Clinical trial NCT01683994
Conditions: Prostatic Neoplasms
Keywords: Angiogenesis Inhibitors Small Molecules Tyrosine Kinase Inhibitor
Sponsor: National Cancer Institute (NCI)
Start date: 2012-09-07; Completion date: 2019-01-16
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate tumors respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer. Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective treatment for this type of cancer.

Objectives:

\- To test the safety and effectiveness of cabozantinib with standard treatments for advanced prostate cancer.

Eligibility:

\- Individuals at least 18 years of age who have advanced prostate cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will also be performed.
* Participants will receive the cancer drugs over 21-day cycles of treatment. They will take docetaxel and cabozantinib on day 1 of each cycle. Each docetaxel infusion will take about 1 hour. They will also take prednisone by mouth twice each day.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take the study drugs for as long as their cancer does not worsen and side effects are not too severe.

Detailed description:
Background:

* Docetaxel is established as first-line chemotherapy in patients with metastatic castrate resistant prostate cancer (CRPC). However; it is increasingly recognized that combining docetaxel with other agents of clinical activities without overlapping toxicities could simultaneously target different cellular signaling pathways vital for tumor survival, producing either additive or synergistic activities.
* Inhibition of angiogenesis, either as a stand-alone approach or in combination with chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several antiangiogenic agents that are now in clinical trials in this population of patients.
* Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its resistance mechanism. It is an inhibitor of multiple receptor tyrosine kinases including tyrosine-protein kinase Met (c-Met), vascular endothelial growth factor receptor 2 (VEGFR2) and rearranged during transfection (RET).
* In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities across many solid tumor types.

Objectives:

* To determine the safety profile of cabozantinib in combination with docetaxel and prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II dose in combination with docetaxel
* To determine the relative efficacy (in terms of progression free survival (PFS)) of docetaxel and cabozantinib compared to docetaxel alone

Eligibility:

* Patients must have progressive metastatic CRPC. There must be radiographic evidence of disease after primary treatment with surgery or radiotherapy. If patients had been on flutamide, they must have disease progression at least 4 weeks after withdrawal. Patients on bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal. Withdrawal criteria apply only to patients on the above anti-androgens for at least the prior 6 months.
* Patients must be at least 18 years of age and able to give informed consent.
* Patients in the Phase II portion of the study must have progressed on abiraterone or enzalutamide

Design:

* The initial phase I portion of this study will test fixed dose docetaxel and prednisone in combination with cabozantinib at three escalating doses. Using a standard 3 + 3 design, three patients will initially be treated at each dose level until MTD has been defined.
* An expansion cohort will then be enrolled at the MTD to further characterize safety, toxicity and pharmacokinetic data and to obtain preliminary information on the efficacy of the combination treatment.
* In Phase II, patients will be enrolled to a randomized two-arm cohort comparing docetaxel in combination with cabozantinib to docetaxel alone with a primary endpoint of PFS.
* The accrual ceiling for the study, including the Phase I dose escalation and the expansion phases as well as the Phase II randomized phase, is set at 81.

Arms: arm 1: combination of cabozantinib, docetaxel and prednisone arm 2: docetaxel + prednisone only arm 3: docetaxel+ prednisone + cabozantinib
Interventions: intervention 1: Cabozantinib intervention 2: Docetaxel intervention 3: Prednisone
Intervention descriptions: intervention 1: Assigned dose given daily during each 21 day cycle. Treatment may continue until disease progression or intolerable toxicity. intervention 2: 75mg/m\^2 intravenous (IV) over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days until disease progression or intolerable toxicity. intervention 3: 5 mg by mouth (PO) twice a day during each 21 day cycle until disease progression or intolerable toxicity.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
1 
Version Date: 2/27/2017 
 
 
CTEP Study #: 9243 
Confidential  
 
Abbreviated Title: Phase I/II XL184 in mCRPC 
CTEP Protocol #: 
9243 
CC Protocol #: 
12-C-0204 Q 
Version Date:  
February 27, 2017 
Title: A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) plus 
Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer 
Coordinating Center: 
Center for Cancer Research 
Principal Investigator: 
William Dahut, M.D. A-F 
Genitourinary Malignancies Branch (GMB) 
Center for Cancer Research 
National Cancer Institute 
Building 10, Room 3-2571 
9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 240-760-6187 
Email: dahutw@mail.nih.gov 
 
Co-Investigators:  
 
Fatima Karzai, M.D., NIMHD A-F 
10 Center Drive, Room 13N240 
Bethesda, MD 20892 
Phone: 301-402-9134 
Email: Fatima.karzai@nih.gov 
Ravi Madan, M.D., GMB, CCR, NCI A-F 
10 Center Drive, Room 13N240 
Bethesda, MD 20892 
Phone: 301-480-7168 
Email: madanr@mail.nih.gov 
Andrea Apolo, M.D., GMB, CCR, NCI A-F 
10 Center Drive, Room 13N240 
Bethesda, MD 20892 
Phone: 301-480-0536 
Email: andrea.apolo@nih.gov 
James Gulley, M.D., Ph.D., GMB, CCR, NCI A-F 
10 Center Drive, Room 13N240 
Bethesda, MD 20892 
Phone: 301-480-7164 
Email: gulleyj@mail.nih.gov 
Howard Parnes, M.D. A-F 
Prostate and Urologic Cancer Research Group 
Division of Cancer Prevention, NCI 
9609 Medical Center Dr, Room 5E302 
Rockville MD 20850  
Phone: 240-276-7045 
Email: parnesh@mail.nih.gov 
 
John Wright, M.D., Ph.D. A-F 
Investigational Drug Branch, CTEP, DCTD, NCI 
9609 Medical Center Dr, Room 5W454 
Rockville MD 20850  
Phone: 240-276-6565 
Email: wrightj@ctep.nci.nih.gov 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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*Liang Cao, Ph.D. GB, CCR, NCI E, F 
37 Convent Drive, Room 6134 
Bethesda, MD 20892-1906 
Phone: 301-435-9039  
E-mail: caoli@mail.nih.gov 
 
*William Figg, Pharm.D., GMB, CCR, NCI E, F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 240-760-6179 
Email: wdfigg@mail.nih.gov 
*Donald P Bottaro, PhD, UOB, CCR, NCI E, F 
10 Center Drive, Room 1W-5832 
Bethesda, MD 20892 
Phone: 301-402-0922 
Email: bottarod@mail.nih.gov 
 
*Cindy Chau, Pharm.D., Ph.D., GMB, CCR, NCI E, F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 301-402-3622 
Email: chauc@mail.nih.gov 
*Jane Trepel, Developmental Therapeutics 
Branch, (DTB), CCR, NCI E, F 
10 Center Drive, Room 2N230 
Bethesda MD, 20892 
Phone: 301-496-1547 
Email: trepelj@mail.nih.gov 
*Douglas Price, Ph.D., GMB, CCR, NCI E, F 
10 Center Drive, Room 5A01 
Bethesda, MD 20892 
Phone: 301-451-5860 
Email: dkprice@mail.nih.gov 
Anna Couvillon, N.P., GMB, CCR, NCI A-F 
10 Center Drive, Room 13N224 
Bethesda, MD 20892 
Phone: 301-443-6211 
Email: couvilla@mail.nih.gov 
Guinevere Chun, R.N., OCD, CCR, NCI A, B, C, E, F 
10 Center Drive, Room 12N226 
Bethesda, MD 20892-1906 
Phone: 240-760-6065  
Email: gchun@mail.nih.gov 
 
Helen Owens, R.N., OCD, CCR, NCI A, B, C, E, F   *Seth Steinberg, PhD E, F 
10 Center Drive, Room 12N226 
 
      Biostatistics and Data Management Section 
Bethesda, MD 20892-1906                                  National Cancer Institute 
Phone: 240-760-6068                                           9609 Medical Center Drive, Room 2W334 
Email: howens@mail.nih.gov                              Rockville, MD 20850 
      Phone: 240-276-5563   
      Email: steinbes@mail.nih.gov 
 
Responsible Research Nurse: 
 
      Helen Owens, R.N., OCD, CCR, NCI 
 
 
Referral Contact/Study Coordinator: 
      Helen Owens, R.N., OCD, CCR, NCI 
 
 
 
 
 
 
      10 Center Drive, Room 12N226 
 
 
 
 
 
 
      Bethesda, MD 20892-1906 
      Phone: 240-760-6068 
      Email: howens@mail.nih.gov 
 
 
* not responsible for patient care 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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Confidential  
A. Obtain information by intervening or interacting with living individuals for research purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for research 
purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
 
Multi-Institution Contacts:  
 
Institutional PI: 
Joseph Kim, M.D. 
 
Prostate and Urologic Cancers Program,  
Signal Transduction Program 
Institution: Yale Comprehensive Cancer Center 
Institution FWA #: 2577 
Yale School of Medicine 
333 Cedar St, Fitkin 1, Rm 121 
New Haven, CT 06520 
Phone Number: 203-737-1600 
E-mail: joseph.kim@yale.edu 
 
IRB Contact: 
Christine Early 
IRB of Record Name: Yale University Human 
Investigations Committee IORG #: 4296 
55 College Street 
New Haven, CT  06510 
Phone Number: 203-785-4688 
Email: hrpp@yale.edu  
 
Pharmacy Contact:  
Thomas Ferencz, RPh, BCOP 
Smillow Cancer Center at Yale New Haven Hospital 
266 So, Frontage Road, Room 8-110 
New Haven, CT, 06510 
Phone Number: 203-200-4455 
Email: Thomas.ferencz@ynhh.org  
 
Institutional Contact:  
Matthew Piscatelli, BS CCRP 
2 Church Street South, Suite 507  
New Haven, CT, 06519 
Phone Number: 203-737-8367 
Email: matthew.piscatelli@yale.edu  


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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CTEP Supplied Agents:     
Drug Name: 
Cabozantinib (XL184) 
IND Number: 
116059 
NSC Number: 
761968 
Sponsor: 
CTEP 
Manufacturer: 
Exelixis 
 
Commercially available agents: 
Docetaxel and prednisone will be supplied by the local site pharmacy. 
 
 
Subjects of Study:        
Number 
Sex  
Age-Range 
81 
Male          
≥18 - 100 
 


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PRÉCIS 
Background: 
• Docetaxel is established as first-line chemotherapy in patients with metastatic castrate 
resistant prostate cancer (CRPC).  However; it is increasingly recognized that combining 
docetaxel with other agents of clinical activities without overlapping toxicities could 
simultaneously target different cellular signaling pathways vital for tumor survival, 
producing either additive or synergistic activities.   
• Inhibition of angiogenesis, either as a stand-alone approach or in combination with 
chemotherapy, has demonstrable antitumor efficacy against CRPC and there are several 
antiangiogenic agents that are now in clinical trials in this population of patients.   
• Cabozantinib (XL184) was developed as an inhibitor of both angiogenesis and of its 
resistance mechanism.  It is an inhibitor of multiple receptor tyrosine kinases including c-
Met, VEGFR2 and RET. 
• In single agent clinical studies, cabozantinib demonstrated, broad anti-tumor activities across 
many solid tumor types.   
Objectives: 
• To determine the safety profile of cabozantinib in combination with docetaxel and 
prednisone, and to determine the maximal tolerated dose (MTD) as recommended phase II 
dose in combination with docetaxel.  
• To determine the relative efficacy (in terms of PFS) of docetaxel and cabozantinib compared 
to docetaxel alone 
Eligibility: 
• Patients must have progressive metastatic CRPC. There must be radiographic evidence of 
disease after primary treatment with surgery or radiotherapy. If patients had been on 
flutamide, they must have disease progression at least 4 weeks after withdrawal. Patients on 
bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal. 
Withdrawal criteria apply only to patients on the above anti-androgens for at least the prior 6 
months. 
• Patients must be at least 18 years of age and able to give informed consent.  
• Patients in the Phase II portion of the study must have progressed on abiraterone or 
enzalutamide 
Design: 
• The initial phase I portion of this study will test fixed dose docetaxel and prednisone in 
combination with cabozantinib at three escalating doses. Using a standard 3 + 3 design, three 
patients will initially be treated at each dose level until MTD has been defined. 
• An expansion cohort will then be enrolled at the MTD to further characterize safety, toxicity 
and pharmacokinetic data and to obtain preliminary information on the efficacy of the 
combination treatment.   


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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• In Phase II, patients will be enrolled to a randomized two-arm cohort comparing docetaxel in 
combination with cabozantinib to docetaxel alone with a primary endpoint of PFS.  
• The accrual ceiling for the study, including the Phase I dose escalation and the expansion 
phases as well as the Phase II randomized phase, is set at 81. 
 


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SCHEMA 
Phase I portion 
Dose Escalation Schedule to determine MTD 
Dose Level 
Dose of cabozantinib 
Level -1 
 
20 mg PO every other day 
Level 1 
20 mg PO daily 
Level 2 
40* mg PO daily 
Level 3 
60 mg PO daily 
At all dose levels, subjects will also take: 
• Docetaxel: 75 mg/m2 IV day 1 of each 21 day cycle 
• Prednisone: 5 mg PO, twice daily 
• *40mg PO daily has been determined to be the MTD for the dose expansion 
cohort. 
 
Randomized Phase II Portion 
Unblinded Randomization 
Arm A* 
Docetaxel 75 mg/m2 
Prednisone 5 mg BID 
Arm B 
Docetaxel 75 mg/m2 
Prednisone 5 mg BID 
Cabozantinib 40 mg PO daily 
 
Patients treated until radiographic progression 


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TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................5 
SCHEMA .........................................................................................................................................7 
1 
OBJECTIVES .........................................................................................................................11 
1.1 
Primary Objective ........................................................................................................ 11 
1.2 
Secondary Objectives ................................................................................................... 11 
2 
BACKGROUND ....................................................................................................................11 
2.1 
Castrate Resistant Prostate Cancer ............................................................................... 11 
2.2 
IND Agent - Cabozantinib (XL184) ............................................................................ 13 
2.3 
Other Agents ................................................................................................................ 21 
2.4 
Rationale ...................................................................................................................... 22 
2.5 
Correlative Studies Background .................................................................................. 23 
3 
PATIENT SELECTION .........................................................................................................25 
3.1 
Eligibility Criteria ........................................................................................................ 25 
3.2 
Screening Evaluation ................................................................................................... 30 
4 
REGISTRATION AND RANDOMIZATION PROCEDURES ............................................31 
4.1 
Registration .................................................................................................................. 31 
4.2 
Randomization (Phase II Only) .................................................................................... 31 
5 
TREATMENT PLAN .............................................................................................................32 
5.1 
Phase I (Closed to Accrual as of Amendment dated 06-11-2014) ............................... 32 
5.2 
Phase II ......................................................................................................................... 32 
5.3 
Agent Administration ................................................................................................... 32 
5.4 
Definition of Dose-Limiting Toxicity .......................................................................... 34 
5.5 
General Concomitant Medication and Supportive Care Guidelines ............................ 36 
5.6 
On Study Assessments ................................................................................................. 40 
5.7 
Duration of Therapy ..................................................................................................... 42 
5.8 
Duration of Follow Up ................................................................................................. 42 
5.9 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 42 
6 
DOSING DELAYS/DOSE MODIFICATIONS ....................................................................44 
6.1 
Cabozantinib ................................................................................................................ 44 
6.2 
Docetaxel Dose Modifications ..................................................................................... 58 
6.3 
Study drug dose holidays ............................................................................................. 59 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................59 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ........................... 59 


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7.2 
Definitions .................................................................................................................... 65 
7.3 
Expedited Adverse Event Reporting to CTEP ............................................................. 68 
7.4 
Routine Adverse Event Reporting to CTEP................................................................. 69 
7.5 
NHLBI IRB and NHLBI Clinical Director (CD) Reporting ........................................ 70 
7.6 
Secondary Malignancy ................................................................................................. 71 
7.7 
Second Malignancy ...................................................................................................... 71 
7.8 
Data and Safety Monitoring Plan ................................................................................. 71 
8 
PHARMACEUTICAL INFORMATION ..............................................................................72 
8.1 
Cabozantinib (XL184) (NSC# 761968) ....................................................................... 72 
8.2 
Commercial Agents ...................................................................................................... 75 
9 
PHARMACOKINETIC, BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
(NCI SITE ONLY) .................................................................................................................76 
9.1 
Pharmacokinetic Studies .............................................................................................. 77 
9.2 
Biomarker Studies ........................................................................................................ 78 
9.3 
Sample Storage, Tracking and Disposition .................................................................. 81 
10 STUDY CALENDAR ............................................................................................................84 
11 MEASUREMENT OF EFFECT ............................................................................................86 
11.1 Antitumor Effect – Solid Tumors ................................................................................ 86 
12 DATA COLLECTION / DATA REPORTING .....................................................................92 
12.1 Data Collection............................................................................................................. 92 
12.2 Data Reporting ............................................................................................................. 93 
12.3 CTEP Multicenter Guidelines ...................................................................................... 94 
12.4 Collaborative Agreements Language ........................................................................... 94 
13 STATISTICAL CONSIDERATIONS ...................................................................................96 
13.1 Study Design/Endpoints ............................................................................................... 96 
13.2 Sample Size/Accrual Rate ............................................................................................ 96 
13.3 Analysis of Secondary Endpoints ................................................................................ 97 
14 HUMAN SUBJECTS PROTECTIONS .................................................................................97 
14.1 Rationale For Subject Selection ................................................................................... 97 
14.2 Participation of Children .............................................................................................. 98 
14.3 Participation of Subjects Unable to Give Consent ....................................................... 98 
14.4 Evaluation of Benefits and Risks/Discomforts ............................................................ 98 
14.5 Risks/Benefits Analysis ............................................................................................... 98 
14.6 Consent and Assent Process and Documentation ........................................................ 99 
15 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS .......................100 


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16 REFERENCES .....................................................................................................................101 
17 APPENDICES ......................................................................................................................106 
17.1 Appendix A: Performance Status Criteria.................................................................. 106 
17.2 Appendix B: Patient Information on Possible Drug Interactions............................... 107 
17.3 Appendix C: Guidelines for Prophylaxis and Treatment for Hypersensitivity Reactions 
(HSR) Associated with Docetaxel ............................................................................. 109 
17.4 Appendix D: CCR Patient Self-Administered Study Agent Compliance Log .......... 114 
17.5 Appendix E: CTEP Multicenter Guidelines ............................................................... 116 
17.6 Appendix F: CCR Problem Report Form .................................................................. 117 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
OBJECTIVES 
1.1 
PRIMARY OBJECTIVE 
• To determine the safety profile of cabozantinib in combination with docetaxel and 
prednisone, and to determine the maximal tolerated dose (MTD) as the recommended 
phase II dose in combination with docetaxel 
• To determine the relative efficacy (in terms of progression free survival) of docetaxel and 
cabozantinib compared to docetaxel alone 
 
1.2 
SECONDARY OBJECTIVES 
• To assess pharmacokinetics of each agent during combination therapy. 
• To evaluate antitumor activities of combination therapy via measurable disease as 
determined by Response Evaluation Criteria in Solid Tumors (RECIST) and Prostate 
Cancer Clinical Trials Working Group Criteria 21. 
• To assess changes in molecular biomarkers in the pathways of receptor tyrosine kinases 
and angiogenesis, as well as the biomarkers for bone metabolism. 
2 
BACKGROUND 
2.1 
CASTRATE RESISTANT PROSTATE CANCER 
Prostate cancer is the most common malignancy and the second leading cause of cancer-related 
deaths in American men. It is estimated that 217,730 men were diagnosed with prostate cancer 
and 32,050 died from this disease in 2010.2 Although the disease is initially responsive to 
androgen deprivation therapy, it invariably progresses and becomes resistant to androgen 
ablation in the majority of patients. This leads to the development of CRPC, which is defined as 
tumor growth despite castrate levels of androgens (serum testosterone < 50 ng/dL).1 Advanced 
CRPC carries significant morbidity and mortality, and often necessitates a transition to the 
treatment with chemotherapy to control tumor growth and prevent disseminated organ 
involvement. The role of chemotherapy in metastatic CRPC was  limited until 2004 when two 
pivotal phase III randomized trials, TAX 327 and SWOG 99-16, demonstrated an overall 
survival benefit of docetaxel (with prednisone or estramustine) compared to mitoxantrone and 
prednisone.3,4 Based on its modest survival benefit, docetaxel obtained FDA approval and was 
established as first-line chemotherapy in patients with metastatic CRPC.   
Strategies to improve clinical efficacy of docetaxel 
It is increasingly recognized that combining docetaxel with other agents of clinical activities 
without overlapping toxicities could simultaneously target different cellular signaling pathways 
vital for tumor survival, producing either additive or synergistic activities. Given the survival 
benefit conferred by docetaxel, it is encouraging that further studies using docetaxel-based 
combination therapies targeting multiple cellular mechanisms concurrently could be a viable 
option for this patient population. In fact, numerous trials have been conducted combining 
docetaxel with different agents of distinct mechanisms of action, including TKIs, angiogenic 
inhibitors, bone-targeted agents, BCL-2 inhibitors, immunologic agents, and vitamin D analogs.5 


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The available data so far has produced inconsistent results. Several phase II trials of combination 
treatment have indicated enhanced anti-tumor activity beyond docetaxel alone, whereas others 
have been proven to be futile. To consolidate the conflicting results published on docetaxel-
based therapies, a recent meta-analysis from 12 randomized combination trials with 2,244 
patients was performed. The trials were selected in the meta-analysis if they were randomized 
control trials studying first-line chemotherapy of histologically confirmed CRPC with docetaxel 
plus prednisone as the control arm. It demonstrated higher PSA response rate and longer overall 
survival in favor of docetaxel-based combinational therapies,6 thus, provided evidence for further 
endeavor to pursue docetaxel-based combination therapies. This opens up to a question that 
which molecular pathways are the most appropriate targets which can be incorporated into 
docetaxel-based regimen for metastatic CRPC patients.  
Anti-angiogenic Agents as Potential Partners for Docetaxel in Combination Therapy 
Targeting angiogenesis in combination therapy 
The significance of angiogenesis in promoting prostate cancer growth and metastasis has been 
well established.  Microvessel density was reported to be substantially higher in prostate cancer 
samples from patients with metastatic disease when compared with those without metastatic 
disease.7 Elevated plasma and urine levels of VEGF-A was found to be associated with 
metastatic progression and reduced survival in patients with prostate cancer,8 thus demonstrated 
the potential to serve as an independent prognostic factor in men with metastatic prostate 
cancer.9 Blocking tumor neovascularization via anti-angiogenic agents, e.g. bevacizumab, has 
been determined as an appealing approach in reducing proliferation and metastatic potential of 
various tumors, including prostate cancer.10 In an attempt to improve patient’s outcome in the 
first-line treatment setting, the benefit of addition of bevacizumab was assessed in the CALGB 
phase III trial (90401), where docetaxel, prednisone and bevacizumab was compared with 
docetaxel and prednisone in 1,050 men with metastatic CRPC. Although addition of 
bevacizumab led to significant improvements in PFS and PSA response rate but no significant 
difference in overall survival was noted.11 The negative result from this seemingly promising 
combination indicates refractoriness and resistance do occur during the course of anti-angiogenic 
treatment. Multiple mechanisms for acquired resistance have been postulated with supportive 
preclinical and clinical evidence. 
Controlling the escape from anti-angiogenesis  
Angiogenesis is a complex process and multiple mediators are involved at different cellular 
interface. The examples of these molecules are the families of VEGF, PDGF, FGF, ANG and 
TIE signaling system, TGF-β signaling, and the NOTCH and WNT signaling pathway, etc.12 
Resistance to VEGF inhibitor, such as bevacizumab, usually ensues as inhibition of angiogenesis 
via a single target which can be potentially overcome by shifting the balance to the production of 
other pro-angiogenic mediators given the redundancy of angiogenic system.12 Indeed, blocking 
neovascularization by VEGF antibody was found to induce hypoxia which in turn up-regulate 
angiogenic factors such as bFGF, chemokines and ephrin, and angiopoietin families, leading to 
anti-angiogenesis rescue.13 To overcome the hurdle of multiple pre-existing or induced pro-
angiogenic factors, we previously took the strategy of dual inhibition of angiogenesis by 
combining docetaxel, prednisone with two other agents of distinct anti-angiogenic properties, 
thalidomide and bevacizumab, in chemotherapy-naïve CRPC patients in a single arm phase II 
trial. Striking results were observed in that 90% of patients achieved PSA decline of > 50% with 
a 60% objective response rate among patients with measurable disease.14 The median time to 


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progression was 18.2 months and median OS was 28.2 months, comparing favorably to what was 
observed in TAX 327 and SWOG 9916.14 Subsequent ongoing phase II trial utilizing same 
strategy of dual angiogenic inhibition (phase II trial of docetaxel, bevacizumab, lenalidomide and 
prednisone in patients with metastatic CRPC) yielded similar activity as of last analysis in 
August 2011 (unpublished data). All patients developed Grade ¾ neutropenia, due to 
overlapping toxicity profiles of docetaxel and thalidomide, in the first trial, which necessitate the 
use of pegfilgrastim in the second trial. The superior antitumor activities from these two trials 
supports further research into this strategy, however, new targets lacking overlapping toxicities 
with docetaxel need to be sought to improve tolerability profile. 
Another mechanism of VEGF-independent tumor angiogenesis was elucidated by Pennacchietti 
et al. in cultured cells and mouse xenograft tumor model. Receptor tyrosine kinase c-Met, a 
protooncogene capable of cell invasion and metastasis upon binding to hepatocyte growth factor 
(HGF), was found overexpressed under hypoxic condition and this overexpression was inversely 
proportional to the blood vessel proximity.15 The up-regulation of c-Met sensitized it to HGF 
stimulation and resulted in increased cell motility and invasiveness (invasive switch).15 Hypoxia-
inducible factors (HIFs)-induced c-Met overexpression is considered a cellular coping 
mechanism in response to low oxygen levels upon selective inhibition of VEGF pathway. 
However, it potentially can serve as an effective outlet for tumor to escape anti-angiogenesis. In 
fact, a paracrine mechanism for HGF stimulation of c-Met has been largely implicated in the 
progression of prostate cancer.16 Upregulation of c-Met expression is frequently observed in 
prostate cancer tissues, particularly in metastatic tumor samples.16 Interestingly, the bone 
metastases expressed significantly more c-Met than did the lymph node metastases.17 AR 
signaling appears to negatively regulate the expression of c-Met as significantly elevated c-Met 
expression was observed during androgen deprivation therapy.18 This may potentiate c-Met-
driven metastasis resulting in the development of more aggressive CRPC. The fact that 
suppression of c-Met via RNA interference resulted in loss of hypoxia-enhanced, HGF-
stimulated cell branching,15 supports the use of combination of anti-angiogenic agents with c-
Met blocking agents for the prevention of both angiogenic and invasive switch and overcome the 
resistance to anti-angiogenesis. 
2.2 
IND AGENT - CABOZANTINIB (XL184)  
The search for dual inhibition of both angiogenesis and its resistance mechanism led to the 
development of XL 184 (Cabozantinib), a potent inhibitor of multiple receptor tyrosine kinases 
including c-Met, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. 
Cabozantinib is orally bioavailable as demonstrated by PK studies in rodent and non-rodent 
models. In vitro assays showed that cabozantinib was a substrate of CYP3A4-mediated 
metabolism. It is unlikely to be a substrate for P glycoprotein (P-gp) but it does appear to have 
the potential to inhibit the P-gp transport activity. It is highly protein-bound (99%) to human 
plasma proteins and its terminal-phase half-life (t1/2, z) values are 59.1 to 136 hours. In in-vivo 
target modulation studies, administration of cabozantinib to mice resulted in dose-dependent 
inhibition of MET, and VEGFR2 with IC50 values of 1.8 nM and 0.035 nM (Investigator 
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2.2.1 Nonclinical Development of cabozantinib 
2.2.1.1 
In Vivo Activity 
Inhibition of VEGF signaling pathway was previously shown to result in more invasive tumors 
in the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that spontaneously 
develops aggressive tumors19.  In RIP-Tag2 transgenic mice, tumors treated with XL184 were 
smaller (P <0.05) than in mice treated with vehicle or an anti-VEGF antibody, but were also less 
invasive (P <0.05) and had no liver metastases 20.  All mice treated with XL184 (n = 6) survived 
until 20 weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached 
that endpoint.  Tumor vascularity decreased after treatment, with reductions ranging from 67% at 
3 mg/kg to 83% at 30 mg/kg for 7 days 21.  Tumors were 35% smaller after XL184 treatment 
than corresponding values for vehicle control mice.  c-Met protein expression in tumors was 
slightly decreased, but phosphorylated c-Met was markedly reduced after treatment for 7 days.   
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four oral 
doses of 100 mg/kg 22.  XL184 increased tumor hypoxia (13-fold) and apoptosis (TUNEL; 2.5-
fold) at 8 and 4 hours after the first and second doses, respectively, when compared to vehicle-
treated tumors.  In addition, XL184 disrupted tumor vasculature by inducing endothelial cell 
death that negatively affected tumor viability.  XL184 treatment resulted in significant tumor 
growth inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) 
when compared to vehicle-treated tumors.  Dose-dependent inhibition was observed for the 3 and 
10 mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg doses.  
A single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 
days after which tumors began growing at a rate similar to vehicle-treated control tumors.  In 
addition, XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell 
line for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors.  The 3 
mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) 
when compared with predose tumor weights.  Subchronic administration of XL184 was well 
tolerated in mice and rats with no signs of toxicity, as determined by stable and/or increasing 
body weights during the treatment period. 
ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-receptor 
NP-1 used in a human prostate tumor xenograft study in mouse bone23.  ARCaP-M cells were 
injected into the tibia of nude mice on Day 1, and on Day 31 animals with established bone 
lesions were randomized to receive XL184 or vehicle daily (qd) for 7 weeks of treatment24.  
Tibiae from vehicle-treated animals exhibited both osteoblastic and osteolytic lesions, whereas 
tibiae from XL184 treated animals appeared mostly normal.  Thus, XL184 treatment blocked 
both osteoblastic and osteolytic progression of ARCaP-M xenograft tumors in bone. 
2.2.1.2 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well 
tolerated doses of XL184 and at plasma exposures comparable to exposure observed in clinical 
trials25.  XL184 produced prolonged inhibition of receptor phosphorylation, such as sustained 
inhibition of c-Met and VEGFR2 for 10 hours after administration of a single dose of XL184.  
This extended inhibition occurred in a manner that was generally predicted by plasma exposure, 
i.e., inhibition was diminished when plasma levels fell below approximately 20 μM for c-Met, 5 
μM for VEGFR2, and 23 μM for TIE-2. 


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Once daily administration of XL184 resulted in significant inhibition of c-Met phosphorylation 
in TT tumors, relative to tumors from vehicle control-treated mice, with maximal inhibition of 
70% seen at 60 mg/kg,25.  Dose-dependent inhibition of phosphorylation of c-Met and RET was 
observed among the 3, 10, and 30 mg/kg dose groups as well.   
c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 hours post 
dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively 
phosphorylated c-Met22.  This effect was reversible, as c-Met phosphorylation returned to basal 
levels by 48 hours after treatment.   
2.2.1.3 
Nonclinical Pharmacokinetics 
In the various xenograft models, plasma exposures were similar and plasma concentrations in the 
range of 3 to 27 μM were associated with efficacy 25.  In rats, plasma concentrations in the range 
of 5 to 15 μM were associated with maximal anti-tumor activity.  Despite the apparent 
requirement for high peak concentrations, trough concentrations as low as 0.1 μM were observed 
at highly efficacious doses in mice.  These results were consistent with in vivo target modulation 
studies in mice which demonstrated long (4- to 10-hour) durations of action, and indicated that 
continuous high exposure was not required to maintain efficacy.   
Dose proportional increases in exposure occurred at oral doses of 3–100 mg/kg in mice and at 3–
30 mg/kg in rats25.  In rats, the oral bioavailability of XL184 dosed as a solid was approximately 
100% of XL184 dosed as a liquid.  In comparison, oral bioavailability was much lower in dogs 
(20%) and monkeys (18%) for the solid versus liquid dosage forms. 
Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area under the 
time-concentration curve from 0 to t hours post-dose [AUC0-t] values) associated with single 
XL184 oral doses in rats increased less than dose-proportionally with increasing dose (100–900 
mg/kg) 25.  With repeat daily oral dosing in rats, systemic exposure (AUC0-t values) increased 
generally dose-proportionally following 14 and 178 dosing days (dose ranges 1–15 mg/kg/day 
and 0.1–1 mg/kg/day, respectively).  The Cmax and AUC0-t values in rats administered 100 mg/kg 
were approximately 2-fold and 3-fold higher, respectively, than for dogs given 2000 mg/kg; 
therefore, the higher systemic exposure to XL184 in rats correlated with the greater toxicity 
observed in this species at lower administered doses. 
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single XL184 oral 
doses in dogs increased less than dose-proportionally with increasing XL184 dose (400–2000 
mg/kg), suggesting possible saturation of systemic absorption 24.  With repeat daily dosing, 
exposure (Cmax and AUC0-24 values) both increased greater than dose-proportionally from 10 to 
100 mg/kg and less than dose proportionally from 100 to 1000 mg/kg following 14 dosing days.   
2.2.1.4 
Toxicology 
In rodents and non-rodents, histopathological changes associated with XL184 administration 
were observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, and adrenal 
and reproductive tract tissues 24.  Histopathological changes present in the bone and pancreas 
were considered secondary to XL184 administration. Adverse effects following oral exposure to 
XL184 were generally dose-related, clinically monitorable, and self-resolving upon 
discontinuation of dosing. In 6-month chronic toxicity studies, treatment-related changes were 
present only in kidney (rats) and reproductive tissues (dog).  In reproductive/developmental 
toxicity studies, XL184 administration resulted in decreased fertility in male and female rats, in 


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embryotoxicity when given to pregnant rats, and in a visceral tissue malformation (small spleen) 
when given to pregnant rabbits. The no-observable-adverse-effect-levels (NOAELs) for the 
chronic toxicity and reproductive/developmental toxicity studies occurred at plasma exposures 
(AUC) below steady-state values measured in subjects with solid tumors administered 175 mg 
XL184 capsule form daily (Study XL184-001). 
In definitive genotoxicity bioassays, XL184 was negative in an S. typhimurium/E.coli bacterial 
mutagenicity study, an in vitro chromosome aberration study using human peripheral blood 
lymphocytes, and an in vivo mouse bone marrow micronucleus study25.  In safety pharmacology 
studies, no adverse effects occurred on neurobehavioral or respiratory functions in XL184-
treated rats or on cardiovascular function in XL184-treated dogs. 
2.2.2 Clinical Experience 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored clinical 
trials with XL184 treatment 1) as a single agent at does ranging from 0.08 to 11.52 mg/kg on an 
intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 mg freebase equivalent weight) on 
a fixed daily dosing schedule and 3) in combination with temozolomide (TMZ) and radiation 
therapy (RT), or with erlotinib (Exelixis Communication, 2011).  The maximum tolerated dose 
(MTD) on once daily (qd) by mouth (PO) dosing schedule was determined to be 175 mg L-
malate salt (or approximately 138 mg freebase equivalent weight). 
Detailed information for each of these studies, including pharmacokinetic data, can be found in 
the Investigator’s Brochure (2011)24.  Safety and efficacy information, from the 2011 
Investigator’s Brochure, is summarized below.  
2.2.2.1 
Phase I Studies 
Study XL184-001 was a phase 1 dose-escalation study in subjects with solid tumors.  Eighty-five 
subjects, across 13 dosing levels (DL) ranging from 0.08 mg/kg qd (using powder-in-bottle [PIB] 
suspension on a 5 days on, 9 days off schedule) to 265 qd (using capsules [25 and/or 100mg] for 
two, 14-day cycles) were enrolled.  The capsule MTD was determined to be 175 mg qd26.  Of the 
35 subjects with medullary thyroid cancer (MTC) and measureable disease enrolled in the dose 
expansion phase, 10 (29%, 95% CI) had confirmed partial responses (cPR) (with a duration up to 
48+ months), 17 (49%) had tumor shrinkage of ≥30%, and stable disease (SD) of at least 6 
months was observed in 15/37 (41%) of the MTC subjects.   
In Study XL184-002, treatment of subjects with newly diagnosed glioblastoma (GB) consisted 
of cabozantinib in combination with TMZ with or without radiation therapy.  Enrollment has 
been terminated and no clinical efficacy data is presented in the 2011 Investigator’s Brochure.  
All adverse events (AEs) were assessed with respect to combination treatment and not the 
individual components.  Nineteen patients were evaluated for AEs, the most common grade 3 or 
higher included neutropenia (21%), thrombocytopenia (16%), leucopenia (16%), and 
hypertension (11%).  Myelosuppression, including prolonged pancytopenia, is a dose-limiting 
toxicity (DLTs) associated with TMZ use.  The frequency at which bone marrow toxicity was 
observed in this study is consistent with the TMZ prescribing information.   
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult 
subjects.  According to a randomization scheme, 56 subjects received single oral doses of the 
assigned treatment of Test (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-mg 


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capsules 30 minutes after administration of a high-fat breakfast) or Reference (175 mg 
cabozantinib, dosed as one 100-mg capsule and three 25-mg capsules under fasting conditions).  
Blood samples were collected up to 504 hours post-dose for each subject after each treatment to 
assess plasma cabozantinib pharmacokinetics.  See “Pharmacokinetics” section for results. 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in 
healthy volunteers.  Subjects received single oral doses of the assigned treatment of Test (100 mg 
cabozantinib, dosed as one 100-mg tablet) or Reference (100 mg cabozantinib, dosed as two 
50-mg capsules), according to a randomization scheme.  Each dosing was administered under 
fasting conditions, and blood samples were collected up to 504 hours post-dose for each subject 
after each treatment to assess plasma cabozantinib PK.  See “Pharmacokinetics” section for 
results. 
In Study XL184-008, subjects with advanced solid tumors (particularly renal cell carcinoma 
[RCC] and differentiated thyroid cancer [DTC]) are evaluated for any potential clinically 
significant drug-drug interaction of cabozantinib on the CYP isozyme CYP2C8.  The effect of qd 
dosing of 175 mg cabozantinib and a single dose of rosiglitazone will be evaluated.  In 11 
patients evaluated for AEs, the most common grade 3 or higher AEs were fatigue (9%), 
hypophosphatemia (27%), blood amylase increase (9%), and hyponatremia (9%). 
In a phase 1 study, CA205-001, Japanese subjects with advanced or metastatic solid tumors for 
whom the standard of care is ineffective or inappropriate, received cabozantinib at a starting dose 
of 75 mg PO qd.  Two of the three subjects in the first cohort experienced DLTs of proteinuria 
and thrombocytopenia.  Because of a change in study sponsor, this study was reinitiated as 
XL184-014.  One additional subject was enrolled as of May 2011 at 50 mg PO qd.   
Study XL184-202 was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib 
and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects.  Of 
the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been 
previously treated with and progressed on erlotinib therapy.  A cPR was observed in 5 subjects 
(8%) and 24 subjects (37%) had SD/PR ≥4 months.  The most common grade 3 or higher AEs in 
the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased 
appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration 
(5%).  Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects 
who had received clinical benefit from erlotinib and subsequently experienced progressive 
disease (PD), received single-agent cabozantinib or cabozantinib with erlotinib.  AEs ≥grade 3 
included dehydration (8%) and hypertension (8%).  One patient, who was treated with single-
agent cabozantinib, had a cPR. 
In the phase I part of this trial (study 9243/12C0204), 20 patients were treated at 3 dose levels (4 
at 20 mg, 8 at 40 mg, and 7 at 60 mg) of cabozantinib in combination with docetaxel and 
prednisone.  The MTD of cabozantinib in combination with docetaxel and prednisone was 
determined to be 40mg.  Two DLTs occurred in the 60 mg cabozantinib cohort. One DLT was 
febrile neutropenia and the other was grade 2 intolerable hand/foot syndrome.  The median age 
was 68 years old (44-84 yrs).  The median baseline PSA was 94.7 ng/mL (0.01-754.1 ng/mL).  
Median Gleason score was 9 (7-10).  Median number of cycles was 9.5 (1-33). Common grade 2 
and grade 3 adverse events possibly related to cabozantinib were: hand/foot syndrome (4/16), 
oral mucositis (4/16), hypophosphatemia (4/16), and fatigue (3/16).    


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2.2.2.2 
Phase 2 Studies 
In a phase 2 study, XL184-201, subjects with progressive or recurrent GB in first or second 
relapse were enrolled to receive cabozantinib qd as a single agent.  Group A received an initial 
dose of 175 mg (Group A), subsequent cohorts (Groups B and C) received an initial dose of 125 
mg.  Forty-six subjects were enrolled in Group A, and a total of 176 subjects were enrolled in 
Groups B/C.  Fifty-seven subjects experienced one or more serious adverse events (SAEs) that 
were assessed to be related to treatment, including five fatal related. 
Study XL184-203 is a phase 2 randomized discontinuation trial.  Subjects are enrolled into one 
of nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) cancer, 
hepatocellular carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic cancer, prostate 
cancer, and small cell lung cancer (SCLC).  Eligible subjects with advanced solid tumors receive 
open-label cabozantinib at starting dose of 100 mg qd for 12 weeks.  Of the 531 subjects enrolled 
in this study as of May 2011, 92 experienced one or more SAEs that were assessed to be related 
to treatment with cabozantinib, including seven fatal related SAEs.  Randomization was 
suspended in the CRPC and ovarian cancer cohorts based on observed high rates of clinical 
activity, and randomized subjects were unblinded.  At the last interim analysis, 171 patients with 
CRPC had been accrued to the study.  DCR at week 12 was 68% with 0 of 171 subjects 
achieving CR, 7 achieving confirmed PR and the remainder with stable disease.  Given the 
encouraging result, a non randomized extension (NRE) cohort was opened for CRPC patients to 
be evaluated at 100 mg and 40 mg daily doses sequentially.  As of June 2012, results were 
available for 93 CRPC patients treated at 100 mg daily cabozantinib in the extension cohort, 62 
(67%) had a bone scan response27.  4 were CRs and 58 were PRs.  15 of these patients also 
showed stable disease on bone scan.  The median duration of response was 5.4 (5.0 – 6.9) 
months.  84 % of patients experienced at least one dose reduction due to adverse events.  One 
patient with extensive liver disease experienced a related grade 3 portal vein thrombosis with 
grade 5 liver failure.  Preliminary evidence supports clinical activity at 40 mg28.  Study XL184-
205 is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in first or second 
relapse.  Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 75 mg qd 
(Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously (Arm 3), and 
125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4).  A total of 19 subjects 
were accrued before the study was terminated.  Three subjects were rolled over to maintenance 
Study XL184-900.  One subject experienced an SAE assessed to be related to treatment with 
cabozantinib.  
Study XL184-301 is a blind trial for subjects with unresectable, locally advanced or metastatic 
MTC, randomized 2:1 to cabozantinib or placebo.  SAEs reported in Study XL184-301 are: one 
grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), one grade 5 cardiac arrest 
following asystolic vagal reaction after aspiration on study medication, and three SAEs of 
acquired trachea-esophageal fistula (two grade 3, one grade 5). 
2.2.2.3 
Phase 3 Studies 
COMET-1 is a randomized, double blind phase 3 trial of cabozantinib in men with metastatic 
castration-resistant prostate cancer (mCRPC) who had previously been treated with and 
progressed after treatment with docetaxel, abiraterone and/or enzalutamide. The primary 
endpoint of the trial was overall survival, and the secondary endpoint was bone scan response as 
assessed by an independent radiology committee.  All patients in the trial had bone metastases, 


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and there was no limit to the number or type of prior treatments.  Patients were randomized 2:1 
to receive cabozantinib (60 mg daily) or prednisone (5 mg twice daily). The trial did not meet its 
primary endpoint of demonstrating a statistically significant increase in overall survival for 
patients treated with cabozantinib as compared to prednisone.  The median overall survival for 
the cabozantinib arm of the trial was 11.0 months versus 9.8 months for the prednisone arm 
(hazard ratio 0.90; 95% confidence interval 0.76 – 1.06; p value 0.212).29  
In the randomized, double-blind phase 3 COMET-2 trial ((NCT01522443), 119 men with 
progressive mCRPC after treatment with docetaxel, abiraterone, and/or enzalutamide, with 
moderate to severe pain were were randomized in a 1:1 fashion to cabozantinib 60 mg po once 
daily or mitoxantrone and prednisone (12 mg/m2 every 3 weeks and prednisone 5 mg every 12 
hours).30  The primary endpoint was pain response. The secondary endpoints were bone scan 
response and overall survival.  The primary endpoint of improving pain was not achieved with 
pain response rates of 15% for cabozantinib vs. 17% for mitoxantrone and prednisone (P = 
0.773). The bone scan response rates were 31% for cabozantinib vs. 5.2 % for mitoxantrone and 
prednisone.  The median overall survival was 9 months for cabozantinib vs 7.9 months for 
mitoxantrone and prednisone.  
While the results of both the COMET-1 and COMET-2 trials were negative, both of these studies 
utilized cabozantinib as a single agent.   We hypothesize the addition of the multikinase inhibitor 
cabozantinib to docetaxel and prednisone could potentially minimize tumor resistance by 
targeting different cellular signaling pathways without overlapping toxicities.  Additionally, 
emerging clinical data suggests mCRPC patients treated with anti-androgen therapy like 
abiraterone or enzalutamide have decreased responses to subsequent therapy with docetaxel due 
to cross-resistance in the androgen pathway targeted by docetaxel, abiraterone, or 
enzalutamide.31   
2.2.2.4 
Adverse Events 
The clinical studies with XL184 are ongoing and thus the AE data from the clinical database as 
of March 1, 2011 and May 4, 2011 do not yet include all SAEs (Exelixis Communication, 2011).  
As of March 2011, AE data are available for 913 subjects who have been dosed with XL184 
(806 in single-agent studies and 107 in combination studies of XL184 with erlotinib, 
rosiglitazone, or TMZ ± radiation) (Investigator’s Brochure, 2011).  Data from the 806 subjects 
who received single-agent XL184 show that the most frequently (>20%) observed AEs 
regardless of causality were fatigue, diarrhea, nausea, decreased appetite, constipation, palmar-
plantar erythrodysesthesia (PPE) syndrome, vomiting, dysphonia, and hypertension.  Effects that 
may be related to the inhibition of VEGF, including hypertension, thromboembolic events, GI 
perforation, fistula formation, hemorrhage, wound dehiscence, and proteinuria, have been 
observed in the single-agent and combination XL184 studies.  The most commonly reported 
SAEs that were assessed as related to study treatment with XL184 (as a single-agent or 
combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein thrombosis 
(DVT), vomiting, nausea, thrombocytopenia, fatigue, wound dehiscence, and PPE syndrome. 
Grade 5 AE data are available for 1404 subjects who have been dosed with cabozantinib as a 
single agent (1286) or in combination (118) through June 1, 2012.  There have been 27 grade 5 
AEs related to study treatment: GI hemorrhage (two subjects), pulmonary hemorrhage (one 
subject), esophageal hemorrhage (one subject), PE (two subjects), respiratory failure (three 
subjects), respiratory disorder (one subject), hemoptysis (one subject), death due to unknown 


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cause (four subjects), intracranial hemorrhage (one subject), intestinal perforation (one subject), 
enterocutaneous fistula (one subject), tracheo-esophageal fistula (one subject), esophageal fistula 
(one subject), hemorrhage (two subjects), hepatic failure (one subject), bronchopneumonia (one 
subject) cardiac arrest (one subject), sepsis (one subject), and diverticular perforation, peritonitis 
(one subject) (Exelixis Communication).  The initial daily doses of drug in these subjects were 
100 mg (8 subjects), 125 mg (8 subjects), 175 mg (11 subjects).  In 2 subjects, the initial dose of 
125 mg was reduced to 50 and 75 mg respectively prior to death. 
2.2.2.5 
Pharmacokinetics 
Pharmacokinetic analysis of 74 patients in trial XL184-001 showed dose proportional increases 
in maximum plasma concentration (Cmax) and AUC both for PIB (dose range 0.08-11.52 mg/kg) 
and the capsule formulation (dose range: 125 to 175 mg)26.  Terminal-phase half-life (t1/2,z) 
values were 59.1 to 136 hours (Investigator’s Brochure, 2011).  After repeat dosing, t1/2,z values 
(mean ± standard deviation) for XL184 were 91.3 ± 33.3 hours (n = 23), and apparent steady-
state plasma levels were reached by Day 1526.  Steady-state clearance for the 175 mg capsule 
dose derived from repeat dose data was 4.2 ± 1.5 L/h.  Patients who received 175 mg capsules 
had four- to five-fold higher steady-state exposure (AUC) compared with Day 1 (7.68 ± 2.85 
mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that XL184 accumulated with 
repeat daily dosing.  There was no significant difference in exposure between patients with MTC 
and those without MTC. 
Based on the preliminary PK data from 23 subjects in XL184-005 who completed both 
treatments, after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib 
appeared to be similar for both tablet and capsule formulations, with approximately mean values 
of 110 hours (Exelixis Communication, 2012).  The median time to the maximum plasma 
concentration (tmax) was 4 hours for the tablet formulation and 5 hours for the capsule 
formulation.  High inter-subject variability for Cmax and the area under the plasma drug 
concentration time curve (AUC) values were observed for both formulations (coefficient of 
variation [CV]% Cmax: 51% for the tablet formulation, 61% for the capsule formulation; CV% 
for the AUC from time zero to the last quantifiable timepoint or to infinity [AUC0-last or AUC0-
inf]: 40-43% for the tablet formulation, 43% for the capsule formulation).  The geometric mean 
Cmax of the tablet formulation was approximately 39% higher than the value observed for the 
capsule formulation.  The geometric mean AUC0-last and AUC0-inf values for the tablet 
formulation were also higher (15% and 19%, respectively) than those observed for the capsule 
formulation.  However, due to the high within-formulation variability observed, no statistical 
difference in exposure between the two formulations was apparent. 
Based on the preliminary PK data from 46 subjects who completed both treatments on trial 
XL184-004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z 
: 131 hours (fed) vs. 128 hours (fasted)].  The high-fat meal significantly increased the median 
tmax to 6 hours from 4 hours (fasted).  The high-fat meal also significantly increased both the 
cabozantinib Cmax and AUC values by 39% and 56%, respectively.  The geometric mean ratio of 
Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last 
fed/fasted was 1.56 (90% CI: 1.34-1.80).  Based on this result, cabozantinib must be taken on an 
empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose). 


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2.3 
OTHER AGENTS 
2.3.1 Docetaxel with prednisone 
Docetaxel as first-line treatment in metastatic CRPC 
Docetaxel, a semi-synthetic taxane with the ability to disrupt microtubule dynamics, possesses 
potent antitumor activity in a variety of malignancies. Its mechanism in prostate cancer is 
thought to be two-fold. First, it acts as a microtubule stabilizer by binding preferentially to Beta-
tubulin, leading to assembly of microtubules without GTP and other various cofactors. This leads 
to static polymerization, which disrupts the normal mitotic process, causing cell arrest in G2/M 
phase and ultimately leads to apoptosis. A second mechanism involves BCL-2, which is an 
oncoprotein that enhances tumor activity via inhibition of apoptosis. The stabilization of 
microtubule structure by docetaxel results in inactivation of BCL2 function via phosphorylation, 
which prevents binding to BAX. Increased free BAX induces activation of the caspase cascade 
leading to apoptosis.32  
In 2004, both Tannock et al. and Petrylak et al. simultaneously published positive results from 
two randomized trials using docetaxel as backbone in metastatic CRPC. In TAX 327, the median 
survival improved from 16.5 months to 18.9 months in patients receiving docetaxel and 
prednisone every three weeks, as compared to patients who received mitoxantrone and 
prednisone. Docetaxel also effectively decreased PSA (P<0.001), relieved pain associated bone 
metastases (P=0.01), as well improved quality of life (P=0.005).33 With an extended follow-up, 
this survival benefit has persisted. In an updated report, median survival was 19.2 months in the 
docetaxel arm, as compared to 16.3 months in the mitoxantrone arm. More patients survived at 3 
years in the docetaxel arm (18.6%) compared with those in the mitoxantrone arm (13.5%).4 
Similar benefit was also observed in SWOG 9616 where the median survival in docetaxel and 
estramustine arm surpassed that of mitoxantrone arm by 1.9 months (17.5 vs. 15.6 months; 
P=0.02).3  
These two large randomized studies were the first to demonstrate survival benefit after long 
battle for active chemotherapeutic agents for men with metastatic CRPC. Undoubtedly, 
docetaxel is effective in this disease. However, the survival improvement is modest with only 
5.9% (86.5% vs. 81.4%) reduction in the rate of death at 3 years with limited survival advantage 
of 2.9 months 4. New strategies are clearly needed to increase the number and duration of the 
response.  
More recently, trials have examined the use of intermittent taxane therapy as a possible 
mechanism to overcome resistance to these agents33,34.  Perhaps more practically, “drug 
holidays” may improve the quality of life for patients and allow them to recover from the 
cumulative toxicity of the chemotherapeutic agents during this period35-37.  There have been 
several trials in prostate cancer that have examined this intermittent approach to chemotherapy 
and have seen favorable results. In a study of 250 patients randomized to 36 mg/m2 of docetaxel 
weekly with high dose calcitriol vs. placebo, arbitrary guidelines were set to have a PSA decline 
>50% and PSA ≤ 4 in order to qualify for a drug holiday. Of the 20% of patients who qualified, 
90.9% were responsive to docetaxel up resumption of treatment38.  The NCI results from a phase 
II study involving docetaxel combined with antiangiogenic agents report a median OS of > 28 
months, which exceeds any contemporary trial that does not employ this intermittent 
strategy11,14.  


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Extensive preclinical and clinical research is ongoing in the identification of the drivers of 
disease progression. Multiple novel agents with distinct cellular or molecular targets or 
implications in tumor microenvironment are being assessed in clinical trials either as single agent 
or in combination with other effective agents.  
2.4 
RATIONALE 
Given the superior clinical activity and unique molecular mechanism of cabozantinib in CRPC 
patients, we hypothesize that addition of cabozantinib to docetaxel and prednisone, in patients 
with metastatic CRPC, will bear acceptable toxicity profile given significant non-overlapping 
range of AEs and potentially minimize tumor resistance and improve survival by targeting 
different cellular pathways simultaneously. This combinational therapy with allowances for the 
incorporation of treatment holidays will represent a safe and effective strategy to maximize 
patients’ benefit and further extend their survival.  
In phase II randomized discontinuation trial, cabozantinib, as a single agent, was dosed at 100 
mg once daily. No recommended dose for combination therapy has been defined. At 100 mg 
dose level, high incidence of fatigue (9%), hand-foot syndrome (8%), and HTN (5%) were noted 
in all advanced solid tumors patients 39. Similar rate of adverse events (AEs) were also observed 
in CRPC cohort with Grade 3/4 AEs being fatigue (11%), HTN (7%), and hand-foot syndrome 
(5%).40 The rate of dose reductions and permanent discontinuations of cabozantinib for AEs 
occurred in 41% and 12% of all patients, and 51% and 10% in CRPC cohort, respectively.39,40 
Thus, we propose to conduct a phase I study to define the MTD of cabozantinib when in 
combination with docetaxel and prednisone. In particular, cabozantinib will be examined at three 
dose levels (20 mg, 40 mg, and 60 mg qd) with an expansion cohort at MTD.  A dose (-1) of 20 
mg qod will be studied if DLT is seen at the 20 mg dose level. 
 
2.4.1 Rationale for evaluating Docetaxel and prednisone vs. Docetaxel and Prednisone with 
Cabozantinib    
Emerging clinical data suggests that mCRPC patients treated with modern anti-androgen therapy 
such as enzalutamide or abiraterone have decreased responses to subsequent therapy.  This is 
likely due to cross-resistance in the androgen pathway which is targeted by these agents as well 
as docetaxel31.  Three separate retrospective analyses demonstrated a median progression free 
survival of 4.6 months or less in patients who were treated with docetaxel after progression on 
abiraterone41-43.  The median overall survival in two of these studies was found to be less than 13 
months41,42.   Although these studies are small and retrospective, they share a consistent and 
uniform finding that docetaxel and prednisone have limited benefits after disease progression on 
abiraterone. 
On the phase I portion of this study, a total of 19 patients were enrolled.  Seventeen patients were 
evaluable (one patient withdrew due to travel and a second patient was not evaluable due to a fall 
injury).  For the 17 patients, median progression free survival is 12.1 months; 6 month PFS is 
76.0% (95% CI: 52.0%-90.3%), 12 month PFS is 55.3% (95% CI:  31.9% - 76.6%).  For the 14 
patients who received abiraterone or enzalutamide, median PFS is 13.6 months; 6 month PFS is 
77.9% (95% CI:  51.3% - 92.2%), 12 month PFS is 62.3% (95% CI:  36.3% - 82.8%). PFS 
results seen in this trial compare favorably to historical previously published data of treatment 
with docetaxel after progression on abiraterone in mCRPC, suggesting the addition of 


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cabozantinb to docetaxel may help overcome acquired resistance.  Further studies will assess if 
there is a molecular signature that identifies patients benefiting from the cabozantinib plus 
docetaxel combination. 
2.4.2 CHAARTED Trial (Rationale for Modification of Exclusion Criteria)  
High-volume hormone-sensitive metastatic prostate cancer has historically been treated using 
hormonal therapy followed by chemotherapy.  The disease however remained poorly prognostic 
in nature.  A shift in the treatment paradigm of these patients occurred with the results of the 
Eastern Cooperative Oncology Group (ECOG) phase III randomized CHAARTED trial, which 
looked at whether the addition of upfront chemotherapy to hormonal therapy improved overall 
survival in patients with hormone-sensitive metastatic prostate cancer.  
A retrospective subanalysis from this trial was reported by Dr. Christopher Sweeney from the 
Dana Farber Cancer Institute, at the 2014 American Society of Clinical Oncology (ASCO) 
Plenary Session.44  In the CHAARTED trial, men with metastatic castrate-sensitive prostate 
cancer were randomized 1:1 to receive androgen deprivation therapy (ADT) alone or to ADT 
with chemotherapeutic drug docetaxel at 75 mg/m2 every 3 weeks for 6 cycles to be started 
within 4 months of starting ADT.   ADT plus docetaxel resulted in a median overall survival of 
57.6 months (HR= 0.61; P = .0003) compared to 44 months in the ADT arm.  Patients were 
stratified according to high-volume vs low-volume disease and the benefit for docetaxel therapy 
was found to be more apparent in the high-volume metastatic group vs the low-volume 
metastatic group.  
Most patients with metastatic castrate-sensitive prostate cancer will progress to a castrate-
resistant state. Previous evidence has also shown that upon progression, docetaxel confers an 
overall survival benefit.33  However, it is unlikely that such survival benefit would be achieved in 
cases where a patient has already been treated with 6 cycles of docetaxel while castrate-sensitive.  
Given the very positive results of the CHAARTED trial and current shift towards initial 
treatment with docetaxel for high-volume hormone-sensitive metastatic disease, we propose 
amending protocol 12-C-0204 to address the initial treatment with docetaxel.  If a patient has 
progressed on docetaxel chemotherapy in the castrate-sensitive state, then they will be excluded 
from this trial on the basis that re-treatment with docetaxel will not confer benefit to the 
metastatic castrate resistant patient.  Additionally, if a patient has progressed to a castration-
resistant state and received docetaxel, they will be excluded from this trial as re-treatment with 
docetaxel has not found to be of benefit in this patient population.  Lastly, a time period of 6 
months will be required between a patient’s completion of the 6th cycle of docetaxel based on 
CHAARTED and the first dose of study treatment (cycle 1, day 1). This time period is based 
upon data seen in other solid tumor types, such as retreatment in ovarian cancer with platinum-
based chemotherapies. 
2.5 
CORRELATIVE STUDIES BACKGROUND 
In addition to the studies listed below, eligible subjects on this protocol may participate in NCI 
protocol 12-C-0080.  Participants in this study will undergo F-18 NaF PET/CT scanning at 
baseline (within 7 days prior to starting therapy).  A subset of these patients (approximately 20) 
will undergo a second baseline scan within 2-5 days of the initial scan.  All participants will then 
undergo subsequent NaF PET/CT scanning at week 8.  These research imaging procedures will 


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be conducted in addition to the clinical imaging procedures listed in the study calendar in section 
10.  The research radiation risks are discussed in the imaging protocol. 
2.5.1 Genetic biomarkers: 
Single nucleotide polymorphisms (SNPs) in genes that play an important role in the drug 
metabolism and disposition of docetaxel and cabozantinib (via cytochrome P450 3A4 and 
ABCB1-mediated pathways) will be evaluated to correlate with efficacy and clinical outcomes. 
Functional SNPs in the VEGFR2 gene could alter antiangiogenic treatment response or outcome 
by affecting the VEGF signaling pathways. Thus, we will determine if VEGFR2 genetic variants 
may be correlated to toxicity and clinical outcomes as we have previously shown in patients 
treated with bevacizumab and sorafenib.45 
2.5.2 Pharmacodynamic biomarkers: 
Plasma levels of several angiogenic biomarkers, including vascular endothelial growth factor-A 
(VEGF-A), soluble VEGFR2 (sVEGFR2), soluble c-Met (sMET), and placental growth factor 
(PIGF), have been shown to be significantly altered after single agent cabozantinib treatment 
(Investigator’s Brochure). Plasma samples will be obtained to measure changes in the molecular 
markers of angiogenesis, as well as c-Met before and after administration of the combination. 
Urinary levels of c-met will also be measured as previous studies have reported it to be a 
potential marker of metastatic prostate cancer. The change in HGF, which is the only known 
ligand of c-Met, will be also measured as a marker for c-Met inhibition. The potential 
relationship between biomarker expression and tumor/PSA response will be explored.  
2.5.3 Markers for bone activities: 
Crosslinked C-telopeptide of type I collagen (CTx) is a marker of osteoclast activity and bone 
resorption, while total Alkaline phosphatase (t-ALP) is a marker for osteoblast activity. The 
significant reduction of serum CTx and t-ALP by cabozantinib was reported in the CRPC cohort 
from a phase II randomized discontinuation trial.40 Osteoclast mediated bone resorption can also 
be assessed by measuring urine N-telopeptide (uNTx), which has been reported as an 
independent prognostic factor for overall survival in patients with bone metastases from CRPC.46 
Samples will be obtained to determine changes in bone turnover from activation of both 
osteoblasts and osteoclasts.  
2.5.4 Circulating Tumor Cells (CTC)  
The changes in CTC counts have been shown to be the most accurate and independent predictor 
of OS in CRPC. CTC enumeration at baseline and post-treatment is prognostic of survival and 
the shedding of cells into the circulation represents an intrinsic property of the tumor, distinct 
from extent of disease. Thus, CTC will be investigated before and after drug administration as an 
experimental endpoint. The data will be used to correlate with clinical response. Molecular 
determinants can also be identified and characterized in CTCs as potential predictive biomarkers 
of tumor sensitivity to therapeutic treatments. CTCs will be isolated at baseline and genetic 
analysis will be performed to determine androgen receptor (AR) expression and activity in tumor 
cells to further understand the clinical response to the combination treatment. 


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3 
PATIENT SELECTION 
3.1 
ELIGIBILITY CRITERIA  
3.1.1 Inclusion Criteria 
3.1.1.1 
Must have metastatic, progressive, castrate resistant prostate cancer (CRPC).  There 
must be radiographic evidence of disease after primary treatment with surgery or 
radiotherapy that has continued to progress radiographically or biochemically (rising 
PSA levels on successive measurements) despite adequate androgen-deprivation 
therapy, which is defined as having undergone bilateral surgical castration or continued 
treatment on GnRH agonists or antagonists..   
Progression must be evidenced and documented by any of the following parameters: 
1. Two consecutively rising PSA values, above the baseline, at a minimum of 1-
week intervals 
2. Appearance of one or more new lesions on bone scan 
3. Progressive measurable disease by RECIST 1.1 
The use of androgen receptor inhibitors is not required prior to study entry.  For those 
patients receiving an anti-androgen agent (flutamide, bicalutamide, or nilutamide), for 
at least 6 consecutive months immediately prior to study entry, and are entering the 
trial due to a rise in PSA, they must demonstrate a continued rise in PSA within 4 
weeks after stopping flutamide and within 6 weeks after stopping bicalutamide or 
nilutamide.  Flutamide, nilutamide and bicalutamide disease progression requirements 
only apply to patients who have been on these drugs for at least the prior 6 months. 
3.1.1.2 
Histopathological confirmation of prostate cancer by the Laboratory of Pathology of 
the NCI, Pathology Department of the Walter Reed National Military Medical Center or 
Yale is required prior to entering this study.  Patients whose pathology specimens are no 
longer available may be enrolled if the patient has a clinical course that is consistent 
with prostate cancer and available documentation from an outside pathology laboratory 
of the diagnosis.  All efforts should be made to have the material forwarded to the 
research team for use in correlative studies in cases where original tissue blocks or 
archival biopsy material is available. 
3.1.1.3 
Patients must have metastatic disease, defined as at least one lesion on bone scan or at 
least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20 
mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers 
by clinical exam. 
3.1.1.4 
Patients must have a performance status of 0 to 2 according to the ECOG criteria (see 
Appendix A) 
3.1.1.5 
Patients must have adequate bone marrow, hepatic, and renal function with: 
• Hemoglobin 
 ≥ 9 g/dL 
• Leukocytes 
 ≥ 3000/μL 
• ANC  
≥ 1500/μL, without CSF support 


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• Platelets 
 ≥ 100,000/μL 
• AST(SGOT) 
 ≤ 2.5 x upper limit of normal (ULN);  
• ALT(SGPT) 
 ≤ 2.5 x upper limit of normal (ULN);  
• Total serum bilirubin   
≤ the upper limit of normal (ULN).  
• Serum albumin  
≥ 2.8 g/dL 
• Serum phosphorus, calcium, 
magnesium, and potassium  
≥ LLN 
• Lipase  
< 2.0 x the upper limit of normal and no 
radiologic or clinical evidence of pancreatitis 
• Creatinine 
≤ 1.5 X institutional upper limits of normal  
OR 
• Creatinine clearance of 
 ≥ 50 ml/min/1.73 m2 for patients with 
 
creatinine levels above institutional normal by 
 
24 hour urine.    
• Urine protein/urine creatinine 
ratio (UPCR) 
≤ 1 
3.1.1.6 
Patients must be at least 18 years of age.  Because no dosing or adverse event data are 
currently available on the use of cabozantinib in combination with docetaxel and 
prednisone in patients <18 years of age, children are excluded from this study, but may 
be eligible for future pediatric trials. 
3.1.1.7 
Patient must be capable of understanding and complying with protocol requirements 
and is willing to give informed consent 
3.1.1.8 
Men treated or enrolled on this protocol must also agree to use adequate contraception 
prior to the study, for the duration of study participation, and 4 months after completion 
of XL184 administration. 
Sexually active subjects and their female partners must agree to use medically 
accepted barrier methods of contraception (eg, male or female condom) during the 
course of the study and for 4 months after the last dose of study drug(s), even if oral 
contraceptives are also used. All subjects of reproductive potential must also agree to 
use both a barrier method and a second method of birth control during the course of 
the study and for 4 months after the last dose of study drug(s). Should a woman 
become pregnant or suspect she is pregnant while her partner is participating in this 
study, she should inform her treating physician immediately. 
3.1.1.9 
Patients enrolled on the randomized portion of the study must have had disease 
progression on arbiraterone or enzalutamide. 


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3.1.2 Exclusion Criteria 
3.1.2.1 
The subject has had evidence within 2 years of the start of study treatment of another 
malignancy which required systemic treatment  
3.1.2.2 
The subject is unable to swallow tablets. 
3.1.2.3 
The subject has tumor invading (or there is concern for invasion of) major blood 
vessel. 
3.1.2.4 
The subject has active brain metastases or epidural disease Subjects with brain 
metastases previously treated with whole brain radiation or radiosurgery or subjects 
with epidural disease previously treated with radiation or surgery who are asymptomatic 
and do not require steroid treatment for at least 2 weeks before starting study treatment 
are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if 
completed at least 3 months before starting study treatment. Baseline brain scans are not 
required to confirm eligibility. 
3.1.2.5 
The subject requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, 
or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤81 mg/day), low-dose 
warfarin (≤1 mg/day), and prophylactic low molecular weight heparin (LMWH) are 
permitted. 
3.1.2.6 
The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) 
>500 ms within 28 days before initiation of protocol therapy.  Note: if initial QTcF is 
found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be 
performed.  If the average of these three consecutive results for QTcF is ≤500 ms, the 
subject meets eligibility in this regard. 
3.1.2.7 
Patients with contraindication to steroid use 
3.1.2.8 
Prior treatment with cabozantinib 
3.1.2.9 
The patient has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or 
nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment. 
3.1.2.10 The subject has received prior treatment with a small molecule kinase inhibitor or a 
hormonal therapy (including investigational kinase inhibitors or hormones) within 14 
days or five half-lives of the compound or active metabolites, whichever is longer, 
before the first dose of study treatment with the exception of patients receiving prior 
abiraterone or ketoconazole.  For patients receiving prior abiraterone or ketoconazole, 
they must discontinue the medication within 5 half-lives of the compound before the 
first dose of study treatment in order to participate in this study.  Note: Subjects with 
prostate cancer currently receiving LHRH or GnRH agonists must be maintained on 
these agents. 
3.1.2.11 The subject has received any other type of investigational agent within 28 days before 
the first dose of study treatment.  
3.1.2.12 The subject has received radiation therapy: 
• to the thoracic cavity or gastrointestinal tract within 3 months before the first 
dose of study treatment 


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• to bone or brain metastasis within 14 days before the first dose of study 
treatment 
• to any other site(s) within 28 days before the first dose of study treatment 
3.1.2.13 The subject has received radionuclide treatment within 6 weeks prior to the first dose 
of the study treatment 
3.1.2.14 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all 
prior therapies, including surgery, except alopecia and other non-clinically significant 
AEs. 
3.1.2.15 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or 
partial thromboplastin time (PTT) test results at screening ≥ 1.3  the laboratory ULN 
within 7 days before the first dose of study treatment. 
3.1.2.16 The subject has experienced any of the following: 
• clinically-significant hematemesis or gastrointestinal bleeding within 6 
months before the first dose of study treatment 
• hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood within 3 months before 
the first dose of study treatment 
• any other signs indicative of pulmonary hemorrhage within 3 months before 
the first dose of study treatment 
3.1.2.17 The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib.  
3.1.2.18 The subject has uncontrolled, significant intercurrent or recent illness including, but 
not limited to, the following conditions: 
a. Cardiovascular disorders including 
i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class 
III (moderate) or Class IV (severe) at the time of screening 
ii. Concurrent uncontrolled hypertension defined as sustained BP >140 mm Hg 
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment 
(BP must be controlled at screening) 
iii. Any history of congenital long QT syndrome 
iv. Any of the following within 6 months before the first dose of study treatment: 
• unstable angina pectoris 
• clinically-significant cardiac arrhythmias 
• stroke (including TIA, or other ischemic event) 
• myocardial infarction 
• thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (e.g. vena cava filter) are not eligible for this 
study) 
b. Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including: 
i. Any of the following within 28 days before the first dose of study treatment 


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• intra-abdominal tumor/metastases invading GI mucosa 
• active peptic ulcer disease 
• inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
• malabsorption syndrome 
ii. Any of the following within 6 months before the first dose of study treatment: 
(1)  history of abdominal fistula 
(2) gastrointestinal perforation 
(3) bowel obstruction or gastric outlet obstruction 
(4) intra-abdominal abscess. Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months ago. 
c. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy or 
concurrent evidence of intraluminal tumor involving the trachea and esophagus. 
d. Other clinically significant disorders such as: 
i. active infection requiring intravenous treatment within 10 days of starting 
protocol treatment 
ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment 
iii. history of organ transplant 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 
days before the first dose of study treatment 
v. history of major surgery as follows: 
(1) Major surgery within 3 months of the first dose of cabozantinib if there 
were no wound healing complications or within 6 months of the first dose 
of cabozantinib if there were wound complications 
(2) Minor surgery within 1 months of the first dose of cabozantinib if there 
were no wound healing complications or within 3 months of the first dose 
of cabozantinib if there were wound complications 
In addition, complete wound healing from prior surgery must be confirmed at 
least 28 days before the first dose of cabozantinib irrespective of the time from 
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3.1.2.19 HIV-positive patients on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with the study agents. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
3.1.2.20 Patients who require taking drugs that are strong inhibitors/inducers of CYP3A4 and 
cannot be switched to an alternative medication. 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will 
be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.  Please refer to patient information sheet in 
Appendix B. 
3.1.2.21 Patients with greater than or equal to grade 2 peripheral neuropathy at baseline. 
3.1.2.22 The subject has had treatment with docetaxel for the treatment of metastatic  castrate-
sensitive prostate cancer within 6 months before the first dose of study treatment. 
3.1.2.23 The subject has had progression of prostate cancer during 6 cycles of  prior docetaxel 
treatment for castrate sensitive disease.  
3.1.2.24 The subject has received chemotherapy for castration-resistant prostate cancer. 
 
3.1.3 Inclusion of Women and Minorities 
Men of all races and ethnic groups are eligible for this trial.  Women are excluded as prostate 
cancer does not exist in this population. 
3.1.4 Recruitment Strategies 
The study will be posted on the CCR website and on clinicaltrials.gov  
3.2 
SCREENING EVALUATION 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening before study treatment administration. Screening evaluations may be 
performed as part of an NIH Screening protocol. This does not include the baseline correlative 
studies that will only be performed after the patient has signed the consent form. 
➢ To be performed 1 week prior to enrollment  
• History and physical exam including weight and vital signs 
• Tumor marker profile: PSA 
➢ To be performed within 16 days prior to enrollment  
• CBC with differential and platelet count, prothrombin time/INR, activated partial 
thromboplastin time 
• Urinalysis and UPCR 


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• Electrolytes, BUN, creatinine, glucose, AST, ALT, bilirubin, calcium, phosphorous, 
albumin, magnesium, alkaline phosphatase, LDH, ionized calcium, amylase, lipase, total 
protein, GGT 
• Thyroid function tests – TSH, total T3, T4 
• 12 lead ECG 
➢ To be performed within 4 weeks prior to enrollment 
• CT scan of chest, abdomen, and pelvis 
• Technetium 99 bone scintigraphy scan 
• Testosterone (baseline only, test must be repeated if more than 8 weeks have elapsed 
between evaluation and C1D1); not required for patients with prior bilateral orchiectomy 
4 
REGISTRATION AND RANDOMIZATION PROCEDURES 
4.1 
REGISTRATION 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
4.1.1 For Participating Site Registration 
Registration will be a two-part process as patients are screened on this protocol. A protocol 
registration form will be supplied by the CCR study coordinator and updates will be provided as 
needed. Subject eligibility and demographic information is required for registration. To initially 
register a subject, after the participant has signed consent, complete the top portion of the form 
and send to CCR study coordinator.  Once eligibility is confirmed, after completion of screening 
studies, complete the remainder of the form which is the eligibility checklist, indicating that the 
patient is being registered for treatment and send to CCR study coordinator. In addition, source 
documents supporting the eligibility criteria must be sent to the CCR study coordinator. The 
CCR study coordinator will notify you either by e-mail or fax that the protocol registration form 
has been received which will include the unique patient/subject ID number. Questions about 
eligibility should be directed to the CCR study coordinator or PI.  Questions related to 
registration should be directed to the CCR study coordinator.  
Subjects that do not meet screening criteria should be removed from the study following the 
procedure in section 5.9.2. 
4.2 
RANDOMIZATION (PHASE II ONLY) 
After confirming eligibility, patients will be randomized on a 1:1 basis to receive either 
docetaxel alone or docetaxel with cabozantinib.  Randomization will be performed by the CRO.   


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5 
TREATMENT PLAN 
5.1 
PHASE I (CLOSED TO ACCRUAL AS OF AMENDMENT DATED 06-11-2014) 
There are two components to this study.   A Phase 1, single-arm, open-label, dose-escalation 
component will study cabozantinib combined with fixed dose docetaxel and prednisone in 
subjects with metastatic CRPC.  This component will consist of two parts: 
• A Dose Escalation part to determine the maximum tolerated dose (MTD). Subjects will 
accrue using a “3 plus 3” design. The evaluation of dose-limiting toxicity (DLT) as defined 
in Section 5.4 occurring within the first 6 weeks of treatment will be used to determine 
changes in dose levels.  However, all available safety, PK, and pharmacodynamic data will 
be considered in the decision to dose escalate, dose de-escalate, or expand the current cohort. 
All patients will be treated with docetaxel at 75 mg/m2 intravenously every three weeks on 
day 1 of each cycle as a cycle, and prednisone 5 mg PO BID on days 1-21.  Patients will 
receive a daily cabozantinib dose of 20 mg in dose level 1, 40 mg in dose level 2, and 60 mg 
in dose level 3 throughout the cycle. If there are 2 or more DLTs at dose level 1, subjects will 
be enrolled on dose level -1 at 20 mg every other day.  All patients will receive 8 mg of oral 
dexamethasone, 12 hours, 3 hours, and 1 hour before docetaxel infusion.  
• An Expansion Stage. Once the MTD is determined, the study will enter the Expansion Stage 
in which up to an additional 6 subjects will be accrued (to a total of up to 24) in order to 
obtain additional safety, PK, and pharmacodynamic data at the MTD. 
Patients will continue to receive study treatment as long as they do not experience disease 
progression and/or unmanageable side effects from the treatment. 
5.2 
PHASE II 
A second component of this study will attempt to determine the relative efficacy of docetaxel, 
prednisone and cabozantinib at the MTD as compared to docetaxel and prednisone (standard of 
care) in mCRPC patients.  In this study patients will be randomized to either of the two treatment 
regimens and then treated until disease progression. 
5.3 
AGENT ADMINISTRATION 
Treatment will be administered primarily on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy.  
Dose Escalation Schedule 
Dose Level 
Dose Cabozantinib  
Level -1 
20 mg every other day 
Level 1 
20 mg daily 
Level 2 
40* mg daily 
Level 3 
60 mg daily 
 


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*40mg daily has been determined to be the MTD and will be the dose in the dose escalation 
phase and the phase II randomized phase.  
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Cabozantinib*** 
none 
** mg 
PO 
** every 
other day or 
daily 
21 days  
(3 weeks) 
Docetaxel 
8 mg of oral 
dexamethasone, 12 
hours, 3 hours, and 
1 hour before 
infusion 
75mg/m2 
IV over 1 hour 
Day 1 of 
each cycle 
Prednisone 
Take with food or 
with milk to reduce 
stomach irritation. 
5 mg 
PO  
Twice daily 
**Doses and intervals as appropriate for assigned dose level. 
*** Not all patients in the phase II portion will be treated with Cabozantinib – 20 patients will be on the 
combination arm and 20 on the single agent docetaxel arm 
5.3.1 Cabozantinib 
Subjects will be instructed to take cabozantinib orally at the appropriate dose level once daily or 
every other day on a 21 day cycle.  As indicated in section 9.1, the first dose of cabozantinib 
should be withheld until the last PK blood draw 24 hours after the docetaxel infusion; the cycle 2 
day 1 dose should be taken just prior to the docetaxel infusion before PK samples are drawn.  If a 
dose is missed, subjects should be instructed not to make it up on the following day.  
Cabozantinib should be taken on an empty stomach, 2 hours before taking cabozantinib and 1 
hour after each cabozantinib dose patients should not eat.  Subjects should be instructed not to 
crush or chew and to avoid both grapefruit and Seville orange products while on the study drug.  
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or 
reduction(s) in their dose in order to continue with study treatment.  
5.3.2 Docetaxel 
Prepare as indicated in section 8.2.1.3. 
Docetaxel 75mg/m2 will be administered intravenously over approximately 60 minutes on cycle 
1 day 1 and repeated every 21 days (i.e. a 3-week cycle).  All patients will receive 8 mg of 
dexamethasone orally 12 hours 3 hours and 1 hour prior to docetaxel infusion.  If a patient 
misses a pretreatment dose of dexamethasone, he may receive dexamethasone 8 mg 
intravenously prior to docetaxel.   
 


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In the event of a hypersensitivity reaction, infusion times may be longer.  Hypersensitivity 
reactions may be managed clinically according to PI discretion.  Please see Appendix C for 
suggested management guidelines (optional). 
To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may be leached from 
PVC containers and administration sets, administer docetaxel only through polyethylene-lined 
administration sets 
5.3.3 Prednisone  
Prednisone should be taken orally twice a day, at 5mg for each dose.  Prednisone should be taken 
at approximately the same time every day.  The doses should be taken about 12 hours apart ± 2 
hours.   Gastric irritation may be reduced if taken before, during, or immediately after meals or 
with milk.  If a dose of prednisone is missed (more than 14 hours have passed since the last 
dose), patients should be instructed not to make up the dose and to resume taking prednisone at 
the next scheduled dose. 
5.3.4 Study Drug Accountability & Compliance 
All oral self-administered investigational agents will be properly accounted for, handled, and 
disposed in accordance with existing federal regulations and principles of Good Clinical 
Practice.  
The investigator will maintain accurate records of receipt of all cabozantinib, including dates of 
receipt (compliance form available in Appendix D).  In addition, accurate records will be kept 
regarding when and how much study treatment is dispensed and used by each subject in the 
study. Reasons for deviation from the expected dispensing regimen must also be recorded. At 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
unused cabozantinib will be reconciled, returned or destroyed in accordance with applicable state 
and federal regulations. 
Drug accountability and subject compliance will be assessed with drug dispensing and return 
records.  
5.4 
DEFINITION OF DOSE-LIMITING TOXICITY 
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) (v4.0). Dose limiting toxicities (DLTs) are defined as 
adverse events occurring during the first two cycles of therapy and related to the study 
medications (attributions: possible, probable, and definite) while fulfilling one of the following 
criteria: 
1. Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 
hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and 
asymptomatic grade 4 uric acid.  
2. A treatment delay of > 2 weeks due to an adverse event (delays due to dental procedures 
are not included) 
3. Grade 4 neutropenia (ANC<500/uL) lasting >5 days. 
4. Febrile neutropenia  


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5. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia < 50K/uL 
requiring platelet transfusion for bleeding will be considered dose limiting. 
6. Any treatment related AEs that lead to dose reduction of either agent (duration or dose) in 
cycles 1 and 2 will be considered a DLT. 
Anemia will not be considered a DLT.  
Hypertension will only be considered a DLT if it is a grade 4 or if clinical management of 
hypertension as defined in 6.1.7.1 mandates a dose reduction. 
With the exception of grade ≤ 3 fatigue and grade ≤ 3 reversible asymptomatic labs, the 
occurrence of a cabozantinib related DLT will lead to removal from protocol therapy unless 
patients can recover to grade 1 or baseline within 2 weeks.  In such cases, patients may continue 
with protocol treatment with a dose reduction.  In the cases of these exceptions, only 1 dose 
reduction will be permitted during the DLT evaluation period. 
A subject will be replaced if the subject does not have a DLT but is not fully evaluable for DLT 
due to missing more than 25% in total of the dosing days due to progressive disease or reasons 
other than cabozantinib-related toxicity. 
Because of the long half-life of cabozantinib, DLTs will be monitored for the first 6 weeks 
(during the first two cycles). 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
Dose escalation will proceed in cohorts of 3–6 patients as defined in the table below. Patients 
may be accrued concurrently within a single dose level. Patients may be enrolled on the next 
higher dose level, provided that at least three patients on the previous dose level have completed 
at least 6 weeks of the combination treatment, and none have experienced a DLT.  If one 
instance of DLT is observed among the initial 3 patients, 3 additional patients must be treated at 
this dose level without further DLT before escalation can proceed to the next dose level. If two 
instances of DLT are observed at a dose level, the MTD has been surpassed, and a total of 6 
patients must be treated at the previous dose level. The MTD is defined at the dose level at which 
no more than 1 of 6 patients experiences DLT at the level below that which had two instances of 
DLT. 
If a patient did not experience DLT and did not finish treatment, he or she will not be evaluable 
for toxicity and will be replaced in the dose level. 
Intrapatient dose escalation may be allowed at the discretion of the principal investigator if the 
following conditions are met: 
a. there is no drug-related toxicity > grade 2 after 3 courses of study treatment at the 
initial dose level;  
b. the higher dose level has been completed by all patients in that cohort and no 
patients experienced a DLT 
c. there is no evidence of disease progression. 
In addition, patients who have their dose escalated will not be evaluated for DLTs as they will 
have previously been evaluated for DLT at their initial dose level and will be more than 3 cycles 
into therapy.  


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Dose Escalation Table 
Number of Patients with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level 
will be declared the maximally administered 
dose (highest dose administered).  Three (3) 
additional patients will be entered at the next 
lowest dose level if only 3 patients were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, 
proceed to the next dose level. 
• If 1 or more of this group suffer DLT, then 
dose escalation is stopped, and this dose is 
declared the maximally administered dose.  
Three (3) additional patients will be entered at 
the next lowest dose level if only 3 patients 
were treated previously at that dose. 
<1 out of 6 at highest dose level 
below the maximally 
administered dose 
This is generally the recommended phase 2 dose. 
At least 6 patients must be entered at the 
recommended phase 2 dose. 
5.5 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
Subjects must inform the investigators of the current or planned use or all other medications 
during the study (including prescription medications, vitamins, herbal and nutritional 
supplements, and over-the-counter medications). 
5.5.1 Concurrent Medications/Interventions 
5.5.1.1 
Anticancer Therapy 
If a subject requires additional systemic anticancer treatment, study treatment must be 
discontinued.  Local intervention is discouraged unless medically unavoidable.  Subjects 
receiving local intervention (e.g., palliative radiation) are allowed to continue to receive study 
treatment at the investigator’s discretion.  
5.5.1.2 
Other Medications 
Subjects must be instructed to inform the investigators of the current or planned use or all other 
medications during the study (including prescription medications, over-the-counter medications, 
vitamins and herbal and nutritional supplements).  It is the responsibility of the investigator to 
ensure that details regarding all medications are documented. 
Bisphosphonates started prior to screening activities or initiated during the course of the study to 
control bone pain may be used with caution. 


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Colony stimulating factors (e.g., erythropoietin and granulocyte colony-stimulating factors) 
administered as dictated by safety purposes are acceptable while the subject is enrolled on study.  
Pain medications administered as dictated by standard practice are acceptable while the patient is 
enrolled on the study.   
No concurrent investigational agents are permitted. 
5.5.1.3 
Potential Drug Interactions 
Cytochrome P450:  Preliminary data from a clinical drug interaction study (Study XL184-008) 
show that clinically relevant steady-state concentrations of cabozantinib appear to have no 
marked effect on the AUC of co-administered rosiglitazone, a CYP2C8 substrate.  Therefore, 
cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not 
anticipated to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared 
to CYP2C8 (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 (but not a CYP2C9 or CYP2D6 substrate), based on data 
from in vitro studies using CYP-isozyme specific neutralizing antibodies.  
Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers.  Co-administration of cabozantinib with strong inducers of 
the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations.  Strong CYP3A4 inducers such as rifampin, cabamezepine, phenobarbital, 
phenytoin, pioglitazone, rifabutin, St. John’s wort and troglitazone should be avoided.  Other 
drugs that induce CYP3A4 should be used with caution because these drugs have the potential to 
decrease exposure (AUC) to cabozantinib.  Selection of alternate concomitant medications with 
no or minimal CYP3A4 enzyme induction potential is recommended.  In addition, caution must 
be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who has been 
concurrently receiving a stable dose of cabozantinib, as this could significantly increase the 
exposure to cabozantinib.  
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 33-
39% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in 
healthy volunteers.  Co-administration of cabozantinib with strong inhibitors of the CYP3A4 
family (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations.  Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib.  Strong CYP3A4 inhibitors 
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 consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/ for a 
list of agents that interact with CYP3A4.   


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Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (e.g., 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known.  
Therefore, these drugs should be used with caution when given with cabozantinib.  
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors 
of 
selected 
CYP450 
isozyme 
pathways 
(Flockhart 
2007; 
http://medicine.iupui.edu/clinpharm/ddis/).  
Protein Binding:  Cabozantinib is highly protein bound (approximately 99.9%) to human plasma 
proteins.  Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase 
in pharmacologic effect).  Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib.  Therefore, concomitant medications that are highly protein bound 
(e.g., diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution.  
Because warfarin is a highly protein bound drug with a low therapeutic index, administration of 
warfarin at therapeutic doses should be avoided in subjects receiving cabozantinib due to the 
potential for a protein binding displacement interaction.  
Drugs Associated with QTc Prolongation:  Treatment with cabozantinib has been associated with 
a mild prolongation of the QTc interval.  Caution should be used when treating subjects on 
cabozantinib with other drugs associated with QTc prolongation (see http://www.qtdrugs.org).  
Additional QTc monitoring is suggested for subjects who are treated concomitantly with QTc 
prolonging drugs. 
Other Interactions:  H2 blockers may be taken concomitantly with cabozantinib with the 
exception of cimetidine, which should be avoided because of its potential to interfere with 
CYP3A4 mediated metabolism of cabozantinib.  In vitro data suggest that cabozantinib is 
unlikely to be a substrate for P glycoprotein (P-gp), but it does appear to have the potential to 
inhibit the P-gp transport activity.  
Additional details related to these overall conclusions are provided in the Investigators Brochure. 
5.5.2 Supportive Care 
General guidelines for the management of cabozantinib related non-hematologic toxicities are 
provided in Section 6.1.1 . As a general approach, it is suggested that all AEs be managed with 
supportive care when possible at the earliest signs of toxicity. For more specific guidelines on 
gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, 
skin disorders (PPE), embolism and thrombus, and hypertension, see below.   
5.5.2.1 
Prophylaxis 
See section 5.3.2 for information on dexamethasone prophylaxis with docetaxel administration. 
5.5.2.2 
Neutropenia 
Growth factors may be used as medically indicated if patient develops fever and neutropenia.  
Dose reduction or interruption of docetaxel is also recommended as described in section 6.2.  
Grade 4 febrile neutropenia will result in being removed from protocol therapy.  See section 5.4.   


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5.5.2.3 
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management. 
Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide47. Some subjects may require concomitant 
therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of opium to control 
diarrhea. When combination therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, a dose reduction and/or dose interruption of cabozantinib should be 
implemented as described in Section 6.1.2.1.  In addition, general supportive measures should be 
implemented including continuous oral hydration, correction of fluid and electrolyte 
abnormalities, small frequent meals, and stopping lactose-containing products not including 
cabozantinib, high fat meals and alcohol.  
5.5.2.4 
Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  A dose reductions and/or dose interruption of cabozantinib 
may be required as described in Section 6.1.2  if antiemetic treatment and/or prophylaxis alone is 
not adequate.  
Agents classified as having the highest therapeutic index (such as 5-HT3 receptor antagonists) 
per ASCO or MASCC/ESMO guidelines for anti-emetics in oncology or dexamethasone are 
recommended48-50. Caution is recommended with the use of aprepitant or fosaprepitant and 
nabilone as cabozantinib exposure may be affected by concomitant administration because 
aprepitant and fosaprepitant are both inhibitors and inducers of CYP3A4, and nabilone is a weak 
inhibitor of CYP3A4. 
5.5.2.5 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis. During treatment with cabozantinib, good oral hygiene and standard local treatments 
such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures 
should be cleaned and brushed often to remove plaque. Local treatment should be instituted at 
the earliest onset of symptoms. When stomatitis interferes with adequate nutrition and local 
therapy is not adequately effective, dose reduction or temporary withholding of cabozantinib 
should be considered. 
5.5.2.6 
Hepatobiliary Disorders 
In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have 
more frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases.  
See section 6.1.3.1 for additional information. 


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5.5.2.7 
Skin Disorders 
All subjects on study should be advised on prophylactic measures for hand-foot syndrome 
including the use of emollients (Ammonium lactate 12% cream or heavy moisturizer twice 
daily), removal of calluses, avoidance of exposure of hands and feet to hot water leading to 
vasodilatation, protection of pressure-sensitive areas of hands and feet, and use of cotton gloves 
and socks to prevent injury and keep the palms and soles dry. 
The onset of PPE is variable with paresthesia (tingling, numbness) being the characteristic initial 
manifestation, which can be accompanied by slight redness or mild hyperkeratosis. PPE 
advances with symmetrical painful erythema and swollen areas (edema) on the palms and soles. 
The lateral sides of the fingers or periungual zones may also be affected. Adequate interventions 
are required to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, 
or necrosis of affected areas. 
Urea 20% cream twice daily and clobetasol 0.05% cream once daily should be used in subjects 
that exhibit toxicity.  NSAIDS, GABA agonists and opioids may be used for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Subjects with skin disorders should be carefully monitored for signs of infection (e.g., abscess, 
cellulitis, or impetigo). 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent. 
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
5.5.2.8 
Embolism and Thrombosis  
Low molecular weight heparin should be used to establish full anticoagulation in subjects on the 
first occurrence of a PE and/or DVT.   Full anticoagulation with warfarin is not permitted and 
venous filters are not recommended.  Treatment can be restarted at the discretion of the 
investigator.  Subjects should permanently discontinue after a second thrombotic event.  
Although routine prophylactic anticoagulation is not necessary for all subjects, prophylactic 
anticoagulation is allowed for individual subjects at the discretion of the investigator. 
5.5.2.9 
Hypertension 
See instructions in Section 6.1.7.1  
5.6 
ON STUDY ASSESSMENTS 
Please see study calendar (section 10) for schedule of the study assessments. 
5.6.1 Electrocardiogram (ECG) Assessments 
ECG assessments will be performed with standard 12-lead ECG equipment according to standard 
procedures. At any time point, if there is an increase in QTc interval to an absolute value > 500 
msec using the Fridericia correction formula, two additional ECGs should be performed 
approximately 2 minutes apart, within 30 minutes. If the average QTc interval calculated by the 
Fridericia formula from the three ECGs is > 500 msec, study treatment must be withheld and a 
cardiology consultation is recommended for evaluation and subject management. Study 
treatment may only be continued if the QTc resolves to 500msec or less and per investigator 


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judgment that continued treatment is appropriate. Abnormalities in the ECG that lead to a change 
in subject management (e.g., dose reduced or withheld, requirement for additional medication or 
monitoring) or result in clinical signs and symptoms are considered clinically significant for the 
purposes of this study and will be recorded on the AE CRF. If values meet criteria defining them 
as serious, they must be reported as SAEs. When an ECG time point coincides with other 
activities, the blood draw will be obtained at the scheduled time point, and the ECG will be 
collected first, followed by vital signs. 
5.6.2 Vital Signs 
Vital signs (body temperature, respiratory rate, and blood pressure and pulse) will be conducted 
at regular intervals. Blood pressure and pulse will be measured after the subject has been sitting 
for at least 5 minutes. 
When vital signs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled time point, and the vitals will be obtained as close to the scheduled 
blood draw as possible. 
5.6.3 Physical Examinations 
A physical examination will include assessments of general appearance, skin, HEENT, 
thorax/lungs, cardiovascular, abdominal, genitourinary, musculoskeletal and neurological 
findings. Any pertinent findings should be documented either in the subject’s medical history (if 
determined to be prior to the first dose of cabozantinib) or as an AE (if new or worsening after 
the first dose of cabozantinib). 
5.6.4 Laboratory Assessments 
Laboratory assessments will include the following: 
• 
Hematology: 
 
CBC with differential 
 
Reticulocytes (if indicated) 
 
Erythrocyte sedimentation rate (if indicated) 
• 
Serum chemistries: 
 
Hepatic panel (Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct 
Bilirubin) 
 
Acute care panel (Sodium, Potassium, Chloride, Total CO2 (Bicarbonate), Creatinine, 
Glucose, Urea nitrogen) 
 
Mineral panel (Albumin, Calcium total, Magnesium total, Phosphorus) 
 
Ionized calcium 
 
Amylase 
 
Lipase 
 
Lactate dehydrogenase (LDH) 
 
Total protein 
 
-glutamyltransferase (GGT) 
• 
Urinalysis and UPCR 
• 
Thyroid function tests - TSH, total T3 and T4 
• 
PT/INR or PTT 
• 
PSA 


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5.7 
DURATION OF THERAPY 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
5.8 
DURATION OF FOLLOW UP 
Once the patient is no longer receiving treatment (as per section 5.9.1), follow up evaluations as 
listed in the study calendar in section 10 will be conducted as appropriate per standard of care at 
the NCI or by the patient’s physician.  The patient may also receive follow-up calls to monitor 
his well-being and progress.  
For patients who are taken off treatment due to treatment toxicities, a follow up evaluation will 
be conducted within a month and if appropriate, the subject will be taken off study. 
5.9 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
5.9.1 Criteria for removal from protocol therapy 
Subjects may discontinue study treatment or withdraw their consent to participate in the study at 
any time without prejudice. The investigator may withdraw a subject from study treatment or 
from the study if, in his or her clinical judgment, it is in the best interest of the subject or if the 
subject cannot comply with the protocol.  
In addition, any of the following conditions require withdrawal of the subject from study 
treatment: 
• An AE or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from treatment 
• Necessity for treatment with other investigational drug or other anticancer 
medications prohibited by protocol 
• Noncompliance with the protocol schedule 
• Participation in another clinical study using anticancer agent(s) 
• Occurrence of cabozantinib related DLT as defined in section 5.4 with the exceptions 
of grade 4 neutropenia lasting > 5 days, grade ≤ 3 fatigue and grade ≤ 3 reversible 
asymptomatic laboratory abnormalities 
• Occurrence of any grade 3 or grade 4 non hematologic AE (except asymptomatic 
grade 3 hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and 
asymptomatic grade 4 uric acid) during cycles 3 and beyond unless the subject is 
unequivocally deriving clinical benefit 


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• Occurrence of grade 4 febrile neutropenia 
• Request by regulatory agencies for termination of treatment of an individual subject 
or all subjects under this protocol 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and 
for 4 months following discontinuation of study treatment 
• Inability to tolerate the administration of cabozantinib  
• Cabozantinib treatment delays > 2 weeks during the DLT evaluation period 
• Cabozantinib treatment delays > 2 weeks during cycles 3 and beyond unless the 
subject was unequivocally benefitting from cabozantinib treatment 
• Progressive disease (PD) 
• Investigator Discretion 
The reason for study treatment discontinuation will be documented. For subjects who 
discontinue or are withdrawn from study treatment, every effort must be made to undertake 
protocol-specified follow-up procedures and end-of-treatment assessments, if possible, unless 
consent to participate in the study is also withdrawn. 
If a subject fails to return for the protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at the minimum a registered letter should 
be sent to the subject (or the subject’s legal guardian) requesting contact with the clinic. 
If a subject is discontinued from study treatment because of an AE considered to be related to 
study treatment and the event is ongoing 30 days after the last dose of study treatment, the event 
must be followed until resolution or determination by the investigator that the event has become 
stable or irreversible. 
5.9.2 Off Study Criteria 
• Investigator Discretion 
• Manufacturer no longer able to supply study agent 
• Completion of all study procedures 
• Participant requests to be withdrawn from study 
• Death 
• Screen failure 
 
If a subject withdraws consent to participate in the study, the reason for withdrawal will be 
documented, no further study procedures or assessments will be performed, and no further study 
data will be collected for this subject, other than the determination of survival status from public 
records such as government vital statistics or obituaries. 
5.9.3 Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 


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sent via encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. 
 
For Participating Sites 
All subjects must be registered through the NCI Central Registration Office (CRO). The CRO is 
open from 8:30am to 5:30pm EST Monday through Friday, excluding federal holidays.  An off-
study form will be supplied by the CCR study coordinator.  Send the completed off-study form 
to the CCR study coordinator. 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
In general, the PI will attempt to attribute the toxicity to the most likely agent. In cases of 
overlapping toxicities (with the exception of hematologic toxicities) of cabozantinib and 
docetaxel, toxicities will be attributed to cabozantinib.  Hematologic toxicities will be attributed 
to docetaxel due to the infrequency of their occurrence in studies with single agent cabozantinib. 
Patients who require a treatment delay of >2 weeks, due to toxicities related to treatment, will 
permanently discontinue treatment on study.  
Patients will remain on study in the case of unavoidable dental procedures that require a 
treatment delay of >2 weeks.  
6.1 
CABOZANTINIB  
Subjects will be monitored continuously for AEs throughout the study. Subjects must be 
instructed to notify their physician immediately for any and all toxicities. 
 
General guidelines for the management of non-hematologic are provided in Table 6.1.1. As a 
general approach, it is suggested that all AEs be managed with supportive care when possible at 
the earliest signs of toxicity. Calcium, magnesium, potassium and phosphorus should be kept 
above the lower limits of the laboratory normal values. For more specific guidelines on 
gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, 
pancreatic disorders including lipase and amylase elevations, skin disorders (PPE), embolism 
and thrombus, hypertension, proteinurea, hemorrhage, rectal and perirectal abscess, 
gastrointestinal (GI) perforation and GI fistula, non-GI fistula, wound healing and surgery, 
osteonecrosis of the jaw (ONJ),  endocrine disorders and management of treatment-emergent 
prolongation of the QTc interval, refer to the appropriate below.  Guidance for the management 
of fatigue, anorexia, weight loss, eye disorders, musculoskeletal and connective tissue disorders, 
nervous system disorders, respiratory/thoracic/mediastinal disorders and congenital, familial and 
genetic disorders can be found in the Cabozantinib Investigator’s Brochure.  
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this is 
clinically indicated or if causality is initially uncertain. Study treatment may be resumed at the 
same dose (or a lower dose per investigator judgment) if the AE is determined not to be related 
to cabozantinib once the investigator determines that retreatment is clinically appropriate and the 
subject meets the protocol re-treatment criteria. 


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Dosing delays and modification instructions for cabozantinib non-hematologic toxicities are 
below.  If study treatment of cabozantinib is restarted after being withheld or interrupted, the 
subject should be instructed not to make up the missed doses of cabozantinib.  
If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within ≤ 2 weeks, 
the subject will have study treatment permanently discontinued.   
The minimum dose of study treatment will be 20 mg every other day. Subjects who cannot 
tolerate 20 mg every other day will have study treatment discontinued. 
The reason for treatment delay and reduced dose must be recorded on the case report form 
(CRF). 


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6.1.1 General Guidelines for the Management of Cabozantinib-Related non-Hematologic 
Toxicities 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level 
Grade 2: 
Grade 2 AEs considered related to 
cabozantinib that are subjectively 
tolerable or easily managed 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level. 
Grade 2 AEs considered related to 
cabozantinib that are intolerable to the 
subject or deemed unacceptable in the 
investigator’s judgment; or are not 
easily managed or corrected 
Dose Interruption and/or Dose Reduction 
• 
After dose reduction, if the AE dose not resolve to Grade ≤1 or 
baseline in 7 to 10 days or worsens at any time, cabozantinib 
dosing should then be interrupted.   
• 
If the AE resolves to baseline or Grade ≤ 1, after dose interruption, 
cabozantinib may be resumed at either the same reduced dose or 
with another dose reduction at the discretion of the investigator. 
• 
If this is a recurring event the dose should be reduced. If the AE 
resolves to Grade ≤1 or baseline without a dose interruption, 
continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
cabozantinib which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
• 
Interrupt cabozantinib and add supportive care as indicated 
• 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤1 within 24 hours, 
cabozantinib may be resumed at either the same dose or with a 
dose reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
• 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized.  Then upon 
resolution of the AE to baseline or Grade ≤1, cabozantinib may be 
resumed at either the same dose or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at 
which time the dose should be reduced 
Grade 3 AEs considered related to 
study treatment that occurred despite 
optimal prophylaxis or is not easily 
managed by medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction 
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit and the subject is not 
within the DLT evaluation period (cycles 1 & 2).  In this case, upon 
recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 


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Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the investigator 
believes that it is in the interest of the subject’s safety.  
 
6.1.2 Diarrhea, Nausea, Vomiting, Stomatitis, and Mucositis 
6.1.2.1 
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management.  
Loperamide is recommended as standard first line therapy.  Alternatively, diphenoxylate/atropine 
can be used.  Additional agents to consider in subjects with diarrhea that is refractory to the 
above include deodorized tincture of opium and octreotide (Benson et al., 2004).  Some subjects 
may require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized 
tincture of opium to control diarrhea.  The dose modification guidance in Table 6.1.1 should be 
followed.  In addition, general supportive measures should be implemented including continuous 
oral hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high fat meals and alcohol.  
6.1.2.2 
Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  The dose modification guidance in Table 6.1.1 should be 
followed.   
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists 
and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and 
glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure.  Caution is also 
recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. 
6.1.2.3 
 
Dehydration 
As of 26 August 2013 dehydration events have been identified with comparable incidence (9%) 
and occurring in a shorter time to onset in the blinded prostate cancer studies (median time to 
onset 38-46 days) than previously experienced with cabozantinib in the MTC development 
program (median time to onset 114.6 days). 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. 
6.1.2.4 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated.  Appropriate correction of local factors should 
be instituted as indicated, such as modification of ill-fitting dentures and appropriate care of 
gingivitis.  During treatment with cabozantinib, good oral hygiene and standard local treatments 
such as non-traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking 
soda) should be maintained.  The oral cavity should be rinsed and wiped after meals, and 
dentures should be cleaned and brushed often to remove plaque. Local treatment should be 
instituted at the earliest onset of symptoms.  When stomatitis interferes with adequate nutrition 
and local therapy is not adequately effective, dose reduction or temporary withholding of 
cabozantinib should be considered. 


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6.1.3 Hepatobiliary Disorders 
Elevations of transaminases have also been observed during treatment with cabozantinib.  In 
general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more 
frequent laboratory monitoring of these parameters.  If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases.  
Since subjects may enter the study with elevations of AST/ALT at baseline, the following 
guideline should be used for dose modifications: 
6.1.3.1 
Transaminase Elevations 
Transaminase elevation 
CTCAE v4.0 
Interventions 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks. 
Then weekly for 4 weeks.  If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment.   Then continue with at least weekly LFTs until resolution 
to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction 
of cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Cabozantinib may then be resumed at a one-dose-level reduction. 
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.   If the subject 
was unequivocally deriving clinical benefit and the subject is not within the DLT 
evaluation period (cycles 1 & 2), the subject may be able to resume treatment at a 
lower dose of cabozantinib as determined by the investigator and sponsor but only 
with sponsor approval. 


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Subjects with AST or ALT above the ULN at baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs for 
4 weeks and weekly for 4 weeks.  If LFTs continue to rise, interrupt study 
treatment.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of cabozantinib 
≥ 1.5 fold increase of AST or 
ALT and at least one of AST 
or ALT is Grade 3 (i.e. AST 
or ALT > 5.0 but ≤ 20.0 x 
ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit and the subject is not within the DLT 
evaluation period (cycles 1 & 2), the subject may be able to resume treatment at a 
lower dose as determined by the investigator and sponsor but only with sponsor 
approval. 
Cabozantinib treatment should also be interrupted when transaminase increases are accompanied 
by progressive elevations of total bilirubin, and/or elevations of coagulation tests 
(e.g., International Normalized Ratio [INR]). Monitoring of transaminases should be intensified 
(2–3 times per week) and cabozantinib should be held until the etiology of the abnormalities is 
determined and these abnormalities are corrected or stabilize at clinically acceptable levels (INR 
< 1.5  ULN, total bilirubin < 1.5  ULN, aminotransferases < 2.5  ULN or baseline).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2xULN), in the 
absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase 
[ALP]) or some other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the 
combined finding (i.e., Hy’s Law cases) represents a signal of a potential for the drug to cause 
severe liver injury. 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study treatment 
held until recovered to Grade ≤ 1 or baseline (or lower). If this occurs within 2 weeks after the 
dosing delay, study treatment may continue at a reduced dose. In subjects without biliary 
obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 3 bilirubin elevation 
after a dose reduction, study treatment must be discontinued. 
6.1.4 Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The 
clinical significance of asymptomatic elevations of enzymes is not known but in general has not 
been associated with clinically apparent sequelae. It is recommended that subjects with lipase 
elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase 
and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated 
with standard supportive measures. 


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6.1.4.1 
Asymptomatic Lipase or Amylase Elevations 
Asymptomatic Lipase or Amylase Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted at 
the same dose or at a reduced dose provided that this occurs within 2 
weeks. 
• 
If retreatment following Grade 3 lipase or amylase elevation is at the same 
dose and Grade 3 or Grade 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase levels have resolved to 
Grade ≤1 or baseline and retreatment must be at a reduced dose 
Grade 4 
• 
If occurring within the DLT evaluation period, permanently discontinue 
cabozantinib 
Otherwise: 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤ 1 or baseline and if resolution occurred within 
4 days, cabozantinib may be restarted at the same dose or a reduced dose.  
If resolution took more than 4 days, the dose must be reduced upon 
retreatment provided that resolution occurred within 2 weeks. 
• 
If retreatment following Grade 4 lipase or amylase elevation is at the same 
dose and Grade 3 or 4 elevations recur, then treatment must be interrupted 
again until lipase and amylase have resolved to Grade ≤ 1 or baseline and 
retreatment must be at a reduced dose. 
 


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6.1.4.2 
Pancreatitis 
Pancreatitis 
Grade 2 and asymptomatic 
Continue at current dose level. More frequent monitoring of lipase and amylase and 
radiographic evaluation is recommended 
Grade 2 symptomatic and 
Grade 3 
• 
If grade 3 pancreatitis occurs during DLT evaluation period, permanently 
discontinue cabozantinib 
Otherwise: 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted at 
a reduced dose if resolution occurred within 2 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was unequivocally 
deriving benefit from cabozantinib therapy and the subject is not within the DLT 
evaluation period (cycles 1 & 2), treatment may resume at a reduced dose agreed to 
by the investigator and sponsor but only with sponsor approval. 
 
 
6.1.5 Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin 
rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported in cabozantinib-treated subjects.  All subjects on study should be advised to use 
prophylactic measures for skin care.  These measures include the use of hypoallergenic 
moisturizing creams, ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of 
hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; and use of 
thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. Subjects 
with skin disorders should be carefully monitored for signs of infection (e.g., abscess, cellulitis, 
or impetigo). 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles.  The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas.  Aggressive management of symptoms 
is recommended, including early dermatology referral. 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent.  
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  


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6.1.5.1 
Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose.  Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Assess subject at least weekly for changes in 
severity.  Subjects should be instructed to notify investigator immediately if 
severity worsens.   
Grade 2 
If tolerable, continue cabozantinib at current dose.  If intolerable, reduce 
cabozantinib dose to next lower level and/or interrupt dosing. Start/continue urea 
20% cream twice daily AND clobetasol 0.05% cream once daily. Add analgesics 
for pain control with NSAIDs/GABA agonists/narcotics if needed. Assess subject 
at least weekly for changes in severity.  If treatment was interrupted (but not 
reduced), treatment may be restarted at the same dose or at one dose level lower 
when reaction decreases to Grade 1 or 0.  If a treatment interruption is again 
required, the dose must be reduced when treatment resumes. Subjects should be 
instructed to notify investigator immediately if severity worsens.  If severity 
worsens at any time, or affects self-care, proceed to the management guidelines for 
Grade 3 PPE.   
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0.  Start/continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Pain control 
with NSAIDs/GABA agonists/narcotics.  Treatment may restart at one dose level 
lower when reaction decreases to Grade 1 or 0. Permanently discontinue subject 
from study if reactions worsen or do not improve within 6 weeks unless the subject 
was unequivocally deriving clinical benefit.  In this situation, the subject may be 
able to resume treatment at a lower dose as determined by the investigator / 
principal investigator and Sponsor, but only with Sponsor approval.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 
6.1.6 Thromboembolic Events 
Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including 
fatal events (please refer to the IB).  Unless DLT as defined in Section 5.4, subjects who develop 
a PE or DVT should have study treatment held until therapeutic anticoagulation with heparins is 
established.  Study treatment may be resumed with a one dose-level reduction in subjects who 
have uncomplicated PE or DVT and are deriving clinical benefit from study treatment.  During 
treatment with anticoagulants, subjects need to be monitored on an ongoing basis for bleeding 
risk and signs of bleeding.  Subjects with life-threatening PE or DVT should have study 
treatment discontinued unless toxicity can be managed and subject is deriving clear clinical 
benefit as determined by the investigator and agreed by the Sponsor.  Venous filters (e.g. vena 
cava filters) are not recommended due to the high incidence of complications associated with 
their use.  Once a subject is fully anticoagulated, treatment can be restarted per investigator 
judgment at one dose lower.  Subjects should permanently discontinue after a second thrombotic 
event.  Although routine prophylactic anticoagulation is not necessary for all subjects, 
prophylactic anticoagulation is allowed for individual subjects at the discretion of the 
investigator. 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been 
observed rarely in studies with cabozantinib.  Cabozantinib should be discontinued in subjects 


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who develop an acute MI or any other clinically significant arterial thromboembolic 
complication. 
6.1.7 Hypertension 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in cabozantinib clinical studies. 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by 
a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement. Subjects with known hypertension should be optimally 
managed prior to study entry.  Clinical judgment should be used in deciding whether new or 
worsened hypertension emerging during treatment with cabozantinib requires immediate therapy, 
or whether therapeutic intervention can be delayed in order to confirm the finding of new or 
worsened hypertension at a second visit before taking new therapeutic action.  It is recommended 
that this second visit occur within 1 week.  Blood pressure should be monitored in a constant 
position visit to visit, either sitting or supine. Cabozantinib dosing should be interrupted in 
subjects with severe hypertension (≥180 mm Hg systolic or ≥120 mm Hg diastolic; or sustained 
≥ 160 mm Hg systolic or ≥ 110 diastolic) who cannot be controlled with medical interventions 
and discontinued in subjects with hypertensive crises or hypertensive encephalopathy. (See next 
Table below). 
6.1.7.1 
Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic) and < 160 mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm Hg 
 
 
• Increase antihypertension therapy (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• Maintain dose of cabozantinib 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 150 systolic or < 
90 diastolic, or if the subject is symptomatic, the dose of 
cabozantinib should be reduced 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
or 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
• Interrupt and/or reduce cabozantinib by one dose level; 
• Increase antihypertension therapy (ie, increase dose of existing 
medications and/or add new antihypertensive medications); 
• Monitor subject closely for hypotension; 
• If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 150 systolic or < 
100 diastolic, dose of cabozantinib should be reduced further. 
≥ 160 mm Hg (systolic) OR 
≥ 100 mm Hg (diastolic)  
• 
Interrupt treatment with cabozantinib 
• 
Increase anti-hypertension therapy (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
• 
Monitor subject closely for hypotension. 
• 
When SBP <150 and DBP <100, restart cabozantinib 


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Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
treatment at the same dose level. 
• 
Once treatment is restarted, if optimal antihypertensive 
therapy (usually to include 3 agents) does not result in blood 
pressure < 150 systolic or < 100 diastolic, cabozantinib should 
be held and restarted at a lower dose when SBP <150 and 
DBP <100.  
Hypertensive crisis or hypertensive 
encephalopathy 
• Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
6.1.8 Proteinuria 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib.  Any level of proteinuria diagnosed by dipstick should be quantified by a UPCR 
(mg/dL protein / mg/dL creatinine).  When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine 
protein and creatinine should be performed to confirm the result. Cabozantinib should be 
discontinued in subjects who develop nephrotic syndrome (proteinuria >3.5 g/day in 
combination with hypoalbuminemia, edema and hyperlipidemia) or any other relevant renal 
disease.  Also, given the nephrotoxic potential of bisphosphonates, these agents should be used 
with caution in patients receiving treatment with cabozantinib.  Details of management are 
described in Table 6.1.8.1 below. 
 


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6.1.8.1 
Management of Treatment Emergent Proteinuria 
Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
• 
No change in treatment or monitoring 
> 1 and < 3.5 
 
• 
No change in study treatment required  
• 
Consider confirming with a 24-hour protein excretion within 7 
days 
• 
Repeat UPCR within 7 days and once every week. If UPCR is < 1 
on two consecutive readings, then UPCR monitoring can revert to 
protocol specific time points. (The second reading is a 
confirmatory reading and can be done within 1 week of the first 
reading.). 
≥ 3.5 
• 
Hold cabozantinib immediately and confirm with 24 hour urine protein 
excretion.  
• 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis of 
nephrotic syndrome, continue to hold cabozantinib and monitor UPCR 
weekly. If UPCR decreases to < 2, restart cabozantinib at a reduced 
dose.  Continue monitoring UPCR once every week until two 
consecutive readings are < 1, then revert to UPCR monitoring 
frequency specified in the protocol. 
Nephrotic Syndrome 
• 
Discontinue cabozantinib treatment. 
UPCR; urine protein/urine creatinine ratio 
 
6.1.9 Hemorrhage 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib. As preventive measures, subjects should be evaluated for potential 
bleeding risk factors prior to initiating cabozantinib treatment and monitored for bleeding events 
with serial complete blood counts and physical examination while on study. Risk factors for 
hemorrhagic events may include (but may not be limited to) the following: 
• Tumor lesions of the lung with cavitations or tumor lesions which invade, encase, or about 
any major blood vessels; non-small cell lung cancer (NSCLC) with squamous cell 
differentiation is known for significant lung cavitations and centrally located tumors that may 
invade major blood vessels. The anatomic location and characteristics of tumor as well as the 
medical history should be carefully reviewed in the selection of subjects for treatment with 
cabozantinib. 
• Recent or concurrent radiation to the thoracic cavity  
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases 
• Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia) 
• Concomitant medication with anticoagulants or other drugs which affect normal hemostasis 
• History of clinically significant hemoptysis 


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Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding 
events or recent hemoptysis (≥ 0.5 teaspoon (2.5ml) of red blood). Treatment with cabozantinib 
should be interrupted if less severe forms of clinically significant hemorrhage occur and, if it 
does not meet DLT criteria as defined in Section 5.4, may be restarted after the cause of 
hemorrhage has been identified and the risk of bleeding has subsided. Therapy of bleeding 
events should include supportive care and standard medical interventions.  
Furthermore, subjects who develop tumors invading a major blood vessel while on study 
treatment must be discontinued from cabozantinib treatment. 
6.1.10 Rectal and Perirectal Abscesses 
These should be treated with appropriate local care and antibiotic therapy.  Cabozantinib should 
be held until adequate healing has taken place unless ≥ grade 3 and occurring in the first 2 cycles 
in which case cabozantinib should be permanently discontinued. 
6.1.11 Gastrointestinal Perforation and GI fistula  
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must be 
confirmed prior to initiating treatment with cabozantinib.  
Discontinue cabozantinib and initiate appropriate management in subjects who have been 
diagnosed with GI perforation or fistula. 
6.1.12 Wound Healing and Surgery 
Surgical and traumatic wounds must have completely healed prior to starting cabozantinib 
treatment and be monitored for wound dehiscence or wound infection while the subject is being 
treated with cabozantinib.  
Treatment with cabozantinib must be interrupted for any wound healing complication which 
needs medical intervention. Treatment with cabozantinib can be resumed once wound healing 
has occurred unless meeting DLT criteria as defined in Section 5.4. Cabozantinib should be 
discontinued in subjects with serious or chronic wound healing complications. 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 3 
weeks (5 half-lives) prior to elective surgery.  
6.1.13 Endocrine Disorders 
Prospective studies of markers of thyroid functions are currently ongoing in two single-agent 
studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate 
that cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (see 
Cabozantinib Investigator’s Brochure).  Routine monitoring of thyroid function and assessments 
for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated 
with cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) 
should follow accepted clinical practice guidelines. 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects.  Monitoring with standard laboratory 
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with cabozantinib is required.  Cabozantinib should be discontinued in subjects with severe or 
life-threatening endocrine dysfunction. 
6.1.14 Guidelines for Prevention of Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients.  Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself.  Cases of 
osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are 
provided in the current version of Investigator’s Brochure.  As a preventive measure, invasive 
dental procedures should be avoided if possible in subjects who have previously been treated 
with or concomitantly receive bisphosphonates or denosumab. In cases where dental procedures 
are unavoidable, the risks and benefits of a dental procedure and the extent of the procedure as 
well as the risk of developing osteonecrosis of the jaw need to be considered when deciding on 
the duration of a temporary treatment interruption of cabozantinib.  If clinically possible, 
treatment with cabozantinib should be held for at least 2 weeks prior to a dental procedure and 
resumed after complete wound healing occurred. 
Subjects with any documented case of osteonecrosis should have study treatment interrupted, 
and appropriate clinical management should be initiated.  Study treatment may be reinitiated if it 
does not meet DLT criteria as defined in section 5.4; however, reinitiation must be discussed 
with and approved by the Sponsor on a case by case basis. 
6.1.15 Guidelines for Management of Treatment-Emergent Corrected QT (QTc) Prolongation 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval.  
Other factors which may contribute to QTc prolongation include 
• Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org). 
• Treatment with CYP 3A4 inhibitors (which may increase cabozantinib drug levels) 
• Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia). 
• Medical conditions which can alter electrolyte status e.g., severe or prolonged diarrhea. 
Subjects having any of these additional risk factors while on cabozantinib must have ECGs 
performed approximately one week after the onset of these factors. 
If at any time on study there is an increase in QTc interval to an absolute value >500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with intervals not 
less than 3 minutes apart.  If the average QTcF from the three ECGs is >500 msec, study 
treatment must be permanently withheld if this occurs during the DLT evaluation period.  
Otherwise, the following actions should be taken: 
• Check electrolytes, especially potassium, magnesium and calcium.  Correct abnormalities 
as clinically indicated. 
• If possible, discontinue any QTc-prolonging concomitant medications. 
• Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise determined 
by consultation with a cardiologist. 


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The Sponsor should be notified immediately of any QTc prolongation event.  
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation has resolved.  Cardiology consultation is recommended for evaluation and subject 
management.  Symptomatic subjects must be treated according to standard clinical practice.  No 
additional study treatment is to be given to the subject until after the event has resolved, the 
subject has been thoroughly evaluated, and further treatment has been agreed to by the Sponsor.  
If any additional study treatment is given (e.g., after correction of electrolyte abnormalities and 
normalization of QTcF), it will be at a reduced dose as agreed to by the investigator and the 
Sponsor. 
6.1.16 Additional information for dose delays or dose reductions: 
Dose delays for reason(s) other than AEs related to cabozantinib, such as surgical procedures 
with no anticancer therapy intent, may be allowed with investigator approval. The acceptable 
length of interruption will be determined by the investigator. 
6.2 
DOCETAXEL DOSE MODIFICATIONS 
Patients should have an ANC 1500 cells/mm3, a platelet count  75,000 cells/mm3 (grade 1 
hematologic toxicity) and resolution of any grade 3 or higher non-hematologic toxicity to < 
grade 1 or baseline in order to initiate another treatment cycle of docetaxel.  
For febrile neutropenia developed within a prior cycle, docetaxel can be continued during future 
cycles at a dosage decreased by 25% and if indicated, with the addition of filgrastim support.  
For grade 4 neutropenia lasting greater than 5 days docetaxel will be held and patients will be 
treated with filgrastim support.  Docetaxel will be resumed at the same dose once neutropenia 
has resolved to ≤ grade 1 or baseline. 
Docetaxel Dose Modifications for Neutropenia without Fever: 
When Neutrophils fall to 
for a Duration of 
Recommended Course 
<1000 but ≥ 500/mcL (Grade 3) 
Any length of time 
No dose reduction for future cycles. 
<500/mcL (Grade 4) 
≤ 5days 
No dose reduction for future cycles. 
<500/mcL (Grade 4) 
> 5 days 
No dose reduction.  DOCETAXEL will be held 
and patients will be treated with filgrastim 
support.  DOCETAXEL will be resumed at the 
same dose once neutropenia has resolved to ≤ 
grade 1 or baseline.    
 
For grade 3 constipation or grade 3 fatigue, treatment can resume with a 25% dose reduction 
after resolution of toxicity to < grade 1 or baseline. Patients will be allowed to continue 
docetaxel treatment at successively reduced doses as long as they do not have progressive 
disease, regardless of the time required for recovery from ADEs.  For dose-limiting toxicities 
related to docetaxel that lead to withholding docetaxel temporarily, cabozantinib may be 
withheld along with docetaxel at the discretion of the investigators for the best interest and safety 
of patients. However, prednisone should not be interrupted.  


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6.3 
STUDY DRUG DOSE HOLIDAYS 
Patients may receive treatment indefinitely, but may have the doses of one or all drugs 
(docetaxel, cabozantinib or prednisone) withheld temporarily for resolution of toxicities or taking 
drug holidays, and potentially resume treatment as long as they do not fulfill the criteria for 
removal from protocol therapy outlined in section 5.9.1. The determination of a drug holiday will 
be at the discretion of the investigator.  
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2.1.1) 
will determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
7.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) 
FOR 
CABOZANTINIB S-MALATE (XL184, NSC 761968) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2438 patients. Below is the CAEPR for 
XL184 (Cabozantinib s-malate). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
      Version 2.3, October 4, 20161 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 


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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal hemorrhage3   
 
 
Gastrointestinal perforation4   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Musculoskeletal and 
connective tissue disorders - 
Other (muscle spasms) 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  


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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 4.0 Term) 
[n= 2438] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
 Pneumothorax6 
  
 
 
 Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
Voice alteration 
 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) 
 
 Skin and subcutaneous tissue 
disorders - Other (hair color 
changes) (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper 
gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients with 
relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases.  


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7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, Mediastinal 
hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS SOC.  
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
 
Adverse events reported on XL184 (Cabozantinib s-malate) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that XL184 (Cabozantinib s-malate) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Febrile neutropenia; Hemolytic uremic syndrome 
CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart 
failure; Left ventricular systolic dysfunction; Myocardial infarction; Myocarditis; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - Other 
(hypopituitarism); Endocrine disorders - Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); 
Hyperthyroidism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic 
obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; 
Gastrointestinal disorders - Other (anal fissure); Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal 
disorders - Other (glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Hemorrhoids; Ileus; 
Pancreatitis; Rectal pain; Rectal ulcer 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Fever; Gait 
disturbance; General disorders and administration site conditions - Other (implant site inflammation); Malaise; 
Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (cholelithiasis); 
Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatitis toxic); Portal vein 
thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - Other (tendon 
injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac troponin 
I increased; Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Investigations - Other (blood lactate dehydrogenase increased); Investigations - Other (D-dimer); Investigations - 
Other (eosinophil count increased); Investigations - Other (glucose urine present); Investigations - Other (urine 
ketone body present); Lymphocyte count decreased; Neutrophil count decreased; Serum amylase increased; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(failure to thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Flank pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue disorders - 
Other (muscle hemorrhage); Musculoskeletal and connective tissue disorders - Other (osteonecrosis); 
Musculoskeletal and connective tissue disorders - Other (rhabdomyolysis); Myalgia; Neck pain; Osteoporosis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); Neoplasms benign, 


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malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Encephalopathy; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; 
Nervous system disorders - Other (cerebral hematoma); Nervous system disorders - Other (hemiparesis); Nervous 
system disorders - Other (spinal cord compression); Nervous system disorders - Other (vocal cord paralysis); 
Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Stroke; Syncope; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Psychiatric 
disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Renal and urinary disorders - Other 
(azotemia); Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(scrotal ulcer/erythema/edema); Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hypoxia; Laryngeal edema; Pharyngeal mucositis; Pleural effusion; 
Pneumonitis; Productive cough; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (nasal septum perforation); Respiratory, thoracic and mediastinal disorders - Other (oropharyngeal 
pain); Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and 
mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Pruritus; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin and subcutaneous tissue 
disorders - Other (psoriasis); Skin and subcutaneous tissue disorders - Other (splinter hemorrhages); Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders - Other 
(bleeding varicose vein); Vasculitis 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
7.1.1 Adverse Event List(s) for Commercial Agent(s) 
7.1.1.1 
Docetaxel 
(See package insert for complete list of side effects) 
The most common adverse reactions across all docetaxel indications are infections, neutropenia, 
anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, 
dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, 
vomiting, mucositis, alopecia, skin reactions, myalgia 
7.1.1.2 
Prednisone 
(See package insert for complete list of side effects) 
Serious side effects of prednisone include hypertension, hyperglycemia, infections, ruptured 
tendons, psychotic reactions, glaucoma, severe edema, gastrointestinal bleeding and allergic 
reactions.  Short term side effects may include headaches and insomnia while long term side 
effects may cause weight gain, exopthalmos, osteoporosis, acne and truncal fat distribution. 
Allergic Reactions 
anaphylactoid or hypersensitivity reactions, anaphylaxis, angioedema. 
Cardiovascular System  
bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, 
congestive heart failure, ECG changes caused by potassium deficiency, edema, fat embolism, 


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hypertension or aggravation of hypertension, hypertrophic cardiomyopathy in premature infants, 
myocardial rupture following recent myocardial infarction, necrotizing angiitis, pulmonary 
edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis. 
Dermatologic  
acne, acneiform eruptions, allergic dermatitis, alopecia, angioedema, angioneurotic edema, 
atrophy and thinning of skin, dry scaly skin, ecchymoses and petechiae (bruising), erythema, 
facial edema, hirsutism, impaired wound healing, increased sweating, Karposi’s sarcoma, lupus 
erythematosus-like lesions, perineal irritation, purpura, rash, striae, subcutaneous fat atrophy, 
suppression of reactions to skin tests, striae, telangiectasis, thin fragile skin, thinning scalp hair, 
urticaria. 
Endocrine  
Adrenal insufficiency-greatest potential caused by high potency glucocorticoids with long 
duration of action (associated symptoms include; arthralgias, buffalo hump, dizziness, life-
threatening hypotension, nausea, severe tiredness or weakness), amenorrhea, postmenopausal 
bleeding or other menstrual irregularities, decreased carbohydrate and glucose tolerance, 
development of cushingoid state, diabetes mellitus (new onset or manifestations of latent), 
glycosuria, hyperglycemia, hypertrichosis, 
hyperthyroidism, 
hypothyroidism, increased 
requirements for insulin or oral hypoglycemic agents in diabetics, lipids abnormal, moon face, 
negative nitrogen balance caused by protein catabolism, secondary adrenocortical and pituitary 
unresponsiveness (particularly in times of stress, as in trauma, surgery or illness), suppression of 
growth in pediatric patients. 
Fluid and Electrolyte Disturbances  
congestive heart failure in susceptible patients, fluid retention, hypokalemia, hypokalemic 
alkalosis, metabolic alkalosis, hypotension or shock-like reaction, potassium loss, sodium 
retention with resulting edema. 
Gastrointestinal  
abdominal distention, abdominal pain,anorexia which may result in weight loss, constipation, 
diarrhea, elevation in serum liver enzyme levels (usually reversible upon discontinuation), 
gastric irritation, hepatomegaly, increased appetite and weight gain, nausea, oropharyngeal 
candidiasis, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of 
the small and large intestine (particularly in patients with inflammatory bowel disease), 
ulcerative esophagitis, vomiting. 
Hematologic  
anemia, neutropenia (including febrile neutropenia). 
Metabolic  
negative nitrogen balance due to protein catabolism. 
Musculoskeletal  
arthralgias, aseptic necrosis of femoral and humeral heads, increase risk of fracture, loss of 
muscle mass, muscle weakness, myalgias, osteopenia, osteoporosis, pathologic fracture of long 


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bones, steroid myopathy, tendon rupture (particularly of the Achilles tendon), vertebral 
compression fractures. 
Neurological/Psychiatric  
amnesia, anxiety, benign intracranial hypertension, convulsions, delirium, dementia 
(characterized by deficits in memory retention, attention, concentration, mental speed and 
efficiency, and occupational performance), depression, dizziness, EEG abnormalities, emotional 
instability and irritability, euphoria, hallucinations, headache, impaired cognition, incidence of 
severe psychiatric symptoms, increased intracranial pressure with papilledema (pseudotumor 
cerebri) usually following discontinuation of treatment, increased motor activity, insomnia, 
ischemic neuropathy, long-term memory loss, mania, mood swings, neuritis, neuropathy, 
paresthesia, personality changes, psychiatric disorders including steroid psychoses or 
aggravation of pre-existing psychiatric conditions, restlessness, schizophrenia, verbal memory 
loss, vertigo, withdrawn behavior. 
Ophthalmic  
blurred vision, cataracts (including posterior subcapsular cataracts), central serous 
chorioretinopathy, establishment of secondary bacterial, fungal and viral infections, 
exophthalmos, glaucoma, increased intraocular pressure, optic nerve damage, papilledema. 
Other  
abnormal fat deposits, aggravation/masking of infections, decreased resistance to infection, 
hiccups, immunosuppresion, increased or decreased motility and number of spermatozoa, 
malaise, insomnia, moon face, pyrexia. 
7.2 
DEFINITIONS 
7.2.1 Adverse Event  
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 


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7.2.1.1 
Adverse Event Characteristics: 
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
• 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in 
the SPEER column, Section Error! Reference source not found.) should be 
reported through CTEP-AERS only if the grade is above the grade provided in 
the SPEER. 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.2.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 


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7.2.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.2.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.2.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
7.2.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.2.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 


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7.3 
EXPEDITED ADVERSE EVENT REPORTING TO CTEP 
7.3.1 Reporting via CTEP-AERS 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting procedures to 
be followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Section 7.3.4). 
7.3.2 In the Event of Lost Internet Connectivity 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
7.3.3 Multi-institutional Studies 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients. 
7.3.4 Expedited Reporting Guidelines  
Use the CC protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
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5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS 
within the timeframes detailed in the table below. 
 
 
 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       ≥ 
24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization       ≥ 
24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
ROUTINE ADVERSE EVENT REPORTING TO CTEP 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 


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7.5 
NHLBI IRB AND NHLBI CLINICAL DIRECTOR (CD) REPORTING 
7.5.1 NHLBI-IRB and NHLBI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the NHLBI-IRB and NHLBI CD: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.5.2 NHLBI-IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NHLBI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research;  
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.5.3 NHLBI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NHLBI IRB. 
7.5.4 NCI Guidance for Reporting Expedited Adverse Events for Multicenter Trials 
The site PI must immediately report to the coordinating center PI any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
drug caused the event within 48 hours of PI awareness of the event.  The Site PI must also report 
any protocol deviations to the coordinating center PI within 7 days of PI awareness. Participating 
centers must also submit the report to their IRB in accordance with their institutional policies.  A 
blank participating site problem form can be found in Appendix F. 


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7.6 
SECONDARY MALIGNANCY 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
7.7 
SECOND MALIGNANCY 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
7.8 
DATA AND SAFETY MONITORING PLAN 
7.8.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations and violations will be immediately reported to the IRB using iRIS and if 
applicable to the Sponsor.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.8.2 Sponsor Monitoring Plan 
Please see section 12.2. 


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8 
PHARMACEUTICAL INFORMATION 
8.1 
CABOZANTINIB (XL184) (NSC# 761968) 
8.1.1 Availability:  
Cabozantinib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
8.1.2 Toxicity:  
Please see section 7.1.1. 
8.1.3 Formulation and preparation:  
Cabozantinib is supplied by Exelixis and distributed by the DCTD.  Cabozantinib is available in 20 
mg and 60 mg tablets.  The tablets are yellow film coated containing cabozantinib malate equivalent 
to 20 mg and 60 mg of cabozantinib.  The 20 mg tablets have a round shape and the 60 mg tablets 
have an oval shape, and they are packaged as 30 tablets per bottle.  Cabozantinib should be 
dispensed in its original container; however, cabozantinib tablets can be dispensed in a pill cup 
with an expiration date not to exceed 24 hours. It can also be repackaged in a pharmacy 
dispensing bottle with expiration date not to exceed 7 days.  The components of the tablets are 
listed the table below. 
 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
8.1.4 Storage: 
Store intact bottles of cabozantinib at controlled room temperature, 20° to 25°C. 
8.1.5 Stability: 
Stability testing of the intact bottles is on-going.  XL184 is stable up to 24 hours when dispensed 
in an open container such as a pill cup, and up to 7 days when dispensed in a closed container 
such as a pharmacy bottle other than the original container. 


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8.1.6 Administration procedures:  
See section 5.3.1 
8.1.7 Incompatibilities:  
Potential Drug Interactions: XL184 is a substrate of CYP3A4.  Coadministration of XL184 with 
medications that are strong inhibitors/inducers of CYP3A4 should be avoided.  Strong CYP3A4 
inducers are rifampin, carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, St. John's 
wort, and troglitazone. Strong CYP3A4 inhibitors include ketoconazole, itraconazole, 
clarithroumycin, indinavir, nefazodone, nelfinavir, and ritonavir. (See the frequently updated 
http://medicine.iupui.edu/clinpharm/ddis/ for current list agents that interact with CYP3A4).  Use 
alternative medications. Avoid grapefruit/ grapefruit juice and Seville oranges while 
participating in this trial.  
In-vitro data indicate that XL184 is unlikely to be a substrate for P-glycoprotein, but it does 
appear to have the potential to inhibit the P-glycoprotein transport activity.  Additional details 
related to these overall conclusions can be found in the investigator brochure. 
XL184 is highly protein bound, 99.9%.  Use caution when coadministering XL184 with 
medications that are highly protein-bound (e.g., diazepam, furosemide, dicloxacillin, and 
propranolol).  Avoid administration of warfarin with XL184 as warfarin is highly protein-bound 
and has a very narrow therapeutic index. 
 
Potential Food Effect 
The effect of food on the bioavailability of cabozantinib was evaluated in healthy adult subjects 
in a Phase 1, open-label, randomized, single-dose, two-treatment, two way crossover study 
(Study XL184-004). Based on the preliminary PK data, a high fat meal did not appear to alter the 
terminal t1/2. but significantly increased the median tmax to 6 hours from 4 hours (fasted). The 
high fat meal also significantly increased both the cabozantinib Cmax and AUC values by 41% 
and 57%, respectively. Based on this result, cabozantinib should be taken on an empty stomach 
(fasting is required 2 hours before and 1 hour after each cabozantinib dose). 
Patient Care Implications:  Do not take grapefruit/ grapefruit juice or Seville oranges while 
participating in this trial.  Inform physician and study healthcare team about current medications 
including over the counter drugs, herbals, or natural medicines. Do not use cimetidine for 
dyspepsia or indigestion.   
 
Molecular Weight: 635.6 
Chemical Name: N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
Molecular Formula: C28H24FN3O5·C4H6O5  
 


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Chemical Structure: 
 
 
Mechanism of action:  
Cabozantinib is a tyrosine kinase inhibitor.  It inhibits multiple RTKs implicated in tumor growth, 
metastasis, and angiogenesis, and targets primarily MET and VEGFR2.  Other targets are RET, 
AXL, KIT, TIE-2, and FLT-3. 
8.1.8 Agent Ordering and Agent Accountability 
8.1.8.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where the 
patient is to be treated.  PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained).  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under 
the name of one lead investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or 
accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 


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8.1.8.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form (DARF).  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
8.2 
COMMERCIAL AGENTS 
8.2.1 Docetaxel (TAXOTERE®) 
(Please see package insert for complete drug information) 
8.2.1.1 
Source 
Docetaxel will be obtained from commercial sources by the local site pharmacy. 
8.2.1.2 
Toxicity: See section 7.1.1.1 
8.2.1.3 
Formulation and Preparation 
8.2.1.3.1 Formulation 
TAXOTERE® (docetaxel) Injection Concentrate, Intravenous infusion (IV) is a sterile, non-
pyrogenic, pale yellow to brownish-yellow, non-aqueous solution in single-use vials containing 
20 mg docetaxel (anhydrous), 0.54 grams polysorbate 80 and 0.395 grams dehydrated alcohol 
solution per milliliter in two presentations: 
1. TAXOTERE® (docetaxel) Injection Concentrate 20 mg docetaxel in 1 mL in 50/50 (v/v) 
ratio polysorbate 80/dehydrated alcohol in a blister pack in one carton (NDC 0075-8003-
01) 
2. TAXOTERE® (docetaxel) Injection Concentrate 80 mg docetaxel in 4 mL in 50/50 (v/v) 
ratio polysorbate 80/dehydrated alcohol in a blister pack in one carton (NDC 0075-8004-
04) 
8.2.1.3.2 Preparation 
Dilute the concentrated drug product: 
1. After removing Taxotere® from refrigeration, allow them to stand at room 
temperature approximately 5 minutes before proceeding 
2. Use only a 21-Gauge needle to withdraw the drug product from a vial 
• Larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and 
introduce particulate matter into the drug product 
3. Aseptically withdraw the amount of concentrated docetaxel solution required for a 
patient’s dose with a calibrated syringe and transfer it into an appropriate parenteral 
product bag or bottle containing a volume of either 0.9% NS or D5W sufficient to 
produce a final docetaxel concentration within the range 0.3 – 0.74 mg/mL 
• Product concentrations must not exceed 0.74 mg docetaxel per milliliter 
• To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which may 
be leached from PVC containers, prepare and store docetaxel injection for 
administration to patients in bottles (glass, polypropylene) or plastic bags 
(polypropylene, polyolefin) 
4. Thoroughly mix the admixture by manual rotation and by gently inverting the product 
container 


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• When prepared as described and stored between 2° – 25°C, docetaxel solutions 
are stable for 4 hours 
 
8.2.1.4 
Storage and Stability 
Store between 2°C and 25°C. Retain in the original package to protect from bright light. Freezing 
does not adversely affect the product. 
8.2.1.5 
Administration Procedures 
See section 5.3.2.  To minimize patient exposure to phthalate plasticizers (e.g., DEHP), which 
may be leached from PVC containers and administration sets, administer docetaxel only through 
polyethylene-lined administration sets 
8.2.1.6 
Incompatibilities 
- 
Hypersensitivity to docetaxal or polysorbate 80; neutrophil counts of <1500/µL.   
- 
Cytochrome P450 3A4 inducers, inhibitors, or substrates: May alter docetaxel 
metabolism. 
8.2.2 Prednisone 
(Please see package insert for complete drug information) 
8.2.2.1 
Source:  
For patient administration oral tablets will be purchased by the local site pharmacy from 
commercial sources. 
8.2.2.2 
Toxicity:  See section 7.1.1.2 
8.2.2.3 
Formulation and preparation:   
Prednisone is supplied as 5 mg tablets. 
8.2.2.4 
Stability and storage:   
Store at 15 - 30˚C, protected from moisture and light. 
8.2.2.5 
Administration procedures:  
See section 5.3.3. 
8.2.2.6 
Incompatibilities:   
Systemic fungal infections and known hypersensitivity to components. 
 
9 
PHARMACOKINETIC, BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
(NCI SITE ONLY) 
All patients enrolling at NCI on phase I (dose-escalation) and on the cabozantinib arm in the 
dose expansion will have blood samples drawn for PK studies.  All patients enrolling at NCI will 
have samples collected for the other studies as described below.  Samples will not be collected 
on patients enrolled outside NCI.   


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9.1 
PHARMACOKINETIC STUDIES 
Blood samples for determination of plasma levels of cabozantinib and docetaxel will be obtained 
from each patient on Day 1 of Cycles 1 and 2 (C1D1, C2D1) at the following time points: before 
infusion, at approximately 5 minutes prior to the end of docetaxel infusion, 15 minutes, 30 
minutes, 3h, 6h, 12h and 24h after the end of docetaxel infusion. The first dose of cabozantinib 
has to be administered on Day 2 of Cycle 1 after blood collection of the last time point (24h) to 
compare docetaxel exposure on C1D1 to C2D1, with and without XL184.  XL184 should be 
taken at the beginning of the docetaxel infusion, prior to drawing PK blood samples on day 1 of 
cycle 2. 
The plasma concentration-time data will be analyzed using WinNonlin software (Pharsight, 
Mountain View, CA). The maximum concentration, time to maximum concentration, the area 
under the curve extrapolated to infinity, and clearance will be calculated. An assessment of a PK 
interaction of cabozantinib with docetaxel will be made by comparison of the derived PK 
parameters of cabozantinib in this study to those for historical data when cabozantinib was given 
alone.  These assessments will be conducted according to the assay technology SOP utilized and 
validated by Exelixis and shared with Dr. Figg’s laboratory for the purpose of conducting this 
study. 
9.1.1 Collection of Specimens 
One 6mL sodium heparin tube (BD, Franklin Lakes, NJ) is collected from each patient on Day 1 
of Cycles 1 and 2 (C1D1, C2D1) at the following time points: before drug administration, at 
approximately 5 minutes prior to the end of docetaxel infusion, and at 15 minutes, 30 minutes, 
3h, 6h, 12h and 24h after the end of docetaxel infusion. 
9.1.2 Handling and Processing of Specimen(s) 
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube and the PK sheet.  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Upon arrival in the Blood Processing Core (BPC), samples will be centrifuged, and the plasma 
transferred into cryovials for storage at -80C until the time of analysis. In addition, samples will 
be barcoded as described in section 9.3.1.  
9.1.3 Site Performing the Study 
The pharmacokinetic analysis will be performed on a research basis in the BPC. 


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9.2 
BIOMARKER STUDIES 
9.2.1 Genetic Biomarkers 
Dr. Figg’s laboratory has extensive experience and expertise in performing pharmacogenetic 
analyses of genes involved in angiogenesis and drug metabolism pathways. Towards this end, 
polymerase-chain reaction (PCR) followed by either restriction fragment length polymorphism 
(RFLP), direct sequencing, or gene array analysis will be used to genotype the single nucleotide 
polymorphisms. 
9.2.1.1 
Collection of Specimen(s) 
One 6ml EDTA tube (BD, Franklin Lakes, NJ) will be collected from patients at baseline (after 
consent, prior to treatment initiation). 
9.2.1.2 
Handling and Processing of Specimens(s) 
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4˚C in the refrigerator. The date and exact time of each blood draw should be recorded 
on the tube. Please page 102-11964 for immediate pick-up.  
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Upon arrival in the BPC, genomic DNA will be extracted and analyzed for genetic 
polymorphisms. 
9.2.1.3 
Site(s) Performing Correlative Study 
The genotyping will be performed on a research basis in the Molecular Pharmacology Section. 
9.2.2 Pharmacodynamic biomarkers: 
The analyses will be performed with assays developed and validated in Dr. Liang Cao’s 
laboratory using electrochemiluminescence technology that provides ultra-high sensitivity and 
very large signal dynamic range. The c-met assay utilized by Dr. Don Bottaro has been 
previously validated in his laboratory and published in studies54,56.  Purified protein standards 
will be used for generating standard curves for concentration determination. 
9.2.2.1 
Collection of Specimens 
Plasma levels of VEGF, PlGF, HGF: 
One 5mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient prior to 
drug administration on C1D1 (baseline), C2D1, C3D1 to measure VEGF and PlGF for anti-
VEGFR2 activity and HGF for anti-c-MET activity. 
Immediately after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then 
store at 4C in the refrigerator. The date and exact time of each blood draw should be recorded 
on the tube.   


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Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
Plasma and urinary levels of soluble met: 
One 5mL EDTA plasma tube (BD, Franklin Lakes, NJ) is collected from each patient prior to 
drug administration on C1D1 (baseline), C2D1, C3D1 to measure soluble c-met. Immediately 
after collection, invert the blood tube 8-10 times. Place the tube on wet ice and then store at 4C 
in the refrigerator. The date and exact time of each blood draw should be recorded on the tube.  
Urine samples (at least 5 mL) will be collected prior to drug administration on C1D1 (baseline), 
C2D1, and C3D1 to measure soluble met. 
Please e-mail Julie Barnes at Julie.barnes@nih.gov and Paula Carter pcartera@mail.nih.gov at 
least 24 hours before transporting samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact Julie Barnes by e-mail or at 240-760-6044. 
9.2.2.2 
Sample Processing 
Plasma levels of VEGF, PlGF, HGF: 
Upon arrival in the BPC, blood samples will be centrifuged for 5 minutes at 1200 x g at 4C.  
Plasma will be aliquoted into 2 cryovials and stored at -80C until the time of analysis. The 
samples will be transferred to Dr. Liang Cao’s lab at Bldg 37/Rm6134 (301-435-9039) for 
analysis. 
Plasma and urinary levels of soluble met: 
Upon arrival in the BPC, blood samples will be centrifuged for 10 minutes at 1300 x g at RT. 
Plasma will be aliquoted into 2 cryovials and stored at -80C until the time of analysis.   
Urine samples will be adjusted to pH 7.5 with Trizma-HCl (Sigma, St. Louis, MO), 2 mol/L, pH 
7.5 using 50 microliters per 2 ml urine volume. Centrifuge urine samples at 3000 x g for 10 min 
at room temperature to remove cells and debris; store samples in appropriately sized plastic 
cryovials (Nunc or Sargent) at -80C. Determine urine creatinine value per standard clinical 
laboratory testing protocol for every sample collected prior to freezing and storage. The samples 
will be transferred to Dr. Don Bottaro’s lab at Bldg 10/Rm 1W-5832 (301-402-0922) for 
analysis. 
9.2.2.3 
Site Performing the Assay 
The pharmacodynamic biomarker analysis studies will be performed on a research basis in the 
laboratories of Dr. Liang Cao (Bldg 37/Room 6134) and Dr. Don Bottaro at Bldg 10/Room 1W-
5832. 


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9.2.3 Markers for Bone Activities 
9.2.3.1 
Collection of Specimen(s) 
Samples will be collected as part of the routine laboratory testing to measure the levels of total 
ALP and bone-specific ALP, and urine samples will be collected to measure uNTx prior to drug 
administration on C1D1 (baseline), C2D1, C3D1, and C5D1 (week 12).  Blood will be collected 
in a 4 mL SST tube and urine will be collected in a 5 mL urine tube.  Please request these 
assessments in CRIS by checking the box “Other Mayo” and listing the test names (Alkaline 
Phosphatase, Bone specific; NTx-Telopeptide, Urine) in the description box.   
9.2.3.2 
Sample Processing 
The processing will be performed by the Clinical Center Laboratory. 
9.2.3.3 
Site Performing the Assay 
The analysis will be performed by the Clinical Center Laboratory. 
9.2.4 Circulating Tumor Cells 
CTC enumeration: 
CTCs will be investigated using immunofluorescence techniques and CTC identification by 
positive expression of epithelial markers and a viability marker and negative expression of 
hematopoietic markers. Jane Trepel has extensive experience in working with CTC technology 
and has developed a platform for accurate detection of CTC enumeration. The Veridex CTC 
analysis is an FDA-approved platform for the capture, analysis, and enumeration of CTCs in 
monitoring metastatic prostate cancer. 
AR analysis in CTC:  
Dr. Liang Cao has expertise in developing new CTC technologies capable of isolating live CTCs 
for molecular analyses. CTCs will be isolated using a novel and patented CTC microchip-based 
technology. The purified CTC will be used for the analysis of androgen receptor expression and 
activity. All the downstream molecular analytic assays have been established and validated. 
9.2.4.1 
Collection of Specimen(s) 
CTC enumeration: Two 7cc lavender top tubes for flow-based CTC analysis will be collected at 
C1D1 pre and C5D1 pre (week 12).  Up to nine patients may have peripheral blood collected at 
the same time points (C1D1 pre and C5D1 pre) in one 7.5cc CellSave Preservative Tube for 
Veridex CTC analysis. 
AR analysis in CTCs: One 5 ml K2ETDA tube will be collected at pre-drug on C1D1 (baseline) 
and forward to Dr. Liang Cao’s laboratory within two hours.   CTCs will be isolated using a 
novel and patented CTC microchip-based technology.  The purified CTC will be used for the 
analysis of androgen receptor expression and activity. All the downstream molecular analytic 
assays have been established and validated.  These studies will be performed by Liang Cao, 
Head of Molecular Targets Core. 
9.2.4.2 
Handling and Processing of Specimens(s) 
CTC enumeration: As soon as possible after the patient is scheduled please send email 
notification to the Trepel lab: Jane Trepel at trepel@helix.nih.gov; Min-Jung Lee at 
leemin@mail.nih.gov that the sample is scheduled. After the sample is drawn please call the 


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Trepel lab at 301-496-1547 to communicate that the sample is ready. Keep the sample on the 
unit at room temperature. The sample will be picked up by the lab and processed for CTC 
enumeration. 
AR analysis in CTCs: As soon as possible after the patient is scheduled please send email 
notification to the Cao lab: Liang Cao at caoli@helix.nih.gov that the sample is scheduled. After 
the sample is drawn please call the Cao lab (Mr. Yunkai Yu at 301.443.2799) to communicate 
that the sample is ready. Keep the sample on the unit at room temperature. The sample needs to 
be picked up by the lab within 2 hours. The blood will be processed for CTC isolation. 
9.2.4.3 
Site(s) Performing Correlative Study 
The flow cytometric analyses will be performed by the Trepel laboratory.  The Trepel lab will 
deliver CellSave tubes to the research nursing staff and arrange for sending the tubes for Veridex 
analysis. 
AR analysis in CTCs will be performed by Dr. Liang Cao’s laboratory in the Molecular Targets 
Core, Genetics Branch, Building 37, Room 6134. 
9.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered and tracked through the CRIS Screens.  Should a CRIS screen not be 
available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed 
in the medical record.  Samples will not be sent outside NIH without IRB notification and an 
executed MTA.  
9.3.1 Blood Processing Core (BPC) - Storage 
All samples will be bar-coded, with data entered and stored in the LABrador (aka LabSamples) 
utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg 
lab personnel, who are issued individual user accounts.  Installation of LABrador is limited to 
computers specified by Dr. Figg. These computers all have a password restricted login screen. 
All Figg lab personnel with access to patient information annually complete the NIH online 
Protection of Human Subjects course.  
 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number; time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
Bar-coded samples are stored in bar-coded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in the LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 


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samples must be returned to the BPC.  It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample 
integrity (i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such 
to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
9.3.2 Handling and Storage for Research Samples Managed by Jane Trepel’s Laboratory 
Using a secure laboratory computerized database and a backup hardcopy process, all specimen 
collection and processing steps are documented and the specific location of each specimen is 
tracked.  Each new specimen collected is assigned a unique 2D barcode identifier that can be 
linked to the original specimen collected and other relevant information within the inventory 
system. To ensure patient confidentiality, only containers used for the initial specimen 
collections will be labeled with patient identifiers. De-identified labels will be applied to all 
subsequent specimen containers.  When specimens are processed and aliquoted, no patient 
information will be included on the new containers. Original specimen containers will be 
discarded. Only de-linked specimens will be stored.  
The inventory process contains other security provisions sufficient to safeguard patient privacy 
and confidentiality. Access to the inventory system and associated documents is restricted to 
appropriate personnel only. SOPs ensure that any changes in the informed consent made by a 
patient and relayed to the PI will be reflected in the inventory system to ensure that specimens 
are destroyed as appropriate. All laboratory personnel are trained to adhere to SOPs and are 
monitored for high-quality performance.  
9.3.3 Molecular Targets Core (Dr. Cao’s Lab) - Storage 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  To ensure 
patient confidentiality, only containers used for the initial specimen collections will be labeled 
with patient identifiers. De-identified labels will be applied to all subsequent specimen 
containers. When specimens are processed and aliquoted, no patient information will be included 
on the new containers.  Samples are labeled with printed consecutive numbers, frozen on dry ice, 
and stored in a -80°C freezer located at the NCI Research Facility, Building 37.   The freezer is 
locked and monitored 24/7 for temperature control.  Samples will be tracked using a limited 
access Excel database.   


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Access to the inventory system and associated documents will be restricted to appropriate 
personnel only. Requests to use specimens stored in the repository must be approved by the IRB. 
SOPs ensure that any changes in the informed consent made by a patient and relayed to the PI 
will be reflected in the inventory system to ensure that specimens are destroyed as appropriate. 
All laboratory personnel will be trained to adhere to SOPs and will be monitored for high-quality 
performance. The PI will submit a report to the IRB in the event that samples are lost or 
destroyed. 


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10 STUDY CALENDAR 
Protocol Activities 
Screening/Eligibility 
(Timepoints relative to 
enrollment) 
Study Treatment Period 
(1 cycle = 3 weeks) 
End of 
Treatment 
≤4 weeks 
prior 
≤ 16 days 
prior  
≤ 1 week 
prior  
Day 1 of every cycle  
Within 30 
days after 
last dose  
Informed consent 
 
 
X 
 
 
Demographics 
X 
 
 
 
 
Medical & Oncology 
History  
X 
 
X 
 
 
Dental Examination 1 
 
X 
 
 
 
Physical examination5 
 
 
X 
X 
X 
Weight 
X 
 
 
X 
X 
Vital signs 
X 
 
 
X 
X 
ECOG performance status 
X 
 
 
X 
X 
Clinical laboratory tests2  
 
X 
 
X 
X 
Urinalysis and UPCR 
 
X 
 
X 
X 
PSA 
 
 
X 
X2 
X 
PT/INR and  PTT 
 
X 
 
X 
 
Thyroid Function tests 
 
X 
 
X 
 
Serum testosterone 
X 
 
 
 
 
12-lead ECG  
 
X 
 
X 
X 
Tumor assessment: CT 
scan3 (chest, abdomen and 
pelvis), 99Tc bone 
scintigraphy 
X 
 
 
X 
(every 3 cycles) 
 
Cabozantinib 
administration 
 
X 
(daily or every other day) 
 
Docetaxel administration 
 
X 
(day 1 of each cycle) 
 
Prednisone administration 
 
X 
(twice daily) 
 
Pharmacokinetics7 
 
 
 
Cycles 1 & 2 only 
 
Correlative studies 
 
 
 
X4 
 
Concomitant medications  
 Continuous 
X 
Adverse events 
Continuous  
X6 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine 
creatinine ratio 
1Dental examination required in patients that have been treated with or are currently taking 
bisphosphonates 
2Clinical laboratory tests include:  CBC, acute care panel, mineral panel, hepatic panel, ionized calcium, 
amylase, lipase, LDH, total protein, GGT.  Refer to section 5.6.4.  In the event the patient’s condition is 


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deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of next cycle of 
therapy. 
3 In order to minimize radiation exposure, if there is no evaluable soft tissue disease on baseline CT, 
future CT scans will not be obtained unless clinically indicated. 
4Correlative blood and urine samples collected at baseline, C1D1, C2D1, C3D1 and C5D1.  See section 
9.2 for additional instructions. 
5Height does not need to be repeated unless there is a clinical indication6 If treatment related toxicity is 
present, adverse event must be followed until resolution, stable or irreversible per investigator discretion. 
7NCI patients enrolled on phase I and on the cabozantinib arm of phase II.  See section 9 for instructions. 


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11 MEASUREMENT OF EFFECT 
11.1 ANTITUMOR EFFECT – SOLID TUMORS 
Although response is not the primary endpoint of this trial, patients with metastatic disease will 
be assessed primarily by CT scan of the chest, abdomen and pelvis and by 99Tc bone 
scintigraphy.  For the purposes of this study, patients should be re-evaluated every 3 cycles. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)59 and Prostate Cancer Clinical Trials Working Group criteria (PCWG2)1.  Changes 
in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with study agents. 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
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‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 


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MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 


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FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at 
least 5 mm.  (Note:  the appearance of one or more new 
lesions is also considered progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 


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11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 Metastatic Bone Lesions 
Disease progression is considered if a minimum of two new lesions is observed on bone scan. 
New lesions seen by the end of cycle 3 or before cycle 4 (after the first staging bone scan) may 
represent disease that was not detected on the pre-study scan, and a confirmatory scan will be 
required in next scheduled staging bone scan unless clinically not indicated. If confirmed, 
progression should be dated by the initial time when the lesions are first detected. If new lesions 
are seen after cycle 3, but no additional lesions are seen on confirmatory scans, the scans from 
after cycle 3 would serve as the baseline scan to evaluate for disease progression1. 
 
11.1.4.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 
 


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For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is 
evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary 
endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease or death is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
12 DATA COLLECTION / DATA REPORTING 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
12.1 DATA COLLECTION 
Data will be collected prospectively and entered into NCI CCR C3D database within 14 days of 
collection.  The NCI principal investigator is responsible for the collection, maintenance and 
quality control of study data. 
Quality assurance complete records must be maintained on each patient treated on the protocol.  
These records should include primary documentation (e.g.: laboratory report slips, X-ray reports, 
scan reports, pathology reports, physician notes, etc.) which confirm that: 
• The patient met all eligibility criteria 
• Signed informed consent was obtained prior to treatment 


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• Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes) 
• Toxicity was assessed according to protocol (laboratory report slips, etc) 
• Response was assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate) 
 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
12.2 DATA REPORTING 
12.2.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP 
on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).    
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
12.2.2 Responsibility for Data Submission 
Study participants are responsible for submitting CDUS data and/or data forms to either the 
Coordinating Center quarterly.  The date for submission to the Coordinating Center will be set by 
them.  CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, and 
timely submission to CTEP by the quarterly deadlines (see Section 12.2.1). 
The Coordinating Center is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   


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12.3 CTEP MULTICENTER GUIDELINES 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix E. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
12.4 COLLABORATIVE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 


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other Collaborator to develop, obtain regulatory approval or commercialize its own 
Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days 
from the date of receipt for review.  Collaborator shall have the right to request that 
publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably 
at least three (3) days prior to submission, but in any case, prior to presentation at the 
meeting or publication in the proceedings.  Press releases and other media presentations 
must also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
Email:  ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 


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13 STATISTICAL CONSIDERATIONS 
13.1 STUDY DESIGN/ENDPOINTS 
The single arm phase I study of fixed dose of docetaxel and prednisone in combination with 
cabozantinib will enroll patients at a maximum of three escalating doses using a standard 3 + 3 
design.  The primary objective is to determine the safety profile of cabozantinib in combination 
with docetaxel and prednisone, and to determine the maximal tolerated dose (MTD) as 
recommended phase II dose in combination with docetaxel.  Once the MTD has been 
determined, 6 additional patients will be enrolled as an expansion at MTD level to further 
characterize the safety, toxicity and pharmacokinetics, as well as to obtain preliminary data on 
the efficacy of the combination treatment.  
After completing the phase I portion, a randomized phase II portion of the trial will be conducted 
to compare docetaxel, prednisone and cabozantinib at the MTD as compared to docetaxel and 
prednisone (standard of care) in mCRPC patients. Based upon results in the literature, patients 
who would be eligible to be randomized on this part of the trial would be expected to have an 
estimated 5 month median progression free survival from docetaxel and prednisone. The goal of 
this portion of the study will be to determine if the use of cabozantinib, docetaxel, and 
prednisone will result in patients having an improved progression free survival, with a 9 month 
median progression free survival.  Kaplan-Meier curves and a two-tailed log-rank test will be the 
primary analysis methods. Assuming exponential progression free survival curves, the hazard 
rate for docetaxel and prednisone alone would be 0.1386, or approximately a 14% probability of 
progressing each month when the median PFS is approximately 5 months.  If we assume that 
adding cabozantinib will increase the median progression free survival time to approximately 9 
months, this corresponds to a hazard rate of 0.0770 and the resulting hazard ratio for the 
comparison of the two overall actuarial curves would be 1.80. Following the principles of a 
phase 2.5 design, to compare these curves and detect a difference with a 0.10 one-tailed log-rank 
test, a total of 29 evaluable subjects per arm (58 total) will need to be randomized over a two 
year period and followed for an additional 18 months from the date of entry of the last patient, 
with occurrence of 52 total progressions in both arms combined, in order to have 80% power to 
compare the curves.  
As a futility rule for early stopping, when 50% of the anticipated events have occurred (26 total 
progressions), the hazard ratio will be determined. If this hazard ratio favors docetaxel and 
prednisone, then no further patients will be randomized as soon as this has been determined. 
13.2 SAMPLE SIZE/ACCRUAL RATE 
Up to 18 subjects may be required to reach the MTD, with an additional 6 subjects required for 
the expansion phase.  Thus, an enrollment of up to 24 subjects is anticipated prior to the 
randomized portion. For the phase II portion, 58 patients will be enrolled with an additional 4 
patients allowed for randomized patients who are not evaluable. Currently, we have 19 patients 
enrolled.  If we enroll an additional 62, this will bring the total accrual required to 81. 
Based on previous efforts and experience in recruiting patients with this disease onto trials at the 
NCI, it is anticipated that 2 to 3 patients will be enrolled to this trial per month. Thus, it is 
expected that accrual for Phase I can be completed in approximately 1 year and the accrual of 62 
patients for Phase II can be completed in 2 years.  Men of all races will be eligible for this study.  
Prostate cancer is not present in women; therefore, they will be excluded from this study. 


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Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
0 
+ 
4 
= 
4 
Not Hispanic or Latino 
0 
+ 
77 
= 
77 
Ethnic Category: Total of all subjects 
0 
(A1) + 
81 
(B1) = 
81 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
 
= 
 
Asian 
0 
+ 
4 
= 
4 
Black or African American 
0 
+ 
35 
= 
35 
Native 
Hawaiian 
or 
other 
Pacific 
Islander 
0 
+ 
 
= 
 
White 
0 
+ 
42 
= 
42 
Racial Category: Total of all subjects 
0 
(A2) + 
81 
(B2) = 
81 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
13.3 ANALYSIS OF SECONDARY ENDPOINTS 
Secondary objectives include: assessment of pharmacokinetics of each agents during 
combination therapy; evaluation of antitumor activities of combination therapy via measurable 
disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST); assessment 
of changes in molecular biomarkers in the pathways of receptor tyrosine kinases and 
angiogenesis, as well as the biomarkers for bone metabolism. 
14 HUMAN SUBJECTS PROTECTIONS  
14.1 RATIONALE FOR SUBJECT SELECTION 
Subjects treated on this study, will be individuals with metastatic prostate cancer, which has 
recurred (or persisted) after appropriate standard treatment.  Individuals of any race or ethnic 
group will be eligible for this study.  Eligibility assessment will be based solely on the patient’s 
medical status.  Recruitment of patients onto this study will be through standard CCR 
mechanisms. No special recruitment efforts will be conducted. 


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14.1.1 NHLBI IRB Multi-Institutional Guidelines 
14.1.1.1 IRB Approvals  
The PI will provide the NHLBI IRB and Central Registration Office with a copy of the 
participating institution’s approved yearly continuing review.  Registration will be halted at any 
participating institution in which a current continuing approval is not on file at the NHLBI IRB. 
14.1.1.2 Amendments and Consents 
The CCR PI will provide the NHLBI IRB with copies of all amendments, consents and approvals 
from each participating institution. 
14.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have prostate cancer, and because of unknown toxicities of cabozantinib in 
combination with docetaxel and prednisone in the pediatric patient. 
14.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 14.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
14.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor and 
improvement in their bony lesions, which may or may not have favorable impact on symptoms 
and/or survival.  Potential risks include the possible occurrence of any of a range of side effects 
which are listed in the Consent Document. The procedure for protecting against or minimizing 
risks will be to medically evaluate patients on a regular basis. 
14.5 RISKS/BENEFITS ANALYSIS 
For patients with castrate-resistant prostate cancer, median survival is in the range of 12-18 
months.  Potential risks include the possible occurrence of any of a range of side effects listed in 
section 7. Although no compensation is available, any injury will be fully evaluated and treated 
in keeping with the benefits or care to which patients are entitled under applicable regulations. 


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14.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The principal investigator or a designee will obtain written informed consent from each subject 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness will be present during the entire informed consent discussion. After the subject has orally 
consented to participation in the trial, the witness’s signature on the form will attest that the 
information in the consent form was accurately explained and understood. 
If new safety information results in significant changes in the risk/ benefit assessment, the 
consent form will be reviewed and updated as necessary. All subjects (including those already 
being treated) will be informed of the new information, be given a copy of the revised form, and 
be asked give their consent to continue in the study. 
It will be documented in the medical record that informed consent has been obtained. 
14.6.1 Telephone Re-Consent Procedure  
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject. An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form. 
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was 
obtained via telephone. A fully executed copy will be returned via mail for the subject’s records. 
A copy of the informed consent document will be kept in the subject’s research record. 
14.6.2 Informed Consent of Non-English Speaking Subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated 
extant IRB approved consent document, the principal investigator and/or those authorized to 
obtain informed consent will use the Short Form Oral Consent Process as described in MAS 
Policy M77-2, OSHRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2).  The 
summary that will be used is the English version of the extant IRB approved consent document.  
Signed copies of both the English version of the consent and the translated short form will be 
given to the subject or their legally authorized representative and the signed original will be filed 
in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a 
family member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
We will request prospective IRB approval of the use of the short form for up to a maximum of 5 
participants in a given language and will notify the IRB at the time of continuing review of the 
frequency of the use of the Short Form. Should we reach the threshold of 5, we will notify the 
IRB of the need for an additional use of the Short Form and that we will have that consent 
document translated into the given inherent language.  


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15 PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide any such publication to Exelixis, Inc. for review 
at least sixty (60) days prior to submission and also comply with any provisions regarding 
publication as are agreed to between the PI’s institution (National Cancer Institute) and Exelixis, 
Inc. in the Clinical Trial Agreement related to this study. The results will be made public within 
24 months of the end of data collection. However, if a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. In any event, a full report of the outcomes 
should be made public no later than three (3) years after the end of data collection. Authorship 
for abstracts and manuscripts resulting from this study will be determined according to 
guidelines established by the International Committee of Medical Journal Editors. 


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16 REFERENCES 
1. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of 
the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2008;26(7):1148-1159. 
2. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: a cancer journal for 
clinicians. 2010;60(5):277-300. 
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17 APPENDICES 
17.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 


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17.2 APPENDIX B: PATIENT INFORMATION ON POSSIBLE DRUG INTERACTIONS 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental cabozantinib.  This clinical trial is sponsored by the National Cancer Institute.  
This form is addressed to the patient, but includes important information for others who care for 
this patient.  
Cabozantinib interacts with many drugs that are processed by your liver.  Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study.  It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Cabozantinib interacts with (a) certain specific enzyme(s) in your liver.  
• The enzyme(s) in question is CYP3A4.  This enzyme breaks down cabozantinib, gradually 
reducing the level of the active drug in your system.    
• Other medicines may affect the activity of the enzyme.  Cabozantinib must be used very 
carefully with these medicines, or you may need to switch to alternate medications. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
• Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/ or 
consult a medical reference to see if any medicine they want to prescribe is on a list of 
drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• Be careful:  


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o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking cabozantinib 
o If you take medications used to treat indigestion, you should avoid using drugs 
such as cimetidine, ranitidine, famotidine, nizatidine omeprazole, lansoprazole, 
dexlansoprazole, esomeprazole, pantoprazole, and rabeprazole.  Instead, you 
should take antacids for the initial treatment of indigestion.  If antacids are not 
adequate, please contact a member of the research team before taking any other 
medications. 
 
Other medicines can be a problem with your study drugs.  
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is Dr. William Dahut and he can be contacted at 301 435 
8183. 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib).  This clinical trial is sponsored by the NCI.  XL184 
(cabozantinib) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib).  This clinical trial is sponsored by the NCI.  XL184 
(cabozantinib) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 


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17.3 APPENDIX C: GUIDELINES FOR PROPHYLAXIS AND TREATMENT FOR HYPERSENSITIVITY REACTIONS (HSR) ASSOCIATED 
WITH DOCETAXEL 
 
Initial Regimen 
HSR Interventions 
Step 1 
HSR Interventions 
Step 2 
HSR Interventions 
Step 3 
For 
ALL 
patients 
who 
have 
not 
experienced 
an 
HSR 
associated 
with 
Docetaxel 
For pts with a H/O a 
single HSR episode 
For pts who experience a HSR 
after 
implementing 
Step 1 
interventions 
For pts with severe or repeated HSR 
episodes after implementing Steps 1 & 2 
interventions 
PREMEDICATION WITH: 
Dexamethasone 8 mg PO for 3 doses at 12 h, 
3 h, & 1 h before starting docetaxel 
OR 
Dexamethasone 8 mg IV 30 – 60 min before 
docetaxel for patients who miss ≥1 oral 
dexamethasone doses 
• 
Reference: study protocol, Section 5.3.2 
PREMEDICATION WITH: 
Dexamethasone 8 mg PO for 2 doses at 12 h & 3 h before 
starting docetaxel 
 + 
Dexamethasone 8 mg IV 30 – 60 min before starting 
docetaxel 
+ 
Diphenhydramine 50 mg IV push 15 – 30 min before 
starting docetaxel 
+ 
Ranitidine 50 mg IV infusion 30 min before starting 
docetaxel 
PREMEDICATION WITH: 
Dexamethasone 8 – 20 mg PO for 2 doses 
between 24 – 36 h and at 12 hours before 
starting docetaxel 
+ 
Dexamethasone 20 mg IV 30 – 60 min before 
starting docetaxel 
+ 
Diphenhydramine 50 – 150 mg IV push 15 – 
30 min before starting docetaxel 
+ 
Ranitidine 50 mg IV infusion 15 – 30 min 
before starting docetaxel 
Docetaxel 75 mg/m2* IV over 60 minutes† 
Docetaxel 75 mg/m2* 
IV over 1 – 2 hours† 
Docetaxel 75 mg/m2* IV over 
4 hours 
• 
Given in two portions‡, as: 
Docetaxel 37.5 mg/m2 IV over 
2 hours, q.2 h for 2 doses 
Docetaxel 75 mg/m2* IV 
• 
Given in three portions‡, as follows: 
1. Docetaxel 5 mg in 10 mL IV via syringe 
pump over 60 min, followed immediately 
afterward by: 
2. Docetaxel 25 mg in 50 mL IV over 
60 min, followed immediately afterward 


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Initial Regimen 
HSR Interventions 
Step 1 
HSR Interventions 
Step 2 
HSR Interventions 
Step 3 
For 
ALL 
patients 
who 
have 
not 
experienced 
an 
HSR 
associated 
with 
Docetaxel 
For pts with a H/O a 
single HSR episode 
For pts who experience a HSR 
after 
implementing 
Step 1 
interventions 
For pts with severe or repeated HSR 
episodes after implementing Steps 1 & 2 
interventions 
by: 
3. Docetaxel 75 mg/m2 (minus 30 mg) IV 
over 120 min 
PRN Orders: 
Hydrocortisone 100 mg IV push q.15 min for 2 doses, PRN docetaxel reaction 
+ 
Diphenhydramine 50 mg IV push q.15 min for 2 doses, PRN docetaxel reaction 
+ 
Ranitidine 50 mg IV, PRN docetaxel reaction 
+ 
Hydromorphone 1 mg IV push q.15 min for 4 doses, PRN pain with docetaxel reaction 
+ 
Aluminum Hydroxide 200 mg + Magnesium Hydroxide 200 mg + Simethicone 20 mg chewable tablet 
1 – 2 tablets q.3 hours, PRN epigastric discomfort (drug name in CRIS is cross-referenced with “Mylanta”) 
* 
Initial (unmodified) docetaxel dosage is identified.  Consult the study protocol or a medically responsible investigator to determine whether docetaxel 
dose/dosage modification is indicated. 


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† 
For each docetaxel product, drug delivery will be attempted over the administration period indicated, but rate titration is permitted.  If rate titration is needed 
to accommodate patient tolerance, the following escalation scheme is recommended: 
Initial Rate: 
25 mL/h for 5 minutes 
Rate Escalation Steps: 
1st 
50 mL/h for 5 minutes 
2nd 
100 mL/h for 5 minutes 
3rd 
200 mL/h for 5 minutes 
4th 
250 mL/h until completed 
‡ 
Docetaxel stability is concentration dependent.  All docetaxel products diluted within the range 0.3 – 0.74 mg/mL are labeled to expire 4 hours after 
preparation was completed. 


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CRIS Chemotherapy/Biotherapy Treatment Note 
For patients WITHOUT a 
prior H/O HSR 
For Step 1 HSR Interventions 
For Step 2 HSR Interventions 
For Step 3 HSR Interventions 
Docetaxel 
_______ mg/m2 
(calculated 
dose 
= 
_______ mg) IV over 60 min 
Docetaxel 
_______ mg/m2 
(calculated dose = _______ mg) 
IV over 1 – 2 hours 
Docetaxel 
_______ mg/m2 
(calculated 
TOTAL dose = _______ mg) continuous IV 
infusion over 2 hours, every 2 hours for 
2 doses 
Docetaxel 
_______ mg/m2 
(calculated 
TOTAL dose = _______ mg) given in 
3 portions, as follows: 
#1 of 3: Docetaxel 5 mg IV over 
60 minutes 
#2 of 3: Docetaxel 25 mg IV over 
60 minutes 
#3 
of 
3: 
Docetaxel 
_______ mg 
(calculated TOTAL dose minus 30 mg 
from products #1 & #2, above) IV over 
2 hours 
Because patient, ____________________, has a history of hypersensitivity reaction with docetaxel administration, they will 
receive pre-medication and docetaxel according to Step #_______ of the guidelines for Prophylaxis and Treatment for 
Hypersensitivity Reactions (HSR) Associated with Docetaxel. 
In the event of a hypersensitivity reaction associated with docetaxel administration: 
1. Immediately STOP docetaxel administration. 
2. Rapidly administer PRN doses of hydrocortisone & diphenhydramine. 
3. Assess patient to determine whether additional PRN meds are indicated. 
4. Reinitiate docetaxel after hypersensitivity signs and symptoms have completely resolved. 
5. In the event of a hypersensitivity reaction, contact: 
Dr. ______________________________at 102-____________. 
Anna Couvillon at 102-10744. 
 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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TAKE HOME Dexamethasone Orders for the Next Treatment Cycle 
For patients WITHOUT a prior H/O HSR 
For Step 1 HSR 
Interventions 
For Step 2 HSR 
Interventions 
For Step 3 HSR Interventions 
Dexamethasone 8 mg PO for 3 doses at 12 h, 
3 h, & 1 h before starting docetaxel 
Dexamethasone 8 mg PO for 2 doses at 12 h & 3 h 
before starting docetaxel 
Dexamethasone 8 – 20 mg PO for 2 doses between 24 – 
36 h and at 12 hours before starting docetaxel 
 
 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
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Confidential  
17.4 APPENDIX D: CCR PATIENT SELF-ADMINISTERED STUDY AGENT COMPLIANCE LOG 
This form is to be updated at every study contact where patient receives or returns study drug.  This form may be used for multiple self-
administered study agents. This form is to be used in conjunction with a note in CRIS about study drug self-administration and case report form 
and will be maintained in the research record.  If patient is bringing back their study drug and you will not be returning that to the pharmacy, 
rather, the patient will be taking it back home with them, please use the form entitled ‘CCR Patient Self-Administered Study Agent Interim 
Compliance Form’. 
 
CC Protocol Number:_________________________             Principal Investigator:______________________ 
 
Protocol Title:_____________________________________________________________________________ 
 
Patient’s Medical Record Number:____________________   Patient’s Name:___________________________ 
 
Patient Study ID:  ________________ 
Cycle Number_____     
 
Date Dispensed 
Amount 
Dispensed 
Dose Form 
(e.g., tablets, 
pills, bottles, 
capsules, vials) 
Date Returned 
Actual 
Amount 
Returned 
Expected 
Amount 
Taken 
Expected 
Amount 
Returned 
Reason for difference 
between actual and expected 
amount returned, if 
applicable 
Site Staff 
Initials 
____/_____/20_____ 
(mm/dd/yyyy) 
 
  
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
115 
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CTEP Study #: 9243 
Confidential  
Date Dispensed 
Amount 
Dispensed 
Dose Form 
(e.g., tablets, 
pills, bottles, 
capsules, vials) 
Date Returned 
Actual 
Amount 
Returned 
Expected 
Amount 
Taken 
Expected 
Amount 
Returned 
Reason for difference 
between actual and expected 
amount returned, if 
applicable 
Site Staff 
Initials 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
 
 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
116 
Version Date: 2/27/2017 
 
 
CTEP Study #: 9243 
Confidential  
17.5 APPENDIX E: CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who 
in turn report to CTEP.  The Coordinating Center will submit AE reports to the Protocol 
Chair for timely review. 
• Audits may be accomplished in one of two ways: (1) source documents and research records 
for selected patients are brought from participating sites to the Coordinating Center for audit, 
or (2) selected patient records may be audited on-site at participating sites.  If the NCI 
chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit.


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
117 
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CTEP Study #: 9243 
Confidential  
17.6 APPENDIX F: CCR PROBLEM REPORT FORM 
CC Protocol #:  
Protocol Title:  
 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g., patient’s home, doctor’s office) 
 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, etc…) 
 
Brief Description of Subject (if 
applicable)  
(Do NOT include personal 
identifiers)  
Sex:  ___ Male  ___ Female 
Age:   
 ___ Not applicable (more than subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
118 
Version Date: 2/27/2017 
 
 
CTEP Study #: 9243 
Confidential  
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   
[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of harm than was previously 
known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 


Abbreviated Title: Randomized Phase I/II XL184 in mCRPC 
119 
Version Date: 2/27/2017 
 
 
CTEP Study #: 9243 
Confidential  
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NHLBI IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
 
DATE:   
 
 

ICF_001.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
12-C-0204 
 PRINCIPAL INVESTIGATOR:  William Dahut, M.D. 
 
 
STUDY TITLE: 
A Phase I and Randomized Phase II Multicenter Study of Cabozantinib (XL184) Plus 
Docetaxel and Prednisone in Metastatic Castrate Resistant Prostate Cancer 
 
 
Continuing Review Approved by the IRB on 02/21/17 
Amendment Approved by the IRB on 05/25/16 (O) 
 
 
 
Date Posted to Web:  03/02/17 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
Why is this study being done?  
Cabozantinib is an agent that slows down the growth of blood vessels that feed tumors.  
Although it has been approved by the Food and Drug Administration to treat medullary thyroid 
cancer, it has not been approved for prostate cancer and its use in this study is experimental. 
Early studies have also shown that prostate tumors respond to cabozantinib.  However when 
cabozantinib was taken alone, it did not shrink prostate tumors better than standard FDA 
approved therapies.  In this study we will be investigating how cabozantinib works in 
combination with the FDA approved standard chemotherapy regimen of docetaxel and 
prednisone in people who have been diagnosed with metastatic (distantly spread) prostate cancer. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 2 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
First we will try to establish safe doses for these drugs when they are taken together.  We also 
hope to understand whether cabozantinib given together with docetaxel works better to treat 
distantly spread prostate cancer than when docetaxel is given alone. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have been diagnosed with progressive 
metastatic prostate cancer. 
How many people will take part in this study?  
Up to 81 subjects will be enrolled in this study.   
 
Description of Research Study 
This study consists of 2 phases.  In phase I, all patients received cabozantinib in combination 
with docetaxel. We started with a low dose of cabozantinib (as described at the end of this 
section below) and gradually increased the dose until we found the highest dose that people 
could take safely. 
 
Now we want to study if adding cabozantinib to docetaxel will result in a better outcome.  In 
phase II, you will be randomized (like flipping a coin) to receive either cabozantinib in 
combination with docetaxel or docetaxel only.  
Before you begin the study: 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  However, there are some extra exams, tests and procedures that you 
will need to have if you take part in this study. If you have had some of them recently, they may 
not need to be repeated.   
 
These tests include: 
• 12-lead electrocardiogram (ECG)  
• Blood and urine tests 
• CT scan (chest, abdomen and pelvis) and a bone scan 
You will need to supply a complete list of your current medications to the study doctor.  This 
includes over-the-counter medications and herbal supplements.  Some medications may interact 
adversely with cabozantinib and it is important that your study doctor and prescribing physician 
be aware of any potential risks so that they can prescribe alternative medications as necessary.  If 
you do not already do so, please consider carrying a list of your medications at all times. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 3 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
During the study: 
If the results show that you can be in the study, and you choose to take part, then you will need 
the following tests and procedures: 
• 
Dental examination  (if you have used or are using a type of medication called a 
bisphosphonate ) – before you receive study drug 
 
You will need the following tests and procedures that are part of regular cancer care.  
These tests will be done day 1 of each cycle. 
• 
Blood tests  
• 
Examination by a doctor 
These tests will be done on day 1 of each cycle 
• 
Urine tests 
• 
ECG 
You will also need these tests and procedures that are part of regular cancer care.  They are being 
done more often because you are in this study.   
• 
Bone scan and CT scan every 3 cycles  
You will need blood and urine tests for research to see how the drug is affecting your body and 
for other research studies. These tests will be done: 
• 
After you have enrolled but before you receive any study drug 
• 
Before you receive the study drug on the following days: Day 1 of cycles 1, 2, 3, 
and 5 
• 
After you receive the study drug at seven timepoints up to 24 hours after the first 
dose on day 1 on cycles 1 and 2, if you are enrolled to phase I or assigned to 
receive cabozantinib during phase II 
You will be provided with a wallet-sized information card (“Information on Possible Drug 
Interactions”) that names your study agent and outlines the specific risk of adverse interactions 
with other drugs or substances.  Should you require any new medications while on study, please 
consult with your study doctor if possible, and present the card to the prescriber (doctor, 
pharmacist, physician’s assistant, or nurse practitioner).  Please check with your 
doctor/prescriber or pharmacist before using any new over-the-counter medications or herbal 
supplements. 
 
You will need to be admitted to the hospital for the first 2 days of cycle 1 and 2 so that we may 
collect blood samples from you. After that, you will receive the medications in this study as an 
outpatient.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 4 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
You will be given docetaxel through an IV catheter (a plastic tube usually inserted in a vein on 
your arm) on day 1 of each cycle.  Each docetaxel infusion will take about 1 hour.  You will also 
be asked to take prednisone by mouth twice each day of each 21 day cycle.  You should take 
prednisone at around the same time every day with the doses approximately 12 hours apart, give 
or take two hours.  Prednisone should, if possible, be taken with food or milk to reduce stomach 
irritation.  If you vomit or miss a dose of prednisone, that is, if more than 14 hours have passed 
since the previous dose, you should not make up that dose.  Instead, you should resume taking 
the drug at the next scheduled dose.   
You will also take an assigned dose of cabozantinib by mouth in combination with the agents 
described above.  The study team will tell you when you should take this dose.  Cabozantinib 
should be taken on an empty stomach (no food should be eaten 2 hours before taking 
cabozantinib and1 hour after taking cabozantinib) and the pills should not be chewed or crushed.  
If you miss a dose or vomit, do not make up that dose even if you think you saw it come out.  
Instead, you should resume taking the drug at the next scheduled dose.   
 
In Phase I of the study, you will be given docetaxel in combination with cabozantinib.  If you are 
enrolled to Phase II of the study, you may or may not receive cabozantinib.  
 
At each study visit, we ask that you bring all remaining cabozantinib tablets with you.    
 
During Phase I of the study, 3 - 6 people will be enrolled  and will take a 20 mg dose of 
cabozantinib once each day of each 21 day cycle.  This is dose level 1.  Based on how people 
tolerate the medication, the dose may be reduced for the next group of people enrolled or it may 
be increased.  We will continue to enroll people until we find the highest dose that 6 people can 
take with only 0 or 1 experiencing intolerable side effects.  We will then enroll 6 additional 
people to the study at that dose to obtain additional safety information about the combination 
therapy and to begin to find out how well the combination therapy works.   
 
In a second phase of the study we will enroll some patients who will be assigned to receive 
docetaxel only and some patients who will receive docetaxel and cabozantinib together. Patients 
will be randomly assigned (like flipping a coin) to receive one of the two regimens. You will 
have an equal chance of being assigned to one of the two regimens. 
 
Unless you experience serious side-effects or your disease progresses (gets worse), there is no 
limit to the number of cycles you may remain on the study regimen.  Therapy may be stopped, 
however, for any of the reasons listed in the stopping therapy section below. 
 
We ask that you: 
• avoid eating or drinking grapefruit and grapefruit products including grapefruit 
juice as well as Seville oranges and their products while enrolled on study as this may 
adversely interact with cabozantinib.  Please read the product label as some products 
may contain grapefruit without your knowledge. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 5 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
• discuss any planned dental procedures with the study team if you are taking or have 
taken in the past a type of drug called a bisphosphonate (e.g. alendronate, risedronate, 
pamidronate, etc.).  Patients taking bisphosphonates and cabozantinib are at higher 
risk for a complication that may lead to the destruction or death of the jawbone. 
You may take antacids and other medications used to treat indigestion with the exception of 
cimetidine.  Please let the study staff know, if you have been taking cimetidine.  You may take 
an alternative medication for the duration of the study.  Please discuss these options with the 
study doctor.  
When you are finished taking the study drugs (treatment) 
After you have taken your last dose of cabozantinib, we will conduct an end of study assessment.  
At this time, you will have a brief examination, your blood and urine will be tested and you will 
have an ECG.  This assessment can be done any time within 30 days after you have completed 
treatment.  After you finish study treatment, your local doctor will provide your cancer care. 
 
Stopping Therapy  
Your participation in this study will continue until either you or your study team decides that this 
medication is not beneficial to you. Your participation is voluntary; so you may stop receiving 
the study drugs at any time, but we ask that you speak to your study team before stopping. Your 
doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease progresses during treatment  
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if you are unable to comply with the protocol requirements 
• if you are unable to tolerate the lowest dose of cabozantinib (20 mg once every other day) 
• if your treatment has been delayed for more than 2 weeks and it is not clear that you have 
been benefiting from cabozantinib 
In this case, you will be informed of the reason therapy is being stopped. 
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Exelixis or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 6 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
Birth Control 
Because the effects of cabozantinib in combination with docetaxel and prednisone on the 
developing human fetus are unknown, men participating in this study must agree to practice an 
effective form of birth control before starting study treatment, during study treatment, and for 4 
months after you finish study treatment.  If you think that your partner is pregnant, you should 
tell your study doctor or nurse at once.   
 
Effective forms of birth control include:  
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
 
You should recognize that no method of birth control besides abstinence provides 100% 
protection from pregnancy. 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
If you choose to take part in this study, there is a risk that: 
• 
You may lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
• You may be asked sensitive or private questions which you normally do not discuss 
The medications used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health.  The docetaxel which is used in this study 
also contains ethanol or alcohol which may cause you to feel drunk during or after treatment.  It 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 7 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
may be necessary to avoid driving, operating any machinery or performing any activities that are 
dangerous for one to two hours after the infusion of docetaxel.  Some medications such as pain 
relievers or sleep aids may interact with the alcohol in docetaxel and may worsen these effects. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• Some side effects may interfere with your ability to have children. 
• Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
Cabozantinib 
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving XL184, more than 20 and up to 100 may have: 
• 
Diarrhea, nausea, vomiting 
• 
Tiredness 
• 
Weight loss, loss of appetite 
• 
Changes in taste or voice 
• 
Redness, pain or peeling of palms and soles 
• 
High blood pressure which may cause blurred vision 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving XL184, from 4 to 20 may have: 
• 
Anemia which may require blood transfusion 
• 
Pain 
• 
Constipation, heartburn 
• 
Dry mouth, skin 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 8 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
• 
Sores in mouth which may cause difficulty swallowing 
• 
Swelling of arms, legs 
• 
Infection 
• 
Bruising, bleeding 
• 
Dehydration 
• 
Muscle spasms 
• 
Dizziness, headache 
• 
Kidney damage which may require dialysis 
• 
Cough, shortness of breath 
• 
Internal bleeding which may cause coughing up blood, black tarry stool or blood in vomit 
• 
Bleeding from multiple sites including the nose 
• 
Hair loss, rash 
• 
Change in hair color 
• 
Blood clot which may cause swelling, pain, shortness of breath 
 
 
RARE, AND SERIOUS 
In 100 people receiving XL184, 3 or fewer may have: 
• 
A tear or hole in internal organs that may require surgery 
• 
Non-healing surgical site 
• 
Damage to the jawbone which may cause loss of teeth 
• 
Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 9 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
Docetaxel 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Docetaxel, more than 20 and up to 100 may have: 
• Swelling of the body 
• Hair loss 
• Change in nails 
• Rash, itching 
• Vomiting, diarrhea, nausea, constipation 
• Sores in mouth which may cause difficulty swallowing 
• Infection, especially when white blood cell count is low 
• Anemia which may require blood transfusions 
• Tiredness 
• Numbness and tingling of the arms and legs 
• Fever 
• Absence of menstrual period 
• Swelling and redness of the arms, leg or face 
• Pain 
• Watering, itchy eyes 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Docetaxel, from 4 to 20 may have: 
• Severe skin rash with blisters and peeling which can involve inside of mouth and other parts 
of the body 
• Belly pain 
• Bruising, bleeding 
• Liver damage which may cause yellowing of eyes and skin 
• Kidney damage which may require dialysis 
• Blood clot which may cause swelling, pain, shortness of breath 
• Abnormal heart rate 
• Shortness of breath, wheezing 
• Chest pain 
 
RARE, AND SERIOUS 
In 100 people receiving Docetaxel, 3 or fewer may have: 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, 
swelling of the face or throat 
• Cancer of bone marrow (leukemia) caused by chemotherapy 
• Scarring of the lungs 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 10 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
Prednisone 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, more than 20 and up to 100 may have: 
• In children and adolescents: decreased height 
• Loss of bone tissue 
• Mood swings 
• Skin changes, acne 
• Swelling of the body, tiredness, bruising 
• High blood pressure which may cause headaches, dizziness, blurred vision 
• Pain in belly 
• Increased appetite and weight gain 
• Weight gain in the belly, face, back and shoulders 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Prednisone, from 4 to 20 may have: 
• Cloudiness of the eye, visual disturbances 
• Glaucoma 
• Infection 
• Non-healing wound 
• Diabetes 
• Damage to the bone which may cause joint pain and loss of motion 
• Kidney stones 
• Heartburn 
 
RARE, AND SERIOUS 
In 100 people receiving Prednisone, 3 or fewer may have: 
• Bleeding from sores in the stomach 
• Broken bones 
 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
We do not know if you will receive personal, medical benefit from taking part in this study.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, 
such as pain, that are caused by the cancer.  Because there is not much information about the 
drug’s effect on your cancer, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 11 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
The study agents, cabozantinib, docetaxel and prednisone will be provided 
by the NCI.  You will receive study treatment at no charge to you. This 
may include surgery, medicines, laboratory testing, x-rays or scans done 
at the Clinical Center, National Institutes of Health (NIH), or arranged for 
you by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have to 
pay for these costs if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will my medical information be kept private?  
Your privacy is very important to us and we will make every effort to protect it.  Your 
information may be given out if required by law. However we will do our best to make sure that 
any information that is released will not identify you. 
There are organizations that may inspect your records.  These organizations are required to make 
sure your information is kept private.  Some of these organizations are: 
• The study sponsor 
• The Food and Drug Administration (FDA) 
• The drug company supporting the study. 
• The local Institutional Review Board, IRB, is a group of people who review the research 
with the goal of protecting the people who participate in the study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of study results.  You can search this Web site at any time. 
Where can I get more information?  
You may visit the NCI Web site at http://cancer.gov/ for more information about clinical trials or 
general information about cancer.  You may also call the NCI Cancer Information Service to get 
the same information at:  1-800-4-CANCER (1-800-422-6237).  
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 12 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using a drug, 
cabozantinib, developed by Exelixis through a joint study with your researchers and the company.  
The company also provides financial support for this study to the NIH. 
 
Use of Specimens and Data for Future Research  
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes.  Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in those who are related to you.  Researchers are interested in how genes affect health 
and disease, and how genes affect how your body responds to treatment. 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research.  However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY: 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 13 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at 
scientific meetings, the people who take part are not named and identified.  In most cases, the NIH 
will not release any information about your research involvement without your written permission.  
However, if you sign a release of information form, for example, for an insurance company, the 
NIH will give the insurance company information from your medical record.  This information 
might affect (either favorably or unfavorably) the willingness of the insurance company to sell you 
insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no long-
term medical care or financial compensation for research-related injuries will be provided by the 
National Institutes of Health, the Clinical Center, or the Federal Government.  However, you have 
the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes 
of Health policies.  In general, patients are not paid for taking part in research studies at the 
National Institutes of Health.  Reimbursement of travel and subsistence will be offered consistent 
with NIH guidelines. 
 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, William Dahut, M.D., Building 10, Room 3-2571, Telephone:  301-435-
8183. You may also call the Clinical Center Patient Representative at (301) 496-2626. If you 
have any questions about the use of your tissue for future research studies, you may also contact 
the Office of the Clinical Director, Telephone:  301-496-4251. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY: 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0204 
CONTINUATION: page 14 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and 
have been given the opportunity to discuss it 
and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and 
have been given the opportunity to discuss it 
and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
 
 
 
 
 
 
 
Signature of Adult Patient/ 
Legal Representative
 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM FEBRUARY 21, 2017 THROUGH FEBRUARY 20, 2018.  
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name