Clinical trial NCT01466036
Conditions: Carcinoid Tumor Pancreatic Neuroendocrine Tumor
Keywords: metastatic
Sponsor: Dana-Farber Cancer Institute
Start date: 2012-07-01; Completion date: 2023-12-01
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cabozantinib works by blocking the growth of new blood vessels that feed a tumor. In addition to blocking the formation of new blood cells in tumors, cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other "anti-angiogenic" drugs. Cabozantinib has been studied or is being study in research studies as a possible treatment for various types of cancer, including prostate cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer.

In this research study, the investigators wish to learn if cabozantinib is effective in treating patients with pancreatic neuroendocrine and carcinoid tumors.

Detailed description:
Subjects will take cabozantinib orally, once per day, in cycles of 28 days.

During each cycle subjects will have the following procedures:

* Physical examination, including measurement of weight and vital signs
* Questions regarding any side effects
* Blood sample (about 1 tablespoon) for routine laboratory tests of blood cell counts, blood chemistries, organ function and blood clotting
* Blood sample (about 4 tablespoons) for research test to measure biomarkers to assess the response to study drug
* Urine sample for routine urine tests to monitor health

On Day 15 (beginning of week 3) during the first 3 cycles:

* Physical examination, including measurement of weight and vital signs
* Questions regarding any side effects
* Blood sample (about 1 tablespoon) for routine laboratory tests of blood cell counts, blood chemistries, organ function and blood clotting
* Blood sample (about 4 tablespoons) for research test to measure biomarkers to assess the response to study drug Subjects will receive a CT scan or MRI every two cycles (every two months) to evaluate disease.

Arms: arm 1: An anticipated 35 patients with pancreatic neuroendocrine tumors receiving cabozantinib arm 2: An anticipated 35 patients with advanced or metastatic carcinoid tumor receiving cabozantinib
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: 60 mg QD orally in cycles of 28 days

Protocol documents:
Prot_SAP_000.pdf: 
[cover page generated for ClinicalTrials.gov only. This page was not part of the IRB approved document 
which follows] 
Identifiers: 
NCT01466036   Unique Protocol ID: 11-274 
Brief Title: 
Cabozantinib in Advanced Pancreatic Neuroendocrine and Carcinoid Tumors 
Full Title:  
An Open-Label, Phase II Study of Cabozantinib (XL184) in Advanced Pancreatic  
Neuroendocrine and Carcinoid Tumors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date document downloaded from OnCore portal: 10/19/2022 
Document Date: Protocol Version: 8/21/2019 


An Open-Label, Phase II Study of Cabozantinib (XL184) in Advanced Pancreatic Neuroendocrine and 
Carcinoid Tumors  
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Protocol Version Date:  8/21/2019 
Local Protocol #: 11-274 
Title: An Open-Label, Phase II Study of Cabozantinib (XL184) in Advanced Pancreatic 
Neuroendocrine and Carcinoid Tumors  
 
Principal Investigator: 
Jennifer Ang Chan, MD, MPH 
Assistant in Medicine, Dana-Farber Cancer Institute, Harvard Medical School 
Dana-Farber cancer Institute 
450 Brookline Avenue, Dana 1220, Boston MA 02215 
617-632-6315 
jang@partners.org 
Co-Investigators: 
David P. Ryan, MD (MGH) 
Thomas Abrams, MD (DFCI) 
Jill Allen, MD (MGH) 
Lawrence Blaszkowsky, MD (MGH) 
Gabriel Brooks, MD (DFCI) 
Jennifer Chan, MD (DFCI) 
Jeffrey W. Clark, MD PhD (MGH) 
Andrea Enzinger, MD (DFCI) 
Peter Enzinger, MD (DFCI) 
Nina Grenon, NP (DFCI) 
Lipika Goyal, MD (MGH) 
Eunice Kwak, MD PhD (MGH) 
Robert Mayer, MD (DFCI) 
Nadine Jackson McCleary, MD (DFCI) 
Jeffrey Meyerhardt, MD (DFCI) 
Kimmie Ng, MD (DFCI) 
Eunice Kwak, MD PhD (MGH) 
Douglas Rubinson, MD (DFCI) 
Deborah Schrag, MD (DFCI) 
Brian Wolpin, MD (DFCI) 
Matthew Yurgelun, MD (DFCI) 
Andrew Zhu, MD, PhD (MGH) 
Ann Donnelly, NP (MGH) 
Michelle Knowles, NP (MGH) 
Caroline Kuhlman, NP (MGH) 
Theresa McDonnell, NP (MGH) 
Emily Olson, NP (MGH) 
Rhaea Photopoulos, NP (MGH) 
Patricia Tammaro, NP (MGH) 
Robin Sommers, NP (DFCI) 
Karen Sommer, NP (DFCI) 
Michael Casey, NP (DFCI) 
 


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SCHEMA ....................................................................................................................................... 4 
1. 
OBJECTIVES ................................................................................................................... 4 
1.1 
Study Design .......................................................................................................... 4 
1.2 
Primary Objectives/Endpoints ............................................................................ 4 
1.3 
Secondary Objectives/Endpoints ......................................................................... 4 
2 
BACKGROUND ............................................................................................................... 4 
2.1 
Investigational Agent ............................................................................................ 4 
2.2 
Study Disease ....................................................................................................... 20 
2.3 
Rationale .............................................................................................................. 21 
2.4 
Correlative Background ..................................................................................... 22 
3. 
PARTICIPANT SELECTION ...................................................................................... 23 
3.1 
Eligibility Criteria ............................................................................................... 23 
3.2 
Exclusion Criteria ............................................................................................... 24 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 25 
4. 
REGISTRATION PROCEDURES ............................................................................... 25 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ........................... 25 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions ......................... 26 
4.3 
General Guidelines for Other Participating Institutions ................................ 26 
4.4 
Registration Process for Other Participating Institutions .............................. 26 
5. 
TREATMENT PLAN ..................................................................................................... 26 
5.1 
Pre-treatment Criteria ........................................................................................ 27 
5.2 
Agent Administration ......................................................................................... 27 
5.3 
 General Concomitant Medication and Supportive Care Guidelines ............ 28 
5.4 
Duration of Therapy ........................................................................................... 30 
5.5 
Duration of Follow Up ........................................................................................ 30 
5.6 
Criteria for Removal from Study ...................................................................... 30 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .. 30 
6.1 
General Guidelines for Treatment Delay, Dose Reduction, or Study Drug 
Discontinuation for Toxicity .............................................................................. 31 
6.2 Management of Adverse Events .............................................................................. 32 
7. 
VISIT SCHEDULE AND ASSESSMENTS ................................................................. 47 
7.1 
Evaluations .......................................................................................................... 47 
7.2 
Study Calendar.................................................................................................... 50 
8. 
MEASUREMENT OF EFFECT ................................................................................... 52 
8.1 
Antitumor Effect ................................................................................................. 52 
8.2 
Translational Medicine Assessments................................................................. 58 
9. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................. 65 
9.1 
Adverse Events .................................................................................................... 65 


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10. 
DATA AND SAFETY MONITORING ........................................................................ 67 
10.1 
Data Reporting .................................................................................................... 67 
10.2 
Safety Meetings ................................................................................................... 68 
10.3 
Monitoring ........................................................................................................... 68 
11. REGULATORY CONSIDERATIONS .............................................................................. 68 
11.1 
Protocol Review and Amendments .................................................................... 68 
11.2 
Informed Consent ............................................................................................... 69 
11.3 
Ethics and Good Clinical Practice (GCP) ......................................................... 69 
11.4 
Study Documentation ......................................................................................... 69 
11.5 
Records Retention ............................................................................................... 70 
11.6 
Multi-center Guidelines ...................................................................................... 70 
11.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)................................................................................................ 70 
12. 
STATISTICAL CONSIDERATIONS .......................................................................... 70 
12.1 
Study Design ........................................................................................................ 70 
12.2 
Rationale for Sample Size .................................................................................. 71 
12.3 
Reporting and Exclusions .................................................................................. 72 
13. 
PUBLICATION PLAN .................................................................................................. 72 
14. 
REFERENCES ................................................................................................................ 73 
15. 
APPENDICES ................................................................................................................. 76 
Appendix A - Performance Status Criteria .................................................................. 76 
Appendix B – Cabozantinib Tablets ............................................................................. 77 
 


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SCHEMA 
 
 
 
 
 
 
 
 
Patients with advanced neuroendocrine tumors (PNET or carcinoid)  
 
 
 
 
with documented radiographic progression.  
  
 
 
 
   
 
 
1. OBJECTIVES 
1.1 Study Design 
The current study is an open-label, Phase II study of patients with advanced carcinoid or 
pancreatic neuroendocrine tumors with progressive disease. A total of 70 patients will be 
enrolled with advanced neuroendocrine tumors:  35 patients with advanced carcinoid tumors and 
35 patients with pancreatic neuroendocrine tumors. The estimated time for accrual of the patients 
is 18-24 months. This study will include a Pre-Treatment Period (screening and baseline 
evaluations), a Treatment Period (consisting of 4-week cycles of cabozantinib administered daily 
orally at a dose of 60 mg, and a Post-Treatment Period (consisting of a post-treatment visit 
30 days [+7] after the last dose of study treatment, with follow-up information obtained every 
12 weeks post last dose thereafter until final survival status is determined). Tumor assessments 
will be performed after the second, fourth, and sixth cycles, then every third cycle (± 5 days) 
following randomization until documented disease progression per RECIST by the investigator 
or end of treatment at the physician’s discretion. 
 
1.2 Primary Objectives/Endpoints 
1.2.1 Evaluate objective response rate of cabozantinib. 
 
1.3 Secondary Objectives/Endpoints 
1.31 
Determine progression-free and overall survival in patients receiving cabozantinib. 
1.32 
Assess safety and tolerability of cabozantinib. 
1.33 
Define molecular and imaging correlates of response, pending funding availability 
including dynamic/ perfusion CT, and circulating biomarkers. 
 
2 BACKGROUND 
2.1 Investigational Agent 
Cabozantinib (XL184) is a new chemical entity that exhibits potent inhibitory activity against 
several receptor tyrosine kinases known to influence tumor growth, metastasis, and angiogenesis. 
The primary targets of cabozantinib are MET and VEGFR2/KDR, with IC50 (concentration 
associated with 50% inhibition) values of 1.8 and 0.035 nM, respectively. The in vitro target 
inhibition profile of cabozantinib is shown in Table 1-1. 
 


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Table 2-1 
Inhibition of Key Protein Kinases by Cabozantinib in Biochemical, Enzymatic Assays 
Kinase 
IC50 ± SEM (nM) 
MET 
1.8 ± 0.2 
VEGFR2/KDR 
0.035 ± 0.007 
RET 
9.8 ± 2.3 
KIT 
4.6 ± 0.5 
VEGFR1/FLT-1  
12.2 ± 0.7  
VEGFR3/FLT-4  
6.0 ± 0.6  
AXL  
7  
TIE-2  
14.3 ± 2.8  
FLT-3  
14.4 ± 0.8  
IC50, concentration required for 50% target inhibition; VEGFR2, vascular endothelial growth factor receptor 2. 
 
Data from pharmacodynamic experiments have shown that cabozantinib inhibits MET and 
VEGFR2 in vivo. Oral administration of cabozantinib resulted in blockade of MET 
phosphorylation in human lung tumor xenografts in nude mice and blockade of VEGFR2 
phosphorylation in mouse lung tissue. The duration of action for cabozantinib was sustained, 
with > 50% inhibition observed 10-24 hours post-dose at a dose level of 100 mg/kg for all targets 
studied. 
 
Treatment with cabozantinib results in anti-angiogenic effects in xenograft tumors, with 
disruption of the vasculature beginning within 24 hours after administration. These effects 
translate into significant tumor growth inhibition or tumor regression after cabozantinib 
treatment in multiple tumor models including MTC (thyroid), breast cancer, lung carcinoma, and 
GB (brain) (Table 1-2). 
 
Table 1-2: Cabozantinib ED50 Values in Tumor Efficacy Models 
Tumor Cell Line 
Species 
Tissue of Origin 
ED50 
(mg/kg/day) 
Treatment Duration 
C6 
Rat 
Brain 
< 1 
qd × 12 
MDA-MB-231 
Human 
Breast 
2 
qd × 14 
H441 
Human 
Lung 
3 
qd × 14 
TT 
Human 
Thyroid 
11 
qd × 21 
ED50, dose associated with 50% tumor growth inhibition; qd, once daily. 
 


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Activity of Cabozantinib in the Transgenic RIP-Tag2 Model System 
Inhibition of the VEGF signaling pathway was previously shown to result in more invasive 
tumors in the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that 
spontaneously develops aggressive tumors (Pàez-Ribes et al. 2009). Treatment with cabozantinib 
for 3 weeks, from age 14 to 17 weeks, significantly blocked liver metastasis in the RIP-Tag2 
model compared with anti-VEGF treatment or vehicle alone. The number of liver metastases was 
5-fold greater in anti-VEGF antibody-treated animals compared with vehicle-treated animals, 
and no liver metastases were detected in cabozantinib-treated animals. In addition, treatment 
with cabozantinib from age 14 to 20 weeks improved survival. Median survival was 14.7 weeks 
for vehicle-treated animals (n = 12) and 16.4 weeks for anti-VEGF antibody-treated animals 
(n = 7; P < 0.05 vs. vehicle), and all cabozantinib-treated animals survived for the full 20 weeks 
of observation (n = 6; P < 0.05 vs. vehicle and anti-VEGF antibody). 
 
Activity of Cabozantinib in a Preclinical Bone Metastasis Model 
The human prostate cancer model ARCaP-M, which expresses both MET and the VEGF 
co-receptor NP-1 (Zhang et al 2010), was used in a prostate tumor xenograft study in bone. 
ARCaP-M cells were injected into the tibiae of nude mice on Day 1, and on Day 31 animals with 
established bone lesions were randomized to receive cabozantinib or vehicle qd for 7 weeks of 
treatment. As shown in the representative x-ray images (Figure 1-1), tibiae from vehicle-treated 
animals exhibited both osteoblastic and osteolytic lesions, whereas tibiae from cabozantinib-
treated animals appeared mostly normal. Thus, cabozantinib treatment blocked both osteoblastic 
and osteolytic progression of ARCaP-M xenograft tumors in bone. 
 
Figure 1-1: 
ARCaP-M Prostate Tumor Model: Vehicle vs. Cabozantinib  
(X-Ray Images) 
 


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Cabozantinib Nonclinical Toxicology 
Cabozantinib nonclinical toxicology has been characterized in single- and repeat-dose studies in 
multiple species. In nonclinical toxicology studies of cabozantinib in rodents and non-rodents, 
histopathological changes associated with cabozantinib administration were observed in 
gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, adrenal, and reproductive 
tract tissues, and secondary changes were observed in bone and pancreas. 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. Details can be found in the Investigator Brochure. 
 
2.1.1 Clinical Experience and Activity 
Cabozantinib has demonstrated broad clinical activity in multiple tumor types, including thyroid, 
breast, ovarian, prostate, and lung cancers, melanoma, glioblastoma (GB), hepatocellular 
carcinoma (HCC), and renal cell carcinoma (RCC). Observations of clinical activity have 
included shrinkage 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, increases in hemoglobin, and improvements in bone 
pain and reductions in narcotic use in subjects with bone metastases. In the Phase 1 
Study XL184-001, with an enriched medullary thyroid cancer (MTC) population, confirmed 
partial response (cPR) (with duration up to 48+ months) was reported in 29% of MTC subjects, 
and stable disease (SD) of at least 6 months was reported in 41% of MTC subjects. In the 
Phase 2 randomized discontinuation trial, Study XL184-203, disease control rates (DCR; defined 
as SD or confirmed response) at Week 12 ranged from 40-73% in the six cohorts for which 
cabozantinib had the greatest activity: non-small cell lung cancer (NSCLC), 40%; breast cancer, 
45%; melanoma, 47%; ovarian cancer, 55%; castration-resistant prostate cancer (CRPC), 68%; 
and HCC, 73%. Please refer to the current version of the Investigator’s Brochure for updated 
information regarding the clinical experience of cabozantinib. 
 
2.1.2 Clinical Safety Profile 
As of 04 May 2011, 1333 subjects have been enrolled in clinical studies with cabozantinib, for 
which serious adverse event (SAE) data are available (1003 subjects in open-label clinical 
studies with cabozantinib and 330 subjects in the blinded Study XL184-301, randomized 2:1 for 
cabozantinib versus placebo). As of 01 March 2011, adverse event (AE) data are available for 
913 subjects who have been dosed with cabozantinib in open-label clinical studies (806 subjects 
in single-agent cabozantinib studies and 107 subjects in combination studies of cabozantinib with 
erlotinib, rosiglitazone, or temozolomide [TMZ] ± radiation). These subjects have been treated 
with cabozantinib at salt weight doses ranging from 0.08 to 11.52 mg/kg on an intermittent 
dosing schedule and from 25 mg (19.7 mg freebase equivalent weight) to 265 mg (209 mg 
freebase equivalent weight) on a fixed daily dosing schedule. Refer to the current version of the 
Investigator’s Brochure for detailed information regarding the safety profile of cabozantinib 
across all studies.  
 


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2.1.2.1 Adverse Events 
The most commonly reported SAEs that were assessed as related to study treatment with 
cabozantinib (as a single-agent or part of a combination treatment) were pulmonary embolism 
(PE), diarrhea, dehydration, deep vein thrombosis (DVT), vomiting, nausea, thrombocytopenia, 
fatigue, wound dehiscence, and PPE syndrome. Ten percent of subjects were reported to have 
discontinued study treatment due to an AE, most frequently fatigue. There have been 15 deaths 
assessed as related to study treatment: GI hemorrhage (two subjects), PE (two subjects), 
respiratory failure (two subjects), respiratory disorder (one subject), hemoptysis (one subject), 
death due to unknown cause (two subjects), intracranial hemorrhage (one subject), intestinal 
perforation (one subject), enterocutaneous fistula (one subject), hemorrhage (presumed to be 
hemoptysis; one subject), and diverticular perforation, peritonitis (one subject). Details for these 
and 13 additional deaths assessed as not related to study treatment are provided in this 
Investigator’s Brochure.  
 
2.1.2.2 Serious Adverse Events 
As of 04 May 2011, of the 1003 subjects enrolled in open-label clinical trials with cabozantinib 
(either as a single-agent or in combination with other therapies), 473 subjects (47%) experienced 
one or more SAEs, and 199 subjects experienced one or more SAE that was assessed as related 
to treatment with cabozantinib. The majority of SAEs were attributed to the underlying cancer. 
The most commonly reported SAEs that were assessed as related to study treatment with 
cabozantinib (as a single-agent or part of a combination treatment) were PE, diarrhea, 
dehydration, deep vein thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound 
dehiscence, and PPE syndrome.  In the blinded study of cabozantinib versus placebo 
(Study XL184-301) in subjects with MTC SAEs of one Grade 4 reversible posterior 
leukoencephalopathy syndrome (RPLS), one Grade 5 cardiac arrest following asystolic vagal 
reaction after aspiration on study medication, and three of acquired tracheo-esophageal fistula 
(two Grade 3, one Grade 5) were reported. 
 
Deaths 
As of 04 May 2011, across all open-label studies (single-agent cabozantinib and cabozantinib in 
combination with other therapies), there have been 15 deaths assessed as related to study 
treatment: GI hemorrhage (two subjects), PE (two subjects), respiratory failure (two subjects), 
respiratory disorder (one subject), hemoptysis (one subject), death due to unknown cause (two 
subjects), intracranial hemorrhage (one subject), intestinal perforation (one subject), 
enterocutaneous fistula (one subject), hemorrhage (presumed to be hemoptysis; one subject), and 
diverticular perforation, peritonitis (one subject). 
 
2.1.3 Clinical Pharmacokinetics 
Pharmacokinetic analysis showed dose proportional increases in maximum plasma concentration 
(Cmax) and area under the plasma concentration time curve (AUC) both for the powder-in-bottle 
(PIB) formulation (dose range: 0.08 to 11.52 mg/kg) and the capsule formulation (dose range: 
125 to 175 mg). Terminal-phase half-life (t1/2, z) values were 59.1 to 136 hours. More detailed 
information regarding cabozantinib PK from all studies and product metabolism in humans may 
be found in the Investigator’s Brochure.   
 


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Pharmacokinetics and Product Metabolism in Humans 
 
2.1.3.1 Phase 1: Study XL184-001  
In Study XL184-001, a preliminary PK analysis has been performed for 74 subjects. The cutoff 
date for the data used for this PK analysis was 02 September 2008. In an analysis of PK data on 
subjects (Cohorts 1-9) receiving cabozantinib as an oral suspension at 0.08 to 11.52 mg/kg on the 
Intermittent 5&9 schedule, values for Cmax and AUC from 0 hours to the last sampling time point 
(AUC0-last) increased generally dose-proportionally. The t1/2, z values were long (range: 59.1 to 
136 hours). 
 
Data from Cohorts 10--13 (175 mg PIB qd; 265 mg PIB qd; 175 mg capsule formulation qd; 
250 mg capsule formulation qd) and the eMTD Cohort (175 mg capsule formulation qd) show 
that drug accumulation (based on Cmax and AUC0-24 values) at steady-state after qd dosing is 
approximately 4- to 6-fold. In addition, exposure values from PIB (Cohort 10) or the capsule 
formulation (Cohorts 12 and eMTD Cohort) are compared in Table 5 2. The data are limited by a 
small sample size but show that cabozantinib exposure (AUC) values from capsule-formulation 
cohorts are about 2-fold greater than those observed in the respective PIB Cohort. 
 
Table 2.1.3.1: Comparison of Exposure from 
PIB (Cohort 10) or Capsule Formulation 
(Cohorts 12 and eMTD Cohort) D19 Cmax  
(ng/mL)  
D19 AUC  
(ng•h/mL)  
Cohort 10  
175 mg qd PIB, n = 3  
1410  
21200  
Cohort 12 and eMTD Cohort  
175 mg qd capsule formulation, n = 19  
2310  
41600  
AUC, area under the plasma drug concentration time curve; Cmax, maximum plasma concentration; eMTD, expanded maximum tolerated 
dose; PIB, powder-in-bottle (formulation); qd, once daily.  
 
2.1.3.2 Phase 1: Study XL184-002 
As of 15 March 2010, PK data were available from three subjects enrolled in the first cohort of 
Arm 1a (cabozantinib 75 mg qd + TMZ 75 mg/m2 qd + radiotherapy). Intensive PK sampling 
was conducted during the concurrent treatment phase on Days 1 and 29. The observed Day 1 
mean exposure values for TMZ were close to published reference values at 75 mg/m2 (ie, Day 1 
AUC: 10.3 ± 0.913 μg•hour/mL vs 12.1 ± 1.1 μg•hour/mL, from Ostermann et al. 2004). 
Similarly, mean steady-state exposure values (AUC) for cabozantinib (18.0 ± 0.818 μg•hour/mL) 
were comparable to those extrapolated from Study XL184-201 (17.5 μg•hour/mL, predicted 
from observed values at 125 mg), a Phase 2 trial in which subjects with GB are receiving 
cabozantinib monotherapy. Sparse PK samples were also available from three subjects in Arm 2a 
(cabozantinib 75 mg qd + TMZ 200 mg/m2/day on Days 1-5 of every 28-day cycle). Results 
show that the mean steady-state concentration values for cabozantinib at 4 hours post- 
cabozantinib dose (801 ± 182 ng/mL) were very close to those extrapolated from 
Study XL184-201 (810 ng/mL, estimated from observed values at 125 mg). Overall, the 
preliminary data show no apparent metabolic (exposure) drug-drug interaction between 
cabozantinib and TMZ. 
 


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2.1.3.3 Phase 1: Study CA205-001 
Pharmacokinetics of cabozantinib were evaluated for three subjects after a single dose on Day 1 
and for two subjects at steady-state on Day  19. Exposure values for Cmax and AUC0-24 were 4- to 
5-fold higher than that observed for Day 1, which was consistent with the observation in 
Study XL184-001 of the magnitude of cabozantinib accumulation after repeated qd dosing. 
 
2.1.3.4 Phase 1: Study XL184-008 
The XL184-008 study is designed as a two-treatment two-period single-sequence crossover 
study to test cabozantinib for inhibition of the CYP2C8 pathway. Rosiglitazone, a known 
CYP2C8 substrate, is administered on Day  1, and PK samples are obtained over 24 hours. 
Starting on Day 2, cabozantinib is administered qd at a dose level of ≥ 125 mg/day (salt weight) 
for 21  days to achieve steady-state levels of cabozantinib. Rosiglitazone is then administered 
again on Day 22, 1 hour after the twenty-first dose of cabozantinib, and PK sampling is repeated 
over a 24-hour period. As of 17 May 2011, preliminary PK data were available from 20 subjects, 
16 of whom were evaluable on both Day 1 and Day 22. Based on the data for these 16 subjects, 
the geometric mean Day 22:Day 1 ratio of rosiglitazone AUC0-24 was 1.00 (90% confidence 
interval [CI]: 0.921.09), and the corresponding ratio for Cmax was 0.92 (90%CI: 0.78-1.09). 
Furthermore, both Cmax and AUC0-24 were similar on Day 1 and Day 22 for 
desmethyl-rosiglitazone, a metabolite of rosiglitazone generated via a CYP2C8 metabolic 
pathway. Based on these preliminary data, there was no evidence for marked inhibition of 
rosiglitazone metabolism, suggesting that cabozantinib does not inhibit the CYP2C8 pathway at 
clinically relevant concentrations. 
 
2.1.3.5 Phase 1b/2: Study XL184-202 
 
Table 2.3.1.5: Exposure (AUC) 
Values in Subjects with 
NSCLC Following 
Administration of Erlotinib or 
Cabozantinib Cohort  
Cabozantinib 
Dose (mg)  
Erlotinib 
Dose (mg)  
Erlotinib 
AUC, 
without 
Cabozantinib 
(μg•h/mL)  
Erlotinib 
AUC, with 
Cabozantinib 
(μg•h/mL)  
Cabozantinib 
AUC 
(μg•h/mL)  
1  
75  
150  
83.9  
(49.8%, n = 3)  
36.6  
(n = 1)  
28.6  
(n = 1)  
2A  
75  
100  
23.6  
(27.1%, n = 
12)  
27.0  
(28.8%, n = 6)  
18.0  
(27.6%, n = 6)  
2B  
50  
150  
38.0  
(35.5%, n = 
16)  
36.0  
(36.4%, n = 
12)  
13.3  
(37.7%, n = 
12)  
3A  
125  
100  
26.9  
(52.8%, n = 
12)  
19.9  
(39.9%, n = 7)  
18.3  
(29.9%, n = 8)  
4A  
125  
50  
12.3  
(n = 2)  
17.1  
(45.5%, n = 3)  
21.6  
(45.5%, n = 3)  
AUC, area under the plasma drug concentration time curve; CV, coefficient of variation.  
Note: AUC values are presented as mean (%CV).  


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As of 17 February 2010, PK data available for 5 cohorts (n = 1–16 subjects/cohort) showed that 
exposures to cabozantinib at doses of 50-125 mg or erlotinib at doses of 50-150 mg were not 
apparently affected by co-administration of both drugs. Exposure (AUC) values of cabozantinib 
at doses of 50-150 mg were close to the levels estimated from PK data of Study XL184-001 in 
which cabozantinib was administered as a single agent (dose range: 0.08 to 11.52 mg/kg). In 
addition, AUC values for erlotinib at doses of 50-150 mg before or after co-administration of 
cabozantinib are not markedly different (Table 2.1.3.5). 
 
Table 2.1.3.5: Cabozantinib Concentration 
Values in Subjects with Glioblastoma 
Concentration Values  
125 mg qd  
175 mg qd  
C1D15 pre-dose  
1260 ± 566 ng/mL (n = 109)  
1680 ± 750 ng/mL (n = 29)  
C1D15 4 hours post-dose  
1370 ± 601 ng/mL (n = 100)  
2020 ± 1060 ng/mL (n = 27)  
qd, once daily.  
 
In addition, intensive PK samples were taken from 15 subjects receiving a capsule dose of 
125 mg qd. Consistent with an approximately 30% lower dose, steady state mean values of Cmax 
and AUC0-24 for 11 of these subjects were approximately 40% lower compared to subjects treated 
at 175 mg qd in Study XL184-001 (Cmax: 1390 ng/mL [125 mg] vs 2310 ng/mL [175 mg]; 
AUC: 26,500 ng•h/mL [125 mg] vs 41600 ng•h/mL [175 mg]). Consistent with the observations 
for sparse sampling at pre-dose and post-dose, an approximately dose-proportional increase in 
Cmax and AUC at steady-state was observed between 125 and 175 mg; a 1.6-fold increase in 
exposure was observed as the dose increased by 1.4-fold. 
 
2.1.3.6 Phase 2: Study XL184-203 
As of 12 June 2011, sparse plasma drug concentration data from the Lead-In Stage of the RDT 
study, XL184-203, were available across all nine tumor type cohorts (n = 149 subjects). Steady-
state trough concentrations on Day 42 (ie, at the end of Week 6) were summarized after 
excluding subjects with documented prior dose holds or dose modifications (Table 2.1.3.6). 
Based on this preliminary analysis, no clear evidence was found to suggest that any one tumor 
type had markedly different steady-state trough concentrations or variability in steady-state 
trough concentrations compared with the other tumor types studied. 
 


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Table 2.1.3.6 
 
 
 
The starting dose of single agent cabozantinib in this study will be 60 mg daily (free base 
weight). While the MTD of single-agent cabozantinib from the Phase 1 study (XL184-001) was 
175 mg, in both the XL184-201 and XL184-203 studies, anti-tumor activity has also been 
observed at starting doses of cabozantinib lower than 175 mg. 
 
Based on in vivo target modulation studies, cabozantinib exhibited IC50 values (concentration 
required for 50% inhibition) between 2 and 7.4 μM for MET, VEGFR2, and RET (Table 2.1.4).  
 


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Table 2.1.4 
 
 
2.1.4 Clinical Pharmacodynamics 
Data from pharmacodynamic experiments show that, in vivo, cabozantinib inhibits key RTKs 
that promote tumor cell proliferation and/or angiogenesis (MET, VEGFR2, TIE-2, and RET). 
This provides support for the hypothesis that the efficacy of cabozantinib against multiple tumor 
types potentially results from inhibition of both tumor cell division and angiogenic responses. In 
general, there was a good correlation between increases in plasma drug concentrations and 
increased inhibition of receptor phosphorylation at the doses tested. Results from dose-response 
experiments in mice indicated that the ED50 of targets was achieved at well tolerated doses of 
cabozantinib at plasma exposure comparable to exposure observed in clinical trials. 
 
2.1.4.1 Pharmacodynamic Findings in Humans:  Phase 1: Study XL184-001  
2.1.4.1.1 Plasma Sample Collection for Pharmacodynamic Analyses  
Plasma samples were analyzed for several biomarkers of response to anti-angiogenic agents, 
including levels of VEGF-A, soluble VEGFR2 (sVEGFR2), and placental growth factor (PlGF). 
Clinical studies have shown increases in VEGF-A and PlGF and decreases in sVEGFR2 in 
response to treatment with anti-angiogenic agents other than cabozantinib (Motzer et al. 2006). 
 
Changes in pharmacodynamic markers consistent with anti-angiogenesis activity were observed 
in Cohorts 6 through 12 and the eMTD Cohort with plasma samples taken on Day 1 pre-dose and 
Day 29. While small cohort sizes presented a challenge for statistical analysis of 
pharmacodynamic marker changes the combined data of Cohorts 12 and the eMTD Cohort (ie, 
subjects enrolled at the MTD) demonstrated that changes in PlGF (↑), VEGF-A (↑), EPO (↑), and 
sVEGFR2 (↓) reached statistical significance. Soluble MET as a potential biomarker of MET 
inhibition was increased upon cabozantinib treatment and changes reached statistical 
significance. Changes in these pharmacodynamic biomarkers were also observed in earlier 
cohorts and reached statistical significance for some time points and/or some cohorts. Analysis 
of potential correlations between maximal tumor shrinkage (unaudited data) and baseline levels 


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of plasma biomarkers revealed that Ang2, EPO, and OPN significantly (P < 0.05) correlate with 
tumor response across multiple tumor types (MTC: n = 29, melanoma: n = 4, colorectal 
carcinoma: n = 3, other n = 10 [with n = 1 per tumor type]) and thus might represent potential 
prognostic biomarkers. Predictive biomarkers correlating with tumor shrinkage could not be 
identified. 
 
Similar data showing modulation of plasma markers of anti-angiogenesis therapy by 
cabozantinib treatment have been obtained from several other clinical studies, including 
XL184-201 (see Section 2.1.4.3) and XL184 202 (not shown). 
 
2.1.4.1.2 Determination of Mutational RET Status in Tumor Tissue and/or Whole Blood Samples  
Germline and somatic RET genotyping was performed on DNA isolated from whole blood 
(n = 29) and tumor (n = 27), respectively, for the subjects with MTC. Activating RET mutations 
were detected in 25/31 (81%) of MTC tumors. Of note, the tumor of one subject with MTC with 
rapid clinical progression demonstrated the P-loop, BRAF activating mutation G469A, the 
absence of a detectable RET mutation, and a 2.2-fold amplification of the MET gene. Of the four 
remaining tumors without detectable RET mutations, one was found to have a 1.7-fold 
amplification in MET. The genotyping data suggest the absence of a correlation between RET 
mutations and either clinical response or time on study.   
 
2.1.4.1.3 Pharmacodynamic Analyses of Surrogate Tissues 
One set of serial skin biopsies was received from a subject enrolled in the eMTD Cohort and was 
analyzed using fluorescence-based IHC. Changes in total MET, RET and KIT were minimal 
during the course of cabozantinib treatment but the activity (as assessed by the phosphorylation 
status) of these cabozantinib targets (decrease compared to baseline: MET: 40%, RET: 40%, 
KIT: 61%) as well as of the downstream signaling molecules AKT (39%) and ERK (55%) was 
statistically significantly reduced in this surrogate tissue. These observations support the on-
target inhibitory effect of cabozantinib. Total levels and phosphorylation of VEGFR2 were not 
affected by cabozantinib treatment in this surrogate tissue.  
 
2.1.4.2 Pharmacodynamic Findings in Humans:  Phase 1b/2: Study XL184-202 
2.1.4.2.1 Molecular Analysis 
Molecular analyses included the determination of EGFR mutations and MET gene copy number 
status. Based on preliminary data, clinical activity of cabozantinib in combination with erlotinib 
was observed in a largely erlotinib-pretreated population, which included patients with the EGFR 
T790M mutation and with and without MET amplification (Wakelee et al. 2010). 
 
2.1.4.3 Phase 2: Study XL184-201 
2.1.4.3.1 Plasma Sample Collection for Pharmacodynamic Analyses 
Plasma samples 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 175 mg. Changes in PlGF (↑), VEGF-A (↑), sVEGFR2 
(↓), and sKIT(↓) reached statistical significance at multiple time points, particularly Days 15 and 
29, on which the largest amount of data was available. Soluble MET as a potential biomarker of 
MET inhibition was modulated (↑) upon cabozantinib treatment and changes reached statistical 


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significance as well, on Day 15 and Day 57 (Cycle 3 Day 1), though changes were less robust 
than those for the analytes listed above. Baseline plasma levels of VEGF-A and PlGF were 
markedly higher in subjects that had received prior treatment with agents that directly target 
VEGF (ie, bevacizumab [n = 6] and VEGF-Trap [n = 1]) compared to subjects who either had no 
prior anti-angiogenic treatment or had treatment with anti-angiogenic agents that do not target 
VEGF directly (14-fold higher for VEGF-A; 2-fold higher for PlGF; both P < 0.001). 
Preliminary analysis of potential correlations between clinical outcome and baseline levels or 
changes during treatment of the plasma proteins did not reveal significant correlations other than 
a trend observed towards lower baseline bFGF in subjects with PR compared to subjects with PD 
in fewer than 8 weeks (P = 0.05). 
 
Results from a similar analysis of plasma samples obtained from subjects treated with a starting 
dose of 125 mg showed statistically significant modulation of plasma biomarkers VEGF-A, 
PlGF, and sVEGFR2, as well as modulation of sKIT and sMET. Mean fold-changes from 
baseline at Day 15 of treatment (pre-dose) were as follows (N = 29): VEGF-A: 1.8-fold increase; 
PlGF: 2.7-fold increase; sVEGFR2: 17% decrease (ratio of 0.83); sKIT: 11% decrease (ratio of 
0.89). As in the 175-mg cohort, baseline plasma levels of VEGF-A and PlGF in the 125-mg 
group were markedly higher in subjects that had received prior treatment with bevacizumab 
[n = 8] compared to subjects who either had no prior anti-angiogenic treatment or had treatment 
with anti-angiogenic agents that do not target VEGF directly [n = 25] (5.7-fold higher for 
VEGF-A; 1.9-fold higher for PlGF; both P < 0.001). 
 
2.1.4.4 Phase 2: Study XL184-203 
2.1.4.4.1 Analysis of Pharmacodynamic Plasma Samples 
Plasma analyses thus far have focused on the crosslinked C-telopeptide of type I collagen (CTx), 
a marker of osteoclast activity and bone resorption. Levels of CTx were reduced in the majority 
of subjects including those with CRPC for whom at least one baseline and a Week 6 or Week 12 
plasma sample could be tested. The effects of cabozantinib on decreasing plasma CTx levels 
appear to be independent of prior or concomitant bisphosphonate treatment or presence of bone 
metastases (Gordon et al. 2011, Hussain et  al. 2011). In addition, total ALP (t-ALP) was 
routinely measured in serum in these subjects. While t-ALP is also generated in the liver, in men 
with CRPC with elevated levels, it correlates well with levels of bone-specific ALP, a marker of 
osteoblast activity and bone formation. Consistent with effects of cabozantinib on osteoblast 
activity, the majority of CRPC subjects with bone metastases and elevated t-ALP levels at 
baseline showed reductions in t-ALP. These effects were independent of prior or concomitant 
bisphosphonate treatment (Hussain et al. 2011). 
 
2.1.4.4.2 Genotyping of Archival Tumor Tissue 
Thus far, select genotyping analyses have been conducted on archival tumor tissue and clinical 
sites have shared their own results when available. Based on the preliminary analysis of 48 
melanoma subjects with both tumor response and BRAF mutation data, clinical activity of 
cabozantinib appears to be independent of BRAF mutation status (Gordon et al. 2011). Clinical 
activity of cabozantinib also appears to be independent of EGFR and KRAS mutation status in 
NSCLC subjects based on the preliminary data (Gordon et al. 2011). However, only 4 of 23 
NSCLC subjects with available EGFR genotyping data and only 3 of 23 NSCLC subjects with 
available KRAS genotyping data were positive for a mutation. In the limited samples tested from 


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the NSCLC Cohort, no MET mutations were detected, and MET amplification status has not 
been analyzed. 
 
2.1.4.5 Phase 3: Study XL184-301 
2.1.4.5.1 Pharmacodynamic Sample Collection and Analysis Plan 
Archival tumor samples to determine the RET mutational status in tumors and a whole blood 
sample to determine the hereditary RET status are being collected from every subject. Plasma 
samples taken at baseline and intermittently while on treatment are being collected to evaluate 
changes in plasma markers of anti-angiogenesis therapy. Data analysis is not yet complete. Refer 
to the current version of the Investigator’s Brochure for information regarding the clinical 
pharmacodynamics of cabozantinib. 
 
2.1.5 Clinical Activity 
Preliminary clinical activity data are available for Studies XL184-001, XL184-201, XL184-202, 
and XL184-203. 
 
XL184-001 
Study XL184-001 was a phase 1 dose-escalation study in subjects with solid tumors. 
Eighty-five subjects, including 37 subjects with MTC (35 with measurable disease), were 
enrolled in the XL184-001 study. Of the 85 subjects, 18 subjects experienced a tumor shrinkage 
of ≥ 30%, including 17 (49%) of 35 subjects with MTC with measurable disease. In the response 
evaluable subset of subjects with MTC, 10 (29%) of 35 subjects had confirmed partial responses 
(cPRs). In addition, 15 subjects with MTC had stable disease (SD) for at least 6 months. 
 
XL184-201 
Study XL184-201 was designed to evaluate the safety and tolerability and antitumor activity of 
cabozantinib in subjects with progressive or recurrent GB. Clinical efficacy data are summarized 
in Table 2.1.5 for 46 subjects who received cabozantinib at a starting dose of 175 mg (Group A) 
and 59 subjects who received cabozantinib at a starting dose of 125 mg qd (Group B). In both of 
these cohorts, radiographic response was evaluated by an IRF review of MRI scans per modified 
Macdonald criteria (Macdonald et al. 1990). An additional cohort with a starting dose of 
125 mg qd (Group C) was also enrolled, but clinical efficacy data have not yet been analyzed. 
 


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Table 2.1.5:  Response Rate and Progression-Free Survival in XL184-201 (N = 105) 
 
Prior Anti-Angiogenic Treatment 
 
Naïve 
Pretreated 
Group 
A 
(n = 34) 
B 
(n = 37) 
A 
(n = 12) 
B 
(n = 22) 
Dose 
175 mg 
125 mg 
175 mg 
125 mg 
ORR, n (%)a 
7 (21) 
11 (30) 
1 (8)b 
0 
Median duration of response, months (range)a 
2.9 
(1.9-12.8) 
5.1 
(0.9+ - 6.7+) 
NE 
NE 
Median progression-free survival, weeksc 
15.9 
16.0 
14.3 
7.9 
Progression-free survival at 6 months, %c 
10 
25 
38 
0 
IRF, independent radiology facility; NE, not estimable; ORR, objective response rate. 
a Per IRF 
b Duration of response = 12.3 months (subject previously treated with vandetanib) 
c Per investigator 
 
XL184-202 
In Study XL184-202, sixty-four subjects were enrolled in the Phase 1 dose-escalation portion of 
the study examining the combination of cabozantinib and erlotinib in NSCLC subjects. All but 
two subjects had been previously treated with and progressed on erlotinib therapy. Nine subjects 
(14%) had a ≥ 30% decrease in the sum of tumor measurements compared with baseline 
measurements. A cPR was observed in 5 subjects (8%). In addition, 24 subjects (37%) had 
SD/PR ≥ 4 months (range, 4.6-23+ months). 
 
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. Additional details about 
the design of Study XL184-202 are presented in Section 5.1.5 of the Investigator’s Brochure v7. 
Two subjects (7%) had a ≥ 30% decrease in the sum of tumor measurements compared with 
baseline measurements (one subject who received treatment with single-agent cabozantinib and 
one subject who received treatment with cabozantinib in combination with erlotinib). A cPR was 
observed in the subject who was treated with single-agent cabozantinib. 
 
XL184-203 
Study XL184-203 is an ongoing Phase 2 randomized discontinuation study of cabozantinib in 
subjects with advanced solid tumors, a total of 531 subjects have been enrolled. An analysis of 
data from the Lead-In Stage for 490 subjects showed clinical activity in multiple tumor types 
including regression of soft-tissue tumor disease, bone scan resolution in subjects with bone 
metastasis, and other signs of clinical benefit (Gordon et al. 2011; Hussain et al. 2011; 
Bukanovich et al 2011). Randomization was suspended in the CRPC and ovarian cancer cohorts 
based on observed high rates of clinical activity, and randomized subjects were unblinded. Non-
randomized expansion (NRE) cohorts have been initiated for these tumor types. 
 


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CRPC Cohort (N = 171) 
The majority (91%) of enrolled subjects had ≥ 2 disease sites; 37% had evidence of disease in 
liver or lung, and 87% had metastasis to bone. Forty-three percent of subjects were pretreated 
with docetaxel, 9% with abiraterone or MDV3100, and 22% with other cytotoxic and/or 
experimental therapies. Seven subjects achieved a cPR at Week 12, and three additional subjects 
achieved PR after the 12-week Lead-In Stage. The overall DCR at Week 12 was 68%. 
Regression of measurable soft-tissue disease was observed in 74% of subjects with at least one 
post-baseline tumor assessment. Changes in PSA appeared to be independent of radiographic 
changes. 
 
In 108 CRPC subjects evaluable for post-baseline bone scan changes, best assessments of bone 
scan were partial or complete resolution in 82 subjects (76%), stable disease in 23 subjects 
(21%), and PD in three 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 (68%) 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 67 of these subjects who 
were evaluable for post-baseline pain improvement, 47 (70%) had pain improvement at Week 6 
or Week 12, and 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. 
 
A positive correlation between bone scan resolution and improvement in clinical symptoms of 
disease was observed. Subjects with bone scan resolution (either complete or partial) were more 
likely to be free of disease progression at 6 months (61% vs. 35%), experience pain relief (83% 
vs. 43%), reduce or eliminate their need for narcotic analgesics (68% vs. 33%), achieve tumor 
regression (78% vs. 58%), and experience substantial declines in markers of bone turnover (60% 
vs. 43%), as compared to those who did not achieve bone scan resolution (stable or progressing 
bone scan). 
 
Reductions of t-ALP and CTx were observed. Of 28 subjects with bone metastases who had 
t-ALP levels at least 2 × ULN, and at least 12 weeks of follow-up, the majority had decreases in 
t-ALP. In addition, of 118 subjects with bone metastases and plasma CTx data, the majority also 
showed a decrease in CTx at Week 6 or Week 12. Reductions in either CTx or t-ALP occurred 
regardless of prior bisphosphonate treatment. The investigator-assessed median PFS of the 
Randomized Stage, from Week 12 onward, was 6 weeks (95% CI: 5–12 weeks) for the placebo 
group (n = 17), and 21 weeks (95% CI: 11 weeks, upper limit not yet reached) for the 
cabozantinib group (n = 14). The hazard ratio of 0.13 (95% CI: 0.03-0.50) strongly favored the 
cabozantinib arm and corresponds to an 87% reduction in the risk of disease progression for 
subjects treated with cabozantinib compared with placebo (P = 0.0007). The overall median PFS 
from Day 1 of starting cabozantinib treatment, excluding subjects randomized to placebo, was 29 
weeks and appeared to be independent of prior docetaxel treatment. 
 


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Ovarian Cancer Cohort (N = 70) 
The majority (93%) of enrolled subjects had the ovary as primary disease site, and 79% had 
serous cell carcinoma differentiation. Forty-nine percent of enrolled subjects were considered 
platinum refractory/resistant, defined as a platinum-free interval of 6 months or less. More than 
half of the subjects (57%) had received ≥ 2 prior lines of platinum-based chemotherapy, 31% had 
received pegylated liposomal doxorubicin or topotecan, and 10% had received prior VEGF 
pathway inhibitors. The overall DCR at Week 12 was 53%. Two of 11 subjects (18%) with 
platinum refractory disease, defined as a platinum-free interval of < 1 month, achieved a 
confirmed response (one CR and one PR). Five of 23 subjects (22%) with platinum-resistant 
disease, defined as a platinum-free interval of 1-6 months, achieved a PR. Ten of 36 subjects 
(28%) with platinum sensitive disease, defined as platinum-free interval > 6 months, achieved a 
PR. The DCR at Week 12 for the platinum-refractory group was 36%, for the resistant group 
39%, and for the sensitive group 67%. A total of 37 patients experienced reductions in the 
ovarian cancer tumor marker CA125, including 8 with decreases greater than 50%. There was no 
consistent concordance between CA125 changes and tumor regression. At the time point of the 
analysis, the median duration of response was not reached with 36 weeks of median follow-up 
(Buckanovich et al. 2011). 
 
Melanoma Cohort (N = 77) 
Fifty-four (70%) of the enrolled melanoma subjects had advanced cutaneous/mucosal melanoma 
and 23 (30%) had advanced primary ocular disease. BRAF mutation was detected in 17 (32%) of 
subjects. The majority of patients (87%) had 0-2 lines of prior therapy and 13% had 3 or more 
lines of therapy. The overall DCR at Week 12 was 47%. Regression of measurable soft-tissue 
disease was observed in 39 of 65 (60%) of subjects with at least one post-baseline tumor 
assessment. During the Lead-In Stage, the first 12 weeks of the study, a cPR was observed in 4 
subjects. Tumor regression appeared to occur regardless of BRAF mutational status. Two out of 
2 patients with bone metastases followed by bone scan experienced partial resolution of bone 
lesions. One patient with symptomatic bone metastases following treatment with ipilimumab 
experienced relief of bone pain on cabozantinib and remains on study with stable disease for 
more than 6 months. Of the 77 enrolled subjects, including those potentially randomized to 
placebo, 27% remained on study at 6 months. 
 
NSCLC Cohort (N = 60) 
The majority (93%) of enrolled subjects had Stage IV disease at diagnosis, and 7% had stage III 
disease. Seventeen (28%) subjects had squamous cell carcinoma differentiation, and 43 (72%) 
had adenocarcinoma or other histologic subtypes. Half of the subjects had 0-2 lines of prior 
therapy, and the other half had 3 or more lines of prior therapy. Prior therapies included 
anti-VEGF pathway therapy (32%) and anti-EGFR therapy (42%). The overall DCR at Week 12 
was 40%. Six subjects (10%) achieved a cPR. Tumor regression appeared to occur regardless of 
either EGFR or KRAS mutational status. Forty percent of subjects in the cohort remained on 
study greater than 3 months. 
 


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HCC Cohort (N = 30) 
All enrolled subjects were Child-Pugh Class A, and 19 (63%) had evidence of extrahepatic 
spread. The majority of subjects (93%) had 0-1 line of prior therapy and 7% had 2 or more lines 
of therapy. Nearly half (47%) of subjects had been treated previously with sorafenib. The overall 
DCR at Week 12 was 73%. Regression of measurable soft-tissue disease per mRECIST was 
observed in 22 of 27 (81%) subjects with at least one post-baseline tumor assessment. Four 
subjects (15%), including subjects with and without prior sorafenib therapy, achieved a cPR. 
Nine of 16 (56%) subjects who had AFP levels ≥ 20 ng/mL at baseline experienced ≥ 50% 
reduction in AFP. Of the 30 subjects in the cohort, 47% remained on study greater than 6 
months. 
 
Breast Cancer Cohort (N = 20) 
The majority (90%) had invasive ductal carcinoma differentiation. Breast tumor tissue was 
positive for estrogen and progesterone receptors (ER+/PR+) for 15 of 20 enrolled subjects (75%) 
and positive for HER2 (HER2+) for 3 subjects (15%). Eighty-five percent had three or more 
lines of therapy, and 40% had been treated previously with anti-VEGF pathway therapy. The 
overall DCR at Week 12 was 45%. Regression of measurable soft-tissue disease was observed in 
15 of 16 (94%) of subjects with at least one post-baseline tumor assessment. During the Lead-In 
Stage, the first 12 weeks of the study, a cPR was observed in 2 subjects. Two of 3 subjects with 
bone metastases followed by bone scan experienced partial resolution on bone scan accompanied 
by symptomatic pain relief. 
 
SCLC (N = 21), Pancreatic Cancer (N = 20), Gastric/GEJ Cancer (N = 21) Cohorts  
Lower DCRs at Week 12 were observed in SCLC (38%), pancreatic cancer (35%), and 
gastric/GEJ cancer (33%). Confirmed partial tumor responses were observed in SCLC (1) and 
gastric/GEJ cancer (1). 
 
Translational Medicine 
Genotyping data in the XL184-001 study suggest the absence of a correlation between RET 
mutations and either clinical response or time on study. In an ongoing analysis in the 
XL184-201 study, genotyping analysis of several genomic alterations frequently found in GB 
revealed that none appear to confer resistance to cabozantinib. 
 
Data from subjects enrolled in ongoing clinical studies demonstrated statistically significant 
changes in plasma biomarkers such as sMET and sKIT. Analysis of serial hair and/or skin 
samples revealed substantial inhibition of the phosphorylation of cabozantinib targets such as 
MET, RET, and KIT, as well as of downstream signaling molecules AKT and ERK, following 
administration of cabozantinib. 
 
2.2 Study Disease 
Neuroendocrine tumors, which include carcinoid tumors and pancreatic neuroendocrine tumors, 
are relatively uncommon, comprising only approximately 1-2% of all malignancies. However, 
this assertion has been revisited in recent years, with the most recent SEER database reporting an 
annual incidence of over 5 per 100,000 [1]. When patients with neuroendocrine tumors present 
with surgically resectable disease, the prognosis is excellent, but unfortunately, a substantial 
fraction of patients with neuroendocrine tumors either present with or develop metastatic disease 


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that is not amenable to curative approaches. In these patients, cytotoxic chemotherapy has been 
of limited efficacy and counterbalanced with substantial toxicities. A variety of other agents have 
been attempted, including somatostatin analogs such as octreotide, tyrosine kinase inhibitors, 
such as sorafenib [2] and sunitinib [3], VEGF antagonists, such as bevacizumab [4], and mTOR 
inhibitors such as temsirolimus [5], and everolimus [6]. Somatostatin analogs are generally 
administered to patients for symptomatic benefit, but have not generally resulted in radiographic 
responses. A strategy of angiogenesis inhibition in particular is compelling in neuroendocrine 
tumors given the highly vascularized nature of neuroendocrine tumors [7-9]. Well-differentiated 
neuroendocrine tumors have a higher microvessel density than poorly differentiated 
neuroendocrine tumors [10, 11]. In addition, pancreatic endocrine tumors also display platelet-
derived growth factor receptors and stem-cell factor receptor (c-kit) [12, 13].  
Metastatic pancreatic neuroendocrine tumors have been demonstrated to express MET, and in 
one small study, 33% of metastatic pancreatic endocrine tumors versus only 17% of non-
metastatic neuroendocrine tumors expressed MET. Greater than 50% of tumors metastatic to 
lymph nodes or liver expressed MET [14]. 
 
The data from clinical trials to date demonstrate possible clinical benefit of antagonism of the 
VEGF pathway in neuroendocrine tumors. In a Phase II trial of 44 patients with metastatic 
carcinoid tumors, the use of bevacizumab was associated with a response rate of 18% and 
progression-free survival (PFS) of 95% versus a response rate of 0% and PFS of 68% for patients 
receiving interferon-based therapy [4]. Similarly, the use of sunitinib, a multitargeted tyrosine 
kinase inhibitor that includes activity against VEGF and KIT, in a Phase II trial of 109 patients 
with advanced neuroendocrine tumors demonstrated partial responses of 16.7% and 2.4% in 
pancreatic neuroendocrine and carcinoid tumors, respectively. Stable disease was achieved in 
83% of patients with carcinoid and 68% of patients with pancreatic neuroendocrine tumors [3]. 
In a recent published Phase III trial of sunitinib versus placebo restricted to patients with 
pancreatic neuroendocrine tumors, the objective response rate was 9.3%, but median progression 
free survival was more than doubled compared to patients treated with placebo (11.4 months 
versus 5.5 months) [15]. 
 
2.3 Rationale 
The antitumor activity of prior VEGF-directed therapies with bevacizumab and sunitinib, along 
with the currently limited treatment options for patients with neuroendocrine tumors make the 
identification of further agents with activity in patients with carcinoid and pancreatic 
neuroendocrine tumors a high priority. We propose to study cabozantinib, which is known to 
inhibit both VEGF, MET, and KIT receptors, in patients with neuroendocrine tumors. Carcinoid 
tumors and pancreatic neuroendocrine tumors have demonstrated markedly different response 
rates in prior trials of sunitinib and everolimus, and a recently published consensus of the 
national cancer institute recommend evaluation separately in clinical trials [16]. Therefore, we 
propose enrolling two cohorts of patients, one with carcinoid tumors, and one with pancreatic 
neuroendocrine tumors. We plan to treat patients with cabozantinib 60 mg (free base weight) per 
day. This dose was selected based on the dose reductions necessary in the XL184-203 clinical 
trial, where over half of patients required a dose reduction to 60 mg. Our primary endpoint will 
be overall response rate, and secondary endpoints will include progression-free and overall 
survival. Patients will be enrolled at the Massachusetts General Hospital Cancer Center and the 
Dana Faber Cancer Institute. 


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2.4 Correlative Background 
There are ongoing efforts to identify biomarkers to predict response to various cancer 
therapeutics and allow for better matching of potentially toxic therapies with patients most likely 
to respond [17]. In particular, predicting and assessing response to antiangiogenic agents is 
vitally important. No validated biological markers (or biomarkers) currently exist for 
appropriately selecting patients with cancer for antiangiogenic therapy. We also lack biomarkers 
able to identify escape pathways that should be targeted after tumors develop resistance to a 
given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging 
biomarkers have emerged from recently completed phase I–III studies [17]. Some of these are 
measured at baseline, for example VEGF gene polymorphisms, soluble VEGF receptor 1 
(sVEGFR1), while others are measured during treatment (such as hypertension, MRI-measured 
Ktrans, circulating angiogenic molecules or collagen IV); all are mechanistically based. Some of 
these biomarkers might be pharmacodynamic, for example, increase in circulating VEGF, 
placental growth factor (PlGF), while others have potential for predicting clinical benefit or 
identifying the escape pathways, for example, stromal-derived factor 1α (SDF1α) or 
Interleukin 6. Most biomarkers are disease and/or agent specific and all of them need to be 
validated prospectively. These need to be explored in larger patient cohorts and in a disease– and 
agent-specific manner. In rectal cancer patients, we previously found that sVEGFR1 may be a 
predictive biomarker of response and toxicity for bevacizumab with radiation and chemotherapy 
[18, 19]. In addition, we found that bevacizumab therapy alone increased the cancer cell 
expression of SDF1α and its receptor CXCR4 [20]. Moreover, high plasma SDF1α concentration 
during treatment was significantly associated with development of distant metastases [21]. 
Bevacizumab induced a sustained elevation in circulating plasma VEGF and PlGF, transiently 
increased sVEGFR2 and IL-6, and decreased sVEGFR1 [18]. The change in plasma PlGF (after 
bevacizumab alone) correlated with pathologic response after treatment, and circulating VEGF 
and IL-6 (after bevacizumab with chemoradiation) showed association with nodal disease status 
after treatment [18]. We found that some of these biomarkers were common across disease types 
and antiangiogenic agent types. For example, bevacizumab increased VEGF, PlGF and 
sVEGFR2 in sarcoma and ovarian cancer patients [22, 23]. On the other hand, while anti-
VEGFR tyrosine kinase inhibitors such as cediranib, sunitinib and sorafenib also increased 
circulating PlGF and VEGF levels in brain tumor, hepatocellular carcinoma and sarcoma 
patients, respectively, they decreased sVEGFR2 and increased SDF1α in all cases [20, 24-26]. 
Similar to rectal cancer, increases in circulating SDF1α correlated with a poor outcome after 
anti-VEGFR therapy [20, 24-26]. These hypotheses-generating data from these exploratory 
studies need to be confirmed in further studies of anti-VEGF agents. We have previously have 
evaluated a battery of biomarkers after bevacizumab treatment in patients with various types of 
cancer: rectal carcinoma [18, 19, 21, 27-30], sarcoma [23], ovarian carcinoma [22], lung 
carcinoma [31], and Schwannoma [32], as well as in breast cancer (trial ongoing, 
#DFCI 07-130). These biomarkers have been evaluated in more than a dozen trials of 
anti-VEGFR tyrosine kinase inhibitors (e.g., sunitinib, sorafenib, vatalanib, cediranib, 
vandetanib)[20, 24-26, 33-35]. In study XL184-001, a Phase I study of cabozantinib 
administered to subjects with advanced malignancies, a preliminary analysis of samples of 
14 subjects revealed statistically significant change in VEGF-A and sVEGFR2 levels. 
 


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Functional imaging may also be a useful tool for the evaluation of treatment response. In 
particular, functional CT has been used at MGH to assess changes in tumor perfusion parameters 
such as blood flow, blood volume, mean transit time and permeability surface area following 
therapy in rectal cancer, where both blood flow and PS product as measured by dynamic CT 
were significantly decreased following treatment with a bevacizumab-containing treatment [18]. 
At MGH, low dose CT perfusion technique has also been utilized in hepatocellular carcinoma, 
where lower mean transit time was significantly associated with progressive disease. In addition, 
bevacizumab therapy was associated with decreases in blood flow, blood volume, and 
permeability surface area product, though only change in mean transit time after bevacizumab 
therapy correlated with clinical outcome [36]. Functional CT has also been utilized in 
neuroendocrine tumors, revealing a correlation between decreases in blood flow and volume 
with anti-VEGF treatment with bevacizumab at day 2 and week 18 [4]. 
 
3. PARTICIPANT SELECTION 
3.1 Eligibility Criteria 
Participants must meet the following criteria on screening and on Day 1 of treatment to be 
eligible to participate in the study: 
 
3.1.1 Locally unresectable or metastatic, histologically-confirmed, carcinoid or pancreatic 
neuroendocrine tumor. Tumors must be considered well- or moderately-differentiated. 
Patients with poorly differentiated neuroendocrine carcinoma are excluded from the 
study. 
3.1.2  A tumor sample is required for enrollment (except for patients diagnosed > 7 years ago). 
 
3.1.3 Must have measurable disease by RECIST criteria 
3.1.4 Must have evidence of progressive disease within 12 months of study entry 
3.1.5 For patients with carcinoid tumors, patients must have progressed on, be currently 
receiving, or be intolerant to octreotide therapy. For patients with pancreatic 
neuroendocrine tumors, the prior or current use of octreotide or somatostatin analogues is 
permitted, but not required.  If the patient is on octreotide, regardless of whether the 
patient has a carcinoid or pancreatic neuroendocrine tumor, the patient must be on a 
stable dose of somatostatin analogue for at least two months. 
3.1.6 Age ≥18 years  
3.1.7 No major surgery or radiation in the prior 4 weeks prior to enrollment 
3.1.8 No prior therapy with cabozantinib  
3.1.9 ECOG Performance status ≤1 
3.1.10 Participants must have adequate organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500/mcL 
• Platelets > 100,000/mcL 
• Total bilirubin </= 1.5X normal institutional limits 
• AST (SGOT) and ALT (SGPT) </=2.5x normal institutional limits, or < 5x if liver 
metastases are present 
• Creatinine </= 1.5x normal institutional limits or creatinine clearance >50mL/min 


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• Urine Protein:Creatinine ratio of <1 
• Lipase <1.5X upper limit of normal 
• Serum Albumin ≥2.8 g/dl 
3.1.11 Sexually active subjects must agree to use medically accepted methods of birth control 
during the course of the study and for 3 months following discontinuation of study 
treatments (excluding women who are not of child bearing potential and men who have 
been sterilized). 
3.1.12 Ability to understand and the willingness to sign a written informed consent document.  
 
3.2 Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
3.2.1 The first dose of study treatment must be at least three weeks since prior chemotherapy, 
including sunitinib or everolimus. 
3.2.2 Major surgery or radiation treatment <4 weeks prior to enrollment. In addition, cannot 
have received radiation to the thorax or gastrointestinal tract within three months of the 
first dose of study treatment. 
3.2.3 Cannot have received radionuclide treatment within 6 weeks of first dose of study 
treatment. 
3.2.4 High grade or poorly differentiated neuroendocrine tumors 
3.2.5 Ongoing immunosuppression with systemic steroids or other immune modulator 
3.2.6  Presence of CNS metastatic disease 
3.2.7 Uncontrolled hypertension defined by SBP>140 or DBP>90 despite titration of 
anti-hypertensive medications 
3.2.8 No uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia other than chronic atrial fibrillation, or psychiatric illness/social situations that 
would limit compliance with study requirements. Congestive heart failure or 
symptomatic coronary artery disease within 3 months prior to enrollment 
3.2.9 Cerebrovascular accident within prior 6 months 
3.2.10 The subject has a history of clinically significant hematemesis or a recent history of 
hemoptysis of > 2.5 mL of red blood or other signs indicative of pulmonary hemorrhage 
or evidence of endobronchial lesion(s). 
3.2.11 The subject has a pulmonary lesion abutting or encasing a major blood vessel. 
3.2.12 History of pulmonary embolism or deep venous thrombosis within the past six months of 
the first dose of study treatment 
3.2.13 The subject requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and 
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. 


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3.2.14 At the time of screening, active peptic ulcer disease or active inflammatory bowel disease 
(including ulcerative colitis or Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis, or appendicitis. 
3.2.15 History of abdominal fistula, gastrointestinal perforation, bowel obstruction, gastric outlet 
obstruction, or intra-abdominal abscess within six months of study enrollment. 
3.2.16 History of GI surgery within the past 28 days. 
days. If > 28 days since GI surgery, must have confirmation of complete healing before initiating 
treatment with study drug. 
3.2.17 Other disorders associated with a high risk of fistula formation, including PEG tube 
placement within 3 months before the first dose of study therapy or concurrent evidence 
of intraluminal tumor involving the trachea or esophagus. 
3.2.18 Other clinically significant disorders such as: 
i. Active infection requiring systemic treatment 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. History of organ transplant 
iv. Concurrent uncompensated hypothyroidism or thyroid dysfunction 
v. History of major surgery within 4 weeks or minor surgical procedures within 1 week 
before randomization 
3.2.19 The subject has a baseline corrected QT interval <500 within 28 days before 
randomization. 
3.2.20 Severely impaired lung function 
3.2.21 Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the 
past 3 years or any currently active malignancy 
3.2.22 Pregnant women are excluded from this study due to the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk of adverse events in 
nursing infants secondary to treatment of the mother with the treatment protocol, 
breastfeeding should be discontinued if the mother is treated on protocol. 
 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
There are no specific provisions for this. Both men and women and members of all races and 
ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registration must occur prior to the initiation 
of therapy. Any participant not registered to the protocol before treatment begins will be 
considered ineligible and registration will be denied. 
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist. 
 


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Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator. If a participant does not 
receive protocol therapy following registration, the participant’s protocol status must be changed. 
Notify the QACT Registrar of participant status changes as soon as possible. 
 
4.2 Registration Process for DF/HCC and DF/PCC Institutions 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Time. In emergency situations when a participant must begin treatment during off-hours 
or holidays, call the QACT registration line at 617-632-3761 and follow the instructions for 
registering participants after hours. 
 
The registration procedures are as follows: 
1. Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
2. Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record. To be eligible for registration 
to the study, the participant must meet each inclusion and exclusion criteria listed 
on the eligibility checklist.  
3. Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
617-632-2295. 
 
Exception: DF/PCC Affiliate sites must fax the entire signed consent form including HIPAA 
Privacy Authorization and the eligibility checklist to the Network Affiliate Office. The Network 
Affiliate Office will register the participant with the QACT. 
1. The QACT Registrar will (a) validate eligibility, (b) register the participant on the study, 
and (c) randomize the participant when applicable. 
2. The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the 
registration and/or randomization.  
 
4.3 General Guidelines for Other Participating Institutions 
Not applicable. 
 
4.4 Registration Process for Other Participating Institutions 
Not applicable. 
 
5. TREATMENT PLAN 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modifications). No investigational or commercial anti-cancer agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. Participants will sign informed consent and screen for eligibility. 
 


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5.1 Pre-treatment Criteria 
Subjects must meet eligibility criteria on the first day of treatment, and have completed all 
required data activities by the first day of treatment. 
 
5.2 Agent Administration 
Cabozantinib 60 mg (free base weight) per day will be administered daily and continuously for a 
cycle length of 28 days. The 60 mg starting dose was derived from the ongoing adaptive 
randomized discontinuation trial, XL184-203, which used 100 mg per day (free base weight), but 
over half of patients required a dose reduction to 60 mg. Participants will keep a drug diary to 
document daily oral dosing of cabozantinib. Subjects will be provided with a sufficient supply of 
study treatment and instructions for taking the study treatment on days without scheduled clinic 
visits. After fasting (with exception of water) for 2 hours, subjects will take study treatment daily 
each morning with a full glass of water (minimum of 8 oz/ 240 mL) and continue to fast for 
1 hour after each dose of study treatment. For missed doses, if it has been more than 12 hours 
since a scheduled dose, patients will be instructed not to take the missing dose. If patients vomit 
after taking their scheduled tablets, they will be instructed not to take another dose on this day 
and continue on their regular dosing schedule. If doses are withheld, the original schedule of 
assessments should be maintained when cabozantinib is restarted. The subject should be 
instructed to not make up the missed doses and to maintain the planned dosing schedule. 
 
Subjects will be monitored continuously for adverse events through 30 days (+7 days) after the 
date of the decision to discontinue study treatment. Subjects will be instructed to notify their 
physician immediately for any and all toxicities. Subjects experiencing one or more AEs due to 
the study treatment may require a dosing delay, or reduction(s), in their dose in order to continue 
with study treatment. Assessment of causality (chronology, confounding factors such as disease, 
concomitant medications, diagnostic tests, and previous experience with the study treatment) 
should be conducted by the PI when possible, before a decision is made to modify the dose or to 
hold dosing temporarily. 
 
5.2.1 Drug formulation – Cabozantinib (XL184) 
Composition, Formulation, and Storage 
Cabozantinib must be stored at room temperature and inventoried according to applicable state and 
federal regulations. 
Investigational Treatment 
Chemical Name:  
Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-
phenyl]-amide (4-fluoro-phenyl)-amide, (L)-malate salt. 
 
 
Cabozantinib is an L-malate salt. In all studies except XL184-203, cabozantinib doses and 
capsule strengths are expressed based on the weight of the cabozantinib salt. However, in Study 
XL184-203, doses and capsule strengths are expressed based on the cabozantinib free base 
equivalent weight. The new standard for Exelixis is to express the dosing in terms of the 
free base weight. The difference between capsule strengths based on freebase or the L-malate 
salt weight (ie, < 2% based on correction for salt equivalent weights) is small relative to the 
variance in mean exposures in subjects administered the same cabozantinib capsule dose 
(approximately 40% coefficient of variation for mean AUC), and is therefore considered to be 
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Cabozantinib Tablets 
Cabozantinib will be supplied as 20 mg tablets. These tablets are in free-base dosing form. The 
cabozantinib tablet components and doses are presented in Appendix B. 
 
5.2.2 Availability 
Cabozantinib is an investigational agent and will be supplied free-of-charge by Exelixis. 
 
5.2.3 Accountability 
Study participants will keep a drug diary to record dosing of cabozantinib. Cabozantinib bottles 
and any unused drug will be brought back to the research staff for accountability. 
 
5.2.4 Destruction and Return 
At the end of the study, unused supplies of Cabozantinib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record Form. 
 
5.3  General Concomitant Medication and Supportive Care Guidelines 
5.3.1 Drug-drug interactions 
Cytochrome P450: Preliminary data from a clinical drug interaction study (Study XL184-008) 
show that clinically relevant steady-state concentrations of cabozantinib appear to have no 
marked effect on the AUC of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, 
cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not 
anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared 
to CYP2C8 (ie, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate 
that cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction 
of CYP1A1 at high cabozantinib concentrations (30 μM). 
 
Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate), based on data 
from in vitro studies using CYP-isozyme specific neutralizing antibodies. Preliminary results 
from a clinical pharmacology study, XL184-006, showed that concurrent administration of 
cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 80% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, 
and St. John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of 
strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used 
with caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended. In addition, caution must be used when discontinuing treatment with a 
strong CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of 
cabozantinib, as this could significantly increase the exposure to cabozantinib. 
 
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 
33-39% 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 


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family (eg, ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations. Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors 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. 
 
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (eg, 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. 
Therefore, these drugs should be used with caution when given with cabozantinib. 
 
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors 
of selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx). 
 
Protein Binding: Cabozantinib is highly protein bound (approximately 99.9%) to human plasma 
proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase 
in pharmacologic effect). Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound (eg, 
diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because 
warfarin is a highly protein bound drug with a low therapeutic index, administration of warfarin 
at therapeutic doses should be avoided in subjects receiving cabozantinib due to the potential for 
a protein binding displacement interaction. 
 
Other Interactions: A relative bioavailability study in dogs suggests that cabozantinib is unlikely 
to be affected by drugs that alter gastric pH. In vitro data suggest that cabozantinib is unlikely to 
be a substrate for P glycoprotein (P-gp), but it does appear to have the potential to inhibit the P-
gp transport activity. 
 
Additional details related to these overall conclusions are provided in the Investigators Brochure. 
 
5.3.2 Use of other cancer treatments on study 
The use of octreotide/somatostatin during the study is permitted as discussed in the inclusion 
criteria. 
 
Other than somatostatin, no other antineoplastic agents will be permitted during this study. No 
concurrent radiation treatment will be permitted, except for palliation or symptom relief after 
completion of Cycle 2. The use of erythropoietin or other specific red blood cell growth factors 
and red blood cell transfusions will be permitted as clinically indicated during the study. 
 
The use of bone marrow colony stimulating factors (such as granulocyte colony-stimulating 
factor or granulocyte-macrophage colony-stimulating factor) is permitted as clinically indicated. 
See Section 6. 


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5.3.3 Supportive medications 
Other concomitant medications may be given as clinically indicated, including supportive 
medications for diarrhea, nausea/vomiting, or other supportive medications. 
 
5.3.4 Use of other medications not specified above 
No treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation or 
systemic steroids for treatment of autoimmune disease) will be permitted during this study; 
however, use of inhalant steroids and steroids given for antiemetic purposes or supportive 
therapy for brain metastases are permitted. 
 
5.4 Duration of Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
Disease progression, 
Intercurrent illness that prevents further administration of treatment, 
Unacceptable adverse event(s), 
Participant decides to withdraw from the study, or 
General or specific changes in the participant's condition render the participant unacceptable for 
further treatment in the opinion of the treating investigator. 
 
5.5 Duration of Follow Up 
Subject survival information will be collected, preferably via office visit or telephone contact, 
every 12 weeks (± 1 week) from the date of last dose of study drug until the subject’s death or 
until the subject is lost to follow-up, or until study closure  (approximately 6 months after the last 
subject terminates treatment). 
 
5.6 Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 5.4 applies. 
The reason for study removal and the date the participant was removed must be documented in 
the study-specific case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator (or Protocol Chair), Jennifer Ang Chan, Pager 
42017 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
Toxicity assessments will be carried out using NCI Common Terminology Criteria for Adverse 
Events (CTCAE v. 4.0) which is available at http://ctep.cancer.gov/reporting//ctc.html). 
 
Subjects will receive cabozantinib orally at a (starting) dose of 60 mg (free base) once daily. In 
all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines 
below. 
 


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6.1 General Guidelines for Treatment Delay, Dose Reduction, or Study Drug 
Discontinuation for Toxicity 
Subjects will be monitored continuously for AEs throughout the study and for 30 days (+ 7 days) 
after the last dose of study treatment, and for any serious adverse event assessed as related to 
study treatment or study procedures, even if the SAE occurs more than 30 days after the last dose 
of study treatment. Subjects will be instructed to notify their physician immediately of any and 
all AEs. Subjects experiencing one or more AEs due to the study treatment may require a dosing 
delay or reduction(s) in their dose in order to continue with study treatment. Assessment of 
causality (chronology and confounding factors such as disease, concomitant medications, 
diagnostic tests, and previous experience with the study treatment) should be conducted by the 
principal investigator (PI) when possible, before a decision is made to modify the dose or to hold 
dosing temporarily. 
 
As a general approach, it is suggested that all AEs be managed with supportive care when 
possible at the earliest signs of toxicity to avoid dose interrupts and reductions if possible. 
 
Re-escalating study treatment after a dose reduction: 
• Subjects may be re-escalated to the previous dose at the discretion of the investigator but not 
sooner than 2 weeks beyond the resolution to Grade ≤ 1 or to the baseline value of AEs. 
• If a subject has been dose-reduced more than once (20 mg qd), dose escalation can only 
occur to the next dose level (40 mg qd). Further dose escalation to the highest dose level is 
allowed only if clinically indicated per investigator’s judgment.  
• If the AEs that previously led to dose reduction(s) recur upon re-escalation, the dose should 
be reduced again and no further dose escalation will be permitted.  
 
Dose re-escalation is not allowed for dose reduction triggered by neutropenia or 
thrombocytopenia. 
 
TABLE 6.1 – Dose reductions 
Starting dose 
1st dose reduction 
2nd dose reduction 
60  mg (free base weight) 
40 mg (free base weight) 
20 mg (free base weight) 
Note: subjects may be re-escalated to the previous dose at the discretion of the investigator no 
sooner than 2 weeks beyond resolution (Grade ≤ 1 or to the baseline value [or lower] of AEs). 
Subjects who cannot tolerate study treatment at 20 mg (free base) PO will be discontinued from 
study treatment. 
 
Discontinuation from study treatment: 
• If the subject does not recover from his or her toxicities to tolerable Grade ≤ 1 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. 
• The minimum dose of study treatment will be 20 mg (free base) qd. Subjects who cannot 
tolerate 20 mg qd will have study treatment discontinued. 
 


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Additional information for dose delays or dose reductions: 
• Dose delays for reason(s) other than AEs related to cabozantinib, such as surgical procedures 
with no anticancer therapy intent, may be allowed with investigator approval. The acceptable 
length of interruption will be determined by the investigator and sponsor. 
 
Warnings, Precautions, and Management of Anticipated Adverse Events 
The general adverse event profile of cabozantinib includes GI symptoms (such as nausea, 
vomiting, and diarrhea), fatigue, anorexia, PPE syndrome, skin rash, elevated ALT and AST, 
increased pancreatic enzymes with rare cases of  pancreatitis, as well as side effects associated 
with inhibition of VEGF signaling such as thrombotic events (eg, PE and DVT), hypertension, 
proteinuria, hemorrhagic events, and rare cases of GI perforation and rectal/perirectal abscess. 
Arterial thromboembolism (TIA, MI) have been reported rarely. 
 
6.2 Management of Adverse Events 
In the absence of an unacceptable cabozantinib-related toxicity and/or clinical signs of disease 
progression, subjects may continue treatment at the discretion of the investigator. Subjects must 
be instructed to notify their physician immediately for any and all toxicities. 
 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are presented 
in the next sections. Each dose reduction of cabozantinib should be to one dose level lower that 
the current dose. Dose reductions of more than one dose level are acceptable if agreed to by the 
Investigator. 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 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. 
 
Events triggering permanent discontinuation of cabozantinib: 
• Development of Grade 4 thromboembolic events 
• Development of an acute MI or any other clinically significant arterial thromboembolic 
complication. 
• Any Grade 4 non-hematologic toxicity, with the exception of Grade 4 asymptomatic 
amylase or lipase elevation, judged to be related to study medication unless the patient is 
deriving clinical benefit from cabozantinib. If the patient is deriving clinical benefit from 
cabozantinib, the toxicity must resolve to Grade ≤1 prior to restarting, and after approval 
by the investigator, treatment at a reduced dose can be considered. 
• Transaminase elevations that are accompanied by evidence of impaired hepatic function 
(bilirubin elevation > 2xULN), in the absence of evidence of biliary obstruction (i.e., 
significant elevation of ALP) or some other explanation of the injury. 


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• Any Grade 4 neutropenia judged to be related to study medication unless the patient is 
deriving clinical benefit from cabozantinib. If the patient is deriving clinical benefit from 
cabozantinib, the toxicity must resolve to Grade ≤1 prior to restarting, and after approval 
by the investigator, treatment at a reduced dose can be considered. 
• Serious and life-threatening bleeding events or recent hemoptysis (≥ ½ tablespoon of 
red blood). 
• Gastrointestinal perforation or gastrointestinal fistula of any Grade 
• Grade 3 toxicities that have not resolved to ≤1 within six weeks 
 
General Guidelines for Non-Hematologic and Hematologic Adverse Events 
General guidelines for the management of non-hematologic and hematologic toxicities are 
provided in Table 6.2.1 and Table 6.2.2, respectively. As a general approach, it is suggested that 
all AEs be managed with supportive care when possible at the earliest signs of toxicity. For more 
specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), 
hepatobiliary disorders, pancreatic disorders (lipase and amylase elevations), skin disorders 
(PPE), embolism and thrombus, hypertension, proteinuria, hemorrhage, rectal and  perirectal 
abscess; gastrointestinal perforation and gastrointestinal fistula, wound healing and surgery, and 
endocrine disorders, refer to the specific subsections below. Guidance for the management of 
fatigue, anorexia, weight loss, non-gastrointestinal fistula, osteonecrosis of the jaw, eye 
disorders, musculoskeletal and connective tissue disorders, nervous system disorders, 
respiratory/thoracic/mediastional disorders and congenital, familial and genetic disorders can be 
found in the Investigators Brochure. 
 
 


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Table 6.2.1 Management of Study Treatment-Related Non-Hematologic Toxicities 
CTCAE Version 4 Grade  
Intervention 
Grade 1: 
Add supportive care as indicated. Continue study treatment at the current 
dose levels. 
Grade 2: 
Grade 2 AEs considered related to 
study treatment that are subjectively 
tolerable or easily managed 
Add supportive care as indicated. Continue study treatment at the current 
dose levels.  
Grade 2 AEs considered related to 
study treatment that are intolerable to 
the subject or deemed unacceptable in 
the investigator’s judgment; or are not 
easily managed or corrected 
Dose reduce 
• If the AE does not resolve to Grade ≤ 1 or baseline in 7 to 10 days or 
worsens at any time, cabozantinib dosing should then be interrupted. 
Then upon resolution to baseline or Grade ≤ 1, the reduced dose 
should be restarted. 
• If the AE resolves to Grade ≤ 1 or baseline without a dose 
interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
study treatment which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
• Add supportive care as indicated 
• AEs that are easily managed (e.g., correction of electrolytes) with 
resolution within 24 hours do not require a dose modification unless 
this is a recurring event, at which time the dose should be reduced. 
• For AEs that require supportive care, the dose should be reduced or 
interrupted while supportive care is initiated and optimized. If a 
treatment interruption is required, then upon resolution to baseline 
or Grade ≤ 1, treatment should be restarted with the reduced dose. 
Grade 3 AEs considered related to 
study treatment that occurred despite 
optimal prophylaxis or is not easily 
managed by medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction. 
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
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 sponsor and only with 
approval by the sponsor. 
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. 
 


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Table 6.2.2: Management of Hematologic Toxicities 
CTCAE Version 4 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 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 resolution to ≤ Grade 1, 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 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 sponsor and only 
with approval by the sponsor. 
ANC, absolute neutrophil count. 
 
Note:  Tables 6.2.1 and 6.2.2 do not account for "Transaminase elevation," "Asymptomatic Lipase or 
Amylase Elevations," “Hand-Foot Skin Reactions,” “Hypertension,” and “Treatment-Emergent 
Proteinuria”, which are discussed later in the text and have separate reference tables. 
 
Diarrhea, Nausea, Vomiting,  Stomatitis, and Mucositis 
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 agents is recommended at the first sign of diarrhea as initial management. 
Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide (Benson et al. 2004). Some subjects may 
require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of 
opium to control diarrhea. When combination therapy with antidiarrheal agents does not control 
the diarrhea to tolerable levels, a dose reduction and/or dose interruption of cabozantinib should 
be implemented as described in Table 6.1. 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 
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Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting. A dose reduction and/or dose interruption of cabozantinib may 
be required as described in Table 6.1 if anti-emetic treatment and/or prophylaxis alone is not 
adequate. 
 
Agents classified as having a high therapeutic index (such as 5-HT3 receptor antagonists, or 
NK-1 receptor antagonists) per ASCO or MASCC/ESMO guidelines for anti-emetics in 
oncology or dexamethasone are recommended (Hesketh et al. 2008, ASCO 2006; Roila et al, 
Annals of Oncology, 2010). Caution is recommended with the use of aprepitant or fosaprepitant 
and nabilone as cabozantinib exposure may be affected by concomitant administration because 
aprepitant and fosaprepitant are both inhibitors and inducers of CYP3A4, and nabilone is a weak 
inhibitor of CYP3A4. 
 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis. During treatment with cabozantinib, good oral hygiene and standard local treatments 
such as a traumatic cleansing, and oral rinses (eg, with a weak solution of salt and baking soda) 
should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures 
should be cleaned and brushed often to remove plaque. Local treatment should be instituted at 
the earliest onset of symptoms. When stomatitis interferes with adequate nutrition and local 
therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib 
should be considered. 
 
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. If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases. 
 
Since subjects may enter the study with elevations of AST/ALT at baseline, the following 
guideline should be used for dose modifications: 
 
Transaminase elevation CTCAE v4.0 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue study treatment with weekly monitoring of liver function 
tests (LFTs) for at least 4 weeks. Then resume the standard 
protocol-defined monitoring of LFTs. 


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Grade 2 
Continue study treatment 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 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. 
Grade 3  
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 2-3 times per week, until 
resolution to Grade ≤ 1. If the subject was clearly deriving clinical 
benefit, the subject may be able to resume treatment at a lower dose 
as determined by the investigator and sponsor but only with sponsor 
approval. 
Subjects with AST or ALT > ULN – 3.0 x ULN at  baseline   
≥ 1.5 fold transaminases increase (at least 
one of AST or ALT) and Grade <3 
Continue study treatment with at least twice weekly monitoring of 
LFTs 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 transaminases increase (at least 
one of AST or ALT) and Grade 3 
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 2-3 times per week, until 
resolution to Grade ≤ 1. If the subject was clearly deriving clinical 
benefit, the subject may be able to resume treatment at a lower dose 
as determined by the investigator and sponsor but only with sponsor 
approval. 
Subjects  AST or ALT > 3.0 – 5.0 x ULN at  baseline   
≥ 1.5 fold transaminases increase (at least 
one of AST or ALT) and Grade 3 
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 2-3 times per week, until 
resolution to Grade ≤ 1. If the subject was clearly deriving clinical 
benefit, the subject may be able to resume treatment at a lower dose 
as determined by the investigator and sponsor but only with sponsor 
approval. 


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Cabozantinib treatment should also be interrupted when transaminase 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 
< 2 × ULN, total bilirubin < 3 × ULN, aminotransferases < 2.5 × ULN or baseline). 
 
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2xULN), in the 
absence of evidence of biliary obstruction (i.e., significant elevation of ALP) or some other 
explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the combined finding 
(i.e., 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 ≥  3 times the upper limit of normal 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 discontinued. 
 
Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The 
clinical significance of asymptomatic elevations of enzymes is not know but, in general have not 
been associated with clinically apparent sequelae, and no specific interventions is required.. It is 
recommended that subjects with lipase elevation and/or symptoms of pancreatitis have more 
frequent laboratory monitoring of lipase and/or amylase (2-3 times per week). Subjects with 
symptomatic pancreatitis should be treated with standard supportive measures. 
 


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Asymptomatic Lipase or Amylase Elevations 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level. More frequent monitoring is recommended 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤ 1 or baseline, cabozantinib may be restarted at 
the same dose or at a reduced dose provided that this occurs within 
6 weeks. 
• 
If asymptomatic grade 3 or 4 elevations recur following retreatment after 
previous grade 3 or grade 4 asymptomaic lipase or amylase elevation, then 
treatment must be interrupted again until amylase and lipase levels have 
resolved to Grade <=1 or baseline.  Retreatment must be at a reduced 
dose; if already at the 20 mg dose level, treatment can resume at 20 mg. 
Grade 4 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤ 1 or baseline, cabozantinib may be restarted at 
the same dose or a reduced dose if resolution occurred within 4 days). 
Otherwise the dose must be reduced upon retreatment provided that 
resolution occurred within 6 weeks. 
• 
If asymptomatic grade 3 or 4 elevations recur following retreatment after 
previous grade 3 or grade 4 asymptomaic lipase or amylase elevation, then 
treatment must be interrupted again until amylase and lipase levels have 
resolved to Grade <=1 or baseline.  Retreatment must be at a reduced 
dose; if already at the 20 mg dose level, treatment can resume at 20 mg. 
 


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Symptomatic Pancreatitis 
Pancreatitis 
Grade 1  
Continue at current dose level.  More frequent monitoring is recommended, 
including radiographic assessment as appropriate.  
Grade 2 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤ 1 or baseline, cabozantinib may be restarted at 
the same dose or at a reduced dose provided that this occurs within 
6 weeks. 
• 
If retreatment following Grade 2 pancreatitis is at the same dose and 
Grade 2 pancreatitis recurs, then treatment must be interrupted again and 
till resolution to Grade ≤ 1 or baseline and retreatment must be at a 
reduced dose. 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤ 1 or baseline , cabozantinib may be restarted 
at a reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was clearly deriving 
benefit from cabozantinib therapy, treatment may resumed at a reduced dose if 
agreed to by both the investigatory and the sponsor. 
 
 
 
Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin 
rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported with cabozantinib. All subjects on study should be advised on prophylactic measures 
including the use of emollients, removal of calluses, avoidance of exposure of hands and feet to 
hot water leading to vasodilatation, protection of pressure-sensitive areas of hands and feet, and 
use of cotton gloves and socks to prevent injury and keep the palms and soles dry. 
 
The onset of PPE is variable with paresthesia (tingling, numbness) being the characteristic initial 
manifestation, which can be accompanied by slight redness or mild hyperkeratosis. PPE 
advances with symmetrical painful erythema and swollen areas (edema) on the palms and soles. 
The lateral sides of the fingers or periungual zones may also be affected. Adequate interventions 
are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, 
or necrosis of affected areas. 
 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo). 
 


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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. 
 
Hand-Foot Skin Reaction and Hand Food Syndrome (PPE) 
No apparent toxicity 
Prophylaxis with Ammonium lactate 12% cream (Amlactin®) twice daily OR 
heavy moisturizer (e.g. Vaseline) twice daily. 
Grade 1 
Continue treatment at current dose if tolerable or reduce to the next lower dose if 
intolerable. 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. If severity 
worsens at any time or if there is no improvement after 2 weeks, proceed to the 
management guidelines for Grade 2 PPE. 
Grade 2 
Reduce study treatment to next lower level or interrupt dosing if not tolerated and 
monitor for changes in severity. Start/continue urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Pain control with NSAIDs/GABA 
agonists/narcotics. Assess subject at least weekly for changes in severity. Subjects 
should be instructed to notify investigator immediately if severity worsens. If 
severity worsens at any time (eg, peeling, blisters, bleeding, edema, or 
hyperkeratosis or affects self-care) or if there is no improvement after 2 weeks, 
proceed to the management guidelines for Grade 3 PPE. If dosing was interrupted, 
treatment may restart at one dose level lower when reaction decreases to Grade 1 or 
0. 
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. 
 
Embolism and Thrombosis  
In clinical studies with cabozantinib, venous thrombotic events (DVT and PE) have been 
observed in less than 10% of subjects, and arterial thromboembolic events (MI and TIA) have 
been reported rarely. In addition, subjects with cancer have a significantly increased likelihood 
of developing thromboembolic complications (De Groot et al, 2009). 
 


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Cabozantinib must be discontinued in subjects who develop Grade 4 thromboembolic events or 
who develop an acute MI or any other clinically significant arterial thromboembolic 
complication. In patients who require therapeutic anticoagulation for Grade 2 or Grade 3 
thromboembolic events, cabozantinib may be continued as follows: Subjects who develop a 
Grade 2 or Grade 3 PE and/or DVT should have study treatment interrupted until full 
anticoagulation is established with low molecular weight heparin (LMWH)  (Full anticoagulation 
with warfarin is not permitted). Venous filters (e.g. vena cava filters) are not recommended due 
to the high incidence of complications associated with their use. Once a subject is fully 
anticoagulated, treatment can be restarted per investigator judgment at one dose lower. Subjects 
should permanently discontinue after a second thrombotic event. Although routine prophylactic 
anticoagulation is not necessary for all subjects, prophylactic anticoagulation is allowed for 
individual subjects at the discretion of the investigator. 
 
 
Hypertension 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in cabozantinib clinical studies. 
 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by 
a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement. Other than for hypertension requiring immediate therapy, the 
presence of new or worsened hypertension should be confirmed at a second visit before taking 
new therapeutic action. Blood pressure should be monitored in a constant position visit to visit, 
either sitting or supine. Cabozantinib dosing should be interrupted in subjects with severe 
hypertension (180 mm Hg systolic or 120 mm Hg diastolic; or sustained ≥ 160 mm Hg systolic 
or ≥ 110 diastolic) who cannot be controlled with medical interventions and discontinued in 
subjects with hypertensive crises or hypertensive encephalopathy. 
 


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Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
• Increase antihypertension therapy  (i.e., 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, dose of cabozantinib should be reduced. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
OR 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
• Reduce cabozantinib by one dose level. 
• Increase antihypertension therapy  (i.e., 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 < 140 systolic or 
< 90 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 < 140 and DBP < 90, restart cabozantinib treatment 
at  one dose level lower 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or 
< 90 diastolic, dose of cabozantinib should be reduced further. 
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 
 
Proteinuria 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib. Development and worsening of proteinuria should be monitored by serial 
urinalysis (qualitative/ semiquantitative assessment by dipstick; quantitative assessment by urine 
protein/urine creatinine ratio [UPCR], or 24-hour urine protein excretion). When a UPCR 
exceeds 1 (mg/dL protein / mg/dL creatinine), a repeat UPCR or a 24-hour urine protein and 
creatinine should be performed to confirm the result. Cabozantinib should be discontinued in 
subjects who develop nephrotic syndrome (proteinuria > 3.5 grams per day in combination with 
low blood protein levels, high cholesterol levels, high triglyceride levels, and edema) or any 
other relevant renal disease. Also, given the nephrotoxic potential of bisphosphonates, these 
agents should be used with caution in patients receiving treatment with cabozantinib. Details of 
management are described in Table 6.2.3. 
 


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Table 6.2.3:  Management of Treatment Emergent Proteinuria 
 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
• 
No change in treatment or monitoring 
> 1 and < 3.5 
 
• 
Confirm with a 24 hour urine protein excretion within 7 days 
• 
If proteinuria of > 1 g/24 hours is confirmed, hold 
cabozantinib and continue with UPCR monitoring. When 
UPCR returns to < 1, restart cabozantinib at a reduced dose. 
Continue monitoring UPCR once every week until 
2 consecutive readings are < 1, then revert to UPCR 
monitoring frequency specified in the protocol. 
≥ 3.5 
 
• 
Hold cabozantinib immediately and confirm with 24 hour 
urine protein excretion. 
• 
Evaluate for nephrotic syndrome. If present, discontinue 
cabozantinib treatment permanently, and monitor subject for 
resolution of nephrotic syndrome. 
• 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without 
diagnosis of nephrotic syndrome, continue to hold 
cabozantinib and monitor UPCR weekly. If UPCR decreases 
to < 1, restart cabozantinib at a reduced dose. Continue 
monitoring UPCR once every week until two consecutive 
readings are < 1, then revert to UPCR monitoring frequency 
specified in the protocol. 
 
Hemorrhage 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib. As preventive measures, subjects should be evaluated for potential 
bleeding risk factors prior to initiating cabozantinib treatment and monitored for bleeding events 
with serial complete blood counts and physical examination while on study. Risk factors for 
hemorrhagic events may include (but may not be limited to) the following: 
• Tumor lesions of the lung with cavitations or tumor lesions which invade, encase, or abut 
major blood vessels of the lung; NSCLC with squamous cell differentiation is known for 
significant lung cavitations and centrally located tumors that may invade major blood 
vessels. The anatomic location and characteristics of tumor as well as the medical history 
should 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 that 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 
 


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Based on the described predisposing risk factors for hemoptysis, many studies with 
antiangiogenic drugs exclude subjects with NSCLC and squamous cell differentiation. Although 
enrollment of subjects with NSCLC with squamous cell differentiation has been allowed on 
cabozantinib studies, cabozantinib studies exclude NSCLC subjects with any of the following: 
tumors abutting, encasing, or invading a major blood vessel; cavitating lesions; history of 
clinically significant hemoptysis; or recent (within 3 months) radiation therapy to the thoracic 
cavity including brachytherapy unless radiation therapy targets bone metastasis. 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ ½ tablespoon of red blood). Treatment with cabozantinib should 
be interrupted if less severe forms of clinically significant hemorrhage occur and may be 
restarted after the cause of hemorrhage has been identified and the risk of bleeding has subsided. 
Therapy of bleeding events should include supportive care and standard medical interventions. 
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major blood vessel 
or who develop cavitation of their pulmonary tumors while on study treatment must immediately 
be discussed with the sponsor to determine the safety of continuing study treatment. 
 
Rectal and Perirectal Abscess 
Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent 
diarrhea. These should be treated with appropriate local care and antibiotic therapy. Cabozantinib 
should be held until adequate healing has taken place. 
 
Gastrointestinal perforation and GI fistula  
Gastrointestinal perforation and GI fistula have been reported with approved drugs that inhibit 
VEGF pathways as well as with cabozantinib. To allow for early diagnosis, subjects should be 
monitored for episodes of abdominal pain, especially if known risk factors for developing GI 
perforation or fistula (Turnage et al. 2008) are present. Such risk factors include (but may not be 
limited to) the following: 
• Intra-abdominal tumor/metastases invading GI mucosa 
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, 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 following abdominal surgery or resolution of intra-abdominal abscess must be 
confirmed prior to initiating treatment with cabozantinib. 
 
Additional risk factors include concurrent use of steroid treatment or non-steroidal 
anti-inflammatory drugs (Rodriguez et al. 2001, Straube et al. 2009). Constipation, consistent 
with symptoms of bowel obstruction, should be monitored and effectively managed. Discontinue 
cabozantinib and initiate appropriate management in subjects who have been diagnosed with GI 
perforation or fistula. 
 


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Wound healing and Surgery 
VEGF 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 prior to starting cabozantinib treatment and be monitored 
for wound dehiscence or wound infection while the subject is being treated with cabozantinib. 
 
Treatment with cabozantinib must be interrupted for any wound healing complication which 
needs medical intervention. Treatment with cabozantinib can be resumed once wound healing 
has occurred unless otherwise prohibited in specific protocols. Cabozantinib should be 
discontinued in subjects with serious or chronic wound healing complications. 
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 
3 weeks (5 half lives) prior to elective surgery. 
 
Endocrine Disorders 
Prospective studies of markers of thyroid functions are currently ongoing in two single-agent 
studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate 
that cabozantinib affects TFTs in a high number of subjects. In Study XL184-203, 17 of 34 
(50%) euthyroid subjects with CRPC developed abnormal thyroid-stimulating hormone (TSH) 
levels 6 weeks after initiation of cabozantinib treatment (6% showed TSH levels between 5 and 
7 mU/L, 44% had TSH > 7 mU/L). The median TSH level at week 6 was 5.2 mU/L 
(range, 0.02-29.7 mU/L). In a Phase 1 combination study  of rosiglitazaone and cabozantinib 
(XL184-008) to determine the potential for a clinically significant drug-drug interaction of 
cabozantinib on the CYP isozyme CYP2C8, subjects with advanced solid tumors (particularly 
RCC and DTC) are enrolled. Among 11 evaluable subjects, the AE of hypothyroidism was 
reported in 55% of subjects. Currently available data are insufficient to determine the cause of 
TFT alterations and its clinical relevance. Routine monitoring of thyroid function and 
assessments for signs and symptoms associated with thyroid dysfunction is recommended for 
subjects treated with cabozantinib. Management of thyroid dysfunction (eg, symptomatic 
hypothyroidism) should follow accepted clinical practice guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects. Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiation and during treatment 
with cabozantinib is recommended. Cabozantinib should be discontinued in subjects with severe 
or life-threatening endocrine dysfunction. 
 
Concomitant Medications and Therapies 
Anticancer Therapy 
If a subject requires additional systemic anticancer treatment, including steroid treatment for 
prostate cancer subjects, study treatment must be discontinued other than the use of octreotide. 
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. Subjects with prostate cancer currently receiving luteinizing hormone-


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releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be 
maintained on these agents. 
 
Other Medications 
Subjects must be instructed to inform the investigators of the current or planned use or all other 
medications during the study (including prescription medications, vitamins, herbal and 
nutritional supplements, and over-the-counter medications). It is the responsibility of the 
investigator to ensure that details regarding all medications are documented. 
 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically prior to 
the first dose of cabozantinib. After the first dose of study treatment, at the discretion of the 
investigator or after the onset of symptoms, treatment (or prophylaxis) with anti-emetic and anti-
diarrheal medications may be undertaken per standard clinical practice. Bisphosphonates are 
allowed if started prior to screening activities or may be initiated during the course of the study 
to control bone pain with agreement from the sponsor. 
 
Colony stimulating factors (eg, erythropoietin and granulocyte colony-stimulating factors) and 
pain medications administered as dictated by standard practice are acceptable while the subject is 
enrolled in the study. However, colony stimulating factors should not be administered 
prophylactically prior to the first dose of study treatment. 
 
No concurrent investigational agents are permitted. 
 
7. VISIT SCHEDULE AND ASSESSMENTS 
Baseline evaluations are to be conducted within 1-week prior to start of protocol therapy. Scans 
must be done ≤ 4 weeks prior to the start of therapy. In the event that the participant's condition 
is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next cycle of therapy. 
 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within + 1 days of the protocol-specified 
date, unless otherwise discussed with the principal investigator. 
 
7.1 Evaluations 
7.1.1 Pretreatment evaluation 
 
Tests to be performed within 28 days prior to initiation of therapy: 
• Radiologic assessment of tumor burden by CT scan or MRI within 28 days prior to 
initiation of therapy. 
• Chromogranin A and 24 hour urine 5-HIAA if applicable will be measured at baseline. 
• Correlative blood samples to be drawn  
• Correlative imaging studies with functional CT (if applicable). This may be performed on 
a subset of consenting patients if funding is obtained, with the testing performed at MGH. 
 


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Tests to be performed within 14 days prior to initiation of therapy: 
• All patients will be assessed by history and physical examination, including height, 
weight, vital signs, and performance status within 14 days prior to initiation of therapy. 
• Baseline hematologic and chemistry profiles, including CBC with differential, platelets, 
and serum chemistries: fasting glucose, sodium, potassium, chloride, bicarbonate, 
creatinine, blood urea nitrogen, albumin, SGOT (AST), SGPT (ALT), total bilirubin, 
alkaline phosphatase, amylase, lipase, and thyroid function testing. 
• Urine protein 
• Serum pregnancy test for women of childbearing potential 
• Electrocardiogram 
• Chromogranin A and 24 hour urine 5-HIAA if clinically indicated 
 
7.1.2 Evaluations during treatment performed every cycle 
• Physical examination 
• Toxicity assessment 
• Vital signs 
• Weight 
• Complete metabolic panel, including bilirubin, ALT, AST, albumin, alkaline 
phosphatase, albumin, total protein, serum glucose, BUN, creatinine, electrolytes 
including Na, K, Cl, HC03, Mg, PO4, Ca, uric acid, amylase, lipase, and thyroid function 
tests. 
• CBC with differential 
• Correlative samples for assessment of response (note: circulating tumor cells will be 
every other cycle for Cycles 2,4 and 6, while circulating biomarkers are drawn on Day#1 
of every cycle). 
• Urine protein 
 
7.1.3 Evaluations during treatment performed on Day#15 of first 3 cycles: 
• Physical examination 
• Toxicity assessment 
• Vital signs 
• Weight 
• Complete metabolic panel, including bilirubin, ALT, AST, albumin, alkaline 
phosphatase, total protein, serum glucose, BUN, creatinine, amylase, lipase, electrolytes 
including Na, K, Cl, HC03, Mg, PO4, Ca, uric acid, and urine protein. 
• CBC with differential 
 
7.1.4 Evaluations after cycles 2, 4, and 6, then every third cycle (2, 4, 6, 9, 12, 15, 18, etc.): 
• Radiologic assessment of tumor burden by CT scan or MRI 
• Chromogranin A and 24 hour urine 5-HIAA if clinically indicated 
• Correlative imaging with functional CT (optional). A second functional CT scan may be 
performed on a subset of consenting patients if funding is available that had a functional 
CT performed prior to initiation of cabozantinib, with the testing performed at MGH. 
 


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7.1.5 Post-treatment evaluation 
• Physical examination 
• Toxicity assessment 
• Vital signs 
• Weight 
• ECOG PS 
• Complete metabolic panel, including bilirubin, ALT, AST, albumin, alkaline 
phosphatase, total protein, serum glucose, BUN, creatinine, electrolytes including Na, K, 
Cl, HC03, Mg, PO4, Ca, and uric acid. 
• CBC with differential 
• Radiologic assessment of tumor burden by CT scan (arterial and venous phase required) 
at the physician’s discretion. An additional liver MRI may be used for those patients with 
isolated liver metastases in whom the CT does not provide accurate information for liver 
disease. All sites of tumor progression or metastases will be noted 
 
• Progression-free and overall survival will be determined 
• Patients who have an ongoing Grade 4 or serious adverse event at the time of 
discontinuation from study drug treatment will continue to be followed at monthly 
intervals, until resolution of toxicity to < Grade 2.Correlative samples for assessment of 
response 
 
 


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7.2 Study Calendar 
 
REQUIRED INFORMATION/EXAMS 
Pre- Study 
Day 1 of 
each cycle a 
Day 15 of each 
cycleb 
Restagingc 
Post-
Treatment 
Follow-upd 
Informed consent 
X 
 
 
 
 
Medical and Oncologic History 
X 
X 
X 
 
X 
Concurrent meds 
X 
 X 
 X 
 
 X 
Physical exam  
(including height, weight, pulse, blood 
pressure, oxygen saturation) 
Xj 
X 
X 
 
X 
ECOG Performance Status 
X 
X 
X 
 
X 
Adverse event evaluation 
 
X 
X 
 
X 
Archived Tumor Tissue 
Xk 
 
 
 
 
EKG 
Xj 
Xg 
 
 
X 
LABORATORY STUDIES 
 
 
 
 
 
CBC w/differential 
Xj 
X 
X 
 
X 
Bilirubin, ALT, AST, Albumin, 
Alkaline Phosphatase, Total protein 
Xj 
X 
X 
 
X 
PT, PTT 
X 
X 
 
 
 
Serum glucose 
Xj 
X 
 
 
X 
BUN, creatinine, electrolytes, including 
Na, K, Cl, HCO3, Mg, PO4, Ca, uric 
acid, amylase, lipase 
Xj 
X 
X 
 
X 
TSH with reflex T4 
Xj 
X 
 
 
X 
Urine protein 
Xj 
X 
X 
 
X 
Chromogranin, Urine HIAA 
Xji 
 
 
Xi 
Xi 
HBsAg, HBSb, HB Core Antibody 
Xj 
 
 
 
 
β-HCGe 
Xj 
 
 
 
 
Correlative Laboratory Samples  
Xh 
Xh 
 
 
Xh 
RADIOGRAPHIC TESTS 
Tumor measurements 
X 
 
 
X 
 
Radiologic evaluation 
X 
 
 
X 
 
Correlative Imaging 
Xf 
 
 
Xf 
 
a. 
Screening assessments must occur within 28 days of start of cabozantinib administration. Pre-registration labs may be used for 
Day#1 of Cycle#1 if obtained within 7 days of starting treatment. For subsequent cycles, labs must be obtained within 48 hours of 
start of treatment  
b. 
Day#15 evaluations to be performed for first three cycles, after which time, only need evaluations on Day #1 
c. 
Restaging after cycles 2, 4, and 6, then every 3rd cycle (i.e. 2, 4, 6, 9, 12, 15, 18, etc.) until the first of 3 years after study 
registration, until disease progression, or end of study treatment. All patients will receive an arterial and venous phase 
Chest/Abdomen/Pelvic CT. A liver MRI with gadolinium may be included at the discretion of the treating physician. 
Radiographic evaluations will be performed after cycles 2, 4, and 6, then every 3rd cycle (i.e. 2, 4, 6, 9, 12, 15, 18, etc.)  
d. 
For patients who discontinue study treatment prior to tumor progression, physical examination, performance status, 
chromogranin A, and radiologic imaging studies should be performed upon discontinuation of study at the physician’s discretion. 
Patients who discontinue treatment at the time of tumor progression should be followed every 6 months with physical exam and 
performance status, with chromogranin A and imaging studies at the discretion of the investigator. 


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e: 
Serum pregnancy test (women of childbearing potential) 
f: 
Patients electing to undergo optional correlative functional imaging, if funding is obtained, will be performed prior to treatment 
with cabozantinib and after two cycles of treatment. 
g.  Cycle#2, Day#1 only 
h.   Plasma biomarker analysis will be drawn at baseline,  on Day#1 of every cycle, and post-treatment.  Circulating tumor cells will 
be drawn at baseline, Day#1 of Cycles 2,4 and 6, and post-treatment. 
i.  
Chromogranin A and Urine HIAA is to be collected on at baseline and after cycles 2, 4, and 6, then every 3rd cycle (i.e. 2, 4, 6, 9, 
12, 15, 18, etc.)  if clinically indicated 
j. 
These assessments are required to be performed 14 days prior to initiation of therapy. 
k. 
Due to a lack of funding, archival tissue will not be collected 
 
EKG Assessments 
EKG assessments will be performed with standard 12-lead EKG equipment according to 
standard procedures. Abnormalities in the EKG that lead to a change in subject management 
(eg, dose reduced or withheld, requirement for additional medication or monitoring) or result in 
clinical signs and symptoms are considered clinically significant for the purposes of this study 
and will be recorded on the AE CRF. If values meet criteria defining them as serious, they must 
be reported as SAEs (Section 9). 
 


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8. MEASUREMENT OF EFFECT 
8.1 Antitumor Effect 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Therasse et al, 
2000). RECIST version 1.1 will be used. Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. For the purposes of this 
study, patients should be reevaluated every 8 weeks. In addition to a baseline scan, confirmatory 
scans should also be obtained no less than 4 weeks following initial documentation of objective 
response 
 
8.1.1 Definitions 
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response. Only those participants who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.} 
 
8.1.2 Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and will be recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, and should be chosen based 
on their suitability for accurate repetitive measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible repeated measurements in which case the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum LD will be used as 
reference to further characterize the objective tumor response of the measurable dimension of the 
disease. 
 
8.1.2.1 Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to < 10 mm. 
 
8.1.2.2 Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 


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8.1.2.3 Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 
8.1.2.4 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as 
references the smallest sum diameters while on study. 
 
8.1.3 Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
8.1.3.1 Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
8.1.3.2 Non-complete response (non-CR)/Non-progression (non-PD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above 
the normal limits. 
 
8.1.3.3 Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. Unequivocal progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. Although a clear 
progression of non-target lesions only is exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status should be confirmed later on by the 
review panel (or study chair). 
 
8.1.3.4 FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 


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b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. Note: A ‘positive’ FDG-PET scan lesion means one 
which is FDG avid with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
 
8.1.4 Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. These techniques can be used to differentiate between PR and 
CR in rare cases (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). The cytological confirmation of the neoplastic origin 
of any effusion that appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive disease. 
 
8.1.5 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
> 4 weeks confirmation* 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 weeks confirmation* 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD
/Not evaluated 
No 
PR 
SD 
Non-CR/Non-PD
/Not evaluated 
No 
SD 
Documented at least once 
> 4 weeks from baseline* 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*Only for non-randomized trials with response as the primary endpoint 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as "symptomatic deterioration". 
Every effort should be made to document the objective progression even after discontinuation of treatment. 
 
 
For patients with Non-measurable Disease (i.e., Not-target Disease): 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
* - Non-CR/Non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 


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8.1.6 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. The same method of assessment 
and the same technique should be used to characterize each identified and reported lesion at 
baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
 
8.1.6.1 Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). For 
the case of skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
 
8.1.6.2 Chest X-ray/Ultrasound  
Ultrasounds should not be used to measure lesions. Ultrasound is not useful in assessment of 
lesion size and should not be used as a method of measurement. Ultrasound examinations cannot 
be reproduced in their entirety for independent review at a later date and, because they are 
operator dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next. If new lesions are identified by ultrasound in the course 
of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. Chest radiographs may be used as a 
method of measurement in addition to MRI of the abdomen, if the primary disease is not in the 
chest, and if there is a concern about radiation exposure due to CT. 
 
8.1.6.3 Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g., for body scans). Use of MRI remains a complex issue. MRI has excellent 
contrast, spatial, and temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, 
the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-
up should be the same as was used at baseline and the lesions should be measured/assessed on 
the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. When both CT and liver MRI are used to evaluate liver disease, the MRI will serve as 
the imaging method to evaluate the size of the lesions within the liver; in this instance, the CT 
will be used to measure the size of the lesions outside of the liver. 
 


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8.1.6.4 PET-CT 
At present, the low dose or attenuation correction CT portion of a combined PET-CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed. 
 
8.1.6.5 Endoscopy and Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, such 
techniques may be useful to confirm complete pathological response when biopsies are obtained 
or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
8.1.6.6 Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers are initially above the upper 
normal limit, they must normalize for a patient to be considered in complete clinical response. 
 
8.1.7 Confirmation Measurement/Duration of Response 
8.1.7.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat studies that should be performed no less than 4 weeks after the criteria for response are 
first met. In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of no less than 6 weeks. 
 
8.1.7.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The duration of overall complete response is measured 
from the time measurement criteria are first met for CR until the first date that progressive 
disease is objectively documented. 
 
8.1.7.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements. 
 
8.1.8 Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time 
of objective disease progression. This will be assessed as a secondary endpoint in the expansion 
cohort treated at the recommended phase 2 dose or MTD. 
 
8.1.9 Response Review 
Central review of scans will be performed using the Tumor metrics Core. 


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8.2 Translational Medicine Assessments 
This study will collect samples for translational medicine assessments in all enrolled subjects. 
Sample types include whole blood, plasma, and tumor tissue. Most of the tumor samples are 
expected to be archival tissue. The sponsor or designee may retain anonymized leftover samples 
(eg, blood, tumor, DNA) for possible future analyses beyond the end of the study to elucidate 
further disease subtypes, drug response and toxicity, and possibly to identify new drug targets 
and additional biomarkers of response to study drug. Samples will be archived according to Food 
and Drug Administration (FDA) regulations, EMEA’s Reflection Paper on Pharmacogenomic 
Samples, Testing and Data Handling (EMEA 2007), and will not carry personal identification 
(eg, Social Security number or name). The samples will be destroyed after 15 years or earlier if 
requested by the subject unless already anonymized prior to the request. 
 
8.2.1 Pharmacodynamic Assessments 
Unless prohibited by local regulations, blood samples will be collected and processed into 
plasma for all subjects for potential analyses of cabozantinib mechanism of action based 
pharmacodynamic biomarkers (eg, sMET, HGF, VEGF-A, PlGF, sVEGFR2, sKIT) as well as 
disease specific markers. Additional exploratory studies may be performed to characterize 
disease subtypes and potential biomarkers of response or resistance. Analyses may include but 
are not limited to quantification and genotyping of circulating plasma DNA, evaluation of micro 
RNAs, and analyses of additional soluble markers. Pharmacodynamic plasma samples will be 
collected at the time points outlined in Study Calendar (Section 7.2). 
 
8.2.2 Tumor Samples and Analyses 
Tumor sample requisition is required for enrollment. Any subjects diagnosed ≥7 years prior to 
the date of screening with no additional tumor tissue collected in the last 7 years are excluded 
from this requirement, but efforts should be made to obtain samples if possible. Archival tumor 
tissue slides (a minimum of 10 consecutive unstained sections of 4-10 microns if available) or a 
tumor tissue paraffin block will be requisitioned for shipment to a central laboratory. In rare 
cases, frozen tissue may also be provided. Alternatively, a new biopsy may be obtained before 
the first dose of cabozantinib. Fine needle aspirates may also be acceptable and collection of 
tumor fluid samples (confirmed as malignant by a cytopathologist) may be considered on a 
case by case basis. Tumor analyses may involve evaluation of the signaling pathways related to 
cabozantinib targets (eg, VEGFR, MET, KIT, RET) and include methods such as genotyping, 
fluorescence in situ hybridization (FISH) and/or Immuno-histochemistry (IHC). Mutation and/or 
amplification status of disease-specific tumor-promoters or suppressors may also be determined 
to characterize the potential impact on response or resistance to cabozantinib (eg, HER2, EGFR, 
KRAS, NRAS, BRAF, PTEN, PIK3CA, TP53, GNAQ, CDKN2A). Broader genome-wide copy 
number and mutation profiling may also be conducted. For paired tumor biopsies 
pharmacodynamic markers such as pMET/MET, pVEGFR2/VEGFR2, pERK/ERK, pAKT/AKT 
and pKIT/KIT may also be analyzed by IHC. In addition, samples from bone or other tissues 
may be used to analyze disease-specific markers. Exploratory analyses of potential biomarkers of 
cabozantinib activity (circulating angiogenic and inflammatory biomarkers VEGF, PlGF, 
sVEGFR1, bFGF, IL-1β, IL-6, IL-8, and TNF-α and sVEGFR2 and SDF1α may be performed 
by measuring proteins in the plasma at baseline and on days 1 and 15 post-treatment for the first 
three cycles, day 1 beyond cycle 3, and at progression in patients with advanced neuroendocrine 


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tumors. Plasma analysis will be carried out for with samples run in duplicate, using established 
protocols in a previous study of bevacizumab in Mullerian carcinoma [22]. Blood-circulating 
cells may be enumerated in fresh samples using a standard flow cytometry protocol. Due to 
funding, DFCI and MGH will not be collecting archival tissue. 
 
8.2.3 Circulating Biomarkers 
8.2.3.1 Plasma Biomarker Analysis 
Plasma samples may be analyzed for potential biomarkers using multiplexed enzyme-linked 
immunosorbent assay (ELISA) kits (96-well plates, 4-10 analytes) or single cytokine ELISA (for 
analytes unavailable in multiplex, e.g., collagen IV, SDF1α). Using these technology, we will be 
able to assess VEGF family members and their soluble receptors, and collagen IV, SDF1α, 
bFGF, sICAM-1, sVCAM-1, PDGF-C, PDGF-B, thrombospondin-1, Ang1, Ang2, IL-1, IL-6, 
IL-8, and TNF-α. This broad array of proteins to be tested will permit complete evaluation of the 
most promising known angiogenic biomarkers. 
 
8.2.4   Peripheral blood will be collected for CTC analysis only for patients being treated at 
Massachusetts General Hospital using the Herringbone-Chip microfluidic platform, as described 
below. Samples will be collected prior to starting on study, followed by Day 1 of cycles 2, 4, and 
6. CTC analyses will be performed in the laboratory of Dr. Daniel Haber. Two 10 mL samples of 
peripheral blood will be collected into vacutainer tubes (Becton-Dickinson) containing the 
anticoagulant EDTA. Samples will be processed through the HB-Chip within 6 hours of 
collection, according to previously established protocols. 
Briefly, a 5 mL aliquot of blood will be placed into an air-tight conical tube on a rocker 
assembly, and approximately 4 mL of blood will be pneumatically driven through the HB-Chip 
at a flow rate of 1.5-2.5 mL/hour. The HB-Chip will then be flushed with 2.5 mL of phosphate-
buffered saline at 2.5 mL/hr to remove nonspecifically bound cells. CTCs on the HB-Chip will 
be fixed, permeabilized, and stained with antibodies. Captured CTCs will then be identified and 
enumerated using the automated detection system. 
  
8.2.4.2  
Blood collection criteria 
8.2.4.2.1 Blood Collection Time Points 
Blood samples will be obtained from each participant prior to imaging at each time point as 
indicated in the study calendar. 
 
8.2.3.2.2 Confidentiality 
The confidentiality of the participant’s identity will be maintained. All collected information will 
be protected per federal regulatory guidelines. Access to study data will be limited to the staff 
working on the study.  All computer data will be maintained in a manner consistent with Title 21 
Code of Federal Regulations Part 11 (21 CRF Part 11). In addition, access to the data 
management system will be limited to designated staff through use of individualized, 
confidential login ID and password. Designated staff will not share login IDs or passwords. 
 


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The data from this study will be maintained until 10 years following completion of the study or 
until the data are no longer required for research. Data will be destroyed as required by the 
Record Retention Policy and federal regulatory guidelines.  Human research subjects are 
protected in accordance with Title 45 CRF Part 46 and Title 21 CFR Part 50. HIPAA regulations 
should be followed according to institutional standards. 
 
8.2.3.2.3 Informed Consent 
Human research subjects are protected by informed consent procedures in accordance with 
Title 45 CFR Part 46 and Title 21 CFR Part 50. The Biomarker consent component of the 
institution-specific, IRB-approved informed consent form grants permission for study 
investigators to request and obtain blood and blood fractionates, and to use those samples for 
research involving molecular studies on the development of cancers and/or for other diseases. 
 
All participants will already have provided a written consent for the collection of blood for this 
biomarker assessment using the institution-specific, IRB-approved informed consent form at the 
time of enrollment.  If blood collection was not included in the original institution-specific, IRB-
approved informed consent form, please inform the Protocol Development and Regulatory 
Compliance department and refer to your local IRB and institutional policy for further guidance. 
 
8.2.3.3 Blood Collection Process 
Each participant will have 2 vials of blood (~8 mL each) collected at the time points listed in the 
study calendar, with the exception of baseline, Day#1 of Cycles 2,4,6, and post-treatment, at 
which times an addition two 10ml vials of blood will be collected for CTC analysis.  The blood 
must be processed and stored within 30-45 minutes after collection. 
 
8.2.3.3.1 Materials and Labeling of Blood Tubes and Cryovials 
All labels will have space for sites to provide the following information: 
• Participant study number 
• Participant initials 
• Time point when sample was collected 
• For the blood tubes, a “BL” and for the plasma cryovials, a “PL” to distinguish which 
label should be used for each tube. 
 
The site will be responsible for obtaining the appropriate tubes for the blood and plasma 
specimens. The list of supply options are as follows: 
 
For Blood Draw Tubes (3 Options) 
1. SARSTEDT Monovette® EDTA KE (9 mL), Part # 02.1333.001; or 
2. Becton-Dickinson VacutainerTM K2E (10 mL), Part # 367525; or 
3. Greiner Bio-One Vacuette® K3E EDTA K3 (9 mL), Part # 455036; and 
 
For Plasma Cryovials (1 Option) 
1. Nunc, Internally Threaded Cryotube, (3.6 mL vials), Fischer Scientific, Part # 12-565-162N. 
 


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8.2.3.3.2 Blood Draw and Centrifugation 
• Prior to the blood draw, the blood vacutainer should be pre-cooled by placing tube in a 
bucket with wet ice. 
• Directly from the participant’s IV line, draw the 2 vials of blood using 2 pre-labeled 
blood vacutainer tubes. 
• Record time of blood draw on Blood Processing Form (BL). 
• Immediately invert the blood tube several times to ensure proper mixing with the 
preservative. 
• Place the blood tube in a bucket filled with wet ice. 
• Centrifuge the blood tube at 700g (2000rpm) for 20 minutes at 4°C with no break at the 
end of centrifugation for plasma extraction. 
• Using a sterile pipette, pipette the top clear layer (careful not to disturb the bottom red 
layer) and aliquot equally into 3 pre-labeled 1.8 mL Nunc cryovials. 
• Visually check the plasma for hemolysis. 
o If the plasma appears to be yellow and clear, please proceed with processing the 
plasma and record the observation on the BL form. 
o If the plasma appears to be dark red, please discard the plasma and sign and date the 
BL form. 
• After the plasma has been extracted, check the red blood cells by sticking two wooden 
applicator sticks in the tube and observe the sticks for clots. Record if there was clotting 
observed, check yes or no on the Blood Processing Form (BL). 
• Record numbers of vials on Blood Processing Form (BL). 
• Immediately store the cryovials into a -80°C freezer*. 
• Record time of freeze, location of the vials (i.e., freezer number, shelf, box number, and 
room #, as applicable) on the Blood Processing Form (BL). 
 
*  If a -80°C freezer is not available on site, the plasma specimens should be shipped to the core 
facility on dry ice the same day as processing. See Section 4.0 for shipping procedures 
 
8.2.3.3.3 Labeling and Storing Specimens 
For tracking purposes, each specimen and its associated forms should be labeled with the site 
number and case number. All cryovials should be stored in a monitored -80° C freezer.  A 
separate freezer box should be set a side for the storage of all the plasma vials. They will be 
shipped in bulk to the testing core facility at completion of study. 
 
8.2.3.3.4 Shipping  Specimens to Core Facility 
When blood collection has been completed for all participants and after the participants go off 
trial the plasma samples should be shipped to the Steele Laboratory at Massachusetts General 
Hospital on dry ice in a Styrofoam box. The Styrofoam container should be packed with at least 
7 pounds of dry ice, and make sure the top is completely covered with dry ice. Seal the 
Styrofoam container within a tight-fitting cardboard shipping box. A copy of the Plasma 
Shipping (PS) Form for each set of samples should be placed within a separate zip-lock plastic 
bag and placed on top of the Styrofoam container lid before the external shipping box is sealed. 
 


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If the site does not have –80°C storage capability, the plasma samples should be sent to the 
Steele Laboratory at Massachusetts General Hospital after the blood has been processed. The 
Styrofoam container should be packed with at least 2 inches of dry ice on the bottom, and 
completely covered on the top with an additional 2 inches or more of dry ice. Seal the Styrofoam 
container within a tight-fitting cardboard shipping box. A copy of the Plasma Shipping (PS) 
Form for each set of samples should be placed within a separate zip-lock plastic bag and placed 
on top of the Styrofoam container lid before the external shipping box is sealed. 
 
If the site does not have facilities and trained personnel for plasma separation, the blood samples 
should be shipped to the Steele Laboratory at Massachusetts General Hospital with cold packs in 
a Styrofoam box within 24 hours (DO NOT FREEZE). Seal the Styrofoam container within a 
tight-fitting cardboard shipping box. A copy of the Plasma Shipping (PS) Form for each set of 
samples should be placed within a separate zip-lock plastic bag and placed on top of the 
Styrofoam container lid before the external shipping box is sealed. 
 
Specimens should be shipped Monday to Wednesday only by overnight FedEx to the Testing 
Core Facility with the original Sample Submission Form (web site | Protocol 6689 Forms). On 
the day of shipment, the study coordinator will notify the Testing Core Facility via e-mail at 
sylvie@steele.mgh.harvard.edu or christina@steele.mgh.harvard.edu or 
FAX (617-724-5841, ATTN: S. Roberge or C. Koppel) so they know to expect the upcoming 
shipment.  Include the estimated date of arrival and the FedEx tracking number. 
 
NOTE:  The subject line of the e-mail/FAX should include the following so that the Testing 
Core Facility staff can distinguish plasma specimens sent by the sites. 
 
Plasma Specimen Shipment--Site Name 
Upon receipt of specimens, the Testing Core Facility will reconcile the materials and notify the 
site study coordinator of missing specimens, damaged specimens, or any concerns to be 
addressed. 
 
8.2.3.4 Shipping Materials and Process 
The appropriate shipping materials for specimens are the following: 
• Storage boxes for plasma tubes (Fisherbrand, 5 3/4” x 5 3/4” x 4 7/8”, Part # 03-395-01, and 
dividers, Part # 03-395-11) 
• Large size zip-locked bags 
• Multi-purpose insulated bio-shippers (Thermosafe Bio-Shippers; dimensions 
14” x 10” x 14”) 
• Biohazard bags 
• M3 carton sealing tape 
• Shipping labels to indicate: “Notice: Keep Frozen” use only for Dry Ice shipments, 
Upright arrows,  “Diagnostic Specimens – Not restricted, Packed in Compliance with 
IATA Packing Instruction 650”, and “Class 9 – Dry Ice” label; and “Keep Refrigerated” 
use only for Cold Pack shipments. 
• Dry ice or Cold Packs 
 


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The packing process for dry ice shipments includes the following:  
• Place all plasma tubes in storage freezer boxes, tape the sides of the boxes. 
• Place one freezer box, each separately, in a large zip-locked bag. 
• Pack the Styrofoam container with at least 7 pounds of dry ice. 
• Place the bagged freezer boxes in the middle of the bio-shipper. (You can fit as many as 
the box allows).; 
• Pack the Styrofoam container with an additional dry-ice on the top of the boxes to cover 
the top. 
• Place a copy of the Plasma Shipping Form (PS) for a single participant inside one 
biohazard bag, in the form slot (use as many forms/bags as necessary to cover the 
contents of the box to be shipped). 
• Close the lid, place all bagged shipping forms on top of the lid, and seal the shipping 
container with tape. 
• Maintain a copy of the transmittal log at the site. 
 
The packing process for cold pack shipments includes the following:  
• Place all blood tubes in storage freezer boxes, tape the sides of the boxes 
• Place one freezer box, each separately, in a large zip-locked bag. 
• Place the bagged freezer boxes in the middle of the bio-shipper (you can fit as many as 
the box allows) 
• Pack the Styrofoam container with 4-6 cold packs surrounding the boxes with the blood 
tubes. 
• Place a copy of the Plasma Shipping Form (PS) for a single participant inside one 
biohazard bag, in the form slot (use as many forms/bags as necessary to cover the 
contents of the box to be shipped). 
• Close the lid, place all bagged shipping forms on top of the lid, and seal the shipping 
container with tape. 
• Maintain a copy of the transmittal log at the site. 
 
8.2.3.4.1 Labeling Shipping Containers 
Label each shipping container with the FedEx shipping label to include the following: 
1. The study coordinator’s return address. 
2. The Testing Core Facility address: 
 
ATTN: Sylvie Roberge or Christina Koppel 
MGH, Cox-734 
100 Blossom St. 
Boston, MA 02114 
Phone: (617) 726-8143 or (617) 724-1353 
Fax: (617) 724-5841 
Pager: 14082 
Email: sylvie@steele.mgh.harvard.edu or christina@steele.mgh.harvard.edu 
 


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1. “Notice: Keep Frozen”, “Class 9 – Dry Ice” stickers or “Keep Refrigerated”, Upright arrows, 
and “Diagnostic Specimens – Not restricted, Packed in Compliance with IATA Packing 
Instruction 650”.  
 
8.2.3.4.2 Summary Shipping Task List 
The following summarizes the tasks to be completed by the site for a scheduled shipment: 
• Prepare transmittal paperwork and retain copies at the site. 
• Send a notification e-mail or FAX to the Testing Core Facility listing the items being 
shipped, including:  the FedEx tracking number, total number of plasma tubes in the 
shipment, and the expected date of arrival. Please note “Specimen Shipment—Site 
Name.” in the e-mail or FAX ‘Subject’ line.  
• Pack the plasma specimens according to instructions above.  
• Label each shipping container with the FedEx shipping label and affix all appropriate 
shipping labels. 
• Maintain a copy of the transmittal log at the site. 
 
8.2.4 Correlative Imaging 
Pending availability of funding, dynamic computed tomography (CT) scans may be offered to all 
patients with lesions that are at least 2 cm in largest diameter before the first cycle and following 
the second cycle of cabozantinib. Functional CT will be performed on a 64-slice multidetector 
row CT scanner (Volume CT, GE Healthcare, Piscataway, NJ). Data will be analyzed on a 
workstation (Advantage Windows, GE) using commercially available CT perfusion 3.0 software, 
which implements a deconvolution approach to calculate regional blood flow, blood volume, and 
permeability-surface area (PS) product. Multiple, non-overlapping regions of interest (ROI) will 
be drawn over the tumor for each of four 10 mm slices (4 cm of volume) and blood perfusion 
values will be obtained. 
 
8.2.5 Pharmacogenetic Blood Sample 
Unless prohibited by local regulations, a blood sample (collected pre-dose on Week  1 Day 1) 
may be utilized for genotyping/single nucleotide polymorphism analysis to correlate genetic 
variation with safety and tolerability or with response to cabozantinib. This may include a 
genome-wide analysis. The sponsor or designee may retain anonymized DNA samples for future 
pharmacogenetic analyses beyond the end of the study. The sample will be archived according to 
FDA regulations, EMEA’s Reflection Paper on Pharmacogenomic Samples, Testing and Data 
Handling (EMEA 2007), and will not carry personal identification (eg, Social Security number 
or name). The samples will be destroyed after 15 years or earlier if requested by the subject 
unless already anonymized prior to the request. 
 


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9. ADVERSE EVENT REPORTING REQUIREMENTS 
9.1 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. 
 
All untoward events that occur after informed consent through 30 days after the last dose of 
study treatment are to be recorded by the investigational site. This requirement includes AEs 
from unscheduled as well as scheduled visits. 
 
Assessment of the relationship of the AE 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. 
• 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. 
 
Serious Adverse Events  
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. 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is immediately life-threatening (ie, in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death). 
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
4. Results in persistent or significant disability or incapacity. 
5. Note: The term “disability” refers to events that result in a substantial disruption of a 
subject’s ability to conduct normal life function. 
6. Is a congenital anomaly or birth defect. 
7. Is an important medical event (IME). Note: The term “important medical event” refers to an 
event that, based upon appropriate medical judgment, may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or require 
intervention to prevent one of the other serious outcomes listed under the definition of 
Serious Adverse Event. Examples of IMEs include intensive treatment in an emergency room 
or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of product dependency or product abuse. 


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Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
should be documented to the extent that information is available. 
• This report must be submitted by the study site to Exelixis or designee within 24 hours, 
even if it is not felt to be drug related. Email: drugsafety@exelixis.com; Fax 650-837-
7392 
• The investigator agrees to provide supplementary information requested by the Exelixis 
Drug Safety personnel or designee. 
• Pregnancy, 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. 
 
Regulatory Reporting 
All serious unexpected adverse drug reactions (unexpected related SAEs) must be reported to the 
Food and Drug Administration (FDA) by the investigator as required by 21 CFR 312.32. 
• These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form). 
 
The final MedWatch Form must be submitted by the study site to Exelixis at the time of 
submission to the FDA to allow Exelixis time to cross-report to Exelixis’ IND. Email: 
drugsafety@exelixis.com; Fax 650-837-7392 
 
Other Safety Considerations 
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. 
 
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. 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. 
 
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. 
 


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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 last dose of 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 last dose of study treatment. 
The status of all other continuing AEs will be documented as of 30 days after the last dose of 
study treatment. 
 
STATISTICAL CONSIDERATIONS 
Analysis Population 
 
Safety Population 
The safety population will consist of all subjects who receive any amount of study treatment. 
 
Safety Analysis 
Safety will be assessed by evaluation of AEs. All safety analyses will be performed using the 
safety population. 
 
Adverse Events 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). 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 v. 4.0. Listings of AEs will be provided. 
 
10. DATA AND SAFETY MONITORING 
10.1 
Data Reporting 
10.1.1 Method 
The QACT will collect, manage, and monitor data for this study. 
 
10.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or electronic) to the 
QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 


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Form 
Submission Timeline 
Follow up/Survival Form 
Within 14 days of the protocol defined follow 
up visit date or call 
 
10.2 
Safety Meetings 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Principal Investigator and 
study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data. 
Information to be provided to the committee may include:  up-to-date participant accrual; current 
dose level information; all Grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring within 30 days for Phase I or II protocols; for gene transfer 
protocols, summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other information (e.g. 
scans, laboratory values) will be provided upon request.  
 
10.3 
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements. 
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion.  
 
11. REGULATORY CONSIDERATIONS 
11.1 
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by a properly constituted IRB governing each study 
location. 
 
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The 
Principal Investigator (or Protocol Chair) will disseminate protocol amendment information to 
all participating investigators. 
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 


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11.2 
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file. 
 
11.3 
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice: 
• ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm  
• US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html 
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html 
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html 
• State laws 
• Institutional research policies and procedures www.dfhcc.harvard.edu/clinical-research-
support/clinical-research-operations-cro/policies-and-procedures 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.  
 
11.4 
Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays. 
 


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11.5 
Records Retention 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
 
11.6 
Multi-center Guidelines 
N/A. 
 
11.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
N/A. 
 
12. STATISTICAL CONSIDERATIONS 
12.1 
Study Design 
 
12.1.1 Primary Endpoint 
The primary efficacy endpoint is the objective response rate (ORR). ORR is defined using the 
RECIST criteria as the proportion of subjects with a confirmed CR or confirmed PR. The point 
estimate of the ORR with a 90% confidence interval based on the exact binomial distribution 
will be presented. 
 
12.1.2 Secondary Endpoints 
12.1.2.1 
Progression-free survival will be defined as the time from administration of the initial 
dose of cabozantinib to evidence of radiographic progression as defined by RECIST criteria or 
death from any cause without evidence of disease progression, whichever occurs first. Cases 
with incomplete follow up or without adequate disease evaluations will be censored at date last 
documented to be progression free. Kaplan Meier estimates of progression-free survival rates 
will be calculated along with their corresponding 95% confidence intervals. Cox proportional 
hazards regression modeling of PFS will be used to assess the effect of cabozantinib on 
progression-free survival while controlling for other confounders. Overall survival determined 
from the time of drug administration to time of death. 
 
12.1.2.2 
Overall survival will be defined as the time from administration of the initial dose of 
cabozantinib until death from any cause. 
 


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12.1.2.3 
Biologic correlative studies of target inhibition (see above) 
All tissue and circulating biomarkers will be correlated with clinical outcome in collaboration 
with our statistician. For imaging, multiple, non-overlapping regions of interest (ROI will be 
drawn over the tumor for each of four 10 mm slices (4 cm of volume) and blood perfusion values 
will be obtained. Descriptive statistics will be provided for all outcome measurements and 
goodness of fit tests (e.g. Chi-square, Kolmogorov Smirnov) will be conducted to assess the 
distribution of the changes in functional imaging. As appropriate, we will use parametric (t-test) 
or nonparametric (Wilcoxon Rank-Sum) tests to compare between the two groups of patients 
stratified by response and PFS status. To test the prognostic effect of changes in these parameters 
on OS and PFS, we will utilize the Cox proportional hazards model. In addition, comparison to 
RECIST based measurement, tumor volume and tumor density will be performed by using well 
established protocols in our department to evaluate the most sensitive image biomarker of 
monitoring response and predicting clinical outcome. 
 
12.1.2.4 
Tolerability and safety analysis 
Preliminary Phase I data revealed excellent tolerability. For the safety analysis, all enrolled 
patients who receive at least one dose of cabozantinib will have information collected on adverse 
events, which will be summarized by dose, severity as assessed by the Common Toxicity Criteria 
for Adverse Events (CTCAE), v. 4.0 and relationship to Study Drug. 
 
12.2 
Rationale for Sample Size 
The data from recent phase II clinical trials of agents targeting the VEGF or mTOR pathways has 
guided our trial design and sample size calculation. The Phase II trial of the VEGF inhibitor, 
bevacizumab in patients with carcinoid tumors revealed a response rate of 18% [4]. A Phase II 
trial of the mTOR inhibitor, everolimus in patients with low grade neuroendocrine tumors 
demonstrated response rates of 20% [37]. Similarly, a phase II trial of sunitinib performed in 
neuroendocrine tumors demonstrated a response rate of 16.7% in pancreatic neuroendocrine 
tumors and 2.4% in patients with carcinoid tumors [3]. More recently, Phase III trials of both 
sunitinib and everolimus have been published in patients with pancreatic neuroendocrine tumors, 
demonstrating lower overall response rates of 5% for everolimus (2% with placebo) and 9.3% 
for sunitinib (0% for placebo) [38, 39]. Notably, despite the low response rate observed with 
these targeted agents to date, 64% of patients receiving everolimus (versus 21% in placebo), and 
a large, but unreported percentage of patients receiving sunitinib demonstrated tumor shrinkage 
that did not meet partial response criteria.  
 
Patients will be stratified depending upon whether they have a pancreatic neuroendocrine tumor 
or carcinoid tumor. For both subgroups, we hypothesize that cabozantinib will have a true 
response rate of greater than or equal to 12%, while the null hypothesize posits that the response 
rate will be ≤2%. The 12% response rate was selected on the basis of the response rate in the 
recent Phase III sunitinib trial in pancreatic neuroendocrine tumors, as well as the experience 
with multiple targeted agents in several phase II trials in patients with carcinoid tumors and 
pancreatic neuroendocrine tumors. A sample size of 35 achieves >80% power to detect a 
difference of 10% using a one-sided binomial test, with type I error of 3% and the population 
proportion under the null hypothesis is 2%. Therefore, 3 or more responders would be necessary 
to reject the null hypothesis. For efficacy evaluation of the study, all treated patients will be 
included when calculating the response rate. Therefore the overall sample size is anticipated to 


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Page 72 of 77 
be approximately 35 subjects for each tumor type, or 70 patients in total. Study patients will 
continue to be followed until progression or death, allowing us to capture all patients for this 
analysis. 
 
Given the data above demonstrating tumor shrinkage and PFS benefit in patients treated with 
sunitinib or everolimus without impressive overall response rates, an overall response rate of 
2%-12% would still be consistent with cabozantinib having activity in neuroendocrine tumors. 
As such, progression-free survival will be examined as one of the secondary endpoints, and we 
have not included a two-phase design in this protocol. 
 
12.3 
Reporting and Exclusions 
12.3.1 Evaluation of toxicity 
All participants will be evaluable for toxicity from the time of their first treatment. Participants 
not completing 2 cycles of therapy due to reasons unrelated to study drugs will not be evaluated 
for DLT, but will be replaced. 
 
12.3.2 Evaluation of response 
All participants included in the study will be assessed for response to treatment, even if there are 
major protocol treatment deviations. Each participant will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 
5) early death from malignant disease, 6) early death from toxicity, 7) early death because of 
other cause, or 9) unknown (not assessable, insufficient data). By arbitrary convention, 
category 9 usually designates the "unknown" status of any type of data in a clinical database. 
 
13. PUBLICATION PLAN 
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 prior to submission and also comply withy any provisions regarding 
publication as 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 according to 
guidelines established by the International Committee of Medical Journal Editors. 


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33. 
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15. APPENDICES 
 
Appendix A - Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 


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Appendix B – Cabozantinib Tablets 
 
Investigational Treatment: Cabozantinib tablets 
 
Chemical Name: N--N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-
hydroxybutanedioate 
 
Exelixis internal number: XL184 
 
Exelixis will provide each investigator with adequate supplies of cabozantinib, which will be 
supplied as 100 mg and 20 mg yellow film coated tablets. 100 mg tablets are caplet-shaped, and 
the 20 mg tablets are round. The components of the tablets are listed in Table 1. 
 
Table 1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
XL-184 Drug Substance (25% drug load as free base) 
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