Clinical trial NCT01822522
Conditions: Advanced Malignant Solid Neoplasm HIV Infection Metastatic Malignant Solid Neoplasm Recurrent Malignant Solid Neoplasm Unresectable Solid Neoplasm
Sponsor: National Cancer Institute (NCI)
Start date: 2013-06-21; Completion date: 2021-05-12
Enrollment: 36 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase I trial studies the side effects and best dose of cabozantinib s-malate in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment and human immunodeficiency virus. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of cabozantinib (XL184) (cabozantinib s-malate) as a single agent in solid tumor participants with human immunodeficiency virus (HIV) infection and to determine the maximal tolerated dose (MTD) in this patient population.

SECONDARY OBJECTIVES:

I. To investigate possible pharmacokinetic interactions between cabozantinib and antiretroviral therapy in persons with HIV infection.

II. To investigate the effects of therapy on participant immune status and HIV viral load.

III. To preliminarily assess objective response rates associated with treatment for commonly represented tumors.

OUTLINE: This is a dose-escalation study.

Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms: arm 1: Patients receive cabozantinib s-malate 20 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens arm 2: Patients receive cabozantinib s-malate 40 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens arm 3: Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on ritonavir-boosted or cobicistat-boosted antiretroviral regimens arm 4: Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens arm 5: Patients receive cabozantinib s-malate 100 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on efavirenz or etravirine-based antiretroviral regimens arm 6: Patients receive cabozantinib s-malate 60 mg PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

This arm includes patients who are on antiretroviral regimens that do not include the agents specified on stratum A or B, or who are not on antiretroviral therapy
Interventions: intervention 1: Cabozantinib S-malate intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 








 
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AMC-087 PROTOCOL SIGNATURE PAGE 
I, __________________, Principal Investigator at site _______, agree to conduct and follow this 
protocol: AMC-087 - Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors in 
Persons with HIV infection (Version 11.0, 18APR2019), as written according to AMC, NCI 
and FDA guidelines. I understand that no deviations from the protocol eligibility criteria or 
waivers for protocol deviations will be permitted. 
 
 
_________________________________ 
 
_____________________ 
Signature 
 
 
 
 
 
Date (mm/dd/yyyy) 
 


 
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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ......................................................................................................... I 
AMC-087 PROTOCOL SIGNATURE PAGE ............................................................................2 
PROTOCOL ROSTER .................................................................................................................6 
PROTOCOL SCHEMA ................................................................................................................9 
1.0 
OBJECTIVES ..................................................................................................................14 
1.1 
Primary Objectives.................................................................................................14 
1.2 
Secondary Objectives.............................................................................................14 
2.0 
BACKGROUND ..............................................................................................................15 
2.1 
HIV-Associated Malignancies ...............................................................................15 
2.2 
CTEP IND Agent: Cabozantinib (XL184) ............................................................15 
2.3 
Nonclinical Development of Cabozantinib (XL184) .............................................16 
2.4 
Clinical Experience ................................................................................................19 
2.5 
Rationale ..............................................................................................................23 
2.6 
Correlative Studies Background ............................................................................24 
3.0 
PARTICIPANT SELECTION .......................................................................................26 
3.1 
Eligibility Criteria ..................................................................................................26 
3.2 
Exclusion Criteria ..................................................................................................28 
3.3 
Inclusion of Women and Minorities ......................................................................32 
4.0 
REGISTRATION PROCEDURES ................................................................................33 
4.1 
General Guidelines.................................................................................................33 
5.0 
TREATMENT PLAN ......................................................................................................34 
5.1 
Agent Administration.............................................................................................34 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................35 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................36 
5.4 
Duration of Therapy ...............................................................................................39 
5.5 
Duration of Follow Up ...........................................................................................39 
5.6 
Criteria for Removal from Study ...........................................................................40 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................41 
6.1 
Cabozantinib (XL184)-Related Adverse Event Management ...............................42 
7.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................57 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR).....................57 
7.2 
Adverse Event Characteristics ...............................................................................62 
7.3 
Expedited Adverse Event Reporting ......................................................................62 
7.4 
Routine Adverse Event Reporting .........................................................................64 
7.5 
Secondary Malignancy...........................................................................................64 
7.6 
Second Malignancy ................................................................................................64 


 
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PHARMACEUTICAL INFORMATION ......................................................................65 
8.1 
CTEP IND Agent ...................................................................................................65 
9.0 
CLINICAL AND LABORATORY EVALUATIONS ..................................................69 
9.1 
Screening/Baseline Evaluations .............................................................................69 
9.2 
Evaluations during Treatment ................................................................................69 
9.3 
Final Evaluations, Off Treatment (within 7 days of last treatment) ......................70 
9.4 
Final Evaluations, Off Study..................................................................................71 
10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ...................................72 
10.1 
Biomarker Studies ..................................................................................................72 
10.2 
Laboratory Correlative Studies ..............................................................................73 
11.0 
MEASUREMENT OF EFFECT ....................................................................................75 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................75 
11.2 
Evaluation of Response for Participants with Kaposi Sarcoma.............................81 
12.0 
STATISTICAL CONSIDERATIONS ...........................................................................84 
12.1 
Study Design/Endpoints.........................................................................................84 
12.2 
Sample Size/Accrual Rate ......................................................................................84 
12.3 
Stratification Factors ..............................................................................................85 
12.4 
Analysis of Secondary Endpoints ..........................................................................85 
13.0 
ROLE OF DATA MANAGEMENT ..............................................................................86 
13.1 
CRF Instructions ....................................................................................................86 
13.2 
Data Quality ...........................................................................................................86 
13.3 
Data Monitoring .....................................................................................................86 
13.4 
Collaborative Agreements Language .....................................................................86 
14.0 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................88 
14.1 
IRB Approval and Informed Consent ....................................................................88 
14.2 
Changes to the Protocol .........................................................................................88 
15.0 
REFERENCES .................................................................................................................89 
APPENDIX I:  
SCHEDULE OF EVALUATIONS ............................................................92 
APPENDIX II:  
PERFORMANCE STATUS CRITERIA .................................................94 
APPENDIX III:  
PARTICIPANT DRUG INFORMATION HANDOUT AND WALLET 
CARD ...........................................................................................................95 
APPENDIX IV:  
PHARMACOKINETIC (PK) SPECIMEN COLLECTION, 
PREPARATION AND SHIPPING INSTRUCTIONS ............................97 
APPENDIX V:  
AMC DATA AND SAFETY MONITORING PLAN ............................100 
APPENDIX VI:  
AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS ..........................103 
APPENDIX VII:  ACSR INFORMED CONSENT ..............................................................106 


 
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APPENDIX VIII:  PARTICIPANT MEDICATION DIARY/CALENDAR .......................111 
APPENDIX IX:  
MEDICATIONS THAT MAY CAUSE QTC PROLONGATION ......113 
 


 
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PROTOCOL ROSTER 
AMC-087 
Phase I Trial of Cabozantinib (XL184) for Advanced Solid Tumors 
in Persons with HIV Infection 
Protocol Chair: 
Protocol Statistician: 
Missak Haigentz, Jr., MD 
Albert Einstein College of Medicine 
Montefiore Medical Center 
111 East 210th Street, Hofheimer Room 100 
Bronx, NY 10467 
Tel: (973) 971-7960 
Fax: (973)-397-2901 
Email: Missak.Haigentz@atlantichealth.org 
Jeannette Lee, PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 781 
Little Rock, AR 72205 
Tel: (501) 526-6712 
Fax: (501) 526-6729 
Email: jylee@uams.edu 
Protocol Co-Chair: 
Study Chair Liaison: 
Elizabeth Chiao, MD, MPH 
Baylor College of Medicine 
2002 Holcombe Blvd 
Houston, TX 77030 
Tel: (713) 794-8666 
Fax: (713) 748-7359 
Email: echiao@bcm.edu 
Yoko Eng, NP 
Research Nurse 
Montefiore Medical Center 
111 East 210th Street, Hofheimer Room 100 
Bronx, NY 10467 
Tel: (718) 920-2090 
Fax: (718) 405-7412 
Email: yeng@montefiore.org 
AMC Pharmacology Core Laboratory: 
Data Management/Operations: 
Michelle A. Rudek, PharmD, PhD 
The SKCCC at Johns Hopkins 
1650 Orleans Street, CRB Room 1M52 
Baltimore, MD 21231-1000 
Tel: (410) 614-6321 
Fax: (410) 502-0895 
Email: mrudek2@jhmi.edu 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: (301) 251-1161 
Fax: (240) 238-2842 
Email: amcpm@emmes.com 
 
 
AMC Biorepository Director: 
Sylvia Silver, DA 
AMC Biorepository Director 
George Washington University Medical 
Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 


 
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PROTOCOL SYNOPSIS 
 
Title: 
Phase I Trial of Cabozantinib (XL184) for Advanced Solid 
Tumors in Persons with HIV Infection 
Phase of Study: 
Phase I  
Participating Institutions: 
This protocol will be open to all AMC member sites.  
Accrual Target: 
16 to 42 participants  
Population: 
 
Participants with incurable recurrent or metastatic solid tumors 
and HIV infection.  
Regimen: 
This is a phase I, dose escalation study of cabozantinib (XL184) 
for advanced solid tumors in persons with HIV infection. 
Cabozantinib will be administered orally as a once daily dose 
continuously for 28-day cycles, according to the Protocol Schema. 
Participants will be stratified into three groups based on which 
HAART therapy they are receiving. The first group (Stratum A) 
will be participants on either ritonavir or cobicistat (potent 
CYP3A4 inhibitor)-containing antiretroviral therapy. Since a 
potential interaction leading to higher drug levels of cabozantinib 
in participants on ritonavir or cobicistat is expected, participants 
will be dose escalated, starting at ~33% of the standard dose (60 
mg), using a classic 3 + 3 phase I clinical trial design. Dose 
increases will be in 20 mg increments to a maximum of 60 
mg/day. The second group (Stratum B) will be participants being 
treated with either efavirenz or etravirine-containing regimens, in 
whom CYP3A4 induction may lead to lower levels of the study 
drug. These participants will be treated at the standard dose of 
cabozantinib, then dose escalated by 20 mg/cohort to a maximum 
of 100 mg/day in a 3 + 3 design. The third group (Stratum C) will 
include participants taking antiretrovirals not specified in Stratum 
A or B, or who are not receiving active antiretroviral therapy. 
These participants will be treated at the standard dose of 60 
mg/day; no dose escalation is planned in this Stratum. 
In this trial, a dose-limiting toxicity (DLT) will be defined as any 
cabozantinib-related grade 3 or 4 non-hematologic toxicity during 
the first cycle of therapy, including grade 3 nausea and/or 
vomiting and grade 3 diarrhea despite prophylaxis and/or 
treatment or any of the following grade 4 hematologic toxicities 
during the first cycle of therapy: thrombocytopenia, neutropenia of 
more than 5 days duration, and neutropenia of any duration with 
fever or documented infection; additionally, treatment delay of 14 
days or greater during Cycle 1 due to unresolved toxicity or any 


 
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dose reduction required during Cycle 1 due to a cabozantinib-
related adverse event will be considered a DLT. 
All participating participants will have pharmacokinetic sampling 
studies. Response evaluation by RECIST 1.1 will be obtained on 
all participants at baseline and at 8 week intervals. 
Duration: 
Treatment may continue indefinitely until one of the following 
criteria applies: 1) unacceptable toxicity (including DLT in cycle 
1); 2) progressive disease; or 3) participant withdrawal or removal. 
Primary Objective: 
To determine the safety and tolerability of cabozantinib (XL184) 
as a single agent in solid tumor participants with HIV infection 
and to determine the maximal tolerated dose (MTD) in this 
participant population. 
Secondary Objectives: 
 
1. To investigate possible pharmacokinetic interactions between 
cabozantinib and antiretroviral therapy in persons with HIV 
infection. 
2. To investigate the effects of therapy on participant immune 
status and HIV viral load. 
3. To preliminarily assess objective response rates associated 
with treatment for commonly represented tumors. 




 
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LIST OF ABBREVIATIONS 
 
ACSR ................................................................................... AIDS and Cancer Specimen Resource 
ADM ................................................................................................... AIDS-defining Malignancies 
AdvantageEDCSM ........................................................................ AMC Internet Data Entry System 
AE .............................................................................................................................. Adverse Event 
AIDS .................................................................................. Acquired Immunodeficiency Syndrome 
ALT ......................................................................................................... Alanine Aminotransferase 
AMC ................................................................................................ AIDS Malignancy Consortium 
AML ..................................................................................................... Acute Myelocytic Leukemia 
ANC ....................................................................................................... Absolute Neutrophil Count 
APC .................................................................................................. Analytical Pharmacology Core 
ART............................................................................................................... Antiretroviral Therapy 
AST ............................................................................................................. Aspartate Transaminase 
AUC ................................................................................................................ Area under the Curve 
B-HCG .................................................................................. Beta-Human Chorionic Gonadotropin 
BP .............................................................................................................................. Blood Pressure 
BUN ................................................................................................................. Blood Urea Nitrogen 
cART ............................................................................................Combined Antiretroviral Therapy 
CAEPR ........................................................... Comprehensive Adverse Events and Potential Risks 
CBC.............................................................................................................. Complete Blood Count 
CDC ............................................................................. Centers for Disease Control and Prevention 
CDUS .................................................................................................. Clinical Data Update System 
CHF ........................................................................................................... Congestive Heart Failure 
cPR ....................................................................................................... Confirmed Partial Response 
CR ...................................................................................................................... Complete Response 
CRF ...................................................................................................................... Case Report Form 
CT ...................................................................................................... Computed Tomography Scan 
CTCAE ..............................................Common Terminology Criteria for Adverse Event reporting 
CTEP ....................................................................................... Cancer Therapy Evaluation Program 
CTEP-AERS ..................................................................... CTEP-Adverse Event Reporting System 
CTMS ......................................................................................... Clinical Trials Monitoring Service 
Oral DARF ......................................................................... Oral Drug Accountability Record Form 
DBP ............................................................................................................ Diastolic Blood Pressure 
DCTD ......................................................................... Division of Cancer Treatment and Diagnosis 
DL ................................................................................................................................ Dosing Level 
DLT ............................................................................................................. Dose-Limiting Toxicity 
DSMB ............................................................................................... Data Safety Monitoring Board 
DTC................................................................................................... Differentiated Thyroid Cancer 


 
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DVT ............................................................................................................. Deep Vein Thrombosis 
ECG...................................................................................................................... Electrocardiogram 
EIACD ............................................................................. Enzyme-Inducing Anti-Convulsant Drug 
ELISA ................................................................................. Enzyme Linked Immunosorbent Assay 
FDA.................................................................................................. Food and Drug Administration 
FDG-PET ...................................................... Fluorodeoxyglucose-Positron Emission Tomography 
GABA ............................................................................................................... γ-aminobutyric acid 
GB ................................................................................................................................ Glioblastoma 
GCSF.................................................................................. Granulocyte Colony-Stimulating Factor 
GEJ ..........................................................................................................Gastroesophageal Junction 
GI ............................................................................................................................. Gastrointestinal 
HAART ................................................................................... Highly Active Antiretroviral therapy 
HCC ........................................................................................................ Hepatocellular Carcinoma 
HGF......................................................................................................... Hepatocyte Growth Factor 
HIV ............................................................................................... Human Immunodeficiency Virus 
HR ................................................................................................................................ Hazard Ratio 
IAM .............................................................................................. Identity and Access Management 
IB.................................................................................................................. Investigator’s Brochure 
IDB ....................................................................................................... Investigational Drug Branch 
IDF ............................................................................................................... Investigator Data Form 
IEC ................................................................................................... Independent Ethics Committee 
IND ...................................................................................... Investigational New Drug Application 
INR ...................................................................................................International Normalized Ratio 
IRB ......................................................................................................... Institutional Review Board 
kg......................................................................................................................................... kilogram 
KS ............................................................................................................................ Kaposi sarcoma 
LDH ............................................................................................................. Lactate Dehydrogenase 
LFT .................................................................................................................... Liver Function Test 
LLN .............................................................................................................. Lower Limit of Normal 
LMWH ........................................................................................... Low Molecular Weight Heparin 
mcL .................................................................................................................................... microliter 
MDS ....................................................................................................... Myelodysplastic Syndrome 
mg ...................................................................................................................................... milligram 
mL ........................................................................................................................................milliliter 
MRI .................................................................................................... Magnetic Resonance Imaging 
MTC ........................................................................................................ Medullary Thyroid Cancer 
MTD ........................................................................................................ Maximum Tolerated Dose 
NADC .................................................................................................. Non-AIDS Defining Cancer 
NCI ............................................................................................................ National Cancer Institute 
NOAEL ................................................................................ No-Observable-Adverse-Event-Levels 


 
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NSAIDS .............................................................................. Nonsteroidal Anti-Inflammatory Drugs 
NSCLC ............................................................................................... Non-Small-Cell Lung Cancer 
NYHA ................................................................................................. New York Heart Association 
OAOP .............................................................................................. Online Agent Order Processing 
ODMC............................................................................. Operations and Data Management Center 
OHAM ......................................................................................... Office of HIV AIDS Malignancy 
ONJ ............................................................................................................ Osteonecrosis of the Jaw 
OTC........................................................................................................................ Over the Counter 
PCNSL ...................................................................... Primary Central Nervous System Lymphoma 
PD ..................................................................................................................... Progressive Disease 
PE ....................................................................................................................Pulmonary Embolism 
PFS ........................................................................................................... Progression-Free Survival 
PIB ......................................................................................................................... Powder-in-Bottle 
PIO ........................................................................................................ Protocol Information Office 
PMB ....................................................................................... Pharmaceutical Management Branch 
PO ...................................................................................................................... Per oral [by mouth] 
PK ........................................................................................................................... Pharmacokinetic 
PPE ............................................................................................. Palmar-Plantar Erythrodysesthesia 
PPI ..................................................................................................................Proton Pump Inhibitor 
PR ............................................................................................................................ Partial Response 
PT ......................................................................................................................... Prothrombin Time 
PTT ..................................................................................................... Partial Thromboplastin Time 
QD ............................................................................................................................................. Daily 
RCC................................................................................................................ Renal Cell Carcinoma 
RPLS ........................................................... Reversible Posterior Leukoencephalopathy Syndrome 
RT ........................................................................................................................ Radiation Therapy 
RTK.......................................................................................................... Receptor Tyrosine Kinase 
SAE ............................................................................................................... Serious Adverse Event 
SBP ............................................................................................................. Systolic Blood Pressure 
SCLC........................................................................................................... Small Cell Lung Cancer 
SD .............................................................................................................................. Stable Disease 
SF ................................................................................................................................ Scatter Factor 
SOC ................................................................................................................... System Organ Class 
SPEER............................................................ Specific Protocol Exception to Expedited Reporting 
TdP .....................................................................................................................Torsades de Pointes 
TFT ................................................................................................................Thyroid Function Test 
TIA .......................................................................................................... Transient Ischemic Attack 
TMZ .......................................................................................................................... Temozolomide 
TSH ...................................................................................................Thyroid-Stimulating Hormone 
UA ..................................................................................................................................... Urinalysis 


 
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ULN ............................................................................................................. Upper Limit of Normal 
UPCR ..................................................................................... Urine Protein/Urine Creatinine Ratio 
µM ................................................................................................................................... micromolar 


 
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1.0 
OBJECTIVES 
1.1 
Primary Objectives 
To determine the safety and tolerability of cabozantinib (XL184) as a single agent in 
solid tumor participants with HIV infection and to determine the maximal tolerated dose 
(MTD) in this participant population. 
1.2 
Secondary Objectives 
1.2.1 To investigate possible pharmacokinetic interactions between cabozantinib and 
antiretroviral therapy in persons with HIV infection. 
1.2.2 To investigate the effects of therapy on participant immune status and HIV viral 
load. 
1.2.3 To preliminarily assess objective response rates associated with treatment for 
commonly represented tumors. 


 
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2.0 
BACKGROUND 
This is a phase I, dose escalation study of cabozantinib (XL184) for advanced solid 
tumors in persons with HIV infection. 
2.1 
HIV-Associated Malignancies 
In addition to the AIDS-defining malignancies (ADMs), which include Kaposi sarcoma, 
non-Hodgkin’s lymphoma and cervical cancer, several non-AIDS defining cancers 
(NADCs) are seen in excess in HIV positive populations, including anal cancer, head and 
neck cancer, hepatocellular carcinoma, and lung cancer (Patel et al., 2008). NADCs are 
increasing in prevalence and as a result have become a major cause of morbidity and 
mortality in persons with HIV-infection (Shiels et al., 2011). In an era of active 
biological therapies for cancer, surprisingly little evidence for treatment of ADMs and 
NADCs exists for HIV infected individuals, as persons with HIV infection and cancer 
have historically been excluded from many cancer trials (Persad et al., 2008; Weiss et al., 
2011). Given this currently underserved patient population, the tolerability of exciting 
novel agents, particularly agents that are likely to have activity in both ADMs and 
NADCs, should be confirmed early on in an effort to broaden inclusion of this patient 
population in future large scale national and international studies. 
2.2 
CTEP IND Agent: Cabozantinib (XL184) 
Cabozantinib (XL184) inhibits multiple receptor tyrosine kinases (RTKs) implicated in 
tumor growth, metastasis, and angiogenesis (Investigator’s Brochure, 2012). The primary 
targets of cabozantinib are MET (c-MET) and vascular endothelial growth factor receptor 
2 (VEGFR2); additional targets include RET, AXL, KIT, and TIE-2. Both c-Met and 
VEGFR2 are important mediators of tumor growth and tumor angiogenesis, and in vivo 
pharmacodynamic activity of cabozantinib against c-Met and VEGFR2 has been 
demonstrated in both preclinical and clinical studies. 
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair (Christensen et al., 2005). Dysregulation of RTKs 
by mutation, gene rearrangement, gene amplification, and overexpression of both 
receptor and ligand have been implicated as causative factors in the development and 
progression of numerous human cancers. 
The RTK c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) 
or scatter factor (SF) (Christensen et al., 2005). c-Met and HGF are each required for 
normal mammalian development and have been shown to be important in cell migration, 
morphogenic differentiation, and organization of three-dimensional tubular structures 
(e.g., renal tubular cells, gland formation, etc.), as well as cell growth, angiogenesis, and 
tumor invasiveness and metastasis. Upregulation of MET is found in a wide range of 
malignancies including thyroid, prostate, ovarian, lung, and breast cancers and is 
associated with more aggressive and invasive phenotypes of cancer cells in vitro and 
metastases in vivo (Investigator’s Brochure, 2012). c-Met-driven metastasis may be 
exacerbated by a number of factors, including tumor hypoxia caused by selective 
inhibition of the VEGF pathway. 
Evidence linking c-Met and HGF as causative or progression factors in human cancers 
include: (1) the overexpression of both receptor and ligand in neoplasms relative to 


 
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surrounding tissues; (2) the correlation of receptor and ligand overexpression with 
disease severity and outcome; (3) genetic alteration of c-Met by mutation of gene 
amplification in multiple cancer types; (4) introduction of c-Met and HGF (or mutant c-
Met) into cell lines, conferred the properties of tumorigenicity and metastatic propensity 
on engineered cells; (5) introduction of c-Met or HGF as transgenes into the germline of 
mice resulted in primary and secondary neoplasms; and (6) the inhibition of c-Met or 
HGF function with dominant-negative receptors, antibody antagonists (both Met and 
HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated phenotypes 
such as motility, invasion and proliferation of tumor cells, and tumor growth and 
dissemination in vivo (Christensen et al., 2005). 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, 
demonstrate dysregulated c-Met activity (Liu et al., 2010), either by means of c-Met 
kinase overexpression (Comoglio et al., 2008), activating c-Met gene mutations and/or 
amplification (Comoglio et al., 2008; Jeffers et al., 1997; Schmidt et al., 1997), or 
increased autocrine and/or paracrine secretion of the c-Met ligand, HGF/SF (Birchmeier 
et al., 2003; Boccaccio and Comoglio, 2006). These alterations have been implicated in 
tumor progression and metastasis, and a high constitutive activation of c-Met has been 
correlated with poor clinical prognosis (Birchmeier et al., 2003). 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability (Roskoski, 2008). Increased 
expression of VEGFR2, often in combination with VEGFR3, has been observed in the 
tumor vascular endothelium in most common human solid tumor types, on tumor cells in 
melanoma and hematological malignancies, and in colitis-associated colon cancer 
(Tugues et al., 2011). High VEGFR2 expression is an unfavorable prognostic biomarker 
in hepatocellular carcinoma (HCC), and correlated with triple-negative (i.e., therapy-
resistant) breast cancer and poor survival. 
2.3 
Nonclinical Development of Cabozantinib (XL184)  
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 tumors (Paez-Ribes et al., 2009). In RIP-Tag2 
transgenic mice, tumors treated with cabozantinib 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 (Sennino et al., 2009). All mice treated with cabozantinib (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 (You et al., 2011). Tumors 
were 35% smaller after cabozantinib 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 (Yakes et al., 2011). Cabozantinib 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, cabozantinib 


 
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disrupted tumor vasculature by inducing endothelial cell death that negatively affected 
tumor viability. Cabozantinib 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, cabozantinib 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 cabozantinib 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 bone (Zhang et 
al., 2010). 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 cabozantinib or 
vehicle daily (qd) for 7 weeks of treatment (Investigator’s brochure, 2012). Tibiae from 
vehicle-treated animals exhibited both osteoblastic and osteolytic lesions, whereas tibiae 
from cabozantinib treated animals appeared mostly normal. Thus, cabozantinib treatment 
blocked both osteoblastic and osteolytic progression of ARCaP-M xenograft tumors in 
bone. 
Nonclinical pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at 
well tolerated doses of cabozantinib and at plasma exposures comparable to exposure 
observed in clinical trials (Investigator’s Brochure, 2010). Cabozantinib 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 cabozantinib. 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. 
Once daily administration of cabozantinib 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 (Investigator’s Brochure, 2010). 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 cabozantinib, 2–
8 hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor 
constitutively phosphorylated c-Met (Yakes et al., 2011). This effect was reversible, as c-
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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 (Investigator’s 
Brochure, 2010). 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 rats (Investigator’s Brochure, 2010). In rats, the oral bioavailability 
of cabozantinib dosed as a solid was approximately 100% of cabozantinib 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 cabozantinib oral doses in rats increased less than dose-
proportionally with increasing dose (100–900 mg/kg) (Investigator’s Brochure, 2010). 
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 cabozantinib 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 
cabozantinib oral doses in dogs increased less than dose-proportionally with increasing 
cabozantinib dose (400–2000 mg/kg), suggesting possible saturation of systemic 
absorption (Investigator’s Brochure, 2012). 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.  
Toxicology 
In rodents and non-rodents, histopathological changes associated with cabozantinib 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid 
tissues, kidney, and adrenal and reproductive tract tissues (Investigator’s Brochure, 
2012). Histopathological changes present in the bone and pancreas were considered 
secondary to cabozantinib administration. Adverse effects following oral exposure to 
cabozantinib 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, cabozantinib administration resulted in 
decreased fertility in male and female rats, in embryotoxicity when given to pregnant 
rats, and in a visceral tissue malformation (small spleen) when given to pregnant rabbits. 
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reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below 
steady-state values measured in subjects with solid tumors administered 175 mg 
cabozantinib capsule form daily (Study XL184-001). 
In 
definitive 
genotoxicity 
bioassays, 
cabozantinib 
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 study (Investigator’s Brochure, 2010). In safety pharmacology studies, no 
adverse effects occurred on neurobehavioral or respiratory functions in cabozantinib-
treated rats or on cardiovascular function in cabozantinib-treated dogs. 
2.4 
Clinical Experience 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored 
clinical trials with cabozantinib 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 (2012). Safety and efficacy information from the 
2012 Investigator’s Brochure is summarized below.  
Phase I studies 
Study XL184-001 was a phase I 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 qd (Kurzrock et al., 2011). Of the 35 subjects with medullary 
thyroid cancer (MTC) and measurable 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 2012 
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 I, open-label, randomized, single-dose, two-treatment, 
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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 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 I, 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 I 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 Ib/II 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 I 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 I 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 II 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. 
Phase II studies 
In a phase II study, XL184-201, subjects with progressive or recurrent GB in first or 
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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 II 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. 
Study XL184-205 is a randomized phase II 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). 
Adverse events 
The clinical studies with cabozantinib 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 cabozantinib (806 in single-agent studies and 107 in combination 
studies of cabozantinib with erlotinib, rosiglitazone, or TMZ ± radiation) (Investigator’s 
Brochure, 2012). Data from the 806 subjects who received single-agent cabozantinib 
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 cabozantinib studies. The most commonly reported 
SAEs that were assessed as related to study treatment with cabozantinib (as a single-
agent or combination) were pulmonary embolism (PE), diarrhea, dehydration, deep vein 
thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, wound dehiscence, and 
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There have been 15 grade 5 AEs related to study treatment: GI hemorrhage (two 
subjects), PE (two subjects), respiratory failure (two subjects), respiratory disorder (one 
subject), hemoptysis (one subject), death due to unknown cause (two subjects), 
intracranial 
hemorrhage 
(one 
subject), 
intestinal 
perforation 
(one 
subject), 
enterocutaneous fistula (one subject), hemorrhage (presumed to be hemoptysis; one 
subject), and diverticular perforation, peritonitis (one subject) (Investigator’s Brochure, 
2012). 
Pharmacokinetics 
Pharmacokinetic analysis of 74 subjects 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) (Kurzrock, 
2011). 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 
cabozantinib were 91.3 ± 33.3 hours (n = 23), and apparent steady-state plasma levels 
were reached by Day 15 (Kurzrock, 2011). Steady-state clearance for the 175 mg capsule 
dose derived from repeat dose data was 4.2 ± 1.5 L/h. Subjects 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 
cabozantinib 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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2.5 
Rationale 
Malignancies were one of the earliest recognized manifestations that lead to the eventual 
description of the acquired immune deficiency syndrome (AIDS) epidemic. Kaposi 
sarcoma (KS) became one of the first entities described in association with AIDS 
(Ziegler, Templeton, and Vogel, 1984). Subsequently, intermediate-grade and high-grade 
non-Hodgkin’s lymphoma (NHL), invasive cervical cancer and primary central nervous 
system lymphoma (PCNSL) were defined by the Centers for Disease Control and 
Prevention (CDC) as “AIDS-defining” conditions (CDC, 2008).  
The introduction of combination active anti-retroviral therapy (cART) in the 1990s has 
enormously impacted the outcomes of HIV infection. In addition to changing the natural 
history of HIV infection, in terms of survival and incidence of opportunistic diseases, it 
has also dramatically decreased the incidence of some virally mediated HIV-associated 
malignancies, such as KS or PCNSL. However, several other cancers that are not AIDS–
defining have been found to have increased incidence in patients with HIV, and therefore 
are considered AIDS-associated malignancies. These include Hodgkin’s disease, 
melanoma, anal, vaginal, liver, lung, oropharyngeal, leukemia, colorectal and renal 
cancer (Patel, Hanson, et al., 2008). 
Management of malignancies in patients with HIV infection presents the clinician with 
many challenges. These include the risk of further immunocompromise with 
chemotherapy; toxicities of treatment; potential of pharmacologic interaction between 
cART and chemotherapy drugs and the risk of intercurrent opportunistic infections. Thus, 
careful pharmacokinetic evaluation of potential new biologic targets against both ADMs 
and NADCs is necessary. 
Cabozantinib (XL184) is small molecule potent inhibitor or multiple receptor tyrosine 
kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis. The agent is a 
potent inhibitor of MET and VEGFR2, with half-maximal inhibitory concentration 
(IC50) values of 1.3 nmol/L and 0.035 nmol/L, respectively (Yakes et al., 2011). 
Cabozantinib strongly inhibits several other kinases that have also been implicated in 
tumor pathobiology, including KIT, RET, AXL, TIE2, and FLT3 (IC50 = 4.6, 5.2, 7, 14.3, 
and 11.3 nmol/L, respectively).  
The RTK pathways inhibited by cabozantinib may apply to broad patient settings. c-MET 
is the receptor for the hepatocyte growth factor (HGF) with tyrosine kinase activity, and 
its activation has been implicated in tumor cell migration, invasion, proliferation and 
angiogenesis (Eder et al., 2009). VEGFR2 is the predominant mediator of VEGF-
stimulated endothelial cell migration, proliferation, survival, and enhanced vascular 
permeability (Roskoski, 2008). In early-phase clinical trials, cabozantinib (XL184) 
monotherapy was associated with partial responses in patients with glioblastoma, 
medullary thyroid cancer (Kurzrock et al., 2011), castrate-resistant prostate cancer, non-
small cell lung cancer, ovarian cancer, breast cancer, and hepatocellular carcinoma. 
Cabozantinib is under phase III investigation for medullary thyroid cancer, with recently 
reported top line data indicating that the primary endpoint of the study, progression-free 
survival (PFS) was met. PFS on the cabozantinib arm was 11. 2 months compared to 4.0 
months on placebo, hazard ratio [HR] 0.28, p < 0.0001 (Schoffski et al., 2012). As of 
March 1, 2011, the most frequently (>20%) observed adverse events (AEs) in 806 


 
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patients treated in single agent, open label cabozantinib studies, regardless of the 
relationship to cabozantinib, 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 healing complications, and proteinuria, have also been observed (Investigator’s 
Brochure, 2012). 
We now propose a phase I, dose escalation trial of cabozantinib in persons with HIV 
infection with advanced solid tumors. Given the broad range of anticancer activity 
observed in early phase studies, access to and evaluations of tolerability of this agent in 
persons with HIV infection is warranted so that such patients may be included on phase 
III trials of this agent. Certainly, effects on HIV/AIDS associated Kaposi sarcoma 
(example of a rare tumor) and hepatocellular carcinoma and non-small cell lung cancer 
(more common in persons with HIV-infection) would be of great clinical interest due to 
cabozantinib's effects on MET and VEGFR. Overexpression of HGF may have a role in 
angiogenesis of Kaposi sarcoma lesions (Naidu et al., 1994) and evidence of 
VEGF/VEGFR2 and HGF/c-MET autocrine loop induction has been observed (Masood 
et al., 1997; Maier et al., 1996). MET mutations have been observed in gastric and liver 
cancer, small cell and non-small cell lung cancer, and metastases of head and neck 
squamous cell carcinoma, and gene amplifications in c-MET have also been observed in 
15-25% of these tumors (Christensen et al., 2005). 
2.6 
Correlative Studies Background 
2.6.1 To investigate possible pharmacokinetic interactions between cabozantinib and 
antiretroviral therapy in persons with HIV infection. 
This study will enroll subjects with HIV infection across three Strata based on 
current antiretroviral regimen CYP3A4 inhibitor (Ritonavir or Cobicistat)-
containing HAART [Stratum A]; CYP3A4 inducer (Efavirenz or Etravirine)-
containing HAART [Stratum B]; and Others [Stratum C]): with designation of 
HAART Stratum effective November 30, 2012. Subjects who are not taking a 
HAART regimen and are eligible for study will be included in Stratum C. The 
study therefore provides an opportunity to evaluate possible pharmacokinetic 
interactions between cabozantinib and antiretroviral therapies. 
There are data suggesting that cabozantinib: 1) is a CYP3A4 substrate, 2) is 
unlikely to induce or inhibit CYP450 enzymes in patients, and 3) inhibits but is 
not a substrate of ABCB1. Given potential for drug-drug interactions with 
antiretroviral agents, pharmacokinetic (PK) sampling studies are proposed for all 
participating patients. Evaluations will occur at steady-state (Cycle 1, Days 22/23) 
given the long half-life of the drug (91.3±33.3hr) which is not conducive to a 
comprehensive assessment after a single dose.  
2.6.2 To investigate the effects of therapy on patient immune status and HIV viral load. 
This trial will include patients with HIV infection, provided patients are receiving 
appropriate treatment and followed by physicians monitoring their care. While it 
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due to either a drug-drug interaction with the antiretrovirals or a 
pharmacodynamic effect, HIV viral load and CD4+ and CD8+ cell counts will be 
monitored to ensure adequate control of the patient’s HIV infection. 
2.6.3 To preliminarily assess objective response rates associated with treatment for 
commonly represented tumors.  
Although not a traditional role for a phase I trial, this study provides an 
opportunity to preliminarily identify a signal of clinical activity of cabozantinib 
for particular malignancies in the setting of HIV infection. Cabozantinib as a 
single agent has known single agent activity in liver and lung cancers, and given 
excess frequency of these diseases in HIV it is expected that subjects with these 
diseases will participate. Other frequent malignancies in persons with HIV 
infection include head and neck cancers, anal cancer, and Kaposi sarcoma, for 
which data with cabozantinib is currently limited. We propose to evaluate 
response outcomes in study participants and report response rates for single agent 
cabozantinib in commonly represented malignancies. 




 
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Serum albumin 
≥2.8g/dL 
Lipase 
<2.0 × ULN and no radiologic or clinical evidence of pancreatitis 
Urine protein/creatinine 
ratio (UPCR) 
≤1 
Serum phosphorus, calcium, 
magnesium, and potassium  
≥ lower limit of normal (LLN)  
Additionally, a CD4+ lymphocyte count > 50/mcL will be required within 2 
weeks of study participation. 
3.1.7 Women of childbearing potential must have a negative pregnancy test within 7 
days before enrollment. Women of childbearing potential include women who 
have experienced menarche and who have not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or 
are not postmenopausal. Postmenopause is defined as amenorrhea ≥12 
consecutive months. Note: women who have been amenorrheic for 12 or more 
months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any 
other reversible reason. 
3.1.8 The effects of cabozantinib on the developing human fetus are unknown. For this 
reason and because tyrosine kinase inhibitors agents as well as other therapeutic 
agents used in this trial are known to be teratogenic, women of child-bearing 
potential and men must agree to use adequate contraception (see below) prior to 
study entry and for the duration of study participation. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately. 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 6 months after completion of 
cabozantinib administration. 
Sexually active participants (men and women) must agree to use medically 
accepted barrier methods of contraception (e.g., male or female condom) during 
the course of the study and for 6 months after the last dose of study drug(s), even 
if oral contraceptives are also used. All participants of reproductive potential must 
agree to use both a barrier method and a second method of birth control during the 
course of the study and for 6 months after the last dose of study drug. 
3.1.9 Participating participants MUST receive appropriate care and treatment for HIV 
infection, including antiretroviral medications, when clinically indicated and 
should be under the care of a physician experienced in HIV management. 
Participants will be eligible regardless of antiretroviral medication (including no 
antiretroviral medication) provided there is no intention to initiate therapy or the 
regimen has been stable for at least 4 weeks with no intention to change the 
regimen within 8 weeks following study entry. As study-specific (antiretroviral-


 
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based) strata fill, however, only participants who are receiving the therapies 
eligible for the remaining open strata will be accrued. 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
3.1.11 Participants must in the opinion of the investigator be capable of complying with 
this protocol. 
3.2 
Exclusion Criteria 
3.2.1 Prior treatment with cabozantinib (XL184). 
3.2.2 The participant has received radionuclide treatment within 6 weeks of the first 
dose of study treatment. 
3.2.3 The participant has received prior treatment with a small molecule kinase 
inhibitor or a hormonal therapy (including investigational kinase inhibitors or 
hormones) within 4 weeks or five half-lives of the compound or active 
metabolites, whichever is longer, before the first dose of study treatment. Note: 
Participants with prostate cancer currently receiving LHRH or GnRH agonists 
may be maintained on these agents. 
3.2.4 The participant has received any other type of investigational agent within 28 
days before the first dose of study treatment. 
3.2.5 The participant has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity 
due to all prior therapies except alopecia and other non-clinically significant AEs. 
3.2.6 The participant has a primary brain tumor. 
3.2.7 The participant has active brain metastases or epidural disease. Participants with 
brain metastases previously treated with whole brain radiation or radiosurgery or 
participants with epidural disease previously treated with radiation or surgery who 
are asymptomatic and do not require steroid treatment for at least 4 weeks before 
starting study treatment are eligible. Participants with treated brain metastasis 
should not take enzyme-inducing anticonvulsive therapies (EIACDs) within 2 
weeks of registration, though non-enzyme inducing anticonvulsive drugs 
such as levetiracetam are allowed. Neurosurgical resection of brain metastases 
or brain biopsy is permitted if completed at least 3 months before starting study 
treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for 
participants with known brain metastases is required to confirm eligibility. 
3.2.8 The participant has prothrombin time (PT)/International Normalized Ratio (INR) 
or partial thromboplastin time (PTT) test ≥1.3 × the laboratory ULN within 7 days 
before the first dose of study treatment. 
3.2.9 The participant 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. 


 
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3.2.10 The participant requires chronic concomitant treatment with the following strong 
CYP3A4 inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, primidone, 
modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. 
John’s Wort. Use of efavirenz or etravirine is permitted for participants 
considered for the CYP3A4-inducer based ART regimen arm (Stratum B) of the 
trial.  
Because the lists of CYP3A4 inducers are constantly changing, it is important to 
regularly 
consult 
a 
frequently-updated 
list 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts 
such as the Physicians’ Desk Reference may also provide this information. As 
part of the enrollment/informed consent procedures, the participant 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 participant is considering a new over-
the-counter medicine or herbal product. 
3.2.11  The participant requires concomitant treatment with the following inhibitors of 
CYP3A4: 
• Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin 
• Antifungals: 
itraconzaole, 
ketoconazole, 
voriconazole, 
fluconazole, 
posaconazole 
• Antidepressants: nefazodone 
• Antidiuretic: conivaptan 
• GI: cimetidine, aprepitant 
• Hepatitis C: boceprevir, telaprevir 
• Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or 
pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids). Use of any of 
anti-retrovirals (delaviridine) or protease inhibitors (ritonavir, indinavir, 
lopinavir/ritonavir, saquinavir, nelfinavir) is permitted. Specifically, ritonavir 
and cobicistat is permitted for participants considered for the CYP3A4-
inhibitor based ART regimen arm (Stratum A) of the trial.  
Because the lists of CYP3A4 inhibitors are constantly changing, it is important to 
regularly 
consult 
a 
frequently-updated 
list 
such 
as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts 
such as the Physicians’ Desk Reference may also provide this information. As 
part of the enrollment/informed consent procedures, the participant 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 participant is considering a new over-
the-counter medicine or herbal product. 
3.2.12 The participant has experienced any of the following: 
• Clinically-significant 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 


 
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• Any other signs indicative of pulmonary hemorrhage within 3 months before 
the first dose of study treatment 
3.2.13 The participant has radiographic evidence of cavitating pulmonary lesion(s). 
3.2.14 The participant has tumor invading or encasing any major blood vessels. 
3.2.15 The participant has uncontrolled, significant intercurrent or recent illness 
including, but not limited to, the following conditions: 
1. Cardiovascular disorders including: 
a) Congestive heart failure (CHF): New York Heart Association (NYHA) 
Class III (moderate) or Class IV (severe) at the time of screening 
b) Concurrent 
uncontrolled 
hypertension 
defined 
as 
sustained 
BP 
> 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days of the first dose of study 
treatment 
c) Any history of congenital long QT syndrome 
d) 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: 
participants with a venous filter (e.g. vena cava filter) are not eligible 
for this study) 
2. Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including: 
a) Any of the following within 28 days before the first dose of study 
treatment 
• Active peptic ulcer disease, 
• Inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
• Malabsorption syndrome 
b) Any of the following within 6 months before the first dose of study 
treatment: 
• Abdominal fistula 
• Gastrointestinal perforation 
• Bowel obstruction or gastric outlet obstruction 
• Intra-abdominal abscess. Note: Complete resolution of an intra-
abdominal abscess must be confirmed prior to initiating treatment with 
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the first dose of study treatment. 
3. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy.  
4. Other clinically significant disorders such as: 
a) Active infection requiring systemic treatment within 28 days before the 
first dose of study treatment. Participants with HIV infection will be 
eligible provided they meet the criteria specified in Section 3.1.10. 
Participants with known Hepatitis B infection should be screened for 
active disease prior to study participation. Participants with known 
Hepatitis C infection must not be actively receiving treatment for the 
infection. 
b) Serious non-healing wound/ulcer/bone fracture within 28 days before the 
first dose of study treatment 
c) History of organ transplant 
d) Concurrent uncompensated hypothyroidism or thyroid dysfunction within 
7 days before the first dose of study treatment 
e) History of major surgery as follows: 
• 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. 
• 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 surgery. 
3.2.16 The participant is unable to swallow tablets that are whole (do not crush or chew 
or administer via NG-tube). 
3.2.17 The participant has a corrected QT interval calculated by the Fridericia formula 
(QTcF) >500 ms within 28 days before randomization. Note: If initial QTcF is 
found to be > 500 ms, two additional ECGs separated by at least 3 minutes should 
be performed. If the average of these three consecutive results for QTcF is ≤500 
ms, the participant meets eligibility in this regard. 
3.2.18 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to cabozantinib (XL184). 
3.2.19 Pregnant women are excluded from this study because cabozantinib (XL184) is a 
tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. 
Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with cabozantinib, breastfeeding 
should be discontinued if the mother is treated with cabozantinib. 




 
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4.0 
REGISTRATION PROCEDURES 
4.1 
General Guidelines 
Sites must have this protocol approved by their Institutional Review Boards (IRB) and be 
registered for study participation with the AMC Operations and Data Management Center 
(ODMC) before they may enroll participants. 
After it has been determined, that the participant is eligible and an informed consent has 
been signed by the participant, the participant must be registered on-line via the AMC 
AdvantageEDCSM Internet Data Entry System (AdvantageEDC). Enrollment and data 
collection will occur via the AMC Internet Data Entry System. 
The participating site will ensure a participant meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist in AdvantageEDC for enrollment. 
Participants will be enrolled on-line via AdvantageEDC no more than 1 week prior to the 
initiation of treatment (enrollment 1 day prior to or on the day of treatment is strongly 
encouraged). Once the eligibility checklist is submitted a system-generated confirmation 
email will be sent to the enroller upon successful completion of the participant 
enrollment. If the on-line system is inaccessible, the site should notify the AMC ODMC 
(via email at amcpm@emmes.com or via phone at 301-251-1161) for further 
instructions. 




 
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* Cabozantinib (XL184) must be taken whole and on an empty stomach. Participants must fast for 2 
hours before and 1 hour following each dose of cabozantinib (XL184). To permit pharmacokinetic 
sampling studies, AM dosing is required during the first cycle of therapy. 
 
AStratum A: Participants taking either ritonavir-boosted or cobicistat-boosted ART regimens 
BStratum B: Participants taking either efavirenz or etravirine-based ART regimens. 
CStratum C: Participants taking any antiretrovirals not specified in Stratum A or B as of November 
30, 2012, and participants who are not taking an ART regimen. 
 
Note: if an antiretroviral is FDA-approved after November 30, 2012, consult the Study 
Pharmacologist for Stratum designation). 
5.1.1 Cabozantinib (XL184) 
Cabozantinib (XL184) must be taken whole and on an empty stomach. 
Participants must fast for 2 hours before and 1 hour following each dose of 
cabozantinib (XL184). To permit pharmacokinetic sampling studies, AM 
dosing is required during the first cycle of therapy. Please refer to Section 
10.2 for additional information regarding required pharmacokinetic 
sampling in Cycle 1. 
5.1.2 Other modalities or procedures 
N/A 
5.2 
Definition of Dose-Limiting Toxicity 
Dose escalation decisions for cabozantinib will be made after evaluation of toxicities in 
the first cycle of therapy. In this trial, a dose-limiting toxicity (DLT) will be defined as 
any cabozantinib-related grade 3 or 4 non-hematologic toxicity during the first cycle of 
therapy, including grade 3 nausea and/or vomiting and grade 3 diarrhea despite 
prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities 
during the first cycle of therapy: thrombocytopenia and neutropenia of any duration (with 
or without fever or documented infection); additionally, treatment delay of greater than 7 
days during Cycle 1 due to unresolved toxicity or any dose reduction required during 
Cycle 1 due to a cabozantinib-related adverse event (including for intolerable 
cabozantinib-related grade 2 non-hematological toxicity – per Table 6-1) will be 
considered a DLT. 
For all participants who experience a DLT or other persistent and severe toxicity, a blood 
sample for pharmacokinetics analysis will be requested from the participant (if feasible). 
The samples should be drawn as close as possible to the time of the event. 
If a DLT occurs in one participant at a particular dose level, up to 3 additional 
participants will be added to that cohort. If a second participant experiences a DLT, the 
maximally tolerated dose (MTD) of the study will have been exceeded. If 2 DLTs are 
experienced at the first cohort, one dose level de-escalation (Dose Level -1) will be 
permitted according to the study schema suggested in the treatment plan. 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6.0. 




 
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palliative radiation) are allowed to continue to receive study treatment at 
the investigator’s discretion. 
5.3.1.2 Other medications 
Participating participants MUST receive medically appropriate care and 
treatment for HIV infection, including antiretroviral medications when 
clinically indicated. Suspension or modification of an antiretroviral 
regimen during study participation will be permitted (after 8 weeks from 
study entry) at the discretion of the physician providing HIV care, 
provided the change and its rationale are carefully documented. However, 
due to potential differences in protocol therapy dosing associated with 
study stratification, therapeutic change to a ritonavir or cobicistat-
containing antiretroviral regimen for a participant enrolled on a different 
study arm will necessitate immediate removal from the study. 
Participants 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. Please 
refer to Section 6.1.15 for guidelines on prevention of osteonecrosis of 
the jaw (ONJ) when participants are receiving bisphosphonates. 
As the study will identify dose-limiting toxicities of this treatment regimen 
during the initial cycle of therapy, prophylactic growth factor (G-CSF) 
administration is not recommended. Based on observed toxicities, 
protocol-specified dose modification guidelines should be followed for 
subsequent therapy cycles. Management of anemia will be at the 
discretion of the treating physician, 
No concurrent investigational agents are permitted. 
5.3.1.3 Potential drug interactions 
CYP450 isozymes: 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of 
CYP2C9. In healthy volunteers, XL184 AUC increased 38% with co-
administration of ketoconazole, a strong inhibitor of CYP3A4, and 
decreased by 77% with a strong CYP3A4 inducer rifampin. Therefore, 
avoid chronic use of strong CYP3A4 inducers such as rifampin, 
dexamethasone, 
phenytoin, 
carbamazepine, 
rifabutin, 
rifampentin, 
phenobarbital, and St. John’s Wort while taking XL184. Avoid chronic 
use of strong CYP3A4 inhibitors such as ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use 
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inducers or inhibitors of CYP3A4 are permitted as per exclusion 
criteria 3.2.10 and 3.2.11. 
[Note: Use caution when discontinuing medication that is a strong inducer 
of CYP3A4 in patients who has been on a stable dose of XL184, as this 
could significantly increase the exposure to XL184.] 
XL184 is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 µM), a 
mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 µM) and CYP2C19 
(Kiapp = 28.8 µM), and a weak competitive inhibitor of CYP3A4 
(estimated Kiapp = 282 µM) in human liver microsomal (HLM). IC50 
values >20 µM were observed for CYP1A2, CYP2D6, and CYP3A4 
isozymes. XL184 is an inducer of CYP1A1 mRNA in human hepatocyte 
incubations,  
Avoid grapefruit/ grapefruit juice and Seville oranges while participating 
in this trial. 
P-glycoprotein/ MRP2: 
In vitro data indicate that XL184 is an inhibitor of P-glycoprotein 
transport activity (IC50 = 7.0 µM). Co-administration of XL184 with a P-
gp substrate may result in an increase in P-gp substrate plasma 
concentration. Therefore, use caution when administering XL-184 with 
drugs known to be P-gp substrates (e.g., fexofenadine, aliskiren, 
ambrisentan, digoxin, colchicine, maraviroc, posaconazole, tolvaptan, 
etc.). 
XL184 is also a substrate of drug transporter MRP2, which may result in 
an increase plasma concentration of XL184 when administered with an 
inhibitor of MRP2. Use caution and monitor adverse events when 
administering XL184 with MRP2 inhibitors such as cyclosporine, 
delavirdine, efavirenz, emtricitabine. 
Protein bound: 
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. 
Antacids, H2-blockers, PPIs: 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers 
or antacids has no clinically-relevant effect on XL184 plasma PK in 
healthy volunteers; thus, concomitant use of these drugs with XL184 is 
allowed. 
QTc prolongation: Use caution when administering XL184 in patients 
with QT prolongation risk, a history of QT interval prolongation, or who 
are receiving antiarrhythmic drugs. Concomitant use of strong CYP3A4 


 
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inhibitors should be avoided as it may increase XL184 plasma 
concentrations. Refer to the protocol for QTcF criteria. 
5.4 
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, 
• Dose-limiting toxicity (DLT requiring discontinuation of therapy, as defined in 
Section 5.2). Dose reductions in the first cycle of therapy for cabozantinib-related 
adverse events are permitted. 
• Other unacceptable adverse event(s), 
• Treatment delay of 14 days or greater during Cycle 1 due to unresolved toxicity (DLT 
definition, Section 5.2). 
• Treatment delay in subsequent cycles > 6 weeks due to toxicity (treatment delays for 
other reasons may be permitted at the discretion of the Study Chairs), 
• Participant decides to withdraw from the study. 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the investigator, including: 
o Necessity for treatment with other anticancer treatment prohibited by the protocol. 
o Change to a ritonavir or cobicistat-containing antiretroviral regimen for a 
participant enrolled on a different study arm (see Section 5.3.1.2). 
o Sexually active participants who refuse to use medically accepted barrier methods 
of contraception (e.g., male condom, female condom) during the course of the 
study and for 6 months following discontinuation of study treatment. 
o Women who become pregnant or are breastfeeding. 
• Request by regulatory agencies for termination of treatment of an individual 
participant or all participants under the protocol. 
• Significant noncompliance with the protocol schedule in the opinion of the 
investigator. 
• The minimum dose of study treatment for Stratum A will be the Dose Level -1 dose, 
and the lowest dose of study treatment for Stratum B and Stratum C will be the Dose 
Level -2 dose. Participants who cannot tolerate the lowest Dose Level dose for the 
specified study Stratum will have study treatment discontinued. 
5.5 
Duration of Follow Up 
Participants will be followed for 30 days after removal from study or until death, 
whichever occurs first. Participants removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 


 
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5.6 
Criteria for Removal from Study 
Participants will be removed from study when any of the criteria listed in Section 5.4 
applies. The reason for study treatment removal and the date the participant was removed 
must be documented in the Off Protocol Treatment Form in AdvantageEDC. 










 
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dose modification guidance in Table 6-1 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. 
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 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. Please also refer to Appendix IX for 
antiemetics to be avoided due to potential for QTc prolongation.  
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. 
6.1.2 Hepatobiliary disorders 
Elevations of transaminases have also been observed during treatment with 
cabozantinib. In general, it is recommended that participants 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 participants who develop elevated transaminases.  
Since participants may enter the study with elevations of AST/ALT at baseline, 
the following guideline should be used for dose modifications: 


















 
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6.1.11 Rectal and perirectal abscess 
Rectal and perirectal abscesses have been reported, sometimes in participants with 
concurrent diarrhea. These should be treated with appropriate local care and 
antibiotic therapy. Cabozantinib should be held until adequate healing has taken 
place.  
6.1.12 Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and non-GI fistula formation have been reported with 
approved drugs that inhibit VEGF pathways as well as with cabozantinib. 
Carefully monitor for episodes of abdominal pain, especially in participants with 
known risk factors for developing GI perforation/fistula or non-GI fistula, to 
allow for early diagnosis. Such risk factors include (but may not be limited to) the 
following: 
GI-perforation/fistula 
1. Intra-abdominal tumor/metastases invading GI mucosa.  
2. Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, 
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis. 
3. History of abdominal fistula, GI perforation, bowel obstruction, or intra-
abdominal abscess. 
4. Prior GI surgery (particularly when associated with delayed or incomplete 
healing). Complete healing following abdominal surgery or resolution of 
intra-abdominal abscess must be confirmed prior to initiating treatment with 
cabozantinib. 
Additional risk factors include concurrent chronic use of steroid treatment or non-
steroidal anti-inflammatory drugs. Constipation indicative of bowel obstruction 
should be monitored and effectively managed.  
Non-GI fistula: 
1. Radiation therapy has been identified as a possible predisposing risk factor for 
non-GI fistula formation in participants undergoing treatment with drugs that 
inhibit VEGF pathways. In addition, participants who have undergone 
extensive surgery may be at increased risk of developing a fistula of the 
involved organs non-GI fistula should be ruled out as appropriate in cases of 
onset of mucositis after start of therapy. 
2. Discontinue all study treatment in participants who have been diagnosed with 
GI or non-GI perforation/fistula. 
6.1.13 Wound healing and surgery 
VEGF inhibitors can cause wound healing complications and wound dehiscence, 
which may occur even long after a wound has been considered healed. Therefore, 
surgical and traumatic wounds must have completely healed prior to starting 
cabozantinib treatment and be monitored for wound dehiscence or wound 
infection while the participant is being treated with cabozantinib.  


 
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Treatment with cabozantinib must be interrupted for any wound healing 
complication that needs medical intervention. Treatment with cabozantinib can be 
resumed once wound healing has occurred unless otherwise prohibited in specific 
protocols. Cabozantinib should be discontinued in participants 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.  
6.1.14 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 participants (see Cabozantinib Investigator’s 
Brochure). Routine monitoring of thyroid function and assessments for signs and 
symptoms associated with thyroid dysfunction is recommended for participants 
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 
participants. Monitoring with standard laboratory tests for endocrine disorders and 
clinical examination prior to initiation and during treatment with cabozantinib is 
required. Cabozantinib should be discontinued in participants with severe or life-
threatening endocrine dysfunction. 
6.1.15 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 participants 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 participants 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. 
Participants with any documented case of osteonecrosis should have study 
treatment interrupted, and appropriate clinical management should be initiated. 
Reinitiation of study treatment must be discussed with and approved by the Study 
Chair on a case by case basis. 


 
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6.1.16 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 that may contribute to QTc prolongation include: 
1. Treatment with other drugs associated with QTc prolongation (see Appendix 
IX). 
2. Treatment with CYP 3A4 inhibitors (which may increase cabozantinib drug 
levels) 
3. Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia). 
4. Medical conditions which can alter electrolyte status e.g., severe or prolonged 
diarrhea. 
Participants 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 withheld and the following 
actions should be taken: 
1. Check electrolytes, especially potassium, magnesium, and calcium. Correct 
abnormalities as clinically indicated. 
2. If possible, discontinue any QTc-prolonging concomitant medications. 
3. Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise 
determined by consultation with a cardiologist. 
The Study Chair should be notified immediately of any QTc prolongation event.  
Participants with QTc prolongation and symptoms must be monitored closely 
until the QTc elevation has resolved. Cardiology consultation is recommended for 
evaluation and participant management. Symptomatic participants must be treated 
according to standard clinical practice. No additional study treatment is to be 
given to the participant until after the event has resolved, the participant has been 
thoroughly evaluated, and further treatment has been agreed to by the Study 
Chair. 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 Study Chair. 


 
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7.0 
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) will determine whether the event requires expedited reporting (via CTEP-AERS) in 
addition to routine reporting (via AdvantageEDC). 
CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 
5.0 can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
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.pd
f for further clarification. Frequency is provided based on 3219 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. 






 
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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. 
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, Hemoptysis, 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) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that XL184 (Cabozantinib) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile 
neutropenia; Hemolytic uremic syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; 
Cardiac disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left 
ventricular systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); 
Endocrine disorders - Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); 
Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; 
Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; 
Enterocolitis; Esophageal ulcer; Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux 
disease; Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders - Other 
(pneumoperitoneum); Gastrointestinal pain; Gingival pain; Hemorrhoids; Ileus; Pancreatitis; 
Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death 
NOS; Edema face; Fever; Gait disturbance; General disorders and administration site conditions 
- Other (general physical health deterioration); General disorders and administration site 
conditions - Other (implant site inflammation); Hypothermia; Malaise; Multi-organ failure; Non-
cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; 
Hepatobiliary disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic 
cirrhosis); Hepatobiliary disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other 
(hepatitis toxic); Hepatobiliary disorders - Other (hepatorenal syndrome); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 


 
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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; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Creatinine increased; 
Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT increased; 
Investigations - Other (D-dimer); Investigations - Other (urine ketone body present); 
Lymphocyte count decreased; Neutrophil count decreased; Serum amylase increased; Thyroid 
stimulating hormone increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; 
Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition 
disorders - Other (failure to thrive); Metabolism and nutrition disorders - Other 
(hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock 
pain; Chest wall pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective 
tissue disorder - Other (muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; 
Rhabdomyolysis 
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); Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration 
impairment; Dysarthria; Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory 
impairment; Nervous system disorders - Other (hemiparesis); Nervous system disorders - Other 
(vocal cord paralysis); Peripheral motor neuropathy; Peripheral sensory neuropathy; Presyncope; 
Seizure; Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; 
Insomnia; Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; 
Glucosuria; Renal and urinary disorders - Other (hemorrhage urinary tract); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive 
system and breast disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; 
Vaginal inflammation; Vaginal perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal 
edema; Oropharyngeal pain; 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 (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); 
Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; 
Pain of skin; Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, 


 
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sloughing of skin and erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin 
hypopigmentation; 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. 
7.2 
Adverse Event Characteristics  
For expedited reporting purposes only 
1. AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
2. Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 7.3 
Attribution of the AE 
1. Definite – The AE is clearly related to the study treatment. 
2. Probable – The AE is likely related to the study treatment. 
3. Possible – The AE may be related to the study treatment. 
4. Unlikely – The AE is doubtfully related to the study treatment. 
5. Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting 
7.3.1 Expedited AE reporting for this study must use CTEP AERS (Adverse Event 
Expedited 
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 7.3.3). 
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. 
7.3.2 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.  
7.3.3 Expedited reporting guidelines 
Use the NCI protocol number and the protocol-specific participant ID assigned 
during trial registration on all reports. 




 
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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 
2For 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 
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. 
7.5 
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: 
1. Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
2. Myelodysplastic syndrome (MDS) 
3. 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.  
7.6 
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. 


 
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8.0 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
8.1 
CTEP IND Agent 
8.1.1 Cabozantinib (XL184) (NSC 761968) 
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
Other Names: Cabozantinib, EXEL-7184, EXEL-02977184  
Classification: Receptor Tyrosine Kinases Inhibitor (RTK) 
CAS Registry Number: 1140909-48-3  
Molecular Formula: C28H24FN3O5.C4H6O5  
 
M.W.: 635.6  
Mode of Action: Cabozantinib 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.  
How Supplied: 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, for treatment 
duration for up to a week, cabozantinib tablets can be dispensed in a pill cup with 
an expiration date not to exceed 24 hours or in a pharmacy dispensing bottle with 
expiration date not to exceed 7 days. 
Cabozantinib (XL184) 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 


 
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Storage: Store intact bottles at controlled room temperature, 200 to 250C. 
Stability: Stability testing of the intact bottles is on-going. Cabozantinib 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.  
Route of Administration: Oral. 
Method of Administration: Take cabozantinib on an empty stomach. 
Participants must fast for 2 hours before and 1 hour after each dose of 
cabozantinib. Do not crush or chew. Do not take missed dose within 12 hours of 
the next dose. 
Potential Drug Interactions: 
CYP450 isozymes 
In vitro, XL184 is a substrate of CYP3A4 and a weak substrate of CYP2C9. In 
healthy volunteers, XL184 AUC increased 38% with co-administration of 
ketoconazole, a strong inhibitor of CYP3A4, and decreased by 77% with a strong 
CYP3A4 inducer rifampin. Therefore, avoid chronic use of strong CYP3A4 
inducers such as rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifampentin, phenobarbital, and St. John’s Wort while taking XL184. Avoid 
chronic use of strong CYP3A4 inhibitors such as ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use alternative 
medications. Use of antiretroviral agents that are strong inducers or 
inhibitors of CYP3A4 are permitted as per exclusion criteria 3.2.10 and 
3.2.11. 
[Note: Use caution when discontinuing medication that is a strong inducer of 
CYP3A4 in patients who has been on a stable dose of XL184, as this could 
significantly increase the exposure to XL184.] 
XL184 is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 µM), a mixed-type 
inhibitor of both CYP2C9 (Kiapp = 10.4 µM) and CYP2C19 (Kiapp = 28.8 µM), and 
a weak competitive inhibitor of CYP3A4 (estimated Kiapp = 282 µM) in human 
liver microsomal (HLM). IC50 values >20 µM were observed for CYP1A2, 
CYP2D6, and CYP3A4 isozymes. XL184 is an inducer of CYP1A1 mRNA in 
human hepatocyte incubations,  
Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this 
trial. 
P-glycoprotein/ MRP2 
In vitro data indicate that XL184 is an inhibitor of P-glycoprotein transport 
activity (IC50 = 7.0 µM). Co-administration of XL184 with a P-gp substrate may 
result in an increase in P-gp substrate plasma concentration. Therefore, use 
caution when administering XL-184 with drugs known to be P-gp substrates (e.g., 
fexofenadine, 
aliskiren, 
ambrisentan, 
digoxin, 
colchicine, 
maraviroc, 
posaconazole, tolvaptan, etc.). 


 
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XL184 is also a substrate of drug transporter MRP2, which may result in an 
increase plasma concentration of XL184 when administered with an inhibitor of 
MRP2. Use caution and monitor adverse events when administering XL184 with 
MRP2 inhibitors such as cyclosporine, delavirdine, efavirenz, emtricitabine. 
Protein bound 
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. 
Antacids, H2-blockers, PPIs 
Co-administration of gastric pH modifying drugs such as PPI, H2-blockers or 
antacids has no clinically-relevant effect on XL184 plasma PK in healthy 
volunteers; thus, concomitant use of these drugs with XL184 is allowed. 
QTc prolongation 
Use caution when administering XL184 in patients with QT prolongation risk, a 
history of QT interval prolongation, or who are receiving antiarrhythmic drugs. 
Concomitant use of strong CYP3A4 inhibitors should be avoided as it may 
increase XL184 plasma concentrations. Refer to the protocol for QTcF criteria.  
Potential Food Effect 
A high fat meal increased both XL184 Cmax and AUC values by 41% and 57%, 
respectively relative to fasted conditions; therefore, XL184 should be taken on an 
empty stomach (fasting is required 2 hours before and 1 hour after each XL184 
dose). 
Participant 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. Refer to the protocol for management of adverse events. 
Availability: Cabozantinib (XL184) is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
Cabozantinib (XL184) is provided to the NCI under a Collaborative Agreement 
between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
8.1.2 Agent ordering and agent accountability 
8.1.2.1 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, 


 
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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. 
8.1.2.2 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 
Investigational Drug Accountability Record Form for Oral Agents (Oral 
DARF). (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.). The Oral DARFs document the drug 
delivery date to the site, inventory at the site, use by each study 
participant, and disposal of the drug (if applicable). The Oral DARF is 
also used to document agent returned by the participant. A site-specific 
accountability record, either manual or electronic, may be used if it 
includes all of the information required on the Oral DARF and if the paper 
printout is identical to the NCI accountability record. A separate Oral 
DARF is required for each protocol using the same agent. The investigator 
will ensure that the drugs are used only in accordance with this protocol. 
8.1.2.3 Dispensing agent – Pharmacy staff should dispense cabozantinib in its 
original container. The pharmacist may dispense the entire intact bottle, a 
pill cup not to exceed 24 hours of medication, or another pharmacy 
dispensing bottle not to exceed 7 days’ worth of medication. If an entire 
intact bottle is dispensed all agents must be returned at the end of the cycle 
and unused agent destroyed. The site staff is responsible for ensuring all 
unused agent is returned and destroyed. 
8.1.2.4 Returns of unused agent - study participants are required to complete the 
participant drug diary and to return all remaining agent and/or empty 
bottles at the end of each cycle of treatment. Site staff will be responsible 
for documenting pill counts at the end of each cycle. The pill count will be 
used to evaluate the information reported in the participant drug diary. 


 
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CLINICAL AND LABORATORY EVALUATIONS 
Schedule of Evaluations is provided in Appendix I. 
9.1 
Screening/Baseline Evaluations 
Unless otherwise specified, the following evaluations must be performed within 1 week 
prior to start of therapy: 
9.1.1 Complete medical history and physical examination, to include concurrent 
medications, medication history for eligibility (including ART regimen for 4 
weeks prior to enrollment), vital signs, height, weight, performance status, CDC 
HIV risk categories, and history of AIDS defining conditions. 
9.1.2 AIDS and Cancer Specimen Resource (ACSR) Consent for optional donation. It 
is required that AMC sites present the ACSR donation option to participants. (See 
Appendix VII for ACSR Informed Consent Form and Appendix VI for ACSR 
Specimen Preparation and Shipping Instructions). 
9.1.3 CBC with differential and platelets, Serum chemistry: albumin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
sodium, total protein and magnesium; Liver function tests: albumin, SGOT 
[AST], SGPT [ALT], total bilirubin, alkaline phosphatase. 
9.1.4 Serum TSH, amylase, lipase  
9.1.5 PT/INR and PTT 
9.1.6 CD4+ and CD8+ lymphocyte counts and HIV viral load within 2 weeks prior to 
the start of therapy 
9.1.7 Serum pregnancy test (for women of childbearing potential) 
9.1.8 Urine dipstick or urinalysis. Proteinuria seen on urine dipstick or UA should 
warrant urine protein/creatinine ratio (UPCR) determination and management 
according to Section 6.1.9.  
9.1.9 Electrocardiogram (ECG) and QTc assessments within 4 weeks prior to the start 
of therapy. 
9.1.10 CT scans to evaluate measurable disease within 4 weeks of start of therapy. CT 
will not be required for participants with KS. 
9.1.11 ONLY in participants with known Kaposi sarcoma, chest X-ray to rule out 
pulmonary Kaposi’s sarcoma. Pulmonary involvement must be asymptomatic or 
minimally symptomatic and not require systemic cytotoxic therapy in the 
judgment of the investigator. Participants with a positive chest X-ray or symptoms 
suggestive of pulmonary disease must have a chest CT performed before study 
entry.  
9.2 
Evaluations During Treatment 
Evaluations may occur within a window of +/- 7 days. Assessments must occur on cycle 
1, days 1, 8, 15, and 22, on Cycle 2, days 1 and 15, and on day 1 of all subsequent cycles 
as indicated in the Schedule of Evaluations (Appendix I).  


 
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9.2.1 Complete medical history and physical examination. To include vital signs, 
weight, performance status, adverse event evaluation). If hypertension (BP 
140/90) is observed, 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. (Refer to Section 6.1.8 for management.) 
9.2.2 CBC with differential and platelets, serum chemistry, amylase and lipase, and 
LFTs defined in 9.1.3. 
9.2.3 Serum TSH. Testing should be performed every 4 weeks (every cycle) beginning 
Cycle 1 Day 1. 
9.2.4 PT/INR and PTT. Testing should be performed every 8 weeks (2 cycles) 
beginning Cycle 1 Day 1. 
9.2.5 CD4+and CD8+ lymphocyte counts and HIV viral load. Samples will be obtained 
locally at time of Pharmacokinetic (PK) Specimen Collection on Cycle 1, Day 22, 
and at 12 week intervals while on study therapy. 
9.2.6 Urine dipstick or urinalysis. Proteinuria seen on urine dipstick or UA should 
warrant urine protein/creatinine ratio (UPCR) determination and management 
according to Section 6.1.9. 
9.2.7 ECG and QTc assessments will be performed weekly during the first cycle of 
therapy, and day 1 of all subsequent cycles. Additional ECGs will be performed 
as indicated in Section 6.1.16 (refer to Appendix IX for a list of drugs that may 
cause QTc prolongation). 
9.2.8 CT scan for tumor measurement performed after every 2 cycles (every 8 weeks) 
of therapy for participants with solid tumors. Participants with cutaneous KS will 
not require CT scans. 
9.2.9 KS participants will be evaluated for response after every other cycle according to 
the requirements in Section 11.2. Chest x-ray will be performed as clinically 
indicated. 
9.2.10 The participant will be given a copy of the participant diary to complete. Collect 
diary upon completion. 
9.2.11 Correlative Studies (See Section 10.0) 
9.3 
Final Evaluations, Off Treatment (within 7 days of last treatment)  
At the completion of all follow-up evaluations, the Off Protocol Treatment Summary 
Form should be completed in AdvantageEDC. 
9.3.1 Complete medical history and physical examination. To include vital signs, 
weight, performance status, adverse event evaluation) 
9.3.2 CBC with differential and platelets, serum chemistry, and LFTs defined in 9.1.3. 
9.3.3 CD4+ and CD8+ lymphocyte counts and HIV viral load 
9.3.4 Serum TSH, amylase, lipase  


 
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9.3.5 PT/INR and PTT 
9.3.6 Urine dipstick or urinalysis. Proteinuria seen on urine dipstick or UA should 
warrant urine protein/creatinine ratio (UPCR) determination and management 
according to Section 6.1.9. 
9.3.7 Electrocardiogram (ECG) and QTc assessments 
9.3.8 CT scan for tumor measurement. Radiologic documentation must be provided for 
participants removed from study for progressive disease. Participants with 
cutaneous Kaposi sarcoma will not require CT scans and will be evaluated for 
response according to Section 11.2. Chest x-ray will be performed as clinically 
indicated. 
9.3.9 Collect diary upon completion. 
9.4 
Final Evaluations, Off Study  
At the completion of all follow-up evaluations, the Off Study Summary Form should be 
completed in AdvantageEDC.  
Participants will be followed for 30 days (±3 days) from the date of study treatment 
discontinuation or until toxicity resolution, whichever is later. Toxicity resolution may be 
monitored by the local site personnel via telephone contact with the participant. 


 
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10.0 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
10.1 
Biomarker Studies 
10.1.1 To investigate possible pharmacokinetic interactions between cabozantinib and 
antiretroviral therapy in persons with HIV infection. 
This study will enroll participants with HIV infection across three Strata based on 
current antiretroviral regimen (Ritonavir or Cobicistat (CYP3A4 inhibitor)-
containing HAART [Stratum A]; Efavirenz or Etravirine (CYP3A4 inducer)-
containing HAART [Stratum B]; and Others [Stratum C]). The study therefore 
provides an opportunity to evaluate possible pharmacokinetic interactions 
between cabozantinib and antiretroviral therapies. 
Pharmacokinetic (PK) sampling studies are proposed for all participating 
participants on the study to assess cabozantinib pharmacokinetics (total and 
possibly unbound concentrations of parent drug and relevant metabolites). In 
addition, when feasible, samples will be requested from the participant at the time 
of disease progression and in the event of DLT or other persistent and severe 
toxicity. Evaluations will occur at steady-state (Cycle 1, Days 22/23) given the 
long half-life of the drug (91.3±33.3hr) which is not conducive to a 
comprehensive assessment after a single dose. If a participant misses a dose of 
cabozantinib during Cycle 1 prior to Cycle 1 Days 22/23 and will continue on 
treatment, Dr. Michelle Rudek should be contacted to determine the optimal 
timing of the PK collection, which may no longer occur on Cycle 1 Days 22/23. 
Since cabozantinib is to be administered continuously, the adjustment may occur 
in the date of the collection but not the 8 samples to be obtained. The exact timing 
will depend on the duration of interruption and proximity to Cycle 1 Days 22/23. 
In some circumstances, the PK collection may be waived due to difficulties in re-
scheduling the PK. 
To permit pharmacokinetic sampling studies, AM dosing is required during 
the first cycle of therapy. Blood samples will be collected prior to the initial AM 
cabozantinib dose and at 4 hours post-dose on Cycle 1 Day 1. Blood sampling for 
steady-state PK determinations will be collected during the dosing interval at pre-
dose (Cycle1, Day 22), 0.5, 1, 2, 4, 6, 8, and 24 hr (Cycle 1, Day 23). For the 
optional samples that are to be obtained at the time of disease progression or in 
the event of toxicity, a blood sample should be drawn as close as possible to the 
time of the event with documentation of the last cabozantinib dose administered. 
For each sample, at least 6 mL of whole blood will be collected in tubes or 
Vacutainers™ containing EDTA as an anticoagulant, kept on ice, and centrifuged 
within 30 min to isolate plasma. Plasma will be frozen in two to three aliquots 
immediately and stored at -70°C (or less) protected from light for later analysis by 
the Analytical Pharmacology Core Laboratory at the Sidney Kimmel 
Comprehensive Cancer Center at Johns Hopkins University under the direction of 
Dr. Michelle Rudek (See Appendix IV Pharmacokinetic (PK) Specimen 
Collection, Preparation and Shipping Instructions). 
Samples will be measured using liquid chromatography/tandem mass 
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Laboratory at the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at 
Johns Hopkins. Relevant individual PK parameters will be estimated using non-
compartmental or compartmental PK methods with the software WinNonlin. For 
each Stratum, the pharmacokinetic variables will be tabulated and descriptive 
statistics (e.g., geometric means and coefficients of variation) calculated for each 
dose level. Pharmacokinetic parameters (i.e., T½, Cl, and AUC) will be compared 
across relevant antiretroviral therapies using nonparametric statistical testing 
techniques. Correlations with toxicity and efficacy will be explored using 
nonparametric statistical testing techniques. Significance for comparisons will be 
at the p<0.05 level.  
10.1.2 To investigate the effects of therapy on participant immune status and HIV viral 
load. 
This trial will include participants with HIV infection, provided participants are 
receiving appropriate treatment and followed by physicians monitoring their care. 
While it is not anticipated that cabozantinib will alter immune reconstitution in 
participants, HIV viral load and CD4+ cell counts will be monitored to ensure 
adequate control of the participant’s HIV infection. Samples will be obtained 
locally at baseline, at time of Pharmacokinetic (PK) Specimen Collection on 
Cycle 1, Day 22, and at 12 week intervals while on study therapy, and at time of 
study discontinuation. 
10.2 
Laboratory Correlative Studies 
10.2.1 To investigate possible pharmacokinetic interactions between cabozantinib and 
antiretroviral therapy in persons with HIV infection. 
10.2.1.1 Collection of specimens 
This study will be performed on all participating participants as 
described in Appendix IV, Pharmacokinetic (PK) Specimen Collection, 
Preparation and Shipping Instructions. Samples will be collected prior to 
the initial cabozantinib dose and at 4 hours post-dose on Cycle 1 Day 1. 
Steady-state PK samples will be collected during the dosing interval at 
pre-dose (Cycle 1, Day 22), 0.5, 1, 2, 4, 6, 8, and 24 hr (Cycle 1, Day 
23). Day 22 and Day 23 PK samples may be collected ± 1 day. If a 
participant misses a dose of cabozantinib during Cycle 1 prior to Cycle 1 
Days 22/23 and will continue on treatment, Dr. Michelle Rudek should 
be contacted to determine the optimal timing of the PK collection, which 
may no longer occur on Cycle 1 Days 22/23. In addition, when feasible, 
samples will be requested from the participant at the time of disease 
progression and in the event of DLT or other persistent and severe 
toxicity. 
10.2.1.2 Handling of specimens 
Specimens will be obtained from the local site as described in Appendix 
IV, Pharmacokinetic (PK) Specimen Collection, Preparation, and 
Shipping Instructions. 


 
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10.2.1.3 Shipping of specimens 
These studies will be performed in an AMC-designated Pharmacology 
Core Laboratory. Specimens will be prepared and shipped from the local 
site as described in Appendix IV, Pharmacokinetic (PK) Specimen 
Collection, Preparation, and Shipping Instructions. 
10.2.1.4 Sites performing correlative study 
All participating sites. 
10.2.2 To investigate the effects of therapy on participant immune status and HIV viral 
load. 
10.2.2.1 Collection of specimens 
All participants will have baseline and follow-up evaluations of CD4+ 
and CD8+ lymphocyte counts and HIV viral load on Cycle 1, Day 22 
(along with Pharmacokinetic (PK) Specimen collection) and at every 12 
weeks during study participation as part of standard HIV care. 
Participants will also have these evaluations performed at time of study 
discontinuation. 
10.2.2.2 Handling of specimens 
Testing will be performed locally. 
10.2.2.3 Sites performing correlative study  
All participating sites. 


 
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11.0 
MEASUREMENT OF EFFECT 
Although response is not the primary endpoint of this trial, participants with measurable 
disease will be assessed by standard criteria. For the purposes of this study, participants 
should be re-evaluated every 8 ± 1 weeks. In addition to a baseline scan, confirmatory 
scans will also be obtained at least 4 weeks following initial documentation of an 
objective response. Participants with solid tumors other than Kaposi sarcoma will be 
followed for response according to Section 11.1, and participants with Kaposi 
sarcoma will be followed for response according to Section 11.2.  
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 8 
weeks. In addition to a baseline scan, confirmatory scans should also be obtained not less 
than 4 weeks following initial documentation of objective response. 
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) [Eur J Ca 45:228-247, 2009]. 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 participants will be evaluable for toxicity from the time 
of their first treatment with cabozantinib (XL184). 
Evaluable for objective response: Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated 
below. (Note: Participants who exhibit objective disease progression prior to the 
end of cycle 1 will also be considered evaluable.) 
Evaluable non-target disease response: Participants 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). 
Note: Tumor lesions that are situated in a previously irradiated area may not be 
considered measurable.  


 
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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 definition, simple cysts. 
‘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 participant, 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 
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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). 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 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 
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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 
participant 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. 
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. However, as this may not necessarily represent a 
new tumor lesion for individuals with ongoing HIV replication, new lesions 
on FDG-PET MUST be confirmed by CT scan to document progressive 
disease. 
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. 


 
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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. 
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 participant 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. 






 
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• A 50% decrease in the sum of the products of the largest perpendicular 
diameters of the marker lesions 
Note: Participants with residual tumor-associated edema or effusion who 
otherwise meet the criteria for complete response will be classified as having a 
partial response. 
11.2.3 Stable disease (SD) is defined as any response not meeting the criteria for CR, 
PR, or progressive disease. 
11.2.4 Progressive disease (PD) is defined as follows: 
For participants with ≤ 50 cutaneous lesions 
1. > 25% increase in the sum of perpendicular diameters of the indicator lesions, 
OR 
2. ≥ 25% increase in the total lesion count, or a minimum of 5 new lesions, 
whichever is greater, OR 
3. ≥ 25% increase in the number of raised lesions (minimum of 5 new raised 
lesions if there are very few raised lesions, for example ≤ 8), whichever is 
greater. 
Note: There are body sites where disease is particularly difficult to evaluate, and a 
few new lesions may be counted in spite of the fact that a participant is not 
actually progressing. For example, lesions of the foot, particularly those which are 
flat, are difficult to evaluate because their intensity may be variable based on how 
much edema is present, how much the person walked the day before, how long 
their feet have been in a dependent position prior to the physical exam, etc. 
For participants with >50 cutaneous lesions 
1. ≥ 25% increase in the sum of the perpendicular diameters of the indicator 
lesions, OR 
2. ≥ 25% increase in the total number of lesions in the prospectively defined 
anatomic sites containing representative numbers of lesions, OR 
3. A total of 5 new lesions in anatomic sites which were previously documented 
as having no evidence of cutaneous disease on the whole body diagram, OR  
4. ≥ 25% increase in the number of raised lesions (minimum of 5 raised lesions 
if there are very few raised lesions, for example <8) whichever is greater. 
Photographic documentation of “gross” or significant progression, particularly 
in areas that were not being followed, will be of particular value. 
In order to classify a response as PR, the participant must have at least a PR in 
either the cutaneous or noncutaneous sites of disease, and no evidence of 
progression as defined in the above criteria. In order to classify a response as a 
CR, the participant must have a CR in both the cutaneous (if applicable) and 
noncutaneous (if applicable) sites of disease and no evidence of progression as 
defined by the above criteria. 


 
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Noncutaneous Progression 
Progressive disease includes new visceral sites of involvement or progression of 
visceral disease or the development of new or increasing tumor-associated edema 
or effusion lasting at least 1 week, which interferes with the participant’s normal 
activities. Progressive visceral disease, for measurable and evaluable disease, 
should be analogous to non-KS response criteria. 
11.2.5 Recurrent disease is defined as the appearance of tumor following documentation 
of a complete remission. 
11.2.6 Time to response is defined as time from the first dose of chemotherapy until 
documentation of first response. 
11.2.7 Time to progression is defined as time from initiation of chemotherapy to 
documentation of first progression. 
11.2.8 Response duration is defined as the time from first documentation of response to 
documentation of first progression. 


 
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12.0 
STATISTICAL CONSIDERATIONS 
12.1 
Study Design/Endpoints 
This is a phase I, dose escalation study of cabozantinib for advanced solid tumors in 
persons with HIV infection. The primary endpoint of the study is the safety and 
tolerability of single agent cabozantinib and to determine the maximal tolerated dose 
(MTD) in this participant population. The study will be a standard phase I dose escalation 
trial with a 3+3 design. The study agent will be administered continuously in 28 day 
cycles.  
Participants will be stratified based on HAART with the currently recommended dosing 
regimen. Participants on ritonavir or cobicistat (potent CYP3A4 inhibitor)-containing 
HAART will be on Stratum A; participants on efavirenz or etravirine (CYP3A4 inducer)-
containing HAART will be on Stratum B, and all other participants (including those 
without antiretroviral therapy) will be on Stratum C. Dose escalation and MTD 
determination will be done for each stratum individually. Participants are considered 
evaluable for the purpose of cohort dose escalations if in the first cycle they either 
experience a dose-limiting toxicity (DLT) (see below), or receive at least 80% of the 
planned treatment dose and are followed for one full cycle without a DLT. Participants 
receiving less than 80% of the treatment dose during cycle 1 without a DLT may be 
replaced for the purpose of safety and PK evaluation at the discretion of the study team.  
Dose escalation decisions for cabozantinib will be made after evaluation of toxicities in 
the first cycle of therapy. In this trial, a dose-limiting toxicity (DLT) will be defined as 
any cabozantinib-related grade 3 or 4 non-hematologic toxicity during the first cycle of 
therapy, including grade 3 nausea and/or vomiting and grade 3 diarrhea despite 
prophylaxis and/or treatment or any of the following grade 4 hematologic toxicities 
during the first cycle of therapy: thrombocytopenia and neutropenia of any duration (with 
or without fever or documented infection); additionally, treatment delay of greater than 7 
days during Cycle 1 due to unresolved toxicity or any dose reduction required during 
Cycle 1 due to a cabozantinib-related adverse event will be considered a DLT. If a DLT 
occurs in one participant at a particular dose level, up to 3 additional participants will be 
added to that cohort. If a second participant experiences a DLT, the maximally tolerated 
dose (MTD) of the study will have been exceeded. If 2 DLTs are experienced at the first 
cohort, dose de-escalation cohorts (up to Dose Level -1 for Stratum A; up to Dose Level -
2 in Stratum B and Stratum C) will be permitted according to the study schema suggested 
in the treatment plan. 
12.2 
Sample Size/Accrual Rate 
No formal statistical hypothesis testing is planned for the primary analysis. Sample size 
estimates are in agreement with those of a traditional phase I dose escalation 3+3 design. 
It is expected that the study will enroll approximately 16 to 42 participants across 
potentially three Strata (Ritonavir or Cobicistat (CYP3A4 inhibitor)-containing HAART 
[Stratum A]; Efavirenz or Etravirine (CYP3A4 inducer)-containing HAART [Stratum 
B]; and Others [Stratum C]). Among the expected 16 to 42 enrolled participants, 4 to 18 
are expected to be enrolled in Stratum A, 6 to 18 are expected to be enrolled in Stratum 
B, and 6 participants are expected to be enrolled in Stratum C.  


 
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Following the determination of the MTD in each stratum, the MTD dose level for each 
stratum may be expanded to 6 to 12 participants according to participant availability for 
further characterization of toxicity, preliminary assessment of response and additional 
translational study samples. A decision to halt accrual because of lack of participant 
availability will be at the discretion of CTEP investigators. 
The estimated accrual rate for this study is 1 - 2 participants/month. 
12.3 
Stratification Factors 
Participants will be stratified based on HAART with the currently recommended dosing 
regimen. Participants on ritonavir or cobicistat (CYP3A4 inhibitor)-containing HAART 
will be on Stratum A; participants on efavirenz or etravirine (CYP3A4 inducer)-
containing HAART will be on Stratum B, and all other participants (including those 
without antiretroviral therapy) will be on Stratum C. Dose escalation and MTD 
determination will be done for each stratum individually.  
12.4 
Analysis of Secondary Endpoints 
Secondary endpoints for this study include response rates and effects of therapy on HIV 
viral load and CD4+ and CD8+ cell counts, as well as the results of pharmacokinetic 
studies. For participants with measurable disease, response evaluations will occur at 2 
cycle intervals via RECIST 1.1. Study treatment may continue indefinitely until one of 
the following criteria applies: 1) unacceptable toxicity (including DLT in cycle 1); 2) 
progressive disease; or 3) participant withdrawal or removal. 
To investigate possible pharmacokinetic interactions between cabozantinib and 
antiretroviral therapy in persons with HIV infection, pharmacokinetic analysis 
calculations will be conducted using WinNonlin (Pharsight Corporation, Mountain View, 
CA) with noncompartmental or compartmental methods. Relevant pharmacokinetic 
parameters will be computed for cabozantinib and relevant metabolites. The 
pharmacokinetic variables will be tabulated and descriptive statistics (e.g., geometric 
means and coefficients of variation) calculated for each dose level. Pharmacokinetic 
parameters (i.e., T½, Cl, and AUC) will be compared across relevant antiretroviral 
therapies using nonparametric statistical testing techniques. Concentrations obtained from 
the time of disease progression and the time of a DLT or other persistent and severe 
toxicity will be treated as independent samples and summarized in a descriptive manner. 
Correlations with toxicity and efficacy will be assessed using nonparametric statistical 
testing techniques. Significance for comparisons will be at the p<0.05 level.  
To investigate the effects of cabozantinib on participant immune status and HIV viral 
load, trends in CD4+ and CD8+ counts and viral load determinations during trial 
participation will be evaluated. A repeated measures analysis of variance will be used to 
assess the effect of cabozantinib on CD4+ and CD8+ cell counts and HIV viral loads 
across time points. Analyses will be done per stratum, where the data are sufficient. If the 
data do not meet the assumptions of normality, Friedman’s test, the nonparametric 
analogue to a repeated measures analysis of variance, will be used. 
Collectively and over each stratum, binomial proportions and their 95% confidence 
intervals will be used to preliminarily assess response rates for single agent cabozantinib 
in malignancies for which at least 4 participants have been enrolled. 


 
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13.0 
ROLE OF DATA MANAGEMENT 
13.1 
CRF Instructions 
Access to the internet data entry system for this study, AdvantageEDC, and instructions 
for recording of study data on CRFs will be provided by the AMC ODMC at 
www.amcoperations.com. Participating institutions are responsible for submitting data 
and/or data forms via AdvantageEDC in accordance with the AMC Data Entry Guide and 
specific form instructions, within the timelines specified by the AMC’s Standards of 
Procedure for Site Performance Measures. 
13.2 
Data Quality 
It is the responsibility of the AMC ODMC to assure the quality of data for the study (See 
Appendix V, AMC Data and Safety Monitoring Plan). This role extends from protocol 
development to generation of the final study database. 
13.3 
Data Monitoring 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific 
CDUS data will be submitted electronically to CTEP on a quarterly basis. 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). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for 
all participants and for providing the data to the Principal Investigator for review. 
13.4 
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.” contained within the terms of award, apply to the use of the Agent(s) in 
this study: 
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 investigational 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 participant or participant’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. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the participant 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”): 


 
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a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NIH, 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 other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational 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 investigational Agent. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively 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. 
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. 
Any data provided to Collaborator(s) for phase III 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. 
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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14.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1 
IRB Approval and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 
56) and the Department of Health and Human Services (DHHS) regulations for the 
Protection of Human Subjects regulations (45 CFR Part 46) must be followed. IRB 
approval of the protocol and the informed consent form must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol and informed consent, before subject 
enrollment. The IRBC must also approve any significant changes to the protocol and 
documentation of this approval must be sent to the AMC ODMC. The IRB must review 
the research project at least once every 365 days during the duration of the project. 
Continuing approval of the project must also be given in writing and provided to the 
AMC ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are subject to inspection during or after completion of the study. AEs 
must be reported to the IRB according to local procedures. The IRB should receive 
notification of completion of the study and final report within 3 months of study 
completion and termination. The Investigator will maintain an accurate and complete 
record of all submissions made to the IRB, including a list of all reports and documents 
submitted. 
Written informed consent will be obtained from the subject. The nature, significance and 
risks associated with the study must be explained to the subject. The informed consent 
will describe the purpose of the study, the procedures to be followed, the risks and 
benefits of participation, all risks of the investigational agent(s) and/or study participation 
as listed in the model informed consent form, and all other elements of informed consent 
as required by regulation. A copy of the consent form will be given to the subject to keep. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
14.2 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. All amendments 
require approval by the IRB/IEC of the treating institution. A copy of the written 
approval of the IRB/IEC must be sent to the AMC ODMC. 


 
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15.0 
REFERENCES 
1. Benson, A.B. 3rd, J.A. Ajani, R.B. Catalano, et al. (2004). Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea. J Clin Oncol. 22:2918-2926.  
2. Birchmeier, C., W. Birchmeier, E. Gherardi, and G.F. Vande Woude. (2003). Met, 
metastasis, motility and more. Nat Rev Mol Cell Biol. 4:915-925. 
3. Boccaccio, C., and P.M. Comoglio. (2006). Invasive growth: a MET-driven genetic 
programme for cancer and stem cells. Nat Rev Cancer. 6:637-645. 
4. Centers for Disease Control (CDC). (2008). Centers for Disease Control: AIDS-defining 
conditions. 
5. Christensen, J.G., J. Burrows, and R. Salgia. (2005). c-Met as a target for human cancer and 
characterization of inhibitors for therapeutic intervention. Cancer Lett. 225:1-26. 
6. Comoglio, P.M., S. Giordano, and L. Trusolino. (2008). Drug development of MET 
inhibitors: targeting oncogene addiction and expedience. Nat Rev Drug Discov. 7:504-
516. 
7. Eder, J.P., G.F. Vande Woude, S.A. Boerner, P.M. LoRusso. (2009). Novel therapeutic 
inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res. 15:2207-2014. 
8. Eisenhauer E.A., P. Therasse, J. Bogaerts, et al. (2009). New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228-247.  
9. Investigator's Brochure. (2010). Investigator's Brochure for XL184. Exelixis, Inc., South San 
Francisco, CA. 
10. Investigator's Brochure. (2012). Investigator's Brochure for Cabozantinib (XL184), v.8. 
Exelixis, Inc., South San Francisco, CA. 
11. Jeffers, M., L. Schmidt, N. Nakaigawa, et al. (1997). Activating mutations for the met 
tyrosine kinase receptor in human cancer. Proc Natl Acad Sci U S A. 94:11445-11450. 
12. Krown S.E., C. Metroka, and Wernz J.C. (1989). Kaposi's sarcoma in the acquired immune 
deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. 
AIDS Clinical Trials Group Oncology Committee. J Clin Oncol. 7:1201-1207. 
13. Kurzrock, R., S.I. Sherman, D.W. Ball, et al. (2011). Activity of XL184 (Cabozantinib), an 
oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 
29:2660-2666. 
14. Liu, X., R.C. Newton, and P.A. Scherle. (2010). Developing c-MET pathway inhibitors for 
cancer therapy: progress and challenges. Trends Mol Med. 16:37-45. 
15. Maier, J., M. Mariotti, P.M. Comoglio, and M.R. Soria. (1996). Interleukin 1 induces an 
autocrine loop hepatocyte growth factor /c-MET in murine Kaposi-like spindle cells. 
Oncogene. 13:1009-1015. 
16. Masood, R., J. Cai, T. Zheng, et al. (1997). Vascular endothelial growth factor/vascular 
permeability factor is an autocrine growth factor for AIDS-Kaposi sarcoma. Proc Natl 
Acad Sci U S A. 94:979-84. 


 
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17. Naidu, Y.M., E.M. Rosen, R. Zitnick, et al. (1994). Role of scatter factor in the pathogenesis 
of AIDS-related Kaposi sarcoma. Proc Natl Acad Sci U S A. 91:5281-5285. 
18. Paez-Ribes M., E. Allen, J. Hudock, et al. (2009). Antiangiogenic therapy elicits malignant 
progression of tumors to increased local invasion and distant metastasis. Cancer Cells. 
15(3):220-231. 
19. Patel, P., D.L. Hanson, P.S. Sullivan, et al. (2008). Incidence of types of cancer among HIV-
infected persons compared with the general population in the United States, 1992-2003. 
Ann Int Med. 148:728-736. 
20. Persad, G.C., R.F. Little, and C. Grady. (2008). Including persons with HIV infection in 
cancer clinical trials. J Clin Oncol. 26:1027-1032. 
21. Roskoski, R., Jr. (2008). VEGF receptor protein-tyrosine kinases: structure and regulation. 
Biochem Biophys Res Commun. 375:287-291. 
22. Schmidt, L., F.M. Duh, F. Chen, et al. (1997). Germline and somatic mutations in the 
tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat 
Genet. 16:68-73. 
23. Schoffski, P., R. Elisei, S. Müller, et al. An international, double-blind, randomized, placebo-
controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid 
carcinoma (MTC) patients (pts) with documented RECIST progression at baseline. J Clin 
Oncol. 30, 2012 (suppl; abstr 5508). 
24. Sennino, B., R.M. Naylor, S.P. Tabruyn, et al. (2009). Abstract A13: Reduction of tumor 
invasiveness and metastasis and prolongation of survival of RIP-Tag2 mice after 
inhibition of VEGFR plus c-Met by XL184. Mol Cancer Ther. 8:A13. 
25. Shiels, M.S., R.M. Pfeiffer, M.H. Gail, et al. (2011). Cancer burden in the HIV-infected 
population in the United States. J Natl Cancer Inst. 103:753-762. 
26. Tugues, S., S. Koch, L. Gualandi, et al. (2011). Vascular endothelial growth factors and 
receptors: anti-angiogenic therapy in the treatment of cancer. Mol Aspects Med. 32:88-
111. 
27. Weiss, S.A., S. Gajavelli, A. Negassa, J.A. Sparano, and M. Haigentz. (2011). Evaluation of 
cancer trial eligibility criteria (with focus on non-AIDS–defining cancers) for inclusion of 
persons with HIV infection. J Clin Oncol. 29 suppl; abstr 6092. 
28. Welles L., M.W. Saville, J. Lietzau J, et al. (1998). Phase II trial with dose titration of 
paclitaxel for the therapy of human immunodeficiency virus-associated Kaposi's 
sarcoma. J Clin Oncol. 16:1112–1121. 
29. Yakes, F.M., J. Chen, J. Tan, et al. (2011). Cabozantinib (XL184), a novel MET and 
VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor 
growth. Mol Cancer Ther. 10:2298-2308 
30. You, W.K., B. Sennino, C.W. Williamson, et al. (2011). VEGF and c-Met blockade amplify 
angiogenesis inhibition in pancreatic islet cancer. Cancer Res. 71:4758-4768. 


 
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31. Zhang, S., H. Zhau, A. Osunkoya, et al. (2010). Vascular endothelial growth factor regulates 
myeloid cell leukemia expression through neuropilin 1-dependent activation of c-Met 
signaling in human prostate cancer cells. Mol. Cancer. 9:9. 
32. Ziegler, J.L., A.C. Templeton, and C.L. Vogel. (1984). Kaposi's sarcoma: a comparison of 
classical, endemic, and epidemic forms. Semin Oncol. 11:47-52. 


 
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APPENDIX I: SCHEDULE OF EVALUATIONS 
The schedule of evaluations below applies to all participants on study. Baseline clinical and 
laboratory evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans 
and x-rays must be done within 4 weeks prior to the start of therapy. In the event that the 
participant’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. Evaluations may occur within a window of +/- 7 
days. Assessments must occur on cycle 1, days 1, 8, 15, and 22, on Cycle 2, days 1 and 15, and 
on day 1 of all subsequent cycles. 
 
Pre- 
Study 
C1/ 
D1 
C1/ 
D8 
C1/ 
D1
5 
C1
D22 
C2/
D1 
C2/
D8 
C2/
D1
5 
C2/
D22 
C3/
D1 
C4/
D1 
C5/
D1 
C6/
D1k 
Treatment 
Discontinuation
p 
Cabozantinib (XL184) 
 
A 
 
 
 
A 
 
 
 
A 
A 
A 
A 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
Concurrent meds 
X 
X------------------------------------------------------------------------------------X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
CBC w/diff, plts, LFTs 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum chemistryb 
Xc 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Urine Dipstick or UAb 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Serum TSH 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Electrocardiogram 
(ECG)d 
Xo 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Adverse event evaluation 
 
X-----------------------------------------------------------------------------------Xj 
X 
Tumor measurements 
X 
Solid tumor measurements are repeated every 8 weeks (2 cycles). KS 
participants will be evaluated for response after every other cycle.  
Documentation (radiologic) must be provided for participants removed 
from study for progressive disease. 
X 
Radiologic evaluation 
Xl 
Radiologic measurements should be performed every 8 weeks (2 cycles) 
m. 
X 
PT/INR, PTT 
X 
Repeat testing should be performed at 8 weeks (end of Cycle 2). 
X 


 
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Amylase and Lipase 
Xc 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
B-HCG 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+and CD8+ 
Lymphocyte Counts and 
HIV Viral Loadf 
Xn 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
ACSR donation 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cabozantinib diaryh 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Pharmacokinetic (PK) 
sampling studiesi 
 
Xi 
 
 
Xi 
 
 
 
 
 
 
 
 
Xj 
A: Cabozantinib (XL184): must be taken on an empty stomach. Participants must be instructed not to eat for at least 2 hours 
before and at least 1 hour after taking cabozantinib. Participants should be instructed to take their cabozantinib dose at 
approximately the same time every day. If a participant misses a dose, the dose may be taken later only if it is within 12 
hours of when the missed dose should have been taken. The missed dose should not be made up if it is within 12 hours of the 
next scheduled dose. 
a: If hypertension (BP 140/90) is observed, 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. (Refer to Section 6.1.8 for management.) 
b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
potassium, magnesium total protein, SGOT [AST], SGPT [ALT], sodium. Proteinuria seen on urine dipstick or UA should 
warrant urine protein/creatinine ratio (UPCR) determination and management according to Section 6.1.9. Calcium, 
magnesium, potassium and phosphorus should be kept above the lower limits of the laboratory normal values. 
c: Urine protein/creatinine ratio (UPCR) to determine eligibility. 
d: ECG and QTc assessments will be performed at baseline, weekly during the first cycle of therapy, and day 1 of all 
subsequent cycles. Additional ECGs will be performed as indicated in Section 6.1.16 (refer to Appendix IX for a list of 
drugs that may cause QTc prolongation). 
e: Serum pregnancy test (women of childbearing potential). 
f:  CD4+ and CD8+ Lymphocyte Counts and HIV viral load will be obtained locally at baseline, on Cycle 1, Day 22 (date of 
PK sampling), every 12 weeks during protocol participation, and at time of treatment discontinuation. 
g: Prestudy Tumor specimen: Donation of the specimen to the ACSR for correlative studies will be strongly recommended. 
Specimens will be submitted to the ACSR as described in Appendix VII. 
h:  Collection of cabozantinib drug diary from previous cycle and distribution of new diary. (Appendix VIII) Collect final diary 
at treatment discontinuation. 
i:  Initial baseline PK sample to be collected prior to the initial AM cabozantinib dose and at 4 hrs post-dose on Cycle 1, Day 1. 
Steady-state PK samples will be collected during the dosing interval at pre-dose (Cycle1, Day 22), 0.5, 1, 2, 4, 6, 8, and 24 
hr (Cycle 1, Day 23). See Appendix IV. 
j:  When feasible, a PK sample should be requested from the participant at the time of disease progression and in the event of 
DLT or other persistent and severe toxicity. 
k:  D1/C6 and all D1 subsequent cycles. 
l:  Pre-study chest X-ray to rule out pulmonary Kaposi’s sarcoma as indicated in Section 9.1.11 Subsequent chest x-rays will be 
performed as clinically indicated for KS participants. 
m:  CT scan for tumor measurement performed after every 2 cycles (every 8 weeks) of therapy for participants with solid 
tumors. Participants with KS will not require CT scans.  
n.  CD4+ and CD8+ lymphocyte counts and HIV viral load to be done within 2 weeks prior to the start of therapy. 
o.  ECG and QTc assessments to be done within 4 weeks prior to start of therapy. 
 
p.  Participants will be followed for 30 days (±3 days) from the date of study discontinuation or until toxicity resolution, 
whichever is later. Toxicity resolution may be monitored by the local site personnel via telephone contact with the 
participant. 




 
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APPENDIX III: PARTICIPANT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Participants, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements  
The participant ____________________________ is enrolled on a clinical trial using the 
experimental study drug, cabozantinib (XL184). 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. 
These are the things that you as a healthcare provider need to know: 
Cabozantinib (XL184) interacts with a certain specific enzyme in your liver, a certain transport 
protein that helps move drugs in and out of cells, and the heart’s electrical activity (QTc 
prolongation). 
1. The enzyme in question is CYP 3A4. Cabozantinib (XL184) is metabolized by CYP3A4 and 
may be affected by other drugs that inhibit or induce this enzyme. 
2. The protein in question are P-glycoprotein (P-gp) and MRP2. Cabozantinib (XL184) is an 
inhibitor of P-gp and may be affected by other drugs that are “substrates.” Cabozantinib 
(XL184) is also a substrate of MRP2 and may be affected by other drugs that are “inhibitor” 
or “inducers” of MRP2. 
3. Cabozantinib (XL184) may affect the heart’s electrical activity causing QTc prolongation. 
The study doctor may be concerned about QTc prolongation and any other medicine that is 
associated with greater risk for having QTc prolongation. 
To the participant: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet. 
Cabozantinib (XL184) may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial. It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study. When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort. It is 
helpful to bring your medication bottles or an updated medication list with you. 
Many health care providers can write prescriptions. You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial. 
These are the things that you and they need to know: 
Cabozantinib (XL184) must be used very carefully with other medicines that use certain liver 
enzyme, transport proteins to be effective or to be cleared from your system or that may 
affect your heart’s electrical activity. Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers to review any medicines and herbal 
supplements that are considered “strong inducers/inhibitors of CYP3A4, substrate of P-gp, or 
any medicine associated with greater risk for having QTc prolongation.” 
 


 
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1. Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to 
determine if there could be any side effects. 
2. Do not drink or eat grapefruit/juice or Seville oranges. 
3. Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine. 
4. Your study doctor’s name is _____________________________________ and he or she can 
be contacted at _____________________________________. 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study 
drug__________________. This clinical trial is sponsored by the NCI. 
__________________ may interact with drugs that are processed by 
your liver, or use certain transport proteins in your body or affect 
the electrical activity of your heart. Because of this, it is very 
important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) 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. 
 
XL184 (cabozantinib) must be used very carefully with other 
medicines that interact with CYP3A4 enzyme, transporter proteins 
(P-gp) and MRP2, or drugs that may trigger your heart’s 
electrical activity (QTc prolongation).  
 Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines  and herbal supplements that are considered “strong 
inducers/inhibitors CYP3A4; P-gp substrates; or drugs that 
cause risks for QTc prolongation.”  
 Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.  
 Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  




 
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3) The plasma fraction will be withdrawn by pipette and divided into 3 polypropylene freezing 
tubes (with each tube receiving approximately equal aliquots and at least 0.5 mL volume). 
4) All sample collection and freezing tubes will be clearly labeled in a fashion that identifies the 
participant, the study period, and the collection date and time. Labels will be fixed to freezing 
tubes in a manner that will prevent the label from becoming detached after freezing. 
5) After processing, samples should be placed into a freezer at approximately –70°C. 
With a black, water resistant, fine-tipped sharpie pen, label each specimen label with the 
following information: 
1. Protocol #: AMC-087 
2. 9 digit Study ID #  
3. Specimen type: "Plasma" 
4. Specimen purpose: “Pharmacokinetic Analysis” (for the 3 aliquots) 
5. Date/Time collected: 
*The nominal time point of the blood draw should be written on the specimen label (e.g., day and 
pre-dose, 1 hour, 2 hour, etc.) In GlobalTraceSM, enter the time collected and be sure to indicate 
the nominal time point in the comments section when adding specimens. 
If there were samples not obtained at the required time points, please inform the Analytical 
Pharmacology Core (APC) Laboratory prior to shipping. 
Shipment 
Samples will be kept at the study site and periodically during the study shipped to the APC 
Laboratory. Unless otherwise stated, samples will be shipped to the APC Laboratory under the 
direction of Michelle A. Rudek, Pharm.D., Ph.D. Specimens should be stored through the 
duration of the PK study (through Cycle 1 Day 23) and shipped as a batch by participant (more 
than one participant/shipment is acceptable if the site has >1 participant on-study). A participant's 
samples should be shipped to the APC lab within 1 month of the last sample's collection date. 
(i.e., if C1D23 sample is collected on 1/1/2013, all of that participant's samples should be at the 
APC lab by 2/1/2013). If a second set of participant samples can be batched by waiting up to 2 
weeks (i.e., 1.5 months), this deviation is allowed.  
Please ship 2 aliquots to the APC laboratory. Once receipt is confirmed, the third/back-up 
aliquot may be shipped (after 2 successful shipments, all 3 aliquots can be shipped at once). 
Overnight shipments should occur on Monday through Wednesday (Tuesday is the preferred 
day) except when the following day is a holiday. A fax or call should be place to the Analytical 
Pharmacology Core Laboratory prior to shipment providing the shipment tracking information. 
Samples should be shipped on dry ice to: 
Analytical Pharmacology Core Laboratory* 
Attn: AMC Cabozantinib Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 


 
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Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 


 
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APPENDIX V: AMC DATA AND SAFETY MONITORING PLAN 
(Version 5.0  January 28, 2014) 
Monitoring the Progress of Trials and the Safety of Participants 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html). All adverse events that meet the NCI’s expedited 
reporting requirements are reported to the Investigational Drug Branch (IDB) of the NCI via the 
Adverse Event Expedited Reporting System (CTEP-AERS) web application. All expedited 
adverse event reports are also required to be submitted to the local Institutional Review Board 
(IRB) of the reporting institution. If NCI holds the IND or no IND is required for a study, the 
AMC site reports serious adverse events directly to the AMC Operations and Data Management 
Center (ODMC) via CTEP-AERS. In some instances, the AMC sites may report serious adverse 
events directly to a commercial sponsor holding the IND, who will then report the event to the 
AMC ODMC. Most AMC protocols require sites to report all serious adverse events via CTEP-
AERS and the AMC ODMC to forward a copy of the report to the sponsor. The AMC ODMC 
also distributes all IND safety reports to all investigators upon receipt, and makes these reports 
available on the password-protected section of the AMC Operations web site. Unless an AMC 
protocol specifies an alternate plan for the review and submission of serious adverse events, all 
serious adverse events received by the AMC ODMC will be reviewed by the AMC Medical 
Monitor at the AMC ODMC prior to submission to NCI and the sponsor. For protocols for which 
the IDB does not have an assigned drug monitor to review serious adverse event reports, in the 
event of disagreement between the reporting physician and the AMC Medical Monitor regarding 
the attribution of the event to the investigational agent(s) (i.e., determination of whether the 
relationship is unrelated, unlikely, possible, probable, or definite), the AMC Medical Monitor will 
provide the final determination of the relationship. 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to 
the Protocol Chair and Co-chair(s) for review on a regular basis. The AMC ODMC compiles 
these events in a tabular format and posts them on the password-protected section of the AMC 
web site where these reports are updated nightly. The AMC web site is accessible to all AMC 
investigators, co-investigators, and their staff. Email notification that this information is available 
on the web site will be sent to all site PIs. It is the responsibility of each site to provide this 
information to their respective IRBs, if required by their IRB. For blinded studies, the serious 
adverse events are reviewed and tabulated without treatment assignment. The AMC Medical 
Monitor will review listings of all reported adverse events on a quarterly basis for safety 
concerns. 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site. The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls. 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the Protocol Chair, AMC Medical Monitor, and Group Statistician determine 
whether these criteria have been met. For phase II trials, stopping the trial for toxicity or efficacy, 
or suspending enrollment pending observation of responses in a multi-stage phase II trial, is based 
on meeting criteria stated in the protocol, and the Protocol Chair, AMC Medical Monitor, and 
Group Statistician determine whether these criteria have been met. 


 
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For phase III trials, the AMC has formed an independent Data Safety and Monitoring Board 
(DSMB). Voting members of the DSMB are physicians, a statistician, and a participant advocate. 
All voting members are from outside the AMC. Nonvoting members are the AMC Group 
Statistician, the Statistician listed on the protocol, an AMC Operations Center staff member, two 
representatives (normally a clinician or statistician) from the Office of HIV AIDS Malignancy 
(OHAM) or from the Cancer Therapy Evaluation Program, Division of Cancer Treatment and 
Diagnosis, of the National Cancer Institute (NCI). The AMC Data Safety and Monitoring Board 
reviews AMC phase III studies in accordance with the National Cancer Institute’s Policy for Data 
Safety and Monitoring. Confidential reports of all phase III trials are prepared by the AMC Group 
Statistician with support from the AMC ODMC. A written report containing the current status of 
each trial monitored, and when appropriate, any toxicity and outcome data, are sent to DSMB 
members by the AMC ODMC within the timelines specified by the AMC DSMB Charter. This 
report addresses specific toxicity concerns as well as concerns about the conduct of the trial. The 
report may contain recommendations for consideration by the DSMB concerning whether to close 
the trial, report the results, or continue accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair to 
the Group Chair and AMC ODMC. The DSMB report contains recommendations on whether to 
close each study reviewed, whether to report the results, and whether to continue accrual or 
follow-up. A primary recommendation (e.g., continue with no change; recommended or required 
modification; stop) must be included in the document. The Group Chair is then responsible for 
notifying the Protocol Chair and relevant Disease-oriented Working Group Chair before the 
recommendations of the DSMB are carried out. In the unlikely event that the Protocol Chair does 
not concur with the DSMB, then the NCI Division Director or designee must be informed of the 
reason for the disagreement. The Study Chair, relevant Disease-oriented Working Group Chair, 
Group Chair, DSMB Chair, and NCI Division Director or designee will be responsible for 
reaching a mutually acceptable decision about the study. CTEP approval of a formal amendment 
will be required prior to any implementation of a change to the study. 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site. It is each site’s responsibility for conveying this information to its 
IRB. 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis. For trials monitored by 
NCI’s Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring 
that participating investigators comply with the protocol requirements for adverse event reporting. 
All AMC investigators certify compliance with NCI and FDA requirements for adverse event 
reporting by signing the AMC Adherence Statement for site membership, the protocol signature 
page for each protocol active at the site, and Form FDA-1572 for CTEP investigator registration 
and IND studies sponsored by AMC investigators. Investigators are responsible for identifying 
and reporting all adverse events to the AMC ODMC, CTEP-AERS, and/or sponsors according to 
the protocol requirements, and assuring compliance with reporting to the local IRB. Protocol 


 
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compliance with adverse event reporting requirements is assessed by the AMC ODMC during 
routine site monitoring visits by reviewing the site’s source documentation. 
The data entry system used for AMC studies, AdvantageEDCSM (a web-based data entry and 
enrollment system), is programmed to notify the site investigator, protocol chair, and AMC 
ODMC via email in the event that a site reports an adverse event that meets expedited reporting 
criteria to NCI and/or FDA. If the site does not follow with a CTEP-AERS report, the AMC 
ODMC contacts sites to request an expedited report. Additionally, the protocol chair, AMC 
ODMC, and the AMC Medical Monitor review reported adverse events on a routine basis to 
identify adverse events reported by sites that require expedited reporting via CTEP-AERS. The 
Protocol Chair, AMC Group Chair, and IND sponsors have general oversight for assuring that 
routine and expedited adverse reporting requirements are met by the responsible parties. 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible 
for the Grant 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options. For phase I and II trials, the 
Protocol Chair also has the option of asking the AMC DSMB to review the study. The AMC 
ODMC will inform the CTEP Protocol Information Office (PIO) when studies are temporarily or 
permanently closed. The Cancer Treatment and Evaluation Program (CTEP) of the National 
Cancer Institute (NCI) must approve all protocol amendments prior to distributing to the AMC 
sites. 
Plans for Assuring Data Accuracy and Protocol Compliance 
All study data for AMC clinical trials are entered directly by AMC site staff into 
AdvantageEDCSM. During data entry, the system performs validation checks on many fields and 
performs consistency checks between select fields. Range checks are placed on each field to 
eliminate entry of out-of-range values. Edit check programs are run on the database on a set 
schedule to identify and resolve inconsistencies between forms or data collected at different 
points in time. AMC ODMC staff routinely interacts with site staff to resolve any data problems. 
In accordance with NCI guidelines, the AMC ODMC conducts monitoring visits at the AMC 
sites to evaluate compliance with regulatory issues, and to review data for specific cases by 
checking source documents. These reports are sent to the site Principal Investigator and to the 
NCI. In the event that major violations are identified, sites are asked to provide a plan to correct 
deficiencies within 30 days. If needed, a repeat site visit is conducted. In the event that a site does 
not correct deficiencies in a pre-determined time frame, the AMC Executive Committee has the 
option of taking action against the site. Possible actions include, but are not limited to, suspending 
enrollment of new participants to AMC trials until deficiencies are corrected; recommending a 
decrease in funding to the site; and requiring specific training for site investigators or staff 
members. 


 
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APPENDIX VI: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) SPECIMEN 
PREPARATION AND SHIPPING INSTRUCTIONS 
A. 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 
cc. The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. 
These shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The 
following instructions below are for use with the recommended STP-210 shipper. If using 
another federally approved diagnostic shipper, please follow instructions provided for 
that specific shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an 
OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON 
SATURDAYS OR SUNDAYS in the GWU/ACSR Lab. 
B. 
SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
Blood specimens 
Draw two 8.5 cc (ml) yellow top [acid citrate dextrose (ACD) solution A] tubes from 
study participant. With a black, water resistant, sharpie pen, label each specimen with the 
following information: 
1. AMC Protocol #087 
2. AMC Participant ID#  
3. Date and time of collection  
4. Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue 
5. Specimen purpose: Donation 
Specimen shipment 
1. Seal the tops of the two 8.5 cc yellow tops with parafilm. 
2. Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
3. Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
4. Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal.” 
5. Place poly-bag containing tubes into the white TYVEK bag and seal. 
6. Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the 
cardboard shipper with clear packing/shipping tape. 
7. Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT.” 
8. Mark “OTHER” in the airbill under “Packaging.” Please use FedEx #: 352207845. 
9. Under 
airbill 
section 
“Special 
Handling” 
indicate 
“YES-SHIPPERS 
DECLARATION NOT REQUIRED.” 
10. Place “From/To” information onto areas provided on the shipper. 


 
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Blood specimens should be shipped by overnight express at room temperature to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
Ross Hall, Room 118 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
 
11. Make certain that shipper is already either pre-labeled with the “UN#3373” stamp, or 
make a paper label with “UN#3373” and affix it to the shipper. 
12. Make certain that the net volume of the specimen being shipped is written in the 
space provided on the shipper or make a separate label with the volume in ml and 
affix to the shipper. 
13. Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
14. RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
15. Place the box in the FedEx pickup area at your site or call to request a package 
pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON THURSDAY AND 
FRIDAY: 
C. 
PREPARATION OF PLASMA AND MONONUCLEAR CELLS 
It is preferable that separation occurs as soon as possible. If necessary, whole blood in 
ACD (yellow top tubes) can be held at room temperature for no more than 24 hours. 
Plasma and PBMC should be separated according to the AMC Biorepository’s SOP on 
Separation of Plasma and Mononuclear Cells, available on the AMC Operations web site. 
Freeze the cell suspension in 0.5 ml aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires the 
use of packaging acceptable for dry ice and Class 9 label with weight of dry ice written 
on package. 


 
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D. 
PREPARATION OF TISSUE SAMPLES 
Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice 
immediately. The specimens may stay on dry ice until being transferred to a -80ºC 
freezer. 
Tissue specimens for donation may be batched for shipping after storage in -80ºC freezer. 
Allowable shipment days are Monday through Thursday. Shipping frozen tissue requires 
the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
TISSUE specimens should be shipped by overnight express to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I Street, NW 
Room 202 
Washington, DC 20037 
Phone: (202) 994-2945 
Fax: (202) 994-5056 
E. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments. 


 
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APPENDIX VII: ACSR INFORMED CONSENT 
Study Title for Study Participants: 
Collecting Blood and Tissue Sample Donations for 
Research for HIV/AIDS-Related Cancers 
Official Study Title: 
Biospecimen Collection and Donation to the AIDS  
and Cancer Specimen Resource (ACSR) 
What is the usual approach to donate blood and/or tissue to the ACSR? 
You are being asked to donate blood and/or tissue for future research. You are being asked to 
donate your blood and/or tissue samples to the ACSR because you have HIV infection and are 
being considered for participation in an AIDS Malignancy Consortium (AMC) clinical trial. The 
AMC works with the ACSR to collect donated samples from persons with HIV infection for 
research studies. People who do not take part in an AMC clinical trial can also donate samples to 
the ACSR. 
What are my other choices if I do not take part in this study? 
It is your choice to donate or not donate your blood and/or tissue samples. You may still take 
part in the AMC clinical study if you choose not to donate blood or biopsy samples to the ACSR.  
You may also choose to donate: 
1. Blood but not tissue, or 
2. Tissue but not blood. 
What is the AIDS and Cancer Specimen Resource (ACSR)? 
The ACSR is a biorepository (biobank) that collects human biological specimens (samples) from 
persons who have HIV or cancers related to HIV/AIDS. The ACSR stores the samples and some 
of the donor’s medical information for use by researchers in future research studies. The 
National Cancer Institute (NCI) has set up the ACSR to assist researchers locate samples needed 
for their studies. 
The ACSR has an independent research panel that approves researchers’ requests to use the 
ACSR’s stored samples for research studies. The ACSR only gives samples and medical 
information to researchers after their projects have been approved. Researchers may use the 
samples to study cancers and other diseases associated with HIV disease. This information may 
help us learn more about the causes of HIV-related diseases and cancers and to develop better 
ways to screen, diagnose, and treat them. 
Why is this study being done? 
The purpose of this study is to collect samples for the ACSR for future research studies. 
Researchers may study samples from the ACSR in combination with hundreds or thousands of 
other samples to explore how biologic or genetic factors may be related to HIV-related diseases 
and cancer. The information might help doctors in the future to identify who will or will not 
benefit from treatment. The samples may be used to learn more about how HIV-related diseases 
and cancers develop. The samples may also lead to new tests or discoveries. Finally, researchers 
may use the samples to study the genetic material from your cancer tissue and compare it to the 
material from your normal tissue (blood) to try to find the differences that exist. These studies 
could make it possible to identify many of the changes that are associated with diseases such as 


 
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cancers. It may also help us tailor treatments to a patient's unique genetic make-up and/or to the 
genetic markers of the tumors. 
What extra tests and procedures will I have if I take part in this study? 
1. If you agree to donate blood, the medical team will draw about 2 tablespoons of blood to give 
to the ACSR. This takes about 10 minutes. 
2. If you agree to donate tissue, your leftover tissue biopsy material will be donated to and 
stored by the ACSR. 
3. Some of your clinical information will be released to the ACSR and entered into their 
database. The information given to the ACSR will not include your name or any information 
that could personally identify you. 
We will only give the ACSR tissue that is left over after making decisions about your treatment 
or diagnosis. The study doctor will not take any extra biopsies just for the ACSR. 
We cannot tell you right now what future research these samples would be used for. Instead, we 
are asking that you give approval to give your samples for future testing without contacting you 
again. The results of whatever research is done on your samples will not be told to you or your 
doctor. The results of the tests will not be placed in your study records. 
How long will ACSR keep my samples? 
Your blood and/or tissue sample will be stored until it is used for research. The samples may be 
stored indefinitely. 
What possible risks can I expect from taking part in this study? 
1. Blood Draw: The risks of drawing blood include temporary discomfort from the needle stick, 
bruising, and, rarely, infection. 
2. Confidentiality: The ACSR will receive study samples with code numbers. There will be no 
personal identifiers on the samples. Then the samples will be re-labeled with a barcode and 
stored for future testing. While the ACSR and researchers who study ACSR samples will 
have no information that could identify you. 
Let your study doctor know of any questions you have about these possible risks. You can ask 
the study doctor questions about side effects at any time. 
What possible benefits can I expect from taking part in this study? 
This study is unlikely to help you. This study may help us learn things that may help people in 
the future. 
The information may help to identify those who are at increased risk and those who may benefit 
from targeted treatment and screening. In turn, these studies could help find ways to prevent or 
improve treatments for HIV-related diseases and AIDS-related cancers. 
Can I stop taking part in this study? 
Yes, you may withdraw your samples from the ACSR at any time. You may contact your AMC 
study coordinator if you would like to withdraw your samples. The coordinator can ask in 
writing that your sample be removed from research use and that any identifiable sample and 


 
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information still in their possession be destroyed. However, if any research has already been 
done using some of your samples, the data will be kept and analyzed as part of those studies. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
What are the costs of taking part in this study? 
There will be no cost to you for donating your samples to the ACSR. You will not be paid for 
taking part in this study. 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The AMC will not offer to pay for medical treatment for injury. 
Your insurance company may not be willing to pay for study-related injury. If you have no 
insurance, you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to seek 
payment for injury even though you are in a study. 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
1. The AIDS Malignancy Consortium (AMC) 
2. The Institutional Review Board, IRB, is a group of people who review the research with the 
goal of protecting the people who take part in the study. 
3. The Office for Human Research Protections and the National Cancer Institute in the U.S. 
To protect your privacy, the AMC does not keep identifying information that links study 
participants to specific samples. As a result, the AMC and ACSR will not be able to link the 
results from studies that use your samples back to you. Thus, information, including genetic 
information, that researchers may obtain in studies that use your samples may not be directly 


 
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linked to you and will not be placed in your medical record. However, some clinical and basic 
information obtained confidentially from the AMC will be attached with these data. It is possible 
that findings may one day help, for example, people of the same race or sex as you. It also is 
possible that genetic factors might come to be associated with people who have HIV and cancer 
through these kinds of studies. 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies 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). 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
Please circle your answer to show whether or not you would like to take part in each option: 
1). I agree to donate my blood to the ACSR for future research that may be used to learn about, 
prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
NO 
2). I agree to donate my blood to the ACSR for future research that may include genetic testing 
to learn about, prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
NO 
3). I agree to donate some of my tissue biopsy material that is not required for my treatment or 
diagnosis to the ACSR for future research that may be used to learn about, prevent, diagnose, 
or treat HIV-related diseases and cancer. 
YES 
NO 
4). I agree to donate some of my tissue biopsy material to the ACSR for future research that may 
include genetic testing to learn about, prevent, diagnose, or treat HIV-related diseases and 
cancer. 
YES 
NO 
My Signature Agreeing to Take Part in the Study 
I have been given a copy of this form. I have read it or it has been read to me. All of my questions 
have been answered to my satisfaction. I have also talked it over with the doctor to my 
satisfaction. I understand that my/the participant’s participation is voluntary. 
 
______________________________________ 
_________________________________ 
Participant’s Name (print) 
 
 
 
Signature and Date 


 
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Statement of professional obtaining consent 
I have fully explained this research study to the participant or guardian of participant. In my 
judgment and the participant’s or guardian’s, there was sufficient access to information, including 
risks and benefits to make an informed decision. 
 
______________________________________ 
_________________________________ 
Name of Professional Obtaining Consent (print) 
Signature and Date 
 


 
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APPENDIX VIII: PARTICIPANT MEDICATION DIARY/CALENDAR 
 
PARTICIPANT’S MEDICATION DIARY – CABOZANTINIB 
 
Today’s date __________________ 
Agent _______Cabozantinib ___________ 
Participant Name_____________________ (initials acceptable) 
Participant Study ID _______________ 
 
INSTRUCTIONS TO THE PARTICIPANT: 
1. Complete one form for each 4 week-period while you take cabozantinib. 
2. You will take your dose of cabozantinib each day in the morning for 4 weeks. You will take ____ 20 mg tablets and ____ 60 mg tablets 
every morning. DO NOT MAKE UP ANY MISSED DOSE, just wait until the next day before taking the next dose. 
3. Medication must be taken on an empty stomach. Participants must fast for 2 hours before and 1 hour following each dose of cabozantinib. 
4. Wash hands immediately after touching the tablet(s). 
5. Record the date, the number of tablets of each size you took, and when you took them.  
6. If you have any comments or notice any side effects, please record them in the Comments column.  
7. Please return this form to your physician when you go for your next appointment. 
Day 
Date 
Time of daily dose 
Check () if taken 
on empty stomach 
(see instruction #3). 
# of tablets taken 
Comments 
20 mg 
60 mg 
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AMC Protocol #___________ 
 


 
AMC #087 (Version 11.0) 18APR2019 
 
112 
NCI Version Date 18APR2019 
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Physician’s Office must complete this section: 
1. 
Date participant started protocol treatment____________________________________________________________________ 
2. 
Date participant was removed from study_____________________________________________________________________ 
3. 
Participant’s planned total daily dose________________________________________________________________________ 
4. 
Total number of tablets taken this month________________________________________________________ 
5. 
Total number of tablets returned________________________________________________________ 
6. 
Physician/Nurse/Data Manager’s Signature ________________________________________________________________