Conditions: Locally Advanced Paraganglioma Metastatic Adrenal Gland Pheochromocytoma Metastatic Paraganglioma Regional Adrenal Gland Pheochromocytoma Unresectable Adrenal Gland Pheochromocytoma Unresectable Paraganglioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This pilot phase II trial studies how well cabozantinib s-malate works in treating patients with pheochromocytomas or paragangliomas that have spread from the primary site to other places in the body and cannot be removed by surgery. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking the growth of new blood vessels necessary for tumor growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate best overall response rate in patients with measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI).

SECONDARY OBJECTIVES:

I. To estimate progression-free survival at 1-year. II. To correlate blood pressure control and change/discontinuation of antihypertensive medications with tumor responses.

III. To correlate symptomatology evaluation by the MD Anderson Symptom Inventory (MDASI) with tumor responses.

IV. To correlate plasma metanephrines and chromogranin A with tumor responses. V. To correlate plasma C-reactive protein and interleukin-6 with symptoms and tumor responses.

VI. Toxicity assessment by the Common Terminology Criteria for Adverse Events (CTCAE).

VII. To correlate both c-MET expression by immunohistochemistry (IHC) as well as MET amplification by fluorescence in situ hybridization (FISH) in archived samples and correlate these biomarkers with overall prognosis and responsiveness to cabozantinib (cabozantinib s-malate).

EXPLORATORY OBJECTIVES:

I. Best overall response rate in patients with bone metastases only (8 patients) as determined by fludeoxyglucose F 18 positron emission tomography/computed tomography (FDG-PET/CT).

II. FDG-PET/CT maximum standard uptake value (SUVmax), advanced volumetric measures including peak standard uptake value (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG).

III. Time to skeletal related events. IV. Incidence of skeletal related events at 4 months and one year. V. Markers of bone turnover (bone specific alkaline phosphatase and C-terminal telopeptide \[CTx\]).

OUTLINE:

Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 4 weeks through week 24 and then every 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30-37 days.

Arms:
arm 1: Patients receive cabozantinib s-malate PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cabozantinib S-malate intervention 2: Laboratory Biomarker Analysis intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2014-0081 
Protocol Title 
A Phase II Study to Evaluate the Effects of Cabozantinib in 
Patients with Unresectable and Progressive Metastatic 
Pheochromocytomas and Paragangliomas 
Protocol Phase 
2 
Protocol Version 
12/MOD001 
Version Date 
February 2020 
Protocol PI 
Camilo Jimenez 
Department 
Endocrine Neoplasia and Hormonal Disorders 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
124740 
Proprietary Information of MD Anderson


1 
 
  
A Phase II Study to Evaluate the Effects of Cabozantinib in Patients with 
Unresectable and Progressive Metastatic Pheochromocytomas and Paragangliomas 
 
PROTOCOL NUMBER: 
2014-0081 
STUDY DRUG: 
Cabozantinib (XL184) 
 
 
SPONSOR:  
The University of Texas MD Anderson Cancer Center 
 
 
DATE FINAL: 
February 2020 
 
 
 
Proprietary Information of MD Anderson


 
2 
 
SYNOPSIS  
TITLE 
A Phase II Study to Evaluate the Effects of Cabozantinib in Patients with 
Unresectable and Progressive Metastatic Pheochromocytomas and Paragangliomas 
 
PROTOCOL NUMBER:  2014-0081 
CLINICAL PHASE 
Phase II  
RATIONALE 
Pheochromocytomas (PHs) and paragangliomas (PGs) are rare neuroendocrine tumors 
originating in the paraganglia. Approximately 15-20% of these tumors are malignant1. 
Patients with metastatic disease exhibit a decreased overall survival, with only 60% of 
patients still living five years after initial diagnosis2.  Malignant PHs and PGs have two 
characteristics: increased angiogenesis3 and predilection for bone metastases4.  
 
Tumor angiogenesis 
 
Approximately 50% of patients with malignant PHs and PGs carry germline mutations of 
the succinate dehydrogenase subunit B (SDHB) gene. These mutations prevent oxidative 
catabolism of succinate into fumarate and electron transport through the internal 
mitochondrial membrane. As a consequence, production of ATP is attenuated leading to 
activation of hypoxia-inducible target genes such as vascular endothelial growth factors 
(VEGFs) and the platelet-derived growth factor beta (PDGF-β).  In addition, genes 
involved in glucose metabolism such as the hexokinase 2 (HK2) and lactate 
dehydrogenase (LDH) are also up-regulated5. Activation of these genes causes abnormal 
and increased tumor angiogenesis, decreased apoptosis, and increased glucose uptake. In 
fact, 18F-FDG-PET/CT scan offers 100% sensitivity for the localization of these tumors6. 
Some sporadic tumors exhibit a similar molecular profile5. 
 
Bone metastases 
 
The skeleton is involved in 80% of patients with malignant PHs and PGs4. In 20% of 
these patients, the skeleton is the only location of metastatic spread4. Bone metastases are 
usually lytic and blastic, expansile, and associated with increased morbidity and 
decreased overall survival4. Up to eighty percent of patients with bone metastases 
develop skeletal related events (SREs) such as: bone pain, fractures, and cord 
compression that need radiation therapy and/or surgery4. Patients experience SREs 
rapidly once bone metastases are developed (median 4.4 months)4. Fifty percent of 
patients who develop an SRE develop a second SRE within a median of 10 months4. 
Palliative radiation therapy and surgery are frequently required to improve pain and 
release cord compression. Molecular targeted therapies and chemotherapy may prevent 
SREs4. 
Proprietary Information of MD Anderson


 
3 
 
 
Experience with molecular targeted therapies 
 
A recently published retrospective intention-to-treat study described potential 
clinical benefits derived from sunitinib in patients with metastatic PHs and PGs7. 
Seventeen patients with progressive disease over a period of 6 months were treated with 
37.5-50 mg of sunitinib daily, 4 weeks on, 2 weeks off. Patients were followed with 
radiographic and biochemical studies every 2 to 3 months. As per RECIST 1.1, 8 patients 
(47%) exhibited clinical benefits: 3 patients had partial responses and 5 had prolonged 
stabilization of disease, including 4 patients with extensive skeletal metastases (but not 
other metastases) identified by18F-FDG-PET/CT scan. The tumors that responded to 
treatment also exhibited more than 30% reduction in glucose uptake 2-3 months after 
initiation of treatment compared with baseline. Patients who experienced partial response 
or prolonged stabilization of disease improved blood pressure and some discontinued 
treatment with antihypertensive medications. Most patients who benefited from sunitinib 
carried SDHB mutations. Unfortunately, most patients who experienced clinical benefits 
later developed tumor progression7. 
 
Hypothesis 
 
Development of tumor progression and resistance to sunitinib may be related to 
the compensatory activation of molecular pathways that are not inhibited by this drug, 
such as the c-MET receptor pathway. MET and VEGFRs cooperate to promote tumor 
angiogenesis and MET upregulation may occur as a response to the VEGFs pathway 
inhibition leading to tumor resistance and growth8. MET activation is a common feature 
of human tumors and it is frequently observed in patients with bone metastases8. 
Molecular analyses of malignant PHs and PGs from a few patients participant of phase 
one clinical trials have found c-MET receptor gene mutations (unpublished data).  
Cabozantinib is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity that 
targets the VEGF, c-MET, and RET receptors. This drug has been recently approved for 
the treatment of progressive metastatic medullary thyroid carcinoma another 
neuroendocrine tumor9. Of interest, cabozantinib has also shown effectiveness in patients 
with castration resistant prostate, breast, and renal cell carcinomas metastatic to the 
skeleton10, 11, 12. Therefore, simultaneous inhibition of MET and VEGFRs by 
cabozantinib may provide a broad spectrum of antineoplastic activity and prevent tumor 
resistance in patients with malignant PHs and PGs.  
 
 
 
TARGET POPULATION 
Patients with malignant PHs and PGs have metastases into visceral organs and/or 
the skeleton. Depending on metastases location, the patients can be classified as follows:  
1. 40% of the patients have only visceral involvement (liver, lungs, lymph 
nodules) 
Proprietary Information of MD Anderson


 
4 
 
2.  40% have visceral and bone metastases 
3.  20% have bone metastases only.  
 
Based on this information, we will divide our study population in two different branches:  
 
1. Main branch: 14 patients with measurable disease (+/- bone metastases)  
2. Exploratory branch: 8 patients with bone metastases only (+/- small non-
measurable lesions).   
 
OBJECTIVES 
The objectives of this study are: 
Primary Endpoint (14 patients with measurable disease) 
 
To estimate best overall response rate by RECIST 1.113 in patients with 
measurable disease determined by a. CT or b. MRI  
 
Secondary Endpoints (All patients) 
1. To estimate progression-free survival at 1-year  
2. To correlate blood pressure control and change/discontinuation of 
antihypertensive medications with tumor responses 
3. To correlate symptomatology evaluation by the MD Anderson symptom 
Inventory (MDASI) with tumor responses  
4. To correlate plasma metanephrines and chromogranin A with tumor responses 
5. To correlate plasma C-reactive protein and interleukin-6 with symptoms and 
tumor responses 
6. Toxicity assessment by the Common Terminology Criteria for Adverse 
Events (CTCAE) 
7. To correlate both c-MET expression by IHC as well as MET amplification by 
FISH in archived samples and correlate these biomarkers with overall 
prognosis and responsiveness to cabozantinib. 
 
Exploratory Endpoints (For patients with only bone metastases n=8) 
1. Best overall response rate in patients with bone metastases only (8 patients) as 
determined by FDG-PET/CT  
2. FDG-PET/CT SUVmax, advanced volumetric measures including SUVpeak, 
metabolic tumor volume (MTV), and total lesion glycolysis (TLG) 
3. Time to skeletal related events 
4. Incidence of skeletal related events at 4 months and one year 
5. Markers of bone turnover (bone specific alkaline phosphatase and CTx) 
 
 
 
 
Proprietary Information of MD Anderson


 
5 
 
STUDY DESIGN 
This is a prospective phase II study 
 
NUMBER OF SUBJECTS 
Approximately 22 subjects will be eligible for this study. 
INCLUSION AND EXCLUSION CRITERIA 
Malignant PH and PG patients will be eligible for enrollment as defined by the 
inclusion and exclusion criteria as follows: 
Inclusion Criteria 
1. 18 years of age or older 
2. Histological confirmation of PH/PG 
3. Locally advanced or metastatic disease not amenable to surgery  
4. Patients enrolled in the main branch should have measurable disease. Patients 
with a predominance of bone disease who have small, non-measurable or small 
measurable lesions other than bone, may be included per the principal 
investigator’s discretion, in the exploratory branch of the study for patients with 
bone metastases only.  
5. Progressive disease per RECIST 1.1 as determined by the investigator within the 
12 months preceding study enrollment   
6. Assessment of all known disease sites, eg, by computerized tomography (CT) 
scan, magnetic resonance imaging (MRI), bone scan as appropriate, and/or FDG-
PET scan within 28 days before the first dose of cabozantinib 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
8. Life expectancy of at least 3 months 
9. Organ and marrow function and laboratory values as follows within 4 days prior 
to the first dose of cabozantinib: 
 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3without colony stimulating 
factor support 
b. Platelets ≥ 100,000/mm3 
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:  
Proprietary Information of MD Anderson


 
6 
 
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. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical 
evidence of pancreatitis 
i. Urine protein/creatinine ratio (UPCR) ≤ 1 
j. Serum phosphorus, calcium potassium ≥ LLN and magnesium ≥ 1.2 
mg/dL 
10. Capable of understanding and complying with the protocol requirements and has 
signed the informed consent document. 
11. Sexually active patients (men and women) must agree to use medically accepted 
barrier methods of contraception (eg, 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 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). 
12. 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, antiestrogens, ovarian suppression or any 
other reversible reason. 
 
Exclusion Criteria 
A subject who meets any of the following criteria is ineligible for the study: 
1.   Received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or 
nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment. 
2.   Prior treatment with cabozantinib 
3.   Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not 
eligible; 
Proprietary Information of MD Anderson


 
7 
 
4. Received radionuclide treatment (i.e. I 131 meta-iodo- benzyl guanidine) within 6 
months of the first dose of study treatment 
 
5. Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 14 days before the first dose of study treatment. 
6. Receipt of any other type of investigational agent within 28 days before the first 
dose of study treatment.  
7. 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. 
8. Prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥ 1.3 × the laboratory ULN within 7 days before 
the first dose of study treatment. 
9. The subject requires concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or 
Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin 
(≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular 
weight heparin (LMWH) are permitted. 
10. The subject requires chronic concomitant treatment of strong CYP3A4 inducers 
(eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort).  
11. 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 of ≥ 0.5 teaspoon (2.5ml) 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 
12. Radiographic evidence of cavitating pulmonary lesion(s) 
13. Tumor invading or encasing any major blood vessels 
14. 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.  
15. Uncontrolled, significant intercurrent 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 
Proprietary Information of MD Anderson


 
8 
 
antihypertensive treatment within 7 days of the first dose of study 
treatment 
iii. Any history of congenital long QT syndrome 
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) 
• myocardial infarction 
• thromboembolic event 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), diverticulitis, cholecystitis, symptomatic 
cholangitis or appendicitis; patients must be completely recovered 
from these conditions 
• malabsorption syndrome 
ii. 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. 
c. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy  
d. Other clinically significant disorders such as: 
i. active infection requiring systemic treatment within 28 days before the 
first dose of study treatment 
Proprietary Information of MD Anderson


 
9 
 
ii. serious non-healing wound/ulcer/bone fracture within 28 days before the 
first dose of study treatment 
iii. history of organ transplant 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 
7 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. 
16. Unable to swallow tablets 
17. A corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms 
within 28 days before first dose of study treatment. Three ECGs must be 
performed. If the average of these three consecutive results for QTcF is ≤ 500 
msec, the subject meets eligibility in this regard. 
18. Pregnant or breastfeeding. 
19. A previously identified allergy or hypersensitivity to components of the study 
treatment formulation. 
20. Unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator or designee. 
21. Evidence within 2 years of the start of study treatment of another malignancy 
which required  systemic treatment except for cured nonmelanoma skin cancer 
or cured in situ cervical carcinoma 
  
22. 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.  
 
ESTIMATED LENGTH OF SUBJECT PARTICIPATION 
Subjects may continue to receive study treatment until disease progression or as 
long as the patient is deriving clinical benefit, as judged by the investigator (case-
by-case decision with approval of the Medical Monitor), or they experience 
unacceptable drug-related toxicity. 
ESTIMATED STUDY DATES 
First study screening visit: November 2014 to last study follow-up visit July 2020 
Proprietary Information of MD Anderson


 
10 
 
INVESTIGATIONAL REGIMEN DOSE/ROUTE/DURATION 
Cabozantinib initiation dose is 60 mg daily by mouth  
Cabozantinib is supplied as 20-mg and 60-mg tablets.  
COMBINATION DRUG(S) 
None  
SAFETY ASSESSMENTS 
Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, 
hematology tests) will be performed every 2 weeks for the first 8 weeks followed 
by assessments every 4 weeks until week 24, then every 8 weeks through week 
52, then every 12 weeks. Other safety evaluations including EKGs and urinalysis 
will be performed at regular intervals. 
Adverse event 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) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. 
TUMOR ASSESSMENTS 
Tumors will be assessed with radiographic studies at baseline and every two 
months through week 52, and then every 12 weeks: 
For patients with measurable visceral metastases CT scans with contrast or 
MRI are required. Measurable disease is defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to 
be recorded). Each lesion must be greater than or equal to 10 mm when 
measured by CT, MRI or caliper measurement by clinical exam; or greater 
than or equal to 20 mm when measured by chest x-ray. Lymph nodes must 
be greater than or equal to 15 mm in short axis when measured by CT or 
MRI. 
For patients with only bone metastases (Exploratory branch) FDG-
PET/CT scan is the only radiographic test required for follow-up. FDG-
PET/CT assessment will include standard assessment of SUVmax, as well 
as advanced volumetric measures including SUVpeak, metabolic tumor 
volume (MTV), and total lesion glycolysis (TLG) 
 
PHARMACOKINETIC ASSESSMENTS 
None. 
Proprietary Information of MD Anderson


 
11 
 
BIOMARKER ASSESSMENTS 
All patients included in this study will have baseline measurements of resting 
plasma metanephrines and chromogranin A. Approximately 60% of patients with 
malignant pheochromocytomas and paragangliomas experience an excessive 
secretion of catecholamines.  In patients with an excessive production of 
metanephrines at baseline, plasma metanephrines will be obtained every two 
months. Chromogranin A will be measured at baseline and every two months in 
all patients. We will correlate biomarkers with overall prognosis, symptoms, and 
responsiveness to cabozantinib. 
 
Translational Research  
1. Deregulation of c-MET can occur via different 
mechanisms, including gene amplification, overexpression, 
and activation of somatic mutations, autocrine or paracrine 
mechanisms, along with interaction of cell surface 
receptors. c-MET has been found to be over-expressed in a 
variety of cancers including lung, breast, and ovarian. The 
most frequent genetic alteration in MET is gene 
amplification. This amplification has been shown to be 
associated with a poorer prognosis in certain cancers. The 
exploratory translational objectives will explore both c-
MET expression by IHC as well as MET amplification by 
FISH and correlate these biomarkers with overall prognosis 
and responsiveness to cabozantinib. This research will be 
performed in archived tumor samples. 
2. Several symptoms associated with pheochromocytoma and 
paraganglioma such as fatigue and decreased appetite may 
be associated with an increased production of Interleukin-6. 
We will measure c-reactive protein (surrogate biomarker of 
interleukin-6) and interleukin 6 at baseline and every two 
months from Day 1. We will correlate these markers with 
symptoms (MDASI) and overall response to cabozantinib. 
 
 
OTHER ASSESSMENTS 
c-MET expression by IHC as well as MET amplification by FISH in archived 
tissue samples 
 
Proprietary Information of MD Anderson


 
12 
 
STATISTICAL METHODS 
This Phase II study's  primary objective is to estimate the best overall response rate in 
patients with measurable disease.  Response will include RECIST 1.1 CR, PR, 
and SD. With 14 patients, the 95% confidence interval for a 45% response rate 
would be (18.9, 71.1%). For the exploratory objective in the small group of 
patients with bone metastases, the 95% confidence interval for a 45% response 
rate with 8 patients would be (10.5, 79.5%). We do not include a formal statistical 
monitoring rule for toxicity given the established safety profile of this drug.  
 
Continuous variables will be summarized using descriptive statistics such as 
mean, standard deviation, median and range. Categorical variables will be 
tabulated by frequencies and the corresponding percentages.  Response rates and 
their 95% confidence intervals will be estimated. Kaplan Meier survival curves 
will be used to estimate survival outcomes.  Cox proportional hazards regression 
analysis may be used to assess the association between survival and covariates of 
interest. The Fisher’s exact test or logistic regression analysis will be used for any 
binary outcomes. T-tests or Wilcoxon rank sum tests will be used to compare 
continuous variables. Longitudinal models may be explored to study change over 
time. 
 
 
 
 
Proprietary Information of MD Anderson


 
13 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................13 
1 
BACKGROUND AND RATIONALE .....................................................................20 
1.1 
Background: .....................................................................................................20 
1.2 
Cabozantinib (XL184) .....................................................................................22 
1.2.1 
Pharmacology ......................................................................................22 
1.2.2 
Cabozantinib Nonclinical Toxicology .................................................23 
1.2.3 
Clinical Experience ..............................................................................23 
1.2.3.1 
Clinical Summary .......................................................................24 
1.2.3.2 
Clinical Safety Profile .................................................................30 
1.1.1.4 
Clinical Pharmacokinetics ..........................................................33 
1.1.1.5 
Clinical Activity ..........................................................................35 
1.1.1.6 
Translational Medicine ...............................................................36 
1.3 Study Population, ...................................................................................................39 
2 
STUDY OBJECTIVES AND DESIGN ...................................................................40 
2.1 
Study Objectives ..............................................................................................40 
2.2 
Study Design ....................................................................................................41 
2.2.1 
Overview of Study Design ...................................................................41 
2.3 
Treatment Assignment .....................................................................................42 
2.4 
Study Sites .......................................................................................................42 
2.5 
Withdrawals .....................................................................................................42 
3 
TREATMENTS ........................................................................................................43 
3.1 
Composition, Formulation, and Storage ..........................................................43 
3.1.1 
Investigational Treatment ....................................................................43 
3.1.2 
Cabozantinib Tablets ...........................................................................43 
3.2 
Dose, Schedule and Route ...............................................................................44 
3.3 
Cabozantinib Dose Modifications, Interruptions, and Discontinuation ...........44 
3.3.1 
Management of Adverse Events ..........................................................46 
3.3.1.1 
Cabozantinib Dose Reinstitution and Reescalation ....................46 
3.3.1.2 
General Guidelines for Non-Hematologic and 
Hematologic Adverse Events ......................................................47 
3.3.1.3 
Cabozantinib Warnings, Precautions, and Guidelines for 
Management of Specific Adverse Events ...................................50 
3.3.1.4 
Hepatobiliary Disorders ..............................................................52 
3.3.1.5 
Fatigue, Anorexia, and Weight Loss ...........................................54 
3.3.1.6 
Skin Disorders .............................................................................55 
3.3.1.7 
Wound Healing and Surgery .......................................................56 
Proprietary Information of MD Anderson


 
14 
 
3.3.1.8 
Hypertension ...............................................................................56 
3.3.1.9 
Thromboembolic Events .............................................................58 
3.3.1.10 
Proteinuria ...................................................................................59 
3.3.1.11 
Corrected QTc Prolongation .......................................................60 
3.3.1.12 
Hypophosphatemia .....................................................................62 
3.3.1.13 
Thyroid Function Disorders ........................................................62 
3.3.1.14 
Hemorrhagic Events ....................................................................62 
3.3.1.15 
GI Perforation/Fistula and Non-GI Fistula Formation ................63 
3.3.1.16 
Osteonecrosis of the Jaw .............................................................64 
3.4 
Concomitant Medications and Therapies .........................................................65 
3.4.1 
Anticancer Therapy ..............................................................................65 
3.4.2 
Other Medications ................................................................................65 
3.4.3 
Allowed Therapies ...............................................................................65 
3.4.4 
Prohibited or Restricted Therapies .......................................................66 
3.4.5 
Potential Drug Interactions ..................................................................67 
3.5 
Compliance ......................................................................................................69 
3.6 
Study Drug Accountability ..............................................................................69 
4 
STUDY POPULATION ...........................................................................................69 
4.1 
Inclusion Criteria .............................................................................................69 
4.2 
Exclusion Criteria ............................................................................................71 
5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................74 
5.1 
Pre-Treatment Period .......................................................................................74 
5.2 
Treatment Period ..............................................................................................75 
5.3 
Post-Treatment Period .....................................................................................77 
5.4 
Laboratory Assessments ..................................................................................78 
5.5 
Tumor Measurements ......................................................................................79 
5.6 
MDASI .............................................................................................................79 
6 
SAFETY ...................................................................................................................81 
6.1 
Adverse Events and Laboratory Abnormalities ...............................................81 
6.1.1 
Adverse Events ....................................................................................81 
6.1.2 
Serious Adverse Events .......................................................................81 
6.1.3 
Serious Adverse Event Reporting to Supporting Company 
Exelixis ................................................................................................83 
6.1.4 
Regulatory Reporting ...........................................................................84 
6.2 
Other Safety Considerations ............................................................................84 
6.2.1 
Laboratory Data ...................................................................................84 
6.2.2 
Pregnancy .............................................................................................84 
6.2.3 
Medication Errors/Overdose ................................................................85 
Proprietary Information of MD Anderson


 
15 
 
6.2.4 
Follow-Up of Adverse Events .............................................................85 
7 
STATISTICAL CONSIDERATIONS......................................................................85 
7.1 
Analysis Population .........................................................................................85 
7.1.1 
Safety Population .................................................................................85 
7.2 
Safety Analysis ................................................................................................86 
7.2.1 
Adverse Events ....................................................................................86 
7.3 
Sample Size ......................................................................................................86 
8 
DATA QUALITY ASSURANCE ............................................................................86 
9 
ETHICAL ASPECTS ...............................................................................................86 
9.1 
Local Regulations ............................................................................................86 
9.2 
Informed Consent.............................................................................................86 
9.3 
Institutional Review Board/Ethics Committee ................................................87 
9.4 
Future Use of Patient Samples .........................................................................87 
10 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................87 
11 
CONDITIONS FOR TERMINATING THE STUDY .............................................87 
12 
STUDY DOCUMENTATION AND RECORDKEEPING .....................................88 
12.1 
Source Documents and Background Data .......................................................88 
12.2 
Audits and Inspections .....................................................................................88 
12.3 
Case Report Forms ...........................................................................................88 
13 
MONITORING THE STUDY ..................................................................................88 
14 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS ...............................................................................................................89 
15 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............89 
16 
REFERENCES .........................................................................................................90 
 
LIST OF TABLES 
Table 3-1: 
Cabozantinib Tablet Components and Composition ................................ 44 
Table 3-2: 
Dose Reductions of Cabozantinib ............................................................. 45 
Table 3-3: 
General Approach to the Management of Cabozantinib-Related 
Non-Hematologic Adverse Events ........................................................... 47 
Table 3-4: 
General Approach to the Management of Cabozantinib-Related 
Hematologic Adverse Events .................................................................... 48 
Table 3-5: 
Management of Transaminase Elevation .................................................. 53 
Proprietary Information of MD Anderson


 
16 
 
Table 3-6: 
Management of Treatment-emergent PPE Syndrome .............................. 56 
Table 3-7: 
Management of Hypertension Related to Cabozantinib ........................... 58 
Table 3-8: 
Management of Treatment-emergent Proteinuria ..................................... 60 
Table 5-1: 
Study Assessments .................................................................................... 76 
 
LIST OF APPENDICES 
Appendix A: Performance Status Criteria ...................................................................... 94 
 
Proprietary Information of MD Anderson


 
17 
 
LIST OF ABBREVIATIONS 
Proprietary Information of MD Anderson


 
18 
 
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 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GGT 
γ-glutamyl transferase 
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 
Proprietary Information of MD Anderson


 
19 
 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
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) 
Proprietary Information of MD Anderson


 
20 
 
1 
BACKGROUND AND RATIONALE 
1.1 
Background:  
Pheochromocytomas (PHs) and paragangliomas (PGs) are rare neuroendocrine tumors 
originating in the paraganglia. Approximately 15-20% of these tumors are malignant1. 
Patients with metastatic disease exhibit a decreased overall survival, with only 60% of 
patients still living five years after initial diagnosis2.  Malignant PHs and PGs have two 
characteristics: increased angiogenesis3 and predilection for bone metastases4.  
Tumor angiogenesis 
Approximately 50% of patients with malignant PHs and PGs carry germline mutations of 
the succinate dehydrogenase subunit B (SDHB) gene. These mutations prevent oxidative 
catabolism of succinate into fumarate and electron transport through the internal 
mitochondrial membrane. As a consequence, production of ATP is attenuated leading to 
activation of hypoxia-inducible target genes such as vascular endothelial growth factors 
(VEGFs) and the platelet-derived growth factor beta (PDGF-β).  In addition, genes 
involved in glucose metabolism such as the hexokinase 2 (HK2) and lactate 
dehydrogenase (LDH) are also up-regulated5. Activation of these genes causes abnormal 
and increased tumor angiogenesis, decreased apoptosis, and increased glucose uptake. In 
fact, 18F-FDG-PET/CT scan offers 100% sensitivity for the localization of these tumors6. 
Some sporadic tumors exhibit a similar molecular profile5. 
Bone metastases 
The skeleton is involved in 80% of patients with malignant PHs and PGs4. In 20% of 
these patients, the skeleton is the only location of metastatic spread4. Bone metastases are 
usually lytic and blastic, expansile, and associated with increased morbidity and 
decreased overall survival4. Up to eighty percent of patients with bone metastases 
develop skeletal related events (SREs) such as: bone pain, fractures, and cord 
compression that need radiation therapy and/or surgery4. Patients experience SREs 
rapidly once bone metastases are developed (median 4.4 months)4. Fifty percent of 
patients who develop an SRE develop a second SRE within a median of 10 months4. 
Palliative radiation therapy and surgery are frequently required to improve pain and 
release cord compression. Molecular targeted therapies and chemotherapy may prevent 
SREs4. 
 
Proprietary Information of MD Anderson


 
21 
 
Experience with molecular targeted therapies 
A recently published retrospective intention-to-treat study described potential clinical 
benefits derived from sunitinib in patients with metastatic PHs and PGs7. Seventeen 
patients with progressive disease over a period of 6 months were treated with 37.5-50 mg 
of sunitinib daily, 4 weeks on, 2 weeks off. Patients were followed with radiographic and 
biochemical studies every 2 to 3 months. As per RECIST 1.1, 8 patients (47%) exhibited 
clinical benefits: 3 patients had partial responses and 5 had prolonged stabilization of 
disease, including 4 patients with extensive skeletal metastases (but not other metastases) 
identified by18F-FDG-PET/CT scan. The tumors that responded to treatment also 
exhibited more than 30% reduction in glucose uptake 2-3 months after initiation of 
treatment compared with baseline. Patients who experienced partial response or 
prolonged stabilization of disease improved blood pressure and some discontinued 
treatment with antihypertensive medications. Most patients who benefited from sunitinib 
carried SDHB mutations. Unfortunately, most patients who experienced clinical benefits, 
later developed tumor progression7. 
Hypothesis 
Development of tumor progression and resistance to sunitinib may be related to the 
compensatory activation of molecular pathways that are not inhibited by this drug, such 
as the c-MET receptor pathway. MET and VEGFRs cooperate to promote tumor 
angiogenesis and MET upregulation may occur as a response to the VEGFs pathway 
inhibition leading to tumor resistance and growth8. MET activation is a common feature 
of human tumors and it is frequently observed in patients with bone metastases8. 
Molecular analyses of malignant PHs and PGs from a few patients participant of phase 
one clinical trials have found c-MET receptor gene mutations (unpublished data).  
Cabozantinib is a tyrosine kinase inhibitor with antiangiogenic and antitumor activity that 
targets the VEGF, c-MET, and RET receptors. This drug has been recently approved for 
the treatment of progressive metastatic medullary thyroid carcinoma another 
neuroendocrine tumor9. Of interest, cabozantinib has also shown effectiveness in patients 
with castration resistant prostate, breast, and renal cell carcinomas metastatic to the 
skeleton10, 11, 12. Therefore, simultaneous inhibition of MET and VEGFRs by 
cabozantinib may provide a broad spectrum of antineoplastic activity and prevent tumor 
resistance in patients with malignant PHs and PGs.  
  
Proprietary Information of MD Anderson


 
22 
 
1.2 
Cabozantinib (XL184) 
1.2.1 
Pharmacology 
Cabozantinib is a potent inhibitor of multiple receptor tyrosine kinases (RTKs) 
implicated in tumor growth, metastasis, and angiogenesis (Investigator’s Brochure, 
version 9, 2013). 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.  
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair14. 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)14. 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. Upregulation 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 (Investigator’s Brochure, version 9, 2013). 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 
Proprietary Information of MD Anderson


 
23 
 
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 vivo14. Principal investigator unpublished data has shown somatic c-met 
mutations in patients with metastatic PHs and PGs. 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, 
demonstrate dysregulated c-Met activity15, either by means of c-Met kinase 
overexpression15, activating c-Met gene mutations and/or amplification16, 17, 18, or 
increased autocrine and/or paracrine secretion of the c-Met ligand, HGF/SF19, 20.These 
alterations have been implicated in tumor progression and metastasis, and a high 
constitutive activation of c-Met has been correlated with poor clinical prognosis19.  
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability21. 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 cancer22. High VEGFR2 
expression is an unfavorable prognostic biomarker in hepatocellular carcinoma (HCC), 
and correlated with triple-negative (i.e., therapy-resistant) breast cancer and poor 
survival. VEGFR2 is highly expressed in malignant PH and PGs23,24. In preclinical 
studies anti-angiogenic medications such as sunitinib induced apoptosis of 
pheochromocytoma cells by inhibiting VEGFR-2/AKT/mTOR pathway. 
1.2.2 
Cabozantinib Nonclinical Toxicology 
In rodents and non-rodents, histopathological changes associated with cabozantinib 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid 
tissues, kidney, and adrenal and reproductive tract tissues, bone, and pancreas 
(Investigator's Brochure, version 9,  2013). Cabozantinib tested negative in bacterial and 
mammalian cell genotoxicity assays in vitro. In reproductive toxicity studies, 
cabozantinib was embryotoxic in rats, produced fetal soft tissue changes in rabbits, and 
decreased fertility in male and female rats. The carcinogenic potential of cabozantinib has 
not been evaluated. 
1.2.3 
Clinical Experience 
Analysis of safety and clinical responses data in 1311 subjects treated with cabozantinib 
in company-sponsored single-agent studies (XL184-001, XL184-008, XL184-201, 
Proprietary Information of MD Anderson


 
24 
 
XL184-203, XL184-205, and XL184-301 [cabozantinib arm]) has been performed. The 
data cut-off for this analysis is February 28, 2013 (Investigator Brochure, Version 9, 
2013). A summary of this analysis is presented here. 
1.2.3.1 
Clinical Summary 
Phase I Studies  
Study XL184-001 was a phase 1 dose-escalation study in subjects with advanced solid 
tumors. Eighty-five subjects, across 13 dosing levels (DL) ranging from 0.08 mg/kg daily 
(using powder-in-bottle [PIB] suspension on a 5 days on, 9 days off schedule) to 265 
daily using the suspension formulation The capsule MTD was determined to be 175 mg 
daily25. Of the 35 subjects with medullary thyroid cancer (MTC) and measureable disease 
enrolled in the dose expansion phase (MTC enrolled throughout the study), 10 (29%, 
95% CI) had confirmed partial responses (PR) (with a duration up to 48+ months), 17 
(49%) had tumor shrinkage of ≥30%, and stable disease (SD) of at least 6 months was 
observed in 15/37 (41%) of the MTC subjects.  
In Study XL184-002, treatment of subjects with newly diagnosed glioblastoma (GB) 
consisted of cabozantinib in combination with TMZ with or without radiation therapy. 
Enrollment has been terminated and no clinical efficacy data is presented in the 2013 
Investigator’s Brochure Version 9.  
In Study XL184-008 which was mostly a clinical pharmacology study, subjects with 
advanced solid tumors (particularly renal cell carcinoma [RCC] and differentiated thyroid 
cancer [DTC]) are evaluated for any potential clinically significant drug-drug interaction 
of cabozantinib on the CYP isozyme CYP2C8. The effect of daily dosing of 175 mg 
cabozantinib and a single dose of rosiglitazone has been by comparing the PK profile of a 
single dose of rosiglitazone before and after administration of ≥ 21 daily doses of 
cabozantinib at ≥ 100 mg/day FBE weight (125 mg malate salt weight). The PK of 
cabozantinib when combined with a single dose of rosiglitazone was also evaluated. 
Secondary and exploratory objectives of Study XL184-008 were to evaluate the safety 
and tolerability of cabozantinib and antitumor efficacy in subjects with relapsed or 
refractory RCC. Twenty-five subjects with RCC were enrolled in the study. Half of the 
subjects had 1-2 lines of prior therapy with systemic agents, and the other half had 3 or 
more lines of prior therapy. The majority of subjects (88%) had prior anti-VEGF 
Proprietary Information of MD Anderson


 
25 
 
anticancer therapies. Of the 25 evaluable subjects at Week 16, seven subjects (28%) 
achieved PRs, 13 subjects had SD (52%), and one subject (4%) had PD as best response. 
The median PFS was 12.9 months (95% CI: 9.9, not applicable) (data on file). The 
median OS was not yet reached with median follow-up of 14.7 months (range: 11.2-21.8 
months). In patients with DTC, PFS has not been reached. A DCR of 73% at 24 weeks 
has obtained (Investigator Brochure, Version 9, 2013).  
 
Study XL184-014 is a phase 1 study currently active in Japan. The study includes 
subjects with advanced solid tumors enrolled in successive cohorts to receive 
cabozantinib administered PO as capsules or tablets in a 3+3 trial design. Subjects are 
treated with continuous 4-week cycles of cabozantinib administered PO qd. Response is 
assessed on Day 29 and every 8 weeks thereafter by modified Response Evaluation 
Criteria inn Solid Tumors (mRECIST) v1.0 criteria. A total of 23 subjects with advanced 
malignancies have been enrolled: NSCLC (n = 9); gastrointestinal stromal tumor (n = 4); 
colorectal cancer (n = 4), pancreatic cancer (n = 2), leiomyosarcoma, duodenal cancer, 
MTC, and thymic cancer (n = 1, each). Four of five heavily pre-treated subjects with 
NSCLC have had a confirmed PR. Of the four subjects with PRs genetic evaluation 
revealed that one subject had an EGFR mutation, one subject was RET-fusion positive, 
and two subjects were ALK fusion positive (Investigator Brochure, Version 9, 2013).. 
Study XL184-202 was a phase 1b/2 trial that evaluated the safety and tolerability of 
cabozantinib and erlotinib administered in combination in non-small-cell lung cancer 
(NSCLC) subjects. Of the 64 subjects enrolled in the phase 1 dose-escalation portion of 
the study, all but two had been previously treated with and progressed on erlotinib 
therapy. A PR was observed in 5 subjects (8%). The ORR for the Phase 1 population was 
8.2% (90% CI: 3.3, 16.5). The median PFS for subjects (mITT Population) was 3.68 
months (95% CI: 3.15, 5.49). The Kaplan-Meier estimate of the probability of a subject 
to be progression-free at 6 months was 29.4% (Investigator Brochure, Version 9, 2013).  
Twenty-eight subjects were enrolled in the Phase 2 portion of the study, in which subjects 
who had received clinical benefit from erlotinib and subsequently experienced PD 
receive single-agent cabozantinib or cabozantinib in combination with erlotinib. A PR 
was observed in one subject who was treated with single-agent cabozantinib. The ORR 
for subjects who received cabozantinib was 6.7% (90% CI: 0.3, 27.9). No objective 
Proprietary Information of MD Anderson


 
26 
 
responses were seen in subjects who received cabozantinib + erlotinib (0/13 subjects). 
The median PFS for subjects (mITT Population) was 1.91 months (95% CI: 1.64, 7.06) 
for the cabozantinib arm and 3.94 months (95% CI: 1.54, 7.26) for the cabozantinib + 
erlotinib arm. The Kaplan-Meier estimate of the probability of a subject to be 
progression-free at 6 months was 30.8% for the cabozantinib arm and 22.0% for the 
cabozantinib + erlotinib arm (Investigator Brochure, Version 9, 2013). 
Phase 2 Studies 
In study XL184-201, subjects with progressive or recurrent GB in first or second relapse 
were enrolled to receive cabozantinib daily as a single agent. Group A received an initial 
dose of 140 mg (175 mg malate salt weight) (Group A), subsequent cohorts (Groups B 
and C) received an initial dose 100 mg (125 mg of malate salt weight). Forty-six subjects 
were enrolled in Group A, and a total of 176 subjects were enrolled in Groups B/C. Study 
objectives included assessments of safety, tolerability, and clinical activity (consisting of 
independent radiology facility [IRF]-determined response assessment and PFS), at the 
two dose levels. Enrollment of this study has been completed. Analysis is ongoing 
(Investigator Brochure, Version 9, 2013).  
 
Study XL184-203 is a phase 2 randomized discontinuation trial. Subjects are enrolled 
into one of nine tumor-specific cohorts: breast cancer, gastric/gastro esophageal (GEJ) 
cancer, hepatocellular carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic 
cancer, prostate cancer, and small cell lung cancer (SCLC). Eligible subjects with 
advanced solid tumors receive open-label cabozantinib at starting dose of 100 mg daily 
for 12 weeks. Primary endpoints were objective response rate (ORR) at Week 12 and 
PFS in the Randomized Stage. An Independent Data Monitoring Committee (IDMC) 
monitored safety in the blinded Randomized Stage. As of October 2011, all subjects have 
been unblinded.  
In 116 CRPC subjects evaluable for post-baseline bone scan changes, best assessments of 
bone scan improvement were observed in 79 subjects (68%), including complete 
resolution (100% reduction of bone scan lesion area [BSLA]) in 14 subjects (12%) and 
partial resolution (≥30% reduction of BSLA) in 65 subjects (56%); SD by bone scan was 
Proprietary Information of MD Anderson


 
27 
 
observed in 33 subjects (28%), and PD by bone scan (≥ 30% increase in BSLA) in four 
subjects (3%). Based on a retrospective survey completed by investigators, the majority 
of the subjects reported reduced bone pain and reduced reliance upon narcotic pain 
medication. There were 83 subjects with bone metastases and bone pain at baseline who 
had at least one post-baseline assessment of pain status. Of these, 56 subjects (67%) had 
pain improvement at either Week 6 or 12. There were 71 subjects who required narcotic 
analgesic medication at baseline for control of bone pain. Among the 55 subjects who 
were evaluable for post-baseline changes in consumption of narcotics, 31 (56%) were 
able to decrease or discontinue narcotic medication (Investigator Brochure, Version 9, 
2013).  
Bone scan improvement was associated with other measures of antitumor effect and 
clinical benefit. Relative to subjects with either stable or progressive bone scans, more 
subjects with complete or partial bone scan resolution had regression of measurable soft 
tissue disease (81% vs 61%), substantial declines in CTx, a marker of bone turnover 
(62% vs 48%), pain relief (93% vs 35%), reduced narcotic use (72% vs 23%), and a 
higher rate of PFS at 6 months (56% vs 41%). Changes in prostate-specific antigen (PSA) 
appeared to be independent of radiographic changes (Investigator Brochure, Version 9, 
2013). 
Two dosing cohorts, 100 mg (N = 93) and 40 mg (N = 51) once daily, were examined in 
the CRPC NRE. The primary endpoint for the CRPC NRE was BSR prospectively 
assessed by an IRF using a computer-assisted detection (CAD) system. Partial BSR was 
defined as ≥30% reduction of BSLA (Investigator Brochure, Version 9, 2013) and 
complete BSR as 100% resolution of the BSLA. Progressive disease (PD) was defined as 
≥ 30% increase in BSLA.  Subjects with IRF identified measurable soft-tissue lesions on 
baseline CT or MRI scans were evaluated for BOR by RECIST 1.1.  
Prospective measurement of subjects’ pain and narcotic use at baseline and throughout 
the study was obtained by patient reports through standardized tools (BPI over IVRS and 
paper pain medication diaries) over 7-day reporting intervals. Bone scan responses in 
evaluable individuals were observed in 67% (100 mg) and 49% (40 mg) of patients. Soft 
tissue regression was observed in 80% (100 mg) and 79% (40 mg) of evaluable 
Proprietary Information of MD Anderson


 
28 
 
individuals.  Pain improved in 67% of patients. This improvement led to a substantial 
reduction of narcotics dose (Investigator Brochure, Version 9, 2013).  
 
Study XL184-205 is a randomized phase 2 trial for subjects with grade IV astrocytic 
tumors in first or second relapse. Subjects received one of four regimens: 20 mg (25 mg 
malate salt weight) daily (Arm 1) continuously, 60 mg (75 mg malate salt weight) daily) 
(Arm 2) continuously,  and 100 mg (125 mg malate salt weight) daily for 2 weeks 
followed by 40 mg (50 mg malate salt weight) daily continuously (Arm 3), and 100 mg 
(125 mg malate salt weight) daily on an intermittent 3 week on/1 week off schedule (Arm 
4). A total of 19 subjects were accrued before the study was terminated. No analysis of 
clinical activity was performed for this study (Investigator Brochure, Version 9, 2013). 
Phase 3 studies 
Study XL184-301 (EXAM trial) is a blind, multicenter, controlled trial for subjects with 
unresectable, locally advanced or metastatic MTC. In this study,  330 subjects with 
unresectable, locally advanced or metastatic MTC were randomized 2:1 to receive either 
cabozantinib 140 mg (175 mg malate salt weight) or placebo administered qd in a double-
blinded fashion (219 cabozantinib, 111 placebo). Subjects were required to have 
documented radiographic disease progression per mRECIST within 14 months prior to 
randomization. The primary objective of this study was to determine PFS in subjects 
treated with cabozantinib compared with placebo. Key secondary objectives were to 
evaluate overall response rate and OS. An IDMC evaluated interim safety and efficacy 
data from this study to protect subject welfare and to identify issues and provide 
recommendations regarding the study design and conduct. Enrollment in this study has 
been completed. Of the enrolled subjects, 323 received study treatment (214 
cabozantinib, 109 placebo). In October 2011, the study was unblinded and the data 
analyzed and assessed for the primary endpoint. At the data cut-off date for the primary 
analysis of efficacy and safety, 113 subjects (98 cabozantinib, 15 placebo) were still on 
study treatment. A subsequent 120-Day Safety Report (XL184-301 Safety Addendum) 
was generated with a data cut-off date of 31 December 2011; at that data cut-off there 
were 73 subjects (65 cabozantinib, 8 placebo) still on study treatment. 
 The median PFS was significantly longer in the cabozantinib-treated patients (11.2 
months) compared with the placebo group (4.0 months) with a response rate of 28% for 
cabozantinib but 0% in placebo-treated patients. Responses were observed regardless of 
Proprietary Information of MD Anderson


 
29 
 
RET mutation status and correlations of radiologic response were made with changes in 
calcitonin and CEA levels from baseline26. Findings from this study led to the approval of 
cabozantinib in the US by the FDA in November 2012 for patients with progressive, 
metastatic MTC.  
Study XL184-307 (COMET-1) is a randomized, double-blind, active comparator-
controlled study (COMET-1), subjects with metastatic CRPC with bone-dominant 
disease who have experienced disease progression on both docetaxel-containing 
chemotherapy and abiraterone or enzalutamide are randomized 2:1 to receive 
cabozantinib 60 mg or prednisone (or prednisolone in some countries) in a double-
blinded fashion. The objective of this study is to evaluate the effect of cabozantinib 
compared with prednisone on OS. No clinical activity data are currently available for this 
study (Investigator Brochure, version 9, 2013). 
 
Study XL184-306 (COMET-2)  is a randomized, double-blind, active comparator-
controlled study; subjects with previously treated symptomatic CRPC are randomized 1:1 
to receive cabozantinib 60 mg or a combination regimen of mitoxantrone plus 
prednisone. The primary objective of this study is to evaluate the effect of cabozantinib 
on pain palliation in subjects with bone metastases and pain related to bone metastases 
despite narcotic use; secondary endpoints are BSR and OS. No clinical activity data are 
currently available for this study (Investigator Brochure, version 9, 2013). 
 
Expanded Access Study 
 
Study XL184-209 enrolled three subjects with progressive, metastatic MTC in order to 
have access to cabozantinib during review by the FDA and before commercial 
availability of cabozantinib. Following FDA approval of cabozantinib and the subsequent 
availability of commercial drug, the study was closed to enrollment, and the remaining 
subjects rolled over to commercial drug. No analysis of clinical activity data will be 
performed for this study. (Investigator Brochure, Version 9, 2013) 
 
Maintenance Study  
 
Proprietary Information of MD Anderson


 
30 
 
Study XL184-900 is a maintenance study in which subjects from studies of cabozantinib 
given as a single-agent, or in combination with erlotinib or with TMZ may enroll. The 
objectives of this study are: 1) to allow subjects who are currently benefitting from 
cabozantinib treatment as a single-agent or in combination, and who are enrolled in 
cabozantinib studies that are closing, to continue to receive cabozantinib treatment; and 
2) to further characterize the long-term safety and tolerability of cabozantinib. Subjects 
who roll over to this study will continue to receive the same doses of cabozantinib and 
any combination therapy that they are receiving on their current study. As of the 28 
February 2013 data cut-off, 34 total subjects had rolled over into the XL184-900 Study 
from six other XL184 studies; 8 from XL184-001, 1 from XL184-002, 14 from XL184-
008, 5 from XL184-201, 3 from XL184-202, and 3 from XL184-205. No clinical activity 
data are available from this study (Investigator Brochure, Version 9, 2013). 
 
1.2.3.2 
Clinical Safety Profile 
Through 28 February 2013, 1311 subjects with cancer had been treated with single-agent 
cabozantinib in open-label or unblinded company-sponsored clinical trials. The subjects 
in that data set were predominately White (87.9%) and male (64.9%) with a median age 
of 61.0 years (Investigator Brochure, Version 9, 2013).  
In Study XL184-301, 323 subjects with MTC have been treated with single-agent 
cabozantinib (n=214) or placebo (n=109). The subjects in that data set were 
predominately White (cabozantinib arm, 89.7%; placebo arm, 89.9%) and male 
(cabozantinib arm, 69.6%, placebo arm, 63.3%) with a median age of 55.0 years (both 
arms).  
Based on data available in the safety addendum of placebo-controlled Study XL184-301 
(data cut-off 31 December 2011), the median duration of exposure was 315.0 days (10.35 
months) and 104.0 days (3.42 months) in cabozantinib-treated subjects and placebo-
treated subjects, respectively. Twenty-five percent of subjects in the cabozantinib arm 
had duration of exposure of 440 days or more compared with 187 days or more in the 
placebo arm. This suggests that cabozantinib treatment is tolerated for prolonged periods 
of time.  
Proprietary Information of MD Anderson


 
31 
 
Dose modifications (reduction or delay) were frequent in the cabozantinib arm of this 
study. Most (80.8%) cabozantinib-treated subjects had a 1-level dose reduction from 140 
mg FBE weight (175 mg malate salt weight) to 100 mg (125 mg malate salt weight) , and 
43.9% had a 2-level dose reduction from 100 mg to 60 mg (75 mg malate salt weight). In 
comparison, 11.0% of placebo-treated subjects had a 1-level dose reduction, and 0.9% 
had a 2-level dose reduction. Overall, one or more dose delays due to an AE occurred in 
68.7% of cabozantinib-treated subjects compared with 17.4% of placebo-treated subjects. 
The median duration of these dose delays was 4.0 days and 8.0 days in cabozantinib-
treated and placebo-treated subjects, respectively (Investigator Brochure, Version 9, 
2013).  
While all subjects were initially treated with a dose of 140 mg, subjects’ final recorded 
dose levels as of discontinuation or the data cut-off were distributed over the three 
protocol-permitted dose levels in the study (140, 100, and 60 mg qd), reflecting the use of 
protocol-defined dose modifications to manage AEs and adjust the dose of each subject 
to his or her degree of tolerance of the study drug. There was a wide range of duration of 
treatment at all dose levels including at the 140 mg dose (Investigator Brochure, Version 
9, 2013). 
1.2.3.2.1 Adverse Events 
 
Adverse Events in Subjects with Solid Tumors Treated with Cabozantinib as Single 
Agent (Pooled Single-Agent, Open-Label Studies)  
 
The most frequently (≥ 20%) observed AEs in 1311 patients participant in single agent 
studies as of February 28, 2013 regardless of causality, were fatigue:  (66.7%), diarrhea 
(63.1%), decreased appetite (51.9%), nausea (51.9%), weight decreased (36.0%), PPES 
(35.9%), vomiting (34.1%), constipation (33.2%), dysgeusia (28.0%), hypertension 
(27.8%), dysphonia (26.3%), abdominal pain (23.3%), aspartate aminotransferase (AST) 
increased (23.0%), dyspnea (21.3%), headache (20.9%), rash (20.4%), and ALT 
increased (20.2%). The safety profile of single-agent cabozantinib is consistent across 
tumor types (Investigator Brochure, version 9, 2013).  
The most frequently (≥ 20%) observed AEs reported as related to cabozantinib, were 
fatigue (60.0%), diarrhea (56.1%), decreased appetite (44.1%), nausea (42.4%), PPES 
Proprietary Information of MD Anderson


 
32 
 
(35.6%), weight decreased (29.1%), dysgeusia (27.1%), hypertension (24.0%), vomiting 
(23.5%), dysphonia (22.0%), and AST increased (20.1%).  
The most common AEs (≥ 5%) reported at severity of Grade 3 and above include fatigue 
(15.9%), diarrhea (11.1%), hypertension (9.7%), PPES (8.9%), lipase increased (6.8%), 
PE (5.9%), abdominal pain (5.5%), decreased appetite (5.3%), and asthenia 
(5.0%)(Investigator Brochure, version 9, 2013).  
 
Adverse Events in Subjects with MTC Treated with Cabozantinib as Single Agent 
Compared with Placebo (XL184-301)  
 
The cut-off date for AE data comparing the two treatment arms, cabozantinib versus 
placebo, in Study XL184-301 was 28 February 2013 (Investigator Brochure, Version 9, 
2013). The most frequent AEs (≥ 30% incidence) in cabozantinib-treated subjects were 
diarrhea (69.6% in cabozantinib-treated subjects vs 35.8% in placebo-treated subjects), 
weight decreased (55.6% vs 11%), palmar-plantar erythrodysesthesia syndrome (52.3% 
vs 1.8%), decreased appetite (48.6% vs 15.6%), nausea (45.8% vs 21.1%), fatigue 
(41.6% vs 30.3%), dysgeusia (34.6% vs 5.5%), hair color changes (33.6% vs 0.9%), and 
hypertension (30.8% vs 4.6%).  
 
1.2.3.2.2 Serious Adverse Events 
Serious Adverse Events in Subjects with Solid Tumors Treated with Cabozantinib as 
Single Agent (Pooled Single-Agent, Open-Label Studies) 
The most commonly reported SAEs (≥ 2%) were pulmonary embolism (5.1%), vomiting 
(3.4%), dehydration (3.2%), pneumonia (3.0%), nausea (3.0%), abdominal pain (2.4%), 
diarrhea (2.4%), deep vein thrombosis (DVT; 2.1%), and convulsion (2.0%)(Investigator 
Brochure, version 9, 2013). 
Serious Adverse Events in Subjects with MTC Treated with Cabozantinib as Single 
Agent Compared with Placebo (XL184-301) 
The most commonly reported SAEs (≥ 2%) occurring on the cabozantinib-treatment arm 
of Study XL184-301 were pneumonia (4.2%), pulmonary embolism (3.3%), mucosal 
Proprietary Information of MD Anderson


 
33 
 
inflammation (2.8%), hypocalcemia (2.8%), dysphagia (2.3%), and dehydration 
(2.3%)(Investigator Brochure, version 9, 2013). 
1.2.3.2.3 Deaths 
 
As of 28 February 2013, 192 fatal SAEs were reported (182 on single-agent cabozantinib 
or cabozantinib in combination with other therapies, 10 on placebo) across all open-label 
or unblinded company-sponsored studies (Studies evaluated include XL184-001, XL184-
002, XL184-008, XL184-014, XL184-201, XL184-202, XL184-203, XL184-205, 
XL184-209, XL184-900, and all clinical pharmacology studies (n=1754). The majority of 
these SAEs were attributed to disease progression (70.3%) (Investigator Brochure, 
Version 9, 2013). 
Fifty-seven subjects had fatal SAEs that were attributed to reasons other than PD. 53 
subjects received cabozantinib and four received placebo. Of the 53 cabozantinib-treated 
subjects, 27 had events assessed as related to cabozantinib study treatment (24 as a single 
agent, 3 in combination with erlotinib) and 26 subjects had events attributed to reasons 
other than PD or study treatment (20 as a single agent, 6 in combination with other 
therapies). Fatal side effects not attributed to disease progression for Cabozantinib-treated 
subjects on open-label or unblinded studies include single cases of GI hemorrhage, 
hemoptysis, PE, intestinal perforation, enterocutaneous fistula, diverticular perforation, 
and peritonitis, 3 patients who had intracranial hemorrhage, and 4 cases who died of 
respiratory failure (Investigator Brochure, Version 9, 2013). 
 
1.1.1.4 
Clinical Pharmacokinetics 
 
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 
Proprietary Information of MD Anderson


 
34 
 
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%) (Investigator Brochure, 
Version 9, 2013).  
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. A PK study of cabozantinib in patients with renal 
impairment (XL184-017) is ongoing. The results of a population PK analysis suggested 
that mild to moderate renal impairment (creatinine clearance value ≥30 mL/min) does not 
have a clinically relevant effect on the clearance of cabozantinib. The PK evaluation of 
cabozantinib in subjects with hepatic impairment (XL184-003) is ongoing; preliminary 
data suggest that subjects with mild hepatic function impairment (Child-Pugh A) show a 
59% higher plasma AUC0-∞ for cabozantinib as compared with matched healthy 
subjects. 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 (Investigator Brochure, Version 9, 2013).  
Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the 
formation of the cabozantinib N-oxide metabolite by >80%. Inhibition of CYP2C9 had a 
minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition 
of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no 
effect on cabozantinib metabolite formation. Cabozantinib AUC was increased 38% with 
coadministration of the strong CYP3A4 inhibitor ketoconazole and decreased 77% with 
coadministration of the strong CYP3A4 inducer rifampin (Investigator Brochure, Version 
9, 2013).  
Proprietary Information of MD Anderson


 
35 
 
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 HLM 
preparations. IC50 values >20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 
isozymes in both recombinant and HLM assay systems. Cabozantinib at steady-state 
plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect 
on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in 
patients with solid tumors (Investigator Brochure, Version 9, 2013).  
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 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 (Investigator Brochure, Version 9, 2013).  
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport 
activities in a bi-directional assay system using MDCK-MDR1 cells (Investigator 
Brochure, Version 9, 2013). 
1.1.1.5 
Clinical Activity 
 In the placebo-controlled Phase 3 study XL184-301 in 330 MTC subjects, a significant 
increase in median PFS was seen in the cabozantinib arm compared with placebo (11.2 vs 
4.0 months; hazard ratio [HR] =0.28; 95 CIs: 0.19, 0.40). Confirmed PRs occurred in 
28% of cabozantinib-treated subjects and none in the placebo arm; responses were 
durable (median duration 14.6 months)26. An unplanned administrative analysis of overall 
survival (OS) performed at the request of the FDA with a data cut-off of 15 June 2012 
(75% of required deaths) showed a trend for improved duration of OS in the cabozantinib 
arm compared with placebo (26.0 months vs 20.3 months; HR = 0.83; 95% CI: 0.60, 
1.14). In the Phase 1 Study XL184-001, with an enriched MTC population, PRs were 
reported in 29% of 35 MTC subjects with measurable disease across all dose levels and 
in 28% of 25 MTC subjects treated at the MTD. The median duration of treatment for the 
subjects in Study XL184-001 with PRs was 17.7 months with one subject receiving 
treatment for 68.4 months on XL184-001 before rolling over onto maintenance trial 
XL184-900 to continue to receive cabozantinib25. 
In addition to MTC, cabozantinib has demonstrated findings consistent with broad 
clinical anti-tumor activity in early Phase 1 and Phase 2 studies in several other tumor 
Proprietary Information of MD Anderson


 
36 
 
types. In a randomized discontinuation trial (RDT) XL184-203, the following disease 
control rates (DCR = complete response [CR] + partial response [PR] + stable disease 
[SD]) at Week 12 were observed in tumor types including non-small cell lung cancer 
(NSCLC), 38%; breast cancer, 48%; melanoma, 46%; ovarian cancer, 53%; 
hepatocellular carcinoma (HCC), 66%; and CRPC, 66%. In Study XL184-008, clinical 
activity was also observed in differentiated thyroid cancer (DTC; DCR = 73% at 24 
weeks) and renal cell carcinoma (RCC; median progression-free survival [PFS] = 12.9 
months). Observations of clinical activity have included decrease of soft tissue tumor 
lesions including visceral metastases, effects on metastatic lesions on bone scan (partial 
or complete bone scan resolution), reduction in serum markers of bone resorption and 
formation, reduction in circulating tumor cells (CTCs) in subjects with prostate cancer 
with increases in hemoglobin, and improvements in bone pain and reductions in narcotic 
use in subjects with bone metastases (Investigator Brochure, Version 9, 2013). 
In the Phase 2 study XL184-203, cabozantinib demonstrated broad clinical activity in 
men with CRPC (Smith et al. 2013). During the RDT phase, the majority of CRPC 
subjects with bone metastases and elevated total alkaline phosphatase (t-ALP) levels at 
baseline showed reductions in t-ALP26. Similarly, during the non-randomized expansion 
(NRE) phase, the majority of CRPC subjects at the 100 mg assigned dose showed 
reductions in circulating bone specific alkaline phosphatase (BSAP)27. These effects were 
independent of prior or concomitant bisphosphonate treatment. Reductions in bone 
biomarkers were also evident in the 40 mg CRPC NRE cohort (Investigator Brochure, 
Version 9, 2013). Effects on bone scan were assessed by an independent reader, and pain 
and narcotic use were prospectively assessed using an interactive voice recording system 
(IVRS) and a diary. Subjects achieved a bone scan response (BSR) in both the 100 mg 
and 40 mg assigned NRE dose cohorts (67% and 49%, respectively). Among subjects 
with baseline pain of at least 4 (0-10 scale by Brief Pain Inventory [BPI]), a majority had 
at least a decrease of 30% in the average daily worst pain compared with baseline in both 
cohorts (100 mg: 64% of subjects; 40 mg: 69% of subjects). In addition, more than half 
of subjects decreased narcotic use (Investigator Brochure, Version 9, 2013). 
1.1.1.6 
Translational Medicine 
 
RET mutations 
Proprietary Information of MD Anderson


 
37 
 
Of the 36 subjects tested in the XL 184-001 study, 67% were found to harbor RET 
mutations in either blood or tumor samples. Of the remaining 12 subjects, three (8%) of 
the subjects showed no evidence of RET mutation in either tumor or blood samples, and 9 
(25%) subjects had inadequate data. These results confirmed the high rate of RET 
mutations associated with this disease. Of the three subjects showing no evidence of RET 
mutation in either tumor or blood samples, two achieved PR (one confirmed) and one 
showed PD as best response, indicating that mutations in RET may not be necessary for 
clinical benefit from treatment with cabozantinib. 
Serial skin biopsies from a patient with MTC enrolled in the expanded MTD (eMTD) 
Cohort and were analyzed using fluorescence-based IHC. Levels of phosphorylated 
targets of cabozantinib, MET, RET, and KIT, were significantly decreased (40%, 40%, 
and 61%, respectively). In addition, decreases in key downstream mediators of 
cabozantinib target receptors were also measured; pERK and pAKT showed decreases of 
55% and 39%, respectively. These effects are similar to those observed inpreclinical 
experiments28, indicating that exposure to cabozantinib results in consistent changes in 
target signaling pathways. 
In the study XL 184-301 (EXAM trial), archival tumor samples to determine RET 
mutational status in tumors and a whole blood sample to determine hereditary RET status 
were collected. RET status was determined in 65% (215/330) of the enrolled subjects. Of 
these 215 subjects, 79% had activating RET mutations and 21% had no RET mutations 
detected. Of 85 evaluated subjects with either no RET mutations or unknown RET status, 
16 were found to have a RAS gene mutation. Cabozantinib had activity across all RET 
and RAS mutational subgroups, and demonstrated response rates of 22-32%, consistent 
with the response rate of subjects in the study overall. Subjects with RET mutations had 
significantly longer median PFS (60 weeks) than subjects who were RET mutation-
negative (25 weeks). Subjects with RAS mutations had a median PFS of 47 weeks, 
indicating that clinical activity measured in the RET mutation-negative subgroup can be 
attributed partially to subjects with RAS mutations (Investigator Brochure, Version 9, 
2013). 
BRAF 
Preliminary analysis of 48 melanoma subjects with both tumor response and BRAF 
mutation data suggests that the clinical activity of cabozantinib is independent of BRAF 
mutation status(Investigator Brochure, Version 9, 2013).. Clinical activity of 
Proprietary Information of MD Anderson


 
38 
 
cabozantinib also appears to be independent of epidermal growth factor receptor (EGFR) 
and KRAS mutation status in NSCLC subjects based on the preliminary data 
(Investigator Brochure, Version 9, 2013). 
Biomarkers of response of anti-angiogenic therapies 
Plasma samples from patients with GB (XL-184-201) were analyzed for several 
biomarkers of response to anti-angiogenic agents, including levels of VEGF-A, 
sVEGFR2, and PlGF. Changes in pharmacodynamic markers consistent with 
cabozantinib on-target effects were observed after cabozantinib administration in 40 
subjects treated with a starting dose of 140 mg FBE weight (175 mg malate salt weight). 
Changes in PlGF (↑), VEGF-A (↑), sVEGFR2 (↓), and soluble KIT (sKIT)(↓) reached 
statistical significance at multiple time points, particularly Days 15 and 29. Soluble MET 
as a potential biomarker of MET inhibition was modulated (↑) upon cabozantinib 
treatment and changes reached statistical significance as well, on Day 15 and Day 57 
(Cycle 3 Day 1) (Investigator Brochure, Version 9, 2013). 
In the study XL 184-301 (EXAM trial), exposure to cabozantinib resulted in significant 
decreases in the levels of the circulating sVEGFR2 and sKIT, consistent with results 
observed in other cabozantinib studies and with other anti-VEGFR2 inhibitors, and a 
modest but statistically significant relationship between plasma cabozantinib exposure 
and pharmacodynamic response was apparent (Investigator Brochure, Version 9, 2013). 
Markers of bone turnover 
Circulating CTx was reduced in the majority of CRPC patients included in the XL-184-
203 study26. Similar changes were seen in NTx. These effects of cabozantinib on 
circulating CTx and NTx levels appear to be independent of prior or concomitant 
bisphosphonate treatment or presence of bone metastases27. Consistent with effects of 
cabozantinib on osteoblast activity, the majority of CRPC RDTsubjects with bone 
metastases and elevated t-ALP levels at baseline showed reductions in t-ALP 
(Investigator Brochure, Version 9, 2013). Similarly, the majority of CRPC NRE subjects 
at the 100 mg assigned dose showed reductions in circulating BSAP26. These effects were 
independent of prior or concomitant bisphosphonate treatment. Reductions in bone 
biomarkers were also evident in the 40 mg CRPC NRE cohort: the median change in CTx 
at Week 12 was a 31% reduction and 50% of evaluable patients exhibited a decrease in 
BSAP at week 12 or later (Investigator Brochure, Version 9, 2013). 
Proprietary Information of MD Anderson


 
39 
 
Circulating tumor cells 
In metastatic prostate cancer, CTC counts at baseline have prognostic value, and changes 
on therapy have been considered to be predictive of treatment benefit29. For the 100 mg 
CRPC NRE cohort, robust reductions in CTCs were observed regardless of prior therapy 
in 62 subjects with baseline CTC counts ≥ 5/7.5 mL of blood and a Week 6 and/or Week 
12 assessment. Fifty-seven subjects (92%) had ≥ 30% decrease in their CTC count, while 
39% of evaluable subjects converted to < 5 CTCs at Week 627. Similarly, for the 40 mg 
CRPC NRE cohort, reductions in CTCs were observed regardless of prior therapy in 39 
subjects with baseline CTC counts ≥ 5/7.5 mL of blood and a Week 6 and/or Week 12 
assessment: 67% demonstrated CTC decrease ≥30% in their CTC count, while 22% of 
evaluable subjects converted to <5 CTCs at Week 6 (Investigator Brochure, Version 9, 
2013). 
1.3 Study Population, 
1.3.1  Study Population for the Study:  
Patients with malignant PHs and PGs have metastases into visceral organs and/or the 
skeleton. Depending on metastases location, the patients can be classified as follows:  
40% of the patients have only visceral involvement (liver, lungs, lymph nodules) 
 40% have visceral and bone metastases 
 20% have bone metastases only.  
 
Based on this information, we will divide our study population in two different branches:  
• 
Main branch: 14 patients with measurable disease (+/- bone metastases)  
• 
Exploratory branch: 8 patients with bone metastases only (+/- small non-
measurable lesions).   
 
 
Proprietary Information of MD Anderson


 
40 
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
 
The objectives of this study are as follows: 
Primary Endpoint (14 patients with measurable disease) 
To estimate best overall response rate by RECIST 1.113 in patients with measurable 
disease determined by a. CT or b. MRI  
Secondary Endpoints (All patients) 
1. To estimate progression-free survival at 1-year  
2. To correlate blood pressure control and change/discontinuation of antihypertensive 
medications with tumor responses 
3. To correlate symptomatology evaluation by the MD Anderson symptom Inventory 
(MDASI) with tumor responses  
4. To correlate plasma metanephrines and chromogranin A with tumor responses 
5. To correlate plasma C-reactive protein and interleukin-6 with symptoms and tumor 
responses 
6. Toxicity assessment by the Common Terminology Criteria for Adverse Events 
(CTCAE) 
7. To correlate both c-MET expression by IHC as well as MET amplification by FISH 
in archived samples and correlate these biomarkers with overall prognosis and 
responsiveness to cabozantinib. 
 
Exploratory Endpoints (For patients with only bone metastases) 
1. Best overall response rate in patients with bone metastases only (8 patients) as 
determined by FDG-PET/CT  
2. FDG-PET/CT SUVmax, advanced volumetric measures including SUVpeak, metabolic 
tumor volume (MTV), and total lesion glycolysis (TLG) 
3. Time to skeletal related events 
4. Incidence of skeletal related events at 4 months and one year 
5. Markers of bone turnover (bone specific alkaline phosphatase and CTx) 
Proprietary Information of MD Anderson


 
41 
 
 
2.2 
Study Design 
2.2.1 
Overview of Study Design 
This is a single-arm, open-label phase II study of cabozantinib in subjects with malignant 
pheochromocytomas and paragangliomas.  The primary endpoint is to estimate best 
overall response rate by RECIST 1.113 in patients with measurable disease determined 
by a. CT or b. MRI. 
The primary objective is to estimate the best overall response rate in patients with 
measurable disease.  Response will include RECIST 1.1 CR, PR, and SD. With 14 
patients, the 95% confidence interval for a 45% response rate would be (18.9, 71.1%). 
For the exploratory objective in the small group of patients with bone metastases, the 
95% confidence interval for a 45% response rate with 8 patients would be (10.5, 79.5%). 
We do not include a formal statistical monitoring rule for toxicity given the established 
safety profile of this drug.  
 
Continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation, median and range. Categorical variables will be tabulated by 
frequencies and the corresponding percentages.  Response rates and their 95% confidence 
intervals will be estimated. Kaplan Meier survival curves will be used to estimate 
survival outcomes.  Cox proportional hazards regression analysis may be used to assess 
the association between survival and covariates of interest. The Fisher’s exact test or 
logistic regression analysis will be used for any binary outcomes. T-tests or Wilcoxon 
rank sum tests will be used to compare continuous variables. Longitudinal models may be 
explored to study change over time. 
Each subject’s course will consist of three periods: 
• A Pre-Treatment Period in which subjects are consented and undergo screening 
assessments to be qualified for the study (Section 5.1); 
• A Treatment Period in which subjects receive study treatment and undergo study 
assessments (Section 5.2); 
Proprietary Information of MD Anderson


 
42 
 
• A Post-Treatment Period in which subjects no longer receive study treatment but 
undergo follow-up study assessments and contacts (Section 5.3). 
2.3 
Treatment Assignment  
It is the responsibility of the investigator to assign a subject number before treating each 
subject with cabozantinib. 
2.4 
Study Sites 
This study will be conducted at one site - The University of Texas MD Anderson Cancer 
Center. 
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; 
• Specific conditions described in the Management of Adverse Events Sections 
3.3.1 and 3.3.1.3; 
• Necessity for treatment with other anticancer treatment prohibited by protocol; 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, 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; 
Proprietary Information of MD Anderson


 
43 
 
• 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; 
• Progressive disease (PD) as determined by the investigator unless the patient is 
deriving clinical benefit as judged by the investigator (case-by-case decision with 
approval of the Medical Monitor). 
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. 
Proprietary Information of MD Anderson


 
44 
 
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) 
Disenegrant 
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.  
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 signing informed consent through 
30 days after the date of the decision to permanently discontinue cabozantinib treatment. 
Subjects will be instructed to notify their physician immediately at the onset of any AE. 
Causality assessment of AEs should include at minimum confounding factors such as 
Proprietary Information of MD Anderson


 
45 
 
disease and concomitant medications. 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 detailed in Section 3.3. Dose 
interruptions and/or reductions should be implemented for unacceptable toxicity. 
Doses may be modified at any time while on study. 
• The assigned dose for cabozantinib is 60 mg/day. 20 mg 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 Sections 3.3.1 and 3.3.1.3, if the investigator feels it is in the interest 
of a subject’s safety and will optimize drug tolerability. 
• Interruption of cabozantinib treatment for AEs may occur at any time per investigator 
discretion. If treatment is interrupted due to 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. 
• Dose interruptions for reason(s) other than AEs (eg, surgical procedures) can be 
longer than 6 weeks per the discretion of the investigator. 
Guidelines for the management of specific AEs are provided in Section 3.3.1.3.  
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 
 
Proprietary Information of MD Anderson


 
46 
 
 
3.3.1 
Management of Adverse Events 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are 
presented in the next sections (Sections 3.3.1 and 3.3.1.3). 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 if agreed to by the Investigator. All AEs should 
also be managed with supportive care at the earliest signs of toxicity considered related to 
the study treatment.  
If study treatment of cabozantinib is restarted after being withheld or interrupted, the 
subject should be instructed not to make up the missed doses of cabozantinib.  
The reason for treatment delay and reduced dose must be recorded on the case report form 
(CRF). 
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this 
is clinically indicated or if causality is initially uncertain. Study treatment may be 
resumed at the same dose (or a lower dose per investigator judgment) if the AE is 
determined not to be related to cabozantinib once the investigator determines that 
retreatment is clinically appropriate and the subject meets the protocol re-treatment 
criteria. 
3.3.1.1 
Cabozantinib Dose Reinstitution and Reescalation 
If the subject recovers from his or her AE and the AE was unrelated to study treatment, 
then study treatment may be restarted with no change in dose.  
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 but no sooner than 2 weeks beyond resolution of AEs that 
led to the dose reduction. Dose re-escalation is not allowed for a drug-related dose 
reduction triggered by myelosuppression or by Grade 4 AEs affecting major organs (eg, 
central nervous system, cardiac, hepatic, renal). 
 
Proprietary Information of MD Anderson


 
47 
 
3.3.1.2 General Guidelines for Non-Hematologic and Hematologic Adverse Events 
Table 3-3: 
General Approach to the Management of Cabozantinib-Related Non-
Hematologic Adverse Events 
Proprietary Information of MD Anderson


 
48 
 
CTCAE v4.0   
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated. Continue cabozantinib at the 
current dose level if the AE is manageable and tolerable. 
Grade 2 AEs which are tolerable 
and are easily managed 
Continue cabozantinib treatment at the current dose level with 
supportive care. 
Grade 2 AEs which are intolerable 
and cannot be adequately managed 
Interrupt cabozantinib treatment or dose reduction. Add 
supportive care as indicated. 
• 
If cabozantinib dosing is interrupted, then upon resolution of 
the AE to baseline or Grade ≤ 1, cabozantinib may be 
resumed at either the same dose or with a dose reduction at 
the discretion of the investigator unless this is a recurring 
event at which time the dose should be reduced 
Grade 3 AEs considered related to 
cabozantinib which occurred 
without optimal prophylaxis or 
which is easily managed by 
medical intervention or resolved 
quickly  
Interrupt cabozantinib treatment and add supportive care as 
indicated: 
• 
For AEs that are easily managed (eg, correction of 
electrolytes) with resolution to baseline or Grade ≤ 1 within 
24 hours, cabozantinib may be resumed at either the same 
dose or with a dose reduction at the discretion of the 
investigator unless this is a recurring event at which time the 
dose should be reduced 
• 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized. Then upon 
resolution of the AE to baseline or Grade ≤ 1, cabozantinib 
may be resumed at either the same dose or with a dose 
reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
Grade 3 AEs considered related to 
study treatment that occurred 
despite optimal prophylaxis or is 
not easily managed by medical 
intervention  
Interrupt cabozantinib treatment until recovery to ≤ Grade 1 or 
baseline, and resume treatment with a dose reduction. 
Grade 4 AEs (except easily 
corrected laboratory abnormalities) 
Permanently discontinue study treatment unless determined that 
the subject is unequivocally deriving clinical benefit. In this case, 
upon recovery to Grade ≤ 1 or baseline, the subject may be 
re-treated at a reduced dose that is to be determined by the 
investigator and  MD Anderson Cancer Center/IND Office, but 
only with MD Anderson Cancer Center/IND Office approval. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined 
above if the investigator believes that it is in the interest of the subject’s safety.  
Table 3-4: 
General Approach to the Management of Cabozantinib-Related 
Hematologic Adverse Events 
Proprietary Information of MD Anderson


 
49 
 
CTCAE v4.0 
Intervention 
Neutropenia 
• 
Grade 3 neutropenia with 
infection requiring IV antibiotic, 
antifungal, or antiviral 
intervention 
• 
Grade 3 neutropenia ≥ 7 days 
• 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤ 1, 
and resume cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia with 
clinically significant bleeding or 
Grade 4 thrombocytopenia 
Interrupt cabozantinib treatment until platelet count is 
≥ 100,000/mm3, and resume cabozantinib treatment at a 
reduced dose. 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to 
Grade ≤ 1 and temperature to ≤ 38.0°C and resume 
cabozantinib treatment at a reduced dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined 
that the subject is unequivocally deriving clinical benefit. In 
this case, upon recovery to Grade ≤ 1 or baseline, the subject 
may be re-treated at a reduced dose that is to be determined by 
the investigator and MD Anderson Cancer Center/IND Office 
but only with MD Anderson Cancer Center/IND Office 
approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined 
that the subject is clearly deriving clinical benefit. In this case, 
upon recovery to Grade ≤ 1 or baseline, the subject may be 
re-treated at a reduced dose that is to be determined by the 
investigator and MD Anderson Cancer Center/IND Office, and 
only with approval by the MD Anderson Cancer Center/IND 
Office. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not 
mandated. Dose reductions or dose delays for anemia should 
be applied as clinically indicated. Supportive care such as red 
blood cell transfusions should be managed in accordance with 
institutional guidelines. 
Proprietary Information of MD Anderson


 
50 
 
CTCAE v4.0 
Intervention 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (ANC < LLN –  1.5 × 109/L); Grade 2 (ANC <1.5 x 109/L  – 1 × 109/L);  
Grade 3 (ANC <1 × 109/L –  0.5 × 109/L); Grade 4 (ANC <0.5 × 109/L ). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x 109/L);  
Grade 3 (Platelet count < 50 - 25 × 109/L); Grade 4 (Platelet count < 25 × 109/L). 
. 
 
3.3.1.3 
Cabozantinib Warnings, Precautions, and Guidelines for Management of 
Specific Adverse Events 
The side effect profile of cabozantinib includes GI symptoms (such as nausea, vomiting, 
and diarrhea, mucositis/stomatitis), fatigue/asthenia, anorexia, weight loss, skin disorders 
including palmar-plantar erythrodysesthesia (PPE) syndrome, elevated liver function tests 
(including alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), 
osteonecrosis, increased pancreatic enzymes with rare cases of overt pancreatitis, thyroid 
function disorders, as well as side effects associated with inhibition of vascular 
endothelial growth factor (VEGF) signaling. The latter of these include arterial and 
venous thrombotic events such as deep vein thrombosis (DVT), pulmonary embolism 
(PE), transient ischemic attack, and myocardial infarction, hypertension, hemorrhagic 
events, proteinuria, wound complications, and rare cases of GI perforation, fistulae 
formation and rectal/perirectal abscess, and reversible posterior leukoencephalopathy 
(RPLS). Please refer to the Investigator’s Brochure for additional details. 
As with all investigational products, unknown AEs may occur. Subjects should be 
monitored closely for all AEs. As with other agents in development, additional AEs are 
unknown. As of 22 October 2013, in studies with cabozantinib angioedema has been 
reported to occur in ~0.1% of subjects treated.  
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating 
therapy with cabozantinib, it will take most subjects 2 to 3 weeks to reach steady state. If 
AEs attributable to cabozantinib occur within the initial 3-week period of dosing, early 
intervention with dose modifications may be justified for AEs that, if worsened, could 
potentially be dangerous or debilitating, because without a dose adjustment, systemic 
exposure of cabozantinib might be expected to increase after the onset of the AE. 
Management of diarrhea, nausea and vomiting, stomatitis and mucositis, hepatobiliary 
disorders (elevated ALT and AST), fatigue, anorexia and weight loss, skin disorders 
Proprietary Information of MD Anderson


 
51 
 
(PPE and rash), wound healing, hypertension, thromboembolic events, proteinuria, QTc 
prolongation, hypophosphatemia, thyroid function disorders are presented in this section 
because these have been observed in previous studies with cabozantinib or represent 
common class effect toxicity. In addition, guidelines to minimize the risk for potential 
serious adverse events (SAEs) such as hemorrhagic events, GI and non-GI perforation 
and fistula formation, wound healing hemorrhagic events, and ONJ are provided in this 
section.  
Please refer to the Investigator’s Brochure for additional practice guidelines and 
management recommendations for side effects potentially related to cabozantinib 
treatment (such as asymptomatic elevations of amylase and lipase, pancreatitis,  rectal 
and perirectal abscess, cardiac disorders, endocrine disorders, eye disorders, 
musculoskeletal and connective tissue disorders, nervous system disorders, respiratory, 
thoracic and mediastinal disorders); available information on potential risk of congenital, 
familial and genetic disorders; and guidelines on management of overdose of 
cabozantinib study treatment.  
Below are guidelines for the treatment and/or prevention of certain treatment-emergent 
AEs of interest that have been associated with, or have a theoretical possibility of 
occurring with, cabozantinib treatment. 
3.3.1.3.1 Gastrointestinal Disorders  
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, 
oral pain, dyspepsia, stomatitis, and dysphagia.  
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. 
Administration of 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 3-2 and Table 3-3. 
In addition, general supportive measures should be implemented including continuous 
oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, 
and stopping lactose-containing products, high fat meals, and alcohol.  
Proprietary Information of MD Anderson


 
52 
 
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 guidelines30,31. 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 3-2 and 
Table 3-3. 
Stomatitis and Mucositis 
Preventive measures include a comprehensive dental examination to identify any 
potential complications before study treatment is initiated. Removal of local factors 
should be instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis.  
During treatment with cabozantinib good oral hygiene and standard local treatments such 
as nontraumatic cleansing and oral rinses (eg, with a weak solution of salt and baking 
soda) should be maintained. The oral cavity should be rinsed 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. 
3.3.1.4 
Hepatobiliary Disorders 
Elevations of transaminases have also been observed during treatment with cabozantinib. 
In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin 
have more frequent laboratory monitoring of these parameters. Other causes that may 
contribute to transaminase elevations should be considered.  If possible, hepatotoxic 
concomitant medications and alcohol should be discontinued in subjects who develop 
elevated transaminases.  
Proprietary Information of MD Anderson


 
53 
 
Because subjects may enter the study with elevations of AST/ALT at baseline, the 
following guidelines in Table 3-5 should be used for dose modifications: 
Table 3-5: 
Management of Transaminase Elevation 
Transaminase 
elevation CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests 
(LFTs) for at least 4 weeks. Then resume the standard protocol-defined 
monitoring of liver function tests (LFTs). 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 
2 weeks. Then weekly for 4 weeks. If LFTs continue to rise within Grade 
2, interrupt cabozantinib treatment. Then continue with at least weekly 
LFTs until resolution to Grade ≤ 1. Study treatment may then be resumed 
at a one-dose-level reduction of cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly 
LFTs until Grade ≤ 2. Then continue with at least weekly LFTs until 
resolution to Grade ≤ 1. Cabozantinib may then be resumed at a one-dose-
level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as 
clinically indicated, at least 2 to 3 times per week, until resolution to 
Grade ≤ 1. If the subject was unequivocally deriving clinical benefit, the 
subject may be able to resume treatment at a lower dose of cabozantinib as 
determined by the investigator and  MD Anderson Cancer Center/IND 
Office but only with  MD Anderson Cancer Center/IND Office approval. 
Subjects with AST or ALT above the ULN but ≤ 3.0 x ULN (ie, Grade 1) at baseline 
≥ 1.5 fold increase of 
AST or ALT AND both 
AST and ALT are ≤ 5.0 x 
ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of 
LFTs for 4 weeks and weekly for 4 weeks. If LFTs continue to rise, 
interrupt study treatment. Then continue with at least weekly LFTs until 
resolution to Grade ≤ 1. Study treatment may then be resumed at a 
one-dose-level reduction of cabozantinib 
≥ 1.5 fold increase of 
AST or ALT and at least 
one of AST or ALT is 
Grade 3 (ie, AST or ALT 
> 5.0 but ≤ 20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs 
until Grade ≤ 2. Then continue with at least weekly LFTs until resolution 
to Grade ≤ 1. Study treatment may then be resumed at a one-dose-level 
reduction of cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as 
clinically indicated, at least 2 to 3 times per week, until resolution to 
Grade ≤ 1. If the subject was unequivocally deriving clinical benefit, the 
subject may be able to resume treatment at a lower dose as determined by 
the investigator and  MD A nderson Cancer Center/IND Office , but only 
with  MD Anderson Cancer Center/IND Office approval. 
Proprietary Information of MD Anderson


 
54 
 
 
 
Cabozantinib treatment should also be interrupted when AST or ALT increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation 
tests (eg, International Normalized Ratio [INR]). Monitoring of transaminases should be 
intensified (2–3 times per week) and cabozantinib should be held until the etiology of the 
abnormalities is determined and these abnormalities are corrected or stabilize at clinically 
acceptable levels (INR < 1.5 × upper limit of normal [ULN], total bilirubin < 1.5 × ULN, 
aminotransferases ≤ baseline grade).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation > 2 × ULN), in 
the absence of evidence of biliary obstruction (ie, significant elevation of alkaline 
phosphatase) or some other explanation of the injury (eg, viral hepatitis, alcohol hepatitis), 
because the combined finding (ie, Hy’s Law cases) represents a signal of a potential for the 
drug to cause severe liver injury. 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study 
treatment held until recovered to Grade ≤ 1 or baseline (or lower). If this occurs within 
6 weeks of the dosing delay, study treatment may continue at a reduced dose. In subjects 
without biliary obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 3 
bilirubin elevation after a dose reduction, study treatment must be permanently 
discontinued. 
3.3.1.5 
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), 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. 
Pharmacological management with psychostimulants such as methylphenidate should be 
considered after disease specific morbidities have been excluded. Note: Chronic use of 
modafinil should be avoided because of its potential to reduce cabozantinib exposure (see 
Investigator’s Brochure).  Refer to Table 3-3 for general management guidelines. 
Proprietary Information of MD Anderson


 
55 
 
Anorexia and weight loss should be managed in accordance to local standard of care 
including nutritional support. Pharmacologic therapy such as megestrol acetate should be 
considered for appetite enhancement.  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. 
3.3.1.6 
Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (also known as hand-foot syndrome), skin 
rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis 
acneiform, and papular rash), pruritus, dry skin, and erythema have been reported in 
cabozantinib-treated subjects. All subjects on study should be advised on prophylactic 
skin care. This includes the use of hypoallergenic moisturizing creams, ointment for dry 
skin, and sunscreen with sun protection factor ≥ 30, avoidance of exposure of hands and 
feet to hot water, protection of pressure-sensitive areas of hands and feet, and use of thick 
cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects 
with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo). 
Early signs of 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 3-6. 
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.  
Proprietary Information of MD Anderson


 
56 
 
Table 3-6: 
Management of Treatment-emergent PPE Syndrome 
Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose. Start urea 20% cream twice daily 
and clobetasol 0.05% cream once daily. Assess subject at least weekly for 
changes in severity. Subjects should be instructed to notify investigator 
immediately if severity worsens. 
Grade 2 
If tolerable, continue cabozantinib at current dose. 
 
If intolerable, reduce cabozantinib dose to next lower level and/or interrupt 
dosing. Start/continue urea 20% cream twice daily and clobetasol 0.05% 
cream once daily. Add analgesics for pain control with NSAIDs/GABA 
agonists/narcotics if needed. Assess subject at least weekly for changes in 
severity. If treatment was interrupted (but not reduced), treatment may be 
restarted at the same dose or at one dose level lower when reaction 
decreases to Grade 1 or 0. If a treatment interruption is again required, the 
dose must be reduced when treatment resumes. 
 
Subjects should be instructed to notify investigator immediately if severity 
worsens. If severity worsens at any time, or affects self-care, proceed to 
the management guidelines for Grade 3 PPE. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. 
Start/continue urea 20% cream twice daily and clobetasol 0.05% cream 
once daily. Pain control with NSAIDs/GABA agonists/narcotics. 
Treatment may restart at one dose level lower when reaction decreases to 
Grade 1 or 0. Permanently discontinue subject from study if reactions 
worsen or do not improve within 6 weeks.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 
 
3.3.1.7 
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. 
3.3.1.8 
Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been 
reported among subjects treated with cabozantinib. 
Proprietary Information of MD Anderson


 
57 
 
Blood pressure should be monitored in a constant position at each visit (either sitting or 
supine). Treatment guidelines for hypertension deemed related to cabozantinib are 
presented in Table 3-7. 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 week. 
 
Proprietary Information of MD Anderson


 
58 
 
Table 3-7: 
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) and < 160 mm 
Hg 
or 
> 100 mm Hg (diastolic) and < 110 mm 
Hg 
 
 
• Increase antihypertension therapy (ie, increase dose of 
existing medications and/or add new antihypertensive 
medications) ; 
• Maintain dose of cabozantinib; 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic 
or < 90 diastolic, or if the subject is symptomatic, the 
dose of cabozantinib should be interrupted and/or 
reduced. 
≥ 160 mm Hg (systolic) and < 180 mm 
Hg 
or 
≥ 110 mm Hg (diastolic) and < 120 mm 
Hg 
• Interrupt and/or reduce cabozantinib by one dose level; 
• Increase antihypertension therapy (ie, increase dose of 
existing medications and/or add new antihypertensive 
medications) ; 
• Monitor subject closely for hypotension; 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 150 systolic 
or < 100 diastolic, dose of cabozantinib should be 
reduced further. 
≥ 180 mm Hg (systolic) 
or 
≥ 120 mm Hg (diastolic ) 
• Interrupt treatment with cabozantinib Add new or 
additional anti-hypertensive medications and/or increase 
dose of existing medications; 
• Monitor subject closely for hypotension; 
• When SBP < 150 and DBP < 100, restart cabozantinib 
treatment at one dose level lower; 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 150 systolic 
or < 100 diastolic, dose of cabozantinib should be 
reduced further. 
Hypertensive crisis or hypertensive 
encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE: If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 
 
3.3.1.9 
Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant 
changes induced by the malignancy or anticancer therapy including inhibitors of VEGF 
pathways. Deep vein thrombosis and PE have been observed in clinical studies with 
Proprietary Information of MD Anderson


 
59 
 
cabozantinib; including fatal events (please refer to the Investigator’s Brochure). Subjects 
who develop a PE or DVT should have cabozantinib treatment held until therapeutic 
anticoagulation with heparins (eg, low molecular weight heparin [LMWH]) is 
established. (Note: Therapeutic anticoagulation with oral anticoagulants, eg, warfarin, or 
oral platelet inhibitors such as clopidogrel is not allowed in this study). Cabozantinib 
treatment may be resumed in subjects who are stable and have uncomplicated PE or DVT 
and are deriving clinical benefit from cabozantinib treatment. During anticoagulation 
treatment, subjects need to be monitored on an ongoing basis for bleeding risk and signs 
of bleeding which may require additional or more frequent laboratory tests in accordance 
to institutional guidelines. If there are any signs of clinically significant bleedings, 
cabozantinib treatment should be permanently discontinued. 
Arterial thrombotic events (eg, transient ischemic attack, myocardial infarction) have 
been observed in studies with cabozantinib. Subjects should be evaluated for preexisting 
risk factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, 
hypertension, coronary artery disease, history of tobacco use, and cardiac or 
thromboembolic events that occurred before initiation of study treatment. Cabozantinib 
treatment should be discontinued in subjects who develop an acute myocardial infarction 
or any other clinically relevant arterial thromboembolic complication. 
3.3.1.10 
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 3-8.   
Proprietary Information of MD Anderson


 
60 
 
Table 3-8: 
Management of Treatment-emergent Proteinuria 
Severity of 
Proteinuria 
(UPCR) 
Action To Be Taken 
≤ 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) 
• 
No change in cabozantinib treatment required;  
• 
Consider confirming with a 24-hour protein assessment 
within 7 days; 
• 
Repeat UPCR within 7 days and once per week. If 
UPCR < 1 on 2 consecutive readings, UPCR monitoring 
can revert to protocol-specific times. (Second reading is 
confirmatory and can be done within 1 week of first 
reading). 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
 
• 
Hold cabozantinib treatment pending repeat UPCR 
within 7 days and/or 24-hour urine protein; 
• 
If ≥ 3.5 on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR 
decreases to < 2, restart cabozantinib treatment at a 
reduced dose and monitoring of urine protein/creatinine 
should continue weekly until the UPCR decreases to < 1.  
Nephrotic syndrome • 
Discontinue cabozantinib treatment. 
UPCR, urine protein to creatinine ratio. 
 
3.3.1.11 
Corrected QTc Prolongation 
The effect of orally administered cabozantinib at 140 mg/day (free-base equivalent) on 
QTc interval was evaluated in a randomized, double-blinded, placebo-controlled phase 3 
study in patients with medullary thyroid carcinoma. A mean increase in QTcF of 10 - 15 
ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc 
relationship could not be definitively established. Changes in cardiac wave form 
morphology or new rhythms were not observed. Accordingly, subjects in this study will 
be monitored for potential QT effects. 
Other factors which may contribute to QTc prolongation include: 
• Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org); 
Proprietary Information of MD Anderson


 
61 
 
• Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug 
levels); 
• Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia); 
• Medical conditions which can alter electrolyte status eg, severe or prolonged 
diarrhea. 
Subjects having any of these additional risk factors while on cabozantinib must have 
electrocardiograms (ECGs) performed approximately one week after the onset of these 
factors. 
If at any time on study there is an increase in QTc to an absolute value > 500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with 
intervals not less than 3 minutes apart. If the average QTc calculated by the Friderica 
formula (QTcF) from the three ECGs is > 500 msec, study treatment must be withheld 
and the following actions should be taken: 
• Check electrolytes, especially potassium, magnesium and calcium. Correct 
abnormalities as clinically indicated; 
• If possible, discontinue any QTc-prolonging concomitant medications; 
• Repeat ECG triplets hourly until the average QTcF is ≤ 500 msec or otherwise 
determined by consultation with a cardiologist. 
The MD Anderson Cancer Center/IND Office  should be notified immediately of any 
QTc prolongation event: 
• Subjects with QTc prolongation and symptoms must be monitored closely until 
the QTc elevation has resolved. Cardiology consultation is recommended for 
evaluation and subject management. Symptomatic subjects must be treated in 
accordance with standard clinical practice. No additional study treatment is to be 
given to the subject until after the event has resolved, the subject has been 
thoroughly evaluated, and further treatment has been agreed to by the MD 
Anderson Cancer Center/IND Office. If any additional study treatment is given 
(eg, after correction of electrolyte abnormalities and normalization of QTcF), it 
will be at a reduced dose as agreed to by the investigator and the MD Anderson 
Cancer Center/IND Office. 
Proprietary Information of MD Anderson


 
62 
 
3.3.1.12 
Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum 
phosphorus should be monitored frequently while receiving cabozantinib. Mild 
hypophosphatemia is usually asymptomatic or symptoms can be non-specific such as 
weakness, bone pain, rhabdomyolysis, or altered mental status. Other causes of 
hypophosphatemia such as poor nutrition, chronic alcoholism, malabsorption, excessive 
antacid use, glucocorticoids use, kidney dysfunction, respiratory alkalosis, vitamin D 
deficiency should be ruled out and/or these causes treated in accordance to standard of 
care. Mild to moderate hypophosphatemia 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. 
3.3.1.13 
Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib and other tyrosine kinase inhibitor treatment as a result of altered thyroid 
hormone regulation by mechanisms that seem to be specific for each agent (Torino et al. 
2009). Preliminary data from ongoing studies indicate that treatment-emergent elevation 
of thyroid stimulating hormone (TSH) by cabozantinib may be dose-dependent in 
fashion. Hyperthyroidism has also been reported. 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 3-232.  
3.3.1.14 
Hemorrhagic Events 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways 
as well as with cabozantinib. In order to mitigate risk of severe hemorrhage, subjects 
should be evaluated for potential bleeding risk factors 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: 
Proprietary Information of MD Anderson


 
63 
 
• Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, 
or abuts major blood vessels. The anatomic location and characteristics of tumor 
as well as the medical history must be carefully reviewed in the selection of 
subjects for treatment with cabozantinib; 
• Recent or concurrent radiation to the thoracic cavity; 
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases; 
• Underlying medical conditions which affect normal hemostasis (eg, deficiencies 
in clotting factors and/or platelet function, or thrombocytopenia); 
• Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis; 
• History of clinically significant hemoptysis. 
Discontinue cabozantinib treatment in subjects who have been diagnosed with a severe 
bleeding complication. 
3.3.1.15 
GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and non-GI fistula formation have been reported with approved 
drugs that inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for 
episodes of abdominal pain, especially among subjects with known risk factors for 
developing GI perforation/fistula, and carefully monitor subjects with known risk factors 
for non-GI fistula, to allow for early diagnosis. Such risk factors include (but may not be 
limited to) the following: 
GI perforation/fistula: 
• Intra-abdominal tumor/metastases invading GI mucosa; 
• Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, 
cholecystitis or symptomatic cholangitis, or appendicitis; 
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-
abdominal abscess; 
• Prior GI surgery (particularly when associated with delayed or incomplete 
healing). Complete healing after abdominal surgery or resolution of 
Proprietary Information of MD Anderson


 
64 
 
intra-abdominal abscess must be confirmed before initiating treatment with 
cabozantinib. 
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal 
anti-inflammatory drugs. Constipation indicative of bowel obstruction should be 
monitored and effectively managed.  
Non-GI fistula: 
Complications from radiation therapy has been identified as a possible predisposing risk 
factor for non-GI fistula formation among subjects undergoing treatment with VEGF 
pathway inhibitors (eg, bevacizumab).  
Discontinue cabozantinib treatment in subjects who have been diagnosed with GI or 
non-GI perforation/fistula. 
3.3.1.16 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have 
been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral 
hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself. 
Osteonecrosis has been reported among subjects treated with cabozantinib, the details of 
which are provided in the current version of Investigator’s Brochure. As a preventive 
measure, invasive dental procedures should be avoided if possible in subjects who have 
previously been treated with or concomitantly receive bisphosphonates or denosumab. 
In cases where dental procedures are unavoidable, the risks and benefits of a dental 
procedure and the extent of the procedure as well as the risk of developing ONJ need to 
be considered when deciding on the duration of a temporary treatment interruption of 
cabozantinib. If clinically possible, treatment with cabozantinib should be held for 
approximately 4 weeks before a dental procedure and resumed after complete healing has 
occurred. 
Subjects with any documented case of osteonecrosis should have study treatment 
interrupted, and appropriate clinical management should be initiated. Reinitiation of 
study treatment must be discussed with and approved by the MD Anderson Cancer 
Center/IND Office on a case-by-case basis. 
Proprietary Information of MD Anderson


 
65 
 
3.4 
Concomitant Medications and Therapies 
3.4.1 
Anticancer Therapy 
Local intervention is discouraged unless medically unavoidable. Subjects receiving local 
intervention (eg, 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 decision to permanently discontinue study treatment 
are to be recorded in the case report forms. 
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 (eg, American Society of Clinical Oncology [ASCO] or [European 
Society for Medical Oncology] ESMO guidelines);  
• Drugs used to control bone loss (eg, bisphosphonates and denosumab) are allowed if 
started before screening activities and may be initiated or exchanged during the 
course of the study as clinically indicated, at PI discretion; 
• Transfusions, hormone replacement, and short term higher doses of corticosteroids 
should be utilized as indicated by standard clinical; 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided 
safely and effectively under the following circumstances:  
o Low dose heparins for prophylactic use are allowed if clinically indicated and 
the benefit outweighs the risk per the investigator’s discretion;  
o Therapeutic doses of LMWH after the first dose of study treatment are allowed 
if clinically indicated (eg, for the treatment of deep venous thrombosis), and 
the benefit outweighs the risk per the investigator’s discretion. For 
Proprietary Information of MD Anderson


 
66 
 
management of thromboembolic complications while on study, refer to section 
3.3.1.9.  
o Accepted clinical guidelines regarding appropriate management while 
receiving anticoagulation therapy with heparins must be followed. This 
includes, but is not limited to, subject education regarding potential adverse 
drug reactions, monitoring laboratory parameters, dose adjustments (eg, due to 
kidney dysfunction);  
o For restrictions on oral anticoagulants see Section 3.4.4. 
• Antacids, H2 blockers, or proton-pump inhibitors should be taken at least 2 hours 
(preferably 4 hours) after taking cabozantinib and at least 14 hours before the next 
dose of cabozantinib, if possible.  
Potential drug interactions with cabozantinib are summarized in Section 3.4.5. 
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 malignant PH 
and PG; 
• Therapeutic doses of oral anticoagulants (eg, warfarin or other coumarin-related 
agents, direct thrombin or direct FXa inhibitors, or antiplatelet agents such as 
clopidogrel, or chronic use of aspirin above low dose levels for cardioprotection 
per local applicable guidelines); 
• Any other systemic anticancer treatment (eg, 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: 
•  
Proprietary Information of MD Anderson


 
67 
 
• Erythropoietic stimulating agents (eg, 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 (Wright 2007); 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease 
cabozantinib concentrations and should be avoided. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended; 
• 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 
(eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, 
and ritonavir) may increase cabozantinib concentrations and should be avoided. 
Grapefruit and Seville oranges may also increase plasma concentrations of 
cabozantinib and should be avoided. 
Additional information on potential drug interactions with cabozantinib is provided in 
Section 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 (ie, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data 
indicate that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for 
possible induction of CYP1A1 at high cabozantinib concentrations (30 μM).  
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 
Proprietary Information of MD Anderson


 
68 
 
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, dexamethasone, 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 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/DrugIn
teractionsLabeling/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 
Proprietary Information of MD Anderson


 
69 
 
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. 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. 
Additional details related to these overall conclusions can be found in the investigator 
brochure. 
Additional details regarding potential drug interactions with cabozantinib can be found in 
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. 
4 
STUDY POPULATION 
4.1 
Inclusion Criteria 
Malignant PH and PG patients will be eligible for enrollment as defined by the inclusion 
and exclusion criteria as follows: 
1. 18 years of age or older 
2. Histological confirmation of PH/PG 
3. Locally advanced or metastatic disease not amenable to surgery  
4. Patients enrolled in the main branch should have measurable disease. Patients 
with a predominance of bone disease who have small, non-measurable or small 
measurable lesions other than bone, may be included per the Principal 
Proprietary Information of MD Anderson


 
70 
 
Investigator’s discretion, in the exploratory branch of the study for patients with 
bone metastases only.  
5. Progressive disease per RECIST 1.1 as determined by the investigator within the 
12 months preceding study enrollment   
6. Assessment of all known disease sites, eg, by computerized tomography (CT) 
scan, magnetic resonance imaging (MRI), bone scan as appropriate, and/or FDG-
PET scan within 28 days before the first dose of cabozantinib 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 . 
8. Life expectancy of at least 3 months 
9. Organ and marrow function and laboratory values as follows within 4 days prior 
to the first dose of cabozantinib: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3without colony stimulating 
factor support 
b. Platelets ≥ 100,000/mm3 
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. Lipase < 2.0 x the upper limit of normal and no radiologic or clinical 
evidence of pancreatitis 
i. Urine protein/creatinine ratio (UPCR) ≤ 1 
j. Serum phosphorus, calcium, potassium ≥ LLN and magnesium ≥ 1.2 
mg/dL 
10. Capable of understanding and complying with the protocol requirements and has 
signed the informed consent document. 
11. Sexually active patients (men and women) must agree to use medically accepted 
barrier methods of contraception (eg, 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 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). 
Proprietary Information of MD Anderson


 
71 
 
12. 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, antiestrogens, 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 (including investigational cytotoxic 
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or 
nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment. 
2. Prior treatment with cabozantinib 
3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not 
eligible; 
4. Received radionuclide treatment (i.e. I 131 meta-iodo- benzyl guanidine) within 6 
months of the first dose of study treatment 
5. Receipt of any type of small molecule kinase inhibitor (including investigational 
kinase inhibitor) within 14 days before the first dose of study treatment. 
6. Receipt of any other type of investigational agent within 28 days before the first 
dose of study treatment.  
7. 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. 
8. Prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥ 1.3 × the laboratory ULN within 7 days before 
the first dose of study treatment. 
9. The subject requires concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or 
Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin 
(≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular 
weight heparin (LMWH) are permitted. 
10. The subject requires chronic concomitant treatment of strong CYP3A4 inducers 
(eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort).  
11. The subject has experienced any of the following: 
a. clinically-significant gastrointestinal bleeding within 6 months before the first 
dose of study treatment 
Proprietary Information of MD Anderson


 
72 
 
b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) 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 
12. Radiographic evidence of cavitating pulmonary lesion(s) 
13. Tumor invading or encasing any major blood vessels 
14. 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.  
15. Uncontrolled, significant intercurrent 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 
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) 
• myocardial infarction 
• thromboembolic event 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), diverticulitis, cholecystitis, symptomatic 
Proprietary Information of MD Anderson


 
73 
 
cholangitis or appendicitis; patients must be completely recovered 
from these conditions 
• malabsorption syndrome 
ii. 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 that 6 months 
before the first dose of study treatment. 
c. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy  
d. Other clinically significant disorders such as: 
i. active infection requiring systemic treatment within 28 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 organ transplant 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 
7 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. 
16. Unable to swallow tablets 
17. A corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms 
within 28 days before first dose of study treatment. Three ECGs must be 
performed. If the average of these three consecutive results for QTcF is ≤ 500 
msec, the subject meets eligibility in this regard. 
18. Pregnant or breastfeeding. 
19. A previously identified allergy or hypersensitivity to components of the study 
treatment formulation. 
Proprietary Information of MD Anderson


 
74 
 
20. Unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator or designee. 
21. Evidence within 2 years of the start of study treatment of another malignancy 
which required  systemic treatment except for cured nonmelanoma skin cancer 
or cured in situ cervical carcinoma 
  
22. 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, 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 receive their first dose of 
cabozantinib on this protocol: 
1. For patients with measurable visceral metastases CT scans with contrast or MRI are 
required. Bone scan is required for patients with visceral metastases who also have 
bone metastases. 
2. For patients with only bone metastases FDG-PET/CT scan is the only radiographic 
test required. FDG-PET/CT assessment will include standard assessment of SUVmax, 
as well as advanced volumetric measures including SUVpeak, metabolic tumor volume 
(MTV), and total lesion glycolysis (TLG) 
3. Laboratory testing (chemistry, hematology tests, interleukin-6, c-reactive protein, 
thyroid function tests, urine analysis, and thyroid function tests)  
4. EKGs will be performed at baseline. 
5. Plasma metanephrines and chromogranin A will be obtained at baseline.  
Proprietary Information of MD Anderson


 
75 
 
6. Evaluation of cancer symptoms by the MD Anderson Symptom Inventory (MDASI) 
will be obtained at baseline  
7. 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 (unless the investigator, with approval of the Medical Monitor, judges the 
patient is deriving clinical benefit), 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. 
Proprietary Information of MD Anderson


 
76 
 
Table 5-1: 
Study Assessments 
 
Study Treatment Period 
 
Post-Treatment 
Period 
Within 28 
days before 
1st Dose of 
Study 
Treatment 
Within 4 days 
before the first 
dose of Study 
Treatment 
Day 1 of Weeks 3, 5, 7, 9, 
then every 4 weeks 
through Week 24, then 
every 8 weeks (± 5 days); 
after week 52, every 12 
weeks (+/- 5 days) 
30 - 37 Days after 
last dose 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical and cancer 
history/demographics 
X 
 
 
 
Physical examination 
X 
X 
X 
X 
Height 
X 
 
 
 
Weight 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
ECOG performance 
status 
X 
X 
X 
X 
Clinical laboratory 
tests1  
X 
X 
X 
X 
Urinalysis and UPCR  
X 
X 
X 
X 
PT/INR, PTT 
X 
X 
X2 
 
TFTs (TSH, free T3, 
free T4)  
X 
X 
X2 
 
12-lead ECG 
X 
X 
X2 
X 
Cabozantinib 
administration 
 
 
X (daily) 
 
Pregnancy test 
X 
X 
X2 
X 
Tumor assessment3 
X 
 
X3  
 
Bone scan4 
X 
 
X3  
 
FDG-PET CT5 
X 
 
X3  
 
Plasma Metanephrines 
and Chromogranin A6 
X 
 
X3  
 
Interleukin-6 and c-
reactive protein, CTx 
X 
 
X3  
 
Concomitant 
medications  
X 
X 
X 
X 
MDASI8 
X 
X 
X (weekly) 
X 
Adverse events 
Continuous 
X 
Follow-up 
 
 
 
X 
Nurse phone call7 
 
 
X (starting after week 24)7 
 
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, amylase, AST, bicarbonate, bilirubin, blood urea nitrogen, calcium, chloride, 
creatinine, glucose, lactate dehydrogenase, lipase, magnesium, phosphorus, potassium, sodium, total bilirubin, total 
Proprietary Information of MD Anderson


 
77 
 
protein). CTx will be done, if patient has bone metastases, at screening and every 8 weeks during the first 52 weeks, 
then every 12 weeks. 
2Every 4 weeks through Week 24, then every 8 weeks through 52 weeks, then every 12 weeks. 
3All sites of known disease must be assessed. To occur every 8 weeks during the first 52 weeks, then every 12 weeks. 
4Patients with both bone and visceral metastases. 
5Patients with bone metastases only. This is the only tumor assessment for patients with bone metastases only. 
6 No additional measurements of plasma metanephrines are needed in patients with normal plasma metanephrines at 
baseline (Non-functioning PH or PG).  
7 Starting after week 24, nursing phone calls to take place every 8 weeks, at the 4 week period between visits (+/- 5 
days). After week 52, phone calls to take place every 12 weeks, at the 6 week period between visits (+/- 5 days). Phone calls will 
comprise AE and concomitant medication assessments. 
8 MDASI questionnaires will be completed if the patient can be contacted and is willing and able to complete the 
questionnaire. While patients are encouraged to complete questionnaires at all scheduled time points, patients may 
refuse to complete a questionnaire at any time. 
 
 
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 (eg, 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 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. 
Proprietary Information of MD Anderson


 
78 
 
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 
• 
amylase 
• 
ALT 
• 
AST 
• 
bicarbonate 
• 
BUN 
• 
chloride 
• 
creatinine 
• 
glucose 
• 
ionized calcium or 
total and corrected 
calcium 
• 
lactate dehydrogenase  
• 
lipase 
• 
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 T3 and T4 
• 
Pregnancy text (urine 
or serum) for women of 
child-bearing potential 
 
 
• 
PT/INR or PTT 
• 
24 hour urine 
collection for protein 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; ESR, erythrocyte sedimentation rate ; GGT, γ-glutamyltransferase; INR, International Normalized Ratio; PT, 
prothrombin time; PTT partial thromboplastin time; RBC, red blood cell; TSH, thyroid stimulating hormone; UPCR, 
urine protein/creatinine ratio; WBC, white blood cell. 
 
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 
Proprietary Information of MD Anderson


 
79 
 
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 Measurements 
Tumor response should be assessed at a frequency of 8 weeks for the first 52 weeks (and 
then every 12 weeks after that) by CT/MRI and based on RECIST 1.1. In patients with 
bone metastases, an FDG-PET scan will be obtained every 8 weeks for the first 52 weeks 
(and then every 12 weeks after that). Subjects continuing to show benefit (complete 
response [CR], partial response [PR], or stable disease [SD]) may continue on study. 
Subjects with PD should have their treatment discontinued (unless the investigator, with 
approval of the Medical Monitor, judges the patient is deriving clinical benefit), and they 
should enter the post-treatment phase of the study. The same method for tumor 
assessment should be employed at every assessment. 
5.6 
MDASI 
We will use paper or a secure electronic method to collect patient questionnaires when 
the patient is in the clinic. We will use an interactive voice response (IVR) system, secure 
web access, or phone calls by field coordinators when patients are away from the clinic. 
The method of collecting the patient questionnaire assessments will be based on patient 
preference and may be varied throughout the study based on patient request. 
Data collection by IVR. IVR systems are programmed to call patients at home for 
symptom assessment. The IVR system asks patients to rate each symptom and 
interference item on the MDASI-Pheo/PGL 0–10 numeric scales using the keypad of a 
touchtone telephone. Participants electing to use the IVR system may be provided with an 
informational brochure outlining the steps to complete an IVR call (Appendix G). A 
telephone number will be provided in the event of questions or problems. Patients will 
also be given a Patient Identification Number (PIN) for access to the system. IVR calls 
will be scheduled at a time that is convenient for the patient. Completion or failure of 
calls will be monitored by the research staff. In the event of missed calls, a notification 
screen will appear in the IVR system to alert the research staff. The research staff will 
then contact the patient by telephone, check on their status and, if possible, complete the 
assessment with the patient during the telephone interview. With the patient’s approval, 
the system then will continue calling the patient at the preset schedule. The IVR symptom 
and interference data will be available on an MD Anderson intranet site with access 
Proprietary Information of MD Anderson


 
80 
 
limited to authorized project staff only. Patient data will be identified by subject study 
number. 
Data collection by secure web access. Study questionnaires may be collected and 
managed using REDCap (Research Electronic Data Capture) electronic data capture tools 
hosted at MD Anderson. REDCap (www.project-redcap.org) is a secure, web-based 
application with controlled access designed to support data capture for research studies, 
providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for seamless 
downloads to common statistical packages; and 4) procedures for importing data from 
external sources. In the case of multi-center studies REDCap uses Data Access Groups 
(DAGs) to ensure that personnel at each institution are blinded to the data from other 
institutions. REDCap (https://redcap.mdanderson.org) is hosted on a secure server by MD 
Anderson Cancer Center's Department of Research Information Systems & Technology 
Services. REDCap has undergone a Governance Risk & Compliance Assessment 
(05/14/14) by MD Anderson's Information Security Office and was found to be 
compliant with Health Insurance Portability and Accountability Act (HIPAA), Texas 
Administrative Codes 202- 203, University of Texas Policy 165, federal regulations 
outlined in 21CFR Part 11, and MD Anderson Institutional Policy #ADM0335. Those 
having access to the data file include the study PI and research team personnel. Users are 
authenticated against MD Anderson's Active Directory system. External collaborators are 
given access to projects once approved by the project sponsor. The application is 
accessed through Secure Socket Layer (SSL). All protected health information (PHI) will 
be removed from the data when it is exported from REDCap for analysis. All dates for a 
given patient will be shifted by a randomly generated number between 0 and 364, thus 
preserving the distance between dates. Dates for each patient will be shifted by a different 
randomly generated number. Following publication, study data will be archived in 
REDCap.  
Completion or failure of electronic questionnaire completion will be monitored by the 
research staff. In the event of missed assessments, the research staff will then contact the 
patient by telephone, check on their status and, if possible, complete the assessment with 
the patient during the telephone interview. With the patient’s approval, the system then 
will continue sending email requests for questionnaire completion to the patient at the 
preset schedule. 
Proprietary Information of MD Anderson


 
81 
 
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 3.3. 
All untoward events that occur after start of study drug through 30 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 events will be documented in the patient’s official medical record and in the 
patient’s essential source document. All grades will be recorded in the electronic 
database (CORe), and the attribution of Not-Related and Related will be assessed. 
Assessment of the relationship of the AR to the study treatment by the investigator is 
based on the following two definitions: 
• Not Related: A not-related AE is defined as an AE that is not associated with the 
study treatment and is attributable to another cause or there is no evidence to 
support a causal relationship; 
• Related: A related AE is defined as an AE where a causal relationship between 
the event and the study treatment is a reasonable possibility. A reasonable causal 
relationship is meant to convey that there are facts (eg, evidence such as 
dechallenge/rechallenge) or other clinical arguments to suggest a causal 
relationship between the AE and study treatment. 
6.1.2 
Serious Adverse Events  
 
Proprietary Information of MD Anderson


 
82 
 
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Topic E2A. 
 
Serious Adverse Event Reporting (SAE) for M. D. Anderson-sponsored IND Protocols: 
 
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 
• 
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 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. 
 
Proprietary Information of MD Anderson


 
83 
 
• 
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 to Supporting Company Exelixis 
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. 
• Investigator shall notify Exelixis within twenty-four (24) hours of making such 
discovery by submitting the 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 an SAE form or 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 informed consent 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; 
o although most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or 
Proprietary Information of MD Anderson


 
84 
 
previously scheduled surgeries or procedures for pre-existing conditions 
that have not worsened after initiation of treatment (eg, 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 (eg, 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 unexpected adverse drug reactions (unexpected related SAEs) must be 
reported to the Food and Drug Administration (FDA) as required by 21 CFR 312.32: 
• These reports are to be filed utilizing the MD Anderson Cancer Center Internal 
SAE Report Form for Prompt Reporting; 
• The MD Anderson Cancer Center Internal SAE Report Form for Prompt 
Reporting must be submitted by the study site to Exelixis within one to two 
business days of submission to the FDA to allow Exelixis time to cross-report to 
Exelixis’ IND. 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 Cancer Center/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. 
Proprietary Information of MD Anderson


 
85 
 
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 
This Phase II study's primary objective is to estimate the best overall response rate in 
patients with measurable disease.  Response will include RECIST 1.1 CR, PR, and SD. 
With 14 patients, the 95% confidence interval for a 45% response rate would be (18.9, 
71.1%). For the exploratory objective in the small group of patients with bone metastases, 
the 95% confidence interval for a 45% response rate with 8 patients would be (10.5, 
79.5%). We do not include a formal statistical monitoring rule for toxicity given the 
established safety profile of this drug.  
 
Continuous variables will be summarized using descriptive statistics such as mean, 
standard deviation, median and range. Categorical variables will be tabulated by 
frequencies and the corresponding percentages.  Response rates and their 95% confidence 
intervals will be estimated. Kaplan Meier survival curves will be used to estimate 
survival outcomes.  Cox proportional hazards regression analysis may be used to assess 
the association between survival and covariates of interest. The Fisher’s exact test or 
logistic regression analysis will be used for any binary outcomes. T-tests or Wilcoxon 
rank sum tests will be used to compare continuous variables. Longitudinal models may be 
explored to study change over time. 
 
7.1 
Analysis Population 
7.1.1 
Safety Population 
The safety population will consist of all subjects who receive any amount of study 
treatment. 
Proprietary Information of MD Anderson


 
86 
 
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 CRFs will be mapped to preferred terms using the 
National Cancer Institute (NCI) CTCAE v4.0. 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 
The sample size will be approximately 22 subjects.  
8 
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). 
 
9 
ETHICAL ASPECTS 
9.1 
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.” 
9.2 
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 
Proprietary Information of MD Anderson


 
87 
 
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. 
9.3 
Institutional Review Board/Ethics Committee  
This study is being conducted under a United States Investigational New Drug 
application or other Clinical Trial Application, as appropriate. This protocol (and any 
modifications) and appropriate consent procedures must be reviewed and approved by an 
IRB/EC. This board must operate in accordance with current local, regional, and federal 
regulations. The investigator will send a letter or certificate of IRB/EC approval to 
Exelixis (or designee) before subject enrollment and whenever subsequent modifications 
to the protocol are made. 
9.4 
Future Use of Patient Samples 
No samples for anything other than safety testing will be collected during this study.  
10 
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). 
11 
CONDITIONS FOR TERMINATING THE STUDY 
Exelixis and MD Anderson Cancer Center/IND Office 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 MD Anderson Cancer Center/IND 
Office and the investigator will arrange the procedures on an individual study basis after 
Proprietary Information of MD Anderson


 
88 
 
review and consultation. In terminating the study, Exelixis and MD Anderson Cancer 
Center/IND Office and the investigator will ensure that adequate consideration is given to 
the protection of the subjects’ interests. 
12 
STUDY DOCUMENTATION AND RECORDKEEPING 
12.1 
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 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. 
12.2 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available, after appropriate notification, to health authority inspectors. The verification of 
the CRF data must be by direct inspection of source documents. 
12.3 
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. PDMS 
and CORe will be used as the eCRFs for this trial. 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 eCRFs. 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 eCRF entry.  
For each subject enrolled, the eCRF must be completed by an authorized delegate from 
the study staff. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data in the eCRFs and in all required reports. 
13 
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 
Proprietary Information of MD Anderson


 
89 
 
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. 
14 
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, names, and addresses. The 
investigator should maintain documents not for submission to Exelixis or designees 
(eg, subjects’ written consent forms) in strict confidence. 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review. 
15 
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 (eg, 
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.
Proprietary Information of MD Anderson


 
90 
 
16 
REFERENCES 
 
1. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and 
sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. 
Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich T, Busaidy N, Cote GJ, Perrier N, 
Phan A, Patel S, Waguespack S, Jimenez C. J Clin Endocrinol Metab. 2011 Mar;96(3):717-25. 
 
2. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. 
Jimenez C, Rohren E, Habra MA, Rich T, Jimenez P, Ayala-Ramirez M, Baudin E. Curr Oncol Rep. 
2013 Aug;15(4):356-71 
 
3. Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma. Favier J, Igaz P, 
Burnichon N, Amar L, Libé R, Badoual C, Tissier F, Bertherat J, Plouin PF, Jeunemaitre X, Gimenez-
Roqueplo AP. Endocr Pathol. 2012 Mar;23(1):34-42 
 
4. Bone metastases and skeletal-related events in patients with malignant pheochromocytoma and 
sympathetic paraganglioma. Ayala-Ramirez M, Palmer JL, Hofmann MC, de la Cruz M, Moon BS, 
Waguespack SG, Habra MA, Jimenez C. J Clin Endocrinol Metab. 2013 Apr;98(4):1492-7 
 
5. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. Dahia 
PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, 
Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, 
Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, 
Nosé V, Li C, Stiles CD. PLoS Genet. 2005 Jul;1(1):72-80. 
 
6. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging 
techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. 
Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, Adams KT, Solis D, 
Lenders JW, Pacak K. J Clin Oncol. 2007 Jun 1;25(16):2262-9 
 
7. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic 
paragangliomas. Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas 
ME, Caramella C, Anderson P, Al Ghuzlan A, Waguespack SG, Deandreis D, Baudin E, Jimenez C. J 
Clin Endocrinol Metab. 2012 Nov;97(11):4040-50. 
 
8. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, 
angiogenesis, and tumor growth. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, 
Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH. Mol 
Cancer Ther. 2011 Dec;10(12):2298-308. 
 
Proprietary Information of MD Anderson


 
91 
 
9. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid 
cancer. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen 
EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Müller T, Ratain MJ, Salgia R. J 
Clin Oncol. 2011 Jul 1;29(19):2660-6. 
 
10. A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone 
metastases. Lee RJ, Saylor PJ, Michaelson MD, Rothenberg SM, Smas ME, Miyamoto DT, Gurski 
CA, Xie W, Maheswaran S, Haber DA, Goldin JG, Smith MR. Clin Cancer Res. 2013 Jun 
1;19(11):3088-94. 
 
11. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized 
discontinuation trial. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, 
Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN 
Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. J Clin Oncol. 
2013 Feb 1;31(4):412-9 
 
12. Cabozantinib as a novel therapy for renal cell carcinoma. Vaishampayan U. Curr Oncol Rep. 2013 
Apr;15(2):76-82. 
 
13. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eisenhauer 
EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. Eur J Cancer. 2009 
Jan;45(2):228-47 
 
14. c-Met as a target for human cancer and characterization of inhibitors for therapeutic 
intervention.Christensen JG, Burrows J, Salgia R. Cancer Lett. 2005 Jul 8;225(1):1-26. Epub 2004 
Nov 11. Review 
 
15. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges.Liu X, Newton RC, 
Scherle PA. Trends Mol Med. 2010 Jan;16(1):37-45. doi: 0.1016/j.molmed.2009.11.005. Epub 2009 
Dec 22. Review. 
16. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Comoglio PM, 
Giordano S, Trusolino L. Nat Rev Drug Discov. 2008 Jun;7(6):504-16. doi: 10.1038/nrd2530. Review. 
17. Activating mutations for the met tyrosine kinase receptor in human cancer. Jeffers M, Schmidt L, 
Nakaigawa N, Webb CP, Weirich G, Kishida T, Zbar B, Vande Woude GF. Proc Natl Acad Sci U S A. 
1997 Oct 14;94(21):11445-50. 
18. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary 
renal carcinomas.Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, 
Proprietary Information of MD Anderson


 
92 
 
Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, 
Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse 
T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, 
Linehan WM, Zbar B.  Nat Genet. 1997 May;16(1):68-73. 
19. Met, metastasis, motility and more. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Nat 
Rev Mol Cell Biol. 2003 Dec;4(12):915-25.  
20. Invasive growth: a MET-driven genetic programme for cancer and stem cells. Boccaccio C, Comoglio 
PM. Nat Rev Cancer. 2006 Aug;6(8):637-45. 
21. VEGF receptor protein-tyrosine kinases: structure and regulation. Roskoski R Jr. Biochem Biophys 
Res Commun. 2008 Oct 24;375(3):287-91.  
22. Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer. 
Tugues S, Koch S, Gualandi L, Li X, Claesson-Welsh L. Mol Aspects Med. 2011 Apr;32(2):88-111. 
23. Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. 
Favier J, Plouin PF, Corvol P, Gasc JM. Am J Pathol. 2002 Oct;161(4):1235-46. 
24. Sunitinib induces apoptosis in pheochromocytoma tumor cells by inhibiting 
VEGFR2/Akt/mTOR/S6K1 pathways through modulation of Bcl-2 and BAD. Saito Y, Tanaka Y, Aita 
Y, Ishii KA, Ikeda T, Isobe K, Kawakami Y, Shimano H, Hara H, Takekoshi K. Am J Physiol 
Endocrinol Metab. 2012 Mar 15;302(6):E615-25 
25. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid 
cancer. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen 
EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Müller T, Ratain MJ, Salgia R. J 
Clin Oncol. 2011 Jul 1;29(19):2660-6 
26. Cabozantinib in progressive medullary thyroid cancer. Elisei R, Schlumberger MJ, Müller SP, 
Schöffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, Niederle B, Cohen 
EE, Wirth LJ, Ali H, Hessel C, Yaron Y, Ball D, Nelkin B, Sherman SI. J Clin Oncol. 2013 Oct 
10;31(29):3639-46. 
27. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized 
discontinuation trial. Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, 
Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN 
Jr, Lin CC, Srinivas S, Sella A, Schöffski P, Scheffold C, Weitzman AL, Hussain M. J Clin Oncol. 
2013 Feb 1;31(4):412-9. 
 
28. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, 
angiogenesis, and tumor growth. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, 
Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH. Mol 
Cancer Ther. 2011 Dec;10(12):2298-308. 
 
29. Circulating tumor cells as biomarkers in prostate cancer. Danila DC, Fleisher M, Scher HI.Clin Cancer 
Res. 2011 Jun 15;17(12):3903-12 
 
Proprietary Information of MD Anderson


 
93 
 
30. American Society of Clinical Oncology (ASCO), Kris MG, Hesketh PJ, Somerfield MR, Feyer P, 
Clark-Snow R, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: 
update 2006. J Clin Oncol. 2006;24(18):2932-47. Erratum in: J Clin Oncol. 2006;24(33):5341-2. 
 
31. Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guideline update for MASCC 
and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results 
of the Perugia consensus conference. Ann Oncol. 2010;21 Suppl 5:v232-43. 
 
32. Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to tyrosine kinase 
inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 2009;6(4):219-28. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proprietary Information of MD Anderson


 
94 
 
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 
Proprietary Information of MD Anderson