derived RET in 
maintenance and proliferation of medullary thyroid carcinoma. J Natl Cancer Inst. 
2004 Aug 18;96(16):1231-9. 
Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases 
from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine 
therapy. J Clin Endocrinol Metab. 2006;91:2892-9. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.  
Elisei R, Cosci B, Romei C, Bottici V, Renzini G, et al. Prognostic significance of somatic RET 
oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. 
J Clin Endocrinol Metab. 2008 Mar;93(3):682-7. 
FDA Guidance for Industry: Multiple Endpoints in Clinical Trials (draft, January 2017). 
FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drug and 
Biologics (May 2007).  
Ghassan A, Meyer T, Cheng A, El-Khoueiry A, Rimassa L, Ryoo B, et al. Cabozantinib (C) 
versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) 

 
 
Protocol XL184-311 
Page 128 of 165 
who have received prior sorafenib: Results from the randomized phase III 
CELESTIAL trial. J Clin Onc 2018. 4 suppl 36:207-207. 
Guilmette J, Nosé V. Hereditary and familial thyroid tumours. Histopathology. 2018 
Jan;72(1):70-81. 
Herdman M, Gudex C, Lloyd A, D, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727-36. 
Hessel C, Mangeshkar M, Motzer R, Escudier B, Powles T, Schwab G, et al. 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 renal cell carcinoma 
(RCC). Ann Onc 2016;27 Suppl 6:815 
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, et al (eds). SEER Cancer Statistics 
Review, 1975-2014, National Cancer Institute. Bethesda, MD, 
https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data 
submission, posted to the SEER web site, April 2017. 
Keefe SM, Cohen MA and Brose MS. Targeting Vascular Endothelial Growth Factor Receptor 
in Thyroid Cancer: The Intracellular and Extracellular Implications. Clin Cancer Res. 
2010;16(3). 
Klubo-Gwiezdzinska J, Junik R, Kopczynska E, Juraniec O, Kardymowicz H. The comparison 
of serum vascular endothelial growth factor levels between patients with metastatic 
and non-metastatic thyroid cancer, and patients with nontoxic multi nodular goiter. 
Eur J Endocrinol. 2007;157(4):521–7.  
Moura MM, Cavaco BM, Pinto AE, Domingues R, Santos JR, et al. Correlation of RET somatic 
mutations with clinicopathological features in sporadic medullary thyroid carcinomas. 
Br J Cancer. 2009 Jun 2;100(11):1777-83 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: 
Thyroid Carcinoma v2. 2017. NCCN.org. 
Nikiforov YE. Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med. 
2011 May;135(5):569-77. 

 
 
Protocol XL184-311 
Page 129 of 165 
Pellegriti G, Frasca F, Regalbuto C, Squatrito S, Vigneri R. Worldwide increasing incidence of 
thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 
2013;2013:965212. 
Pierotti MA, Bongarzone I, Borello MG, Greco A, Pilotti S, Sozzi G. Cytogenetics and 
molecular genetics of carcinomas arising from thyroid epithelial follicular cells. 
Genes Chromosomes Cancer. 1996 May;16(1):1-14 
Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 
2015 Jul 1;121(13):2137-46.  
Ringel MD, Hayre N, Saito J, et al. Over expression and over activation of Akt in thyroid 
carcinoma. Cancer Res 2001;61:6105–11. 
Rivkees SA, Mazzaferry EL, Verburg FA, Reiners C, Luster M, Breuer CK, et al. The treatment 
of differentiated thyroid cancer in children: emphasis on surgical approach and 
radioactive iodine therapy. Endocr Rev. 2011;32(6):798-826. 
Roman BR, Morris LG, Davies L. The Thyroid Cancer Epidemic. Curr Opin Endocrinol 
Diabetes Obes. 2017;24 (5), 332-336.  
Schöffski P, Gordon M, Smith D, Kurzrock R, Daud A, Vogelzang N, et al. Phase II randomised 
discontinuation trial of cabozantinib in patients with advanced solid tumours. Eur J 
Cancer 2017:86:296-304. 
Schlumberger M, Brose M, Elisei R,et al. Definition and management of radioactive 
iodine-refractory DTC. Lancet Diabetes Endocrinol. 2014;2:356-8. 
Schlumberger M, Tahara M, Wirth LJ. Lenvatinib in radioiodine-refractory thyroid cancer. 
N Engl J Med. 2015 May 7;372(19):1868. 
SEER Cancer Stat Facts: Thyroid Cancer. Version 2. 2017. National Cancer Institute. Bethesda, 
MD, http://seer.cancer.gov/statfacts/html/thyro.html 
Sennino B, Ishiguro-Oonuma T, Wei Y, et al: Suppression of tumor invasion and metastasis by 
concurrent inhibition of c-Met and VEGF signaling in pancreatic neuroendocrine 
tumors. Cancer Discov 2012a;2:270–287.  

 
 
Protocol XL184-311 
Page 130 of 165 
Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev 
Cancer 2012; 12: 699–709.  
Sherman SI. Thyroid carcinoma. Lancet. 2003 Feb 8;361(9356):501-11.  
Shojaei F, Lee JH, Simmons BH, Wong A, Esparza CO, Plumlee PA, Feng J, Stewart AE, 
Hu-Lowe DD, Christensen JG. HGF/c-Met acts as an alternative angiogenic pathway 
in sunitinib-resistant tumors. Cancer Res. 2010 Dec 15;70(24):10090-100. 
Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary 
thyroid carcinomas lacking evidence of progression to poorly differentiated or 
undifferentiated tumor phenotypes. Clin Cancer Res. 1998;4(2):287–294. 
Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in 
development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 
2010 Dec;11(12):834-48. 
Turnage RH, Richardson KA, Li BD, McDonald JC. Abdominal wall, umbilicus, peritoneum, 
mesenteries, omentum, and retroperitoneum. In: Townsend CM, Beauchamp RD, 
Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery. 18th ed. St. Louis, Mo: 
WB Saunders; Chapter 43, 2008. 
Verburg FA, Santen H, Luster M. Pediatric papillary thyroid cancer: current management 
challenges. Onco Targets Ther. 2017;10:165-175. 
World Health Organization; International Agency for Research on Cancer. Cancer incidence, 
mortality, and prevalence worldwide. Globocan 2012 [cited 30 January 
2018]. http://globocan.iarc.fr/ 
Wright JR, Ung Y, Julian J, et al. Randomized, double-blind, placebo-controlled trial of 
erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin 
Oncol 2007;25:1027–1032.  
Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013; 
13(3): 184–199. 

 
 
Protocol XL184-311 
Page 131 of 165 
Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, et al. BRAF mutation predicts a 
poorer clinical prognosis for papillary thyroid cancer. Clin Endocrinol Metab. 
2005 Dec; 90(12):6373-9 
Zhou L, Liu X, 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 
Zhou ZH, Cui XN, Xing HG, Yan RH, Yao DK, Wang LX. Changes and prognostic value 
ofserum vascular endothelial growth factor in patients with differentiated thyroid 
cancer. Med Princ Pract 2012;22(1):24–8. 
 
 

 
 
Protocol XL184-311 
Page 132 of 165 
20 
APPENDICES 

 
 
Protocol XL184-311 
Page 133 of 165 
Appendix A: Schedule of Assessments 
The schedule of required assessments is presented in this appendix. Following randomization, assessments for safety and patient 
reported outcomes are to occur corresponding with study weeks (eg, Week 5 Day 1 [W5D1]) which are fixed from Week 1 Day 1 
(W1D1) defined as the date of the first dose of study treatment. W1D1 should occur within 3 days after randomization (see 
Section 6.1). All assessments for radiographic efficacy (CT, MRI, bone scans) will be scheduled based on the date of randomization 
(see Section 5) 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 for the first 
8 weeks and within ± 5 days of the nominal visit day from W9D1 on, unless otherwise indicated. If study treatment is held or missed 
after W1D1, assessments should continue following the schedule described below. 
Unscheduled safety assessments are to be performed weekly (or more frequently as clinically indicated). Other unscheduled visits are 
permitted whenever necessary. See Section 5.6 for further details. 
See Appendix B for Schedule of Assessments during the Crossover Phase and Appendix C for Schedule of Assessments during the 
Maintenance Phase. 
 
 

 
 
Protocol XL184-311 
Page 134 of 165 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 9 (± 5 days) 
30-Day Post-
Treatment 
Follow-Up 
(+14 days) 
Extended          
Follow-Up 
W3D1 
W5D1 
W7D1 
W9D1 
Informed consent 
(Section 12.2) 
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                              (pr
ior to first dose; 
symptom directed) 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Vital signs (Section 5.7.3) 
≤ 10 days 
X                 
(prior to first dose) 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
ECOG performance status 
(Section 5.7.2) 
≤ 10 days 
X                 
(prior to first dose) 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
12-lead ECG (Section 5.7.4)c  
≤ 14 days 
Xd             
(prior to first dose) 
 
X 
 
X 
Every 12 weeks 
(W21D1, W33D1, etc) 
X 
 
Hematology                                   
by central labe (Section 5.7.5) 
≤10 days 
Xd             
(prior to first dose) 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Chemistry                                      
by central labe (Section 5.7.5) 
≤ 10 days 
Xd             
(prior to first dose) 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
PT/INR and PTT                           
by central labe (Section 5.7.5)       
≤ 10 days 
Xd             
(prior to first dose) 
 
X 
 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Urinalysis by local 
labe (Section 5.7.5) 
≤ 10 days 
Xd             
(prior to first dose) 
X 
X 
 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Urine chemistry including 
UPCR by central 
labe (Section 5.7.5) 
≤ 10 days 
Xd             
(prior to first dose) 
X 
X 
 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Serum or urine pregnancy test       
by local labe (Section 5.7.5) 
≤ 7 days 
(serum required) 
Xd             
(prior to first dose; 
serum required) 
 
X 
 
X 
Every 4 weeks 
(W13D1, W17D1, etc) 
X 
 
Thyroid function test                     
by central labe (Section 5.7.5) 
≤ 28 days 
Xd             
(prior to first dose) 
X 
X 
 
X 
Every 8 weeks 
(W17D1, W25D1, etc) 
X 
 
Thyroglobulin 
by central labf (Section 5.7.5)       
≤ 28 days 
 
 
X 
 
X 
Every 8 weeks 
(W17D1, W25D1, etc) 
 
 
Follicle stimulating hormone by 
central labe, g (Section 5.7.5) 
≤ 28 days 
 
 
 
 
 
 
 
 

 
 
Protocol XL184-311 
Page 135 of 165 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 9 (± 5 days) 
30-Day Post-
Treatment 
Follow-Up 
(+14 days) 
Extended          
Follow-Up 
W3D1 
W5D1 
W7D1 
W9D1 
Tumor 
tissueh                                  (Section 
5.7.10) 
X 
X 
 
 
 
 
 
 
 
Tumor assessment:  
CT/MRI  
Chest, Abdomen, Pelvis, 
Neck  (Section 5.7.6) 
≤ 28 days 
CT (or MRI) of CAPN will be performed in all subjects at screening and every 8 weeks (± 7 days) after randomization during the first 
12 months on study. Upon completion of 12 months on study, these assessments will be performed every 12 weeks (± 14 days). If MRI of 
the abdomen and pelvis is performed at screening, then a CT of the chest and neck must be performed as well. Additional imaging of 
potential disease sites should be performed whenever radiographic disease progression is suspected. 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Radiographic tumor assessments are to continue until the later of investigator-assessed radiographic disease progression per RECIST 1.1 that 
is confirmed per real-time BIRC review or the date of the decision to permanently discontinue study treatment; however, radiographic tumor 
assessments may cease at the time of first systemic nonprotocol anticancer therapy, if given before these milestones occur. 
Tumor assessment:  
MRI/CT  
Brain                                               (S
ection 5.7.6) 
≤ 28 days 
 
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 following the same post-baseline frequency as the imaging for CAPN. MRI is the 
preferred method for brain. If CT of the brain is performed instead of MRI, ambiguous results must be confirmed by MRI. (Note: In order 
to meet the eligibility requirements of the study, brain metastasis must have been treated and stable for at least 4 weeks before 
randomization. Subjects without documented brain metastasis during the screening assessment are not required to undergo post-
randomization brain imaging unless clinically indicated.) 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Radiographic tumor assessments are to continue until the later of investigator-assessed radiographic disease progression per RECIST 1.1 
that is confirmed per real-time BIRC review or the date of the decision to permanently discontinue study treatment; however, radiographic 
tumor assessments may cease at the time of first systemic nonprotocol anticancer therapy, if given before these milestones occur. 
Tumor assessment:  
Bone scan  
Whole body  
 (Section 5.7.6) 
≤ 28 days 
Technetium bone scans will be performed at screening in all subjects and after randomization only in subjects with known bone metastasis 
every 24 weeks (± 14 days). Technetium bone scans are also to be performed for clinical symptoms indicative of new bone metastases. 
Bone scan findings alone cannot be used for the determination of progression or response per RECIST version 1.1 and need to be 
corroborated by CT or MRI. 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Bone scan evaluations will end on the date of last CT/MRI scan. If the bone scan schedule doesn’t coincide with the last CT/MRI scan, no 
additional bone scan is needed after the last CT/MRI scan has been performed. 
HRQOL                                      
EQ-5D-5Li (Section 5.7.7) 
 
X 
(prior to first 
dose) 
Every 4 weeks through W25D1 followed by every 8 weeks.  
 These assessments are to be performed regardless of whether study treatment is given, reduced, held, or discontinued. 
HRQOL will no longer be collected for subjects who transition to the Crossover Phase or if the study transitions to the 
Maintenance Phase.  

 
 
Protocol XL184-311 
Page 136 of 165 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 9 (± 5 days) 
30-Day Post-
Treatment 
Follow-Up 
(+14 days) 
Extended          
Follow-Up 
W3D1 
W5D1 
W7D1 
W9D1 
PK blood 
samplesj                   (Section 
5.7.9) 
 
 
X 
X 
 
X 
 
 
 
Pharmacogenetic blood 
samplek  (Section 5.7.10) 
 
X                
(prior to first dose) 
 
 
 
 
 
 
 
Plasma biomarker samples 
(Section 5.7.10) 
 
X                
(prior to first dose) 
 
X 
 
X 
 
 
 
ctDNA (Section 5.7.10) 
 
X                
(prior to first dose) 
 
X 
 
X 
 
 
 
CTC blood samples                  
(Section 5.7.10) 
 
X                
(prior to first dose) 
 
X 
 
X 
 
 
 
Concomitant medication 
(Section 7) 
Document concomitant 
medication (including 
transfusions) taken 
from 28 days before 
randomization through 
30 days after the date of 
the decision to 
discontinue study 
treatment 
 
 
 
 
 
 
 
 
Health Care Resource 
Utilizations (Section 5.7.8) 
 
Collection of start and stop dates or length of stay of hospital admissions, emergency room visits, and intensive care 
unit admissions associated with SAEs from randomization until AE follow-up is discontinued. 
 
Adverse events                
(Section 8) 
Document new or worsening AEs from informed consent through 30 days after the date of the decision to permanently discontinue study treatment (related SAEs at 
any time). AE information will be collected at study visits and may also be collected at any time over the phone or by spontaneous subject report. On W1D1 AEs will 
be documented pre- and post-dose. Certain AEs and all SAEs that are ongoing 30 days after of the date of the decision to permanently discontinue study treatment are 
to be followed until resolution or determination by the Investigator that the event is stable or irreversible (see Section 8.3). 
Blinded study treatment 
 
Cabozantinib/placebo will be given in clinic on W1D1 and taken once daily at home thereafter until study treatment 
is discontinued. For subjects in the cabozantinib arm, study treatment will continue in an unblinded fashion if the 
investigator continues treatment after BIRC-confirmed radiographic progression and the subject is subsequently 
unblinded to determine treatment arm for crossover eligibility. 
 
Dispense/return of oral study 
drug and compliance 
accounting (Section 6.4) 
 
X 
X 
X 
X 
X 
Every 4 weeks 
(W13D1, W17D1, 
etc) 
 
 

 
 
Protocol XL184-311 
Page 137 of 165 
 
Pre-randomization 
Post-randomization 
Assessment: 
Screeninga 
(before 
randomization) 
W1D1  
(≤ 3 days after 
randomization) 
(± 3 Days) 
 
After Beginning of 
Week 9 (± 5 days) 
30-Day Post-
Treatment 
Follow-Up 
(+14 days) 
Extended          
Follow-Up 
W3D1 
W5D1 
W7D1 
W9D1 
Survival, post-study treatment 
(Sections 5.4 and 5.7.11) 
 
 
 
 
 
 
 
 
Subjects will be 
contacted every 
12 weeks 
(± 7 days)  after 
follow-up visit 
until death 
BIRC, blinded independent radiology committee; CAPN, chest/abdomen/pelvis/neck; CRF, case report form; CT, computed tomography; CTC, circulating tumor 
cell; ctDNA, circulating DNA; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; HRQOL, health-related quality of life; IRB/EC, 
Institutional Review Board/Ethics Committee; MRI, magnetic resonance imaging; PK, pharmacokinetics; PT/INR, prothrombin time/international normalized 
ratio; PTT, partial thromboplastin time; RECIST, Response Evaluation Criteria in Solid Tumors; UPCR, urine protein/creatinine ratio. 
a Results of screening assessments must be reviewed before randomization to confirm that the subject meets the eligibility criteria. 
b Informed consent may be obtained greater than 28 days prior to randomization, but must be provided before any study-specific procedures are performed;  
however evaluations performed as part of routine care prior to informed consent can be utilized as screening evaluations if permitted by the site’s IRB/EC 
policies. 
c Additional ECGs should be performed if clinically indicated. 
d This assessment is intended to confirm suitability for treatment after randomization. If this assessment has been performed during screening within 10 days 
(7 days for pregnancy test, 14 days for physical examination and 12-lead ECG, and 28 days for thyroid function test) prior to first dose (W1D1), this 
assessment does not need to be performed on W1D1 unless the subject’s clinical status has changed (eg, onset of new symptoms indicative of clinical 
deterioration). If the assessment is performed on W1D1, the results must be available to and reviewed by the Investigator prior to any treatment being 
administered.  
e See Section 5.7.5 and the Laboratory Manual for more detailed information on laboratory assessments. 
f Thyroglobulin data will not be shared with the Investigator.  
g For women under the age of 55 years to confirm menopause as needed.  
h Available tumor tissue (most recently acquired before subject enrollment in the study will be obtained during screening or at enrollment.  
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 or if completed on the day of the visit prior to seeing the study site personnel.  
j For each specified time point, the PK sample should be collected approximately 8 or more hours after the previous dose of study treatment and should be 
collected prior to study treatment administration. The investigator will ask the subject for the date and time of the most recent prior dose of study treatment, 
and this information will be recorded on the appropriate CRF page.  
k The sample may also be used to facilitate tumor biomarker analyses or for assay development.  
 
 

 
 
Protocol XL184-311 
Page 138 of 165 
Appendix B: Crossover Phase - Eligibility Criteria and Schedule of Assessments 
At the time of investigator-determined radiographic progression per RECIST 1.1, investigators may request from the Sponsor’s 
medical monitor (or designee) confirmation of BIRC-determined radiographic PD. 
For subjects with BIRC-confirmed radiographic progression: 
• Upon authorization from Sponsor’s medical monitor (or designee), investigators may unblind the individual subject via the 
IRT system 
• Unblinded subjects randomized to placebo have the following options: 
• Such subjects may be provided by the Investigator the opportunity, if eligible (see criteria below), to enter the Crossover 
Phase to receive cabozantinib and undergo study assessments as defined herein. 
• Such subjects who are ineligible or opt not to crossover to receive cabozantinib are to have study treatment discontinued 
and proceed with post-treatment assessments as described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the investigator believes the subject is still 
deriving clinical benefit. Study assessments are to continue per the schedule of assessments in Appendix A. 
Subjects without radiographic progression per BIRC will not be unblinded and are to continue to receive blinded study treatment and 
undergo study assessments according to the schedule in Appendix A. 
Screening of placebo subjects for crossover to cabozantinib will continue until the transition of the study to the Maintenance Phase. 
Assessments for the Crossover Phase are outlined in Table 20-1. 
Data for the Crossover Phase, will be summarized separately and will not be included as part of the primary evaluation of either arm. 

 
 
Protocol XL184-311 
Page 139 of 165 
Eligibility Criteria for Crossover to Cabozantinib Following Treatment with Placebo 
(Note that the numbering of the criteria is maintained from the start of the study [Section 4.2 Inclusion Criteria and Section 4.3 
Exclusion Criteria]. “Not applicable” rows below refer to eligibility criteria from the start of the study that are not relevant for the 
Crossover Phase as these subjects have either already fulfilled the criteria upon study entry, or the criteria are not a requirement for the 
Crossover Phase.) 
Inclusion Criteria 
1. Not applicable 
2. Not applicable 
3. Not applicable 
4. Not applicable 
5. Not applicable 
6. 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 
7. Not applicable 
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1  

 
 
Protocol XL184-311 
Page 140 of 165 
9. Adequate organ and marrow function based upon meeting all of the following laboratory criteria within 7 days before crossover:  
a. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without receipt of granulocyte colony-stimulating factor support within 
2 weeks before screening laboratory sample collection 
b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks before screening laboratory sample 
collection 
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection 
d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × ULN. ALP ≤ 5 × ULN if the subject has 
documented bone metastases 
e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease ≤ 3 × ULN 
f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault (see 
Table 5-2 for Cockcroft-Gault formula) 
g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) 
10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff of the reference range or less than 0.50 
mIU/L (< 0.50 μIU/mL), whichever is lower, within 28 days before crossover. 
(Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be targeted.) 
11. Not applicable 
12. Not applicable 
13. Not applicable 
Exclusion Criteria 
1. Not applicable 
2. Not applicable 
3. Not applicable 
4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before crossover. 
Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not 
eligible (eg, radiation esophagitis or other inflammation of the viscera) 

 
 
Protocol XL184-311 
Page 141 of 165 
5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including 
radiosurgery) and stable for at least 4 weeks before crossover. Eligible subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of crossover 
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors 
(eg, clopidogrel), except for the following allowed anticoagulants:  
• Low-dose aspirin for cardioprotection (per local applicable guidelines) and LMWH 
• Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are on a stable dose of 
LMWH for at least 6 weeks before crossover and who have had no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor 
7. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: 
a. Cardiovascular disorders: 
i. Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, serious 
cardiac arrhythmias 
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment 
iii. Stroke (including TIA), MI, or other ischemic event, or thromboembolic event (eg, DVT, pulmonary embolism) within 6 
months before crossover. Subjects with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and treated 
with LMWH for at least 6 weeks. 
b. Gastrointestinal disorders (eg, malabsorption syndrome or gastric outlet obstruction) including those associated with a high 
risk of perforation or fistula formulation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, 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.  
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to crossover  
c. Clinically significant hematemesis or hemoptysis of  > 0.5 teaspoon (> 2.5 mL) of red blood or history of other significant 
bleeding within 3 months before crossover 
d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation 
e. Lesions invading major pulmonary blood vessels 

 
 
Protocol XL184-311 
Page 142 of 165 
f. Other clinically significant disorders such as: 
• Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired 
immunodeficiency syndrome related illness, or chronic hepatitis B or C infection  
• Serious non-healing wound/ulcer/bone fracture 
• Malabsorption syndrome  
• Moderate to severe hepatic impairment (Child-Pugh B or C) 
• Requirement for hemodialysis or peritoneal dialysis 
• Uncontrolled diabetes mellitus 
• History of solid organ transplantation 
8. Complete wound healing from major surgery must have occurred 4 weeks before crossover and from minor surgery (eg, simple 
excision, tooth extraction) at least 10 days before crosover. Subjects with clinically relevant ongoing complications from prior 
surgery cannot be crossed over 
9. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before crossover.   
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 3 consecutive results for QTcF will be used to 
determine eligibility.  
10. Pregnant or lactating females 
11. Not applicable 
12. Previously identified allergy or hypersensitivity to components of the study treatment formulations 
13. Not applicable 

 
 
Protocol XL184-311 
Page 143 of 165 
Table 20-1: Schedule of Assessments Crossover Phase  
This schedule is to be followed for subjects who crossover from the placebo arm to receive cabozantinib. W1D1 will be the first day 
of crossover cabozantinib treatment. In the absence of toxicity, all scheduled safety visits should occur within ± 3 days of the nominal 
time for the first 9 weeks and within ± 5 days of the nominal visit day thereafter, unless otherwise indicated. If study treatment is 
interrupted or missed after W1D1, assessments should continue following the schedule described below.  
 
Crossover 
Screening  
(before 
crossover)a 
W1D1  
 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment Follow-
Up (+14 d) 
Extended 
Follow-Up 
Informed consent (Section 12.2) 
X b 
 
 
 
 
 
 
 
 
Interval medical history  
Xc 
 
 
 
 
 
 
 
 
Physical exam (PE) + weight  
(Section 5.7.2) 
≤ 7 days  
 
X (prior to first dose; 
symptom-directed PE) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Vital signs (Section 5.7.3) 
≤ 7 days 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
ECOG performance status 
(Section 5.7.2) 
≤ 7 days 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
12-lead ECG (Section 5.7.4)d 
≤ 7 days 
X (prior to first dose)e 
X 
X 
 
X 
 
X 
 
Hematology by central lab 
(Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Chemistry by central lab 
(Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
PT/INR and PTT by central lab 
(Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Urinalysis by local lab (Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Urine chemistry including UPCR by 
central lab (Section 5.7.5) f 
≤ 7 days 
Xd                     
(prior to first dose) 
X 
X 
 
X 
Every 4 weeks 
(W13D1, W17D1, 
etc) 
X 
 
Serum pregnancy test by local lab 
(Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
 
X 
 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 

 
 
Protocol XL184-311 
Page 144 of 165 
 
Crossover 
Screening  
(before 
crossover)a 
W1D1  
 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment Follow-
Up (+14 d) 
Extended 
Follow-Up 
Thyroid function test by central 
lab (Section 5.7.5) f 
≤ 7 days 
X (prior to first dose)e 
 
 
 
X 
Every 8 wks  
(W17D1, W25D1 etc) 
X 
 
Tumor assessment:  
CT/MRI  
Neck, Chest, Abdomen, 
Pelvis  (Section 5.7.6) 
Re-establish 
baseline based upon 
the most recent set 
of scans performed 
prior to unblinding 
for crossover; if 
these scans are > 8 
weeks prior to first 
crossover dose, new 
scans are required to 
establish the 
crossover baseline 
CT (or MRI) of CAPN are to continue every 8 weeks (± 7 days) during the first 12 months after crossover. Upon completion of 
12 months in the Crossover Phase, these assessments will be performed every 12 weeks (± 14 days). Additional imaging of potential 
disease sites should be performed whenever radiographic disease progression is suspected. 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Radiographic tumor assessments are to continue after crossover until the later of investigator-assessed radiographic disease progression 
per RECIST 1.1 or the date of the decision to permanently discontinue study treatment; however, radiographic tumor assessments may 
cease at the time of first systemic non protocol anticancer therapy, if given before these milestones occur. 
Tumor assessment:  
MRI/CT  
Brain 
(Section 5.7.6) 
Re-establish 
baseline based upon 
the most recent set 
of scans performed 
prior to unblinding 
for crossover; if 
these scans are > 8 
weeks prior to first 
crossover dose, new 
scans are required to 
establish the 
crossover baseline  
MRI (or CT) scans of the brain are only required in subjects with known brain metastasis and performed every 8 weeks (± 7 days) 
during the first 12 months after crossover. Upon completion of 12 months in the Crossover Phase, these assessments will be performed 
every 12 weeks (± 14 days). MRI is the preferred method for brain. If CT of the brain is performed instead of MRI, ambiguous results 
must be confirmed by MRI. 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Radiographic tumor assessments are to continue after crossover until the later of investigator-assessed radiographic disease progression 
per RECIST 1.1 or the date of the decision to permanently discontinue study treatment; however, radiographic tumor assessments may 
cease at the time of first systemic non protocol anticancer therapy, if given before these milestones occur. 
Tumor assessment:  
Bone scan  
Whole body  
 (Section 5.7.6) 
Re-establish 
baseline based upon 
the most recent set 
of scans performed 
prior to unblinding 
for crossover; if 
these scans are > 8 
weeks prior to first 
crossover dose, new 
scans are required to 
establish the 
crossover baseline 
Technetium bone scans are to continue every 24 weeks (± 14 days) after crossover only in subjects with known bone metastasis. 
Technetium bone scans are also to be performed for clinical symptoms indicative of new bone metastases. Bone scan findings alone 
cannot be used for the determination of progression or response per RECIST version 1.1 and need to be corroborated by CT or MRI. 
 
Assessments are to be performed per the protocol-defined schedule regardless of whether study treatment is given, reduced, held, or 
discontinued. 
 
Bone scan evaluations will end on the date of last CT/MRI scan. If the bone scan schedule doesn’t coincide with the last CT/MRI scan, 
no additional bone scan is needed after the last CT/MRI scan has been performed. 
Concomitant medications (Section 7) 
 
 
 
 
 
 
 
 
 
Health Care Resource Utilizations 
(Section 5.7.8) 
 
 
 
 
 
 
 
 
 
Adverse events (Section 8) 
 
 
 
 
 
 
 
 
 

 
 
Protocol XL184-311 
Page 145 of 165 
 
Crossover 
Screening  
(before 
crossover)a 
W1D1  
 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment Follow-
Up (+14 d) 
Extended 
Follow-Up 
Cabozantinib 
 
Given in clinic on W1D1 and taken once daily at home thereafter until study treatment is discontinued 
 
Dispense/return of oral study drug and 
compliance accounting (Section 6.4) 
 
X 
X 
X 
X 
X 
Every 4 wks 
 
 
Survival, post-study treatment 
(Section 5.4 and 5.7.11) 
 
 
 
 
 
 
 
 
Every 
12 wks 
CAPN, chest/abdomen/pelvis/neck; CRF, case report form; CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; 
ICF, informed consent form; IRB/EC, Institutional Review Board/Ethics Committee; MRI, magnetic resonance imaging; PT/INR, prothrombin time/international 
normalized ratio; PTT, partial thromboplastin time; RECIST, Response Evaluation Criteria in Solid Tumors; UPCR, urine protein/creatinine ratio. 
a Screening assessments must be reviewed by the investigator before crossover to confirm that the subject meets the crossover eligibility criteria. Only subjects 
randomized to the placebo arm who opt to crossover to receive cabozantinib will undergo crossover screening. Subjects randomized to the cabozantinib arm 
and subjects randomized to the placebo arm who do not crossover will continue their original study assessments per Appendix A according to the Week and 
Day from time of first dose of blinded treatment. 
b In addition to informed consent obtained for the main study, informed consent specific for the Crossover Phase must be obtained. Informed consent may be 
obtained greater than 28 days prior to crossover, 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. The Investigator must ensure 
that the subject consents on the most recent version of the ICF. 
c Interval medical history will be collected for subjects randomized to the placebo arm who undergo screening for crossover and who have discontinued blinded 
study treatment > 30 days prior to W1D1 of crossover. All adverse events that were experienced ≤ 30 days after the date of decision to discontinue any study 
treatment (blinded or unblinded) will be collected on the adverse event CRF. 
d Additional ECGs should be performed if clinically indicated 
e This assessment is intended to confirm suitability for treatment after crossover. If this assessment has been performed during screening within 7 days prior to 
first dose of unblinded cabozantinib (W1D1), this assessment does not need to be performed on W1D1 unless the subjects’ 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.  
f See Section 5.7.5 and separately provided Central Laboratory Manual for more detailed information on laboratory assessments. If the investigator suspects the 
subject is clinically deteriorating during the screening period, additional unscheduled laboratory tests (eg, albumin, bilirubin) should be performed by the local 
laboratory before crossover to confirm that the subject remains suitable for study treatment and amenable to study participation commensurate with the goals 
of the clinical trial. 
 

 
 
Protocol XL184-311 
Page 146 of 165 
Appendix C: Maintenance Phase 
After the primary efficacy endpoints have been analyzed and upon determination by the Sponsor that sufficient data have been 
collected to adequately evaluate all study endpoints to establish, for regulatory purposes, the safety and efficacy profile of the 
experimental drug within this study, the study will begin to transition to the Maintenance Phase.  
As a transitional step prior to initiation of the Maintenance Phase, all blinded study subjects will be unblinded and study sites will be 
notified of their randomized treatment assignments.  
• Unblinded subjects randomized to placebo have the following options: 
o Such subjects may be provided by the Investigator the opportunity, if eligible (see Appendix B), to enter the Crossover Phase 
to receive cabozantinib and undergo study assessments per Appendix B.  
o Such subjects who are ineligible or opt not to cross over to receive cabozantinib are to have study treatment discontinued and 
proceed with post-treatment assessments as described in Appendix A. 
• Unblinded subjects randomized to cabozantinib may continue on study treatment if the investigator believes the subject is still 
deriving clinical benefit. Study assessments are to continue per in Appendix A. 
After the date the entire study is unblinded, study sites will have 8 weeks to determine eligibility and begin administration of crossover 
cabozantinib treatment to eligible subjects randomized to placebo; subsequently no further crossover will be allowed. 
Once the W9D1 visit has elapsed in the Crossover Phase for the last placebo subject who crossed over to receive cabozantinib, and 
upon site notification by the Sponsor, the transition period will end and the study will enter the study Maintenance Phase. 
Subjects remaining on study treatment will continue to receive it until a criterion for protocol-defined discontinuation has been met 
(protocol Section 3.6.1). Subjects are to undergo periodic safety assessments (including local laboratory tests) and tumor assessments; 
the nature and frequency of these assessments are to be performed per standard of care. It is the Investigator’s responsibility to ensure 
that subject visits occur frequently enough and adequate assessments are performed to ensure subject safety. 

 
 
Protocol XL184-311 
Page 147 of 165 
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 Visit at the time the transition to the Maintenance Phase, will undergo the final safety 
assessment at the post-treatment follow-up visit. Upon initiation of the Maintenance Phase, no further follow-up is required for any 
subject who has completed the Post-Treatment Follow-Up Visit. 
In order to continue to collect important safety information on subjects still enrolled in the study, reporting of SAEs and other 
reportable events (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 
protocol Section 8.2 (though SAE reporting timeline requirements do not apply to non-serious events reported in these categories): 
• Adverse Events, whether serious or not, leading to study treatment discontinuation 
• Adverse Events, whether serious or not, leading to study dose modification (ie, causing study treatment to be interrupted, delayed, 
or reduced) 
Other non-serious AEs will not be collected by the Sponsor as they are unlikely to meaningfully change the safety profile established 
in earlier phases of this study. 
Study drug accountability is to continue as described in Section 6.4. 
See Maintenance Phase Schedule of Assessments (Table 20-2). 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 to ensure adherence to GCP, protocol compliance, adequate subject safety 
follow-up, study drug accountability, and reporting of SAEs and other reportable events. 

 
 
Protocol XL184-311 
Page 148 of 165 
During the Maintenance Phase no data are to be entered into CRFs; the study clinical database will be closed upon initiation of the 
Maintenance Phase. Study central laboratory samples are not to be obtained. 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 reader vendor. 
Table 20-2: Schedule of Assessments: Maintenance Phase 
 
Assessment 
Study Period / Visit 
While Subject is Receiving Study Treatment 
(Until Treatment Permanently Discontinued) 
Post-Treatment 
Follow-Up Visit 
Study treatment dispensing and drug accountability 
Every 4 weeks 
a 
Study treatment 
Daily until a criterion for discontinuation is met 
 
Safety evaluation 
Clinical exam and local laboratory assessments per SOC 
Frequency per standard of care 
a 
Reporting of SAEs and other reportable events 
(pregnancy and medication errors with sequelae)  
Submit reports to Sponsor per Section 8.2 
Reporting of adverse events, whether serious or not: 
• leading to study treatment discontinuation 
• leading to study dose modification (ie, causing study 
treatment to be interrupted, delayed, or reduced) 
Submit reports to the Sponsor per the same process as for reporting SAEs in 
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 
 
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 imaging vendor. 
a Post-treatment follow-up visit 30 days (+14 days) after the decision to discontinue study treatment. Subjects should return all unused study medication and 
should undergo a safety evaluation per standard of care and as clinically directed in the opinion of the PI. 
 

 
 
Protocol XL184-311 
Page 149 of 165 
Appendix D: Medically Accepted Methods of Contraception 
In Inclusion Criterion #12 (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 4 months after the last dose 
of study treatment. 
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 4 months after the last dose of study treatment. Local laws and 
regulations may require use of alternative and/or additional contraception methods.  
Note: Hormonal contraception, including intrauterine devices and intrauterine hormone releasing 
systems, may be susceptible to interaction with the study treatment, which may reduce the 
effectiveness of the contraceptive method. Hormonal contraception is permissible only when 
there is sufficient evidence that the study treatment and other study medications will not alter 
hormonal exposures such that contraception would be ineffective or result in increased exposures 
that could be potentially hazardous. In this case, alternative methods of contraception should be 
utilized.  
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 

 
 
Protocol XL184-311 
Page 150 of 165 
Highly effective contraceptive methods that are user independent: 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation 
• 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 treatment. 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, as specified in Section 5.7.5. Acceptable 
alternate methods of highly effective contraception must be discussed in the event 
that any of these subjects chooses to forego complete abstinence. 

 
 
Protocol XL184-311 
Page 151 of 165 
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 
 

 
 
Protocol XL184-311 
Page 152 of 165 
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 
4 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 4 months after the last dose of study treatment. 
• Female partners of males subjects in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 4 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 4 months after the last dose of study treatment. Refrain from 
donating sperm for the duration of the study treatment and until 4 months after the last dose of 
study treatment. 

 
 
Protocol XL184-311 
Page 153 of 165 
Appendix E: Potential Drug Interactions with Cabozantinib 
Strong Inhibitors of CYP3A4 
Strong Inducers of CYPA4 
Antivirals 
Boceprevir 
Cobicistat 
Conivaptan 
Danoprevir 
Dasabuvir 
Elvitegravir 
Indinavir  
Lopinavir  
Nelfinavir 
Ombitasvir  
Paritaprevir 
Ritonavir  
Saquinavir 
Telaprevir  
Tipranavir   
Anti-Fungals 
Itraconazole 
Ketoconazole 
Posaconazole 
Voriconazole 
Antibiotics 
Clarithromycin 
Telithromycin 
Troleandomycin 
Conivaptan 
Diltiazem 
Grapefruit Juice 
Idelalisib 
Nefazodone 
Carbamazepine 
Efavirenz 
Enzalutamide 
Erythromycin 
Mitotane 
Modafinil 
Nevirapine 
Oxcarbazepine 
Phenytoin 
Rifampin 
St. John’s wort 
This table is not all-inclusive. Please refer to the Flockhart drug interaction tables and FDA 
websites for the most updated lists of substrates, inducers, and inhibitors of selected CYP450 
isozyme pathways: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm.  
 
 

 
 
Protocol XL184-311 
Page 154 of 165 
Appendix F: ECOG Performance Scale  
Score 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 

 
 
Protocol XL184-311 
Page 155 of 165 
Appendix G: Guidelines for Best Supportive Care 
The following general guidelines should be utilized to provide subjects with BSC:  
Analgesia 
• Pain assessment with prescriptions for nonnarcotic or narcotic analgesics, as required, except 
that nonsteroidal anti-inflammatory agents should not be used in treatment of pain, because 
they are known to induce renal failure in patients with decompensated liver disease 
• Management of toxicities from analgesic medication including constipation, nausea or 
gastritis 
Treatment of infections 
• Antibiotics for peritonitis, pneumonia and other infections, as required 
Nutritional support 
Psychological support 
• Management of depression and anxiety by medication and/or counseling as clinically 
appropriate 
Anemia 
• Transfusions may be given to maintain hemoglobin as clinically indicated, but erythroid 
growth factors should not be used 
 

 
 
Protocol XL184-311 
Page 156 of 165 
Appendix H: Response Evaluation Criteria in Solid Tumors Version 1.1 
Adapted from Eisenhauer 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, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as nonmeasurable.  

 
 
Protocol XL184-311 
Page 157 of 165 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline. Target lesions are to be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which 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 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 < 10 mm are considered non-pathological and are not to be recorded or 
followed.  
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. 

 
 
Protocol XL184-311 
Page 158 of 165 
Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. Computed tomography or MRI must be used to corroborate findings 
by these modalities. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
Lesions with prior local treatment 
• Lesions situated in a previously irradiated area 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 

 
 
Protocol XL184-311 
Page 159 of 165 
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. 
Ultrasound: Ultrasound will not be used for response assessment in this study. 
Bone scans: 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 
PD in this study. 
Cytology, Histology: The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for response or 
SD will be considered malignant unless cytologically confirmed.  
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 given, reduced, held, or discontinued, 
including for subjects randomized to placebo who cross over to receive cabozantinib (Appendix 
B). 
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. 

 
 
Protocol XL184-311 
Page 160 of 165 
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. 
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. 
 

 
 
Protocol XL184-311 
Page 161 of 165 
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 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. 
 

 
 
Protocol XL184-311 
Page 162 of 165 
 
 
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). Confirmation of bone scan 
findings must be obtained by performing CT or MRI of the area of 
concern. Preferred method for confirmation is MRI. 
No 
• 
No new lesions present at follow-up. 
CT, computed tomography; MRI, magnetic resonance imaging. 
 
Evaluation of Overall Time Point Response (TPR) 
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 
Non-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 time point. 
* Subjects with an overall response of CR or PR must have a repeat tumor assessment performed no less 
than 4 weeks after the criteria for response are first met. However, the presence or absence of 
confirmation is not considered when assigning a time point response. 

 
 
Protocol XL184-311 
Page 163 of 165 
Confirmation 
For subjects with an overall response of PR or CR at a given time point, a repeat assessment 
should be performed no less than 4 weeks after the criteria for response are first met. However, 
the presence or absence of confirmation is not considered when assigning a time point response.  
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. 
 

 
 
Protocol XL184-311 
Page 164 of 165 
Appendix I: EuroQol questionnaire EQ-5D-5L, USA (English) Sample Version 
Under each heading, please check 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  
 
 
 
 

 
 
Protocol XL184-311 
Page 165 of 165 
• We would like to know how good or bad your health is  
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 
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 
This document (and all copies thereof) is the property of Exelixis, Inc. and contains valuable trade secrets 
and confidential information, including proprietary technical and business information (hereinafter 
"Confidential Information"). By accepting this document, you agree that the Confidential Information 
contained herein will not be disclosed to others without prior written authorization from Exelixis, Inc. and 
shall only be used for the purposes intended by the document. 
 
 
X184-311: Statistical Analysis Plan 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Cabozantinib 
(XL184) in Subjects with Radioiodine-Refractory Differentiated Thyroid Cancer Who 
Have Progressed after Prior VEGFR-Targeted Therapy 
 
Version 1.0 Final 
Date: 09 September 2020 
 
 
 
Prepared by:  
 
______________________________ 
______________ 
 
 
 
Kamalika Banerjee 
 
 
                  Date 
 
 
 
Director, Biostatistics, Exelixis 
 
 
 
 
 
 
Approved by: 
 
______________________________ 
______________ 
Colin Hessel 
 
 
 
Date 
 
 
 
Sr. Vice President, Development Operations,  
 
 
 
Exelixis 
 
 
Approved by: 
 
______________________________ 
______________ 
Leo Faoro, MD, MBA 
 
 
Date 
 
 
 
Vice President, Clinical Development,  
                                                      Exelixis 
 
 
 
Approved by: 
 
______________________________ 
______________ 
Gisela Schwab, MD  
 
 
Date 
President, Product Dev and Medical Affairs 
& CMO, Exelixis 
 
 
 
Approved by: 
 
______________________________ 
______________ 
Lisa Sauer  
 
 
                   Date 
Sr. Vice President, Regulatory Affairs &  
Quality Assurance, Exelixis 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
Page 2 of 72 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .....................................................................................................2 
LIST OF TABLES ...............................................................................................................4 
LIST OF APPENDICES ......................................................................................................4 
LIST OF ABBREVIATIONS ..............................................................................................6 
1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY ............................9 
2 
STUDY DESCRIPTION ............................................................................................9 
2.1 
Study Design ......................................................................................................9 
2.2 
Study Treatment ...............................................................................................11 
2.3 
Study Objectives and Endpoints ......................................................................12 
2.3.1 
Primary Efficacy Endpoints .................................................................12 
2.3.2 
Additional Endpoints ...........................................................................12 
2.4 
Power and Sample Size Justification ...............................................................13 
2.5 
Randomization and Blinding ...........................................................................14 
3 
ANALYSIS POPULATIONS ..................................................................................15 
3.1 
Intent to Treat Population ................................................................................15 
3.2 
Overall Response Rate Intent to Treat Population ...........................................15 
3.3 
Safety Population .............................................................................................15 
3.4 
Overall Response Rate Safety Population .......................................................15 
3.5 
Per Protocol Population ...................................................................................16 
4 
GENERAL CONVENTIONS ..................................................................................16 
4.1 
Analyses, Reports, Treatment Periods and Summary Groups .........................16 
4.2 
Definition of Baseline ......................................................................................18 
4.3 
Definition of Study Day ...................................................................................19 
4.4 
Visit Window Calculation................................................................................20 
4.5 
Missing and Partial Data ..................................................................................20 
4.6 
Safety Observation Period ...............................................................................20 
4.7 
Definition of Prior, Concomitant, and Subsequent Therapy ............................21 
4.8 
Software ...........................................................................................................21 
4.9 
Changes to Planned Analyses ..........................................................................21 
5 
STUDY POPULATION SUMMARIES ..................................................................22 
5.1 
Enrollment........................................................................................................22 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
Page 3 of 72 
 
5.2 
Disposition .......................................................................................................22 
5.3 
Demographic and Baseline Characteristics .....................................................22 
5.4 
Medical History ...............................................................................................24 
5.5 
Cancer History and Current Disease Status .....................................................24 
5.6 
Baseline Laboratory Values .............................................................................25 
6 
TREATMENTS AND MEDICATIONS ..................................................................25 
6.1 
Prior Non-Radiation Anticancer Therapy ........................................................25 
6.2 
Prior Radiation Therapy ...................................................................................27 
6.3 
Prior Radioactive-Iodine Therapy ....................................................................28 
6.4 
Prior and Concomitant Medications (Excluding Anticancer Therapy) ...........28 
6.5 
Study Treatment Exposure ...............................................................................28 
6.6 
Study Treatment Modifications .......................................................................29 
6.7 
Study Treatment Non-Compliance and Dosing Errors ....................................31 
6.8 
Non-Protocol Anticancer Therapy ...................................................................31 
6.9 
Post-randomization Radiotherapy, Surgery/Procedure ....................................32 
6.10 
Concomitant Transfusions ...............................................................................32 
7 
CROSSOVER BASELINE CHARACTERISTICS .................................................32 
8 
EFFICACY ANALYSES .........................................................................................32 
8.1 
Primary Efficacy Endpoints .............................................................................32 
8.1.1 
Objective Response Rate (ORR) .........................................................33 
8.1.2 
Progression-Free Survival (PFS) .........................................................36 
8.2 
Control of Type I Error ....................................................................................44 
8.3 
Interim Analyses ..............................................................................................45 
8.4 
Additional Endpoints .......................................................................................45 
8.4.1 
Overall Survival ...................................................................................45 
8.4.2 
Duration of Objective Response ..........................................................46 
8.4.3 
Time to Objective Response ................................................................46 
8.4.4 
Time to Second Disease Progression or Death (PFS2) ........................47 
8.4.5 
Biomarkers ...........................................................................................48 
8.4.6 
Health-Related Quality of Life (HRQOL) ...........................................48 
8.4.7 
Health Care Resource Utilization ........................................................50 
8.4.8 
Pharmacokinetics (PK) ........................................................................50 
8.5 
Subgroups ........................................................................................................51 
9 
SAFETY SUMMARIES ...........................................................................................52 
9.1 
Adverse Events ................................................................................................53 
9.2 
Events to Monitor ............................................................................................57 
9.3 
Treatment-emergent Adverse Events Adjusted by Treatment Duration ..........57 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
Page 4 of 72 
 
9.4 
Deaths ..............................................................................................................58 
9.5 
Laboratory Assessments ..................................................................................58 
9.5.1 
Variables ..............................................................................................58 
9.5.2 
Analysis................................................................................................59 
9.6 
Vital Signs ........................................................................................................61 
9.6.1 
Variables ..............................................................................................61 
9.6.2 
Analysis................................................................................................61 
9.7 
ECOG Performance Status ..............................................................................62 
9.8 
Electrocardiogram (ECG) ................................................................................62 
9.9 
IMPACT OF COVID-19 PANDEMIC ...........................................................62 
10 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ..............62 
11 
DATA QUALITY ASSURANCE ............................................................................63 
12 
REFERENCES .........................................................................................................64 
 
LIST OF TABLES 
Table 1:  Protocol Version History ..................................................................................... 9 
Table 2:  SAP Version History ........................................................................................... 9 
Table 3: Schema for Efficacy Summaries ........................................................................ 17 
Table 4:   Schema for Safety Summaries .......................................................................... 18 
Table 5: Primary Estimand Attribute for ORR ................................................................. 34 
Table 6: Primary Estimand Attribute for PFS................................................................... 37 
Table 7: Alternative Estimand Attribute for PFS ............................................................. 38 
Table 8:   Event and Censoring Rules for Primary and Sensitivity Analyses of 
Primary PFS Estimand .............................................................................. 42 
Table 9:   Event and Censoring Rules for Supplementary Analyses of Alternative 
PFS Estimands .......................................................................................... 43 
Table 10:    Definitions for Differential Sensitivity Analyses of PFS to Further 
Evaluate Potentially Informative Censoring (based on PFS-EP-1) .......... 44 
Table 11: PFS2 Event Dates ............................................................................................. 47 
Table 12: Summaries for ETM ......................................................................................... 57 
 
LIST OF APPENDICES 
Appendix A: Date Imputation Rules................................................................................. 65 
Appendix B: Rounding Rules for Reported Percentages .................................................. 68 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
Page 5 of 72 
 
Appendix C: Imputation Rules for Laboratory Values Outside of Quantification 
Range ........................................................................................................ 69 
Appendix D: EQ-5D-5L Index Value Conversion Guidelines ......................................... 70 
Appendix E: Estimands Terminology ............................................................................ 71 
Appendix F: List of Events to Monitor to Summarize ..................................................... 72 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 6 of 72 
 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
ATA 
Adequate tumor assessment 
ATC 
Anatomical Therapeutic Chemical 
BIRC 
Blinded independent radiology committee 
BMI 
Body mass index 
BOR 
Best overall response 
BSC 
Best supportive care 
CAPN 
Chest abdomen pelvis neck 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
CT 
Computerized tomography 
ctDNA 
Circulating DNA 
CTC 
Circulating tumor cell 
CTCAE 
Common terminology criteria for adverse events 
CTMS 
Clinical trial management system 
DBP 
Diastolic blood pressure 
DSR 
Disease stabilization rate 
DTC 
Differentiated Thyroid Cancer 
EBRT 
External beam radiation therapy 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ECG 
Electrocardiogram 
ER 
Emergency room visit 
ETM 
Events to monitor 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 7 of 72 
 
FDA 
Food and Drug Administration 
FTC 
Follicular thyroid carcinoma 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltransferase 
HCRU 
Health care resource utilization 
HGB 
Hemoglobin 
HR 
Hazard ratio 
HRQOL 
Health Related Quality of Life 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-To-Treat 
IRT 
Interactive Response Technology 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LLQ 
Lower limit of quantitation 
MRI 
Magnetic resonance imaging 
MedDRA 
Medical Dictionary for Regulatory Activities 
NE 
Not evaluable 
NPACT 
Non-protocol anticancer therapy 
OITT 
Objective response rate intent-to-treat 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive Disease 
PFS 
Progression-free survival 
PFS2 
Time to second disease progression or death 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death-ligand 1 
PK 
Pharmacokinetic 
PR 
Partial response 
PTC 
Papillary thyroid carcinoma 
qd 
Once daily 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 8 of 72 
 
QOL 
Quality of Life 
RAI 
Radioactive Iodine 
RECIST 
Response evaluation criteria in solid tumors 
RMP 
Risk management plan 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
SmPC 
Summary of product characteristics 
TEAE 
Treatment emergent-adverse event 
TKI 
Tyrosine kinase inhibitor 
TNM 
Tumor node metastasis 
TSH 
Thyroid-stimulating hormone 
UE 
Unable to evaluate 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UPCR 
Urine protein/creatinine ratio 
VAS 
Visual analogue scale 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
WHO-DD 
World Health Organization drug dictionary 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 9 of 72 
 
1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY 
This study is being conducted under the sponsorship of Exelixis, Inc. Exelixis is responsible 
for statistical design and planning. Statistical programming and analyses are being 
conducted under contract by Array Inc. in conjunction with Exelixis, Inc.  
This version of the Statistical Analysis Plan (SAP) is based on the original protocol dated 
April 30, 2018. 
Table 1:  Protocol Version History 
Date 
Version 
Primary Reason(s) for Amendment 
30 April 2018 
Original Protocol  Not Applicable 
 
Table 2:  SAP Version History 
Date 
Version 
Primary Reason(s) for Amendment 
09 September  2020 Original 
Not Applicable 
 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is a Phase 3 multicenter, randomized, double-blinded, placebo-controlled trial of 
cabozantinib in subjects with radioiodine (RAI) refractory differentiated thyroid cancer 
(DTC). Best supportive care (BSC) will be provided for subjects on both treatment arms. 
The multiple primary efficacy endpoints for the study are progression-free survival (PFS) 
and objective response rate (ORR) assessed per blinded independent radiology committee 
(BIRC). Approximately 300 subjects will be randomized in a 2:1 ratio to receive either 
cabozantinib or placebo.  
Each subject’s course of treatment will consist of the following periods: 
Pre-treatment Period: Potential subjects will be screened to determine if they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 28 
days before randomization unless otherwise specified. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 10 of 72 
 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly 
assigned in a 2:1 ratio to receive blinded study treatment cabozantinib or placebo. Subjects 
on both treatment arms will be treated with BSC. This excludes non-protocol anticancer 
therapy (NPACT). 
Crossover Phase: As subjects in the study population have limited treatment options, and to 
minimize the potential for differential dropout among subjects randomized to placebo with 
respect to the PFS endpoint as assessed by BIRC, the study will allow eligible subjects 
randomized to placebo to crossover to receive cabozantinib upon experiencing radiographic 
disease progression (PD) per RECIST 1.1 that is confirmed by the BIRC. To facilitate this: 
 A real-time dual-reader adjudicated BIRC review of radiographic images per RECIST 
1.1 will be employed to document objective radiographic progression 
contemporaneously with subject study participation. 
 At the time of investigator-determined radiographic progression per RECIST 1.1, 
investigators may request from the Sponsor’s medical monitor (or designee) 
confirmation of BIRC-determined radiographic PD. 
 For subjects with BIRC-confirmed radiographic progression: 
 Upon authorization from Sponsor’s medical monitor (or designee), investigators may 
unblind individual subjects via the Interactive Response Technology (IRT) system. 
 Unblinded subjects randomized to placebo have the following options: 
 Such subjects may be provided by the Investigator the opportunity, if eligible 
(see Protocol Appendix B), to enter the Crossover Phase to receive cabozantinib 
and undergo study assessments per Protocol Appendix B. 
 Such subjects who are ineligible or opt not to crossover to receive cabozantinib 
are to have study treatment discontinued and proceed with post-treatment 
assessments as described in Protocol Appendix A. 
 Unblinded subjects randomized to cabozantinib may continue on study treatment if 
the investigator believes the subject is still deriving clinical benefit. Study 
assessments are to continue per Protocol Appendix A. 
 Subjects without radiographic progression per BIRC will not be unblinded and are to 
continue to receive blinded study treatment and undergo study assessments according to 
the schedule in Protocol Appendix A. Safety assessments will continue, efficacy 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 11 of 72 
 
assessments will be per standard of care if allowed per local regulation; PK, biomarker, 
and health-related quality of life (HRQOL) will be discontinued. 
Further, the entire study may be unblinded if the PFS endpoint results are sufficiently 
compelling, with similar options for subjects to cross-over (or continue) to receive 
cabozantinib after unblinding. 
End of Study Treatment: Subjects will receive blinded study treatment or unblinded 
treatment with cabozantinib as long as they continue to experience clinical benefit in the 
opinion of the investigator or until there is unacceptable toxicity or the need for non-
protocol systemic anticancer treatment. Treatment may continue after radiographic PD per 
RECIST 1.1 as determined by the investigator in the absence of non-protocol systemic 
anticancer treatment 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 risk. 
Post-Treatment Period: A post-treatment follow-up visit will occur 30 (+14) days after the 
date of the decision to discontinue study treatment. See protocol ‘Study Design’ Section 3 
for details. 
Maintenance Phase: After the primary efficacy endpoints of ORR and PFS have been 
analyzed and declared to be successful and upon determination by the Sponsor that 
sufficient data have been collected to adequately evaluate all study endpoints to establish, 
for regulatory purposes, the safety and efficacy profile of the experimental drug within this 
study, the study will begin to transition to the Maintenance Phase. 
As a transitional step prior to initiation of the Maintenance Phase, all blinded study subjects 
will be unblinded and study sites will be notified of their randomized treatment assignments. 
Subjects on the placebo arm, if eligible will have the opportunity to cross over to receive 
cabozantinib treatment.   See protocol ‘Study Design’ Section 3 for details. 
2.2 
Study Treatment 
Eligible subjects will be randomized in a 2:1 ratio to the following treatment arms: 
 Cabozantinib arm: Oral cabozantinib (60 mg) daily (qd)  
 Placebo arm: Oral cabozantinib-matched placebo qd  

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 12 of 72 
 
In addition, all subjects will also receive BSC. 
2.3 
Study Objectives and Endpoints 
The primary objective of this study is to evaluate the effect of cabozantinib compared with 
placebo on PFS and ORR in subjects with RAI-refractory DTC who have progressed after 
prior VEGFR-targeted therapy. 
This study has two primary efficacy endpoints. The trial will be declared a success if the null 
hypothesis is rejected for either of these endpoints; rejection of the null hypotheses for both 
endpoints is not required. The protocol refers to these as “co-primary” endpoints, but per 
recent conventions these are “multiple primary” endpoints (FDA Guidance for Industry: 
Multiple Endpoints in Clinical Trials [draft, January 2017]). This plan employs this FDA 
convention. 
2.3.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are: 
 
Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) by BIRC (see Section8.1.2.4) 
  Objective response rate (ORR) per RECIST 1.1 by BIRC (see Section 8.1.1.1) 
2.3.2 
Additional Endpoints 
 Overall survival (OS) 
 Duration of objective tumor response 
 Safety and tolerability (see Section 9) 
 Pharmacokinetics (PK) (see Section 8.4.8) 
 Relationship of baseline and post-baseline changes in serum thyroglobulin (Tg), will  
be performed (see Section 8.4.5) 
 Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, 
and global health as assessed by the EuroQol Health questionnaire instrument (EQ-
5D-5L) (see Section 8.4.6) 
 Health care resource utilization (see Section 8.4.7) 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 13 of 72 
 
2.4 
Power and Sample Size Justification 
The study is designed to provide adequate power for both co-primary endpoints of ORR and 
PFS. It is estimated that 100 subjects would be adequate to evaluate the co-primary endpoint 
of ORR alone, and 300 subjects will be needed to evaluate the co-primary endpoint of PFS. 
Thus, to allow an earlier evaluation of ORR, this study employs a “trial within a trial 
design” (Hessel et al 2016). The primary analysis of ORR will be limited to the first 100 
subjects randomized to the study and defined as the OITT population. Analysis of ORR is 
expected to occur 6 months after the last subject is enrolled in this population.  
For ORR, 100 subjects provide a 2-sided 0.01 test of difference in proportions with > 90% 
power to reject the null hypothesis of no difference in ORR, assuming a true ORR of 2% in 
the placebo arm and 35% in the cabozantinib arm (a 33 percentage point difference), a 
pooled variance estimate, and a 2:1 allocation ratio.  
For the primary endpoint of PFS, assuming exponential distribution, proportional hazards, 
and a 2:1 treatment allocation ratio (cabozantinib:placebo), 193 events are required to 
provide 90% power to detect an HR of 0.61 using the log-rank test and a 2-sided 
significance level of 0.04. This corresponds to a 36% reduction in the risk of progression or 
death, or a 64% improvement in median PFS from 5.5 months to 9.0 months. Under this 
design and with the application of the fallback method (see Section 8.2) the minimum 
observed effects that would result in statistical significance for PFS are: 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 14 of 72 
 
 If Ho is rejected for ORR and PFS is tested at the 5% level under the fallback method, 
the minimum observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information 
Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0013 
0.474 
5.5 
11.6 
Final 
100% 
0.0496 
0.742 
5.5 
7.4 
 If Ho is not rejected for ORR and PFS is tested at the original 4% allocation, the 
minimum observed effect that would result in statistical significance for PFS is: 
 
 
 
 
Median PFS (months) 
Analysis 
Information 
Fraction 
p-value 
HR 
Placebo 
Cabozantinib 
Interim 
43% 
0.0008 
0.469 
5.5 
11.7 
Final 
100% 
0.0397 
0.738 
5.5 
7.5 
With a constant accrual rate of 20 subjects per month and using a 2:1 treatment allocation 
ratio, a total of 300 subjects (200 in the cabozantinib arm, 100 in the placebo arm) are 
required to observe the required number of PFS events within the planned study duration (15 
months accrual; approximately 20 months to observe the required events). 
Power and sample size estimates were calculated using EAST v5 by Cytel Software. 
2.5 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study of cabozantinib in subjects 
with RAI-refractory DTC after prior VEGFR-TKI therapy. Cabozantinib-matched placebo 
will be given in the placebo arm to blind (mask) study treatment. 
Until individual subjects or the study has been unblinded (see Section 2.1), 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 
Protocol Section 8.2.2), IRT system administration, and drug supply management. 
Sponsor personnel will remain blinded until the earlier of successful rejection of the null 
hypothesis for the ORR or the time of primary PFS analysis.    Should the analysis of ORR 
reject the null hypothesis, limited sponsor personnel will be unblinded for the purposes of 
data analysis and submission to Regulatory agencies.  Unblinded full-study data will not be 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 15 of 72 
 
released to or shared with the operational study teams at Exelixis, the CRO, investigators, or 
study subjects until after the analysis of the PFS endpoint. 
When an individual subject has been deemed eligible at the study site, the site representative 
will use the designated interactive response technology (IRT) to enroll the subject into the 
study. Eligible subjects will be randomly assigned in a 2:1 ratio to receive either 
cabozantinib or placebo.  
Randomization will be by permuted blocks stratified by the following factors: 
 
Receipt of prior Lenvatinib (yes or no)  
 
Age at informed consent (≤ 65 years vs. > 65 years)  
 
3 
ANALYSIS POPULATIONS 
3.1 
Intent to Treat Population 
The Intent-To-Treat (ITT) population is defined as all randomized subjects regardless of 
whether any study treatment or the correct study treatment was received.  
3.2 
Overall Response Rate Intent to Treat Population 
The Overall response rate Intent-To-Treat (OITT) population is defined as the first 100 
randomized subjects regardless of whether any study treatment or the correct study 
treatment was received.  
3.3 
Safety Population 
The Safety population will include all randomized subjects who receive any amount of study 
treatment (either cabozantinib or cabozantinib-matched placebo). Analyses based on the 
Safety population will be performed according to the actual treatment received. Subjects 
who receive both treatments in error will be summarized in the cabozantinib group.  
3.4 
Overall Response Rate Safety Population 
The Overall response rate Safety (O-Safety) population will include the subjects included in 
the OITT population receiving any amount of study treatment (either cabozantinib or 
cabozantinib-matched placebo). 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 16 of 72 
 
3.5 
Per Protocol Population 
A Per Protocol population is not defined or planned for the study. 
 
4 
GENERAL CONVENTIONS 
The statistical principles applied in the design and planned analyses of this study are 
consistent with International Conference on Harmonization (ICH) E9 guidelines (ICH 
1998). 
Continuous data will be summarized using descriptive statistics (number of observations, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum). 
Frequencies and percentages will be used for summarizing categorical (discrete) data.  
Confidence intervals, when presented, will generally be constructed at the 95% level. For 
binomial variables, the Clopper-Pearson’s method will be employed unless otherwise 
specified.  
A month is operationally defined to be 30.4375 days. Six months is operationally defined to 
be 183 days. 
All summaries will be presented by treatment arm unless otherwise specified. 
4.1 
Analyses, Reports, Treatment Periods and Summary Groups 
Up to four analyses milestones are planned over the course of the study, with treatment 
periods shown below: 
1. Primary ORR + interim PFS  [Blinded treatment period] 
2. Final PFS [Blinded treatment period except for subjects who were individually 
unblinded for potential crossover] 
3. Safety update for 120-day report [Blinded treatment period] 
4. Final safety update, upon  initiation of the Maintenance Phase [Blinded and Open-
label treatment periods] 
 
Up to four study reports are planned: 
1. Primary clinical study report (CSR), written the first time the null is rejected for 
either of the primary efficacy endpoints, or if all primary testing is completed 
without rejection of either null. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 17 of 72 
 
2. CSR efficacy addendum, written if analyses #2 is successful subsequent to success of 
ORR in analysis #1 
3. 120-Day safety update written to include results from analysis #3 
4. Final CSR safety addendum, written to include analysis #4  
Details on the interim analysis of PFS and the control of type 1 error are provided in 
Sections 8.3 and 8.2. 
Data collected for this study can be grouped by the following two treatment periods in which 
it was obtained: 
Blinded Period: In this phase of the study subjects receive either cabozantinib or placebo 
and the treatment identity is unknown to them. 
Open-label Period: At the time of investigator-determined radiographic progression per 
RECIST 1.1 that is confirmed by BIRC subjects may be individually unblinded. Further, the 
entire study may be unblinded if the PFS endpoint results are sufficiently compelling. At 
such time, subjects will have the following options: 
 Subjects randomized to the placebo arm may discontinue study treatment (if still on 
treatment) or, if eligible, cross over to receive cabozantinib after unblinding 
 Subjects randomized to the cabozantinib arm still receiving study treatment may 
discontinue study treatment or continue to receive cabozantinib  
For both treatment arms the date of registration for treatment with unblinded cabozantinib 
recorded in the IRT will define the start of the Open-Label Period.  
Efficacy summaries (other than OS) will be based on data obtained in the Blinded Period for 
the two treatment arms – cabozantinib and placebo. 
Table 3: Schema for Efficacy Summaries 
 
Treatment Period: 
Blinded Period 
 
Group: 
Subjects randomized to 
cabozantinib 
(Cabozantinib arm) 
Subjects randomized to placebo 
(Placebo arm) 
Start Date of Period 
Randomization Date 
 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 18 of 72 
 
Safety summaries (adverse events, exposure, etc.) will be categorized in the following 
groups: 
(a) Subjects randomized to and treated with cabozantinib (Cabozantinib arm),  
(b) Subjects randomized to placebo but receiving cabozantinib after crossover (Placebo 
crossover arm),  
(c)  Subjects who received cabozantinib at any time, i.e., subjects randomized to and 
receiving cabozantinib, and the subjects randomized to placebo and receiving cabozantinib 
after crossover, and 
 (d) Subjects randomized to and receiving placebo until crossover or end of treatment  
 
Table 4:   Schema for Safety Summaries 
 
Treatment:  
Cabozantinib 
Placebo 
 
Group: 
Subjects 
randomized to 
and receiving 
cabozantinib 
(Cabozantinib 
arm) 
Subjects 
randomized to 
placebo but 
receiving 
cabozantinib after 
crossover (Placebo 
crossover arm) 
All subjects 
receiving 
cabozantinib 
including 
crossover 
subjects (All 
Cabozantinib 
arm) 
Subjects 
randomized to 
and receiving 
placebo 
(Placebo arm) 
Start Date of 
Period: 
Date of 1st dose 
of cabozantinib 
Date of 1st dose of 
cabozantinib after 
crossover 
Date of 1st dose 
of cabozantinib 
Date of 1st dose 
of placebo 
End Date Of 
Period: 
Earlier of the date 
of last date of 
exposure to 
cabozantinib+30 
days, or date of 
withdrawal of 
consent by 
subject, or date of 
death, or date of 
data cut-off 
Earlier of the last 
date of exposure to 
open-label 
cabozantinib +30 
days,  or date of 
withdrawal of 
consent by subject, 
or date of death, or 
date of data cut-off 
Earlier of the last 
date of exposure 
to cabozantinib 
+30 days, or date 
of withdrawal of 
consent by 
subject, or date of 
death, or date of 
data cut-off 
Earlier of the 
last date of 
exposure to 
placebo, or date 
of withdrawal of 
consent by 
subject, date of 
death,  or date of 
receipt of open-
label 
cabozantinib -1, 
or date of data 
cut-off.    
4.2 
Definition of Baseline 
In general, for efficacy endpoints the last observed measurement prior to randomization will 
be considered the baseline measurement. Exception to this rule are efficacy biomarkers such 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 19 of 72 
 
as pharmacogenetics blood samples, biomarker samples, bone marker samples and blood 
samples for potential circulating tumor cell (CTC) analyses. These samples per schedule of 
assessment were collected after randomization but prior to the Dose Day 1 (see definition 
Table 4 above), hence the baseline measurements will be with respect to this date. For 
subjects who did not take any study treatment, any biomarker sample available prior to 
randomization will be considered as baseline observation. 
For safety endpoints the last observation before Dose Day 1 will be considered the baseline 
measurement unless otherwise specified. For assessments on Dose Day 1 where time is not 
captured, a nominal pre-dose indicator, if available, will serve as sufficient evidence that the 
assessment occurred prior to Dose Day 1. 
Assessments on Dose Day 1 where neither time nor a nominal pre-dose indicator are 
captured will be considered prior to Dose Day 1 if such procedures are required by the 
protocol to be conducted before first dose. 
For placebo subjects who crossover to receive cabozantinib, the second baseline will be 
defined as the last date of observation prior to the first date of open-label cabozantinib. 
4.3 
Definition of Study Day 
For efficacy data summaries for: (a) ORR/PFS in the blinded phase and (b) OS, Study Day 
is defined with respect to the randomization date. For visits (or events) that occur on or after 
randomization, study day is defined as (date of visit [event] – date of randomization + 1). 
For visits (or events) that occur prior to randomization, study day is defined as (date of visit 
[event] – date of randomization). There is no Study Day 0. To explore efficacy endpoints 
such as ORR or PFS for placebo subjects who cross over to receive cabozantinib in the 
open-label phase Study Day will be calculated with respect to date of registration for cross 
over in the IRT. 
For the various safety data summaries, Dose Day 1 is defined in Table 4 of Section Error! 
Reference source not found. above. Dose day for visits (or events) that occur on or after 
Dose Day 1, is defined as (date of visit [event] – Dose Day 1 + 1).  Dose day for visits (or 
events) that occur prior to Dose Day 1, is defined as (date of visit [event] – Dose Day 1). 
There is no Dose Day 0.  
For listings (such as for adverse events [AEs]) that include the derivation of “days since last 
dose,” this is defined as (event date – date of last dose). Events that occur on the same day as 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 20 of 72 
 
the last dose of study drug will therefore be described as occurring zero days from the last 
dose of study drug. 
4.4 
Visit Window Calculation 
Analyses will be according to actual visit dates and times. The planned analyses do not 
require the calculation of visit windows. However, for analyses that require a particular visit 
as planned, measurements included in that visit must have occurred during the acceptable 
window defined for the visit in the protocol, unless otherwise specified in this plan. 
4.5 
Missing and Partial Data 
In general, other than for partial dates, missing data will not be imputed and will be treated 
as missing. The algorithms for imputation of partial dates vary depending upon the 
parameter. These are presented in Appendix A.  
4.6 
Safety Observation Period 
The safety observation period is defined as follows for the summaries described above in 
Section 4.1: 
The safety observation period for subjects randomized to and receiving any cabozantinib  is 
defined as the time between the date of first dose of cabozantinib to the earlier of the date of  
last dose of cabozantinib +30 days, or date of withdrawal of consent by subject, or date of 
death, or date of data cut-off. 
The safety observation period for all subjects receiving placebo only during the blinded 
treatment period is defined as the time between the date of first dose of placebo to the earlier 
of the date of  last dose of placebo, or date of withdrawal of consent by subject, date of 
death, or date of receipt of open-label cabozantinib -1, or date of data cut-off. 
Subjects crossing over from placebo to cabozantinib will have data from the crossover 
period summarized independently. The post-crossover safety observation period of all 
subjects receiving cabozantinib after crossing over from placebo is defined as the time 
between the date of first dose of open-label cabozantinib to the earlier of the date of last 
dose of open-label study treatment +30 days, or date of withdrawal of consent by subject, or 
date of death, or date of data cut-off. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 21 of 72 
 
Generally only the safety data (including adverse events, laboratory results, vital signs, 
ECG, ECOG PS, concomitant medications and etc.) reported during the safety observation 
period will be analyzed and summarized, unless otherwise specified in this plan.   
4.7 
Definition of Prior, Concomitant, and Subsequent Therapy 
For the purpose of inclusion in summary tables, incomplete medication or radiation start and 
stop dates will be imputed as detailed in Error! Reference source not found.. Based on 
imputed start and stop dates: 
 Prior medications/radiation therapies are defined as medications with a stop date 
occurring before the date of first dose of blinded study treatment. 
 Concomitant medications/radiation therapies are defined as medications that stop or 
continue on or after date of first dose day through the end of safety observation 
period.  
 Concomitant and Subsequent non-radiation anticancer therapies/radiation therapies 
are defined as those that stop or continue on or after the date of randomization. 
Medications/radiation therapies may be summarized as prior, concomitant and/or 
subsequent.  
4.8 
Software 
All analyses will be conducted using SAS Version 9.3 or higher. 
4.9 
Changes to Planned Analyses 
Substantive changes to the analyses described in the protocol or in approved versions of this 
plan will be fully documented in a revised version of the plan approved by the Sponsor prior 
conducting unblinded analyses. 
Clarifications, minor corrections, and operational considerations necessary to accurately 
conduct the analyses that do not materially change the nature of the analysis will be 
documented in an addendum to this plan that will also be approved by the Sponsor prior to 
unblinding the study to conduct the analyses. Any analyses not documented in the SAP or 
the addendum will be considered exploratory. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 22 of 72 
 
Since Overall Survival (OS) is not a primary endpoint in this study, an exploratory analysis 
for Time to Second Disease Progression or Death (PFS2) has been incorporated upon 
recommendation of EU Regulatory agencies as an intermediate clinical endpoint.  
5 
STUDY POPULATION SUMMARIES 
5.1 
Enrollment 
Subjects are defined to be enrolled at randomization. Enrollment will be summarized by 
country, site, and protocol version for the OITT and ITT populations. 
5.2 
Disposition 
Subject disposition will be summarized categorically and will include the number and 
percentage of subjects in the OITT, ITT and O-Safety and Safety populations.  
The reasons for blinded study treatment discontinuation, open-label treatment 
discontinuation, discontinuation of radiographic follow-up and survival follow-up 
discontinuation will also be summarized categorically. 
All screen failure subjects will be summarized with the reason for screen failure. 
5.3 
Demographic and Baseline Characteristics 
Summaries of demographics, stratification factors and baseline characteristics will be 
presented for subjects in the OITT, ITT and O-Safety and Safety populations.  
[A] The demographic characteristics include: 
o Age (continuous) 
o Age category 1 
 16 - < 18 years 
 ≥ 18 years 
o Age category 2 
 < 45 years 
 ≥ 45 years 
o Age category 3 
 < 75 years 
 ≥ 75 years 
o Age category 4 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 23 of 72 
 
 
< 65 years 
 
≥ 65 years 
o 65 to <75 years 
o 75 to <85 years 
o ≥85 years 
o Sex 
 Male 
 Female 
 Not reported 
o Ethnicity 
 
Hispanic or Latino 
 
Not Hispanic or Latino 
 
Not Reported 
o Race 
 
American Indian or Alaska Native 
 
Asian 
 
Black or African American 
 
Native Hawaiian or Other Pacific Islander 
 
White 
 
Not Reported 
 
Other 
o Geographic Region 
 Asia  
 North America (USA/Canada) 
 Europe  
 Rest of the world 
 
Note for this study birth date is not collected but age in years is collected at informed 
consent. 
[B] Categorical summaries of the following stratification factors will be presented as 
recorded (a) in the IRT during randomization (b) on the CRF (c) cross tabulation of the 
2  stratification factors per IRT (d) cross tabulation of the 2 stratification factors per 
CRF:  
o Receipt of prior Lenvatinib (Yes, No) 
o Age at informed consent (≤ 65 years, > 65 years) 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 24 of 72 
 
[C] Baseline characteristics include: 
o Height in centimeters (cm) – descriptive statistics 
o Weight in kg – descriptive statistics 
o Body mass index (BMI) in kg/meter2, calculated as (weight in kg*1000)/(Height in 
cm)2 –descriptive summary: 
o ECOG PS: 0, 1, Missing 
o Smoking history - Categorical summary for subjects classified as Current, Former or 
Never will be presented 
o Alcohol use – Categorical summary for subjects classified as Current, Former or 
Never will be presented 
5.4 
Medical History 
General medical history data will be coded per MedDRA and a subject data listing will be 
provided. 
5.5 
Cancer History and Current Disease Status 
Cancer history and current disease characteristics data collected on the cancer history CRF 
will be summarized categorically or with descriptive statistics as appropriate. The following 
summaries are planned for the OITT, ITT and O-Safety and Safety populations:  
 Diagnosis of DTC by histology or cytology (Yes, No) 
 Diagnosis of DTC subtypes (Papillary thyroid carcinoma [PTC], Follicular thyroid 
carcinoma [FTC]) 
 Variants of PTC by histology (follicular variant, tall cell, columnar cell, cribriform-
morular, solid, oxyphil, Warthin-like, trabecular, tumor with nodular fasciitis-like 
stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated) 
 Variants of FTC by histology (Hürthle cell, clear cell, insular, and poorly 
differentiated) 
 Time in years to randomization since initial diagnosis of DTC as identified by 
histology or cytology (Note: Incomplete diagnosis dates will be imputed as detailed 
in Error! Reference source not found.) 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 25 of 72 
 
 Time in months to randomization since last recurrence of DTC as identified by 
histology or cytology 
 TNM staging at initial diagnosis, last recurrence and current evaluation of DTC 
 Summaries for tumor assessment at screening per Investigator and BIRC are: 
o Extent of disease per target/non-target lesions  
 Bone 
 Important visceral sites   
 Lungs 
 Liver 
 All other sites 
 Incidence of all other sites will be individually reported 
o Number of target lesions (1, 2, ≥ 3) 
o Number of non-target anatomic sites (1, 2, ≥ 3) 
o Has measurable disease  (Yes, No) 
5.6 
Baseline Laboratory Values 
Descriptive statistics will be provided for baseline laboratory values for TSH and 
thyroglobulin for the OITT and ITT populations. In addition, TSH baseline values (mUI/L) 
will also be summarized by frequencies and percentages of subjects in the following 
categories for the same populations. 
 ≤0.1 mUI/L 
  0.1 - <0.5 mUI/L 
 ≥0.5 mUI/L 
6 
TREATMENTS AND MEDICATIONS 
6.1 
Prior Non-Radiation Anticancer Therapy 
Prior non-radiation anticancer therapies will be coded per World Health Organization drug 
dictionary (WHO-DD).   
The following will be summarized categorically or with descriptive statistics as appropriate 
for all subjects in the OITT, ITT, O-Safety and Safety population: 
 Indication (disease under study, other) 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 26 of 72 
 
 Therapy type (systemic, local, unknown, other) 
 Context of therapy (neoadjuvant, adjuvant, locally advanced or metastatic setting) 
 Number of prior systemic non-radiation anticancer regimens for DTC per subject (0, 
1, ≥2) and descriptive statistics 
 Number of prior VEGFR-TKI agents for DTC per subject (0,1,  ≥2) and descriptive 
statistics 
 Number of prior PD-1/PD-L1 agents (0,1, ≥2) and descriptive statistics 
 Received either sorafenib or lenvatinib for prior treatment of DTC (Yes, No) 
 Received prior sorafenib for DTC (Yes, No) 
 Duration on sorafenib for DTC (< 1 month, 1 - <3 months, 3 - <6 months, ≥6 
months) and descriptive statistics 
 Received prior lenvatinib for DTC (Yes, No) 
 Duration on lenvatinib for DTC (< 1 month, 1 - <3 months, 3 - <6 months, ≥6 
months) and descriptive statistics 
 Number of subjects receiving sorafenib only for DTC 
 Number of subjects receiving lenvatinib only for DTC 
 Received prior sorafenib and lenvatinib for DTC(Yes) 
o Received sorafenib before receiving lenvatinib 
o Received lenvatinib before receiving sorafenib 
 Best response on the most recent regimen for DTC 
 Descriptive summaries in months for the time from progression on most recent non-
radiation anti-cancer regimen for DTC to randomization 
 Descriptive summaries in months for the time from the end of most recent non-
radiation anti-cancer regimen for DTC to randomization 
 Number of subjects with progression while receiving sorafenib or lenvatinib for DTC 
at any time 
 Number of subjects with progression of disease while receiving sorafenib or 
lenvatinib as most recent anti-cancer treatment for DTC 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 27 of 72 
 
 Descriptive summaries in months for the time from progression on sorafenib or 
lenvatinib as the most recent non-radiation anti-cancer agent for DTC to 
randomization 
 Number and percent of subjects who progressed on the most recent prior VEGFR-
TKI therapy for DTC (Yes, No) 
 Descriptive summary for total duration of treatment in months on prior VEGFR-
TKIs for DTC 
 Categorical summaries for total duration of treatment in months on prior VEGFR-
TKIs for DTC as follows: 
o < median,  ≥ median  
 Descriptive summaries in months for the time from the end of most recent VEGFR-
TKI therapy for DTC to randomization 
 Descriptive summaries in months for the time from progression on most recent 
VEGFR-TKI therapy for DTC to randomization 
 Categorical summaries for time from progression on the most recent VEGFR-TKI 
therapy for DTC to randomization 
o ≤3 months 
o >3 months 
 Reason for stopping the most recent anti-cancer agent for DTC (progression, 
toxicity, completion, other) 
All prior non-radiation anticancer agents will be summarized categorically by Anatomical 
Therapeutic Chemical (ATC) Class Text and WHO-DD base substance preferred name by 
treatment arm and type of therapy (Local, Systemic, Unknown) for all subjects in the OITT, 
ITT, O-Safety  and Safety populations. 
6.2 
Prior Radiation Therapy 
Data obtained from the history of radiation therapy CRF will be summarized categorically or 
with descriptive statistics as appropriate for all subjects in the OITT, ITT, O-Safety and 
Safety populations: 
 Number of prior radiation therapies for DTC per subject (1, 2, ≥3) and descriptive 
statistics 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 28 of 72 
 
 Subject incidence of radiation therapy by indication (Disease under study and Other) 
 Subject incidence of radiation therapy type (External beam radiation therapy 
[EBRT], Internal radiation therapy [Brachytherapy], Radioisotope therapy) received 
for DTC or Other indications  
 Subject incidence of site type (Bone, Soft-tissue, Systemic, Unknown) of radiation 
received for DTC or Other indications  
 Number and percent for anatomic sites that received radiation 
 Descriptive summaries for time in months from the end of most recent radiation 
therapy for DTC to randomization 
6.3 
Prior Radioactive-Iodine Therapy 
The number of subjects who have previously received radioactive iodine or radioisotope 
therapy will be summarized..  The number of subjects deemed ineligible for radioactive-
iodine (RAI) therapy and the same deemed refractory to RAI therapy will be summarized. 
The reason for considering the subject refractory to or ineligible for RAI therapy will also be 
tabulated.  Descriptive statistics for the time the subjects were deemed to be refractory to or 
ineligible for RAI therapy to randomization will also be provided. Categorical summaries 
will also be provided for number of subjects < median time from RAI refractory status to 
randomization and ≥median time from RAI refractory status to randomization.  Descriptive 
statistics will also be provided for time from end of prior RAI therapy to randomization.  All 
summaries will be provided for the OITT, ITT and O-Safety and Safety populations.  A data 
listing will also be provided. 
6.4 
Prior and Concomitant Medications (Excluding Anticancer Therapy) 
Medications recorded on the CRFs will be coded using the WHO-DD. Prior and 
concomitant medications, other than prior and subsequent anticancer therapies, will be 
summarized by treatment group in the Safety population by ATC and WHO-DD base 
substance preferred name. In addition, prior medications will also be summarized in the O-
ITT, ITT and O-Safety populations by ATC and WHO-DD base substance preferred name. 
Anticancer therapies are addressed in Sections 6.8 and 6.9 of this plan. 
6.5 
Study Treatment Exposure 
Study treatment exposure will be summarized with descriptive statistics in the O-Safety and 
Safety populations as follows. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 29 of 72 
 
Definition of duration (in days) of exposure per subject, including dose holds per subject, is 
defined in the table below:  
 
 
Treatment:  
Cabozantinib 
Placebo 
 
Group: 
Subjects 
randomized 
to and 
receiving 
cabozantinib 
(Cabozantinib 
arm) 
Subjects 
randomized to 
placebo but 
receiving 
cabozantinib 
after crossover 
(Placebo 
crossover arm) 
All subjects 
receiving 
cabozantinib 
including 
crossover 
subjects (All 
Cabozantinib 
arm) 
Subjects 
randomized to and 
receiving placebo 
(Placebo arm) 
Start Date  
Date of 1st 
dose of 
cabozantinib 
Date of 1st dose 
of cabozantinib 
after crossover 
Date of 1st dose 
of cabozantinib 
Date of 1st dose of 
placebo 
End Date  
Date of 
decision to 
discontinue  
final 
cabozantinib 
(blinded/open-
label) 
Date of decision 
to discontinue 
open-label 
cabozantinib 
Date of decision 
to discontinue 
final 
cabozantinib 
(blinded/open-
label) 
Date of decision to 
discontinue blinded 
placebo 
 Duration of exposure in months is defined as (duration of exposure in days as calculated 
above/30.4375) 
 Average daily dose per subject (mg/day) of study treatment, calculated as (total dose in 
mg received / (duration of exposure in days) 
 Percent dose intensity per subject calculated as 100*(average daily dose mg/day) / (60 
mg/day) 
 Duration (in months) of exposure per subject, excluding dose holds defined, as (duration 
of exposure in days – total number of days with 0 mg of dose received during this 
interval) /30.4375 
6.6 
Study Treatment Modifications 
Treatment modifications (holds and reductions) for study treatment will be summarized in 
the O-Safety and Safety populations. Only modifications due to AE, and protocol-defined 
dose levels, will be summarized. 
The following summaries will be presented:  

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 30 of 72 
 
i. 
For dose reductions due to AE     
Categorical summaries for: 
 Number of subjects with any dose reduction 
 Number of subjects who received each dose level 
 Categorization of subjects by: 
 Lowest non-zero dose level received   
 Last non-zero dose level received  
 Last dose level received (including dose holds)  
Descriptive statistics for: 
 Number of dose reductions per subject 
 Duration of treatment in months for each dose level (60 mg, 40 mg, 20 mg, 0 
mg), defined for each subject as (cumulative number of days treatment was 
taken at each dose level) / 30.4375 
 Time from first dose to first dose level reduction (first receipt of 40mg) 
(days) – amongst those who ever received 40mg 
 Time from first dose to second dose level reduction (first receipt of 20mg) 
(days)  - amongst those who ever received 20mg 
ii. 
Summaries for dose holds due to AE:  
 Descriptive statistics for number of dose holds (0mg dose level) due to an AE 
 Descriptive statistics for duration of total and each dose hold  per subject due 
to an AE, calculated as (stop date of hold – start date of hold + 1)  
 Categorical summary for subjects with duration of  holds due to an AE that 
can be classified as any number of days,  ≥ 7 days,  ≥ 14 days, and  ≥ 21  days 
 Descriptive statistics for time to first dose hold, time to first dose hold that 
was   ≥ 7 days, ≥ 14 days, and ≥ 21 days. The time to dose hold is calculated 
as (start date of the hold – first dose date + 1)   
 Descriptive statistics for time to second dose hold, time to second dose hold 
that was ≥ 7 days, ≥ 14 days, and  ≥ 21  days 
iii. 
Summaries for dose modifications (defined as a reduction or hold) due to AE:  
 Frequency counts and percentages for subjects with any dose modifications 
 Descriptive statistics for number of dose modifications (0-3) 
 Descriptive statistics for time to the first dose modification  
 Descriptive statistics for time to the second dose modification 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 31 of 72 
 
 
6.7 
Study Treatment Non-Compliance and Dosing Errors 
Treatment non-compliance and dosing errors for reasons other than AE will be summarized 
in the O-Safety and Safety populations. Frequency counts and percentages will be presented 
by treatment groups for: 
 Subjects with dose hold (0 mg) due to non-compliance 
 Subjects who received dose > maximum allowed dose level at any time (overdose) 
 Subjects who received non-protocol specified dose level (< maximum allowed dose 
level) at any time due to subject non-compliance due to reasons other than AE, 
site/logistic error or other reason 
 Subjects who received wrong dose (≤ maximum allowed dose level) at any time due 
to subject non-compliance due to reasons other than AE, site/logistic error or other 
reason 
6.8 
Non-Protocol Anticancer Therapy 
For the purpose of supporting safety evaluations: 
Concomitant (see definition in Section 4.7.) non-radiation NPACT will be summarized by 
ATC text and WHO Drug base substance preferred name in the O-Safety and Safety 
populations.  
For the purpose of supporting efficacy evaluations: 
Concomitant and subsequent (see definition in Section 4.7.) NPACT, including radiation 
therapy, will be summarized by treatment group in the OITT and ITT populations as 
follows: 
 Based on the non-radiation therapy received subjects will be categorized into one or 
more of the following categories:  systemic, local, or unknown and all NPACTs 
falling under these categories will be summarized by ATC text and WHO Drug 
based substance preferred name  
 Time to first systemic NPACT will be summarized by descriptive statistics 
 Frequency counts and percentages will be presented for radiation therapy indication, 
type and site  

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 32 of 72 
 
6.9 
 Post-randomization Radiotherapy, Surgery/Procedure 
Post-randomization radiation therapy and surgery/procedures that impacted the target 
lesion(s) (Yes, No, Unknown) will be summarized by treatment group for subjects in the 
OITT, ITT, O-Safety and Safety populations. 
6.10 
Concomitant Transfusions 
Concomitant transfusions will be summarized by transfusion type and treatment group for 
subjects in the O-Safety and Safety populations. 
7 
CROSSOVER BASELINE CHARACTERISTICS 
The following descriptive summaries will be provided for the placebo subjects in the ITT 
population who crossover to receive cabozantinib upon confirmed radiographic progression 
and also for the cabozantinib subjects who continue on study drug beyond progression: 
 Number of subjects receiving open-label cabozantinib  
 Age 
 Frequency counts and percentages of ECOG status at the assessment immediately 
prior to crossover or receipt of open-label cabozantinib 
 Time to progression while on randomized study treatment 
 Number of target lesion locations prior to crossover per Investigator’s assessment 
(including thyroid) 
o 1 
o 2 
o ≥3 
8 
EFFICACY ANALYSES 
The multiple primary efficacy endpoints for this study are duration of PFS and ORR per 
BIRC. Formal hypothesis tests are planned for these endpoints. Data as described in Section 
Error! Reference source not found. will be considered. 
8.1 
Primary Efficacy Endpoints 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 33 of 72 
 
8.1.1 
Objective Response Rate (ORR) 
8.1.1.1 
Definition 
For each subject, best overall response (BOR) is defined as the best tumor assessment 
category as determined per RECIST 1.1 that occurs through the first overall timepoint 
response of PD and prior to any of the censoring events defined for the primary analysis of 
PFS as described in Section8.1.2. Tumor assessment categories are ranked as: confirmed 
complete response (CR), confirmed partial response (PR), stable disease (SD), progressive 
disease (PD) and not evaluable (NE). To be classified as confirmed CR or confirmed PR, 
confirmation must have occurred on a subsequent visit that is ≥ 28 days after the response 
was first observed. To be classified as SD, at least one overall timepoint response of SD 
must be documented ≥ 49 days after randomization. 
The ORR is defined as the proportion of subjects with a BOR of confirmed CR or confirmed 
PR. 
8.1.1.2 
Primary Estimand 
The difference in proportions between treatment conditions in subjects in ORR (best overall 
response of confirmed complete or partial response) per RECIST 1.1 in the targeted patient 
population: 
 irrespective of whether the assigned study treatment was given 
 irrespective of clinical deterioration 
 irrespective of whether local radiation was given to bone 
 irrespective of surgical resection of non-target lesions 
 irrespective of receipt of local non-protocol anti-cancer medications other than for 
disease under study 
 prior to any surgical resection of target tumor lesions 
 prior to receipt of systemic non-protocol anti-cancer medications 
 prior to receipt of local non-protocol anti-cancer medications for disease under study 
 prior to receipt of local radiation to soft tissue for disease under study 
 prior to loss to radiographic follow-up 
 prior to death 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 34 of 72 
 
Derived as follows: 
Table 5: Primary Estimand Attribute for ORR 
Estimand attribute 1 
Primary definition for study 
Population 
Subjects randomized into the study intended to include patients with radioiodine-
refractory differentiated thyroid cancer who have progressed after prior VEGFR-
targeted therapy. 
Endpoint 
Radiographic response per RECIST 1.1  
Intercurrent events 
Event 
Strategy 
Receipt of assigned study treatment 
Treatment policy 
Receipt of local radiation to bone 
Treatment policy 
Surgical resection of non-target tumor lesions 
Treatment policy 
Death 
Treatment policy 
Loss to radiographic follow up 
Treatment policy  
Receipt of local non-protocol anti-cancer medications 
other than for disease under study 
Treatment policy 
Surgical resection of target tumor lesions 
While on treatment* 
Receipt of systemic non-protocol anti-cancer 
medications 
While on treatment* 
Receipt of local non-protocol anti-cancer medications 
for disease under study 
While on treatment* 
Receipt of local radiation to soft tissue for disease 
under study 
While on treatment* 
Population summary 
Difference in proportions of subjects with a best overall response of confirmed 
complete response or confirmed partial response per RECIST 1.1 between 
treatment conditions. 
Estimator 
Fisher’s exact test 
1 See Appendix E for estimand terminology 
* A modified version of the “while on treatment” strategy is employed for these intercurrent events. Only data 
prior to the occurrence of these intercurrent events is of interest, but under the ITT principle, receipt of study 
treatment itself is not considered. 
8.1.1.3 
Hypothesis  
The hypotheses to be evaluated in the analysis of the ORR are as follows: 
H0:  ORRCabozantinib ≤ ORRPlacebo 
HA:  ORRCabozantinib > ORRPlacebo 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 35 of 72 
 
where ORRCabozantinib and ORRPlacebo are the ORRs for the cabozantinib and placebo arms, 
respectively. 
8.1.1.4 
Primary Analysis 
The primary analysis of ORR is based on tumor assessments per BIRC and will include all 
subjects in the OITT population.  
Hypothesis testing for ORR will be performed using the Fisher’s exact test at the 2-sided 
α=0.01 level of significance. If a sufficient number of responders are observed, analysis 
using the Cochran-Mantel-Haenszel (CMH) method to adjust for stratification factors per 
IRT may also be conducted.  
Point estimates of ORR for each treatment arm, the difference in ORR between the two 
treatment arms, and associated confidence intervals will be provided. The odds ratio and its 
confidence intervals will also be shown. The 2-sided 95% and 99% CIs for the point 
estimate will be calculated using exact methods. The 2-sided 95% and 99% CIs for the 
difference in ORR between the two treatment arms and for the odds ratio will be calculated 
by asymptotic methods. 
If the p-value for the two-sided Fisher’s exact test is less than 0.01 and the point estimate for 
ORR in the cabozantinib arm is higher than that in the placebo arm, the null hypothesis of 
no difference in ORR will be rejected and it will be inferred that ORR is superior in the 
cabozantinib arm compared with the placebo arm. 
The study will proceed to full enrollment of 300 subjects irrespective of the results of the 
ORR analysis in the OITT population. 
8.1.1.5 
Sensitivity Analyses 
The analysis of ORR based on tumor assessments per RECIST 1.1 per investigator will also 
be analyzed following the same principles as outlined for the primary analysis described in 
Section 8.1.1.4  In addition, ORR will also be analyzed descriptively for the ITT population 
at the time of final PFS analysis. 
The concordance in ORR assessment between BIRC and investigator will be summarized 
for the OITT population. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 36 of 72 
 
8.1.1.6 
Supportive Analyses 
Waterfall plots displaying maximum percent tumor reduction since baseline in target lesions 
will be generated for tumor assessment data per BIRC and per investigator.  
These plots will include subjects with a tumor assessment at baseline and at least one post-
baseline visit. For each subject, data on or before the progression/censoring date of the 
respective PFS analyses described in Section8.1.2.1 will be excluded from the waterfall 
plots.  
The disease stabilization rate (DSR) defined as the sum of ORR and proportion of subjects 
with stable disease for at least 15weeks will also be summarized for the ITT population. The 
odds ratio of DSR will also be provided with corresponding 95% confidence interval.  
The ORR may also be summarized for crossover subjects during their course of treatment 
with open-label cabozantinib for the ITT population upon observance of sufficient 
responses. 
8.1.2 
Progression-Free Survival (PFS) 
The primary efficacy analysis for PFS will include all subjects in the ITT population.  
8.1.2.1 
Definitions and Conventions 
For tumor assessment, CT or MRI of chest/abdomen/pelvis/neck (CAPN) will be performed 
at screening and every 8 weeks (± 7 days) after randomization during the first 12 months on 
study.  Upon subject completion of 12 months on study, these assessments will be 
performed every 12 weeks (± 14 days). 
The recorded date of radiographic progression is the date of the tumor assessment visit at 
which progression is declared.  If multiple scan dates are associated with a tumor assessment 
visit, the earliest assessment date within the set will be chosen as the progression date. 
Only adequate tumor assessments (ATAs) will be considered in the determination of 
radiographic progression and censoring dates. For the purpose of this study, an ATA is 
defined as one that results in a time point assignment of: response (complete or partial), 
stable disease/(non-CR, non-PD), or progression. For PFS, ATA is based on soft tissue 
evaluation by CT/MRI.  

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 37 of 72 
 
8.1.2.2 
Primary Estimand 
The primary estimand for PFS is the difference in survival functions between treatment 
conditions in the duration of radiographic progression-free survival in the targeted 
population: 
 irrespective of whether the assigned study treatment was given 
 irrespective of clinical deterioration 
 irrespective of whether local radiation was given to bone 
 irrespective of surgical resection of non-target lesions 
 irrespective of local non-protocol anti-cancer treatment other than for disease under 
study 
 had surgery to resect tumor lesions not occurred 
 had systemic non-protocol anti-cancer treatment not been given  
 had local non-protocol anti-cancer treatment for disease under study not been given  
 had local radiation to  soft tissue not been given 
Derived as follows: 
Table 6: Primary Estimand Attribute for PFS 
Estimand attribute 1 
Primary definition 
Population 
Subjects randomized into the study intended to include patients with radioiodine-
refractory DTC who have progressed after prior VEGFR-targeted therapy. 
Endpoint 
Duration of radiographic progression-free survival 
Intercurrent events 
Event 
Strategy 
Receipt of assigned study treatment 
Treatment policy 
Clinical deterioration  
Treatment policy 
Receipt of local radiation to bone 
Treatment policy 
Surgical resection of non-target tumor lesions 
Treatment policy 
Receipt of local non-protocol anti-cancer medications other 
than for disease under study 
Treatment policy 
Surgical resection of target tumor lesions 
Hypothetical 
Receipt of systemic non-protocol anti-cancer medications 
Hypothetical 
Receipt of local non-protocol anti-cancer medications for 
disease under study 
Hypothetical 
Receipt of local radiation to soft tissue for disease under study 
Hypothetical 
Population summary 
Difference in survival functions between treatment conditions. 
1 See Appendix E for estimand terminology 
 
8.1.2.3 
Alternative Estimands 
Two alternative estimands for PFS are defined as below, arising from changes in strategy for 
handling some intercurrent events. Shaded cells differ from primary estimand. Alternative 
estimand 1 changes the strategy for selected clinical intercurrent events to “composite,” 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 38 of 72 
 
resulting in an endpoint that comprises radiographic and clinical progression (as well as 
death). Alternative estimand 2 changes the strategy to “composite” only for systemic non-
protocol anti-cancer medications, yielding an endpoint that comprises radiographic 
progression, death, or initiation of systemic NPACT. 
Table 7: Alternative Estimand Attribute for PFS 
Estimand 
attribute  
Alternative 1 definition 
Alternative 2 definition 
Population 
Subjects randomized into the study intended to 
include patients with radioiodine-refractory DTC 
who have progressed after prior VEGFR-targeted 
therapy. 
Subjects randomized into the study intended to 
include patients with radioiodine-refractory DTC 
who have progressed after prior VEGFR-targeted 
therapy. 
Endpoint 
Duration of radiographic and clinical progression-
free survival 
Time to radiographic progression, death, or initiation 
of systemic NPACT 
Intercurrent 
events 
Event 
Strategy 
Event 
Strategy 
Receipt of assigned study 
treatment 
Treatment 
policy 
Receipt of assigned study 
treatment 
Treatment policy 
Clinical deterioration  
Composite 
Clinical deterioration  
Treatment policy 
Receipt of local radiation to 
bone 
Treatment 
policy 
Receipt of local radiation to 
bone 
Treatment policy 
Surgical resection of non-target 
tumor lesions 
Treatment 
policy 
Surgical resection of non-target 
tumor lesions 
Treatment policy 
Receipt of  
local non-protocol anti-cancer 
medications other than for 
disease under study 
Treatment 
policy 
Receipt of  
local non-protocol anti-cancer 
medications other than for 
disease under study 
Treatment policy 
Surgical resection of target 
tumor lesions 
Composite 
Surgical resection of target 
tumor lesions 
Hypothetical 
Receipt of systemic non-
protocol anti-cancer 
medications 
Composite 
Receipt of systemic non-
protocol anti-cancer medications 
Composite 
Receipt of  
local non-protocol anti-cancer 
medications for disease under 
study 
Composite 
Receipt of  
local non-protocol anti-cancer 
medications 
Hypothetical 
Receipt of local radiation to soft 
tissue for disease under study 
Composite 
Receipt of local radiation to soft 
tissue for disease under study 
Hypothetical 
Population 
summary 
Difference in survival functions between treatment 
conditions. 
Difference in survival functions between treatment 
conditions. 
8.1.2.4 
Primary Definition 
For the primary analysis directed toward the primary estimand, duration of PFS is defined as 
the time from randomization to the earlier of either the date of radiographic progression per 
BIRC or the date of death due to any cause.  
PFS (months) = (earliest date of progression, death, censoring – date of randomization + 
1)/30.4375 
General censoring rules for the primary analysis of PFS are described below, with details 
provided in Table 8(analysis ID PFS-EP-1): 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 39 of 72 
 
 Subjects who receive systemic NPACT, or local NPACT for disease under study, or 
non-protocol radiation therapy for disease under study(other than to bone) or surgery 
to resect target lesions before experiencing an event will be right censored at the date 
of the last ATA on or prior to the date of initiation of subsequent therapy/surgery. If 
there is no such tumor assessment after randomization, the subject will be right 
censored on the date of randomization. 
 Subjects who have not experienced an event (and are not otherwise censored) at the 
time of data cutoff will be right censored on the date of their last tumor assessment 
after randomization that is on or prior to the data cutoff. If there is no such tumor 
assessment after randomization, the subject will be right censored on the date of 
randomization.   
 Subjects who miss two or more ATAs (operationally defined as an interval of 126 
days in the first year and 196 days after the first year without an ATA) followed by 
an event (progression or death) will be right censored on the date of their most-recent 
ATA prior to the missing assessments. If there is no such tumor assessment after 
randomization, the subject will be right censored on the date of randomization.   
8.1.2.5 
Hypothesis  
The hypotheses to be evaluated in the analysis of the PFS are:  
H0: S(t)cabozantinib = S(t)placebo  
HA: S(t)cabozantinib ≠ S(t)placebo  
 
where S(t)𝐶𝑎𝑏𝑜𝑧𝑎𝑛𝑡𝑖𝑛𝑖𝑏 and S(t)𝑃𝑙𝑎𝑐𝑒𝑏𝑜 are the survivor functions for PFS for the 
cabozantinib and placebo arms, respectively. 
8.1.2.6 
Primary Analysis 
The primary analysis of PFS (designated PFS-EP-1) is event-based and will be conducted 
after at least 193 events (progression per RECIST 1.1 per BIRC or deaths) have been 
observed in the ITT population. The actual number of events may be higher due to the 
logistics of identifying events and predicting cutoff dates for analysis.  
The hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided α=0.04 or 0.05 level of significance (see Section 8.2 for details 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 40 of 72 
 
regarding the α-level). The stratification factors are as described in Section 2.5 and the 
values used for analysis will be those recorded in the IRT. 
The median duration of PFS and the associated 96% or 95% confidence interval (CI) for 
each treatment arm will be estimated using the Kaplan-Meier method. The stratified hazard 
ratio (HR) and its 96% or 95% CI will be estimated using a Cox proportional-hazard model 
with treatment group as the independent variable and stratified by the same randomization 
stratification factors as were used for the log-rank test.  
If the p-value for the stratified log-rank test is less than the critical value for rejecting the 
null hypothesis and the HR (λ cabozantinib/ λ placebo) is < 1, the null hypothesis will be 
rejected and it will be inferred that PFS is superior in the cabozantinib arm compared to the 
placebo arm. 
The critical p-values (and observed HR) for rejecting the null hypothesis are described in 
Section 2.4 . The actual critical values will depend upon the true number of events observed 
at each analysis.  
The above analysis will also be provided for the OITT population.  
8.1.2.7 
Sensitivity Analyses 
Event and censoring definitions for the primary analysis (PFS-EP-1) and 3 sensitivity 
analyses (PFS-EP-2, PFS-EP-3, PFS-EP-4) directed at the primary estimated for PFS are 
provided in Table 8.  
The three sensitivity analyses evaluate the impact of different assumptions or conditions that 
potentially influence the estimate of the primary estimand:   
 The PFS-EP-2 definition evaluates the influence of potentially inconsistent tumor 
assessment intervals between arms. For subjects who experience radiographic 
progression, it assigns the date of the scheduled visit as the event date, rather than the 
date of recorded progression. 
 The PFS-EP-3 definition evaluates the influence of the assessor of radiographic 
progression, and is based up RECIST 1.1 evaluations by the investigator rather than 
the BIRC. 
 The PFS-EP-4 definition evaluates the influence of the missing tumor assessments. It 
classifies subjects who experience ≥ 2 consecutive missing scheduled ATA 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 41 of 72 
 
immediately prior to documented radiographic progression as having an event, rather 
than being censored, at the date of the last ATA prior to the missing visits. 
Event and censoring definitions for 3 supplemental analyses (PFS-EA1-1, PFS-EA2-1, PFS-
EA2-1) directed at the two alternative estimands for PFS are provided in Table 9.  
 The PFS-EA1-1 definition is the primary analysis of alternative estimand 1.  
 The PFS-EA2-1 definition is the primary analysis of alternative estimand 2. 
 The PFS-EA2-2 definition is a sensitivity analysis of alternative estimand 2, similar 
to PFS-EP-4 (defined above). 
Four additional “differential” sensitivity analyses (PFS-EP-11, PFS-EP-12, PFS-EP-13, 
PFS-EP-14) directed at the primary estimand will be conducted to evaluate the impact of 
potentially informative censoring. These analyses are based on the primary analysis PFS-
EP-1 but with selected censored subjects re-classified as events, differentially by treatment 
arm, as shown in Table 10. These are highly conservative definitions intended to evaluate 
potential bias. The directions of treatment effects are of key interest rather than the values of 
inferential statistics.  
All sensitivity and supplemental analyses will include all subjects in the ITT population. 
Tabulated summaries of survival times, hazard ratios, and log rank test statistics as well as 
graphs of survival functions will be presented. 
The concordance in assessment of radiographic progression and the date between BIRC and 
investigator will be summarized for the ITT population. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 42 of 72 
 
Table 8:   Event and Censoring Rules for Primary and Sensitivity Analyses of Primary PFS Estimand 
Estimand 
Primary 
Primary 
Primary 
Primary 
Analysis type 
Primary 
Sensitivity 
Sensitivity 
Sensitivity 
Analysis 
purpose 
Primary 
Evaluate assessment time 
bias 
Evaluate assessor bias 
Evaluate potentially 
informative censoring 
Analysis ID 
PFS-EP-1 
PFS-EP-2 
PFS-EP-3 
PFS-EP-4 
Analysis name 
rPFS per BIRC 
Uniform dates 
rPFS per Investigator 
rPFS per BIRC despite 
missing ATA 
Estimand 
endpoint 
Radiographic PD 
Radiographic PD 
Radiographic PD 
Radiographic PD 
Population 
ITT 
ITT 
ITT 
ITT 
Situation 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
Outcome 
Date of 
Outcome 
Radiographic 
PD 
per RECIST 1.1 
per BIRC 
Event 
date of 
recorded PD 
event 
date of 
scheduled visit 
(or next 
scheduled visit 
if between 
visits) 
NA 
NA 
event 
date of 
recorded PD 
Radiographic 
PD 
per RECIST 1.1 
per Investigator 
NA 
NA 
NA 
NA 
event 
date of 
recorded PD 
NA 
NA 
Death 
event 
date of death 
event 
date of death 
event 
date of death 
event 
date of death 
  
Intercurrent events (excluding those with Treatment Policy strategy for all estimands) 
Clinical 
deterioration 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
Systemic 
NPACT 
(medications) 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
Local NPACT 
for disease 
under study 
(medications) 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
censored 
date of last 
ATA* before 
first initiation 
of therapy 
Surgical 
resection of 
target tumor 
lesion(s) 
censored 
date of last 
ATA* before 
target lesion 
resection 
censored 
date of last 
ATA* before 
target lesion 
resection 
censored 
date of last 
ATA* before 
target lesion 
resection 
censored 
date of last 
ATA* before 
target lesion 
resection 
Local radiation: 
to soft tissue for 
disease under 
study 
censored 
date of last 
ATA* local 
radiation of 
soft tissue for 
disease under 
study 
censored 
date of last 
ATA* local 
radiation of 
soft tissue for 
disease under 
study 
censored 
date of last 
ATA* local 
radiation of 
soft tissue for 
disease under 
study 
censored 
date of last 
ATA* local 
radiation of 
soft tissue for 
disease under 
study 
  
Missing data 
No baseline 
ATA 
censored 
date of rand. 
censored 
date of rand. 
censored 
date of rand. 
censored 
date of rand. 
≥ 2 consecutive 
missing 
scheduled ATA 
immediately 
prior to analysis 
event 
censored 
date of last 
ATA* before 
missing visits 
censored 
date of last 
ATA* before 
missing visits 
censored 
date of last 
ATA* before 
missing visits 
event 
date of last 
ATA* before 
missing visits 
  
Observation ongoing 
None of the 
above 
censored 
date of last 
ATA* 
censored 
date of last 
ATA* 
censored 
date of last 
ATA* 
censored 
date of last 
ATA* 
ATA, adequate tumor assessment; BIRC, blinded independent review committee; ITT, intent-to-treat; NA, not applicable; PD, progressive 
disease; NPACT, non-protocol anti-cancer therapy (medications including radiopharmaceuticals but excluding local radiation) 
Date of recorded PD = see SAP text. 
* or date of randomization if no post-randomization ATA 
Blue cells indicate changes from primary analysis. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 43 of 72 
 
Table 9:   Event and Censoring Rules for Supplementary Analyses of Alternative PFS Estimands 
Estimand 
Alternative 1 
Alternative 2 
Alternative 2 
Analysis type 
Supplementary 
Supplementary 
Supplementary 
Analysis purpose 
Alternate progression definition 
Alternate progression definition 
Evaluate potentially informative 
censoring 
Analysis ID 
PFS-EA1-1 
PFS-EA2-1 
PFS-EA2-2 
Analysis name 
Investigator claims 
rPFS or sNPACT 
rPFS or sNPACT despite missing 
ATA 
Estimand endpoint 
Radiographic or clinical PD 
Radiographic PD or initiation of 
systemic NPACT 
Radiographic PD or initiation of 
systemic NPACT 
Population 
ITT 
ITT 
ITT 
Situation 
Outcome 
Date of Outcome 
Outcome 
Date of 
Outcome 
Outcome 
Date of Outcome 
Radiographic PD 
per RECIST 1.1 
per BIRC 
NA 
NA 
event 
date of recorded 
PD 
event 
date of recorded 
PD 
Radiographic PD 
per RECIST 1.1 
per Investigator 
event 
date of recorded 
PD 
NA 
NA 
NA 
NA 
Death 
event 
date of death 
event 
date of death 
event 
date of death 
  
Intercurrent events (excluding those with Treatment Policy strategy for all estimands) 
Clinical deterioration 
event 
date of 
determination of 
clinical 
deterioration 
NA 
NA 
NA 
NA 
Systemic NPACT 
(medications) 
event 
date of first 
initiation of 
therapy 
event 
date of first 
initiation of 
therapy 
event 
date of first 
initiation of 
therapy 
Local NPACT for 
disease under study 
(medications) 
event 
date of first 
initiation of 
therapy 
censored 
date of last 
ATA* before 
first initiation of 
therapy 
censored 
date of last ATA* 
before first 
initiation of 
therapy 
Surgical resection of 
target tumor lesion(s) 
event 
date of last ATA* 
before target 
lesion resection 
censored 
date of last 
ATA* before 
target lesion 
resection 
censored 
date of last ATA* 
before target 
lesion resection 
Local radiation: 
to soft tissue for 
disease under study 
event 
date of last ATA* 
before non-target 
lesion resection 
censored 
date of last 
ATA* before 
non-target lesion 
resection 
censored 
date of last ATA* 
before non-target 
lesion resection 
  
Missing data 
No baseline ATA 
censored 
date of rand. 
censored 
date of rand. 
censored 
date of rand. 
≥ 2 consecutive 
missing scheduled 
ATA immediately prior 
to analysis event 
censored 
date of last ATA* 
before missing 
visits 
censored 
date of last 
ATA* before 
missing visits 
event 
date of last ATA* 
before missing 
visits 
  
Observation ongoing 
None of the above 
censored 
date of last ATA* 
censored 
date of last 
ATA* 
censored 
date of last ATA* 
ATA, adequate tumor assessment; BIRC, blinded independent review committee; ITT, intent-to-treat; NA, not applicable; PD, progressive 
disease; NPACT, non-protocol anti-cancer therapy (medications including radiopharmaceuticals but excluding local radiation) 
Date of recorded PD = see SAP text. 
* or date of randomization if no post-randomization ATA 
Blue cells indicate changes from primary analysis. 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 44 of 72 
 
Table 10:    Definitions for Differential Sensitivity Analyses of PFS to Further Evaluate Potentially 
Informative Censoring (based on PFS-EP-1) 
Estimand 
Primary 
Analysis type 
Sensitivity 
Analysis purpose 
Differential analyses to explore potentially informative censoring 
Analysis strategy 
 Selected censored subjects in primary analysis reclassified as events, differentially by assigned treatment arm, 
as shown below (green cells) 
Analysis ID 
PFS-EP-11 
PFS-EP-12 
PFS-EP-13 
PFS-EP-14 
Censoring category for 
subjects censored in PFS-
EP-1 in PITT Population 
Experimental 
Control 
Experimental 
Control 
Experimental 
Control 
Experimental 
Contr
rPD per INV but not BIRC 
At recorded 
date of first 
rPD per INV 
  
At recorded 
date of first 
rPD per INV 
  
At recorded 
date of first 
rPD per INV 
At recorded 
date of first 
rPD per INV 
At recorded 
date of first 
rPD per INV 
  
Discontinued radiographic 
assessment for reasons other 
than rPD and no sNPACT 
At date of last 
ATA 
  
At date of last 
ATA 
  
At date of last 
ATA 
  
At date of last 
ATA 
  
sNPACT prior to rPD per 
INV or BIRC 
  
  
At date of first 
sNPACT 
At date 
of first 
sNPACT 
  
  
At date of first 
sNPACT 
  
ATA, adequate tumor assessment; BIRC, blinded independent review committee; rPD, radiographic progressive disease per RECIST 1.1; 
INV, investigator; sNPACT, systemic non-protocol anti-cancer therapy (medications including radiopharmaceuticals) 
* or date of randomization if no post-randomization ATA  
 
8.2 
Control of Type I Error 
The multiplicity issue resulting from analysis of two primary endpoints (PFS and ORR) will 
be addressed by applying a modified Bonferroni procedure (dividing the alpha between the 
two primary endpoints). 
ORR will be tested at the 2-sided 1% alpha significance level and PFS will be tested at the 
2-sided 4% alpha significance level.  
Additionally, the fallback method for alpha allocation (FDA 2017) will be implemented as 
follows: 
 If the null hypothesis is rejected for ORR its alpha allocation of 1% will be passed to 
PFS which will then be tested at the 5% level. 
 If the null hypothesis is not rejected for ORR, then PFS will be tested at its original 
alpha allocation of 4%. 
 An interim analysis (See Section8.3) is planned for the second primary endpoint of PFS. 
The interim analysis will be interpreted at an alpha of 5% only if the primary null 
hypothesis for ORR is rejected. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 45 of 72 
 
The primary objectives of the study will be declared as met if at least one hypothesis is 
rejected at its respective alpha level. All other statistical evaluations of efficacy will be 
considered exploratory. 
8.3 
Interim Analyses 
A single interim analysis of PFS is planned at the time of the primary ORR analysis. 
Approximately 43% of the planned total PFS events are expected to have been observed at 
that time. Rejection of the null hypothesis for PFS at the interim analysis is not expected; it 
is intended to allow evaluation of PFS at the time of the primary analysis of ORR. Inflation 
of Type 1 error arising from repeated analyses of PFS will be controlled by a Lan-DeMets 
O’Brien Fleming alpha spending function, using the actual information fraction at the 
interim analysis. 
8.4 
Additional Endpoints 
8.4.1 
Overall Survival 
8.4.1.1 
Definition  
Duration of OS is defined as the time from randomization to death due to any cause. For 
subjects who are alive at the time of data cutoff but are permanently lost to follow-up, 
duration of OS will be right censored at the date the subject was last known to be alive. 
Those who withdraw consent from survival follow-up and are alive will be right censored at 
the date the subject withdrew consent from survival follow-up, unless date of death can be 
obtained from public records. Subjects alive on or after the data cutoff or those who died 
after the data cutoff will be right censored at the date of data cutoff.  
OS (months) = (earliest date of death or censoring – date of randomization + 1)/30.4375   
8.4.1.2 
Analysis 
The analysis of OS will include all subjects in the OITT and ITT populations.  
The summaries (median and 95% CI for median, stratified and unstratified HRs and their 
95% CI) and graphs described in Section 8.1.2.6 will be generated for OS. Log-rank p-
values will be calculated and will be presented for descriptive purposes; formal inferences 
will not be drawn. 
At the time of the analysis of ORR, if the null hypothesis for ORR is rejected an 
administrative interim analysis of OS will be performed with the primary purpose of 
evaluating the potential for detriment to survival with cabozantinib treatment. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 46 of 72 
 
A sensitivity analysis for OS will be conducted censoring for receipt of any subsequent anti-
cancer therapy in the ITT population. 
In addition, exploratory OS analysis will be conducted adjusting for crossover of placebo 
subjects to cabozantinib as a time-dependent covariate for the ITT population.  Additional 
exploratory OS analysis may also be conducted to adjust for the crossover to cabozantinib 
utilizing the inverse probability of censoring weights (IPCW) or rank preserving structural 
failure time model (RPSFTM), if feasible.  
8.4.2 
Duration of Objective Response  
Duration of objective response is defined as the time from the first documentation of 
objective response that is subsequently confirmed at a visit that is ≥ 28 days later to disease 
progression or death due to any cause.  
 
Duration of response (months) = (earliest date of progressive disease or death due to any 
cause or censoring – date of first objective response + 1)/30.4375  
  
Duration of objective response will be computed only among subjects who experience an 
objective response (confirmed CR or confirmed PR). For DOR per BIRC the dates of 
progression and censoring are shown in column PFS-EP-1 of Table 8, and for DOR per 
investigator the dates of progression and censoring are shown in column PFS-EP-3 of Table 
8 . 
 
Duration of objective response will be analyzed using the same analysis method (Kaplan-
Meier) as for the analysis on PFS for OITT and ITT populations (see Section 8.1.2.6).  
 
8.4.3 
Time to Objective Response  
Time to objective response is defined as the time from randomization to the first 
documentation of objective response that is subsequently confirmed at a visit that is 
≥ 28 days later to disease progression or death due to any cause.  
 
Time to objective response (months) = (date of first objective response   - date of 
randomization + 1)/30.4375  
  

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 47 of 72 
 
Time to objective response will be computed only among subjects in the OITT and ITT 
populations who experience an objective response (confirmed CR or confirmed PR), and 
arithmetic methods (not Kaplan-Meier) will be used. 
8.4.4 
Time to Second Disease Progression or Death (PFS2) 
The time to second disease progression or death (PFS2) is defined as the time from 
randomization to the date of the earliest of the following events: start of second subsequent 
non-radiation anti-cancer therapy, second objective disease progression, or death.  For 
placebo subjects who have crossed over to receive cabozantinib, cabozantinib will be 
considered as the first subsequent therapy.  For subjects randomized to cabozantinib who 
continue on study treatment after their first disease progression, the start date of their first 
subsequent therapy will be considered to be a potential event date. Subjects alive and for 
whom a PFS2 event has not been observed will be censored at the last time known to be 
alive. The definition of event dates for PFS2 is provided in the table below. 
Table 11: PFS2 Event Dates 
Randomized 
Treatment 
Condition 
PFS2 Event date 
Placebo 
No Crossover 
Earlier of: 
a) Death 
b) 2nd documented date of progression 
c) Start date of 2nd Non-protocol Anti-cancer therapy 
(NPACT) 
Crossover 
Earlier of: 
a) Death 
b) 1st documented date of progression after initiation of 
cabozantinib 
c) Start date of 1st NPACT after initiation of cabozantinib 
Cabozantinib 
Discontinue after 1st 
documented disease 
progression 
Earlier of: 
a) Death 
b) 2nd documented date of progression 
c) Start date of 2nd NPACT 
Continue on open-
label cabozantinib 
after 1st documented 
Earlier of: 
a) Death 
b) 1st documented date of progression after starting open-

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 48 of 72 
 
disease progression 
label cabozantinib 
c) Start date of 1st NPACT after starting open-label 
cabozantinib 
The analysis of PFS2 will include all subjects in the ITT population done 
contemporaneously with the primary PFS analysis.  
The summaries (median and 95% CI for median, stratified and unstratified HRs and their 
95% CI) and graphs described in Section 8.1.2.6 will be generated for PFS2. Log-rank p-
values will be calculated and will be presented for descriptive purposes; formal inferences 
will not be drawn. 
8.4.5 
Biomarkers 
Baseline and changes from baseline for thyroglobulin will be summarized. Descriptive 
statistics (mean, standard deviation and median) will be presented by treatment group using 
all available data from protocol-defined time-points (i.e., baseline, W5D1, and W9D1).   
A waterfall plot of best percentage change (i.e., best percentage decrease) from baseline will 
be presented for each treatment group using the OITT and ITT populations. In all 
calculations, best change from baseline will be based only on protocol-defined time-points 
i.e., baseline, W5D1, and W9D1.  
 
8.4.6 
Health-Related Quality of Life (HRQOL) 
Health-related quality of life (HRQOL) will be assessed by the EuroQol Health 
questionnaire instrument (EQ-5D-5L). The questionnaire will be self-completed by the 
subjects at various time points until disease progression and will provide a generic measure 
of health for clinical appraisal (see protocol Section 5.7.7). The EQ-5D-5L questionnaire has 
two pages: a descriptive page which assesses on an increasing severity scale of 1-5 changes 
in the following five questions (dimensions): mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The second page has a 0-100 visual analogue scale 
(VAS) which records the subjects self-rated health between 100 (best health you can 
imagine) and  0 (worst health you can imagine) and serves as quantitative measure of health 
by the subject (see protocol Appendix F and EQ-5D-5L User Guide, Version 3.0  [2019]).  
To compare the two treatment arms the following summaries are planned at each time point 
for each of the 6 questions: 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 49 of 72 
 
Within each treatment arm:   
 Descriptive statistics (number of observations, mean and standard deviation)  
 Rate of completion for the questionnaire at each time point. This is defined as total 
number of subjects who answered all questions on the EQ-5D-5L questionnaire / the 
expected total number of subjects still on study at the visit 
 Mean change from baseline at each time point and the corresponding 95% CI and p-
value from one-sample t-test   
 Effect size for change from baseline within arm, calculated as (mean of change in 
score/pooled standard deviation for baseline scores).  An effect size greater than ≥ 
0.3 will be considered potentially clinically meaningful  
 Shift in the severity scale since baseline  
Across treatment arms   
 The difference in the effect sizes will be presented  
 Difference in mean change from baseline for the questions at the time point will be 
evaluated by a two sample t-test  
 Line plots for mean±standard error and the corresponding mean for change from 
baseline over time. Data from both treatment arms will be displayed on the same 
plot. In addition, these plots will also show the average state of the subjects at 3 
landmark points, namely, around end of treatment, around progression and around 30 
days post treatment  follow-up for the two treatment arms 
 Percentage of subjects in Level 1 (no problem) vs. Levels 2-5 (any problems) will be 
summarized over time  
 Percentage of subjects with any problems (Level 2-5) will be compared between the 
treatment arms using a bar chart 
 
The EQ-5D-5L may be converted into a single index (EQ-Index) value normalized across 
different countries where the index is validated. See Appendix D for conversion details. For 
EQ-VAS and EQ-Index, descriptive statistics for change from baseline at each time will be 
presented. Plots for mean±standard error and mean change from baseline±standard error 
over all time points for the two treatment arms will be generated.  
Repeated-measures mixed-effects models will be used to explore treatment differences over 
time for the blinded phase of the study only.  These analyses will include the outcome 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 50 of 72 
 
variable of QOL score change from baseline.  The predictors (fixed effects) will be the 
baseline scores, treatment arms, visit, and randomization strata described in Section 2.5.  
The individual subject nested within the planned treatment arm will be the random effect.  
All available data will be included for the analysis.  The estimated least squares means for 
the two treatment arm and their difference, the p-values comparing the 2 treatment arms and 
the effect size will be presented. No adjustment will be made for multiple comparisons. An 
effect size of differences in the ≥ 0.3 range will be considered potentially clinically 
meaningful. All summaries will be provided for the OITT and ITT populations.   
8.4.7 
Health Care Resource Utilization  
For this study the following health care resource utilization (HCRU) parameters collected 
during the study observation period will be summarized for the Safety population: 
 Type of admission (hospital, intensive care unit (ICU), emergency unit) 
 Descriptive statistics of number of hospital visits per subject 
 Descriptive statistics of number of ICU visits per subject 
 Descriptive statistics of number of emergency room (ER) visits per subject 
 Total person-years of observation 
 Total days of hospitalization 
 Days of hospitalization per person-year 
 Total days of ICU visit 
 Days of ICU visit per person-year 
Person-years total is calculated as the sum of  [(end date of safety observation period – first 
dose date +1)/365.25] across all subjects in the given treatment group.  For placebo 
crossover subjects, total person-year is calculated as the sum of [(end date of safety 
observation period – first dose date of open-label cabozantinib +1)/365.25] across all 
subjects who have crossed over.  To calculate the per person year value for a subject for a 
HCRU parameter, the numerator is the sum of the days or visits for that subject for the 
parameter; and the denominator is the applicable person-years of observation as defined.  
8.4.8 
Pharmacokinetics (PK)  
Pharmacokinetics analyses are outside the scope of this plan.  A separate PK analysis plan 
and report will be provided. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 51 of 72 
 
 
8.5 
Subgroups 
The following subgroups based on baseline characteristics and stratification factors will be 
explored for the primary efficacy endpoints and Overall Survival.  Summary tables will be 
provided for the OITT and ITT populations. Forest plots will be provided for hazard 
ratios/odds ratio as applicable. 
o Receipt of prior lenvatinib per CRF 
 
Yes 
 
No 
o Receipt of prior sorafenib per CRF 
 
Yes 
 
No 
o Receipt of prior sorafenib  and lenvatinib  per CRF 
 
Yes 
 
No 
o Age category per CRF 
 ≤ 65 years 
 
> 65 years 
o Sex 
 Male 
 Female 
o Race 
 Asian 
 Black or African American 
 White 
 Rest of the races reported/Not Reported 
o Regions 
 Asia  
 USA/Canada/Europe  
 Rest of the world 
 
o ECOG Performance status at baseline:  
 0  
 1 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 52 of 72 
 
o Prior VEGFR-TKI anticancer therapy agents for DTC per subject per history of non-
radiation anticancer therapy CRF (0, 1, ≥2) 
o Prior receipt of RAI (Yes, No) 
o Histology 
 Papillary 
 Follicular 
o Bone Metastasis per Investigator 
 No 
 Yes 
o Important Visceral Metastasis per Investigator 
 No  
 Yes 
o Liver Metastasis per Investigator 
 No 
 Yes 
o Lung Metastasis per Investigator 
 No 
 Yes 
 
9 
SAFETY SUMMARIES  
All safety analyses will be performed on data as described in Section 4.6 for subjects in the 
Safety population. No formal statistical comparison between the two treatments arms is 
planned.  
 
Safety and tolerability will be assessed by the incidence of treatment emergent-adverse 
events (TEAEs), changes in laboratory parameters and vital signs from baseline, and ECOG 
PS. 
 
An Independent Data Monitoring Committee (IDMC) will monitor safety of the subjects 
during the study on a regular basis. The committee will operate independently from the 
Sponsor and the clinical investigators. 
 
The primary responsibility of the IDMC is to review the accumulating safety data on a 
regular and an ad hoc basis and make recommendations to the Sponsor regarding the 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 53 of 72 
 
continued conduct of the study. Safety data will be provided at regular intervals to the 
IDMC in the form of summary reports or data listings from the Sponsor (blinded) or its 
designated representative (unblinded). 
 
Details regarding IDMC membership, schedule and format of meetings, format for 
presentation of data, access to interim data, method and timing of providing interim reports 
to the IDMC, and other issues relevant to committee operations are described in the IDMC 
charter. 
 
The IDMC members will use their expertise, experience, and judgment to evaluate the safety 
data from the trial and to recommend to the Sponsor whether the trial should continue or be 
stopped early for safety. No formal statistical rules recommending early stopping for safety 
are planned. 
 
9.1 
Adverse Events  
Adverse event terms recorded on the CRF will be mapped to preferred terms and system 
organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The severity 
of AEs will be measured by CTCAE version 5 guidelines. The investigator will judge each 
event to be “not related” or “related” to study treatment. 
 
A TEAE is defined as any event with an onset date on or after the date of the first dose of 
study drug or any ongoing event on the date of the first dose of study drug that worsens in 
severity after the date of the first dose of study drug.  
 
Only TEAEs with an onset date through the end of the safety observation period (see 
Section 4.6) will be tabulated in summary tables.  
 
For the purpose of calculating treatment emergence and inclusion in summary tables, 
incomplete onset dates will be imputed as detailed in Appendix A. 
 
For AE reporting, percentages ≥10% will generally be presented as integers, those <10% 
will be presented with 1 decimal place (e.g. X.X%). Rounding rules are provided in 
Appendix B. The calculations of percentages will be based on original unrounded values. 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 54 of 72 
 
An overall summary of adverse events will be provided with the number and percent of 
subjects who experienced the following types of events during the safety observation period 
(unless otherwise noted as “at any time” below) in each treatment arm: 
 
 Subjects with a TEAE 
 Subjects with a Related TEAE 
 Subjects with a Serious TEAE 
 Subjects with a Serious Related TEAE at any time 
 Subjects with a Worst-Grade 3 or 4 TEAE  
 Subjects with a Worst-Grade 3 or 4 Related TEAE 
 Subjects with a Worst-Grade 4 TEAE   
 Subjects with a Worst-Grade 4 Related TEAE 
 Subjects with a Grade 5 TEAE (death) ≤ 30 days after the last dose of the study 
treatment 
 Subjects with a Grade 5 TEAE (death) judged not to be causally related to disease 
under study ≤ 30 days of last dose of the study treatment 
 Subjects with a Related Grade 5 TEAE at any time (all treatment-related deaths) 
 Subjects with a Related Grade 5 TEAE (death) ≤ 30 days after the last dose of the 
study treatment 
 Subjects with a TEAE leading to Dose Modification 
 Subjects with a TEAE leading to Dose Reduction 
 Subjects with a TEAE leading to Dose Hold 
 Subjects with TEAE leading to Treatment Discontinuation 
 TEAEs not causally related to disease under study 
o TEAEs related to study treatment 
o TEAEs not related to study treatment 
 TEAEs causally related to disease under study 
o TEAEs related to study treatment 
 
The following summaries of AEs will be provided: 
 
TEAE included 
Row-levels (sorted by) 
Columns will Display 
Subject Incidence by SOC, Preferred Term and Severity 
All 
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related  
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Serious  
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Subject Incidence by Preferred Term and Severity 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 55 of 72 
 
TEAE included 
Row-levels (sorted by) 
Columns will Display 
All 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 1, Grade 2, Grade 3, 
Grade 4, Grade 5 
Related  
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related  
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Serious 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related and Serious 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose reduction 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose reduction 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose hold 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose hold 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose modification 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose modification 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Not Causally Related to Disease 
Under Study  Leading to Study 
Treatment Discontinuation  
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Not Causally Related to Disease 
Under Study and Related to 
Study Treatment and Leading to 
Study Treatment Discontinuation 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Not Causally Related to Disease 
Under Study and Not Related to 
Study Treatment and Leading to 
Study Treatment Discontinuation 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Causally Related to Disease 
Under Study and  Leading to 
Study Treatment Discontinuation 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Causally Related to Disease 
Under Study and Related to 
Study Treatment and Leading to 
Study Treatment Discontinuation 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Subject Incidence of AEs with Odds ratio, Relative Risk  and Risk Difference  
All 
PT 
(descending frequency of difference) 
Worst severity: 
All grades, Grades 3/4 
≤ 30 days after the last dose of 
study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
AEs  judged not to be causally 
related to disease under study≤ 
30 days of last dose of study 
treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
Related to study treatment at 
any time 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
Related to study treatment and ≤ 
30 days after the last dose of 
study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
Subject Incidence by Special Criteria  
Events with an increase  in the 
experimental  arm of  ≥5% (All 
Grades) or ≥2% (Grade 3/4) 
SOC and PT 
(SOC per MedDRA standard, PT within 
SOC by decreasing difference in 
percent  for All Grades) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Subject incidence of non-serious 
adverse event with  frequency in 
SOC and PT 
(SOC per MedDRA standard, PT within 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 56 of 72 
 
TEAE included 
Row-levels (sorted by) 
Columns will Display 
the experimental arm of ≥ 5% 
(Any Grade) 
SOC by decreasing frequency in 
percent for All Grades) 
All 
PT 
(descending frequency of difference in 
percent between the two arms for All 
Grades) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of difference in 
percent between the two arms for  
Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
 
The following data listings will also be provided with indicators for grade, relationship, 
seriousness, dose day of the event start/stop, days since last dose, actions taken with study 
treatment: 
 All AEs 
 Grade 5 AEs (deaths) 
 Serious AEs other than death 
 All AEs that led to treatment discontinuation 
All adverse events summaries will also be provided for the O-Safety population.  
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 57 of 72 
 
9.2 
Events to Monitor 
The sponsor has defined a set of events to monitor (ETM) to track adverse events known to 
be associated with TKIs or VEGF pathway inhibition that have potentially serious 
consequences, or were determined to warrant ongoing routine surveillance. Each ETM is a 
grouped clinical term comprising a broad set of AEs that are related pathophysiologically 
and provide a consistent, reproducible, and transparent compilation of safety information 
over time. These ETMs may also be identified in the current cabozantinib product labeling 
(MTC US package insert and EU SmPC) or in the EU RMP document as known or potential 
risks and precautions.  
The following summaries will be provided for ETMs (Appendix F) for the Safety and O-
Safety Populations: 
Table 12: Summaries for ETM 
TEAE included 
Row-levels (sorted by) 
Columns 
Subject Incidence by SOC, Preferred Term and Severity 
All ETM AEs 
ETM and PT 
(ETM , PT within ETM by descending 
frequency) 
Worst severity: 
All Grades, Grade 3-4, Grade 4, Grade 5 
All ETMs of  Grade >=3 
ETM and PT 
(ETM, PT within ETM by descending 
frequency) 
Worst severity: 
Grade >=3, Grade 3, Grade 4, Grade 5 
Subject Incidence by Special Criteria  
All ETM AEs by age (≤65 years, 
>65 years), ECOG, region, race, 
sex 
ETM and PT 
(ETM , PT within ETM by descending 
frequency) 
Worst severity: 
Any Grades, Grade 3-4, Grade 4, Grade 5 
Time to First Occurrence 
All ETM AEs and Grade >=3 
Time to first occurrence of Adverse Events to 
Monitor by Group Term 
 
 
9.3 
Treatment-emergent Adverse Events Adjusted by Treatment Duration 
Summaries will be provided for all TEAEs, TEAEs with Grade 3 and above,  and serious 
TEAEs adjusted for treatment exposure for the safety population.  The AE rate 
(episode/subject-year) will be calculated as (Total occurrence for an AE episode/Total 
Subject-years for the respective treatment group).  Total subject years for the respective 
treatment group is calculated as the sum of treatment exposure time in (years) for all 
subjects in the given treatment group.  Treatment exposure in years is calculated as 
(treatment exposure in days as defined in Section 6.5/365.25).  A single episode of an AE is 
defined from onset through resolution, or, if ongoing, to the end of the reporting period. 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 58 of 72 
 
9.4 
Deaths 
All subject deaths (Grade 5 TEAEs) will be summarized for all subjects in the Safety and O-
Safety populations.    
Deaths will be summarized in two main categories as follows: 
 Deaths after receipt first dose of study treatment and ≤ 30 days after the date of 
receipt of the last dose of study treatment  
 Deaths > 30 days after the date of receipt of last dose of study treatment  
 
In addition, under each category causality to study disease  will also be summarized.  
All reported subject deaths will be listed. 
9.5 
Laboratory Assessments 
9.5.1 
Variables 
The following treatment-emergent laboratory abnormalities will be summarized. A 
treatment emergent laboratory abnormality is defined as any laboratory abnormality with an 
onset date on or after the date of the first dose of study drug.  
 
Category 
Abnormality 
SDTM 
LBTESTCD 
Grading 
System 
Hematology 
WBC increased 
WBC decreased 
WBC 
CTCAE 
 
ANC decreased 
NEUT 
CTCAE 
 
Lymphocytes increased 
Lymphocytes decreased 
LYM 
CTCAE 
 
Platelets decreased 
PLAT 
CTCAE 
 
Hemoglobin increased 
Hemoglobin decreased 
HGB 
CTCAE 
Serum chemistry 
Albumin decreased 
ALB 
CTCAE 
 
ALP increased 
ALP 
CTCAE 
 
Amylase increased 
AMYLASE 
CTCAE 
 
ALT increased 
ALT 
CTCAE 
 
AST increased 
AST 
CTCAE 
 
Calcium, corr increased 
Calcium, corr decreased 
CACORR 
 
CTCAE 
 
 
 
 
 
Creatinine increased 
CREAT 
CTCAE 
 
GGT increased 
GGT 
CTCAE 
 
Glucose increased 
Glucose decreased 
GLUC 
CTCAE 
 
LDH increased 
LDH 
Sponsor 
 
Lipase increased 
LIPASE 
CTCAE 
 
Magnesium increased 
Magnesium decreased 
MG 
CTCAE 
 
Phosphate decrease 
PHOS 
CTCAE 
 
Potassium  increased 
K 
CTCAE 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 59 of 72 
 
Category 
Abnormality 
SDTM 
LBTESTCD 
Grading 
System 
Potassium decreased 
 
Sodium increased 
Sodium decreased 
NA 
CTCAE 
 
Total bilirubin increased 
BILI 
CTCAE 
 
Uric acid  increased2 
CYURIAC 
CTCAE 
Urine chemistry 
UPCR increased 
PROTCRT 
Sponsor 
Endocrinology1 
Thyroid Stimulating Hormone increased 
Thyroid Stimulating Hormone decreased 
TSH 
HLN 
1 TSH is held in the SDTM “chemistry” laboratory category; will use HLN = high, low, normal classification based on normal 
range 
2 Uric acid increases will be graded only as Grade 1 or Grade 4. Grade 2 is not defined per CTCAE v4 and Grade 3 cannot be 
distinguished from Grade 1 based upon the result alone. 
 
 
Sponsor-defined grades are to be applied to the following analytes: 
LDH 
 Grade 1 if >ULN to ≤ 2xULN 
 Grade 2 if >2xULN to ≤ 3xULN 
 Grade 3 if >3xULN 
UPCR 
 Grade 1 if  ≥ 17.0 to ≤ 121.0 mg/mmol 
(≥0.15 to ≤1.0 mg/mg) 
 Grade 2 if  >121.0 to ≤ 396.0 mg/mmol 
(>1.0 to <3.5 mg/mg) 
 Grade 3 if  >396.0 mg/mmol  
 
(>3.5 mg/mg) 
 
9.5.2 
Analysis 
All laboratory data parameters and visits will include flags for values above or below 
laboratory reference ranges. Toxicity grades will be assigned programmatically by applying 
the CTCAE v 5 guidelines. Only results with assessment dates through the end of the safety 
observation period (see Section 4.6) will be tabulated in summary tables for the Safety and 
O-Safety populations.  
Laboratory summaries will be presented in SI units. Continuous laboratory test results will 
be summarized by treatment group using descriptive statistics for actual values and for 
changes from baseline by scheduled visit.  For test results which are below or above the 
quantification level, the imputed values as described in Appendix C will be used for deriving 
the grade and then summarized. Line graphs for mean change from baseline ± standard 
deviation will also be presented at each scheduled visit (with visits shown on x-axis) for the 
following laboratory parameters.  
o Renal function 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 60 of 72 
 
 Blood urea nitrogen (BUN) 
 Creatinine 
o Liver function panel 
 Total bilirubin 
 ALT  
 AST 
Tables summarizing the incidence of laboratory abnormalities by baseline and maximum 
post-baseline CTCAE grade over all records will be presented.  In addition, the following 
summaries will also be presented: 
A] Liver function abnormalities will be assessed as follows: 
 Shift from baseline based on normal ranges  
 Summaries of subjects meeting Hy’s Law laboratory screening criteria as shown 
below: 
o >3× ULN (ALT or AST), >2× ULN Total Bilirubin, and <2× ULN ALP 
o >3× ULN (ALT or AST), >2× ULN Total Bilirubin, and ≥2× ULN ALP 
o >3× ULN (ALT or AST), >2× ULN Total Bilirubin, and  missing  ALP 
B] For renal failure surveillance, a summary of subjects meeting renal failure laboratory 
screening criteria as shown below will be provided: 
 Serum creatinine >= 3.0xULN and >= 2.0x baseline value or 
 eGFR ≤ 50% of the baseline value or 
 eGFR < 30 mL/min/1.73 m2  and ≥ 25% reduction from  the baseline value 
eGFR = 186 x (Creatinine in mmol per L / 88.4)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.210 if black)  [from the UK CKD eGuide on the Renal 
Association website: http://egfrcalc.renal.org/] 
C] Categorical summaries for baseline status for TSH and Free T4 will be presented. In 
addition categorical summaries for post-baseline TSH and Free T4 status among 
subjects with TSH and Free T4 in the normal range at baseline will also be presented. 
 
For descriptive summaries for change from baseline analyses, only central lab results will be 
considered. For analyses of shift in grade from baseline or worst grade after baseline, all 
available results will be considered regardless of whether from the central or local lab. 
 
Summary Type 
Include central 
lab results? 
Include local 
lab results? 
Subject-Incidence of Treatment Emergent Laboratory 
Y 
Y 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 61 of 72 
 
 
Summary Type 
Include central 
lab results? 
Include local 
lab results? 
Abnormalities in Selected Laboratory Tests by CTCAE 
Grade 
Change from Baseline in Laboratory Values 
Y 
N 
Shift from Baseline in Laboratory Values by CTCAE 
Grade 
Y 
Y 
Shift from Baseline in Laboratory Values by 
High/Low/Normal 
Y 
Y 
Shift from Baseline in Laboratory Values by Sponsor-
defined Grades 
Y 
Y 
Subject-Incidence of Laboratory Abnormalities with a 
Between-Arm Difference of ≥5% (All Grades) or ≥2% 
(Grades 3-4) 
Y 
Y 
9.6 
Vital Signs 
9.6.1 
Variables 
The following vital signs will be summarized. 
 Weight 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
9.6.2 
Analysis 
Subject incidence of clinically meaningful changes since baseline for weight and blood 
pressure will be presented for the Safety and O-Safety populations as shown below: 
 Proportion of subjects with weight loss ≥ 10% after first dose 
 Subjects with at least 2 post-baseline assessments and who got worse since baseline 
and met the following blood pressure criteria on 2 or more visits (need not be 
consecutive) after first dose (JNC criteria were modified to include single 
measurement per time point when triplicate assessments were unavailable; JAMA 
2003:289:2560): 
o Pre-hypertension: SBP 120-139 mmHg or DBP 80-89 mmHg 
o Stage 1: SBP 140-159 mmHg or DBP 90-99 mmHg 
o Stage 2: (SBP >= 160 mmHg and DBP <120) or DBP 100-119 mmHg 
o Stage 3: DBP >= 120 mmHg 
Only results with assessment dates through the end of the safety observation period (see 
Section 4.6) will be considered for the summaries. 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 62 of 72 
 
9.7 
ECOG Performance Status 
For the purpose of evaluating safety, ECOG will be summarized as shift from baseline tables 
for, at minimum, the worst value recorded after the initiation of study treatment. Only results 
with assessment dates through the end of the safety observation period (see Section 4.6) will 
be tabulated in summary tables for the Safety and O-Safety populations. 
Frequencies of ECOG worsening of ≥ +1 and +2 change from baseline to worst value after 
first dose will also be summarized. 
9.8 
Electrocardiogram (ECG) 
Only results with assessment dates through the end of the safety observation period (see 
Section 4.6) will be considered for summaries. The following categorical summaries will be 
presented for the Safety and O-Safety populations:  
  Number of subjects with triplicate average QTc > 500 ms after first dose per 
investigator 
 Number of subjects with change from baseline in QTc > 60 ms after first dose per 
investigator  
For the above summaries, the most-recent average value from triplicate measurements taken 
before first dose will be used as baseline. If no triplicate measurements were taken before 
first dose, the most-recent single value taken before first dose will be used as baseline. 
9.9 
IMPACT OF COVID-19 PANDEMIC 
Summaries and analyses to describe and/or assess the impact of the COVID-19 pandemic 
will be included in a future amendment to this plan.   These may include tabulations of 
COVID-19 related protocol deviations and patterns of missing data, summaries of COVID-
19 AEs, the addition of a per-protocol population, and comparative analyses of selected 
endpoint before, during and after the pandemic.   
10 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
Important protocol deviations as pre-specified in the study Protocol Deviation Management 
Plan. In accordance with ICH E3, Important eligibility deviations (as documented on study 
CRFs and Important post-randomization protocol deviations tracked in the study clinical 
trial management system (CTMS) will be identified and listed separately by study center and 
subject. Important deviations will be summarized for the OITT and ITT populations by 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 63 of 72 
 
deviation code (a standardized description e.g. “did not satisfy eligibility criteria” or 
“received prohibited medication”)  
11 
DATA QUALITY ASSURANCE 
The Clinical, Data Management, Biostatistics, and Medical Writing departments at Exelixis 
and designees will work diligently and collaboratively to ensure that the data collected and 
analyzed for this study are of the highest quality. In addition to electronic evaluation of the 
data and verification of data from source documents at the respective sites, a data review 
meeting will be held to review the data and correct significant data anomalies before the 
study database is locked or data are extracted for the purpose of analysis. 

 
XL184-311 Statistical Analysis Plan Version 1.0 Final / Exelixis, Inc. /09 September 2020 
   Page 64 of 72 
 
12 
REFERENCES 
Chobanian AV, Bakris GL, et al. The Seventh Report of the Joint National Committee On 
Prevention, Detection, Evaluation, And Treatment of High Blood Pressure:The 
JNC 7 Report. JAMA 2003 May 21; 289(19):2560-72. 
Clopper, C. and Pearson, S. The use of confidence or fiducial limits illustrated in the case of 
the Binomial. Biometrika 1934;26: 404-413. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, USDHHS, NIH, 
NCI; publish date May 28, 2009 (v4.03: June 14, 2010). 
FDA Guidance for Industry: Multiple Endpoints in Clinical Trials (draft, January 2017). 
FDA Guidance for Industry: E9 (R1) Statistical Principles for Clinical Trials: Addendum: 
Estimands and Sensitivity Analysis in Clinical Trials (Draft, June 2017)FDA 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drug 
and Biologics (December 2018).  
International Conference on Harmonization ICH E9: Statistical principles for clinical trials 
(05 February 1998 [Europe], September 1998 [FDA]). 
Reenen MV, Janssen B et al. EQ-5D-5L User Guide, Version 3.0, 2019 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 65 
of 72 
 
 
Appendix A: Date Imputation Rules 
Incomplete Cancer Diagnosis Date 
If year is missing (or completely missing): do not impute 
If only day is missing: set to 15th of the month. 
If day and month are missing: set to July 1st. 
If either imputation rule above results in a diagnosis date > informed consent: 
 
set diagnosis date to the date of informed consent - 1. 
 
Incomplete Adverse Event Onset Date 
Assumption: For on-study Adverse Events. 
If year is missing (or completely missing): set to the date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
 
If year = year of first dose: set the date to the first dose date. 
 
If year < year of first dose: set month and day to December 31st. 
 
If year > year of first dose: set month and day to January 1st. 
If month and year are present and day is missing: 
 
If year = year of first dose, and: 
If month = month of first dose: set day to day of first dose. 
 
 
If month < month of first dose: set day to last day of month. 
 
 
If month > month of first dose: set day to 1st day of month. 
 
If year < year of first dose: set day to last day of month. 
 
If year > year of first dose: set day to 1st day of month. 
For all other cases: set to date of first dose. 
 
Incomplete Concomitant Medication Start Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
Set month and day to January 1st. 
If year and month are present and day is missing: 
Set day to 1st day of month. 
 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 66 
of 72 
 
Incomplete Concomitant Medication End Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
Set month and day to December 31st. 
If year and month are present and day is missing: 
Set day to last day of the month.  
 
Incomplete Subsequent Anticancer Therapy Start Date 
Assumption: Anticancer therapies reported on the Subsequent Anticancer Therapy CRF. 
If year is missing (or completely missing): set to date decision to discontinue study treatment + 1 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
If year > year of the last dose: Set month and day to January 1st. 
If year = year of the last dose: Set month and day to date of decision to discontinue study 
treatment + 1 
If year and month are present and day is missing: 
Set day to 1st day of month if the resulting imputed date is greater than date of decision to 
discontinue study treatment or if the month is before the month of date of decision to 
discontinue study treatment and year is same or before the year of the date of decision to 
discontinue study treatment. Otherwise set the imputed date to date of decision to 
discontinue study treatment  + 1 
 
Incomplete Death Date 
Identify date of last known alive (LA) prior to death from the following: 
 Date of decision to discontinue study treatment from End of Treatment CRF 
 Date of last radiographic assessment from End of Radiographic Follow Up CRF 
 Date last known alive from Survival Follow Up CRF 
 Date of last lab assessment from the Labs dataset 
 
If year is missing (or completely missing):  set to date of LA + 1 
If only day is missing: set to the maximum of the first of month or LA + 1 
If month and day are missing: 
If year of LA = year of death 
Set death date to date of LA + 1 
If year of most-recent contact < year of death 
Set month and day to Jan 1st. 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 67 
of 72 
 
Incomplete Study Treatment Start Date  
Define previous sequential dosing “milestone” as the latest of previous dose stop date, previous 
dose hold stop date, date of first dose or randomization date. 
If year is missing (or completely missing): set to date of previous sequential dosing “milestone” + 
1 
 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set to January 1st 
If year and month are present and day is missing: set to the first day of the month 
If the imputed date is before the previous sequential dosing “milestone”: set to the date of previous 
sequential dosing “milestone” + 1 
 
Incomplete Study Treatment Stop Date  
Define next sequential dosing “milestone” as the earliest of next dose start date, next dose hold 
start date, date of last dose from EOT CRF or the cutoff date. 
If year is missing (or completely missing): set to date of next sequential dosing “milestone” - 1 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set to December 31st 
If year and month are present and day is missing: set to the last day of the month 
If the imputed date is after the next sequential dosing “milestone”: set to the date of next sequential dosing 
“milestone” - 1 
 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 68 
of 72 
 
Appendix B: Rounding Rules for Reported Percentages  
For percentages ≥10%: 
 Values >= X.5 or above round to X+1. 
 Values >X but <X.5 round to X. 
For percentages <10%: 
 Values >= X.Y5 or above round to X.Y+0.1. 
 Values >X.Y but <X.Y5 round to X.Y. 
 
 
 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 69 
of 72 
 
Appendix C: Imputation Rules for Laboratory Values Outside of Quantification 
Range 
 Lab values below the lower level of quantification (LLQ) that are reported as 
“<LLQ” or “≤LLQ” in the database will be imputed by LLQ x 0.99 for analysis 
purposes. However the original value will also be maintained. 
 
 Lab values above the upper level of quantification (ULQ) that are reported as 
“>ULQ” or “≥ULQ” in the database will be imputed by ULQ x 1.01 for analysis 
purposes. However the original value will also be maintained. 
  
  

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 70 
of 72 
 
Appendix D: EQ-5D-5L Index Value Conversion Guidelines  
The EQ-index conversion algorithm (EQ-5D-5L User Guide Version 3.0 September 
2019. Available from: http://www.euroqol.org/about-eq-5d/publications/user-
guide.html): 
 
o Calculate health state 
o Each of the 5 dimensions comprising the EQ-5D descriptive system is 
divided into 5 levels of perceived problems: 
 
 Level 1: indicating no problem 
 Level 2: indicating slight problems 
 Level 3: indicating moderate problems 
 Level 4: indicating severe problems 
 Level 5: indicating extreme problems 
 
o A unique health state is defined by combining 1 level from each of the 5 
dimensions. 
For example, state 11111 indicates no problems on any of the 5 
dimensions, while state 12345 indicates no problems with mobility, slight 
problems with washing or dressing, moderate problems with doing usual 
activities, severe pain or discomfort and extreme anxiety or depression.  
Note that missing values will be coded as ‘9’.  Ambiguous values will be 
treated as missing values. 
 
o EQ-index values for each country = health state * the country specific 
conversion factors for each dimension (EQ-5D-5L Index Value Calculator, 
version 1) 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 71 
of 72 
 
Appendix E: Estimands Terminology 
Source: ICH E9 R1 
 
Estimand Attributes: 
# 
Estimand Attribute 
1 
The population, that is, the patients targeted by the scientific question. 
2 
The variable (or endpoint), to be obtained for each patient, that is required to 
address the scientific question. 
3 
The specification of how to account for intercurrent events to reflect the scientific 
question of interest. 
4 
The population-level summary for the variable which provides, as required, a basis 
for a comparison between treatment conditions. 
 
 
Strategies for Addressing Intercurrent Event(s): 
 
Strategy 
Description 
Treatment 
policy 
The occurrence of the intercurrent event is irrelevant: the value for the 
variable of interest is used regardless of whether or not the 
intercurrent event occurs. 
Composite 
The occurrence of the intercurrent event is taken to be a component of 
the variable, i.e. the intercurrent event is integrated with one or more 
other measures of clinical outcome as the variable of interest. 
Hypothetical 
A scenario is envisaged in which the intercurrent event would not 
occur: the value to reflect that scientific question of interest is that 
which the variable would have taken in the hypothetical scenario 
defined. 
Principal 
stratum 
The target population might be taken to be the principal stratum (see 
Glossary) in which an intercurrent event would not occur. 
While on 
treatment 
Response to treatment prior to the occurrence of the intercurrent event 
is of interest. 

 
XL184-311 Statistical Analysis Plan Version 1.0 / Exelixis, Inc. /09 September 2020  
 
Page 72 
of 72 
 
Appendix F: List of Events to Monitor to Summarize 
(i) 
Abscess – All 
(ii) 
Abscess – Intra-abdominal and pelvic 
(iii) 
Arterial thrombotic events 
(iv) 
Venous and mixed/unspecified thrombotic events 
(v) 
 Fistula  
(vi) 
Gastrointestinal perforations 
(vii) 
Hemorrhage of severity grade 3 and  above 
(viii) 
Osteonecrosis of the jaw (ONJ) or ONJ-related events 
(ix) 
Palmar-Plantar Erythrodysethesia (PPE) Syndrome 
(x) 
Proteinuria 
(xi) 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
(xii) 
Wound complications 
(xiii) 
Hypertension 
(xiv) 
Diarrhea 
(xv) 
QT prolongation