Clinical trial NCT03964337
Conditions: Prostate Cancer Prostate Cancer Adenocarcinoma Non-Metastatic
Sponsor: Duke University
Start date: 2020-03-17; Completion date: 2021-06-04
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective, randomized, open-label, phase II trial of cabozantinib in subjects with untreated, high risk prostate cancer undergoing radical prostatectomy. This multicenter study will enroll 30 subjects. Duke is the lead site for this trial. There will be a second site selected TBD.

Patients will be assigned (first 9 subjects only) or randomized 2:1 to either: (1) cabozantinib 40 mg by mouth daily for 4 weeks, followed by a 2 week drug washout period before prostatectomy (n = 20), or (2) immediate prostatectomy within 12 weeks of registration (n = 10). The first 9 subjects (6 subjects assigned to cabozantinib treatment, 3 subjects assigned to immediate prostatectomy) will constitute the Safety Lead-In Cohort, which will be only accrued at Duke. After six subjects have received cabozantinib and completed the 57-85 day safety visit without triggering a stopping rule, subjects may be accrued at the ex-Duke site.

The primary goal is to compare pathologic apoptotic indices (cleaved caspase-3) in prostatectomy specimens from patients who undergo immediate prostatectomy (controls) versus those who receive with cabozantinib followed by prostatectomy. The secondary objective is to conduct immune phenotypic profiling on the peripheral blood and tumor microenvironment in prostatectomy specimens from both groups. A statistical analysis will be used to compare the apoptotic indices between the two groups.

Detailed description:

Arms: arm 1: Experimental group will received cabozantinib for 4 weeks, followed by a 2 week drug washout before a prostatectomy. arm 2: Control group will receive an immediate prostatectomy.
Interventions: intervention 1: Cabozantinib intervention 2: Radical Prostatectomy
Intervention descriptions: intervention 1: Cabozantinib 40 mg by mouth daily for 4 weeks. intervention 2: Radical prostatectomy as part of routine medical care.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 A PHASE II, OPEN-LABEL RANDOMIZED STUDY OF 
IMMEDIATE PROSTATECTOMY VS. CABOZANTINIB 
FOLLOWED BY PROSTATECTOMY IN MEN WITH HIGH-
RISK PROSTATE CANCER (SPARC) 
NCT03964337  
  
   
 
 
 
 
Sponsor: 
PI – Duke Cancer Institute 
Funding Source: 
Study Drug Source: 
Exelixis 
Exelixis 
Protocol Source: 
PI – Duke Cancer Institute 
Duke IRB#: 
IND#: 
Exelixis#: 
Pro00101042 
Exempt 
IST 64 
 
 
 
Principal Investigator 
Michael Harrison, MD 
DUMC 103861 
Durham NC 27710 
michael.harrison@duke.edu 
Phone (919) 668-4667 
Fax (919) 660-0178 
 
  
 
Urology Co-Principal Investigator 
Michael Abern, MD 
michael.abern@duke.edu  
 
Statistician 
Yuan Wu, PhD 
yuan.wu@duke.edu 
 
 
 
Version 1.0 
 
 04 February 2019 
 
Version 6.1 
 
01 November 2021 
Version 1.1 
 
11 March 2019 
Version 2.0 
 
27 June 2019 
Version 3.0  
 
19 August 2019 
Version 4.0 
 
01 October 2019 
Version 4.1 
 
05 November 2019 
Version 5.0 
 
26 October 2020 
Version 6.0 
 
10 January 2021 


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Responsible Study Personnel 
Principal Investigator 
Michael Harrison, MD 
michael.harrison@duke.edu 
 
Multi Site Management 
Carol Winters, RN, OCN, CCRC  
Nancy Hight, BA, ACRP-CP        
2424 Erwin Rd, Hock Plaza 7045 
Durham, NC 27705 
Tel: (919)668-8577, (919)668-3018  Fax:  (919)668-7117 
GU-multisite@duke.edu 
 
 
 
 
 
External Sites Participating in This Study 
TBD 
 
 
 
 
 
 
 
 
 
 


  
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Table of Contents 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................ 3 
2 
INTRODUCTION ............................................................................................................................................ 3 
2.1 
Introductory statement .................................................................................................................... 3 
2.2 
Study Rationale .................................................................................................................................. 5 
2.3 
Hypotheses ......................................................................................................................................... 6 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 7 
4 
STUDY DESIGN ............................................................................................................................................. 9 
4.1 
Overall Design .................................................................................................................................... 9 
4.2 
Correlative studies .......................................................................................................................... 10 
4.3 
Dose .................................................................................................................................................... 13 
4.4 
Prostatectomy .................................................................................................................................. 13 
4.5 
Definition of evaluable subjects .................................................................................................. 13 
5 
Target POPULATION .................................................................................................................................. 14 
5.1 
Inclusion Criteria ............................................................................................................................. 14 
5.2 
Exclusion Criteria ............................................................................................................................ 14 
6 
study assessments ....................................................................................................................................... 16 
6.1 
Schedule of EVENTS (SoE) ........................................................................................................... 18 
6.2 
informed consent ............................................................................................................................ 22 
6.3 
screening- both arms ..................................................................................................................... 22 
6.4 
subject registration AND ENROLLMENT................................................................................... 23 
6.5 
lead site registration And ENROLLMENT ................................................................................. 23 
6.6 
institutional registration ................................................................................................................ 24 
6.7 
TREATMENT PERIOD ..................................................................................................................... 24 
6.8 
Day 1 - ARM A only ........................................................................................................................... 24 
6.9 
Day 15 - ARM A ONLY .................................................................................................................... 24 
6.10 
Day 29 - ARM A only ....................................................................................................................... 25 
6.11 
Day 43 - ARM A only ....................................................................................................................... 25 
6.12 
Day 50 - ARM A only ....................................................................................................................... 25 
6.13 
Safety follow up visit - ARM A only ............................................................................................ 26 
6.14 
Day 1 - ARM B only ......................................................................................................................... 26 
6.15 
Relapse Free Survival follow up period ..................................................................................... 26 
6.16 
end of Study ...................................................................................................................................... 27 
7 
STUDY INTERVENTION ............................................................................................................................ 27 
7.1 
Composition, Formulation, and Storage ................................................................................... 27 
7.2 
Investigational Treatment: Cabozantinib .................................................................................. 27 
7.3 
cabozantinib administration ......................................................................................................... 27 
7.4 
cabozantinib dose modifications, interruptions, and discontinuation ......................................... 28 
7.4.1 
Cabozantinib Dose Reinstitution and Reescalation .................................................. 30 
7.4.2 
Guidelines for Management of Potential Adverse Events ....................................... 30 
8 
concomitant Therapy ................................................................................................................................... 40 
8.1 
Allowed, Prohibited and restricted therapies ........................................................................... 40 
8.2 
Potential Drug Interactions with Cabozantinib ........................................................................ 42 
8.3 
Study Treatment Accountability .................................................................................................. 44 


  
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9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 44 
9.1 
Discontinuation of Study Intervention ....................................................................................... 44 
10 
SAFETY ......................................................................................................................................................... 44 
10.1 
Adverse Events and Laboratory Abnormalities ...................................................................... 44 
10.1.1 
Adverse Events (AEs) ................................................................................................... 44 
10.1.2 
Serious Adverse Events (SAEs) .................................................................................. 45 
10.1.3 
RelatioSHip to Study Treatment .................................................................................. 46 
10.1.4 
Serious Adverse Event Reporting ............................................................................... 46 
10.1.5 
Regulatory Reporting ..................................................................................................... 47 
10.2 
Other Safety Considerations ............................................................................................................ 47 
10.2.1 
Laboratory Data .............................................................................................................. 47 
10.2.2 
Pregnancy/Lactation Exposure .................................................................................... 47 
10.2.3 
Medication Errors/Overdose ......................................................................................... 48 
10.2.4 
Follow-Up of Adverse Events ....................................................................................... 48 
10.3 
Safety Monitoring ............................................................................................................................... 48 
11 
STATISTICAL CONSIDERATIONS .......................................................................................................... 48 
11.1 
Statistical Methods ............................................................................................................................ 48 
12 
Data Quality  ASSURANCE ........................................................................................................................ 49 
13 
Study Committees ........................................................................................................................................ 49 
13.1 
Monitoring ........................................................................................................................................... 50 
13.2 
Safety Oversight Committee ............................................................................................................ 50 
13.3 
Data Management and Processing ................................................................................................. 51 
13.3.1 
Study Documentation .................................................................................................... 51 
13.3.2 
Case Report Forms (CRFs) .......................................................................................... 51 
13.3.3 
Data Management Procedures and Data Verification .............................................. 51 
13.3.4 
Study Closure ................................................................................................................. 52 
14 
Administrative and ETHICAL considerations ........................................................................................... 52 
14.1 
Local Regulations .............................................................................................................................. 52 
14.2 
Informed Consent .............................................................................................................................. 52 
14.3 
Institutional Review Board/Ethics Committee ................................................................................ 53 
14.4 
Protocol Amendments ....................................................................................................................... 53 
14.5 
Records Retention ............................................................................................................................. 53 
14.6 
Conflict of Interest .............................................................................................................................. 54 
14.7 
CONDITIONS FOR MODIFYING THE PROTOCOL ................................................................... 54 
14.8 
CONDITIONS FOR terminating THE study ................................................................................... 54 
14.9 
STUDY DOCUMENTATION AND RECORD-KEEPING ............................................................. 54 
14.9.1 
investigator’s files and retention of documents .......................................................... 54 
14.9.2 
source documents and background data ................................................................... 55 
14.9.3 
audits and inspections ................................................................................................... 55 
14.9.4 
case report forms ........................................................................................................... 55 
14.10 
data and safety Monitoring the study .............................................................................................. 56 
14.11 
confidentiality OF TRIAL DOCUMENTS AND SUBJECT RECORDS ...................................... 56 
14.12 
PUBLICATIONS OF DATA AND PROTECTION OF TRADE SECRETS ................................. 56 
15 
abbreviations ................................................................................................................................................. 58 
16 
references ...................................................................................................................................................... 59 
17 
AppendiCES .................................................................................................................................................. 61 
17.1 
Appendix A:  ECOG and Karnofsky Performance Scale Criteria ............................................... 61 


  
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PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A  Phase II, open-label randomized study of immediate prostatectomy vs. 
cabozantinib followed by prostatectomy in men with high-risk prostate 
cancer. 
Study Description: 
Subjects will be assigned (Safety Lead-In Cohort) or randomized  to either: 
(1) cabozantinib 40 mg PO daily for 4 weeks, followed by a 2 week drug 
washout period before prostatectomy (n = 20), or (2) immediate 
prostatectomy (n = 10). The Safety Lead-In Cohort will consist of 6 
subjects receiving cabozantinib prior to prostatectomy. The randomized 
portion will consist of the remaining cabozantinib prior to prostatectomy 
subjects (n=14) and immediate prostatectomy subjects (n=10).  
Primary Objective: 
 
To compare pathologic apoptotic indices (cleaved caspase-3) in 
prostatectomy specimens from patients who undergo immediate 
prostatectomy (controls) versus those treated with cabozantinib followed 
by prostatectomy. 
Secondary Objective: 
To conduct immune phenotypic profiling on the peripheral blood and 
tumor microenvironment in prostatectomy specimens from patients who 
undergo immediate prostatectomy versus those treated with cabozantinib 
prior to prostatectomy.  
Exploratory Objectives: 
1. To estimate the pathologic complete response rate (pCR) and 
≤pathologic T2 (≤pT2) rate in each arm.  
2. To evaluate relapse-free survival in each arm. 
3. To compare apoptosis (TUNEL), proliferation (Ki-67), and 
microvessel density (CD31) indices in prostatectomy specimens 
from patients who undergo immediate prostatectomy versus 
those treated with cabozantinib prior to prostatectomy.  
4. To measure expression levels of c-MET, VEGF, and HGF, as well as 
activation status of c-MET in prostate tissue.  
5. To describe changes in plasticity signaling markers associated with 
prostate tumors, including vimentin, AR, SNAIL, AXL, and N-
cadherin with cabozantinib exposure.  
6. To evaluate PTEN and p53 genomic and protein expression status 
in tumor tissue 
7. To demonstrate that cabozantinib is safe and tolerable in patients 
undergoing radical prostatectomy.  
8. To demonstrate that surgery is safe and feasible in patients 
undergoing treatment with cabozantinib. 
9. To collect plasma angiome samples (multiplex ELISA) for analysis 
and correlation with primary and key secondary endpoints.  
10. To describe gene expression patterns (in particular those 
associated with apoptosis, androgen receptor signaling, c-MET 
activation, and a c-MET-specific endocytosis panel) correlated 
with cabozantinib administration using RNA sequencing.  


  
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11. To explore changes in serum and intratumoral androgen 
concentrations related to cabozantinib treatment.  
12. To collect cell-free DNA (cfDNA) for analysis and correlation with 
primary and key secondary endpoints.  
Endpoints: 
Primary:  Apoptotic index by cleaved caspase-3 
 
Secondary: Description of immune biomarkers, including: 
• 
Immune phenotyping of paired peripheral blood and tumor 
tissue: Myeloid-derived suppressor cells (MDSCs), neutrophils, M1 
macrophages, and M2 macrophages in tumor tissue 
• 
Immunohistochemical (IHC) analysis of CD8+, programmed death 
ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4), interleukin-1 receptor antagonist (IL-1RA) and B7H3 in 
tumor tissue 
• 
Neutrophil chemotactic factors (CXCL12 and HMGB1) and MDSC-
promoting cytokines (CCL5, CCL12, CD40) in tumor tissue  
 
Exploratory: 
1. Rates of pCR and ≤pT2 
2. Relapse-free survival rate at 3 years 
3. Quantification of TUNEL, Ki-67, and CD31 staining 
4. Quantification of c-MET, VEGF, HGF, and activated c-MET in 
prostatectomy tissue 
5. Correlation of vimentin, AR, SNAIL, AXL,  and N-cadherin with 
cabozantinib exposure 
6. Measurement of PTEN and p53 genomic and protein expression 
status in tumor tissue 
7. Adverse events by CTCAE v5.0, dose intensity of cabozantinib 
8. Blood loss at prostatectomy and duration of hospital stay 
9. Angiome biomarkers 
10. Gene expression patterns using RNA sequencing 
11. Serum and intratumoral androgen concentrations 
12. Alterations in cfDNA 
Study Population: 
Eligible patients will have histologic evidence of adenocarcinoma of the 
prostate and be deemed candidates for curative radical prostatectomy.  
They will have intermediate-or high-risk, clinically localized disease and 
have not received prior treatment for prostate cancer.  
Phase: 
Phase II 
Description of 
Sites/Facilities Enrolling 
Participants: 
This is a multicenter study of 30 evaluable subjects. Duke is the lead site 
for this trial. Subjects who do not receive 21 out of 28 days of planned 
study drug administration and proceed to radical prostatectomy within 14 
(+3) days of their last dose of study drug (Arm A only) or do not proceed 
to radical prostatectomy (Arm B only) will be replaced. There will be a 
second site selected TBD.  
Description of Study 
Intervention: 
Patients will be assigned (Safety Lead-In Cohort) or randomized to either: 
(1) cabozantinib 40 mg PO daily for 4 weeks, followed by a 2 week drug 


  
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washout period before prostatectomy (n = 20), or (2) immediate 
prostatectomy within 12 weeks of registration (n = 10). The Safety Lead-In 
Cohort will consist of 6 subjects receiving cabozantinib prior to 
prostatectomy. The randomized portion will consist of the remaining 
cabozantinib prior to prostatectomy subjects (n=14) and immediate 
prostatectomy subjects (n=10). 
Study Duration: 
We estimate an accrual period of 1 year, with last patient last visit at 22 
months and final report at 25 months. 
Participant Duration: 
Screening Phase:  Six weeks (42 days) 
Treatment Phase (including prostatectomy) 
• 
Arm A (cabozantinib):  up to 85 days 
• 
Arm B (immediate prostatectomy): 1 day 
Follow-up Phase: 3 years post-prostatectomy for relapse-free survival 
1.2 
SCHEMA 
   
 
 
 
2 
 
INTRODUCTION 
2.1 
INTRODUCTORY STATEMENT  
Prostate cancer is the most common cancer and second leading cause of cancer death in men, with 
approximately 165,00 new cases and 29,000 deaths in 2018 1.  Radiotherapy and radical prostatectomy 
have been the gold standards for primary treatment of localized disease.  Androgen deprivation therapy 
(ADT; lowering of serum testosterone to <50 ng/dl) is used for localized prostate cancer in combination 
with radiotherapy, biochemically recurrent (M0) prostate cancer after primary therapy (both with and 


  
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without radiotherapy), and for metastatic castration-sensitive prostate cancer (mCSPC). In contrast, 
neoadjuvant ADT has not shown benefit over prostatectomy alone and adjuvant ADT post-
prostatectomy is controversial. After prostate cancer recurrence ADT is typically continued 
intermittently or continuously life-long 2. Both docetaxel and abiraterone acetate plus prednisone have 
recently demonstrated benefits when added to ADT for mCSPC 3. Enzalutamide and apalutamide have 
both been approved for M0 castration resistant prostate cancer (CRPC) 4. Five therapies, including an 
immunotherapy, two androgen receptor signaling inhibitors, two cytotoxic chemotherapies, and a 
radiopharmaceutical, are approved for metastatic (M1) CRPC:  sipuleucel-T, abiraterone plus 
prednisone, enzalutamide, docetaxel, cabazitaxel, and radium-223 5.  
Aside from sipuleucel-T, which improves overall survival without inducing measureable tumor 
regression, there are no immunotherapies approved for prostate cancer.  Immune checkpoint inhibitors 
(ICIs) have demonstrated substantial benefits and have been approved in multiple other solid tumors; 
however, they have not shown benefit in prostate cancer:  a large phase II study of the PD-1 inhibitor 
pembrolizumab demonstrated an overall response rate of just 5% 6 and two phase III studies of the 
CTLA-4 inhibitor ipilimumab failed to meet their primary endpoint of improving overall survival 7,8. 
However, in both studies there were other signs of antitumor activity in a specific subset.  The prevailing 
conventional wisdom is that prostate cancer is generally a “cold” tumor and so, for ICIs to demonstrate 
benefit, either subsets of “hot” tumors must be selected or ICIs must be combined with other therapies 
that render the tumor more “hot” by affecting different parts of the cancer immunity cycle. Preclinically, 
cabozantinib has been shown to target myeloid-derived suppressor cells (MDSCs) and synergize with ICIs 
(cocktail of anti-PD-1 and anti-CTLA4 antibodies) in a CRPC model 9. Cabozantinib has also been 
demonstrated to eradicate tumors in a PTEN/p53-deficient murine prostate cancer model through 
activation of neutrophil-mediated antitumor innate immunity 10. Cabozantinib has demonstrated single 
agent activity in prostate cancer in a phase II study 11.  Cabozantinib was also tested in a phase III 
randomized (2:1) trial in men with progressive mCRPC after docetaxel and abiraterone plus prednisone 
and/or enzalutamide (N=1,028). Although cabozantinib failed significantly improve overall survival, its 
activity was demonstrated as measured by bone scan response, radiographic progression free survival, 
symptomatic skeletal related events, circulating tumor cell conversions, and bone biomarkers 12. Thus, 
since neither cabozantinib nor ICIs have improved overall survival alone, cabozantinib may fill an unmet 
need in prostate cancer by synergizing with ICIs.   
Cabozantinib (Cabometyx) is approved for treatment of patients with advanced renal cell carcinoma 
(RCC) and patients with hepatocellular carcinoma (HCC) who have been previously treated with 
sorafenib13. Cabozantinib (Cometriq) is approved for treatment of patients with progressive, metastatic 
medullary thyroid cancer (MTC)14. Cabometyx is supplied as a tablet and Cometriq is supplied as a 
capsule; the two are not equivalent. The most commonly reported (≥ 25%) adverse reactions with 
cabozantinib (Cabometyx) in RCC studies are: diarrhea, fatigue, nausea, decreased appetite, 
hypertension, palmar-plantar erythrodysesthesia (PPE), weight decreased, vomiting, dysgeusia, and 
stomatitis15.  In the COMET-1 study in heavily pre-treated mCRPC patients, the most common (≥ 25%) 
adverse events with cabozantinib were decreased appetite, nausea, diarrhea, fatigue, vomiting, 
asthenia, decreased weight, constipation, anemia, PPE syndrome, hypertension, dysphonia, and 


  
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dysgeusia 12. SAEs were reported by 62% of patients in the cabozantinib arm. The following SAEs 
occurred at an incidence of at least 2% higher with cabozantinib compared with prednisone 
(comparator): pulmonary embolism (6.2% v 0.9%), vomiting (4.1% v 1.8%), fatigue (2.9% v 0.9%), and 
dehydration (2.9% v 0.3%). Study drug discontinuations because of AEs were reported for 33% of 
patients in the cabozantinib group. AEs leading to dose reductions or interruptions were reported for 
88% of patients in the cabozantinib group, and AEs that led to dose reductions were reported for 67% of 
patients. Grade 5 AEs occurring within 30 days of the last study drug dose were reported in 15% of 
patients in the cabozantinib group and were most commonly considered disease related. The authors 
concluded that the safety data from the COMET-1 trial were consistent with those observed in earlier 
trials of cabozantinib in mCRPC, with no new or unexpected AEs observed.  
 
2.2 
STUDY RATIONALE  
The COMET-1 study of cabozantinib in heavily pre-treated metastatic castration-resistant prostate 
cancer (mCRPC) patients did not meet its primary endpoint of improved overall survival compared with 
prednisone; however, cabozantinib did demonstrate activity in improving bone scan response, 
radiographic progression-free survival, symptomatic skeletal events, circulating tumor cell conversions, 
and bone biomarkers.12 Furthermore, in subgroup analysis the point estimate of the unstratified hazard 
ratio for death for those with visceral metastases favored cabozantinib (HR=0.77; 95% CI: 0.54 to 1.09). 
Improved benefit of cabozantinib in visceral disease subgroups has also been demonstrated in two 
randomized trials in metastatic renal cell carcinoma.16,17 While much of the development of cabozantinib 
in prostate cancer focused on its effects in bone,18-20 we hypothesize that understanding its effects in 
soft tissue may contribute novel insights and shed light on a possible path forward for further 
development of cabozantinib in prostate cancer. 
 
Neoadjuvant or pre-surgical studies permit in vivo assessment of response and mechanism of action 
after a short window of treatment.21 We have demonstrated the safety and feasibility of using the 
VEGFR TKI sunitinib in the neoadjuvant or pre-prostatectomy setting.22 Compared with soft tissue and 
bone biopsies, such an approach has the advantage of providing more plentiful amounts of whole-tumor 
and stromal tissue for analysis. Cabozantinib may function in prostate cancer partly through modulation 
of critical stromal interactions within the tumor microenvironment.  
 
Study of the effects of cabozantinib in early stage prostate cancer, specifically in soft tissue 
prostatectomy specimens, may complement the knowledge gained from ongoing and completed studies 
in advanced disease. Other groups are currently studying cabozantinib in advanced prostate cancer 
(mCRPC), with the goals of: (1) determining the lowest effective dose of cabozantinib and correlating 
bone scan changes with MR imaging (Matthew R. Smith, MD, PhD, et al.); (2) developing cabozantinib 
biomarkers from bone and soft tissue biopsies and comparing 11C-acetate and 18F-fluoride PET/CT to 
monitor cabozantinib treatment response (Beatrice Knudsen and Evan Yu, PCF Creativity Award; Philip 
Febbo, Tia Higano et al., PCF Challenge award); and (3) investigating bone – tumor interactions and the 
development of resistance (Leland Chung et al., PCF Challenge award).  


  
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Understanding the effects of cabozantinib in soft tissue prostatectomy specimens may also confirm 
important in vitro and in vivo observations in prostate cancer models, providing rationale for novel 
combinations with cabozantinib. For example, emerging data in a chimeric mouse model of mCRPC 
suggest that cabozantinib may inactivate myeloid derived suppressor cells (MDSCs) and synergize with 
immune checkpoint blockade (specifically, anti-CTLA4 + anti-PD-1) to overcome de novo resistance.9 
Mechanistically, this stemmed from upregulation of interleukin-1 receptor antagonist and suppression 
of MDSC-promoting cytokines secreted by prostate cancer cells. A separate study in a pTEN/p53-
deficient murine model of advanced prostate cancer has demonstrated that cabozantinib induces tumor 
clearance by triggering a neutrophil-mediated anti-cancer innate immune response.10 Cabozantinib also 
affects M1 macrophage polarization mouse models of prostate cancer.23 Finally, an in vivo and in vitro 
study suggested synergy between cabozantinib and the androgen receptor (AR) signaling inhibitor 
enzalutamide in CRPC.24 Data like these must be confirmed in prospective clinical trials in humans with 
prostate cancer.  
 
The HGF/cMET pathway appears to be generally immunosuppressive. MET is expressed by immature 
CD14+ monocytes which can acquire an immunosuppressive phenotype when exposed to HGF secreted 
by tumor stromal and/or and mesenchymal stem cells. Neutralization of HGF secretion by mesenchymal 
stem cells reverses this suppression of effector T-cell proliferation and triggers a shift to a TH1-activated 
T-cell phenotype.25,26 Also, HGF secreted by tumor cells and by mesenchymal stem cells can result in the 
expansion of MDSCs (harboring cMET). This effect is likely mediated, at least in part, by phosphorylation 
of STAT3 (part of the HGF/cMET signal transduction pathway).25 APC, such as dendritic cells, also express 
cMET which can be activated by HGF subsequently suppressing APC function, including both antigen 
presenting capacity and antigen-dependent T-cell responses both in vitro and in vivo.27,28  cMET on 
tumor cells is associated with VEGF-A production which also has immunosuppressive properties. 
In order to provide rationale for combination of cabozantinib with novel immunotherapies and AR-
targeted therapies, a hypothesis-generating study of the effects of cabozantinib in soft tissue is clearly 
warranted. Therefore, with the goal of determining the soft tissue, stromal, cellular, immunologic, 
molecular and genetic effects of cabozantinib in patients with clinically localized prostate cancer, we 
propose the following prospective, randomized, open-label, phase II trial of cabozantinib in subjects 
with untreated, high risk prostate cancer prior to undergoing radical prostatectomy. 
2.3 
HYPOTHESES 
We hypothesize that in those treated with cabozantinib followed by prostatectomy compared with 
immediate prostatectomy: 
1. Apoptotic index (cleaved caspase-3) will be 2-fold higher in prostate cancer tissues following 
cabozantinib as compared with men proceeding to immediate radical prostatectomy. 
2. Infiltration of neutrophils and release of neutrophil chemotactic factors (CXCL12 and HMGB1) 
will be 2-fold higher in prostate cancer tissues following cabozantinib as compared with men 
proceeding to immediate radical prostatectomy.  


  
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3. Interleukin-1 receptor antagonist will be upregulated and MDSC-promoting cytokines will be 
suppressed in prostate cancer tissues following cabozantinib as compared with men proceeding 
to immediate radical prostatectomy. 
4. The M1 macrophage population will be decreased without affecting the M2 macrophage 
population in prostate cancer tissues following cabozantinib as compared with men proceeding 
to immediate radical prostatectomy. 
5. Pathologic complete responses (pCRs) will be observed in the minority population of men 
harboring the TP53 mutant / PTEN null localized prostate cancer and will be associated with 
myeloid immune cell activation in the prostate and peripheral blood.  
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To compare pathologic apoptotic 
indices in prostatectomy specimens 
from patients who undergo 
immediate prostatectomy versus 
those treated with cabozantinib 
followed by prostatectomy. 
 
Apoptotic index by cleaved caspase-3 
To evaluate the activity 
of cabozantinib in 
prostate tumors by 
understanding its 
ability to cause cell 
death. 
Secondary 
 
 
To conduct immune phenotypic 
profiling on the peripheral blood 
and tumor microenvironment in 
prostatectomy specimens from 
patients who undergo immediate 
prostatectomy versus those 
treated with cabozantinib prior to 
prostatectomy.  
Description of immune biomarkers, 
including: 
• 
Immune phenotyping of 
paired peripheral blood and 
tumor tissue: Myeloid-
derived suppressor cells 
(MDSCs), neutrophils, M1 
macrophages, and M2 
macrophages in tumor tissue 
• 
Immunohistochemical (IHC) 
analysis of CD8+, 
programmed death ligand-1 
(PD-L1), cytotoxic T-
lymphocyte-associated 
protein 4 (CTLA-4), 
interleukin-1 receptor 
antagonist (IL-1RA) and B7H3 
in tumor tissue 
• 
Neutrophil chemotactic 
factors (CXCL12 and HMGB1) 
and MDSC-promoting 
To confirm pre-clinical 
observations,9,10,23 
understand the effects 
of cabozantinib on the 
immune 
microenvironment, and 
evaluate the rationale 
for combination of 
cabozantinib with 
immune checkpoint 
inhibitor (ICI) therapy.  


  
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
cytokines (CCL5, CCL12, 
CD40) in tumor tissue  
Exploratory  
 
 
1. To estimate the pathologic 
complete response rate (pCR) 
and ≤pathologic T2 (≤pT2) 
rate in each arm.  
1. Rates of pCR and ≤pT2 
 
1. To understand the 
efficacy of 
cabozantinib as 
measured by key 
clinical pathologic 
endpoints. 
2. To evaluate relapse-free 
survival in each arm. 
2. Relapse-free survival rate at 3 
years 
2. To understand the 
efficacy of 
cabozantinib as 
measured by a key 
clinical endpoint. 
3. To compare apoptosis (TUNEL), 
proliferation (Ki-67), and 
microvessel density (CD31) 
indices in prostatectomy 
specimens from patients who 
undergo immediate 
prostatectomy versus those 
treated with cabozantinib prior 
to prostatectomy.  
3. Quantification of TUNEL, Ki-67, 
and CD31 staining 
 
 
3. To describe the 
effects of 
cabozantinib on 
tumor tissue as 
measured by other 
standard 
pathologic 
parameters. 
4. To measure expression levels 
of c-MET, VEGF, and HGF, as 
well as activation status of c-
MET in prostate tissue. 
4. Quantification of c-MET, VEGF, 
HGF, and activated c-MET in 
prostatectomy tissue 
 
4. To evaluate effects 
on the c-MET/HGF 
axis. 
5. To describe changes in 
plasticity signaling markers 
associated with prostate 
tumors, including vimentin, 
AR, SNAIL, AXL, and N-
cadherin, with cabozantinib 
exposure 
5. Correlation of changes in 
vimentin, AR, SNAIL, AXL,  and 
N-cadherin with cabozantinib 
exposure 
5. To describe effects 
on markers of 
epithelial-
mesenchymal 
transitions (EMT). 
6. To evaluate PTEN and p53 
genomic and protein 
expression status in tumor 
tissue 
6. Measurement of PTEN and p53 
genomic and protein 
expression status in tumor 
tissue 
6. To evaluate 
whether 
cabozantinib may 
be more active in a 
subset of 
pTEN/p53-deficient 
tumors.10 
7. To demonstrate that 
cabozantinib is safe and 
tolerable in patients 
7. Adverse events by CTCAE v5.0, 
dose intensity of cabozantinib. 
7. To demonstrate 
that cabozantinib is 
safe and tolerable 
in patients 


  
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
undergoing radical 
prostatectomy.  
undergoing radical 
prostatectomy. 
8. To demonstrate that surgery 
is safe and feasible in patients 
undergoing treatment with 
cabozantinib. 
8. Blood loss at prostatectomy 
and duration of hospital stay. 
8. To demonstrate 
that surgery is safe 
and feasible in 
patients 
undergoing 
treatment with 
cabozantinib. 
9. To collect plasma angiome 
samples (multiplex ELISA) for 
analysis and correlation with 
primary and key secondary 
endpoints. 
9. Angiome biomarkers. 
9. To collect samples 
for possible later 
analysis and 
correlation with 
key endpoints 
10. To describe gene expression 
patterns (in particular those 
associated with apoptosis, 
androgen receptor signaling, 
c-MET activation, and a c-
MET-specific endocytosis 
panel) correlated with 
cabozantinib administration 
using RNA sequencing 
analysis.  
10. Gene expression patterns. 
10. To collect samples 
for possible later 
analysis and 
correlation with 
key endpoints. 
11. To explore changes in serum 
and intratumoral androgen 
concentrations related to 
cabozantinib treatment.  
11. Serum and intratumoral 
androgen concentrations. 
11. To collect samples 
for possible later 
analysis and 
correlation with 
key endpoints.12 
12. To collect cell-free DNA 
(cfDNA) for analysis and 
correlation with primary and 
key secondary endpoints. 
12. Alterations in cfDNA 
12. To collect samples 
for possible later 
analysis and 
correlation with 
key endpoints. 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This is a prospective, randomized, open-label, phase II trial of cabozantinib in subjects with untreated, 
high risk prostate cancer undergoing radical prostatectomy.  This multicenter study will enroll 30 
subjects. Duke is the lead site for this trial. There will be a second site selected TBD. Patients will be 


  
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assigned or randomized to either: (A) cabozantinib 40 mg PO daily for 4 weeks, followed by a 2 week 
drug washout period before prostatectomy (n = 20), or (B) immediate prostatectomy (n = 10). The Safety 
Lead-In Cohort will consist of 6 subjects receiving cabozantinib prior to prostatectomy. The randomized 
portion will consist of the remaining cabozantinib prior to prostatectomy subjects (n=14) and immediate 
prostatectomy subjects (n=10). 
 
The first 6 subjects assigned to cabozantinib treatment will constitute the Safety Lead-In Cohort, which 
will be only accrued at Duke.  Of these subjects, the first 3 subjects will be enrolled sequentially (that is, 
after each prior subject completes the day 57-85 safety visit).  This will constitute the Safety Lead-In 
Cohort Part A.  After 3 cabozantinib treatment patients are accrued sequentially (Part A), the remaining 
3 cabozantinib treatment subjects will be accrued non-sequentially, constituting the Safety Lead-In 
Cohort Part B.  
 
 If there are ≥2 dose-limiting toxicities (DLTs) in the first 6 subjects receiving cabozantinib, the trial will 
be stopped for safety purposes (first stopping rule).  DLTs are defined as CTCAE v5 grade ≥2 wound 
dehiscence or wound complication, any grade fistula, grade ≥2 hemorrhage of any type, grade ≥3 
infections [except urinary tract infections (UTIs) which are expected in this population], any AE that 
leads to permanent discontinuation of cabozantinib, or other grade ≥3 cabozantinib-related 
perioperative complications. The DLT period is defined as day 1 of drug through day 57 of the protocol 
(inclusive). The seventh subject randomized to cabozantinib may not be enrolled until the sixth subject 
completes the day 57-85 safety visit and the Duke principal investigator agrees that the stopping rule 
should not be put into effect.  
 
After six subjects have received cabozantinib and completed the 57-85 day safety visit without triggering 
a stopping rule, subjects may be accrued at ex-Duke site(s). A second stopping rule will be triggered if 
there are ≥3 DLTs in the first 12 subjects treated with cabozantinib.  In the event that a stopping rule is 
triggered, thorough review of the cabozantinib-treated patients’ files will be performed and the Duke 
principal investigator will consider whether the trial can be redesigned or should be permanently 
discontinued.   
 
4.2 
CORRELATIVE STUDIES 
 
Please see the lab manual for further details of these analyses.  
 
Apoptosis  
Cleaved Caspase-3.  Caspase-3 is a central downstream executor of both the intrinsic and extrinsic 
apoptosis pathways, and is responsible for the proteolytic cleavage of key effector molecules such as 
nuclear poly (ADP-ribose) polymerase (PARP).29  Cleavage of the zymogen form of caspase-3 to its active 
p17 and p12 fragments by caspase 8,9,10, or 12 is essential for downstream induction of apoptosis.  The 
primary endpoint is comparison of apoptosis in prostatectomy specimens in cabozantinib-treated 
patients versus controls.   


  
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Comprehensive Immune Profiling 
We will focus on comprehensive immune profiling of available samples representing the cabozantinib-
treated and untreated tumor microenvironment (TE) as well as baseline and longitudinal PBMC samples 
in cabozantinib-treated and untreated patients in an attempt to identify both:  (1) baseline signatures 
that predict which patients might benefit from cabozantinib, as well as (2) pharmacodynamic signatures 
that could provide mechanistic insights regarding therapeutic responses. The TE (tissue) will be analyzed 
in the laboratory of Dr. Jiaoti Huang (Duke Chair of Pathology).  The profiling platform to be used to 
analyze the peripheral blood (PBMC) samples will be highly standardized, polychromatic flow cytometry 
assays that have been developed by the Duke Immune Profiling Core (DIPC; Director:  Kent Weinhold, 
PhD) specifically for monitoring immune signatures in the context of immune checkpoint blockade trials.  
 
Pathologic Response 
Complete pathologic response (pCR) is defined as complete resolution of all cancerous glands in the 
prostatectomy specimen.  Patients treated with cabozantinib who have pCR will be defined as 
extraordinary responders.  Tissue from these patients’ prostate biopsy will be collected for analysis and 
correlation with key correlative endpoints.  
 
Relapse-free Survival 
After completion of the treatment period (if applicable), prostatectomy, and safety follow up period (if 
applicable), patients will be followed for relapse-free survival, so that this rate may be estimated at 3 
years (landmarked from the prostatectomy).  Relapse is defined as biochemical recurrence (AUA 
guidelines), radiographic evidence of metastasis (in the opinion of the investigator), new treatment for 
prostate cancer or death.  According to AUA guidelines, a biochemical recurrence is defined as a serum 
PSA ≥0.2 ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/mL. 
 
Apoptosis  
TUNEL.  Apoptotic index will be assessed in tissue biopsies and prostatectomy specimens from all 
patients using the TdT nick-end labeling technique.  
 
Proliferation 
Ki-67.  Proliferation index (PI) will be assessed in tissue biopsies and prostatectomy specimens from all 
patients. 
 
Angiogenesis 
CD31.  We will perform immunohistochemistry staining for CD31, an angiogenesis marker, in tissue 
biopsies and prostatectomy specimens from all patients on formalin-fixed tissue sections that are 
consecutive to those stained for apoptosis and proliferation.  
 
HGF-c-MET Axis 
c-MET.  Tumor specimens will be evaluated for c-MET, HGF, and phospho-c-MET expression as a 
measure of pharmacodynamic response to cabozantinib treatment.   


  
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HGF/phospho-c-MET double stain.  HGF is the ligand of the c-MET receptor and controls its activity 
through paracrine activation.  HGF is secreted by prostate stromal cells and by inflammatory cells in the 
prostate stroma.  HGF is also secreted by vascular smooth muscle cells.  Stroma will be evaluated for 
expression of HGF as a measure of pharmacodynamic response to cabozantinib treatment.  
 
Plasma Angiome 
Blood for use in the plasma angiome multiplex ELISA will be collected as described previously.30 Samples 
will be stored for possible future processing in the Phase I Biomarker Laboratory at Duke (Director: 
Andrew Nixon, PhD), Molecular Reference Laboratory for the Alliance Oncology Cooperative Group, a 
national clinical trial research group sponsored by the National Cancer Institute.   
 
Gene Expression Analysis 
The Affymetrix® U133A 2.0 Microarray, or similar, will be used for all analyses. Microarray hybridization 
and scanning will be performed as previously described.31  A k-nn (nearest neighbor) analysis will be 
performed to identify genes that have their expression most closely associated with cabozantinib 
administration.  Random permutation testing will be used to determine if the number of genes 
identified as having expression differences associated with cabozantinib administration is greater than 
would be expected by chance alone.  Additional analyses can be performed to determine if particular 
patterns of gene expression are associated with response to cabozantinib.  This analysis can initially be 
performed using pathologic response to cabozantinib as a dichotomous variable based on pre-
established criteria.  In this analysis, genes are identified in the control and cabozantinib-treated 
prostatectomy specimens that are most closely associated with response to cabozantinib using k-nn, 
similar to the analysis above.  Using a similar dichotomous variable analysis, expression patterns will be 
correlated with VEGF and c-MET, HGF, and phospho-c-MET levels.  Finally, we will test genes associated 
with apoptosis, androgen receptor signaling, c-MET activation,32,33 and a c-MET-specific endocytosis 
panel34,35 for correlation with response to cabozantinib.  These studies will be performed and analyzed 
by Dr. Jennifer Freedman at the Duke Cancer Institute, Assistant Professor of Medicine and Research 
Scientist in the Genitourinary Oncology Laboratory.  Dr. Freedman completed a postdoctoral fellowship 
in the Duke Institute for Genome Sciences and Policy (IGSP) and has experience analyzing gene 
expression and pathway signatures in human solid tumors.  
 
Mesenchymal Markers 
An exploratory endpoint of this study will be to describe changes in mesenchymal markers associated 
with cabozantinib treatment.  We hypothesize that patients treated with cabozantinib will have 
evidence of mesenchymal markers to a lower degree than controls, indicative of a mesenchymal-
epithelial transition (MET).   
 
Intratumoral Androgens 
The importance of ongoing steroidogenesis within prostate tumors, despite anorchid serum androgen 
levels, is now appreciated.36 Two recently reported studies of androgen suppression in the neoadjuvant-
to-prostatectomy setting demonstrated that the androgen receptor (AR) axis is still active despite near 


  
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total ablation of tissue dihydrotestosterone (DHT) levels and impressive rates of pCR and near-pCR.37,38 
Given the apparent inverse relationship between the AR and c-MET,39 we hypothesize that patients 
treated with cabozantinib will have increased intratumoral androgen concentrations relative to the 
prostatectomy specimens of controls. In prostatectomy specimens, tissue androgen and androgen 
precursor levels (i.e. testosterone, DHT, DHEA, etc.) will be store for possible analysis by mass 
spectrometry (MS) using methods previously described.40 The same androgen levels in serum will also 
be measured at baseline and prior to prostatectomy.  
 
Cell-free DNA (cfDNA) 
We will collect double-spun platelet poor plasma EDTA samples for circulating cfDNA analysis. Samples 
will be stored at -80°C for later analysis in a non-CLIA format.   
 
4.3 
DOSE 
 
The first 6 subjects will constitute the Safety Lead-In Cohort and be assigned to cabozantinib 40 mg PO 
daily for 4 weeks, followed by a 2 week drug washout period before prostatectomy. The remaining 
subjects will be randomized  to either: (1) cabozantinib 40 mg PO daily for 4 weeks, followed by a 2 
week drug washout period before prostatectomy (n = 14), or (2) immediate prostatectomy (n = 10). The 
dose of cabozantinib is based on information from both the dose escalation and phase II randomized 
discontinuation trials in mCRPC patients.41 This dose escalation trial by Smith et al. indicated that the 
impressive bone scan changes are demonstrated at the 40 mg dose with better tolerability that reported 
at the 100 mg dose. Because of this and the relatively high number of dose reductions and grade 3 
adverse events on the phase III trial (COMET-1),12  we believe that the 40 mg dose may have a more 
favorable risk-benefit ratio in the population of men with localized prostate cancer. The minimum two 
week washout period is based on both cabozantinib’ s terminal half-life of approximately 120 hours 
(cabozantinib [XL-184] IB, Version 9.0) and extrapolation from neoadjuvant trials of anti-angiogenic 
agents in renal cell carcinoma.42,43 
 
4.4 
PROSTATECTOMY 
 
Subjects will undergo a radical prostatectomy as part of their routine medical care at Day 43 (Arm A, 
cabozantinib) or Day 1 (Arm B, immediate prostatectomy). The surgeon must plan to use robotic or 
laparoscopic techniques with a low risk for conversion to open prostatectomy, in the opinion of the 
treating surgeon.  
 
4.5 
DEFINITION OF EVALUABLE SUBJECTS 
 
Arm A subjects must complete 21 out of 28 days of planned cabozantinib dosing and proceed to 
prostatectomy within 14 (+3) days of their last dose of cabozantinib in order to be evaluable for this 
study’s endpoints. Arm B subjects must receive a prostatectomy in order to be evaluable. Subjects who 
are not evaluable will be replaced.  


  
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5 
TARGET POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
1. Male, age ≥ 18 years old. 
2.  Karnofsky Performance Status (KPS) of ≥ 70. 
3. Histologic evidence of adenocarcinoma of the prostate who are deemed candidates for curative 
radical prostatectomy.  
4. Planned robotic or laparoscopic prostatectomy technique.  
5. Low risk for conversion to open prostatectomy, in the opinion of the treating surgeon.  
6. Intermediate-high or high risk, clinically localized disease by the following criteria:  
• 
Prostate cancer in at least 2 cores with a Gleason score ≥ 7 (4+3 or 3+4) in at least 1 of those 
cores.  
• 
No definite evidence of metastasis, in the opinion of the investigator. 
7.    Adequate organ function as defined by the following criteria within 14 days prior to first dose of 
study treatment:  
• 
Aspartate transaminase (AST) and  alanine transaminase (ALT) ≤3 x local laboratory upper limit 
of normal (ULN) 
• 
Total serum bilirubin ≤1.5 x ULN, (for subjects with Gilbert’s disease ≤ 3  ULN) 
• 
Absolute neutrophil count (ANC) ≥1500/L without granulocyte colony-stimulating factor 
support. 
• 
White blood cell count ≥ 2500/mm3 
• 
Serum albumin ≥ 2.8 g/dl 
• 
Platelets ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL  
• 
Serum calcium ≤12.0 mg/dL  
• 
Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30mL/min. 
• 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).  
8. Written Authorization for Use and Release of Health and Research Study Information (HIPAA 
authorization per institutional requirements) 
9. Evidence of a personally signed and dated informed consent document indicating that the subject 
has been informed of all pertinent aspects of the trial. 
10. Willing/able to adhere to the prohibitions and restrictions specified in this protocol. 
11. Agrees to use a condom (even men with vasectomies) and another effective method of birth control 
if subject is having sex with a woman who is pregnant or a woman of childbearing potential while on 
study drug and for 4 months following the last dose of study drug. 
 
5.2 
EXCLUSION CRITERIA 
Subjects cannot have the following: 
1. Prior treatment for prostate cancer.  
2. Major surgery or radiation therapy within 4 weeks of Day 1 on study.  
3. Planned radiation therapy until at least 4 weeks after prostatectomy.  


  
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4. NCI CTCAE v5.0 grade 3 hemorrhage within 4 weeks of Day 1 on study.  
5. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3  the laboratory ULN 
within 14 days before Day 1 on study (Arm A subjects only) or within 14 days of the completion 
of screening (Arm B subjects only) 
6. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and Factor 
Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). However, low-dose aspirin for cardio 
protection is allowed (per local applicable guidelines). 
7. History of or known metastatic prostate cancer.  
8. QTcf interval > 500 msec on baseline EKG.  
9. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited 
to, the following conditions:  
a. Cardiovascular disorders: 
i. Symptomatic congestive heart failure (CHF) New York Heart Association Class 3 
or 4, unstable angina pectoris, ongoing cardiac dysrhythmias of NCI CTCAE grade 
≥2. coronary/peripheral artery bypass graft (CABG), within 6 months prior to 
screening. 
ii. Stroke (including transient ischemic attack [TIA]), cerebrovascular accident 
(CVA), myocardial infarction (MI), or other ischemic event, or thromboembolic 
event (e.g., deep venous thrombosis, pulmonary embolism (PE)) within 6 
months prior to screening.  
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation 
or fistula formation:  
i. 
Evidence of tumor invading the GI tract, active peptic ulcer disease, 
inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction 
of the pancreatic duct or common bile duct, or gastric outlet obstruction. 
ii. 
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed before 
first dose. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) 
of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) 
within 12 weeks before first dose. 
d. Serious non-healing wound/ulcer/bone fracture.  
e. Other clinically significant disorders that would preclude safe study participation. 
10. Hypertension that cannot be controlled by medications (>140/90 mm Hg despite optimal 
medical therapy). 
11. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal 
range with medication. 
12. Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. 
QOL, are allowed. 
13. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that 
may increase the risk associated with study participation or study drug administration, or may 


  
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interfere with the interpretation of study results, and in the judgment of the investigator would 
make the subject inappropriate for entry into this study. 
14. Inability to swallow tablets. 
15. Diagnosis of another malignancy within 2 years before first dose of study treatment, except for 
superficial skin cancers, or localized, low grade tumors deemed cured and not treated with 
systemic therapy. 
 
6 
STUDY ASSESSMENTS 
 
The first 6 subjects assigned to cabozantinib treatment will constitute the Safety Lead-In cohort, which 
will be only accrued at Duke.  Of these subjects, the first 3 subjects will be enrolled sequentially (after 
each prior subject completes the day 57-85 safety visit). This will constitute the Safety Lead-In Cohort 
Part A. After 3 cabozantinib treatment patients are accrued sequentially, the remaining 3 cabozantinib 
treatment subjects will be accrued non-sequentially, constituting the Safety Lead-In Cohort Part B.     
 
If there are ≥2 dose-limiting toxicities (DLTs) in the first 6 subjects receiving cabozantinib, the trial will be 
stopped for safety purposes (first stopping rule).  DLTs are defined as CTCAE v5 grade ≥2 wound 
dehiscence or wound complication, any grade fistula, grade ≥2 hemorrhage of any type, grade ≥3 
infections [except urinary tract infections (UTIs) which are expected in this population], any AE that 
leads to permanent discontinuation of cabozantinib, or other grade ≥3 cabozantinib-related 
perioperative complications. The DLT period is defined as day 1 of drug through day 57 of the protocol 
(inclusive). The seventh subject receiving cabozantinib may not be enrolled until the sixth subject 
completes the day 57-85 safety visit and the Duke principal investigator agrees that the stopping rule 
should not be put into effect. From the seventh subject on, subjects may be accrued at ex-Duke site(s). A 
second stopping rule will be triggered if there are ≥3 DLTs in the first 12 subjects treated with 
cabozantinib.  In the event that a stopping rule is triggered, thorough review of the cabozantinib-treated 
patients’ files will be performed and the Duke principal investigator will consider whether the trial can 
be redesigned or should be permanently discontinued.   
 
Subjects assigned or randomized to receive cabozantinib will receive 28 days of study drug.  The 
washout time between the last dose of cabozantinib and surgery will be 14 days (window: +3 days). 
Reasons for early discontinuation of cabozantinib may include evidence of disease progression, 
unacceptable toxicity associated with cabozantinib, withdrawal of consent, or other reasons that may 
impact on the subject’s ability to undergo prostatectomy.   
Subjects will be monitored closely for toxicity, and the cabozantinib dose may be adjusted from the 40 
mg dose level to 20 mg daily according to individual patient tolerance.   Patients will be assessed for 
adverse events every 2 weeks for the 4 weeks during cabozantinib treatment and at approximately 3 
weeks and 4-6 weeks following the final day of cabozantinib administration.   
Plasma and serum correlative studies will generally be drawn at baseline, day 29, and day 57-85 in the 
cabozantinib arm and baseline in the immediate prostatectomy arm.  Tissue will be collected for analysis 
at prostatectomy on both arms.   


  
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See Figures 2 and 3 below for full details of study assessments. 
 
 


  
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6.1 
SCHEDULE OF EVENTS (SOE) 
 Figure 2: SCHEDULE OF EVENTS 
Arm A:  Cabozantinib 
 
Assessment 
Screening 
Day 
Relapse-
free Follow 
up 
 
D -42 to -1 
 
1 
(+/- 3 
days) 
15 
(+/- 3 
days) 
29 
(+/- 3 
days) 
43 
(+ 3 
days) 
50 
(+/- 3 
days)1 
57-85 
Safety 
Follow 
Up Visit 
3 year follow 
up (from 
prostatectomy)
2 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
Interval history3 
 
X 
X 
X 
 
X 
X 
 
Concomitant medicines 
X 
X 
X 
X 
 
X 
X 
 
Physical exam and vital 
signs4 
X 
X5 
X 
X 
 
X 
X 
 
Karnofsky Performance 
Status (KPS) 
X 
X5 
X 
X 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
Randomization6 
X 
 
 
 
 
 
 
 
Toxicity assessment 
 
X 
X 
X 
 
X 
X 
 
Dispensing of 
cabozantinib7 
 
X 
 
 
 
 
 
 
Prostatectomy8 
 
 
 
 
X 
 
 
 
Phone call or chart 
review9 
 
 
 
 
 
 
 
X 
Laboratory assessments 
 
 
 
 
 
 
 
 
CBC with differential10 
X11 
X 
X 
X 
 
X 
X 
 
Serum chemistries (CMP) 
10 
X11 
X 
X 
X 
 
X 
X 
 
Coagulation factors10 
X11 
X 
 
 
 
 
 
 
PSA10 
X 
X 
 
X 
 
 
X 
 
Testosterone10 
X 
 
 
X 
 
 
X 
 
Thyroid function testing10 
 
X 
 
X 
 
 
X12 
 
Urine Protein Creatinine 
Ratio10 
X11 
X 
X 
X 
 
X 
X 
 
Correlative/Research 
studies 
 
 
 
 
 
 
 
 
Plasma/serum cfDNA, 
immune, androgen, and 
angiome correlates13 
X 
 
 
X 
 
 
X 
 
Retrieval of archival 
prostate biopsy tissue14 
 
 
 
 
 
 
X 
 


  
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1. In conjunction with the usual post-operative visit to remove the patient’s foley catheter. 
2. Follow up will occur every 3 months (+/- 1 month). Follow up may be obtained by a phone call, clinic visit 
or chart review. 
3. Interval history consists of the following: 
a. Medical history collected as clinically indicated during standard of care clinic visits, which may 
include disease related symptoms (i.e. pain, changes in urination) and drug related side effects 
(i.e. bleeding, diarrhea, fatigue, etc.).   
b. Select imaging to rule out metastatic disease will be done as clinically indicated. Subjects will not 
routinely receive bone scan, CT, or MRI imaging unless there is clinical concern for possible 
metastatic disease.  
c. 
Interval history during the safety follow-up visit to include review of hospital course while patient 
underwent prostatectomy.  
4. Vital signs must be performed at screening, day 1, day 15, day 29, day 50, and day 57-85 visit by a medical 
professional. Blood pressure, temperature, pulse, respiratory rate, height (at screening only) and weight 
will be collected. 
5. Day 1 physical exam and KPS do not have to be repeated if screening physical exam and KPS were 
performed within 7 days prior to Day 1 visit.  Vitals signs must be completed on Day 1 regardless of when 
they were collected during screening.  
6. Randomization may take place any time before or on day 1, after the patient is confirmed to be eligible.  
7. Cabozantinib will be administered at 40 mg daily for 28 days. A pill diary will be provided to the subject. 
Study drug will be dispensed directly from the clinic. Unused drug will be returned to the clinic. 
8. Prostatectomy will occur 2 weeks (14 + 3 days) after the last dose of cabozantinib. Tissue will be procured 
for pathologic, molecular, and immunologic assessments. 
9. Relapse free survival follow up may be captured over the telephone, clinic visit or chart review every 3 
months +/- 1 month. 
10. Laboratory assessments at the times indicated include: 
Complete blood count (CBC) with differential 
Serum chemistries (CMP): Sodium, Potassium, Chloride, Bicarbonate, blood urea nitrogen (BUN), 
Creatinine, Glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, 
alkaline phosphatase, and LDH.   
Coagulation Factors: PT/INR or PTT will be drawn at baseline only.   
PSA 
Testosterone 
Thyroid function testing:  Will include TSH and T4. 
Urine Protein Creatinine Ratio: UPCR=(Urine protein mg/dl)/ (urine creatinine mg/dl) = numerically 
equivalent to gm protein excreted in urine over 24 hours.   
Notes: Screening labs (except testosterone) must be completed within 7 days of day 1, or they must 
be repeated on day 1. 
11. CBC with differential, CMP, coagulation factors and urine protein creatinine ratio must be completed 
within 14 days of Day 1 if subject is assigned or randomized to Arm A: Cabozantinib.  
12. Thyroid function tests (TFTs) will be repeated at the safety follow up visit in those who require clinical 
intervention due to alteration in TFTs at an earlier time point. 
13. Immune and androgen correlates will only be collected at baseline and on Day 29.  
14. For extraordinary responders (i.e. pCRs) we will obtain archival tissue from their pre-prostatectomy 
prostate biopsy if available. 
 
 
 
 
 


  
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FIGURE 3:  SCHEDULE OF EVENTS 
 
Arm B:  Immediate Prostatectomy 
 
Assessment 
Screening 
Day 
Relapse free 
Follow up 
 
D-42 to -1 
 
11  
3 year follow up (from 
prostatectomy) 
Informed Consent 
X 
 
 
Medical History and 
Demographics 
X 
 
 
Interval history2 
 
X 
 
Concomitant Medicines 
X 
 
 
Physical Exam3 
X 
 
 
Karnofsky Performance 
Status (KPS) 
X 
 
 
ECG 
X 
 
 
Randomization4 
X 
 
 
Prostatectomy5 
 
X 
 
Phone call or chart review6 
 
 
X 
Laboratory assessments 
 
 
 
CBC with differential7,8 
X 
 
 
Serum chemistries (CMP) 
7,8 
X 
 
 
Coagulation factors7,8 
X 
 
 
PSA7 
X 
 
 
Testosterone7 
X 
 
 
Urine Protein Creatinine 
Ratio7, 8 
X 
 
 
Correlative/Research 
studies 
 
 
 
Plasma/serum cfDNA, 
immune, androgen and 
angiome correlates 
X 
 
 
 
1 
For this arm, “Day 1” is defined as the day on which the prostatectomy is performed. While the end of 
screening is labelled as Day -1 and the prostatectomy as Day 1, these days are not intended to be 
consecutive. It is expected that there will be intervening days in order to allow scheduling of the 
prostatectomy.   
2 
Interval history consists of the following: 
a. 
Medical history collected as clinically indicated during standard of care clinic visits, which may include 
disease related symptoms (i.e. pain, changes in urination) and drug related side effects (i.e. bleeding, 
diarrhea, fatigue, etc.).   
b. 
Select imaging to rule out metastatic disease will be done as clinically indicated. Subjects will not 
routinely receive bone scan, CT, or MRI imaging unless there is clinical concern for possible metastatic 
disease.  


  
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3 
Vital signs must be performed at screening visit by a medical professional.  Blood pressure, temperature, 
pulse, respiratory rate, height and weight will be collected. 
4 
Randomization may take place any time before or on day 1, after the patient is confirmed to be eligible. 
5 
With tissue procurement for pathologic, molecular, and immunologic assessments. 
6 
Relapse free survival follow up may be captured over the telephone, clinic visit or chart review every 3 
months +/- 1 month. 
7 
Laboratory assessments at the times indicated include: 
Complete blood count (CBC) with differential 
Serum chemistries (CMP): Sodium, Potassium, Chloride, Bicarbonate, blood urea nitrogen (BUN), 
Creatinine, Glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, 
alkaline phosphatase, and LDH.   
Coagulation Factors: PT/INR or PTT.   
PSA 
Testosterone 
Urine Protein Creatinine Ratio: UPCR=(Urine protein mg/dl)/ (urine creatinine mg/dl) = numerically 
equivalent to gm protein excreted in urine over 24 hours.   
8 
CBC with differential, CMP, coagulation factors and urine protein creatinine ratio must be completed within 
14 days of the completion of screening if the subject randomized to Arm B: Immediate Prostatectomy. 
 
6.2 
INFORMED CONSENT 
Authorized study personnel should fully explain the scope of the study to each subject before obtaining 
informed consent.  Subjects should be advised of any known risks inherent in the planned procedures, of 
any alternative treatment options, of their right to withdraw from the study at any time for any reason, 
and of their right to privacy.  
When obtaining informed consent, study personnel should: 
First: Confirm that the subject is a potential candidate for study participation. 
Next: Obtain dated and signed informed consent. 
Finally: Confirm that the subject is eligible as defined in Section 5.0 (Inclusion/Exclusion Criteria).  A 
record of subjects who fail to meet entry criteria (i.e., screening failures) will be maintained. 
For subjects consented at the lead site ONLY, registration in the Duke clinical trial subject registry (i.e. 
Oncore) must be completed within 1 business day of the subject providing informed consent. 
6.3 
SCREENING- BOTH ARMS 
The screening examination will take place within 42 days of initiation of therapy or surgery.  An 
informed consent form must be signed by the subject before any study-specific screening procedure 
takes place.  
Subject data to be collected at the Screening Examination includes:   
• 
Informed consent process utilizing a signed and dated IRB-approved ICF  
• 
Confirmation of inclusion/exclusion criteria 


  
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• 
Medical history including concomitant illnesses and oncologic history.  Oncologic history must 
include specific documentation of prostate cancer histologic diagnosis. 
• 
Prior and concomitant medications and non-pharmacologic treatments taken within 4 weeks of 
screening will be recorded.   
• 
ECG 
• 
Sample collection for the following laboratory evaluations (all standard-of-care except PT/INR 
and PTT): 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
o Testosterone and PSA levels.   
o Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test. 
• 
Correlative samples will be drawn at screening.  See lab manual for details. 
• 
Physical examination to be conducted and height (cm), weight (kg), and vital signs (including 
temperature [C], blood pressure [mmHg], heart rate [beats per minute],  respiratory rate 
[breaths per minute]. Height will be collected at screening only. 
• 
Karnofsky Performance Status (KPS) 
 
Once the subject completes the screening examinations and is determined to be eligible, he will be 
assigned or randomized to arm A or arm B and enrolled.   
 
Arm A 
• 
Cabozantinib will be administered orally at 40 mg daily for 28 days 
• 
14 day + 3 days washout prior to prostatectomy 
• 
Prostatectomy  
 
Arm B 
• 
Immediate prostatectomy 
 
6.4 
SUBJECT REGISTRATION AND ENROLLMENT 
After signing informed consent, subjects will be registered with the lead site (Duke) and with their study 
site/institution.  A record of subjects who fail to meet entry criteria (i.e., screen failures) will be 
maintained.   
 
6.5 
LEAD SITE REGISTRATION AND ENROLLMENT 
Subject registration for all subjects signing informed consent will be completed by Duke University 
Medical Center Genitourinary Oncology Group. Following consent, documents will be submitted for 
review and registration of subject. Consented subjects will be assigned a unique study ID at registration.  


  
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Subjects will be enrolled only after all pre-treatment screening evaluations are completed, all eligibility 
criteria are met and the lead site reviews the Eligibility Checklist.  Once the subject has signed consent 
and been found to meet all eligibility criteria with the approval from the lead site, the subject will be 
randomized, except for the Safety Lead-In Cohort subjects which will be assigned.  Treatment must not 
commence until the subject has received approval from the lead site. 
6.6 
INSTITUTIONAL REGISTRATION 
Subject registration at each study site/institution will be conducted according to the institution’s 
established policies.  Prior to registration, subjects will be asked to sign and date an Institutional Review 
Board (IRB)-approved consent form.  Subjects must be registered with their local site/institution and 
with the lead site before beginning any treatment or study activities. 
6.7 
TREATMENT PERIOD  
 
 
 
 
 
 
 
 
 
 
6.8 
DAY 1 - ARM A ONLY 
The following must be performed on Day 1 prior to dose of cabozantinib: 
• 
Interval history 
• 
Physical examination including major body systems. The Day 1 physical examination does not 
need to be performed if the screening physical examination was performed within 7 days of the 
Day 1 visit.  
• 
Karnofsky Performance Status (KPS), body weight, and vital signs (temperature, blood pressure, 
heart rate, respiratory rate). The Day 1 KPS evaluation does not need to be performed if the 
screening KPS evaluation was performed within 7 days of the Day 1 visit.  
• 
Assessment of concomitant medications, toxicities and treatments  
• 
Dispense study drug to the patient 
• 
Sample collection for the following laboratory evaluations if not done for screening with 7 days: 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
o PSA level 
o Thyroid function testing:  TSH and T4. 
 
6.9 
DAY 15 - ARM A ONLY 
The following must be performed on Day 15: 
• 
Interval history 
• 
Physical examination including major body systems. 


  
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• 
Karnofsky Performance Status (KPS), body weight, and vital signs (temperature, blood pressure, 
heart rate, respiratory rate) 
• 
Sample collection for the following laboratory evaluations: 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
• 
Assessment of concomitant medications, toxicities and treatments  
6.10 DAY 29 - ARM A ONLY 
The following procedures must be performed on Day 29: 
• 
Interval history 
• 
Physical examination including major body systems   
• 
Karnofsky Performance Status (KPS), body weight, and vital signs 
• 
Sample collection for the following laboratory evaluations: 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
o PSA level 
o Testosterone level 
o Thyroid function testing:  TSH and T4. 
• 
Assessment of concomitant medications, toxicities and treatments  
• 
Plasma/serum biomarker studies 
6.11 DAY 43 - ARM A ONLY 
The following procedures must be performed on Day 43: 
• 
Prostatectomy 
• 
Tissue procurement at the time of surgery for pathologic and research assessments. 
 
6.12 DAY 50 - ARM A ONLY 
The following procedures must be performed on Day 50: 
• 
Interval history 
• 
Physical examination including major body systems   
• 
Karnofsky Performance Status (KPS), body weight, and vital signs 


  
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• 
Sample collection for the following laboratory evaluations: 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
• 
Assessment of concomitant medications, toxicities and treatments 
 
6.13 SAFETY FOLLOW UP VISIT - ARM A ONLY 
At the post-surgery follow-up visit, the following procedures should be performed: 
• 
Interval history (to include review of hospital course while patient underwent prostatectomy) 
• 
Assessment of any adverse events and tumor-related signs and symptoms 
• 
Physical examination including major body systems   
• 
Karnofsky Performance Status (KPS), body weight, and vital signs and other tests as necessary to 
follow unresolved or evaluate new adverse events 
• 
Sample collection for the following laboratory evaluations: 
o Complete blood count (CBC) with differential:   WBC count with differential, platelet 
count, hemoglobin, and hematocrit. 
o Serum chemistries:  Sodium, potassium, chloride, blood urea nitrogen (BUN) or urea, 
creatinine, glucose, carbon dioxide (CO2) or bicarbonate, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), albumin, total bilirubin, alkaline phosphatase, 
LDH. 
o Urine protein creatinine ratio 
o PSA level 
o Testosterone level 
o Thyroid function testing:  TSH and T4. Thyroid function tests (TFTs) will be performed 
only for subjects who require clinical intervention due to alteration in TFTs at an earlier 
time point. 
• 
Assessment of concomitant medications, toxicities and treatments 
• 
Plasma/serum biomarker studies 
• 
For extraordinary responders we will obtain archival tissue from their prostate biopsy pre 
prostatectomy  
 
6.14 DAY 1 - ARM B ONLY 
The following procedures must be performed on Day 1: 
• 
Prostatectomy 
• 
Tissue procurement at the time of surgery for pathologic and research assessments 
6.15 RELAPSE FREE SURVIVAL FOLLOW UP PERIOD  


  
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 Arm A and Arm B subjects will be followed for relapse free survival for 3 years from date of 
prostatectomy. Follow up will occur every 3 months (+/- 1 month). Follow up may be obtained by a 
phone call, clinic visit or chart review. 
 
6.16 END OF STUDY 
Reasons to discontinue the subject prior to 3 years include: biochemical progression, disease 
progression, new treatment for prostate cancer, withdrawal, or death. This determination may require 
obtaining outside records and interpretation by the investigator. 
 
7 
STUDY INTERVENTION 
7.1 
COMPOSITION, FORMULATION, AND STORAGE 
At study sites, all study medication will be stored as described in the appropriate prescribing information 
and inventoried in accordance with applicable state and federal regulations. 
7.2 
INVESTIGATIONAL TREATMENT: CABOZANTINIB   
Cabozantinib tablets are supplied as film-coated tablets containing cabozantinib malate equivalent to 20 
mg and contain microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, croscarmellose 
sodium, colloidal silicon dioxide, magnesium stearate and Opadry® yellow. The 20-mg tablets are round. 
Doses of 40 mg will comprise two 20-mg tablets. The components of the tablets are listed in Table 7-1.  
Table 7-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/wa 
Cabozantinib Drug Substance (25% drug load as free base) 
Active 
Ingredient 
31.68 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose Anhydrous (60M) 
Filler 
19.42 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.00 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
6.00 
Colloidal Silicon Dioxide 
Glidant 
0.30 
Magnesium Stearate 
Lubricant 
0.75 
Opadry® yellow film coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, and iron oxide 
yellow 
Film 
Coating 
4.00 
a weight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose 
 
7.3 
CABOZANTINIB ADMINISTRATION 
 Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily. Study drug will be 
provided by Exelixis. Study drug should at all times be kept in the original packaging. Study drug will be 


  
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dispensed directly in clinic and returned at the end of 28 days.  Cabozantinib will be supplied as 20 mg 
tablets in bottles of 30 tablets. Subjects will be given two bottles for their 28 day dosing.  Doses of 40 mg 
will comprise two 20 mg tablets. A pill diary will be provided to keep accurate information on drug 
administration and any notes that the subject adds to the diary.  
Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to eat for at least 2 
hours before and at least 1 hour after taking cabozantinib.  Subjects should be instructed to take their 
cabozantinib dose at approximately the same time every day.  If a subject misses a dose, the dose may 
be taken later only if it is within 12 hours of when the missed dose should have been taken.  The missed 
dose should not be made up if it is within 12 hours of the next scheduled dose.   
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The tablets should not 
be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be avoided by 
subjects taking cabozantinib. 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Table 7.3  
7.4 
CABOZANTINIB DOSE MODIFICATIONS, INTERRUPTIONS, AND DISCONTINUATION 
The following should be taken into consideration in decisions regarding dose modifications (reductions 
or interruption): 
• 
As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity considered related to the study treatment. Should this be ineffective, dose interruptions 
and/or reductions should be considered to prevent worsening of toxicity.  
• 
The assigned starting dose for cabozantinib is 40 mg/day. One dose reduction level of cabozantinib 
to 20 mg/day is permitted (see Table 7-2). 
• 
Dose modification criteria for cabozantinib are shown in Table 7-3. Dose interruptions and/or 
reductions should be implemented for unacceptable toxicity. Doses may be modified at any time 
while a subject is on treatment. 
• 
Dose reductions or interruptions may also occur in the setting of lower grade toxicity than defined in 
Table 7-3, if the investigator feels it is in the interest of a subject’s safety and will optimize drug 
tolerability. 
• 
Interruption of cabozantinib treatment for cabozantinib-related AEs may occur at any time per 
investigator discretion. If treatment is interrupted due to related AEs for more than 1 week, 
cabozantinib should be discontinued unless there is unequivocal evidence that the subject is 
benefitting. In this situation, a subject may be able to restart therapy with a dose reduction upon 
resolution of the toxicity per the discretion of the investigator. 


  
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Guidelines for the management of specific AEs are provided in Section 7.4.2. 
Table 7-2: 
Dose Reductions of Cabozantinib 
Assigned Dose 
First Dose Level Reduction 
Second Dose Level Reduction 
40-mg cabozantinib oral qd 
20-mg cabozantinib oral qd 
No dose reduction permitted 
Cabozantinib will be discontinued if a daily dose of 20-mg cabozantinib (minimum dose) is not tolerated 
 
Table 7-3: 
Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.5.0 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib treatment at 
the current dose level if AE is manageable and tolerable. 
Grade 2 AEs which are 
tolerable and are easily 
managed 
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed  
Continue cabozantinib treatment at the current dose level with 
supportive care. 
 
At the discretion of the investigator, cabozantinib should be dose 
reduced or interrupted. 
Note: It is recommended that dose holds be as brief as possible.  
Grade 3 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be easily 
managed with a dose reduction and optimal medical care.  
Note: It is recommended that dose holds be as brief as possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory 
abnormalities) 
Subjects should have cabozantinib interrupted immediately.  
Discontinue cabozantinib unless the following criteria are met:  
• 
Subject is deriving clear clinical benefit as determined by the 
investigator 
• 
Toxicity can be managed with a dose reduction following 
recovery to Grade 1 (or baseline) and optimal medical care  
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 7.4.2 For re-
treatment criteria of study treatment after a dose hold see Section 7.4.1. 
aStudy treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib treatment or 
had an unclear relationship to cabozantinib treatment. 


  
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7.4.1 CABOZANTINIB DOSE REINSTITUTION AND REESCALATION 
If the subject recovers from his or her toxicities to CTCAE v.5.0 Grade ≤ 1 or to the baseline value (or 
lower) and the toxicity was unrelated to study treatment, then study treatment may be restarted with 
no change in dose.  
If the subject recovers from his or her toxicities to Grade ≤ 1 or to the baseline value (or lower) the 
toxicity was deemed possibly related to study treatment, then study treatment may be restarted at a 
reduced dose (see Table 7-2 for the schedule of dose reductions). 
Subjects receiving a daily dose of 20 mg may be restarted at the same dose if deemed safe at the 
discretion of the investigator. Subjects unable to tolerate a daily dose of 20 mg should discontinue study 
treatment. 
Re-escalation to the previous dose, (but not higher than 40 mg/day) may be allowed at the discretion of 
the investigator for AEs which have resolved or recovered to Grade 1 (or baseline value) and deemed 
tolerable and easily managed by optimized supportive treatment. Dose re escalation is not allowed for a 
drug-related dose reduction triggered by Grade 4 hematologic toxicities or by Grade 4 AEs affecting 
major organs (e.g., central nervous system, cardiac, hepatic, renal). 
7.4.2 GUIDELINES FOR MANAGEMENT OF POTENTIAL ADVERSE EVENTS 
Subjects on Arm A receiving cabozantinib will be monitored for AEs from the time of taking the first dose 
of study drug through their last follow-up visit (30 days after the date of the last dose of cabozantinib 
treatment). Subjects will be instructed to notify their physician immediately at the onset of any AE. 
Seriousness, severity grade, and relationship to study treatment of AEs will be determined by the 
investigator. AE severity will be graded by the investigator in accordance with CTCAE v.5.0.  
Management of severe or intolerable adverse reactions may require temporary dose reduction and/or 
interruption for cabozantinib.  
7.4.2.1 CABOZANTINIB 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in descending order 
of frequency were diarrhea, fatigue, decreased appetite, nausea, weight decreased, PPES, vomiting, 
constipation, hypertension, dysgeusia, dysphonia, asthenia, and dyspnea. For a full description of the 
safety profile of cabozantinib, refer to the Cabozantinib Investigator’s Brochure. 
Other medically important but less frequent AEs including arterial thrombotic AEs (e.g., transient 
ischemic attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs (e.g., deep vein 
thrombosis [DVT] and pulmonary embolism), severe hemorrhagic events, proteinuria, wound healing 
complications, gastrointestinal (GI) perforation, abscesses including intra-abdominal and pelvic abscess, 
GI and non-GI fistula formation, osteonecrosis, and reversible posterior leukoencephalopathy syndrome 
(RPLS). 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects treated with 
cabozantinib in descending order of frequency were anemia, AST increased, ALT increased, 
hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, 
lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, hyponatremia, ALP increased, 
leukopenia, and hyperglycemia. 


  
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Adverse events may occur within the first few weeks in the course of treatment with cabozantinib, as 
cabozantinib is expected to reach steady state exposure at approximately 2 weeks following first dose. 
Events that generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, 
hypertension, PPES, abdominal pain, mucosal inflammation, constipation, diarrhea, and vomiting. 
Adverse events should be managed with supportive care at the earliest signs of toxicity. Dose reductions 
and treatment interruptions should be considered. Dose reductions are recommended for events that, if 
persistent, could become serious or intolerable (Section 7.3). 
Cabozantinib should be discontinued for the following AEs: visceral perforation or fistula formation, 
severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, hypertensive 
emergency, persistent uncontrolled hypertension despite optimal medical management, and RPLS. 
7.4.2.2 GASTROINTESTINAL DISORDERS 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After starting treatment 
with cabozantinib, subjects should be monitored for early signs of GI perforation such as abdominal 
pain, nausea, emesis, constipation, and fever especially if known risk factors for developing GI 
perforation or fistula (Turnage and Badgwell 2016) are present. Discontinue cabozantinib and initiate 
appropriate management in subjects who have been diagnosed with GI perforation or fistula. 
Diarrhea: Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Guidelines for the evaluation and 
management of diarrhea are shown in Table 7-4. Administration of antidiarrheal/antimotility agents is 
recommended at the first sign of diarrhea as initial management. Some subjects may require 
concomitant treatment with more than one antidiarrheal agent. When therapy with antidiarrheal agents 
does not control the diarrhea to tolerable levels, cabozantinib should be temporarily interrupted or dose 
reduced. When the diarrhea is controlled, retreatment with cabozantinib may be acceptable per 
investigator decision. In addition, general supportive measures should be implemented such as 
continuous oral isotonic hydration, correction of fluid and electrolyte abnormalities, small frequent 
meals, and stopping lactose-containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which increase 
the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be emphasized. Regular 
examinations of the perianal region should be performed whenever diarrhea has occurred during 
treatment with cabozantinib. Infections of the perianal region should be treated per local guidelines. 


  
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Table 7-4:  
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg 
followed by 2 mg after each episode of diarrhea [maximum: 16 mg 
loperamide per day]) 
• 
Dietary modifications (e.g., small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add solid 
foods and discontinue or decrease antidiarrheal treatment after 
12 h diarrhea-free interval 
o 
Diarrhea not resolving: Continue/resume antidiarrheal treatment  
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend clinic 
• 
Rule out infection (e.g., stool sample for culture) 
o 
Administer antibiotics as needed (e.g., if fever or Grade 3-4 
neutropenia persists > 24 h) 
• 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or 
to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower grade diarrhea consider hospitalization 
and IV hydration 
• 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider 
restarting study treatment at reduced dose 
o 
Diarrhea not resolving: Start and or continue antidiarrheal 
treatment (e.g., loperamide 4 mg followed by 2 mg after each 
episode of diarrhea [maximum: 16 mg loperamide per day]). 
Consider starting second line antidiarrheal or referral to 
gastroenterologist 
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment or 
prophylaxis of nausea and vomiting, along with supportive care. Dehydration and electrolyte 
abnormalities may be associated with vomiting and monitoring for and correction of fluid and 
electrolyte disturbances should be implemented. Antiemetic medications should be assessed for 
potential drug interactions (refer to Section 8.2 for further details). 
Dehydration: Dehydration events have been identified with comparable incidence and occurring in a 
shorter time to onset in the prostate cancer studies than previously experienced with cabozantinib in 
other tumor types. Extra monitoring/medical management including electrolyte monitoring and/or early 
dose reduction of patients exhibiting dehydration symptoms and those with risk factors for dehydration 
is indicated. 
7.4.2.3 NON-GASTROINTESTINAL FISTULA 


  
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Complications from radiation therapy especially of the thoracic cavity including mediastinum have been 
identified as a possible predisposing risk factor for non-GI fistula formation in subjects undergoing 
treatment with VEGF pathway inhibitors. 
Discontinue cabozantinib and initiate appropriate management in subjects who have been diagnosed 
with a non-GI fistula. 
7.4.2.4 HEMORRHAGE 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with 
cabozantinib. Subjects should be monitored for bleeding events with serial complete blood counts and 
physical examination while on study. The risk of hemorrhage in cabozantinib-treated subjects with brain 
metastases has not been thoroughly analyzed. Subjects enrolled with treated and stable brain 
metastases should be monitored with a high index of suspicion if symptoms that could be due to a CNS 
hemorrhage occur. 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events or 
recent hemoptysis (≥ 2.5 mL of red blood). 
7.4.2.5 THROMBOEMBOLIC EVENTS  
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by the 
malignancy or anticancer therapy. DVT and pulmonary embolism have been observed in clinical studies 
with cabozantinib, including fatal events. Subjects who develop a pulmonary embolism and/or DVT 
should have study treatment interrupted until therapeutic anticoagulation is established. Treatment 
with cabozantinib may be resumed in subjects with pulmonary embolism or DVT if it is determined that 
the event is uncomplicated and that the subject is deriving clinical benefit from cabozantinib treatment 
and that anticoagulation does not place them at a significant risk that outweighs the benefit of resuming 
treatment per discretion of the investigator and according to individual protocols. Low molecular weight 
heparins are the preferred management for thrombotic events; oral anticoagulants (e.g., warfarin or 
other coumarin-related agents, direct thrombin or direct FXa inhibitors, or antiplatelet agents, or 
chronic use of aspirin above low dose levels for cardioprotection per local applicable guidelines) are not 
allowed. 
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with cabozantinib. Further 
treatment with cabozantinib should be discontinued in subjects who develop an acute MI, cerebral 
infarction, or any other clinically significant arterial thromboembolic complication. 
7.4.2.6 HYPERTENSION 
Table 7-5 provides treatment guidelines for hypertension deemed related to cabozantinib. Blood 
pressure should be monitored in a constant position visit to visit, either sitting or supine in a relaxed 
setting. Decisions to reduce or interrupt the dose of study treatment must be based on BP readings 
taken by a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement.  
Cabozantinib should be discontinued in subjects with hypertensive emergency. 
 


  
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Table 7-5: 
Management of Hypertension Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic)a and < 160 mm 
Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm 
Hg 
 
• 
Optimize antihypertensive medications by adding new 
or additional antihypertensive medications and/or 
increase dose of existing medications. 
• 
Reduce cabozantinib treatment by one dose level if 
optimal antihypertensive therapy (usually to include 3 
agents) does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic 
• If subject is symptomatic interrupt cabozantinib 
treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
cabozantinib treatment per investigator discretion 
• 
Add new or additional anti-hypertensive medications 
and/or increase dose of existing medications and 
monitor subject closely for hypotension. If optimized 
antihypertensive therapy (usually to include 3 agents) 
does not result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic, cabozantinib treatment should 
be dose reduced further or interrupted 
• 
Cabozantinib treatment should be dose interrupted if 
upper limits of systolic BP (≥ 160 mm Hg) are 
sustained and not adequately manageable or if 
systolic BP is > 180 mm Hg or diastolic BP > 110 mm 
Hg, or if subject is symptomatic 
• Re-start cabozantinib treatment at the most tolerable 
dose and re-escalate only if BP falls to and is sustained 
at < 150 mm Hg systolic and < 100 mm Hg diastolic 
Hypertensive emergencyc 
• 
Discontinue cabozantinib treatment 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP >150 or 
diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols. 
c Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending end-organ 
damage (e.g., myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, 
encephalopathy, kidney damage). 
 
 
7.4.2.7 STOMATITIS AND MUCOSITIS 
Preventive measures may include a comprehensive oral examination to identify and treat any potential 
risk for complications before study treatment is initiated. Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. 


  
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During treatment with cabozantinib, good oral hygiene and standard local treatments such as 
non-traumatic and non-irritating cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained. Lips should be kept moisturized with lip balm. The use of lipstick, lip-gloss, 
and Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral culture if 
oral infection is suspected and treat infection as clinically indicated.  
7.4.2.8 SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Wound healing and surgery: Cabozantinib has the potential to cause wound healing complications and 
wound dehiscence which may even occur long after a wound has been considered healed. Therefore, 
surgical and traumatic wounds must not only be completely healed prior to starting cabozantinib 
treatment but must also be monitored for wound dehiscence, wound infection and other signs of 
impaired wound healing while the subject is being treated with cabozantinib. If dehiscence occurs, 
cabozantinib treatment should not be restarted until complete healing has taken place.  
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot syndrome), skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular 
rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported with 
cabozantinib. All subjects on study should be advised on prophylactic measures including the use of 
emollients, removal of calluses, avoidance of exposure of hands and feet to hot water leading to 
vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of cotton gloves and 
socks to prevent injury and keep the palms and soles dry. 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and swollen 
areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas. Analgesics may be required for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. Treatment 
recommendations in response to PPES are summarized in Table 7-6. 


  
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Table 7-6: 
Management of Hand-Foot Syndrome (PPES) Associated with Cabozantinib 
CTCAE v.5.0 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if PPES is 
clinically insignificant and tolerable. Otherwise, cabozantinib should be 
reduced to the next lower dose level.a Start urea 20% cream twice daily 
AND clobetasol 0.05% cream once daily. Reassess at least weekly; if PPES 
worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2  
Cabozantinib treatment may be continued if PPES is tolerated. 
Cabozantinib should be dose reduced or interrupted if PPES is 
intolerable. Continue urea 20% cream twice daily AND high potency 
steroid cream (e.g., clobetasol 0.05%) once daily and add analgesics 
(e.g., NSAIDs/gamma-aminobutyric acid agonists) for pain control if 
needed. Reassess at least weekly; if PPES worsens or affects self-care, 
proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 
0. Continue treatment of skin reaction with high potency steroid cream 
(e.g., clobetasol 0.05%) twice daily AND analgesics. Resume study drug at 
a reduced dose if PPES recovers to Grade ≤ 1. Discontinue subject from 
study treatment if PPES does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory 
drug; PPES, palmar plantar erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
 
7.4.2.9 OSTEONECROSIS 
Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors include 
use of bisphosphonates and denosumab, chemotherapy and anti-angiogenic drugs, use of 
corticosteroids, local radiotherapy, and dental or orofacial surgery procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or 
periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing 
of the mouth or jaw after dental surgery may also be manifestations of osteonecrosis. 
Advise subjects regarding oral hygiene practice and to quickly report symptoms to investigator. Caution 
should be used in subjects receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment with cabozantinib should be interrupted for at least 4 weeks prior to the procedure and 
resumed after complete wound healing has occurred. Bone healing may often require a protracted time. 
Cabozantinib will be permanently be discontinued in subjects who develop osteonecrosis of the jaw. 
 


  
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7.4.2.10 PROTEINURIA 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring UPCR. 
Table 7-7 provides treatment guidelines for proteinuria deemed related to cabozantinib.  
Cabozantinib should be discontinued in subjects who develop nephrotic syndrome (proteinuria > 3.5 
grams per day in combination with low blood protein levels, high cholesterol levels, high triglyceride 
levels, and edema).  
Table 7-7: 
Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
 
 
• 
Consider confirming with a 24-h protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg 
or urine protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine 
collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider interrupting cabozantinib 
treatment if UPCR remains > 2 mg/mg despite a dose reduction 
until UPCR decreases to < 2 mg/mg. Restart cabozantinib treatment 
at a reduced dose after a dose interruption. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done 
within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) 
for 1 month, check urine protein/creatinine per protocol or as 
clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR within 
7 days and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until 
the UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and 
< 2 mg/mg for 1 month or is determined to be stable (< 20% 
change) for 1 month, check urine protein/creatinine per protocol or 
as clinically indicated. 
Nephrotic syndrome 
• 
Discontinue cabozantinib treatment 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 


  
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7.4.2.11 NERVOUS SYSTEM DISORDERS 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on nonclinical 
Good Laboratory Practice (GLP)-compliant toxicology studies. Dysphonia, dysgeusia, headache, 
dizziness, confusional state, convulsion, depression, memory impairment, hypoesthesia, peripheral 
neuropathy, insomnia, ataxia, and encephalopathy have been observed in clinical studies with 
cabozantinib. The development of any new or progressive, unexplained neurological symptoms should 
be assessed for underlying causes. 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, headache, 
visual disturbances, confusion or altered mental function. Cabozantinib treatment should be 
discontinued in subjects with RPLS. 
7.4.2.12 HEPATOCELLULAR TOXICITY 
Elevation of aminotransferases (ALT and AST): Evaluation of subjects with elevated transaminases or 
bilirubin should be individualized and guided by the presence of specific risk factors such as liver 
conditions (e.g., liver cirrhosis, metastases to the liver, thrombosis of portal or hepatic vein, 
hepatocellular carcinoma, hepatitis), concomitant hepatotoxic medication, alcohol consumption, and 
cancer related causes.  
Cabozantinib should be interrupted for related CTCAE Grade 3 or higher hepatic injury (transaminase 
increase to > 5  ULN) and when transaminase increases are accompanied by progressive elevations of 
total bilirubin, and/or elevations of coagulation tests (e.g., International Normalized Ratio [INR]). More 
frequent monitoring of transaminases should be considered and cabozantinib should be interrupted 
until the etiology of the abnormalities is determined and these abnormalities are corrected or stabilize 
at clinically acceptable levels. Cabozantinib should be discontinued if hepatic dysfunction is not reversed 
despite interruption of study treatment. Elevations of aminotransferases when hepatic metastases are 
present may not require dose modifications if there are no progressive changes in the 
aminotransferases (less than a doubling) and if there are no progressive elevations in serum bilirubin 
concentration or coagulation factors. Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total 
bilirubin without other explanation (such as initial findings of cholestasis and obstructive disease, viral 
hepatitis, pre-existing or acute liver disease, or another drug capable of causing the observed injury) can 
indicate drug-induced liver injury (DILI). Study drug should be permanently discontinued in cases 
determined to be DILI according to Hy’s Law review. 
7.4.2.13 INFECTIONS AND INFESTATIONS 
Infections are commonly observed in cancer subjects. Predisposing risk factor include a decreased 
immune status (e.g., after myelosuppressive anticancer therapies, splenectomy), destructive growth of 
the underlying malignancy including bone marrow infiltration with suppression of normal 
hematopoiesis, as well as the presence of IV devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until adequate healing has taken place. 
7.4.2.14 BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated complications have 
been observed after administration of cabozantinib and may be managed with dose interruptions 


  
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and/or dose reductions. Subjects with hematologic toxicities may require additional or more frequent 
laboratory tests according to institutional guidelines. 
Dose reductions or dose interruptions for hematological toxicities are not mandated but can be applied 
as clinically indicated. Supportive care for thrombocytopenia or anemia, such as transfusions, may be 
managed according to institutional guidelines. The use of colony-stimulating growth factors should be 
considered. Febrile neutropenia or evidence of infection associated with neutropenia must be assessed 
immediately and treated appropriately and in a timely manner according to institutional guidelines. 
7.4.2.15 FATIGUE 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression and/or 
anxiety), poor nutrition, dehydration, sleep disturbance, and hypothyroidism should be ruled out and 
treated according to standard of care. Pharmacological management should be considered after disease 
specific morbidities have been excluded when not prohibited.  
7.4.2.16 WEIGHT LOSS 
Anorexia and weight loss should be managed according to local standard of care including nutritional 
support. Pharmacologic therapy should be considered for appetite enhancement when not prohibited 
by a particular protocol. 
7.4.2.17 CORRECTED QT PROLONGATION 
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a placebo-
controlled study in subjects with MTC. A mean increase in QTcF of 10-15 ms was observed after 4 weeks 
after initiating cabozantinib treatment. A concentration-QTc relationship could not be definitively 
established. Changes in cardiac wave form morphology or new rhythms were not observed. No 
cabozantinib-treated subjects in this study had a QTcF > 500 ms. Review of the larger safety database 
(~5000 subjects exposed to cabozantinib in clinical trials and in post-marketing experience) confirmed 
the absence of safety concerns associated with QT prolongation. There were no events of torsades de 
pointes reported. 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value > 500 ms, two additional ECGs 
must be performed with intervals not less than 3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms, the following actions must be taken: 
• 
Interrupt cabozantinib treatment 
• 
Hospitalize symptomatic subjects (e.g., with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology evaluation and 
management 
• 
Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• 
Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities as clinically 
indicated 


  
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• 
Check concomitant medications for any medication that may have contributed to QT prolongation, 
and if possible, discontinue these medications (http://www.qtdrugs.org) 
• 
Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise determined by 
consultation with a cardiologist or appropriate expert. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation and 
symptoms have resolved. Cabozantinib treatment may be restarted at a reduced dose level if all of the 
following conditions are met: 
• 
Symptoms are determined to be unrelated to the QT interval prolongation 
• 
The QTcF value > 500 ms is not confirmed  
• 
Cabozantinib treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 ms. 
• 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 2 
weeks for 1 month, then according to the protocol-defined time points. 
Cabozantinib treatment must be permanently discontinued if either of the following applies: 
• 
Cardiac evaluation confirms that symptoms are the consequence of QT interval prolongation 
• 
Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced dose 
7.4.2.18 ELECTROLYTE DISORDERS 
Serum electrolyte disorders including hyponatremia, hypokalemia, hypomagnesemia, and 
hypophosphatemia have been reported during treatment with cabozantinib, and serum electrolyte 
levels should be monitored frequently while receiving cabozantinib. Clinically relevant electrolyte 
disorders should be managed according to the dose modification guidelines as outlined in Section 7.3 or 
as clinically indicated. Standard clinical practice guidelines should be used for management of 
electrolyte disorders and may include oral or intravenous replacement.  
7.4.2.19 ENDOCRINE DISORDERS 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has been observed with 
cabozantinib treatment. Currently available data are insufficient to determine the mechanism of thyroid 
function test alterations and its clinical relevance. Management of thyroid dysfunction 
(e.g., symptomatic hypothyroidism) should follow accepted clinical practice guidelines. 
7.4.2.20 ANGIOEDEMA 
Angioedema should be managed according to standard practice. The subject should be observed until 
symptoms resolve, with particular attention to maintaining an open airway.  
 
8 
CONCOMITANT THERAPY 
8.1 
ALLOWED, PROHIBITED AND RESTRICTED THERAPIES 


  
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Allowed Therapy 
• 
Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
• 
Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical guidelines 
(e.g., ASCO or ESMO guidelines).  
• 
Bisphosphonates can be used to control bone loss or hypocalcemia if the benefit outweighs the risk 
per the investigator’s discretion. 
Note: osteonecrosis of the jaw has been reported in subjects using bisphosphonates (Section 
7.4.2.9). Oral examinations are recommended at screening to determine eligibility and periodically 
during the study. In addition, subjects should be advised regarding oral hygiene practice and to 
quickly report symptoms to the investigator. Frequent monitoring for potentially overlapping 
toxicities with study treatment is recommended.  
• 
Transfusions and hormone replacement should be utilized as indicated by standard clinical practice. 
• 
Individualized anticoagulation therapy with heparin is allowed if it can be provided safely and 
effectively under the following circumstances:  
o Therapeutic doses of LMWH after first dose of study treatment are allowed if clinically 
indicated (e.g., for the treatment of deep venous thrombosis), and the benefit outweighs the 
risk per the investigator’s discretion. For management of thromboembolic complications 
while on study, refer to Section 7.4.2.5.  
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not limited to, 
subject education regarding potential adverse drug reactions, monitoring laboratory 
parameters, dose adjustments (e.g., due to kidney dysfunction).  
o For restrictions on oral anticoagulants see below. 
Potential drug interactions with cabozantinib are summarized in Section 8.2. 
Prohibited or Restricted Therapy 
The following therapies are prohibited during the 28 day treatment with cabozantinib on ARM A: 
• 
Any investigational agent or investigational medical device. 
• 
Oral anticoagulants (e.g., warfarin or other coumarin-related agents, direct thrombin or direct FXa 
inhibitors, or antiplatelet agents such as clopidogrel, or chronic use of aspirin above low dose levels 
for cardioprotection per local applicable guidelines). 


  
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• 
Any nonprotocol systemic anticancer treatment (e.g., chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer under 
investigation). 
The following therapies should be avoided during the 28 day treatment with cabozantinib on ARM A. 
• 
Please review medications taken by the subject with your pharmacist/physician as this is not an all 
inclusive list of medications that may interact with cabozantinib.  
• 
Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be used based 
on a report of increased risk of tumor recurrence/progression associated with erythropoietin 
(Wright et al 2007). 
• 
Concomitant medications that are known to prolong the QTc interval should be avoided in subjects 
who receive cabozantinib until they have permanently discontinued cabozantinib treatment (refer 
to http://www.qtdrugs.org for a list of drugs which have the potential to prolong the QTc interval). 
• 
Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John’s Wort) 
may significantly decrease cabozantinib concentrations and should be avoided. Selection of 
alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is 
recommended.  
• 
Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who 
has been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the 
exposure to cabozantinib.  
• 
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., boceprevir, 
conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, telithromycin, and voriconazole) 
may increase cabozantinib concentrations and should be avoided. Grapefruit, star fruit, and Seville 
oranges may also increase plasma concentrations of cabozantinib and should be avoided. 
Additional information on potential drug interactions with cabozantinib is provided in Section 8.2. 
8.2 
POTENTIAL DRUG INTERACTIONS WITH CABOZANTINIB 
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) show that clinically 
relevant steady-state concentrations of cabozantinib appear to have no marked effect on the area under 
the plasma concentration-vs-time curve (AUC) of co-administered rosiglitazone, a CYP2C8 substrate. 
Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is 
not anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared to 
CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is 
unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at high 
cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, CYP2C8, 
CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. Results from a clinical 


  
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pharmacology study, XL184-006, showed that concurrent administration of cabozantinib with the strong 
CYP3A4 inducer, rifampin, resulted in an approximately 77% reduction in cabozantinib exposure (AUC 
values) after a single dose of cabozantinib in healthy volunteers. Chronic co-administration of 
cabozantinib with strong inducers of the CYP3A4 family (e.g., phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations. The chronic use of strong CYP3A4 inducers should be avoided. Other drugs that induce 
CYP3A4 should be used with caution because these drugs have the potential to decrease exposure (AUC) 
to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme 
induction potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration of 
cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in the 
cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-
administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., boceprevir, conivaptan, 
posaconazole, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
saquinavir, ritonavir, lopinavir, telaprevir, telithromycin, and voriconazole) may increase cabozantinib 
concentrations. Grapefruit, star fruit and Seville oranges may also increase plasma concentrations of 
cabozantinib and should be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that 
inhibit CYP3A4 should be used with caution because these drugs have the potential to increase exposure 
(AUC) to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme inhibition potential is recommended.  
Please refer to the drug interaction tables at the following websites for lists of substrates, inducers, and 
inhibitors of selected CYP450 isozyme pathways: 
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab
eling/ucm080499.htm).  
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly 
protein bound drugs should be used with caution with cabozantinib because there is a potential 
displacement interaction that could increase free concentrations of cabozantinib and/or a co-
administered highly protein-bound drug (and a corresponding increase in pharmacologic effect). 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting recommendations 
should be followed. In vitro data suggest that cabozantinib is unlikely to be a substrate for 
P-glycoprotein, but it does appear to have the potential to inhibit the P-glycoprotein transport activity. 
Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered 
substrates of P-glycoprotein. Additional details related to these overall conclusions can be found in the 
investigator brochure. 


  
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Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-relevant effect 
on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of gastric pH modifying 
agents (i.e., PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects administered 
cabozantinib. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure. 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. Administration 
of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma concentrations. 
8.3 
STUDY TREATMENT ACCOUNTABILITY 
The investigator or designee will maintain accurate records of receipt of all study treatment including 
dates of receipt. In addition, accurate records will be kept regarding the date, lot number, and how 
much study treatment is dispensed and used by each subject in the study. Reasons for deviation from 
the expected dispensing regimen must also be recorded. At completion of the study, to satisfy 
regulatory requirements regarding drug accountability, all unused study treatment will be reconciled 
and destroyed according to applicable state, federal, and local regulations. 
 
9 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
  
9.1 
DISCONTINUATION OF STUDY INTERVENTION 
At any time, the study may be terminated by the study sponsor, the sponsoring institution, or by 
Exelixis. Should this be necessary, Exelixis and the investigator will arrange the procedures on an 
individual study basis after review and consultation. In terminating the study, Exelixis and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ interests. 
Upon study termination, the investigator(s) shall cease enrolling subjects into the study, and shall 
discontinue conduct of the study as soon as is medically practicable. 
10 SAFETY 
10.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
10.1.1 ADVERSE EVENTS (AES) 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, 
or disease temporarily associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. An adverse event can arise from any use of the drug (e.g. off-label use, 
use in combination with another drug) and with any route of administration, formulation, or dose, 


  
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including an overdose. This definition also includes AEs associated with medication errors and uses of 
the investigational product outside what is in the protocol, including misuse and abuse. Pre-existing 
medical conditions that worsen during the study should be recorded as AEs. Abnormal laboratory 
values, ECG findings, or vital signs are to be recorded as AEs if they meet the criteria described in this 
protocol. All untoward events that occur from the first dose of study drug through 30 days after the 
decision to discontinue study treatment (or the date the subject is deemed to be a screen failure) are to 
be recorded by the investigational site. This requirement includes AEs from unscheduled as well as 
scheduled visits and includes the new onset of or increase in pain during this period. 
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 current version of 
the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE). 
10.1.2 SERIOUS ADVERSE EVENTS (SAES) 
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:  
• 
Result in death; 
• 
Is life-threatening (i.e., in the opinion of the investigator, the AE places the subject at risk of 
death; it does not include an event that, had it occurred in a more severe form, might have 
caused death); 
• 
Requires inpatient hospitalization or results in prolongation of an existing hospitalization; 
o Note: While most hospitalizations necessitate reporting of an SAE, some hospitalizations 
do not require SAE reporting, as follows: elective or previously scheduled surgeries or 
procedures for pre-existing conditions that have not worsened after initiation of 
treatment (e.g., a previously scheduled ventral hernia repair); pre-specified study 
hospitalizations for observation; or events that result in hospital stays of fewer than 24 
hours and that do not require admission (e.g., an ER visit for hematuria that results in a 
diagnosis of cystitis and discharge home on oral antibiotics).  SAEs must, however, be 
reported for any surgical complication resulting in prolongation of the hospitalization. 
• 
Results in persistent or significant disability or incapacity: 
o Note: The term “disability” refers to events that result in a substantial disruption of a 
subject’s ability to conduct normal life function. 


  
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• 
Is a congenital anomaly or birth defect; 
• 
Is an important medical event (IME):  
o 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. 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. 
10.1.3 RELATIOSHIP TO STUDY TREATMENT 
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 or there is no evidence to support a causal 
relationship; 
• 
Related: A related AE is defined as an AE where a causal relationship between the event and 
the study treatment is a reasonable possibility. A reasonable causal relationship is meant to 
convey that there are facts (e.g., evidence such as dechallenge/rechallenge) or other clinical 
arguments to suggest a causal relationship between the AE and study treatment. Possibly and 
probably related AEs should be documented as related. 
10.1.4 SERIOUS ADVERSE EVENT REPORTING 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this must be 
documented on an SAE Report Form and include the following: (i) all SAEs that occur after starting 
cabozantinib and through 30 days after the decision to discontinue study treatment and (ii) any SAEs 
assessed as related to study treatment or study procedures (for patients on the cabozantinib arm), from 
the time of informed consent, even if the SAE occurs more than 30 days after the decision to 
discontinue study treatment. The prostatectomy is considered a standard of care procedure, not a study 
procedure. SAEs solely related to the prostatectomy will not be collected.  
All SAEs that are assessed by the PI as related to drug or study procedure and all pregnancy/lactation 
reports regardless of outcome must be sent to the Duke Safety Desk within one (1) business day of the 
PI’s knowledge of the event. The Duke Safety Desk will report to Exelixis within one (1) business day of 
the receipt of the report. The reports must be sent to drugsafety@exelixis.com or fax 650-837-7392. 
• 
The PI will perform adequate due diligence with regard to obtaining follow-up information on 
incomplete reports. All follow-up information must be sent to Exelixis within one (1) business 


  
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day of the PI’s receipt of the new information. Upon Exelixis request, the PI will query for follow-
up information. 
10.1.5 REGULATORY REPORTING 
The Investigator will assess the expectedness of each related SAE. The current cabozantinib Reference 
Safety Information (Appendix K of the most recent approved Investigator Brochure) will be used as the 
reference document for assessing the expectedness of the event with regard to cabozantinib. All serious 
unexpected adverse drug reactions (unexpected related SAEs) must be reported to all appropriate 
regulatory authorities and Ethics Committees  by the investigator as required by 21 CFR 312.32 or by 
Directive 2011/20/EC: 
• 
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) or a CIOMS-1 
form; 
• 
Exelixis reserves the right to upgrade the Investigator assessment of an SAE based on Exelixis 
assessment. 
• 
Institutions and PIs shall promptly provide all information requested by Exelixis regarding all 
adverse events occurring during the conduct of the study.  
• 
The PI is responsible for complying with all regulatory authority reporting requirements for the 
study that are applicable to the sponsor of a clinical trial. The PI shall provide a copy of all 
responses to regulatory agency requests, periodic reports, and final study reports to Exelixis 
within one (1) business day of the submission.   
• 
Exelixis will provide relevant product safety updates and notifications, as necessary. In the case 
of multi-center studies, it is the responsibility of the sponsoring PI/Institution to disseminate 
these updates to participating PIs. 
10.2 OTHER SAFETY CONSIDERATIONS 
10.2.1 LABORATORY DATA 
All laboratory data required by this protocol and any other clinical investigations should be reviewed. 
Any abnormal value that leads to a change in subject management (e.g., 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. 
10.2.2 PREGNANCY/LACTATION EXPOSURE 
Pregnancy in partner, although not an SAE, should be reported to Exelixis. The partner will be asked to 
sign a pregnant partner form allowing collection of her information and the offspring. The outcome of a 
pregnancy (for the partner of a subject) and the medical condition of any resultant offspring must be 
reported to Exelixis, if the pregnant partner agrees. Any birth defect or congenital anomaly must be 


  
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reported as an SAE, and any other untoward events occurring during the pregnancy must be reported as 
AEs or SAEs, as appropriate. 
10.2.3 MEDICATION ERRORS/OVERDOSE 
Any overdose, or study drug administration error that results in an AE, even if it does not meet the 
definition of serious, requires reporting within one (1) business day to Exelixis. 
10.2.4 FOLLOW-UP OF ADVERSE EVENTS 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after the 
decision to discontinue study treatment must be followed until either resolution of the event or 
determination by the investigator that the event has become stable or irreversible. This follow-up 
guidance also applies to related SAEs that occur more than 30 days after the decision to discontinue 
study treatment. The status of all other continuing AEs will be documented as of 30 days after the 
decision to discontinue study treatment. 
10.3 SAFETY MONITORING 
Safety data will be monitored by the PI, urology co-PI and statistician by regular reviews. This monitoring 
is separate, but complementary to the stopping rules.   
A safety assessment will at the following time points: 
• 
The first 6 subjects receiving cabozantinib treatment have completed the day 57-85 safety visit. 
• 
The first 12 subjects receiving cabozantinib treatment have completed the day 57-85 safety visit. 
• 
The first 18 subjects receiving cabozantinib treatment have completed the day 57-85 safety visit. 
The statistician or their designee will compile a report of all AEs documented on study, including any 
SAEs and DLTs. The PI and urology co-PI will review the report and determine if the safety data warrant 
a change to the study. Enrollment will not be suspended for the safety assessments.  
11 STATISTICAL CONSIDERATIONS 
11.1 STATISTICAL METHODS 
Safety Lead-In and Stopping Rules.  The first 6 subjects assigned to cabozantinib treatment will 
constitute the Safety Lead-In cohort, which will be only accrued at Duke.  Of these 6 subjects receiving 
cabozantinib, the first 3 subjects will be enrolled sequentially (after each prior subject completes the day 
57-85 safety visit).  After this, the remaining 3 subjects receiving cabozantinib may be enrolled non-
sequentially in the cohort.  If there are ≥2 dose-limiting toxicities (DLTs) in the first 6 subjects, the trial 
will be stopped for safety purposes (first stopping rule).  DLTs are defined as CTCAE v5 grade ≥2 wound 
dehiscence or wound complication, any grade fistula, grade ≥2 hemorrhage of any type, grade ≥3 
infections [except urinary tract infections (UTIs) which are expected in this population], any AE that 
leads to permanent discontinuation of cabozantinib, or other grade ≥3 cabozantinib-related 


  
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perioperative complications. The DLT period is defined as day 1 of drug through day 57 of the protocol 
(inclusive). The seventh subject randomized to cabozantinib may not be enrolled until the sixth subject 
completes the day 57-85 safety visit and the Duke principal investigator agrees that the stopping rule 
should not be put into effect. From the seventh subject on, subjects may be accrued at ex-Duke site(s). A 
second stopping rule will be triggered if there are ≥3 DLTs in the first 12 subjects treated with 
cabozantinib.  In the event that a stopping rule is triggered, thorough review of the cabozantinib-treated 
patients’ files will be performed and the Duke principal investigator will consider whether the trial can 
be redesigned or should be permanently discontinued.   
Sample Size Justification.  The primary endpoint of this randomized phase II study is the 
apoptotic index by cleaved caspase-3 in prostatectomy specimens following 4 weeks of treatment with 
cabozantinib compared with prostatectomy specimens of untreated patients.  The target sample size of 
convenience is 30 patients where the randomization allocation ratio will be 2:1 cabozantinib-to-control. 
The randomization will not be stratified on any variable. The null hypothesis is that the mean apoptotic 
indices are equal between the two groups. The percent of tumor cells positive for cleaved caspase 3 
staining for each patient will be evaluated for the primary objective.  The 6 subjects assigned during the 
Safety Lead-In Cohort are included in the 30 patient sample size and 2:1 randomization allocation ratio.  
Based on data from a prior, unpublished pre-prostatectomy study of sunitinib, we expect the 
controls to have minimal staining (i.e., ≤5%).   In the proposed study we will enroll 10 controls and 20 
cabozantinib-treated patients to demonstrate increased staining (i.e., >5%).   A two sample t-test will be 
used to compare group means. With 10 and 20 evaluable patients in the control and cabozantinib-
treated groups, respectively, the test will provide 70% power to detect a mean (for positive tumor cells 
percentage) difference of one-fold standard deviation based on a two-sided type I error of 0.05; or 96% 
power to detect an one-and-half fold standard deviation difference.  Assuming a 10% unevaluable rate, 
we will enroll up to 33 patients total to have 30 evaluable patients. 
Data Analysis.  Box plots and statistical summaries of apoptotic (cleaved caspase-3, TUNEL), 
proliferation (Ki-67), and MVD (CD31) indices will be presented. In addition, the t-test will be used to 
compare the two arms on apoptotic index, proliferation and MVD indices. Further, the Chi-square test 
will be used to compare the two treatment arms on pathologic complete response rate (pCR) and 
pathologic T2 (pT2) rate.  The angiome, gene expression, cell-free DNA and mesenchymal markers 
analyses will be reported descriptively as the trial’s limited sample size will not permit definitive 
analyses for these exploratory objectives. The t-test will be used to compare the two arms’ serum and 
tissue androgen and androgen precursor levels. 
   
12 DATA QUALITY  ASSURANCE 
Accurate and reliable data collection will be ensured by verification and crosscheck of the CRFs against 
the investigator’s records by the study monitor (source document verification) and by the maintenance 
of a drug–dispensing log by the investigator. 
13  STUDY COMMITTEES 


  
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13.1 MONITORING 
This clinical research study will be monitored both internally by the PI and institutionally by the Duke 
Cancer Institute (DCI).  In terms of internal review the PI will continuously monitor and tabulate 
adverse events.  Appropriate reporting to the Duke University Medical Center IRB will be made.  If an 
unexpected frequency of Grade III or IV events occur, depending on their nature, action appropriate 
to the nature and frequency of these adverse events will be taken.  This may require a protocol 
amendment, dose de-escalation, or potentially closure of the study.  The PI of this study will also 
continuously monitor the conduct, data, and safety of this study to ensure that: 
• 
Interim analyses occur as scheduled; 
• 
Stopping rules for toxicity and/or response are met; 
• 
Risk/benefit ratio is not altered to the detriment of the subjects; 
• 
Appropriate internal monitoring of AEs and outcomes is done; 
• 
Over-accrual does not occur; 
• 
Under-accrual is addressed with appropriate amendments or actions; 
• 
Data are being appropriately collected in a reasonably timely manner. 
DCI review and monitoring of this protocol occurs in accordance with the NCI-approved Data and 
Safety Monitoring Plan.  Briefly, protocol review begins with an initial review by the Cancer Protocol 
Committee (CPC), which assesses the ethics and safety of the protocol.  Documentation of these 
assessments will be maintained.  Formal, independent monitoring will be conducted by the DCI 
Monitoring Team after the first 3 subjects are enrolled, followed by annual monitoring of 1-3 
subjects until the study is closed to enrollment and subjects are no longer receiving study 
interventions that are more than minimal risk.  DCI Monitoring Team reports and additional 
data/safety/toxicity reports submitted by the PI will be reviewed by the Safety Oversight Committee 
(SOC) on an annual basis.  Additional monitoring may be prompted by findings from monitoring 
visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns.  Monitoring 
visits may also be initiated upon request by DUHS and DCI Leadership, CPC, SOC, the Duke Office of 
Audit, Risk and Compliance, a sponsor, an investigator, or the IRB.   All study documents must be 
made available upon request to the DCI Monitoring Team and other authorized regulatory 
authorities, including but not limited to the National Institute of Health, National Cancer Institute, 
and the FDA.  Every reasonable effort will be made to maintain confidentiality during study 
monitoring 
13.2 SAFETY OVERSIGHT COMMITTEE 
The Duke Cancer Institute SOC is responsible for annual data and safety monitoring of DUHS 
sponsor-investigator Phase I and II, therapeutic interventional studies that do not have an 
independent Data Safety Monitoring Board (DSMB).  The primary focus of the SOC is review of safety 
data, toxicities and new information that may affect subject safety or efficacy.  Annual safety reviews 
includes but may not be limited to review of safety data, enrollment status, stopping rules if 
applicable, accrual, toxicities, reference literature, and interim analyses as provided by the sponsor-


  
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investigator.  The SOC in concert with the DCI Monitoring Team oversees the conduct of DUHS 
cancer-related, sponsor-investigator therapeutic intervention and prevention intervention studies 
that do not have an external monitoring plan, ensuring subject safety and that the protocol is 
conducted, recorded and reported in accordance with the protocol, standing operating procedures 
(SOPs), Good Clinical Practice (GCP), and applicable regulatory requirements. 
13.3 DATA MANAGEMENT AND PROCESSING 
13.3.1 STUDY DOCUMENTATION 
Study documentation includes but is not limited to source documents, case report forms, monitoring 
logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records. 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories and at medico-technical departments involved in the clinical trial.  When possible, 
the original record should be retained as the source document.  However, a photocopy is acceptable 
provided that it is a clear, legible, and an exact duplication of the original document. 
13.3.2 CASE REPORT FORMS (CRFS) 
The electronic CRF will be the primary data collection document for the study.  The CRFs will be 
updated in a timely manner following acquisition of new source data.  Only the key personnel 
delegated on the delegation of authority log are permitted to make entries, changes, or corrections 
in the CRF. 
An audit trail will be maintained automatically by the electronic CRF management system.  All users 
of this system will complete user training, as required or appropriate per regulations. 
13.3.3 DATA MANAGEMENT PROCEDURES AND DATA VERIFICATION 
Users of the electronic CRF will have access based on their specific roles in the protocol.   


  
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Completeness of entered data will be checked automatically by the eCRF system, and users will be 
alerted to the presence of data inconsistencies.  Additionally, the data manager and project manager 
will cross-reference the data to verify accuracy.  Missing or implausible data will be highlighted for 
the PI requiring appropriate responses (i.e. confirmation of data, correction of data, completion or 
confirmation that data is not available, etc.). 
The database will be reviewed and discussed prior to database closure, and will be closed only after 
resolution of all remaining queries.  An audit trail will be kept of all subsequent changes to the data. 
13.3.4 STUDY CLOSURE 
       Following completion of the studies, the PI will be responsible for ensuring the following activities: 
- 
Data clarification and/or resolution 
- 
Accounting, reconciliation, and destruction/return of used and unused study drugs 
- 
Review of site study records for completeness 
- 
Shipment of all remaining laboratory samples to the designated laboratories 
 
14 ADMINISTRATIVE AND ETHICAL CONSIDERATIONS 
14.1 LOCAL REGULATIONS 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” (GCP) ICH 
E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct of the study 
complies with the basic principles of GCP as outlined in the current version of 21 Code of Federal 
Regulations, subpart D, Part 312, “Responsibilities of Sponsors and Investigators” Part 50, “Protection of 
Human Subjects” and Part 56, “Institutional Review Boards.” 
The protocol, informed consent form, advertising material, and additional protocol-related documents 
must be submitted to the DUHS Institutional Review Board (IRB) and DCI Cancer Protocol Committee 
(CPC) for review.  The study may be initiated only after the Principal Investigator has received written 
and dated approval from the CPC and IRB. 
The Principal Investigator must submit and obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent form.  The CPC should be informed about any 
protocol amendments that potentially affect research design or data analysis (i.e. amendments affecting 
subject population, inclusion/exclusion criteria, agent administration, statistical analysis, etc.). 
The Principal Investigator must obtain protocol re-approval from the IRB within 1 year of the most 
recent IRB approval.  The Principal Investigator must also obtain protocol re-approval from the CPC 
within 1 year of the most recent IRB approval, for as long as the protocol remains open to subject 
enrollment. 
14.2 INFORMED CONSENT 


  
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The informed consent form must be written in a manner that is understandable to the subject 
population.  Prior to its use, the informed consent form must be approved by the IRB. 
The Principal Investigator or authorized key personnel will discuss with the potential subject the purpose 
of the research, methods, potential risks and benefits, subject concerns, and other study-related 
matters.  This discussion will occur in a location that ensures subject privacy and in a manner that 
minimizes the possibility of coercion.  Appropriate accommodations will be made available for potential 
subjects who cannot read or understand English or are visually impaired.  Potential subjects will have 
the opportunity to contact the Principal investigator or authorized key personnel with questions, and 
will be given as much time as needed to make an informed decision about participation in the study. 
Before conducting any study-specific procedures, the Principal Investigator or designee must obtain 
written informed consent from the subject or a legally acceptable representative.  The original informed 
consent form will be stored with the subject’s study records, and a copy of the informed consent form 
will be provided to the subject.   
If new safety information results in significant changes in the risk/benefit assessment, the consent form 
should be reviewed and updated as necessary. All subjects (including those already being treated) 
should be informed of the new information, should be given a copy of the revised form, and should give 
their consent to continue in the study. 
14.3 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE  
This study is being conducted under a United States Investigational New Drug application or other 
Clinical Trial Application, as appropriate. This protocol (and any modifications) and appropriate consent 
procedures must be reviewed and approved by an IRB/EC. This board must operate in accordance with 
current local, regional, and federal regulations. The investigator will send a letter or certificate of IRB/EC 
approval to Exelixis (or designee) before subject enrollment and whenever subsequent modifications to 
the protocol are made.     
14.4 PROTOCOL AMENDMENTS 
All protocol amendments must be initiated by the Principal Investigator and approved by the IRB prior to 
implementation.  IRB approval is not required for protocol changes that occur to protect the safety of a 
subject from an immediate hazard.  However, the Principal Investigator must inform the IRB and all 
other applicable regulatory agencies of such action immediately. 
The CPC will be informed about any protocol amendments that potentially affect research design or 
data analysis (i.e. amendments affecting subject population, inclusion/exclusion criteria, agent 
administration, etc.). 
14.5 RECORDS RETENTION 


  
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The Principal Investigator will maintain study-related records for a period of at least six years after study 
completion per Duke policy.   
14.6 CONFLICT OF INTEREST 
The Principal Investigator and Sub-Investigators must comply with applicable federal, state, and local 
regulations regarding reporting and disclosure of conflict of interest.  Conflicts of interest may arise from 
situations in which financial or other personal considerations have the potential to compromise or bias 
professional judgment and objectivity.  Conflicts of interest include but are not limited to royalty or 
consulting fees, speaking honoraria, advisory board appointments, publicly-traded or privately-held 
equities, stock options, intellectual property, and gifts. 
The Duke University School of Medicine’s Research Integrity Office (RIO) reviews and manages research-
related conflicts of interest.  The Principal Investigator and Sub-Investigators must report conflicts of 
interest annually and within 10 days of a change in status, and when applicable, must have a 
documented management plan that is developed in conjunction with the Duke RIO and approved by the 
IRB/IEC. 
14.7 CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications (including protocol amendments) may be made and will be prepared, reviewed, 
and approved by representatives of the investigator. Protocol modifications or amendments must be 
reviewed and approved by Exelixis prior to implementation. 
All protocol modifications must be submitted to the IRB/EC for information and approval in accordance 
with local requirements and to regulatory agencies if required. Approval must be obtained before any 
changes can be implemented, except for changes necessary to eliminate an immediate hazard to study 
subjects or those that involve only logistical or administrative aspects of the trial (e.g., change in monitor 
or change of telephone number). 
14.8 CONDITIONS FOR TERMINATING THE STUDY  
At any time, the study may be terminated by the study sponsor, the sponsoring institution, or by 
Exelixis. Should this be necessary, Exelixis and the investigator will arrange the procedures on an 
individual study basis after review and consultation. In terminating the study, Exelixis and the 
investigator will ensure that adequate consideration is given to the protection of the subjects’ interests. 
Upon study termination, the investigator(s) shall cease enrolling subjects into the study, and shall 
discontinue conduct of the study as soon as is medically practicable. 
14.9 STUDY DOCUMENTATION AND RECORD-KEEPING 
14.9.1 INVESTIGATOR’S FILES AND RETENTION OF DOCUMENTS   


  
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Study documentation includes but is not limited to source documents, case report forms (CRFs), 
monitoring logs, appointment schedules, study team correspondence with sponsors or regulatory 
bodies/committees, and regulatory documents that can be found in the DCI-mandated “Regulatory 
Binder”, which includes but is not limited to signed protocol and amendments, approved and signed 
informed consent forms, FDA Form 1572, CAP and CLIA laboratory certifications, and clinical supplies 
receipts and distribution records 
Source documents are original records that contain source data, which is all information in original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source documents include but are not limited to hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical trial.  When possible, the original record 
should be retained as the source document.  However, a photocopy is acceptable provided that it is a 
clear, legible, and an exact duplication of the original document. 
An electronic case report form (CRF) will be the primary data collection document for the study.  Only 
the key personnel delegated on the delegation of authority log are permitted to make entries, changes, 
or corrections in the CRF.  For electronic CRFs, an audit trail will be maintained by the electronic CRF 
management system. 
14.9.2 SOURCE DOCUMENTS AND BACKGROUND DATA 
Upon request, the investigator will supply its licensees and collaborators with any required background 
data from the study documentation or clinic records. This is particularly important when CRFs are 
illegible or when errors in data transcription are suspected. In case of special problems or governmental 
queries or requests for audit inspections, it is also necessary to have access to the complete study 
records, provided that subject confidentiality is protected. 
14.9.3 AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this study must be made available, after 
appropriate notification, to qualified personnel from the Exelixis Quality Assurance Unit (or designee) or 
to health authority inspectors. The verification of the CRF data must be by direct inspection of source 
documents. 
14.9.4 CASE REPORT FORMS 
For enrolled subjects, all and only data from the procedures and assessments specified in this protocol 
and required by the CRFs should be entered on the appropriate CRF. Data from some procedures 
required by the protocol, such as physical examinations and laboratory results, will be recorded only on 
the source documents and will not be transcribed to CRFs. Additional procedures and assessments may 


  
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be performed as part of the investigator’s institution or medical practice standard of care and may not 
be required for CRF entry.  
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI or 
authorized delegate from the study staff. 
All paper forms should be typed or filled out using indelible ink and must be legible. Errors should be 
crossed out but not obliterated, the correction inserted, and the change initialed and dated by the 
investigator or his or her authorized delegate.  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data in the 
CRFs and in all required reports. 
14.10 DATA AND SAFETY MONITORING THE STUDY  
Data and Safety Monitoring will be performed in accordance with the external site Data and Safety 
Monitoring Plan, provided under separate cover.   
14.11 CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The Principal Investigator will ensure that subject privacy and confidentiality of the subject’s data will be 
maintained.   
To protect privacy, every reasonable effort will be made to prevent undue access to subjects during the 
course of the study.  All research related interactions with the participant will be conducted by qualified 
research staff who are directly involved in the conduct of the research study. 
To protect confidentiality, subject files in paper format will be stored in secure cabinets under lock and 
key accessible only by the research staff. Electronic records of subject data will be maintained using a 
dedicated web-access secure database, which is housed in an encrypted and password-protected server 
behind the Duke firewall. Access to electronic databases will be limited to delegated personnel.  The 
security and viability of the IT infrastructure will be managed by the DCI and/or Duke Medicine.   
Upon completion of the study, research records will be archived and handled per institutional policy.     
Subject names or identifiers will not be used in reports, presentations at scientific meetings, or 
publications in scientific journals. 
14.12 PUBLICATIONS OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the study 
results; provided that the PI will provide Exelixis with a copy of any proposed publication or release: (a) 
for abstracts, slide presentations or posters, at least five (5) business day prior to submission (in the case 
of abstracts) or first public presentation (in the case of slide presentations and posters); and (b) at least 
thirty (30) days in advance of first submission and each subsequent submission in the case of 


  
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manuscripts and also comply with any provisions regarding publication that are agreed to between the 
PI’s institution (e.g., institution name.) and Exelixis, Inc. in the Clinical Trial Agreement related to this 
study.  
 
 
 


  
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15 ABBREVIATIONS 
  
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IND 
Investigational New Drug Application 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOE 
Schedule of Events 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


  
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17  APPENDICES 
17.1 APPENDIX A:  ECOG AND KARNOFSKY PERFORMANCE SCALE CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able 
to 
continue 
all 
predisease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease 
1 
Symptoms, 
but 
ambulatory. 
Restricted in physically strenuous 
80 
Normal activity with effort, some 
signs or symptoms of disease 


  
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activity but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
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 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  
> 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