A Phase II Study to Evaluate the Effects of Cabozantinib in Patients With Unresectable/Metastatic Adrenocortical Carcinoma
Phase: PHASE2
Conditions: Metastatic Carcinoma in the Adrenal Cortex, Stage III Adrenal Cortex Carcinoma AJCC v8, Stage IV Adrenal Cortex Carcinoma AJCC v8, Unresectable Adrenal Cortex Carcinoma
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2016-0741 
Protocol Title 
A Phase II Study to Evaluate the Effects of Cabozantinib in 
Patients with Unresectable/Metastatic Adrenocortical 
Carcinoma 
Protocol Phase 
2 
Protocol Version 
MOD005 
Version Date 
December 2020 
Protocol PI 
Mouhammed Habra 
Department 
Endocrine Neoplasia and Hormonal Disorders 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
137080 
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Page 1 of 62 
  
 
A PHASE II STUDY TO EVALUATE THE EFFECTS OF CABOZANTINIB IN 
PATIENTS WITH UNRESECTABLE/METASTATIC ADRENOCORTICAL 
CARCINOMA 
PROTOCOL NUMBER:2016-
0741 
 
STUDY DRUG: 
Cabozantinib (XL184) 
 
 
SPONSOR: THE 
UNIVERSITY OF TEXAS MD 
ANDERSON CANCER 
CENTER 
 
 
 
DATE FINAL: 
December 2020 
 
 
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TABLE OF CONTENTS 
A PHASE II STUDY TO EVALUATE THE EFFECTS OF CABOZANTINIB IN 
PATIENTS WITH UNRESECTABLE/METASTATIC ADRENOCORTICAL 
CARCINOMA ...........................................................................................................1 
TABLE OF CONTENTS .....................................................................................................2 
1 
BACKGROUND AND RATIONALE .......................................................................9 
1.1 
Background ........................................................................................................9 
1.2 
Cabozantinib (XL184) .....................................................................................13 
1.2.1 
Pharmacology ......................................................................................13 
1.2.2 
Cabozantinib Nonclinical Toxicology .................................................14 
1.2.3 
Clinical Experience ..............................................................................14 
1.2.3.1 
Clinical Summary .......................................................................14 
1.2.3.2 
Clinical Safety Profile .................................................................14 
1.2.3.3 
Clinical Pharmacokinetics ..........................................................15 
1.2.3.4 
Clinical Activity ..........................................................................16 
1.3 
Rationale ..........................................................................................................17 
1.3.1 
Rationale for the Study, Dose, and Schedule .......................................17 
2 
STUDY OBJECTIVES AND DESIGN ...................................................................18 
2.1 
Study Objectives ..............................................................................................18 
2.2 
Study Design ....................................................................................................19 
2.2.1 
Overview of Study Design ...................................................................19 
2.3 
Blinding and randomization .............................................................................19 
2.4 
Study Sites .......................................................................................................19 
2.5 
Withdrawals .....................................................................................................19 
2.5.1 
Replacements .......................................................................................20 
3 
TREATMENTS ........................................................................................................20 
3.1 
Composition, Formulation, and Storage ..........................................................20 
3.1.1 
Investigational Treatment ....................................................................20 
3.1.2 
Cabozantinib Tablets ...........................................................................20 
3.2 
Dose, Schedule and Route ...............................................................................20 
3.3 
Cabozantinib Dose Modifications, Interruptions, and Discontinuation ...........21 
3.3.1.1 
Cabozantinib Dose Reinstitution and Reescalation ....................23 
3.3.2 
Warnings and Precautions and Guidelines for the Management of 
Adverse Events ....................................................................................24 
3.3.2.1 
Guidelines for Management of Potential Adverse Events ..........25 
3.3.2.2 
Gastrointestinal Disorders ...........................................................25 
3.3.2.3 
Hepatobiliary Disorders ..............................................................26 
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3.3.2.4 
Hematological Disorders ............................................................27 
3.3.2.5 
Fatigue, Anorexia, and Weight Loss ...........................................27 
3.3.2.6 
Skin Disorders .............................................................................27 
3.3.2.7 
Wound Healing and Surgery .......................................................28 
3.3.2.8 
Hypertension ...............................................................................28 
3.3.2.9 
Thromboembolic Events .............................................................30 
3.3.2.10 
Proteinuria ...................................................................................30 
3.3.2.11 
Corrected QTc Prolongation .......................................................31 
3.3.2.12 
Hypophosphatemia .....................................................................32 
3.3.2.13 
Thyroid Function Disorders ........................................................33 
3.3.2.14 
Hemorrhagic Events....................................................................33 
3.3.2.15 
GI Perforation/Fistula and Non-GI Fistula Formation................34 
3.3.2.16 
Osteonecrosis of the Jaw .............................................................34 
3.3.2.17 
Angioedema ................................................................................35 
3.3.2.18 
Musculoskeletal and Connective Tissue Disorders ....................35 
3.3.2.19 
Respiratory, Thoracic and Mediastinal Disorders ......................35 
3.4 
Concomitant Medications and Therapies.........................................................35 
3.4.1 
Anticancer Therapy ..............................................................................35 
3.4.2 
Other Medications ................................................................................35 
3.4.3 
Allowed Therapies ...............................................................................35 
3.4.4 
Prohibited or Restricted Therapies .......................................................37 
3.4.5 
Potential Drug Interactions ..................................................................38 
3.5 
Compliance ......................................................................................................39 
3.6 
Study Drug Accountability ..............................................................................39 
4 
STUDY POPULATION ...........................................................................................40 
4.1 
Inclusion Criteria .............................................................................................40 
4.2 
Exclusion Criteria ............................................................................................41 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................43 
5.1 
Pre-Treatment Period .......................................................................................43 
5.2 
Treatment Period ..............................................................................................44 
5.3 
Post-Treatment Period .....................................................................................46 
5.4 
Laboratory Assessments ..................................................................................48 
5.5 
Tumor Assessment ...........................................................................................49 
5.6 
Outside Physician Participation During Treatment .........................................49 
6 
SAFETY ...................................................................................................................50 
6.1 
Adverse Events and Laboratory Abnormalities ...............................................50 
6.1.1 
Adverse Events ....................................................................................50 
6.1.2 
Serious Adverse Events .......................................................................50 
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6.1.3 
Serious Adverse Event Reporting ........................................................51 
6.1.4 
Regulatory Reporting ...........................................................................52 
6.2 
Other Safety Considerations ............................................................................52 
6.2.1 
Laboratory Data ...................................................................................52 
6.2.2 
Pregnancy .............................................................................................52 
6.2.3 
Medication Errors/Overdose ................................................................52 
6.2.4 
Follow-Up of Adverse Events .............................................................52 
7 
STATISTICAL CONSIDERATIONS......................................................................52 
7.1 
Analysis Population .........................................................................................52 
7.1.1 
Safety Population .................................................................................53 
7.2 
Safety Analysis ................................................................................................53 
7.2.1 
Adverse Events ....................................................................................53 
7.3 
Sample Size ......................................................................................................53 
7.4 
Safety and Futility Monitoring.........................................................................53 
7.5 
Analysis Plan ...................................................................................................54 
8 
OTHER ANALYSES ...............................................................................................55 
9 
DATA QUALITY ASSURANCE ............................................................................57 
10 
STUDY COMMITTEES ..........................................................................................57 
11 
ETHICAL ASPECTS ...............................................................................................57 
11.1 
Local Regulations ............................................................................................57 
11.2 
Informed Consent.............................................................................................57 
11.3 
Institutional Review Board/Ethics Committee ................................................57 
11.4 
Future Use of Patient Samples .........................................................................58 
12 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................58 
13 
CONDITIONS FOR TERMINATING THE STUDY .............................................58 
14 
STUDY DOCUMENTATION AND RECORDKEEPING .....................................58 
14.1 
Investigator’s Files and Retention of Documents ............................................58 
14.2 
Source Documents and Background Data .......................................................59 
14.3 
Audits and Inspections .....................................................................................59 
14.4 
Case Report Forms ...........................................................................................59 
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15 
MONITORING THE STUDY ..................................................................................59 
16 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...59 
17 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............60 
18 
REFERENCES .........................................................................................................61 
 
 
 
 
LIST OF TABLES 
Table 3-1: 
Cabozantinib Tablet Components and Composition ................................ 20 
Table 3-2: 
Dose Reductions of Cabozantinib ............................................................. 22 
Table 3-3: 
Dose Modifications of Cabozantinib for Treatment-Related AEs ............ 23 
Table 3-4: 
Management of Treatment-Emergent Hand-Foot Syndrome (PPES) ...... 28 
Table 3-5: 
Management of Hypertension Related to Cabozantinib ........................... 29 
Table 3-6: 
Management of Treatment-emergent Proteinuria ..................................... 31 
Table 5-1: 
Study Assessments .................................................................................... 45 
Table 7-1: 
Stopping boundaries for PFS4 and study-related toxicity ........................ 53 
Table 7-2: 
Operating Characteristics (based on simulations from 10,000 trials) ....... 54 
 
LIST OF APPENDICES 
Appendix A: Performance Status Criteria ...................................................................... 62 
 
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LIST OF ABBREVIATIONS 
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AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration time curve 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CHF 
congestive heart failure 
CrCl 
creatinine clearance 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DLT 
dose-limiting toxicity 
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ESC 
Exelixis Safety Committee 
ESMO 
European Society of Medical Oncology 
 
 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
 
 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Conference on Harmonisation 
IME 
important medical event 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LFT 
liver function test 
LHRH 
luteinizing hormone-releasing hormone 
LMWH 
low molecular weight heparin 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
NCI 
National Cancer Institute 
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NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PD 
progressive disease 
PE 
pulmonary embolism 
PI 
principal investigator 
PPE 
palmar-plantar erythrodysesthesia 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
once daily 
ONJ 
osteonecrosis of the jaw 
QTc 
corrected QT interval 
QTcF 
QTc calculated by the Friderica formula 
RBC 
red blood cell 
RPLS 
reversible posterior leukoencephalopathy syndrome 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
TFT 
thyroid function test 
TIA 
transient ischemic attack 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UPCR 
urine protein/urine creatinine ratio 
VEGF(R) 
vascular endothelial growth factor (receptor) 
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1 
BACKGROUND AND RATIONALE 
1.1 
Background 
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis and limited 
response to therapy (1-3). Recurrence after surgical resection is very common in patients presenting with 
localized disease and systemic therapy is the primary treatment for patients with recurrent or advanced 
disease. The combination of cisplatin/etoposide/doxorubicin/mitotane is the current standard of care for 
metastatic ACC. This combination has a suboptimal response rate of 23% with median time to 
progression of about 5 months while second line therapy (streptozocin with mitotane) has response rate of 
9% with median time to progression of about 2 months (4).  
In order to understand factors related to chemotherapy resistance and to identify better treatment 
options, we recently studied the role of hepatocyte growth factor (HGF) and its receptor (cMET) in ACC. 
Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in 
human ACC samples was positively associated with cancer-related biologic processes, including 
proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC 
cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin 
RNA-mediated knockdown or pharmacologic inhibition of cMET with cabozantinib suppressed cell 
proliferation and tumor growth (Figure 1)(5).  
 
 
 
Figure 1: Increased HGF/cMET signaling is 
associated with enhanced proliferation, tumor 
growth, and reduced apoptosis in adrenocortical 
carcinoma .A, cell viability measured by MTT 
assay ofNCI-H295R cells cultured at different 
concentrations of recombinant human HGF for 
7 days. B, knockdown of MET expression by 
lentiviral shRNAs decreases adrenocortical 
carcinoma cell proliferation. C, knockdown of 
MET expression by lentiviral shRNAs 
decreases percentages of adrenocortical 
carcinoma cells in G2–M or S-phase. D, cell-
cycle progression analysis showing the 
important role of cMET in adrenocortical 
carcinoma cell proliferation. E, mean tumor 
volume in mice at different weeks after 
xenografting of H295R–GFP–shRNA or 
H295R-cMET-shRNA cells (5 mice per group). 
F, mean tumor weights in mice 6 weeks after 
xenografting of H295R-GFP-shRNA or 
H295R-cMET-shRNA cells (5 mice per group; 
left) and representative images of xenografted 
tumors harvested from the mice (right; scale 
bars, 5mm). G, mean volumes of tumors formed 
from xenografted H295R cells at different 
weeks after treatment of randomized control 
and cabozantinib treated mice (6mice per 
group). H, mean weights of tumors from 
randomized control and cabozantinib-treated 
mice after 6 weeks of treatment (6 mice per 
group; left) and representative images of 
xenografted tumors harvested from the mice 
(right; scale bars, 5 mm). Statistical significance 
of data in F and H was calculated by one-way 
ANOVA (Reference Phan L et al. Cancer 
Research 2015). 
 
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Moreover, exposure of ACC cell line to commonly used treatments in ACC (mitotane, cisplatin, 
or radiation) rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., 
CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. 
Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma 
growth and resistance to commonly used treatments (5). Targeting cMET, alone or in combination with 
other drugs, could provide a breakthrough in the management of this aggressive cancer.  
 
Based on these preclinical data, we have recently used cabozantinib outside clinical trial to treat a 
patient with progressive ACC that failed multiple lines of treatment (Figure 2A). Within 4 weeks of 
cabozantinib use, target lesions stopped growing and slightly reduced in size (one target lesion in left 
upper quadrant reduced from 8.3 cm in greatest dimension at baseline to 7 cm and second target lesion in 
the upper pole of the right kidney reduced from 7.3 cm in greatest dimension to 6.6 cm)(Figure 2B). This 
patient had grade 1 fatigue and mucositis and continued to have very good performance status (ECOG 1) 
while on cabozantinib 60 mg daily. Cabozantinib was maintained and radiological stability was 
demonstrated stable disease for 12 months on therapy. 
 
 
 
 
 
 
Hypothesis  
Figure 2: A. ACC 
progression prior to 
cabozantinib use (upper 
panel target lesion in left 
upper quadrant and lower 
panel target lesion 2 in 
upper pole of right kidney). 
B. response of target 
lesions to cabozantinib 60 
mg daily. 
The response was 
preserved at 12 months on 
treatment 
 
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cMET activation is correlated with cancer hallmarks in ACC and appears to be an important 
mechanism in resistance to therapy. cMET and VEGFRs cooperate to promote tumor angiogenesis and 
cMET up-regulation may occur as a response to the VEGFs pathway inhibition leading to tumor 
resistance and growth(6).  
Cabozantinib is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity that targets 
the VEGF, c-MET, and RET receptors. Cabozantinib drug is approved for the treatment of medullary 
thyroid carcinoma and was recently approved in renal cell carcinoma (7, 8). Receptor tyrosine kinases 
(RTKs) regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair (12). Dysregulation of RTKs by mutation, gene rearrangement, gene 
amplification, and overexpression of both receptor and ligand have been implicated as causative factors in 
the development and progression of numerous human cancers. The RTK c-Met, encodes the high-affinity 
receptor for hepatocyte growth factor (HGF) or scatter factor (SF) (12). c-Met and HGF are each required 
for normal mammalian development and have been shown to be important in cell migration, morphogenic 
differentiation, and organization of three-dimensional tubular structures (e.g., renal tubular cells, gland 
formation, etc.), as well as cell growth, angiogenesis, and tumor invasiveness and metastasis. Up-
regulation of MET is found in a wide range of malignancies including thyroid, prostate, ovarian, lung, and 
breast cancers, and is associated with more aggressive and invasive phenotypes of cancer cells in vitro 
and metastases in vivo (see latest version of the Investigator’s Brochure). C-Met-driven metastasis may 
be exacerbated by a number of factors, including tumor hypoxia caused by selective inhibition of the 
VEGF pathway.  
Evidence linking c-Met and HGF as causative or progression factors in human cancers include: 
(1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; (2) the 
correlation of receptor and ligand overexpression with disease severity and outcome; (3) genetic alteration 
of c-Met by mutation of gene amplification in multiple cancer types; (4) introduction of c-Met and HGF 
(or mutant c-Met) into cell lines, conferred the properties of tumorgenicity and metastatic propensity on 
engineered cells; (5) introduction of c-Met or HGF as transgenes into the germline of mice resulted in 
primary and secondary neoplasms; and (6) the inhibition of c-Met or HGF function with dominant-
negative receptors, antibody antagonists (both Met and HGF), and biologic antagonists (e.g., NK4) have 
reversed cancer-associated phenotypes such as motility, invasion and proliferation of tumor cells, and 
tumor growth and dissemination in vivo (12). A wide variety of human cancers, including brain, 
colorectal, gastric, and lung, demonstrate dysregulated c-Met activity (13), either by means of c-Met 
kinase overexpression (14), or increased autocrine and/or paracrine secretion of the c-Met ligand, 
HGF/SF . These alterations have been implicated in tumor progression and metastasis, and a high 
constitutive activation of c-Met has been correlated with poor clinical prognosis (15).  
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, proliferation, 
survival, and enhanced vascular permeability(16). Increased expression of VEGFR2, often in combination 
with VEGFR3, has been observed in the tumor vascular endothelium in most common human solid tumor 
types, on tumor cells in melanoma and hematological malignancies, and in colitis-associated colon cancer 
(17) . High VEGFR2 expression is an unfavorable prognostic biomarker in hepatocellular carcinoma 
(HCC), and correlated with triple-negative (i.e., therapy-resistant) breast cancer. The expression of VEGF 
and VEGFR-2 as well as microvessel density were higher in ACC compared to benign adrenal neoplasms 
(18). Despite of this, targeting VEGF signaling alone had limited clinical efficacy in ACC (19). 
Therefore, simultaneous inhibition of cMET and VEGFRs by cabozantinib provides a broad spectrum of 
antineoplastic activity and its use in ACC is appealing based on recently published preclinical data and 
early reports of human experience.  
As an exploratory objective, we also aim to generate crucial preliminary data about the changes in 
immune markers in association with cabozantinib study. The adrenal gland can be recognized by the 
immune system and develop autoimmune adrenalitis and adrenal insufficiency (Addison’s disease). 
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Mononuclear cells infiltrating (mainly CD3+)  the adrenal glands on autopsies are more common in 
people 60 years and older (63%) compared to subjects <49 years old (7%). CD4+ cells are more common 
than CD8+ cells and are thought to have been activated by interleukin 2 receptor(20). In Merkel cell 
carcinoma, higher CD3+ and CD8+ immune infiltrates at the periphery of tumor were associated with 
improved overall survival (21).  Tyrosine kinase inhibitors are increasingly used in multiple malignancies. 
Imatinib mesylate has known clinical benefits in gastrointestinal stromal tumors (GIST) and has been 
reported to have direct effects on tumor cells as well as indirect immunostimulatory effects on 
lymphocytes and high densities of CD3+ tumor infiltrating cells correlated with PFS (22). The number of 
infiltrating FoxP3(+) regulatory T cells and macrophages is even higher in  in metastatic GIST compared 
to primary lesions. Imatinib and sunitinib increased the secretion of anti-inflammatory IL-10 in 
macrophage cultures thus affecting the tumor microenvironment (23). Similarly, cabozantinib has direct 
effect on tumor cells as well as immunomodulatory effect that enhances the sensitivity of tumor cells to T 
cell-mediated lysis (24). Clinical trials using immunotherapy in ACC are emerging and it remains unclear 
if prior use of immunotherapy will affect the response to TKIs in ACC or if using TKIs can enhance the 
response to subsequent immunotherapy. Thus, data generated from patients in this study can further our 
understanding of the complex effect of TKIs on tumor immune infiltrate and could lead to new treatment 
combinations in the future.  
Analyses of tumor and blood samples: These studies will be performed at MDACC in collaboration with 
Dr. Ignacio Wistuba who is supervising the Translational Molecular Pathology - Immunoprofiling 
Laboratory (TMP-IL). Patient samples will be collected to perform immunologic analyses. The study will 
allow for the collection of blood samples to be drawn at the time of routine blood-draw to assess circulating 
immune markers. Whole blood, plasma, serum, peripheral blood mononuclear cells (PBMCs) and other 
secreted markers (such as cytokines) may be collected at 3 time points (before  and during treatment and at 
time of disease progression) and processed at the TMP-IL for further downstream analyses.  
Optional biopsies will be used for immune-profiling analysis (core needle biopsies (CNBs). Fresh tissue 
samples will be sent immediately after collection to TMP-IL. Core biopsy is typically performed using 21-
18 gauge needle and with condition permitting, up to 5 cores should be collected, including 2 for clinical 
processing and 3 additional passes will be attempted to obtain the research core samples.   
Cores 1 and 2: Immediate and overnight fixation in 10% buffered formalin for paraffin embedding, 
usually within 20-24 hour after fixation. For biopsies performed on Friday, fixation time may 
extend to 48 hours (FFPE samples) 
Cores 3-4: Flash freezing in liquid nitrogen.  
Core 5: Flow cytometry analysis of TIL and TME on fresh tissue. 
 
All tissue specimens collected will be reviewed by reference pathologists. At least, three types of QC 
activities for specimens collected will be performed: a) histology/cytology examination of the tissues and 
cells to confirm the presence of tumor cells, as well as their abundance (tumor cellularity); b) tissue 
quality assessment of fresh specimens for extraction of DNA, RNA and proteins, and to prepare histology 
specimens such as whole sections for immunohistochemistry and immunofluorescence; and, c) quality 
assessment of DNA, RNA and protein extracted. All histology stained samples will be scanned and digital 
images will be available for review. 
Using immunohistochemistry (IHC) and multiplex immunofluorescence (IF) approach that is available 
in the TMP-IL (Drs. Wistuba and Jaime Rodriguez Canales), we will quantitatively assess multiple immune 
markers. Fresh frozen tissues will be also used for analysis of immune markers. IHC and IF will be 
performed using autostainers. All antibodies used will be optimized for IHC/IF by examination of positive 
and negative controls and testing of the antibodies standard methods, including Western blotting. All 
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pathology slides will be scanned into a digital image scanner and analyzed using image analysis software; 
IHC analysis will be performed using the Aperio Image Toolbox™ (Leica Biosystems) and IF analysis 
using the Vectra Inform™ (Perkin-Elmer) software. Nucleic acids (DNA and RNA) and protein extraction: 
Blood (plasma and PMBCs) and tumor (CNB) samples will be subjected to extraction using standard 
methods. 
DNA and RNA quantity and integrity will be assessed using NanoDrop 1000 
spectrophotometer (Nanodrop technologies) and Pico-green analyses.  Also, protein lysate will be 
extracted using standard methods. 
High order flow cytometry panels will focus on 1) delineation of major immune cell types (T cells, B cells, 
NK cells, DC), 2) determination of T cell differentiation status and limited functionality (IFNγ, TNFα, GB) 
and 3) defining the expression level of costimulatory and coinhibitory molecules on T cells and their 
respective receptors such as PD-L1 on infiltrating myeloid cells or tumor. Briefly, 50 cc of heparinized 
peripheral blood from cancer patients prior to the initiation of treatment, during treatment, and at time of 
progression will be processed fresh (within 24h of being drawn) for PBMC isolation by ITB. PBMCs will 
be cryopreserved and stored in Liquid Nitrogen until use. Flow cytometric analysis will be conducted 
retrospectively on cryopreserved PBMCs. When appropriate, cells will be thawed and stained immediately. 
All time points belonging to a patient will be stained and acquired at the same time to avoid any technical 
variation (sample at time of progression will be omitted for responders if analysis needs to be completed 
when patient is still responding). We expect that half of the study participants will agree to have the optional 
biopsies and we anticipate to collect blood samples from all participants. 
 
 
 
In another exploratory objective, we will attempt to assess the role of genetic variants of drug disposition 
genes on the PK of cabozantinib.For the past decades, pharmacogenomic association studies have 
revealed a significant influence of genetic variants on the disposition of various drugs prescribed in the 
cancer care setting (e.g. tacrolimus, irinotecan, 5-fluorouracil and 6-MP).  This continues to be an 
increasingly popular area of pharmacological research.  Cabozantinib is a substrate for both cytochrome 
P450 3A4 (CYP3A4) and the drug transporter MRP2, and maybe a substrate for other obscure drug 
metabolizing enzymes and transporters.  Hypothetically, single nucleotide polymorphisms (SNPs) in 
these genes may affect cabozantinib PK.  However, there is a dearth of data regarding these potential 
genetic associations.  To preliminary assess for potential associations, a single blood sample (~ 10 ml) 
will be collected at the patient’s first clinic visit for exploratory pharmacogenomic testing.  Whole blood 
will be collected into pre-labelled lavender-top collection tubes.  Genomic DNA will be isolated from 
each blood sample using the GenElute Blood Genomic DNA Kit (Sigma-Aldrich Co), or similar DNA 
extraction kit, in the Pharmaceutics Research Laboratory (Division of Pharmacy, Department of 
Pharmacy Research) by trained research staff.  Isolated DNA will be transferred to pre-labelled, de-
identified cryovials and frozen at -80ºC in the Pharmacy Research Laboratory freezer prior to shipment.  
DNA samples will be shipped by research staff in the Pharmacy Research Laboratory to an external 
laboratory (Avera Institute for Human Genetics, Sioux Falls, SD) for analysis of over 2,000 
polymorphisms in drug disposition genes using the powerful DMET™ Plus Array (Affymetrix). 
Preliminary pharmacogenomic data will be a crucial step towards further understanding the disposition of 
cabozantinib in cancer patients.  
1.2 
Cabozantinib (XL184) 
1.2.1 
Pharmacology 
Full details can be found in the latest version of the Investigator’s Brochure. Cabozantinib is a 
potent inhibitor of multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and 
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angiogenesis (see latest version of the Investigator’s Brochure). The primary targets of cabozantinib are 
MET (c-MET) and vascular endothelial growth factor receptor 2 (VEGFR2); additional targets include 
RET, AXL, KIT, and TIE-2. Both c-Met and VEGFR2 are important mediators of tumor growth and 
tumor angiogenesis, and in vivo pharmacodynamic activity of cabozantinib against c-Met and VEGFR2 
has been demonstrated in both preclinical and clinical studies.  
1.2.2 
Cabozantinib Nonclinical Toxicology 
Full details can be found in the latest version of the Investigator’s Brochure. The carcinogenic 
potential of cabozantinib is being evaluated in an ongoing two-year bioassay in rats. No carcinogenic 
signal was observed in the rasH2 transgenic mouse model following cabozantinib dosing for 26 
weeks. 
1.2.3 
Clinical Experience 
Cabozantinib has two FDA approved indications. First FDA approval for cabozantinib 
(Cometriq) was on November 29, 2012 to treat medullary thyroid carcinoma and on 21 March 2014, it 
was approved by the European Commission for the treatment of adult subjects with progressive, 
unresectable locally advanced or metastatic MTC. Recently cabozantinib (Cabometyx) was FDA 
approved and on April 25, 2016 for the treatment of advanced renal cell carcinoma in patients who have 
received prior anti-angiogenic therapy.  
A summary of 15 clinical studies of cabozantinib for oncology is included in the latest version of 
theInvestigator's Brochure). In addition, there are eleven clinical pharmacology studies; nine were 
conducted in healthy subjects alone, one study was conducted that included healthy subjects and subjects 
with renal impairment, and one study was conducted that included healthy subjects and subjects with 
hepatic impairment. In addition to these company-sponsored clinical studies, twenty-six investigator-
sponsored trials (ISTs) and thirteen National Cancer Institute-Cancer Therapy Evaluation Program (NCI-
CTEP) trials have enrolled subjects in oncology indications.  
1.2.3.1 
Clinical Summary 
Details of all studies may be found in the latest version of the Investigator’s Brochure. 
1.2.3.2 
Clinical Safety Profile 
A pooled analysis through 29 February 2016 included 2410 subjects with cancer who had 
been treated with single-agent cabozantinib in company-sponsored clinical trials. The subjects in that 
dataset were predominately White (83.4%) and male (77.5%) with a median age of 64.0 years. For 
ongoing studies, serious adverse event (SAE) data are summarized in the latest version of the 
Investigator's Brochure.  
1.2.3.2.1 Adverse Events 
The severity of AEs was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 
versions 3.0 and 4.0, and AE and SAE PTs were coded with the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17.0 for all studies. For AEs and SAEs, multiple occurrences of the same 
event in any individual subject are counted once at the highest grade reported. Events that were assessed 
as possibly related or probably related to cabozantinib are reported as “related,” and events that were 
assessed as not related or unlikely related to cabozantinib are reported as “not related.”  In 2410 subjects 
treated with single-agent cabozantinib, AEs seen in ≥ 10% of subjects are summarized in the latest 
version of the  Investigational Brochure. 2404 (99.8%) subjects had at least one AE while drug related 
AEs happened in 2324 (96.4%) subjects. 1512 subjects( 62.7%) had ≥ grade 3 AEs.  Most common drug 
related AEs include diarrhea 1300 (53.4%), fatigue 1281 (53.2%), nausea 1062(44.1%), decreased 
appetite 1080 (44.8%), vomiting 612(25.4%), weight loss 671 (27.8%), palmar-plantar 
erythrodysaesthesia syndrome 819(34%), constipation 345(14.3%), hypertension 603(25%), dysgeusia 
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605(25.1%), dysphonia 520(21.6%), asthenia 434(18%), dyspnea (187(7.8%), anemia 217(9%), 
stomatitis446(18.5%), abdominal pain 232(9.6%),aspartate aminotransferase increase 382(15.9%), back 
pain 56(2.3%), mucosal inflammation 423(17.6%), pain in extremity 180 (7.5%), headache 149(6.2%), 
alanine aminotransferase elevation 343 (14.2%), rash 300(12.4%), hypothyroidism 301(12.5%), cough 
84(3.5%), peripheral edema 101(4.2%), dizziness 154(6.4%), arthralgia 76(3.2%), dyspepsia 224(9.3%), 
hypokalemia 136(5.6%), dry mouth 231 (9.6%), urinary tract infection 31( 1.3%), dry skin 219(9.1%), 
hypomagnesemia 170(7.1%), dehydration 139(5.8%), muscle spasms 147(6.1%), hair color change 
243(10.1%), pyrexia 44(1.8%), and insomnia 82(3.4%).    
 
1.2.3.2.2 Serious Adverse Events 
In 2410 subjects, drug related serious adverse events experienced by 602 subjects (25%) treated with 
single-agent cabozantinib excluding events of disease progression. This included 516 subjects (21.4%) 
who had ≥ grade 3 SAE.   
These drug related SAEs are summarized in the latest version of the Investigational Brochure and 
included pulmonary embolism in 85 patients (3.5%), vomiting 40 patients(1.7%), nausea 47 patients( 
2%), dehydration 41 (1.7%), general health deterioration 13(0.5%), pneumonia 5(0.2%), anemia 
17(0.7%), abdominal pain 13(0.5%), diarrhea 42(1.7%), deep vein thrombosis 21(0.9%), fatigue 
27(1.1%), asthenia 20(0.8%), back pain 1, dyspnea 7(0.3%), pyrexia 5(0.2%), urinary tract infection 
4(0.2%), acute renal failure 7(0.3%), convulsion 5(0.2%), hyponatremia 15(0.6%), decreased appetite 
19(0.8%), sepsis 5(0.2%), bone pain 0, metastatic pain 1, pleural effusion 7(0.3%), and confusion 
7(0.3%).  
  
1.2.3.2.3 Deaths 
In cancer subjects treated with single agent cabozantinib, death was reported in 10 out of 2410 subjects 
(0.4%) including death related to AEs in 3 (0.1%). Sudden death was seen in 2 patients (0.1%). [(see 
latest version of the Investigator's Brochure)]. 
1.2.3.3 
Clinical Pharmacokinetics 
Cabozantinib pharmacokinetics as single agent in clinical studies are summarized in [(see latest version of 
the Investigator's Brochure)]. 
Population PK analysis of cabozantinib was performed using data collected from 289 cabozantinib-treated 
subjects from XL184-301, XL184-001, and XL184-201 with solid tumors including MTC following oral 
administration of 140 mg daily doses. The predicted effective half-life is approximately 55 hours, V/F is 
approximately 349 L, and CL/F at steady-state is estimated to be 4.4 L/h. The terminal half-life (for 
predicting drug washout) is approximately 120 hours. Following oral administration of cabozantinib, 
Tmax ranged from 2 to 5 hours post-dose. Repeat daily dosing of cabozantinib at 140 mg for 19 days 
resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared with a single dose 
administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound in human 
plasma (≥ 99.7%) (see latest version of the Investigator Brochure).  
The PK evaluation of cabozantinib in the pediatric population is ongoing. A population PK analysis did 
not identify clinically relevant differences in clearance of cabozantinib between females and males or 
between Whites (89%) and non-Whites (11% [<4% were Asian]). Cabozantinib PK was not affected by 
age (20-86 years).  
Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, 
approximately 81% of the total administered radioactivity was recovered with 54% in feces and 27% in 
urine.  
Results from a PK study of cabozantinib in subjects with renal impairment indicated that the 
ratios of geometric least squares (LS) mean for maximum plasma concentration (Cmax) and AUCs 
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(AUC0-t and AUC0-inf) were 19% and 30% higher, respectively, for subjects with mild renal impairment 
compared to subjects with normal renal function. For subjects with moderate renal impairment, both 
Cmax and AUCs appeared to be similar when compared to subjects with normal renal function 
(differences: < 3% and < 7%, respectively). Results from a PK evaluation of cabozantinib in subjects with 
hepatic impairment indicated that exposure (AUC0-inf) of cabozantinib was increased by about 81% and 
63% in subjects with mild and moderate hepatic impairment, respectively.  
A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted 
conditions in healthy subjects administered a single 140-mg oral cabozantinib dose.  
Cabozantinib is a substrate of cytochrome P450 (CYP3A4) in vitro. Inhibition of CYP3A4 reduced the 
formation of the cabozantinib N-oxide metabolite by > 80%.  
Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 in vitro reduced the 
formation of the cabozantinib N-oxide metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect 
on cabozantinib metabolite formation (ie, a < 20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation. In 
healthy volunteers, cabozantinib AUC was increased 38% with co-administration of the strong CYP3A4 
inhibitor ketoconazole (XL184-007) and decreased 77% with co-administration of the strong CYP3A4 
inducer rifampin (XL184-006). 
  
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor 
of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of 
CYP3A4 (estimated Kiapp = 282 μM) in human liver microsome (HLM) preparations. The IC50 value was 
10.1 μM for CYP2B6 and IC50 values were > 20 μM for CYP1A2, CYP2D6, and CYP3A4 isozymes. 
Cabozantinib at steady-state plasma concentrations (≥ 100 mg/day daily dosing for a minimum of 21 
days) showed no effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and 
AUC) in subjects with solid tumors (XL184-008). Cabozantinib is an inducer of CYP1A1 mRNA in 
human hepatocyte incubations (ie, 75-100% of CYP1A1 positive control β-naphthoflavone induction), 
but not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated 
enzyme activities.  
Administration of the PPI esomeprazole resulted in no clinically-relevant effect on cabozantinib 
plasma PK in healthy volunteers (XL184-018).  
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport 
activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have 
the potential to increase plasma concentrations of co-administered substrates of P-gp.  
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. Therefore, concomitant use of MRP2 inhibitors (eg, cyclosporine, delaviridine, 
efavirenz, emtricitabine) should be approached with caution, and subjects taking MRP2 inhibitors 
should be monitored for AEs.  
 
Of interest, There was a differences in PK parameters from the two PopPK analyses ( RCC patients and 
MTC patients) and appears to be result of higher clearance in MTC subjects, but the reason for this is not 
known (see latest version of the Investigator Brochure).  
1.2.3.4 
Clinical Activity 
In phase 3 clinical trial in subjects with progressive MTC (214 on cabozantinib vs. 109 placebo),   the 
estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (HR 0.28; 95% 
CI, 0.19 to 0.40; p < .001). Prolonged PFS with cabozantinib was observed across all subgroups including 
by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). The final analysis of the 
secondary endpoint of OS included 218 events (217 were required) and showed a trend for increased 
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survival in the cabozantinib arm. The estimated median OS for the cabozantinib arm was 26.6 months 
versus 21.1 months for the placebo arm (HR = 0.85; 95% CI 0.64, 1.12; p = 0.2409).  
In phase 3 trial of 119 subjects with advanced castrate resistant prostate carcinoma with bone metastases, 
the enrollment was stopped before the planned study population size of 246; a total of 119 subjects were 
enrolled. The primary analysis for the ITT population (n=119) did not demonstrate an improvement in the 
proportion of subjects with a pain response at Week 6 confirmed at Week 12 the cabozantinib arm 
compared with the mitoxantrone plus prednisone arm; the proportions of subjects experiencing a 
confirmed pain response were 15% and 17% for the two arms, respectively.  
The secondary endpoints were BSR per IRF and OS. BSR was defined as a ≥ 30% decrease in total bone-
scan lesion area compared with baseline without soft-tissue disease progression. The analysis of BSR per 
IRF at Week 12 without progression in soft tissue per mRECIST 1.1 demonstrated a greater improvement 
in the cabozantinib arm (31%; 95% CI: 20%, 43%) compared with the mitoxantrone plus prednisone arm 
(5%; 95% CI: 0%, 11%). In the analysis of OS that included 78 deaths out of the 196 pre-specified deaths, 
the stratified HR was 0.70 (95% CI: 0.44, 1.10).  
In phase 3 study in renal cell carcinoma, 658 patients were randomized to either everolimus or 
cabozantinib. Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus with 
median duration of treatment of 7.6 months with cabozantinib and 4.4 months with everolimus. Dose 
reductions were needed in 60% of subjects treated with cabozantinib and the median average daily dose 
was 44 mg of cabozantinib. The rate of treatment discontinuation due to adverse events not related to 
renal-cell carcinoma was 9% in the cabozantinib group. 
1.2.3.5 
Translational Medicine 
Details can be found in the latest version of the Investigator’s Brochure. 
1.3 
Rationale 
1.3.1 
Rationale for the Study, Dose, and Schedule  
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis and limited 
response to therapy (1-3). Recurrence after surgical resection is very common in patients presenting with 
localized disease and systemic therapy is the primary treatment for patients with recurrent or advanced 
disease. The combination of cisplatin/etoposide/doxorubicin/mitotane is the current standard of care for 
metastatic ACC. This combination has a suboptimal response rate of 23% with median time to 
progression of about 5 months while second line therapy (streptozocin with mitotane) has response rate of 
9% with median time to progression of about 2 months (4).  
In order to understand factors related to chemotherapy resistance and to identify better treatment 
options, we recently studied the role of hepatocyte growth factor (HGF) and its receptor (cMET) in ACC. 
Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in 
human ACC samples was positively associated with cancer-related biologic processes, including 
proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of ACC 
cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin 
RNA-mediated knockdown or pharmacologic inhibition of cMET with cabozantinib suppressed cell 
proliferation and tumor growth (Figure 1)(5). Moreover, exposure of ACC cell line to commonly used 
treatments in ACC (mitotane, cisplatin, or radiation) rapidly induced pro-cMET expression and was 
associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further 
implicating cMET in the anticancer drug response. Together, these data suggest an important role for 
HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments 
(5). Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the 
management of this aggressive cancer. 
Based on these preclinical data, we have recently used cabozantinib outside clinical trial to treat a 
patient with progressive ACC that failed multiple lines of treatment (Figure 2A). Within 4 weeks of 
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cabozantinib use, target lesions stopped growing and slightly reduced in size (one target lesion in left 
upper quadrant reduced from 8.3 cm in greatest dimension at baseline to 7 cm and second target lesion in 
the upper pole of the right kidney reduced from 7.3 cm in greatest dimension to 6.6 cm)(Figure 2B). This 
patient had grade 1 fatigue and mucositis and continued to have very good performance status (ECOG 1) 
while on cabozantinib 60 mg daily. Cabozantinb was maintained and radiological stability was 
demonstrated for 12 months on therapy. 
Hypothesis  
cMET activation is correlated with cancer hallmarks in ACC and appears to be an important 
mechanism in resistance to therapy. cMET and VEGFRs cooperate to promote tumor angiogenesis and 
cMET up-regulation may occur as a response to the VEGFs pathway inhibition leading to tumor 
resistance and growth(6).  
Cabozantinib is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity that targets 
the VEGF, c-MET, and RET receptors. This drug was approved for the treatment of medullary thyroid 
carcinoma and recently approved in renal cell carcinoma (7, 8). Therefore, simultaneous inhibition of 
cMET and VEGFRs by cabozantinib provides a broad spectrum of antineoplastic activity and its use in 
ACC is appealing based on recently published preclinical data and preliminary human experience.  
We also hypothesize that cabozantinib use has immunomodulatory effect on ACC that can 
include a change in tumor infiltrating lymphocytes profile. The optional biopsies from few patients has 
the potential of furthering our understanding about the effect of cabozantinib on tumor immunity and 
could open the door for combination therapy in the future.  
The study plan is to use cabozantinib with initiation dose is 60 mg daily by mouth. The dose can 
be reduced to 40 mg then 20 mg a day based on tolerability and adverse effects. Subjects may continue to 
receive study treatment until they experience unacceptable drug-related toxicity or disease progression.  
Considering the possibility mitotane induction of CYP3A4 that can reduce cabozantinib levels, subjects 
who used mitotane within 6 months of study participation will have PK levels (obtained on day 1 and day 
29+/- 5 days) analyzed after collection to allow increasing cabozantinib dose to 80 mg a day if AUC for 
plasma cabozantinib was < 50% of expected AUC. Further dose titration in these subjects to 60 mg, 40 
mg and 20 mg will be done based on tolerability and adverse effects. In the remaining study subjects 
(estimated 12 out of 18 patients), samples will be analyzed a-posteriori after completing study enrollment.   
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
The objectives of this study are as follows: 
Primary objective: To estimate progression free survival at 4 months 
Secondary objectives:  
1. Best overall response rate  
2. Overall survival (O.S) 
3. Toxicity assessment by the Common Terminology Criteria for Adverse Events 
(CTCAE) V4.0 
Exploratory objectives:  
1. Pharmacokinetics of cabozantinib plasma levels to assess correlation with response to 
therapy 
2. Steroid hormone biomarkers as markers of disease response.  
3. Study the effect of cabozantinib on immune markers by obtaining optional biopsy and 
blood samples collection at baseline, during therapy and at time of progression. 
4. Pharmacogenomics of drug disposition gene variants that potentially influence 
cabozantinib PK.  
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2.2 
Study Design 
2.2.1 
Overview of Study Design 
This is an open label Phase II clinical trial using cabozantinib in patients with unresectable/advanced 
ACC. 
2.3 
Blinding and randomization 
N/A 
2.4 
Study Sites 
This study will be conducted The University of Texas MD Anderson IND Office 
2.5 
Withdrawals 
Subjects may discontinue study treatment or withdraw their consent to participate in the study at any time 
without prejudice. The investigator may withdraw a subject from study treatment or from the study if, in 
his or her clinical judgment, it is in the best interest of the subject or if the subject cannot comply with the 
protocol.  
In addition, any of the following conditions require discontinuation of the subject from study treatment: 
• 
An AE or intercurrent illness that in the opinion of the investigator warrants the subject’s 
withdrawal from study treatment; 
• 
The investigator believes it  is not in the best interest of the subject to continue on study 
• 
Specific conditions described in the Management of Adverse Events Sections 3.3.2 and 3.3.2.1; 
• 
Necessity for treatment with other anticancer treatment prohibited by protocol; 
• 
Sexually active subjects who refuse to use medically accepted barrier methods of contraception 
(e.g, male condom, female condom) during the course of the study and for 4 months after 
discontinuation of study treatment; 
• 
Women who become pregnant or are breastfeeding; 
• 
If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 weeks, the 
subject will have study treatment discontinued unless there is unequivocal evidence that the 
subject is benefitting. In this situation, a subject may be able to restart therapy with a dose 
reduction upon resolution of the toxicity and with agreement of the principal investigator / MD 
Anderson IND Office; 
• 
Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol; 
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator; 
• 
The minimum dose of study treatment will be 20 mg once daily (qd). Subjects who cannot 
tolerate 20 mg qd will have study treatment discontinued; 
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• 
Progressive disease (PD) or the subject no longer experiences clinical benefit as determined by 
the investigator 
2.5.1 
Replacements 
NA 
3 
TREATMENTS 
3.1 
Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the pharmacy manual and inventoried in 
accordance with applicable state and federal regulations. 
3.1.1 
Investigational Treatment  
 
Chemical Name:  
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
 
3.1.2 
Cabozantinib Tablets  
Exelixis internal number: XL184 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate equivalent to 20 
mg and 60 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, hydoxypropyl 
cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and Opadry® yellow. All 
tablet strengths are prepared from a common blend and are distinguished by shape. The 20 mg tablets are 
round and the 60 mg tablets are oval. The components of the tablets are listed in Table 3-1. 
Table 3-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disinegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
3.2 
Dose, Schedule and Route 
Subjects will receive cabozantinib orally at a (starting) dose of 60 mg once daily, on a continuous basis.  
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Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to eat for at least 2 
hours before and at least 1 hour after taking cabozantinib.  Subjects should be instructed to take their 
cabozantinib dose at approximately the same time every day.  If a subject misses a dose, the dose may be 
taken later only if it is within 12 hours of when the missed dose should have been taken.  The missed dose 
should not be made up if it is within 12 hours of the next scheduled dose.   
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The tablets should not 
be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be avoided by subjects 
taking cabozantinib. 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 3.3 below. 
3.3 
Cabozantinib Dose Modifications, Interruptions, and Discontinuation 
Subjects will be monitored for AEs from the time of from the time of first study intervention through their 
last follow-up visit (30 days after the date of the last dose of cabozantinib treatment.) Subjects will be 
instructed to notify their physician immediately at the onset of any AE. Causality assessment of AEs will 
be determined by the investigator. AE severity will be graded by the investigator in accordance with 
CTCAE v.4.0.  
The following should be taken into consideration in decisions regarding dose modifications (reductions or 
interruption): 
• 
As a general approach all AEs should be managed with supportive care at the earliest signs of toxicity 
considered related to the study treatment. Should this be ineffective, dose interruptions and/or 
reductions should be considered to prevent worsening of toxicity.  
• 
Dose modification criteria for cabozantinib are shown in Table 3-3. Dose interruptions and/or 
reductions should be implemented for unacceptable toxicity. Doses may be modified at any time 
while a subject is on treatment. 
• 
The assigned starting dose for cabozantinib is 60 mg/day. 2 dose reduction levels of cabozantinib are 
permitted (see Table 3-2). 
• 
Dose reductions or interruptions may also occur in the setting of lower grade toxicity than defined in 
Table 3-3, if the investigator feels it is in the interest of a subject’s safety and will optimize drug 
tolerability. 
• 
Interruption of cabozantinib treatment for cabozantinib-related AEs may occur at any time per 
investigator discretion. If treatment is interrupted due to related AEs for more than 6 weeks, 
cabozantinib should be discontinued unless there is unequivocal evidence that the subject is 
benefitting. In this situation, a subject may be able to restart therapy with a dose reduction upon 
resolution of the toxicity per the discretion of the investigator. 
• 
Dose interruptions for reason(s) other than related AEs (e.g., surgical procedures) can be longer than 
6 weeks per the discretion of the investigator. 
• Considering the possibility mitotane induction of CYP3A4 that can reduce cabozantinib 
levels, subjects who used mitotane within 6 months of study participation will have PK levels 
(obtained on day 1 and day 29+/- 5 days) analyzed after collection to allow increasing 
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cabozantinib dose to 80 mg a day if AUC for plasma cabozantinib was <50% of expected 
AUC provided AE levels are ≤ grade 1. Further dose titration in these subjects to 60 mg, 40 mg 
and 20 mg will be done based on tolerability and adverse effects. The remaining study 
participants will have their samples analyzed after completing study enrollment.  
• 
 
Guidelines for the management of specific AEs are provided in Section 3.3.2.  
Table 3-2: 
Dose Reductions of Cabozantinib 
Assigned dose 
First Dose Level Reduction 
Second Dose Level Reduction 
60-mg cabozantinib oral qd 
40-mg cabozantinib oral qd 
20-mg cabozantinib oral qd 
qd, once daily 
Cabozantinib should be discontinued if a qd dose of 20-mg cabozantinib (minimum dose) is not 
tolerated 
 
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Table 3-3: 
Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.4.0 Grade 
Recommended Guidelines for Management a 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib 
treatment at the current dose level if AE is manageable 
and tolerable. 
Grade 2 AEs which are tolerable 
and are easily managed 
 
Grade 2 AEs which are intolerable 
and cannot be adequately 
managed  
Continue cabozantinib treatment at the current dose level 
with supportive care. 
 
At the discretion of the investigator, cabozantinib should 
be dose reduced or interrupted. 
Note: It is recommended that dose holds be as brief as 
possible.  
Grade 3 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Cabozantinib should be interrupted unless the toxicity 
can be easily managed with a dose reduction and optimal 
medical care. Resume cabozantinib following recovery to 
Grade 1 (or baseline). 
Note: It is recommended that dose holds be as brief as 
possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Subjects should have cabozantinib interrupted 
immediately.  
Discontinue cabozantinib unless the following criteria are 
met:  
• 
Subject is deriving clear clinical benefit as 
determined by the investigator and agreed by the 
MD Anderson IND Office 
• 
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care  
AE, adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided in 
Section 3.3.2. For re-treatment criteria of study treatment after a dose hold see Section 3.3.1.1. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to 
cabozantinib treatment or had an unclear relationship to cabozantinib treatment. 
 
3.3.1.1 
Cabozantinib Dose Reinstitution and Reescalation 
If the subject recovers from his or her toxicities to CTCAE v.4.0 Grade ≤ 1 or to the baseline value (or 
lower) and the toxicity was unrelated to study treatment, then study treatment may be restarted with no 
change in dose.  
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If the subject recovers from his or her toxicities to Grade ≤ 1 or to the baseline value (or lower) the 
toxicity was deemed possibly related to study treatment, then study treatment may be restarted at a 
reduced dose (see Table 3-2 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 should discontinue study 
treatment. 
 
Re-escalation to the previous dose, (but not higher than 60 mg/day) may be allowed at the discretion of 
the investigator and agreement of the MD Anderson IND Office for AEs which have resolved or 
recovered to ≤ Grade 1 (or baseline value) and deemed tolerable and easily managed by optimized 
supportive treatment. Dose re-escalation is not allowed for a drug-related dose reduction triggered by 
Grade 4 hematologic toxicities or by Grade 4 AEs affecting major organs (e.g., central nervous system, 
cardiac, hepatic, and renal). 
3.3.2 
Warnings and Precautions and Guidelines for the Management of Adverse Events 
The most frequent adverse events experienced by ≥ 20% of subjects treated with cabozantinib were 
diarrhea, fatigue, nausea, decreased appetite, vomiting, weight decreased, PPES, constipation, 
hypertension, dysgeusia, dysphonia, and asthenia. 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects treated with 
cabozantinib include anemia, AST increased, ALT increased, hypothyroidism, hypokalemia, 
hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, lipase increased, lactate 
dehydrogenase (LDH) increased, neutropenia, ALP increased, hyponatremia, and leukopenia. Mild to 
moderate QTc interval prolongation (10-15ms) has also been observed with a QT interval calculated by 
the Fridericia formula (QTcF) not exceeding 500 ms. Prolonged QTc appears to be a very rare event and 
no torsades de pointes have been reported (see latest version of the Investigator Brochure).  
 
Subjects may also experience medically important but less frequent adverse events including arterial and 
venous thrombotic AEs (eg, DVT, pulmonary embolism [PE], transient ischemic attack [TIA], and 
myocardial infarction [MI]), severe hemorrhagic events, proteinuria, wound healing complications, GI 
perforation, abscesses including intra-abdominal and pelvic abscess, GI and non-GI fistulae formation, 
osteonecrosis, and reverse posterior leukoencephalopathy syndrome (RPLS). 
Cabozantinib treatment should be permanently discontinued for the following adverse events: visceral 
perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic 
syndrome, malignant hypertension, hypertensive emergency, persistent uncontrolled hypertension despite 
optimal medical management, osteonecrosis of the jaw (ONJ), and RPLS. 
Guidelines for the management of AEs (i.e., dose interruptions and dose reductions) are presented in the 
next sections. Each dose reduction of cabozantinib should be to one dose level lower that the current dose. 
Dose reductions of more than one dose level are acceptable per Investigator judgment. All AEs should 
also be managed with supportive care at the earliest signs of toxicity.   Adverse reactions are presumed to 
be attributable to study drug. Adverse events classified as “not related” are defined as AEs that are, 
without question, not associated with the study treatment and definitely attributable to another cause. 
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating therapy with 
cabozantinib, it will take most subjects 2 to 3 weeks to reach steady state. If AEs attributable to 
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cabozantinib occur within the initial 3-week period of dosing, early intervention with dose modifications 
may be justified for AEs that, if worsened, could potentially be dangerous or debilitating, because without 
a dose adjustment, systemic exposure of cabozantinib might be expected to increase after the onset of the 
AE.   
Events that generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, 
hypertension, PPES, abdominal pain, mucosal inflammation, constipation, diarrhea and vomiting. In 
addition, earlier onset for events of dehydration was observed in subjects with CRPC when compared 
with subjects with other tumor types. 
3.3.2.1 
Guidelines for Management of Potential Adverse Events 
Sections 3.3.2.2 – 3.3.2.19 present management guidelines or warnings/precautions for the following 
cabozantinib treatment-emergent adverse events/serious adverse events of particular interest 
• 
Gastrointestinal disorders (diarrhea, nausea and vomiting , dehydration [prostate cancer studies], 
stomatitis and mucositis) 
• 
Hepatobiliary disorders (elevated ALT and AST)  
• 
Hematological disorders 
• 
Fatigue, anorexia, and weight loss 
• 
Skin disorders (palmar-plantar erythrodysesthesia syndrome [PPES] and rash) 
• 
Wound healing and surgery 
• 
Hypertension 
• 
Thromboembolic events (venous and arterial) 
• 
Proteinuria 
• 
QTc prolongation 
• 
Hypophosphatemia 
• 
Thyroid function disorders  
• 
Hemorrhagic events 
• 
Osteonecrosis of the jaw (ONJ) 
• 
Angioedema 
• 
Musculoskeletal and connective tissue disorders 
• 
Respiratory, thoracic, and mediastinal disorders 
 
Please refer to the latest version of the Investigator’s Brochure for additional practice guidelines and 
management recommendations for these and other AEs potentially related to cabozantinib treatment (e.g. 
intra-abdominal and pelvic abscess; nervous system disorders; infections and infestations; and respiratory 
thoracic and mediastinal disorders) use in specific populations, and overdose and first aid measures for 
accidental cabozantinib exposure. 
As with all investigational products, unknown AEs may occur. Subjects should be monitored closely for 
all AEs. As with other agents in development, additional AEs are unknown.  
3.3.2.2 
Gastrointestinal Disorders  
The most common non-hepatobiliary GI AEs reported in clinical studies with cabozantinib regardless of 
causality are diarrhea, nausea, decreased appetite, vomiting, constipation, stomatitis and abdominal pain.  
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Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly formed or 
loose stool or an increased frequency of bowel movements. 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 per Table 3-3. 
In addition, general supportive measures should be implemented including hydration, correction of fluid 
and electrolyte abnormalities, small frequent meals, and stopping lactose-containing products, high fat 
meals, and alcohol.  
Nausea and Vomiting 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and vomiting or as 
prophylaxis to prevent emesis, along with supportive care in accordance to clinical practice guidelines. 
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists and 
dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids induce 
CYP3A4 and thus could lower cabozantinib exposure (see Sections 3.4.4). Caution is also recommended 
with the use of nabilone, which is a weak inhibitor of CYP3A4. When therapy with antiemetic agents 
does not control the nausea or vomiting to tolerable levels, study treatment should be temporarily 
interrupted or dose reduced per Table 3-3.Dehydration may be associated with vomiting and monitoring 
for and correction of fluid and electrolyte disturbances should be implemented. 
Dehydration  
Dehydration events have been identified with comparable incidence and occurring in a shorter time to 
onset in the prostate cancer studies than previously experienced with cabozantinib in other tumor types. 
Extra monitoring/medical management including electrolyte monitoring and/or early dose reduction of 
patients exhibiting dehydration symptoms and those with risk factors for dehydration is indicated. 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive oral examination to identify and treat any potential 
risk for complications before study treatment is initiated. Appropriate correction of local factors should be 
instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis.  
During treatment with cabozantinib good oral hygiene and standard local treatments such as nontraumatic 
cleansing and oral rinses (e.g., with a weak solution of salt and baking soda) should be maintained. The 
oral cavity should be rinsed after meals, and dentures should be cleaned and brushed often to remove 
plaque. Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as indicated by local guidelines. When stomatitis 
interferes with adequate nutrition and local therapy is not adequately effective, dose reduction or 
temporary withholding of cabozantinib should be considered per Table 3-2 and Table 3-3. 
3.3.2.3 
Hepatobiliary Disorders 
Elevations of ALT, 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.  
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Subjects on this study may enter with increased ALT/AST serum levels up to 3 × ULN. Dose reductions 
of study treatment should be considered in any subject who develops drug-related Grade 2 elevated ALT, 
AST, or bilirubin lasting longer than 1 week. A subject who develops Grade ≥ 3 elevated ALT, AST, or 
bilirubin should have study treatment held and restarted at a reduced dose (see Table 3-2) after ALT, 
AST, and bilirubin levels resolve to at least Grade ≤ 1 or baseline. In subjects with recurrence of drug-
related Grade ≥ 3 elevated ALT, AST, or bilirubin at the lowest dose level, study treatment should be 
discontinued. In subjects who develop ALT/AST elevations > 3 × ULN in combination with a bilirubin 
elevation > 2 × ULN without reasonable other explanation, drug-induced liver injury should be suspected 
and cabozantinib treatment interrupted. Reinstitution of study treatment after recovery of ALT, AST, and 
bilirubin to Grade 1 or baseline level is at the discretion of the investigator. 
3.3.2.4 
Hematological Disorders 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated complications have 
been observed after administration of cabozantinib and may be managed with dose interruptions and/or 
dose reductions. Use of granulocyte colony-stimulating factor support for neutrophil recovery is allowed 
per investigator discretion and in accordance with accepted guidelines after the first incidence of 
clinically relevant cytopenia. 
Complete blood counts with differentials and platelets should be performed regularly. Subjects with 
hematologic toxicities may require additional or more frequent laboratory tests according to institutional 
guidelines. Results of such tests are to be forwarded to the local laboratory data management vendor. 
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. 
Dose reductions or dose interruptions for anemia are not mandated but can be applied as clinically 
indicated. Supportive care such as red blood cell transfusions may be managed according to institutional 
guidelines. 
3.3.2.5 
Fatigue, Anorexia, and Weight Loss 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as anemia, 
deconditioning, emotional distress (depression and/or anxiety), poor nutrition, sleep disturbance, and 
hypothyroidism should be ruled out and/or these causes treated in accordance to standard of care. 
Individual non-pharmacological and/or pharmacologic interventions directed to the contributing and 
treatable factors should be given. Note: Chronic use of modafinil should be avoided because of its 
potential to reduce cabozantinib exposure (see latest version of the Investigator’s ).  Refer to Table 3-3 for 
general management guidelines. 
Anorexia and weight loss should be managed in accordance to local standard of care including nutritional 
support. If fatigue, anorexia, or weight loss cannot be adequately managed, study treatment should be 
temporarily interrupted or dose reduced per Table 3-2 and Table 3-3. 
3.3.2.6 
Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot syndrome), skin rash 
(including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular 
rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported in cabozantinib-
treated subjects. All subjects on study should be advised on prophylactic skin care. This includes the use 
of hypoallergenic moisturizing creams, ointment for dry skin, and sunscreen with sun protection factor 
≥ 30, avoidance of exposure of hands and feet to hot water, removal of calluses, protection of pressure-
sensitive areas of hands and feet, and use of thick cotton gloves and socks to prevent injury and to keep 
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the palms and soles dry. Subjects with skin disorders should be carefully monitored for signs of infection 
(eg, abscess, cellulitis, or impetigo). 
Early signs of hand-foot syndrome could be tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms and 
soles. The lateral sides of the fingers or peri-ungual zones may also be affected. Adequate interventions 
are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or 
necrosis of affected areas. Aggressive management of symptoms is recommended, including early 
dermatology referral. Treatment guidelines for PPE related to study treatment are presented in Table 3-4. 
In the case of study treatment-related skin changes (eg, rash, hand-foot syndrome), the investigator may 
request that additional assessments be conducted with the subject’s consent. These assessments may 
include digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated 
until the skin changes resolve.  
Table 3-4: 
Management of Treatment-Emergent Hand-Foot Syndrome (PPES) 
CTCAE v.4.0 Grade  
Action To Be Taken  
Grade 1 
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced 
to the next lower dose level. Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Reassess at least weekly; if PPES 
worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2  
Study treatment may be continued if PPES is tolerated. Study treatment 
should be dose reduced or interrupted if PPES is intolerable. Continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily and 
add analgesics (e.g., NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPES worsens or 
affects self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with clobetasol 0.05% cream twice 
daily AND analgesics. Resume study drug at a reduced dose if PPES 
recovers to Grade ≤ 1. Discontinue subject from study treatment if PPES 
does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory 
drug; PPES, palmar plantar erythrodysesthesia syndrome. 
 
 
3.3.2.7 
Wound Healing and Surgery  
VEGFR inhibitors can cause wound healing complications and wound dehiscence which may occur even 
long after a wound has been considered healed. Therefore, surgical and traumatic wounds must have 
completely healed before starting cabozantinib treatment and be monitored for wound dehiscence or 
wound infection while the subject is being treated with cabozantinib. If possible, cabozantinib treatment 
should be stopped for at least 28 days prior to major surgery. 
3.3.2.8 
Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been reported among 
subjects treated with cabozantinib. 
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Treatment guidelines for hypertension deemed related to cabozantinib are presented in Table 3-5. Blood 
pressure should be monitored in a constant position at each visit (either sitting or supine). In general, 
subjects with known hypertension should be optimally managed before study entry. Decisions to decrease 
or hold the dose of study treatment must be based on blood pressure readings taken by a medical 
professional and must be confirmed with a second measurement at least 5 minutes after the first 
measurement.  Other than for hypertension requiring immediate therapy, the presence of new or worsened 
hypertension should be confirmed at a second visit before taking therapeutic action. It is recommended 
that this second visit occurs within 1-2 weeks. 
Cabozantinib should be discontinued in subjects with hypertensive crises or hypertensive encephalopathy. 
Table 3-5: 
Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib 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 cabozantinib by one dose level 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 emergency b 
• 
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 Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of 
progressive or impending end-organ damage (e.g., myocardial infarction/ischemia, intracranial 
hemorrhage, cerebral ischemia, pulmonary edema, encephalopathy, kidney damage). 
 
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3.3.2.9 
Thromboembolic Events 
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in 
clinical studies with cabozantinib, including fatal events. Subjects who develop a pulmonary 
embolism and/or DVT should have study treatment interrupted until therapeutic anticoagulation 
is established. Treatment with cabozantinib may be resumed in subjects with pulmonary 
embolism or DVT if it is determined that the event is uncomplicated and that the subject is 
deriving clinical benefit from cabozantinib treatment and that anticoagulation does not place 
them at a significant risk that outweighs the benefit of resuming treatment per discretion of the 
Investigator and according to individual protocols. Therapeutic doses of LMWH or the direct 
factor Xa oral inhibitors rivaroxaban, edoxaban, or apixaban are allowed for management of 
thrombotic events. Other oral anticoagulants including coumarin agents (e.g., warfarin), direct 
thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, platelet inhibitors 
(e.g., clopidogrel), and chronic use of aspirin above low dose levels for cardioprotection per local 
applicable guidelines are not allowed, until 4 weeks after cabozantinib has been permanently 
discontinued. See Section 3.4.4 for additional restrictions on anticoagulation therapy.  
 
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with cabozantinib. 
Subjects should be evaluated for pre-existing risk factors for arterial thrombotic events such as 
diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, history of tobacco use, 
and cardiac and/or thromboembolic events that occurred prior to initiation of study treatment. 
Further treatment with cabozantinib should be discontinued in subjects who develop an acute MI, 
cerebral infarction, or any other clinically significant arterial thromboembolic complication. 
3.3.2.10 
Proteinuria 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and other 
inhibitors of VEGF pathways. Management guidelines are provided in Table 3-6.   
Cabozantinib should be permanently discontinued in subjects who develop nephrotic syndrome 
(proteinuria > 3.5 grams per day in combination with hypoalbuminemia and peripheral edema 
[hyperlipidemia and thrombotic disease may also be present]) or any other relevant renal disease. 
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Table 3-6: 
Management of Treatment-emergent Proteinuria 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
• 
Consider confirming with a 24-hour protein assessment within 7 
days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg 
or urine protein ≤ 2 g/24 hours on 24-hour urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 hours on 24-hour 
urine collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider holding cabozantinib treatment if 
UPCR remains > 2 mg/mg despite a dose reduction until UPCR 
decreases to < 2 mg/mg. Restart cabozantinib treatment at a reduced 
dose after a dose hold unless otherwise approved by MD Anderson 
IND Office. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done 
within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 
1 month, check urine protein/creatinine per protocol or as clinically 
indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Hold cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until 
the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and 
< 2 mg/mg for 1 month or is determined to be stable (< 20% change) 
for 1 month, check urine protein/creatinine per protocol or as 
clinically indicated. 
Nephrotic syndrome 
• 
Discontinue all study treatment 
UPCR, urine protein/creatinine ratio. 
 
3.3.2.11 
Corrected QTc 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. 
Unless otherwise specified in certain protocols, only subjects with a baseline QTcF ≤ 500 msec are 
eligible for cabozantinib research studies. Cabozantinib should be used with caution in subjects with QT 
prolongation risk, a history of QT interval prolongation, or who are taking antiarrhythmics or drugs 
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known to prolong the QT interval. Concomitant treatment with strong CYP3A4 inhibitors, which may 
increase cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an increase of > 60 
ms above baseline, two additional ECGs must be performed with intervals not less than 3 min apart 
within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above baseline, the 
following actions must be taken: 
• 
Withhold study treatment 
• 
Immediately notify the MD Anderson IND Office 
• 
Hospitalize symptomatic subjects (e.g., 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 or increase of > 60 ms above baseline is not confirmed according to 
protocol procedures 
• 
Study treatment has been interrupted through a minimum of 1 week following the return of the QTcF 
to ≤ 500 msec or return to ≤ 60 ms above baseline. 
• 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
• 
Sponsor has reviewed all available information and has agreed to the continuation of study treatment 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 2 weeks 
for 1 month, then according to the protocol-defined time points. 
All study treatment must be permanently discontinued if either of the following applies: 
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• 
Recurrence of QTcF prolongation (confirmed by central ECG lab) after reinitiation of study treatment 
at a reduced dose 
3.3.2.12 
Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus should be 
monitored frequently while receiving cabozantinib. Other causes of hypophosphatemia should be ruled 
out and/or these causes treated in accordance to standard of care. Mild to moderate hypophosphatemia 
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should be managed by oral replacement including food that are high in phosphate (diary items, meats, 
beans) and/or oral phosphate supplements in accordance to standard clinical practice guidelines.  
Clinically relevant hypophosphatemia should be managed in accordance to the dose modification 
guidelines as outlined in Table 3-2 and Table 3-3 or as clinically indicated. 
3.3.2.13 
Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with cabozantinib 
therapy and other tyrosine kinase inhibitors as a result of altered thyroid hormone regulation by 
mechanisms that seem to be specific for each agent. Currently available data are insufficient to determine 
the mechanism of TFT alterations and its clinical relevance. Routine monitoring of thyroid function and 
assessments for signs and symptoms associated with thyroid dysfunction is recommended before 
initiation and during treatment with cabozantinib. Management of thyroid dysfunction (eg, symptomatic 
hypothyroidism) should follow accepted clinical practice guidelines and dose modification guidelines as 
outlined in Table 3-2 and Table 3-3.  
3.3.2.14 
Hemorrhagic Events 
Hemorrhagic events have been reported with cabozantinib. In order to mitigate risk of severe hemorrhage, 
subjects should be evaluated for potential bleeding risk factors before initiating cabozantinib treatment 
and monitored for bleeding events with serial complete blood counts and physical examination while on 
study. Risk factors for hemorrhagic events may include (but may not be limited to) the following: 
• 
Tumor of the lung with cavitary lesions or tumor lesions which invades or encases major blood 
vessels. The anatomic location and characteristics of tumor as well as the medical history must be 
carefully reviewed in the selection of subjects for treatment with cabozantinib; 
• 
Recent or concurrent radiation to the thoracic cavity; 
• 
Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease and ulcerative 
colitis; 
• 
Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting factors 
and/or platelet function, or thrombocytopenia); 
• 
Concomitant medication with anticoagulants or other drugs which affect normal hemostasis; 
• 
History of clinically significant hemoptysis. 
The risk of hemorrhage in cabozantinib-treated subjects with brain metastases has not been thoroughly 
analyzed. Though the incidence of CNS hemorrhage events in a study of subjects with GB was higher 
than observed in general population of subjects with cancer treated with cabozantinib, it is not clear how 
the risk of hemorrhage in GB translates to a risk of hemorrhage for subjects with brain metastases. 
Currently, brain metastases of carcinomas are not contraindications to the use of cabozantinib, but 
subjects with brain metastases should be monitored with a high index of suspicion if symptoms that could 
be due to a CNS hemorrhage occur. 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events or 
recent hemoptysis (≥ 5 mL of red blood). 
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3.3.2.15 
GI Perforation/Fistula and Non-GI Fistula Formation 
Gastrointestinal perforation/GI fistula: Prior to initiation of treatment with cabozantinib, subjects should 
be carefully evaluated for potential risk factors including (but not limited to) the following: 
• 
Tumors invading GI or respiratory tracts 
• 
Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease), 
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis  
• 
History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
• 
Ongoing visceral complications from prior radiation therapy 
• 
Prior GI surgery (particularly when associated with delayed or incomplete healing) 
Complete healing following abdominal surgery and/or resolution of intra-abdominal abscess must be 
confirmed prior to initiating treatment with cabozantinib.  
After starting cabozantinib, subjects should be monitored for early signs of GI perforation such as 
abdominal pain, nausea, emesis, constipation, and fever especially if known risk factors for developing GI 
perforation or fistula are present.  
Discontinue cabozantinib treatment in subjects who have been diagnosed with GI perforation/fistula. 
Non-GI fistula formation: Complications from radiation therapy has been identified as a possible 
predisposing risk factor for fistula formation in subjects undergoing treatment with cabozantinib. 
Subjects with any clinically relevant ongoing complications from prior radiation therapy (ie, radiation 
esophagitis or other inflammation of the viscera) should not be treated with cabozantinib. 
Radiation therapy to the thoracic cavity (including mediastinum) should be avoided within 3 months of 
starting treatment with cabozantinib (excluding local radiation for bone metastases). Fistula should be 
ruled out as appropriate in cases of onset of severe mucositis or difficulty swallowing after start of 
therapy. Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with a non-GI fistula. 
Discontinue cabozantinib treatment in subjects who have been diagnosed with non-GI fistula. 
3.3.2.16 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported in subjects treated with cabozantinib. Additional risk 
factors for ONJ have been identified including the use of bisphosphonates and denosumab, chemotherapy, 
corticosteroids, local radiotherapy, and dental or orofacial surgery procedures.   
Osteonecrosis of the jaw can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or 
periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing 
of the mouth or jaw after dental surgery may also be manifestations of ONJ. 
Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib 
therapy. Advise subjects regarding oral hygiene practice and to quickly report symptoms to investigator. 
Caution should be used in subjects receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be held for at least 4 weeks prior to the procedure and resumed after 
complete wound healing has occurred. Bone healing may often require a protracted time. 
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3.3.2.17 
Angioedema 
Angioedema should be managed according to standard practice. The subject should be observed until 
symptoms resolve, with particular attention to maintaining an open airway.  
3.3.2.18 
Musculoskeletal and Connective Tissue Disorders 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on nonclinical 
GLP-compliant toxicology studies. The development of new or progressive, unexplained musculoskeletal 
symptoms such as pain or weakness should be assessed for underlying causes. 
Rhabdomyolysis has been reported. Cabozantinib should be discontinued in subjects with serious and 
life-threatening rhabdomyolysis and interrupted if less severe forms occur when there are no other clear 
causes. Reinitiation of cabozantinib treatment must be discussed with and approved by the MD Anderson 
IND Office. Therapy of rhabdomyolysis should include supportive care and standard medical 
intervention. 
3.3.2.19 
Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea has been reported in clinical studies with cabozantinib. Symptoms should be managed according 
to locally accepted clinical practice including an assessment for underlying causes. Pulmonary embolism 
should be considered as possible causes for new onset dyspnea given the risk of thrombosis associated 
with inhibition of VEGF signaling. Furthermore, fistula formation (Section 03.3.2.15) and pneumonia 
have been reported in subjects treated with cabozantinib and should be considered as clinically indicated 
in subjects presenting with pulmonary symptoms. 
3.4 
Concomitant Medications and Therapies 
3.4.1 
Anticancer Therapy 
Local intervention is discouraged unless medically unavoidable. Subjects receiving local intervention 
(e.g., palliative radiation) are allowed to continue to receive study treatment at the investigator’s 
discretion.  
3.4.2 
Other Medications 
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 the first dose of study treatment through 30 days after the date of the last dose of study 
treatment are to be recorded in the medical record. 
3.4.3 
Allowed Therapies  
• 
Antiemetics and antidiarrheal medications are allowed prophylactically in accordance to standard 
clinical practice if clinically indicated;  
• 
Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (e.g., American Society of Clinical Oncology [ASCO] or [European Society for Medical 
Oncology] ESMO guidelines);  
• 
Drugs to control hormonal excess symptoms (spironolactone, metyrapone, mifepristone, and 
ketoconazole). If using strong CYP3A4 inhibitor such as ketoconazole is unavoidable, cabozantinib 
dose needs to be reduced by 20 mg. Resuming prior dose level can be done 2-3 days after 
discontinuing ketoconazole.  
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• 
Drugs used to control bone loss (e.g., bisphosphonates and denosumab) are allowed if started before 
screening activities but may not be initiated or exchanged during the course of the study and require 
principal investigator’s approval; 
• 
Transfusions, hormone replacement, and short term higher doses of corticosteroids should be utilized 
as indicated by standard clinical practice; 
• Individualized anticoagulation therapy with heparin or direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and effectively 
under the following circumstances: 
o At the time of first dose of study treatment: 
• 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. 
• Therapeutic doses of LMWH or the direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed if the subject has 
no evidence of brain metastasis, has been on a stable dose of the 
anticoagulant for at least 1 week, and has had no clinically 
significant hemorrhagic complications from the anticoagulation 
regimen or the tumor. See Section 3.4.4 for prohibited 
anticoagulants. 
o After first dose of study treatment: 
• 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. 
• Therapeutic doses of LMWH or the direct factor Xa oral inhibitors 
rivaroxaban, edoxaban, or apixaban are allowed if clinically 
indicated (e.g., for the treatment of DVT), and the benefit 
outweighs the risk per the Investigator’s discretion. See section 
3.3.2.9 for management of thromboembolic complications while 
on study. See section 3.4.4  for prohibited anticoagulants. 
o Accepted clinical guidelines regarding appropriate management while receiving 
any kind of anticoagulation therapy must be followed. This includes, but is not 
limited to, subject education regarding the potential adverse drug reactions, 
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monitoring laboratory parameters, dose adjustments (e.g., due to kidney 
dysfunction). Caution is warranted in settings associated with an increased risk for 
bleeding such as gastrointestinal cancers, urothelial cancers, gastrointestinal 
mucosal abnormality (e.g., mucositis), renal or hepatic impairment, 
thrombocytopenia, arterial hypertension, or prior history of gastrointestinal bleed. 
For direct factor Xa inhibitors, the potential for drug-drug interaction with other 
concomitant medications, as well as gastrointestinal absorption, should be 
considered. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) 
should not be used concomitantly with heparin or factor Xa inhibitors due to the 
increased risk for bleeding complications. The risks and benefits of the use of 
anticoagulants should be reassessed on a regular basis. For more information 
regarding the use of anticoagulants, refer to the prescribing information of the 
anticoagulant and accepted clinical practice guidelines. 
3.4.4 
Prohibited or Restricted Therapies  
The following therapies are prohibited while the subject is on study: 
• 
Any investigational agent or investigational medical device; 
• 
Any drug or herbal product used specifically for the treatment of ACC ; 
• Oral anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., 
dabigatran), direct factor Xa inhibitor betrixaban, platelet inhibitors (e.g., clopidogrel), and 
chronic use of aspirin above low dose levels for cardio-protection per local applicable 
guidelines), until 4 weeks after cabozantinib has been permanently discontinued. 
• 
Any other systemic anticancer treatment (e.g., chemotherapy, immunotherapy, radionuclides) and 
local anticancer treatment such as surgery, ablation, or embolization.  
The following therapies should be avoided if possible, while the subject is on study: 
• 
Palliative external radiation to bone metastasis for bone pain should not be routinely performed while 
on study but can be considered as a treatment for non-target lesions at the investigator’s discretion.  
• 
Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be used based on 
a report of increased risk of tumor recurrence and/or progression associated with erythropoietin; 
• 
Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) 
may significantly decrease cabozantinib concentrations and should be avoided if possible. Selection 
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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, because this could significantly 
increase the exposure to cabozantinib; 
• 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib 
concentrations and is not permitted. Grapefruit and Seville oranges may also increase plasma 
concentrations of cabozantinib and should be avoided. Ketoconazole use will be permitted to treat 
Cushing syndrome if clinically unavoidable. Cabozantinib dose needs to be reduced by 20 mg when 
using ketoconazole. Resuming prior dose level is permitted 2-3 days after discontinuing 
ketoconazole.  
 
Additional information on potential drug interactions with cabozantinib is provided in Section 3.4.5. 
3.4.5 
Potential Drug Interactions 
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 area 
under the plasma drug concentration time curve (AUC) of co-administered rosiglitazone, a CYP2C8 
substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by 
inference, is not anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values 
compared with CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data 
indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction 
of CYP1A1 at high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, CYP2C8, 
CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. Results from a clinical 
pharmacology study, XL184-006, showed that concurrent administration of cabozantinib with the strong 
CYP3A4 inducer, rifampin, resulted in an approximately 77% reduction in cabozantinib exposure (AUC 
values) after a single dose of cabozantinib in healthy volunteers. Chronic co-administration of 
cabozantinib with strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations. The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce 
CYP3A4 should be used with caution because these drugs have the potential to decrease exposure (AUC) 
to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme 
induction potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration of 
cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in the 
cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-
administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase cabozantinib 
concentrations. Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib 
and should be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that inhibit 
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CYP3A4 should be used with caution because these drugs have the potential to increase exposure (AUC) 
to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme 
inhibition potential is recommended.  
In addition, cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated 
metabolism of cabozantinib. 
Please refer to the drug interaction tables at the following websites for 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/DrugInteractionsLabeli
ng/ucm080499.htm   
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly 
protein bound drugs should be used with caution with cabozantinib because there is a potential 
displacement interaction that could increase free concentrations of cabozantinib and/or a co-administered 
highly protein-bound drug (and a corresponding increase in pharmacologic effect). 
Other Interactions:  
Food may increase exposure levels of cabozantinib by 57%, fasting recommendations should be followed. 
Subjects should fast (with the exception of water) for at least 2 hours after eating the evening meal before 
taking their dose of cabozantinib. After the 2-hour fast and before going to bed, subjects are to take 
cabozantinib with a full glass of water (minimum of 8 oz or 240 mL) with no more food intake for one 
hour post-dose. 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein, but it does appear 
to have the potential to inhibit the P-glycoprotein transport activity. Therefore, cabozantinib may have the 
potential to increase plasma concentrations of co-administered substrates of P-glycoprotein.  
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. Administration 
of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma concentrations. 
Additional details regarding potential drug interactions with cabozantinib can be found in the latest 
version of the investigator brochure. 
3.5 
Compliance 
Drug accountability and subject compliance will be assessed with drug dispensing and return records.  
3.6 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all cabozantinib, 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 cabozantinib will be reconciled and destroyed in accordance with applicable state and federal 
regulations and in accordance to MD Anderson institutional policies and procedures for drug destruction. 
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4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
A subject must fully meet all of the following criteria to be eligible for the study: 
1. The subject is ≥ 18 years old on the day of consent 
2. Histological confirmation of ACC based on either:  i). Weiss Score of ≥ 3 in patients who had 
earlier surgical resection (Lin-Weiss-Bisceglia system will be used for oncocytic ACC) OR 
ii). biopsy results compatible with ACC in the context of clinical setting highly suggestive of 
ACC (adrenal mass > 4 cm invading surrounding organs or associated with distant metastases).  
3. Locally advanced or metastatic disease not amenable to surgery with curative intent with 
measurable disease per RECIST 1.1 (9) as determined by the investigator based on an assessment 
of all known disease sites by computerized tomography (CT) scan or magnetic resonance imaging 
(MRI) of chest/abdomen/pelvis within 28 days before the first dose of cabozantinib. In patients 
with IV contrast allergy or borderline renal function, CT without IV contrast or 18 FDG PET CT 
may be used as clinically indicated 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2  
5. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, 
unless AE(s) are clinically non-significant and/or stable on supportive therapy 
6. Life expectancy of at least 3 months 
7. Organ and marrow function and laboratory values as follows within 28 days prior to the first dose 
of cabozantinib:  
a. Absolute neutrophil count (ANC) ≥ 1500/mm
3without colony stimulating factor support  
b. Platelets ≥ 100,000/mm
3  
c. Hemoglobin ≥ 9 g/dL  
d. Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert’s 
disease, bilirubin ≤ 3.0 mg/dL  
e. Serum albumin ≥ 2.8 g/dl  
f. Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine 
clearance estimation, the Cockcroft and Gault equation should be used:  
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72). Female: Multiply 
above result by 0.85 
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN  
h. No radiologic or clinical evidence of pancreatitis  
i. 
Urine protein/creatinine ratio (UPCR) ≤ 1 
j. 
Serum phosphorus ≥ 2.5mg/dl, cCalcium≥ 8mg/dL, magnesium≥ 1.2mg/dL, and 
potassium ≥ 3.0 meq/L ( CTCAE V4.03 grade1 cut off levels).  
8. Capable of understanding and complying with the protocol requirements and has signed the 
informed consent document.  
9. Sexually active patients (men and women) must agree to use medically accepted barrier methods 
of contraception (e.g. male or female condom) during the course of the study and for 4 months 
after the last dose of study drug(s), even if oral contraceptives are also used. All sexually active 
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subjects of reproductive potential must agree to use both a barrier method and a second method of 
birth control during the course of the study and for 4 months after the last dose of study drug(s). 
a.  Women of childbearing potential must have a negative pregnancy test at screening. 
Women of childbearing potential include women who have experienced menarche and 
who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined 
as amenorrhea ≥ 12 consecutive months. Note: women who have been amenorrheic for 
12 or more months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other 
reversible reason. 
4.2 
Exclusion Criteria  
A subject who meets any of the following criteria is ineligible for the study: 
1. Received cytotoxic chemotherapy, radiation therapy, or targeted therapy (including 
investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies), or 
other investigational agent within 28 days of study enrollment. 
2. For patients who received mitotane within 6 months of consenting, mitotane should have been 
stopped at least 28 days prior to study enrollment AND to have mitotane serum level of < 2 mg/L.  
3. Prior treatment with cabozantinib or other cMET inhibitors 
4. 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 the first dose of 
study treatment. Eligible subjects must be neurologically asymptomatic and without 
corticosteroid treatment at the time of the start of study treatment. 
5. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior 
therapies except alopecia and other non-clinically significant AEs. 
6. Prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time 
(PTT) test ≥ 1.3 × the laboratory ULN within 28 days before the first dose of study treatment.  
 
7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin 
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors 
(e.g., clopidogrel). Allowed anticoagulants are the following: 
a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH). 
b. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases 
who are on a stable dose of the anticoagulant for at least 1 week before first dose 
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of study treatment without clinically significant hemorrhagic complications from 
the anticoagulation regimen or the tumor. 
8. Severe and uncontrolled Cushing syndrome despite medical management (e.g.: systolic blood 
pressure >160mmHg or hyperglycemia with fasting glucose above 300mg/dL)..  
9. The use of strong CYP3A4 inhibitor (with the exception of ketoconazole). 
10. The subject has experienced any of the following: a. clinically-significant gastrointestinal 
bleeding within 6 months before the first dose of study treatment; b. hemoptysis≥ 0.5 
teaspoon(2.5 mL) of red blood within 3 months before the first dose of study treatment; c. any 
other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study 
treatment.  Tumor invading any major blood vessel at the time of study enrollment.  
11. Evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or 
anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first 
dose of cabozantinib, or the subject with radiographic evidence of cavitating pulmonary lesion(s); 
or subjects with tumor invading or encasing any major blood vessels.  
12. Uncontrolled, significant concurrent or recent illness including, but not limited to, the following 
conditions: a. Cardiovascular disorders including i. Congestive heart failure (CHF): New York 
Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening ii. 
Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 
mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of 
study treatment iii. Any history of congenital long QT syndrome or iv. Any of the following 
within 6 months before the first dose of study treatment: • unstable angina pectoris • clinically-
significant cardiac arrhythmias• stroke (including TIA, or other ischemic event) within 90 days of 
the first dose of study treatment • myocardial infarction • clinically significant thromboembolic 
event within 42 days of randomization requiring therapeutic anticoagulation. (Note: subjects with 
a venous filter (e.g. vena cava filter) are not eligible for this study) b. Gastrointestinal disorders 
particularly those associated with a high risk of perforation or fistula formation including: i. Any 
of the following within 28 days before the first dose of study treatment • intra-abdominal 
tumor/metastases invading GI mucosa • active peptic ulcer disease; patients must be completely 
recovered • inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), acute 
pancreatitis, pancreatic duct or common bile duct obstruction, acute diverticulitis, acute 
cholecystitis, symptomatic cholangitis or recent appendicitis within 1 month of first dose of 
cabozantinib; patients must be completely recovered from these conditions • clinically significant 
malabsorption syndrome, c. Endocrine disorders, uncontrolled Cushing syndrome despite of 
adequate medical therapy 
13. Any of the following within 6 months before the first dose of study treatment: • abdominal fistula 
• gastrointestinal perforation •bowel obstruction or gastric outlet obstruction •intra-abdominal 
abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to 
initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the 
first dose of study treatment. . •Other disorders associated with a high risk of fistula formation 
including PEG tube placement within 90 days before the first dose of study therapy  
14. Other clinically significant disorders such as: i. active infection requiring systemic antibiotic 
treatment within 14 days before the first dose of study treatment ii. serious non-healing 
wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii. history of 
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organ transplant iv. Concurrent uncompensated hypothyroidism or thyroid dysfunction (TSH 
above 10) within 28 days before the first dose of study treatment v. Major surgery within 12 
weeks before the first dose of study treatment. Complete wound healing from major surgery must 
have occurred 1 month before the first dose of study treatment. Minor surgery within 28 days 
before the first dose of study treatment with complete wound healing at least 10 days before the 
first dose of study treatment. Subjects with clinically relevant ongoing complications from prior 
surgery are not eligible.  
15. Unable to swallow tablets  
16. A corrected QT interval calculated by the Fridericia formula (QTcF) >500 milliseconds within 28 
days before first dose of study treatment.  
17. Pregnant or breastfeeding.  
18. A previously identified allergy or hypersensitivity to components of the study treatment 
formulation.  
19. Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or 
designee.  
20. Evidence within 2 years of the start of study treatment of another malignancy which required 
systemic treatment except for breast ductal carcinoma-in situ, cured non-melanoma skin cancer, or 
cured in situ cervical carcinoma  
21. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
which, in the judgment of the investigator, would have made the patient inappropriate for entry into 
this study.  
 
5 
STUDY ASSESSMENTS AND PROCEDURES 
5.1 
Pre-Treatment Period 
 During the Pre-Treatment Period, during which the participant will follow the schedule found in table 5-
1, subjects are consented and qualified (screened) for the study. Informed consent must be obtained 
before initiation of any clinical screening procedure that is performed solely for the purpose of 
determining eligibility for this study. Evaluations performed as part of routine care before informed 
consent can be considered as screening evaluations if done within the defined screening period, and if 
permitted by the site’s institutional review board (IRB)/ethics committee (EC) policies.  
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion criteria at 
screening and on Study Day 1 before study treatment administration. The following assessments will be 
conducted before subjects receiving their first dose of cabozantinib on this protocol: 
1. For patients with measurable visceral metastases CT scans with contrast or MRI including 
chest/abdomen/and pelvis are required.  
2. Demographics 
3. Medical and cancer history/demographics 
4. Height 
5. Weight 
6. Vital Signs 
7. ECOG Performance Status 
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8. Clinical laboratory testing  
• 
chemistry panel (albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, , magnesium, phosphorus, potassium, 
sodium, total bilirubin, total protein) 
• 
hematology tests(CBC, differential, platelets) 
• 
adrenal hormonal assessment 
• 
urinalysis and UPCR 
• 
thyroid function tests (TSH, free T4) 
• 
pregnancy test (urine or serum) for women of child-bearing potential 
• 
PT/INR, PTT 
• 
Serum mitotane level if used mitotane within 6 months 
9. 
ECGs  
10. 
Physical examination, safety and adverse events evaluation will be performed at baseline. 
For each subject, the Pre-Treatment Period ends upon receipt of the first dose of study treatment or final 
determination that the subject is ineligible for the study. 
5.2 
Treatment Period  
During the Treatment Period subjects will receive cabozantinib until either disease progression, the 
occurrence of unacceptable drug-related toxicity or for other reason(s) for subject withdrawal as described 
in Section 2.5. Subjects should be instructed to immediately inform the principal investigator (PI) of any 
AEs. Subjects experiencing dizziness, sleepiness, or other symptoms that could influence alertness or 
coordination should be advised not to drive or operate other heavy machinery. 
The following schedule of assessments applies to all subjects (Table 5-1). More frequent assessments 
should be obtained if clinically indicated. 
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Table 5-1: 
Study Assessments 
 
 
 
Study Treatment Period 
Post-
Treatment 
Period 
 
Within 28 
days 
before 1st 
Dose of 
Study 
Treatment 
Day 1 
Day 1 of 
Weeks 3, 
5, then 
every 4 
weeks 
 (± 5 days) 
 
 
 
Day 1 of 
Week 5  
(± 5 days) 
 
 
 
Day 1 of 
Week 9 
(± 5 days) 
 
 
 
At 
Progression 
(+ 5 days) 
30 - 37 
Days after 
last dose 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical and cancer 
history/demographics 
X 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
X 
Vital signs 
X 
 
X 
 
 
 
X 
ECOG performance 
status 
X 
 
X 
 
 
 
X 
Clinical laboratory 
tests1  
X 
 
X2 
 
 
 
X 
Urinalysis and 
UPCR10  
X 
 
X2 
 
 
 
X 
PT/INR, PTT 
X 
 
X12 
 
 
 
 
TFTs (TSH, free T4)  
X 
 
X2 
 
 
 
 
12-lead ECG8 
X 
 
X 
 
 
 
X 
Cabozantinib 
administration 
 
X 
X (daily) 
 
 
 
 
Pregnancy test 
X 
X9 
X2 
 
 
 
X 
Tumor assessment3 
X 
 
X (every 8 
weeks) 
 
 
 
 
Adrenal hormonal 
profile4 
X 
 
X (every 8 
weeks) 
 
 
 
 
Serum mitotane 
level5 
X 
 
 
 
 
 
 
Concomitant 
medications  
X 
X 
X 
 
 
 
X 
Adverse events 
Continuous 
X 
Immunologic 
assessments11 
 
X11 
 
 
 
 
X11 
 
X11 
 
Pharmacogenetic 
assessment11 
X11 
 
 
 
 
 
 
Pharmacokinetic 
assessment6 
 
 
X6 
 
 
 
X6 
 
 
 
 
Optional biopsy7 
X7 
 
 
X7 
 
X7 
 
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ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; PT/INR, prothrombin 
time/International Normalized Ratio; PTT, partial prothrombin time, TFT, thyroid function test; UPCR, 
urine protein/urine creatinine ratio 
1Laboratory tests should include a standard hematology panel (CBC, differential, platelets) and chemistry 
panel (albumin, alkaline phosphatase, ALT, AST, bicarbonate, blood urea nitrogen, calcium, chloride, 
creatinine, glucose, , magnesium, phosphorus potassium, sodium, total bilirubin, total protein)  
2Every 8 weeks (+/-5 days) after the first 12 weeks  
3All sites of known disease must be assessed with CT or MRI. In patients with IV contrast allergy or 
borderline renal function, CT without IV contrast or 18 FDG PET CT may be used as clinically indicated. 
4 No additional measurements of adrenal hormones (ACTH, cortisol, aldosterone, plasma renin activity, 
DHEA-sulfate, testosterone in women, estradiol in men and postmenopausal women) 
 are needed in patients with normal profile at baseline (Non-functioning ACC).  
5 No need for mitotane measurement in patients who have been off mitotane for > 6 months or never 
received mitotane.  
6Full pharmacokinetic assessment on day 1 and day 29(+/- 5 days) then one trough level every 12 weeks 
(+/- 6 weeks); On day 1 and 29 (+/- 5 days): PK blood samples (10 mL) are to be collected within 15 
minutes prior to dosing of cabozantinib and at the following time points following ingestion of the dose: 1 
hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), and 8 hours (±15 minutes) post-dose.    
7 Optional imaging guided biopsy from an accessible tumor site to be done at baseline, 29 days (+/- 5 
days), and at time of progression.  
8 If QTcF interval within normal range at baseline and subsequent ECGs at weeks 3 and 5, then no need 
for routine ECG monitoring. ECGs may be ordered as needed if there is other clinical indication.   
9 Within 48 hours prior to day 1   
10 Consider 24-hour urine collection for protein if UPCR>1mg/mg 
11 A 50 cc blood sample to be collected for immunologic testing at screening, at week 9 day 1(+/- 5 days), 
and at progression (+ 5 days). A 10 cc to be collected for pharmacogenetic screening at screening only. 
12 If abnormal at baseline or clinically indicated  
 
If the subject is unable to have a study assessment taken within the defined time window due to an event 
outside of his or her control (e.g., clinic closure, personal emergency, inclement weather, vacation), the 
assessment should be performed as close as possible to the required schedule.  
Regular tumor assessments should be performed in accordance to the guidelines in Section 5.5 to 
determine if PD is present.  
The Treatment Period ends when a subject receives his or her last dose of study treatment; the subject 
then enters the Post-Treatment Period. 
5.3 
Post-Treatment Period 
Subjects will return to the study site 30 to 37 days after their last dose of cabozantinib to complete 
end-of-study assessments. 
Laboratory and physical examinations will be performed. Remaining study treatment will be returned by 
the subject, and treatment compliance will be documented. Additional follow-up will occur for subjects 
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with AEs related to study treatment that are ongoing at the time of this visit, and for subjects with SAEs 
related to study treatment that occur after the time of this visit. 
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5.4 
Laboratory Assessments 
Laboratory panels are composed of the following:  
Hematology 
• 
WBC count with 
differential (including 
at minimum: 
neutrophils, basophils, 
eosinophils, 
lymphocytes, 
monocytes) 
• 
hematocrit 
• 
platelet count 
• 
RBC count 
• 
hemoglobin 
 
 
Serum chemistry 
• 
albumin 
• 
ALP 
• 
ALT 
• 
AST 
• 
bicarbonate 
• 
BUN 
• 
chloride 
• 
creatinine 
• 
Glucose  
• 
 calcium 
• 
 
• 
magnesium 
• 
phosphorus 
• 
potassium 
• 
sodium 
• 
total bilirubin 
• 
total protein 
 
Urinalysis 
• 
appearance 
• 
color 
• 
pH 
• 
specific gravity 
• 
ketones 
• 
protein 
• 
UPCR 
• 
glucose 
• 
bilirubin 
• 
nitrite 
• 
creatinine 
• 
urobilinogen 
 
• 
occult blood 
(microscopic 
examination of 
sediment will be 
performed only if the 
results of the 
urinalysis dipstick 
evaluation are 
positive) 
Other 
• 
TSH, Free T4 
• 
Pregnancy test (urine 
or serum) for women 
of child-bearing 
potential 
 
 
• 
PT/INR or PTT 
• 
24 hour urine 
collection for proteina 
• 
Adrenal hormones 
profile(ACTH, 
cortisol, aldosterone, 
plasma renin activity, 
DHEA-sulfate, 
testosterone in 
women, estradiol in 
men and 
postmenopausal 
women) 
• 
Mitotane level*  
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, 
blood urea nitrogen; ESR, INR, International Normalized Ratio; PT, prothrombin time; PTT partial 
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thromboplastin time; RBC, red blood cell; TSH, thyroid stimulating hormone; UPCR, urine 
protein/creatinine ratio; WBC, white blood cell. 
*Only if prior mitotane use within 6 months.  
a Consider 24-hour urine collection for protein if UPCR>1 mg/mg 
 
Abnormalities in clinical laboratory tests that lead to a change in subject management (eg, dose delayed 
[withheld] or reduced, requirement for additional medication, treatment or monitoring) are considered 
clinically significant for the purposes of this study, and will be recorded on the Adverse Events Case 
Report Form (CRF). If laboratory values constitute part of an event that meets criteria defining it as 
serious, the event (and associated laboratory values) must be reported as an SAE. 
5.5 
Tumor Assessment 
Serial imaging studies will be used to assess measurable disease per RECIST 1.1 criteria (9).  Contrast-
enhanced computerized tomography (CT) scan or magnetic resonance imaging (MRI) of 
chest/abdomen/pelvis will be obtained every 8 weeks (+/- 5 days) after the start of study drug 
administration. In patients with IV contrast allergy or borderline renal function, CT without IV contrast or 
18 FDG PET CT may be used as clinically indicated. 
5.6 
Outside Physician Participation During Treatment 
• 
MDACC Physician communication with the outside physician is required prior to the patient 
returning to the local physician. This will be documented in the patient record. 
• 
A letter to the local physician outlining the patient's participation in a clinical trial will request 
local physician agreement to supervise the patient's care. 
• 
Protocol required evaluations outside MDACC will be documented by telephone, fax or e-
mail.  Fax and/or e-mail will be dated and signed by the MDACC physician, indicating that they 
have reviewed it. 
• 
Changes in drug dose and/or schedule must be discussed with and approved by the MDACC 
physician investigator, or their representative prior to initiation, and will be documented in the 
patient record. 
• 
A copy of the informed consent, protocol abstract, treatment schema and evaluation during 
treatment will be provided to the local physician. 
• 
Documentation to be provided by the local physician will include drug administration records, 
progress notes, reports of protocol required laboratory and diagnostic studies and documentation 
of any hospitalizations. 
• 
The home physician will be requested to report to the MDACC physician investigator all life 
threatening events within 24 hours of documented occurrence. 
• 
Patients will return to MDACC every 8 weeks for evaluation. 
 
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6 
SAFETY 
6.1 
Adverse Events and Laboratory Abnormalities 
6.1.1 
Adverse Events  
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has been 
enrolled in a clinical study and who may have been given 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. Pre-existing 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 6.2.1. 
All untoward events that occur after the first protocol intervention through 30 days after the decision to 
discontinue study treatment (or the date the subject is deemed to be a screen failure) are to be recorded by 
the investigational site. This requirement includes AEs from unscheduled as well as scheduled visits. 
Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
The investigator (or physician designee) is responsible for verifying and providing source documentation 
for all adverse events and assigning the attribution for all adverse events according to MDACC standards.  
• 
. 
6.1.2 
Serious Adverse Events  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or the sponsor, it results 
in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in the view of the initial reporter, at 
immediate risk of death from the adverse experience as it occurred. It does not include an adverse experience that, had it occurred in a 
more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
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• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. Any important medical event can and 
should be reported as an SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must be reported to the IRB in accordance 
with the timeframes and procedures outlined in “The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the 
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a written report submitted within 24 
hours (next working day) of knowledge of the event to the Safety Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific intervention, until 30 days after the last dose of drug, 
unless the participant withdraws consent. Serious adverse events must be followed until clinical recovery is complete and laboratory 
tests have returned to baseline, progression of the event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that are related to the study treatment must be reported 
to the IND Office. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND Office) according to 21 CFR 
312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
6.1.3 
Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this should be 
documented to the extent that information is available. The PI or designee will be responsible for 
assigning attribution of adverse events to the study agent.  
 
• 
Investigator shall notify Exelixis within twenty-four (24) hours of making such discovery by 
submitting a completed SAE report form and any other pertinent SAE information as indicated on 
the SAE reporting form; 
• 
This report must be submitted by Institution to Exelixis at e-mail: drugsafety@exelixis.com or 
fax 650-837-7392, even if it is not felt to be drug related; 
• 
Pregnancy (for a subject or for the partner of a subject), although not itself an SAE, should also 
be reported on a pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects or congenital abnormalities; 
• 
SAEs that must be recorded on an SAE Reporting form include the following: 
o all SAEs that occur after first protocol intervention and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen failure); 
o any SAEs assessed as related to study treatment or study procedures, even if the SAE 
occurs more than 30 days after the decision to discontinue study treatment; 
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o although most hospitalizations necessitate reporting of an SAE, some hospitalizations do 
not require SAE reporting, as follows: elective or previously scheduled surgeries or 
procedures for pre-existing conditions that have not worsened after initiation of treatment 
(e.g., a previously scheduled ventral hernia repair); pre-specified study hospitalizations 
for observation; or events that result in hospital stays of fewer than 24 hours and that do 
not require admission (e.g., an emergency room visit for hematuria that results in a 
diagnosis of cystitis and discharge to home on oral antibiotics). SAEs must, however, be 
reported for any surgical or procedural complication resulting in prolongation of the 
hospitalization. 
6.1.4 
Regulatory Reporting 
All serious adverse events must be reported to Exelixis using e-SAE form generated by MD Anderson 
Cancer Center. E-mail: drugsafety@exelixis.com; Fax 650-837-7392. 
6.2 
Other Safety Considerations 
6.2.1 
Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should be reviewed. 
Any abnormal value that leads to a change in subject management (eg, dose reduction or delay or 
requirement for additional medication or monitoring) or that is considered to be of clinical significance by 
the investigator should be reported as an AE or SAE as appropriate. 
6.2.2 
Pregnancy 
If a subject becomes pregnant during the study, she will be taken off study treatment and will be followed 
through the end of her pregnancy. The investigator must inform the MD Anderson IND Office 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. 
6.2.3 
Medication Errors/Overdose 
Any study drug administration error or overdose that results in an AE, even if it does not meet the 
definition of serious, requires reporting within 24 hours to Exelixis or designee. 
6.2.4 
Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after the 
decision to discontinue study treatment must be followed until either resolution of the event or 
determination by the investigator that the event has become stable or irreversible. This follow-up 
guidance also applies to related SAEs that occur > 30 days after the decision to discontinue study 
treatment. The status of all other continuing AEs will be documented as of 30 days after the decision to 
discontinue study treatment. 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Analysis Population 
This is an investigator-initiated, open label, pilot clinical trial to evaluate the efficacy and safety of 
cabozantinib given in patients with unresectable/metastatic ACC. The primary objective of our study is 4-
month progression-free survival (PFS4) rate in patients with unresectable/metastatic ACC who will 
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receive cabozantinib. The secondary objectives are to determine the safety and toxicity, overall survival 
(OS), and to estimate overall response rate (ORR). 
7.1.1 
Safety Population 
The safety population will consist of all subjects who receive any amount of study treatment. 
7.2 
Safety Analysis 
Safety will be assessed by evaluation of AEs. All safety analyses will be performed using the safety 
population. 
7.2.1 
Adverse Events 
Adverse event terms recorded on the eCRFs in the Prometheus database will be mapped to preferred 
terms using the NCI CTCAE v.4. 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 v4.0. Listings of AEs will be provided.  
7.3 
Sample Size 
This is a pilot clinical trial and is not powered for significance in statistical comparison as there is 
insufficient existing evidence to predict the likely outcomes.  The maximum number of subjects to be 
recruited for the study is 18.  
 
It is expected for the current trial that the drug will achieve a minimum PFS4 of 20% while the maximum 
toxicity rate should be below 30%.PFS4 is defined as no disease progression or death within the first 4 
months of the proposed treatment. If the trial is not terminated early, a posterior 90% credibility interval 
for the primary endpoint PFS4 rate will have a width of 0.271, given 3 patients achieving PFS4 under the 
assumption of 20% PFS4 rate. 
 
7.4 
Safety and Futility Monitoring 
The PFS4 and toxicity rates will be monitored simultaneously using the Bayesian approach of Thall, 
Simon, Estey (10) as extended by Thall and Sung (11), an effective and flexible method which has been 
successfully applied in hundreds of clinical trials at UT-MD Anderson and other institutions. The prior 
probabilities of PFS4 and toxicity for the experimental regimen are modeled by beta distributions 
(Beta(0.20, 0.80) and Beta(0.25 0.75), respectively). Denoting the probabilities of PFS4 and study drug-
related toxicity rate of the experimental treatment by {p(PFS4,E) , p(TOX,E)}, the following decision 
criteria will be applied:  
the trial will be stopped early either due to futility if  
Prob{ p(PFS4,E) < 0.20 | data} > 0.90, 
or due to toxicity if  
Prob{ p(TOX,E) > 0.25 | data} > 0.90. 
The above futility and toxicity monitoring rules will be implemented by a cohort size of 3, starting from 
the 6th enrolled patient. Patients will be monitored according to the stopping boundaries for PFS4 or 
study drug-related toxicity specified in Table 7-1. For example, the patient enrollment will be stopped if 
more than 3 severe toxicities (Grade 4) are observed among the first 6 patients. The patient enrollment 
will continue unless the stopping boundary is reached for evaluable subjects. The corresponding operating 
characteristics are listed in the Table 7-2. 
 
Table 7-1: 
Stopping boundaries for PFS4 and study-related toxicity 
Number of patients evaluated  
Stop if # of PFS4 observed  
Stop if # of toxicity observed  
6 
0  
4-6  
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9  
0 
5-9  
12  
0-1  
6-12  
15  
0-1  
7-15  
18  
Always stop with this many patients  
 
Table 7-2: 
Operating Characteristics (based on simulations from 10,000 trials) 
True PFS4 Rate 
True Toxicity Rate Prob (stop the trial early) 
Average number of 
patients treated 
0.1 
0.10 
0.720 
10.5 
 
0.30 
0.774 
9.9 
 
0.50 
0.930 
8.1 
0.25 
0.10 
0.243 
15.5 
 
0.30 
0.387 
14.2 
 
0.50 
0.809 
10.1 
0.4 
0.10 
0.057 
17.4 
 
0.30 
0.237 
15.9 
 
0.50 
0.763 
10.9 
 
The above stopping boundaries were calculated using MultcLean (v.2.1.0) design software 
(http://biostatistics.mdanderson.org/Software Download).  
 
The Investigator is responsible for completing a Safety/Efficacy Summary Report, and submitting it to the 
IND Office Medical Affairs and Safety Group, for review and approval.  This should be submitted after the 
first 6 evaluable patients per cohort, complete 4 months of study treatment, and every 3 evaluable patients 
per cohort, thereafter. On every summary submission, toxicity will be assessed after one month, and 
efficacy after four months of therapy. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under “MD 
Anderson IND Office correspondence”.  
 
 
7.5 
Analysis Plan  
Summary statistics will be provided for continuous variables. Frequency tables will be used to summarize 
categorical variables. The distribution of time-to-event endpoints will be estimated using the method of 
Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the 
log-rank test. Additional exploratory subgroup analysis will be conducted if necessary. 
Safety data will be reviewed after 6, 9, 12 and 15 patients have completed 1 month of 
cabozantinib, while efficacy data will be after 6, 9, 12 and 15 patients have completed 4 months 
of cabozantinib. If the number of PFS4 required for moving the trial to next stage has not been achieved, 
the patient enrolment will be halted until enough responses observed. Toxicity evaluation will be based on 
the incidence of severity and type of AEs (including physical and laboratory). Data from all subjects who 
receive any study drug will be included in the safety analyses. Subjects who entered the study and did not 
take any of the study drug and had this confirmed, will not be evaluated for safety.  
 
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8 
OTHER ANALYSES 
Blood samples for pharmacokinetics and pharmacogenetics studies will be collected during study course. 
However, analysis is planned to occur after data is completely collected, except in the subset of subjects 
who previously used mitotane within 6 months of study participation. This subset’s PK samples will be 
analyzed shortly after collection to guide cabozantinib dosing.  
PK profiles will be obtained on first dose (Day 1) and at steady-state (Day 29 +/- 5 days) after starting 
study drug. In addition, 1 blood sample will be collected every 12 weeks (+/- 6 weeks) to measure 
cabozantinib trough levels. If feasible, blood samples will be collected at the time of disease progression 
or significant toxicity (CTACE grade 3 or more).  For determining PK profiles, PK blood samples (10 
mL) are to be collected within 15 minutes prior to dosing of cabozantinib and at the following time points 
following ingestion of the dose: 1 hour (±15 minutes), 2 hours (±15 minutes), 4 hours (±15 minutes), and 
8 hours (±15 minutes) post-dose.  Blood samples (~10 ml) for the determination of steady-state trough 
concentrations of cabozantinib will be collected immediately prior to the patient’s first dose of the day.  
The time and date of the patient’s prior dose, and time and date of blood sampling will be clearly 
documented in the patient’s medical chart.  At each collection point, whole blood (10 mL) will be 
collected into pre-chilled lavender-top (or similar) collection tubes and immediately placed on wet ice.  
Within 30 minutes of collection, chilled tubes will be centrifuged at 1,500 x g for 15 min at 4ºC.  Plasma 
(supernatant) will be immediately transferred to pre-labelled cryovials and stored at -80ºC until assayed.     
Plasma concentrations of cabozantinib will be measured by a validated liquid chromatography-mass 
spectrometry (LC-MS/MS) assay in a validated laboratory (World Wide Clinical Trials [WWCT], Austin, 
Texas). All PK samples will be split into two ~2.5 mL plasma samples, with only one (primary) 
sample being shipped to WWCT for analysis and the other (backup) retained in pre-labelled 
cryovials and stored at -80ºC. All samples that will be analyzed after study completion will be also stored 
at -80ºC until assayed.   
In most study subjects (estimated 12 out of 18 patients), samples will be analyzed a-posteriori after 
completing study enrollment.  In subjects who were on mitotane therapy within 6 months of study 
participation, PK samples will be analyzed after collection to allow PK derived dosing as detailed earlier.   
 
 
Analyses of immune markers in tumor and blood samples: These studies will be performed at MDACC in 
collaboration with Dr. Ignacio Wistuba who is supervising the Translational Molecular Pathology - 
Immunoprofiling Laboratory (TMP-IL). Patient samples will be collected to perform immunologic 
analyses. The study will allow for the collection of blood samples to be drawn at the time of routine blood-
draw to assess circulating immune markers. Whole blood, plasma, serum, peripheral blood mononuclear 
cells (PBMCs) and other secreted markers (such as cytokines) will be collected at 3 time points (before 
treatment (during screening), at week 9 day 1 visit (+/- 5 days)  and at time of disease progression (+ 5 
days), and processed at the TMP-IL for further downstream analyses.  
Optional biopsies will be used for immune-profiling analysis (core needle biopsies (CNBs). Fresh tissue 
samples will be sent immediately after collection to TMP-IL. Core biopsy is typically performed using 21-
18 gauge needle and with condition permitting, up to 5 cores should be collected, including 2 for clinical 
processing and 3 additional passes will be attempted to obtain the research core samples.  Core biopsy will 
be performed only when the desired tissue focus is deemed amenable to safe biopsy and low risk for 
complications.  
Cores 1 and 2: Immediate and overnight fixation in 10% buffered formalin for paraffin embedding, 
usually within 20-24 hour after fixation. For biopsies performed on Friday, fixation time may 
extend to 48 hours (FFPE samples) 
Cores 3-4: Flash freezing in liquid nitrogen.  
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Core 5: Flow cytometry analysis of TIL and TME on fresh tissue. 
 
All tissue specimens collected will be reviewed by reference pathologists. At least, three types of QC 
activities for specimens collected will be performed: a) histology/cytology examination of the tissues and 
cells to confirm the presence of tumor cells, as well as their abundance (tumor cellularity); b) tissue 
quality assessment of fresh specimens for extraction of DNA, RNA and proteins, and to prepare histology 
specimens such as whole sections for immunohistochemistry and immunofluorescence; and, c) quality 
assessment of DNA, RNA and protein extracted. All histology stained samples will be scanned and digital 
images will be available for review. 
Using immunohistochemistry (IHC) and multiplex immunofluorescence (IF) approach that is available 
in the TMP-IL (Drs. Wistuba and Jaime Rodriguez Canales), we will quantitatively assess multiple immune 
markers. Fresh frozen tissues will be also used for analysis of immune markers. IHC and IF will be 
performed using autostainers. All antibodies used will be optimized for IHC/IF by examination of positive 
and negative controls and testing of the antibodies standard methods, including Western blotting. All 
pathology slides will be scanned into a digital image scanner and analyzed using image analysis software; 
IHC analysis will be performed using the Aperio Image Toolbox™ (Leica Biosystems) and IF analysis 
using the Vectra Inform™ (Perkin-Elmer) software. Nucleic acids (DNA and RNA) and protein extraction: 
Blood (plasma and PMBCs) and tumor (CNB) samples will be subjected to extraction using standard 
methods. 
DNA and RNA quantity and integrity will be assessed using NanoDrop 1000 
spectrophotometer (Nanodrop technologies) and Pico-green analyses.  Also, protein lysate will be 
extracted using standard methods. 
High order flow cytometry panels will focus on 1) delineation of major immune cell types (T cells, B cells, 
NK cells, DC), 2) determination of T cell differentiation status and limited functionality (IFNγ, TNFα, GB) 
and 3) defining the expression level of costimulatory and coinhibitory molecules on T cells and their 
respective receptors such as PD-L1 on infiltrating myeloid cells or tumor. Briefly, 50 cc of heparinized 
peripheral blood from cancer patients prior to the initiation of treatment, during treatment, and at time of 
progression will be processed fresh (within 24h of being drawn) for PBMC isolation by ITB. PBMCs will 
be cryopreserved and stored in Liquid Nitrogen until use. Flow cytometric analysis will be conducted 
retrospectively on cryopreserved PBMCs. When appropriate, cells will be thawed and stained immediately. 
All time points belonging to a patient will be stained and acquired at the same time to avoid any technical 
variation (sample at time of progression will be omitted for responders if analysis needs to be completed 
when patient is still responding). We expect that half of the study participants will agree to have the optional 
biopsies and we anticipate to collect blood samples from all participants. 
 
In another exploratory objective, we will attempt to assess the role of genetic variants of drug disposition 
genes on the PK of cabozantinib.  For the past decades, pharmacogenomic association studies have 
revealed a significant influence of genetic variants on the disposition of various drugs prescribed in the 
cancer care setting (e.g. tacrolimus, irinotecan, 5-fluorouracil and 6-MP).  This continues to be an 
increasingly popular area of pharmacological research.  Cabozantinib is a substrate for both cytochrome 
P450 3A4 (CYP3A4) and the drug transporter MRP2, and maybe a substrate for other obscure drug 
metabolizing enzymes and transporters.  Hypothetically, single nucleotide polymorphisms (SNPs) in 
these genes may affect cabozantinib PK.  However, there is a dearth of data regarding these potential 
genetic associations.  To preliminary assess for potential associations, a single blood sample (~ 10 ml) 
will be collected at the patient’s first clinic visit for exploratory pharmacogenomic testing.  Whole blood 
will be collected into pre-labelled lavender-top collection tubes.  Genomic DNA will be isolated from 
each blood sample using the GenElute Blood Genomic DNA Kit (Sigma-Aldrich Co), or similar DNA 
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extraction kit, in the Pharmaceutics Research Laboratory (Division of Pharmacy, Department of 
Pharmacy Research) by trained research staff.  Isolated DNA will be transferred to pre-labelled, de-
identified cryovials and frozen at -80ºC in the Pharmacy Research Laboratory freezer prior to shipment.  
DNA samples will be shipped by research staff in the Pharmacy Research Laboratory to an external 
laboratory (Avera Institute for Human Genetics, Sioux Falls, SD) for analysis of over 2,000 
polymorphisms in drug disposition genes using the powerful DMET™ Plus Array (Affymetrix). 
Preliminary pharmacogenomic data will be a crucial step towards further understanding the disposition of 
cabozantinib in cancer patients.  
 
9 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be ensured 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. This trial will be monitored by the MDACC IND Office 
in accordance with the ICH Note for Guidance on Good Clinical Practice (ICH Topic E6, 1996). 
The IND office will perform reviews at regular intervals to ensure the validity and integrity of 
the trial data 
10 
STUDY COMMITTEES 
NA 
11 
ETHICAL ASPECTS 
11.1 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” (GCP) 
ICH E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct of the study 
complies with the basic principles of GCP as outlined in the current version of 21 Code of Federal 
Regulations, subpart D, Part 312, “Responsibilities of Sponsors and Investigators” Part 50, “Protection of 
Human Subjects” and Part 56, “Institutional Review Boards.” 
11.2 
Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain written 
informed consent from each subject participating in this study after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study. In the case where the subject is unable to 
read, an impartial witness should be present during the entire informed consent discussion. After the 
subject has orally consented to participation in the trial, the witness’s signature on the form will attest that 
the information in the consent form was accurately explained and understood. 
The CRF for this study contains a section for documenting informed subject consent, and this must be 
completed appropriately. If new safety information results in significant changes in the risk/benefit 
assessment, the consent form should be reviewed and updated as necessary. All subjects (including those 
already being treated) should be informed of the new information, should be given a copy of the revised 
form, and should give their consent to continue in the study. 
11.3 
Institutional Review Board/Ethics Committee  
This study is being conducted under a United States Investigational New Drug application or other 
Clinical Trial Application, as appropriate. This protocol (and any modifications) and appropriate consent 
procedures must be reviewed and approved by an IRB/EC. This board must operate in accordance with 
current local, regional, and federal regulations. The investigator will send a letter or certificate of IRB/EC 
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approval to Exelixis (or designee) before subject enrollment and whenever subsequent modifications to 
the protocol are made. 
11.4 
Future Use of Patient Samples 
No samples for anything other than safety testing will be collected during this study.  
12 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications may be made and will be prepared, reviewed, and approved by representatives of 
the investigator. 
All protocol modifications must be submitted to the IRB/EC for information and approval in accordance 
with local requirements and to regulatory agencies if required. Approval must be obtained before any 
changes can be implemented, except for changes necessary to eliminate an immediate hazard to study 
subjects or those that involve only logistical or administrative aspects of the trial (eg, change in monitor 
or change of telephone number). 
13 
CONDITIONS FOR TERMINATING THE STUDY 
Exelixis 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, Exelixis and the investigator will arrange 
the procedures on an individual study basis after review and consultation. In terminating the study, 
Exelixis and the investigator will ensure that adequate consideration is given to the protection of the 
subjects’ interests. 
14 
STUDY DOCUMENTATION AND RECORDKEEPING 
14.1 
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 include the subjects’ hospital/clinic records; physicians’ and nurses’ 
notes; the appointment book; original laboratory, ECG, 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 at least the latest of 2 years 
following the marketing application approval date for the study treatment in the indication being 
investigated, 2 years after the investigation is completed or discontinued, or for a time consistent with 
local regulatory requirements. After that period, the documents may be destroyed subject to local 
regulations with prior written permission from Exelixis. If the investigator wants to assign the study 
records to another party or move them to another location, Exelixis 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 Exelixis to store these in a 
sealed container outside of the study site so that they can be returned sealed to the investigator in case of a 
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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. 
14.2 
Source Documents and Background Data 
Upon request, the investigator will supply its licensees and collaborators with any required background 
data from the study documentation or clinic records. This is particularly important when CRFs are 
illegible or 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. 
14.3 
Audits and Inspections 
The investigator should understand that source documents for this study should be made available, after 
appropriate notification, to qualified personnel from the Exelixis Quality Assurance Unit (or designee) or 
to health authority inspectors. The verification of the CRF data must be by direct inspection of source 
documents. 
14.4 
Case Report Forms  
For enrolled subjects, all and only data from the procedures and assessments specified in this protocol and 
required by the CRFs should be entered on the appropriate CRF. Data from some procedures required by 
the protocol, such as physical examinations and laboratory results, 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 and may not be 
required for CRF entry.  
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI or 
authorized delegate from the study staff. 
All paper forms should be typed or filled out using indelible ink and must be legible. Errors should be 
crossed out but not obliterated, the correction inserted, and the change initialed and dated by the 
investigator or his or her authorized delegate.  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data in the 
CRFs and in all required reports. 
15 
MONITORING THE STUDY 
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 should 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. 
16 
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, subjects should be 
identified by identification codes and not by their names. The investigator should keep a subject 
enrollment log showing codes and names. The investigator should maintain documents not for 
submission to Exelixis or designees (e.g., subjects’ written consent forms) in strict confidence. 
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All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review. 
17 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide any such publication to Exelixis, Inc. for review 
at least sixty (60) days before submission and also comply with any provisions regarding 
publication that are agreed to between the PI’s institution (e.g., institution name.) and Exelixis, 
Inc. in the Clinical Trial Agreement related to this study. The results will be made public within 
24 months of the end of data collection. However, if a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. In any event, a full report of the outcomes 
should be made public no later than three (3) years after the end of data collection. Authorship 
for abstracts and manuscripts resulting from this study will be determined in accordance to 
guidelines established by the International Committee of Medical Journal Editors.
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18 
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Appendix A: 
Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, 
able to carry on all predisease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry out 
work of a light or sedentary 
nature (eg, light housework, 
office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed > 50% of the time. 
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead 
ECOG, Eastern Cooperative Oncology Group 
 
 
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