Conditions: Carcinoma, Renal Cell
Keywords: Renal Cell Carcinoma RCC Personalized therapy targeted inhibitors
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This is for subjects with metastatic Renal Cell Cancer (RCC). There are four Food and Drug Administration (FDA) approved drugs for first-line therapy of Renal Cell Cancer (RCC) and two for second-line therapy. Each of these drugs targets a specific molecular pathway. At present oncologists select therapy based on current guidelines. There is a new method for trying to use biomarker information from the subject's tumor to select the best drug to treat the subject. This process is investigational, which is why this study is being done.

Biomarkers are genes, proteins and other molecules that affect how cancer cells grow, multiply, die and respond to other compounds in the body. These biomarkers build a tumor profile or "fingerprint" of the subject's tumor. A new focus in cancer care is personalized treatment, where doctors select a drug based on the subject's tumor's unique "fingerprint" which is more likely to be effective in fighting the tumor. Selecting the treatment the subject is more likely to respond to requires a thorough understanding of the relationship between biomarker and treatment effect. The PI wants to gather data to understand that relationship to help treat future cancer patients. The purpose of this study is to evaluate efficacy of treatments that are selected based on tumor profiles.

Detailed description:
This will be a prospective, one-arm, proof of concept study designed to evaluate the efficacy of algorithm-based allocation (based on genomic/proteomic profile) of first-line therapy in renal cell carcinoma (RCC).

After eligibility review, patients will receive one of the four first-line therapy agents based on their tumor's molecular profile as determined using fresh biopsy tissue from an accessible metastatic site. Upon disease progression, patients will then receive one of two second-line agents based on their tumor's molecular profile.

Because this is a proof-of-concept study, the sample size is based on feasibility of accrual. The clinic should be able to recruit 100 patients within a reasonable timeframe for the study. The number of patients receiving each drug will vary based on the frequency of molecular alterations in the population. Therefore, groups will not be compared with one another - the research goal is to determine whether the progression-free survival (PFS) for each drug is improved over the PFS reported in FDA approval trials for each drug when they are assigned based on molecular analysis.

Arms:
arm 1: Subjects will receive one of the four first-line therapy agents based on their tumor's profile. The first-line agents are sunitinib, temsirolimus, sorafenib, or pazopanib. These are all routine drugs for RCC treatment and will be given at their approved doses and dosing schedules.

Upon disease progression, subject's tumor(s) will be biopsied again to create another tumor profile. The second-line agents are everolimus or axitinib. Both of these are routine drugs for RCC treatment and will be given at their approved doses and dosing schedules.

Interventions: intervention 1: Sunitinib intervention 2: Temsirolimus intervention 3: Sorafenib intervention 4: Pazopanib intervention 5: Everolimus intervention 6: Axitinib
Intervention descriptions: intervention 1: One 50-mg capsule taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off intervention 2: 25 mg by an IV infusion over 30-60 minutes, once a week intervention 3: 400 mg (2 tablets) orally twice daily without food intervention 4: 800 mg orally once a day without food, at least 1 hour before or 2 hours after a meal intervention 5: 10 mg orally once daily with or without food intervention 6: 5 mg orally twice daily

Protocol document:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-14-0665 
IRB APPROVAL DATE: 08/11/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Targeting of Renal Cell Cancer with Specific Inhibitors: A Model for Selective Adaptive 
Medicine Based on Molecular Alterations 
 
 
NCT02560012 
 
              Version Date: 08/11/2016 
 
 


IRB NUMBER: HSC-MS-14-0665 
IRB APPROVAL DATE: 08/11/2016 
 
Targeting of Renal Cell Cancer with Specific Inhibitors: A Model for Selective Adaptive 
Medicine Based on Molecular Alterations 
 
 
 
Clinical Protocol No. GU-14-102 
 
 
 
Principal Investigator: 
Robert Amato, D.O. 
Professor, Department of Internal Medicine, Division of Oncology 
 
 
 
Co-Investigators: 
 
Interventional Radiology 
Alan Cohen, M.D. 
The University of Texas Health Science Center at Houston 
 
Diagnostic Radiology 
Varaha S. Tammisetti, M.D. 
The University of Texas Health Science Center at Houston 
 
Eduardo Matta, M.D. 
The University of Texas Health Science Center at Houston 
 
Collaborators: Reynolds 
Brobey, Ph.D. Postdoctoral 
Research Fellow, 
The University of Texas Health Science Center at Houston 
 
 
 
Mehdi Dehghani, Ph.D. 
Research and Development Director, CompanionDx Reference Laboratory 
 
Nwabugwu S. Ochuwa, Pharm.D., BCOP 
Clinical Specialist in Oncology, UT Memorial Hermann Cancer Center 
 
 
 
Version 1: October 3, 2014 
Version 2: May 10, 2016 
Version 3: July 14, 2016 
 
 
 
The study is to be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP) and other applicable regulatory requirements. 
 
Signature:  
 
Date:  
 
Robert Amato, D.O. 


IRB NUMBER: HSC-MS-14-0665 
IRB APPROVAL DATE: 08/11/2016 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................2 
LIST OF ABBREVIATIONS ........................................................................................................5 
SYNOPSIS .................................................................................................................................7 
1 
BACKGROUND ............................................................................................................11 
1.1 
Current and Novel Response Assessment Methodologies (Figure 1)..........................11 
1.2 
PRELIMINARY STUDIES ...........................................................................................13 
1.2.1 
Background On Therapeutic Agents ....................................................................15 
2 
OBJECTIVES................................................................................................................16 
2.1 
Primary .......................................................................................................................16 
3 
PATIENT ELIGIBILITY .................................................................................................17 
3.1 
Inclusion Criteria .........................................................................................................17 
3.2 
Exclusion Criteria ........................................................................................................18 
4 
STUDY DESIGN ...........................................................................................................19 
4.1 
DETERMINATION OF MOLECULAR ALTERATIONS ................................................19 
4.1.1 
First-Line Molecular Targeted Agents ..................................................................20 
4.1.2 
Gene Mutation Detection and mRNA Expression Profiling Using NGS ................23 
4.1.3 
Proteomics...........................................................................................................23 
4.2 
First-Line Therapy.......................................................................................................24 
4.3 
Second-Line Therapy..................................................................................................25 
4.4 
Dosing ........................................................................................................................26 
4.5 
Definition of End of Study............................................................................................26 
5 
VISIT SCHEDULE AND ASSESSMENTS ....................................................................26 
5.1 
Study Flow ..................................................................................................................26 
5.1.1 
Schedule of Assessments (See Appendix D) .......................................................26 
5.1.2 
Screening ............................................................................................................27 
5.1.3 
Treatment Period .................................................................................................27 
5.2 
Tumor Assessment .....................................................................................................29 
5.2.1 
Safety ..................................................................................................................29 
6 
REMOVAL FROM STUDY ............................................................................................29 
6.1 
Off-Treatment .............................................................................................................29 
6.2 
Off-Study ....................................................................................................................29 
7 
SAFETY MONITORING AND REPORTING..................................................................30 
7.1 
Adverse Events...........................................................................................................30 
7.2 
Adverse Event Definition.............................................................................................30 
7.3 
Evaluating Adverse Events .........................................................................................30 
7.3.1 
Determination of Severity.....................................................................................31 
7.3.2 
Determination of Relatedness ..............................................................................31 
7.4 
Serious Adverse Events..............................................................................................32 
7.5 
Reporting ....................................................................................................................32 
8 
7.6 
Unanticipated Problem Reporting ...............................................................................33 
DATA AND PROTOCOL MANAGEMENT ....................................................................33 
8.1 
Protocol Compliance ...................................................................................................33 
8.2 
Data Collection ...........................................................................................................33 
8.3 
Database Management...............................................................................................34 
9 
8.4 
Site Monitoring ............................................................................................................34 
STATISTICAL CONSIDERATIONS ..............................................................................34 
9.1 
Study Design ..............................................................................................................34 
9.2 
Analysis of Primary Endpoint ......................................................................................34 
9.3 
Interim Analysis and Monitoring ..................................................................................35 


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10 
ETHICAL CONSIDERATIONS......................................................................................35 
10.1 
Ethical Compliance .....................................................................................................35 
10.2 
IRB Review .................................................................................................................35 
10.3 
Recruitment ................................................................................................................35 
10.4 
Informed Consent .......................................................................................................36 
10.5 
Confidentiality .............................................................................................................36 
10.6 
Publication of Study Results .......................................................................................37 
10.7 
Retention of Documents..............................................................................................37 
11 
REFERENCES ..............................................................................................................38 
12 
APPENDIX A: NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 41 
13 
APPENDIX B: ECOG Performance Status..................................................................42 
14 
APPENDIX C: RECIST 1.1 Guidelines ........................................................................43 
15 
APPENDIX D: SCHEDULE OF ASSESSMENTS .........................................................44 
16 
APPENDIX E: DRUG INFORMATION ..........................................................................47 
16.1 
Everolimus ..................................................................................................................47 
16.2 
Sunitinib ......................................................................................................................47 
16.3 
Sorafenib ....................................................................................................................47 
16.4 
Temsirolimus ..............................................................................................................48 
16.5 
Pazopanib...................................................................................................................48 
16.6 
Axitinib ........................................................................................................................49 
16.7 
Cabozatinib.................................................................................................................49 
16.8 
How Supplied..............................................................................................................49 
16.8.1 
Everolimus ...........................................................................................................49 
16.8.2 
Sunitinib ...............................................................................................................49 
16.8.3 
Sorafenib .............................................................................................................50 
16.8.4 
Temsirolimus .......................................................................................................50 
16.8.5 
Pazopanib............................................................................................................50 
16.8.6 
Axitinib .................................................................................................................50 
16.8.7 
Cabozatinib..........................................................................................................50 
16.9 
Storage .......................................................................................................................50 
16.9.1 
Everolimus ...........................................................................................................50 
16.9.2 
Sunitinib ...............................................................................................................50 
16.9.3 
Sorafenib .............................................................................................................50 
16.9.4 
Temsirolimus .......................................................................................................51 
16.9.5 
Pazopanib............................................................................................................51 
16.9.6 
Axitinib .................................................................................................................51 
16.9.7 
Cabozatinib..........................................................................................................51 
16.10 
Monitoring of Toxicities ............................................................................................51 
16.10.1 
Management of stomatitis/oral mucositis/mouth ulcers.....................................51 
16.10.2 
Management of nausea/vomiting......................................................................52 
16.10.3 
Management of anemia....................................................................................52 
16.10.4 
Management of diarrhea ..................................................................................52 
16.10.5 
Management of Hypertension...........................................................................52 
16.10.6 
Management of Fatigue (lethargy, malaise, asthenia) ......................................53 
16.10.7 
Management of infections ................................................................................53 
16.10.8 
Management of noninfectious pneumonitis.......................................................53 
16.10.9 
Management of thyroid dysfunction ..................................................................53 
16.10.10 
Hemorrhage/bleeding/coagulopathy .................................................................53 
16.10.11 
Venous thrombosis...........................................................................................54 
16.10.12 
Arterial thrombosis ...........................................................................................54 
16.11 
Management of Everolimus-specific toxicities .........................................................54 


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16.12 
Management of sunitinib-specific toxicities ..............................................................55 
16.13 
Follow-up for toxicities .............................................................................................56 
16.14 
Dose interruption for surgery or surgical procedures ...............................................56 
16.15 
Other concomitant medications ...............................................................................56 
16.15.1 
Everolimus .......................................................................................................57 
16.15.2 
Sunitinib ...........................................................................................................57 
16.15.3 
Sorafenib..........................................................................................................58 
16.15.4 
Temsirolimus ....................................................................................................58 
16.15.5 
Pazopanib ........................................................................................................58 
16.15.6 
Axitinib .............................................................................................................59 
16.15.7 
Cabozatinib ......................................................................................................59 
16.16 
STUDY MEDICATION COMPLIANCE ....................................................................59 
16.17 
References..............................................................................................................60 
17 
Appendix F: OBTAINING BIOPSY TISSUE FOR MOLECULAR DIAGNOSITCS .......61 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
Twice a day 
BP 
blood pressure 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood cell count 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CNS 
Central nervous system 
eCRF 
Electronic Case Report Form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IFN 
Interferon 
IL-6 
Interleukin-6 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
L 
Liter 
LDH 
Lactate dehydrogenase 
mL 
Milliliter(s) 
MRI 
Magnetic resonance imaging 
NGS 
Next-generation sequencing 
NCI 
National Cancer Institute 
NK (cell) 
Natural killer cell 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PFS 
Progression-free survival 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RCC 
Renal cell cancer 
SAE 
Serious adverse event 
TNF 
Tumor necrosis factor 


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Abbreviation 
Term 
ULN 
Upper limit of normal 
US 
United States 
VEGRF 
Vascular endothelial growth factor receptor 
WBC 
White blood cell count 


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SYNOPSIS 
 
Protocol number: 
Title: 
Targeting of Renal Cell Cancer with Specific Inhibitors: A Model for Se- 
lective Adaptive Medicine Based on Molecular Alterations 
Study Sites: 
Single center, US 
Patient Population: 
Renal cell cancer patients 
Number of Patients: 
100 
Study Duration: 
32 months 
Study Design: 
This will be a prospective, one-arm, proof of concept study designed to 
evaluate the efficacy of algorithm-based allocation (based on genom- 
ic/proteomic profile) of first-line therapy in renal cell carcinoma (RCC). 
After eligibility review, patients will receive one of the four first-line ther- 
apy agents based on their tumor’s genomic/proteomic profile. Upon dis- 
ease progression, patients will then receive one of two second-line 
agents based on their tumor’s genomic/proteomic profile. 
Because this is a proof-of-concept study, the sample size is based on 
feasibility of accrual. The clinic should be able to recruit 100 patients 
within a reasonable timeframe for the study. The number of patients 
receiving each drug will vary based on the frequency of molecular alte- 
rations in the population. Therefore, groups will not be compared with 
one another – our research goal is to determine whether the progres- 
sion-free survival (PFS) for each drug is improved over the PFS re- 
ported in FDA approval trials for each drug when they are assigned 
based on molecular analysis. 
Rationale 
Treatment for RCC is administered empirically. Administration of FDA- 
approved drugs based on results of testing for DNA, RNA, and protein 
markers should result in better outcomes for patients and reduce the 
burden of treatment relative to empiric therapy. 
Objectives: 
Primary 
 
Biomarker-guided selection of molecular-targeted agents for the 
treatment of renal cell carcinoma 
Dosing and Administration: 
See Appendix E 
Eligibility Criteria: 
Inclusion Criteria 
Subjects may be included in the study only if they meet all of the follow- 
ing inclusion criteria: 
 
Pathologically confirmed renal cell carcinoma. 
 
No prior systemic and/or investigative therapy of any kind. 
o Patients with primary tumor in place are strongly 
encouraged to undergo nephrectomy prior to initiation 
of study agent. 
o Prior palliative radiotherapy to metastatic lesion(s) is 
permitted. Patient must have adequately recovered 
from the acute toxicities of this treatment. 
o All major surgery of any type and/or radiotherapy must 
be completed at least 4 weeks prior to registration. 


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 
Must have progressive metastatic disease 
 
 
ECOG performance status ≤2 
 
 
Women of childbearing potential and male patients must use 
acceptable methods of contraception—tubal ligation, vasecto- 
my, barrier contraceptive with spermicide—while on study and 
for 3 months after the last dose of study therapy. Oral, implant- 
able, or injectable contraceptives may be affected by cytoch- 
rome P450 interactions, and are therefore not considered effec- 
tive for this study. 
 
 
Age ≥18 years 
 
 
Required Initial Laboratory Values: 
 
o Granulocytes 
≥1,500/µL 
 
o Platelet Count 
≥100,000/µL 
 
o Hemoglobin 
≥9 g/dL 
 
o AST/ALT 
≤ 2.5 times the upper limit of 
normal (ULN) 
 
o Alk. Phos. 
≤ 2.5 x ULN 
 
o Serum bilirubin 
≤ 1.5 x ULN 
 
o Amylase/Lipase 
within normal range 
 
o Urinalysis 
≤ 1+ protein 
 
o 
Pregnancy test for womenNegative 
 
o Serum creatinine 
≤ 1.5 x ULN 
 
o Electrocardiogram (ECG)  no active ischemia 
 
o Echocardiogram 
ejection fraction ≥40% 
 
o Pulmonary function tests 
 
o Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 
mmol/L AND fasting triglycerides ≤2.5 x ULN. NOTE: In 
case one or both of these thresholds are exceeded, the 
patient can only be included after initiation of appropri- 
ate lipid lowering medication. 
 
 
No clinical symptoms of hypothyroidism 
 
Signed informed consent prior to the performance of any study- 
specific procedures 
Exclusion Criteria 
 
Ongoing hemoptysis, or cerebrovascular accident within 12 
months prior to study entry, or peripheral vascular disease with 
claudication occurring upon walking less than one city block, or 
history of clinically significant bleeding. 
 
 
Deep venous thrombosis or pulmonary embolus within 12 
months prior to study entry and no ongoing need for full-dose 
oral or parenteral anticoagulation. For maintenance of catheter 
patency daily prophylactic aspirin or low-dose coumadin (1-2 
mg) is allowed. 
 
 
Evidence of current central nervous system (CNS) metastases. 


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All patients must undergo a CT scan of the brain (with contrast, 
if possible) within 42 days prior to registration. Any imaging ab- 
normality indicative of active CNS metastases will exclude the 
patient from the study. 
 
Significant cardiovascular disease defined as congestive heart 
failure (New York Heart Association Class II, II or IV) angina 
pectoris requiring nitrate therapy, or recent myocardial infarction 
(within the preceding 6 months prior to study entry). 
 
Uncontrolled hypertension (defined as blood pressure of ≥160 
mmHg systolic and/or ≥90 mmHg diastolic on medication). 
Document over 48 hours with minimum of 3 readings. 
 
Ongoing requirement for systemic corticosteroid therapy (ex- 
cept replacement therapy for adrenal insufficiency) or other im- 
munosuppressants are not permitted. Topical and/or inhaled 
steroids are allowed. 
 
Uncontrolled psychiatric disorder. 
 
Delayed healing of wounds, ulcers, and/or bone fractures. 
 
―Currently active‖ second malignancy other than non-melanoma 
skin cancers. Patients are not considered to have a ―currently 
active‖ malignancy if they have completed anti-cancer therapy 
and are considered by their physician to be a less than 30% risk 
of relapse. 
 
Pregnant or nursing. Because there is an unknown but potential 
risk for adverse events in nursing infants secondary to treat- 
ment of the mother, breastfeeding should be discontinued if the 
mother is treated. 
 
Other concurrent severe and/or uncontrolled medical disease 
which could compromise participation in the study (i.e., uncon- 
trolled diabetes, severe infection, severe malnutrition, ventricu- 
lar arrhythmias, chronic liver or renal disease, active upper GI 
tract ulceration). 
 
A known history of HIV seropositivity. 
 
Impairment of gastrointestinal function or gastrointestinal dis- 
ease that may significantly alter the absorption of oral molecular 
targeted agents (e.g., ulcerative disease, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome or small bowel re- 
section). 
Study Evaluations: 
Safety 
Safety will be assessed by vital sign measurements, clinical laboratory 
tests, physical examinations and the incidence and severity of adverse 
events (graded according to CTCAE v 4.0.). 
Anti-tumor Activity 
Anti-tumor activity will be assessed via PFS. Tumor response and pro- 
gression will be defined according to RECIST 1.1 criteria. 
Correlative studies 
Next-generation sequencing analysis using a specific RCC panel will be 
conducted to assess molecular alterations in patient samples. 


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Protocol Discontinuation Criteria: 
Off-treatment may occur due to one or more of the following (note: 
patients off-treatment should continue to be followed for all protocol 
assessments): 
 
Adverse event 
 
Progression of disease (compared to baseline assessment) 
 
Investigator decision 
 
Non-compliance with protocol 
Off-study may occur due to one or more of the following: 
 
Death 
 
Lost to follow-up 
 
Withdrawal of consent 
 
Completion of protocol study period 
 
Administrative study closure 
Statistical Methods 
Analysis of Primary Endpoint 
The primary endpoint will be PFS on both first-line and second-line 
therapy. The PFS is defined as the time elapsed between treatment 
initiation and tumor progression or death from any cause, with censor- 
ing of patients who are lost to follow-up. The median PFS will be deter- 
mined for each drug in both first-line and second-line therapy, and sur- 
vival curves will be plotted using the Kaplan-Meier method. PFS will be 
reported as median and 95% confidence interval. 
Analysis of the secondary endpoint, exploratory endpoints, and sub- 
group will be carried out using appropriate statistical methods and de- 
scriptive statistics. 
Interim Analysis and Monitoring 
The data will be reviewed by the expert committee after 50% of the pa- 
tients are enrolled. The committee will review safety and efficacy data. 
Ineffective treatment arms, if any, will be dropped. 


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1 
BACKGROUND 
Significant issues remain unanswered at key decision points in the management of patients with 
renal cell cancer (RCC). As many as 20%–30% of RCC patients who are treated surgically de- 
velop metastases. In addition, up to 50% of patients with RCC present with stage III (locally ad- 
vanced) or stage IV disease, and the 5-year survival rates for these patients are <2%.1 The ap- 
proval of molecular targeted agents for the treatment of advanced RCC has provided many the- 
rapeutic options. Improved understanding of cancer biology and advances in biotechnology in 
recent years have brought us ever closer to the concept of personalized treatment of RCC. A 
key component of personalized treatment is the development of biomarkers that can guide the 
application of new and existing treatments. This requires a thorough understanding of the rela- 
tionship between the biomarker and a treatment effect.2 
 
The goal of our multidisciplinary research program is to improve therapeutic outcomes in pa- 
tients with renal epithelial neoplasms by using a genomics and proteomics approach to detect 
mutational target abnormalities in these tumors and thus to improve therapeutic success by se- 
lecting the treatments most appropriate for an individual’s molecular profile. These gene and 
protein alterations can be classified into a number of clinically targetable pathways or functional 
groups: cell-cycle-associated factor alterations, PI3K/mammalian target of rapamycin (mTOR) 
pathway alterations, growth factor receptor alterations, or Ras/MAPK pathway alterations.1 
 
Targeted therapies have introduced a paradigm shift in the management of metastatic RCC. 
Efficacy and tolerability data for sunitinib, sorafenib, pazopanib, temsirolimus, everolimus, axiti- 
nib, and cabozatinib have provided pivotal first -and second-line data supporting the benefits of 
novel targeted therapies for the management of metastatic RCC. It is difficult to sort out the ra- 
tionale supporting the use of one first-line agent relative to another. It is even more challenging 
to identify a rationale for choosing the subsequent line of therapy. Sequencing schemes for pa- 
tients with clear cell or even non-clear cell histological subtype are generally chosen empirically, 
and it remains unknown which sequence(s) are more effective than others.2 
 
There are several issues of clinical importance that have not been adequately addressed to 
date regarding targeted therapy for RCC. (1) The optimum sequence of administration of effec- 
tive agents remains unknown. (2) Biomarkers known to be predictive of treatment response will 
be used for selecting treatments. (3) Biomarkers predictive of therapeutic effectiveness need to 
be established. Prognostic biomarkers separate patients into subgroups with expected failure 
risk and demonstrate that this separation can improve outcome by indicating the need for more 
aggressive treatment. Biomarker-assessed assignment is restricted to patients with the specific 
biomarker values. 
 
Traditionally, two important endpoints in clinical trials are tumor shrinkage (objective response) 
and time to disease progression (progression-free survival [PFS]). Targeted antiangiogenic 
therapy for metastatic RCC is cytostatic rather than cytotoxic, which results in decreased angi- 
ogenesis/tumor growth, therefore decreasing tumor enhancement but not significantly shrinking 
the tumor. RECIST 1.1 is a size-based response evaluation criteria; thus, there is poor correla- 
tion between response category assessed on RECIST 1.1 and clinical benefit from targeted 
therapy. Therefore, newer response assessments have been developed to incorporate changes 
in enhancement and development of necrosis rather than relying on tumor regression. This 
would help better discriminate patients with early tumor progression from those with progression 
free disease and increased survival.3-9 
 
1.1 
Current and Novel Response Assessment Methodologies (Figure 1) 


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._.•....._...,...n.i.._ 
......... ....
re po
 
 
RECIST 1.1- SIZE based 
CHOI criteria -SIZE OR DENSITY 
BASED 
 
 
 
Target 
I ions 
Imaging 
ca tegorie 
R    ponse   valua tion 
 
Ta rget 
I ion 
imaging  r    
ponse 
categories 
 
 
 
 
·Tumor ize 
IOmm 
-Maximum o/5 
larget lesions 
(maxlmum2 
P"rorgon) 
-Tumor    ze ;>15 
mm 
-Maximum of 10 
target  lesions 
-Portal phase 
-R   I 
 
 
Cool noc lnNt tht crltedl tot CR. PR 
or PO 
No aymptocn.toc dcotrriontion 
•ttn"bu....,.tonunorr 
 
 
Prugn' ..,\. •  _r 
 
"*"" .._.._ .. 
NII 
1 
 
 
 
 
 
 
Modified Choi criteria -SIZE and 
ENHANCEMENT 
SACT criteria -SIZE,DENSITY, 
ENHANCEMENT AND 3D 
VOLUMETRIC MEASUREMENTS 
 
 
Target 
l ions 
Imaging  
 Re ponse 
eva luation 
 
 
Targ  t 
lesions 
 
imaging 
response 
ca t gories 
 
 
Respon 
 
 
valuation 
 
 
 
 
Tu m or   ize15 
m m 
-Maxim um of 
10 targ II   i ns 
-A rterial phase 
-ROI 
 
-Tumor   ize 
10m m 
-Maximum 
oflO target 
lesions 
(maxim umS 
per organ) 
-P  rtal pha 
-VOl 
-Lung lesions 
were not 
measu red 
using VOl 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
:!'!: 
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Figure 1. Diagrams summarizing various response criteria used in response assessment to targeted an- 
tiangiogenic therapy in metastatic renal cell carcinoma. Reprinted from Blanca et al, Metastatic Renal Cell 
Carcinoma: Radiologic Findings and Assessment of Response to Targeted Antiangiogenic Therapy by 
using Multidetector CT, RadioGraphics 2013; 33:1691–1716 
 
 
Molecular profiling holds promise for guiding oncologists in the choice of individualized therapy 
for each patient. This profiling can be explored at different levels, such as the gene expression 
(genomics) and protein expression (proteomics) level. Each of these levels gives different but 
complementary information about the molecular characteristics of an individual tumor. The clini- 
cal applications of molecular profiling include categorizing prognosis, predicting treatment effi- 
cacy, and subgrouping of patients. Molecular profiling is the key to better understanding the init- 
iation and prognosis of RCC, which can lead to the development of targeted therapy options. 
 
 
1.2 
PRELIMINARY STUDIES 
Comprehensive analysis of the genome sequence of individual cancers has helped uncover the 
specific mutations that contribute to the malignant phenotype, identify new targets for therapy, 
and increase the opportunities for choosing the optimal treatment for each patient. Dividing each 
tissue sample into subtypes with unique molecular alterations associated with different out- 
comes and different responses to particular therapies will improve outcomes. 
 
Emerging preclinical evidence suggests that resistance is mediated via tumor and environmen- 
tal changes that enable continued perfusion and tumor growth that becomes less reliant on 
VEGF over time.10 Furthermore, elements downstream of receptor blockade, such as hypoxia- 


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inducible factor (HIF) and protein kinase B (Akt), in addition to pathways independent of VEGF 
or mTOR, could drive tumor growth despite adequate blockade of these targets. For example, 
von Hippel-Lindau (VHL) renal cysts can be precursors to RCC.11 The VHL gene encodes a tu- 
mor suppressor protein (pVHL) that interacts with HIF, a ―master regulator‖ of many genes.12 
The inactive form of the VHL gene is linked to tumor development through loss of pVHL. Thus, 
loss of pVHL is a key signaling event leading to tumor progression in RCC that involves multiple 
growth factors.13,14 
 
These considerations provide a rational basis for sequential therapy targeting these escape 
elements. Specifically, drugs targeting VEGF ligand and its downstream effectors, including the 
VEGF receptor 2 and PI3K-mTOR, have become the cornerstone of renal cancer treatment. 
Understanding these key molecular pathways implicated in the tumorigenesis of RCC has crys- 
tallized in the development of more effective therapies (Figure 2). We will concentrate on sur- 
veying the targets and attendant pathways of the following drugs and their effects on interre- 
lated and downstream signaling molecules: first-line therapies approved for metastatic RCC, 
including Sorafenib (a Raf kinase inhibitor),15 Sunitinib (inhibits VEGFR2, PDGF receptor 
[PDGFR], FMS-like tyrosine kinase 3 [FLT-3], and c-Kit; down-regulates the expression of p- 
STAT3; and inhibits T regulatory cells and myeloid-derived suppressor cells),16 Temsirolimus 
(highly specific for inhibition of mTOR kinase),17 and Pazopanib (inhibits a broad spectrum of 
kinases, including VEGFR1-3, PDGFR-α and -β, and c-Kit).18 Approved second-line therapies 
include Everolimus (highly specific for inhibition of mTOR kinase),19 Axitinib (an inhibitor of 
VEGFR1-3, PDGF receptor, and cKIT),20 and Cabozatinib (an inhibitor of the tyrosine kinases 
MET, VEGF receptors, AXL, and RET).21 
 
 
 
 
We hypothesize that assessing the functionality and activity of key cancer signaling proteins can 
identify biomarkers that will assist oncologists in selecting the most appropriate therapy for indi- 
vidual patients. We further propose that detecting driver mutations, gene expression profiling, 
and evaluating the activity of involved signaling proteins will permit a better understanding of the 


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key signaling networks associated with cancer cell survival, uncontrolled cell growth, metastas- 
es, and therapeutic resistance; this information could be used to more accurately predict patient 
outcomes. 
 
Previous studies have indicated that the tissue of origin may be less relevant to response to 
therapy and prognosis than the causative mutations from a metastatic site. Therefore, we will 
collect tissue throughout the trial and incorporate a real-time assessment of biomarkers to assist 
in directing therapy. This is particularly important in RCC, which is often treated with a sequence 
of agents. Repeated testing of tissues will provide evidence supporting the best order in which 
to administer treatment agents. 
 
1.2.1 Background On Therapeutic Agents 
Table 1. Approval studies for RCC drugs. 
 
Drug 
Development 
stage 
Approval 
trial 
Targets 
PFS, 
mos. 
Setting 
Reference 
Sorafenib 
Approved 
Phase III: vs. 
placebo 
VEGFR1-3, 
PDGFR, Kit, 
FLT3, RET, 
RAF 
5.5 
Second line, 
ccRCC after 
cytokines 
15 
Sunitinib 
Approved 
Phase III: vs. 
IFN-α 
VEGFR1-3, 
PDGFR, Kit, 
FLT3, RET 
11 
First line, 
ccRCC 
16 
Temsirolimus 
Approved 
Phase III: 
alone vs. IFN- 
α vs. plus 
IFN-α 
mTOR 
5.5 
First line, 
poor prog- 
nosis, any 
histology 
17 
Pazopanib 
Approved 
Phase III: vs. 
placebo 
VEGFR1-3, 
PDGFR, Kit 
9.2 
First line, 
ccRCC 
18 
Axitinib 
Approved 
Phase III: vs. 
sorafenib 
VEGFR1-3, 
PDGFR, Kit 
4.8 
Second line, 
after TKI or 
cytokines 
19 
Everolimus 
Approved 
Phase III: vs. 
placebo 
mTOR 
4 
After TKI 
progression 
or intoler- 
ance 
20 
Cabozatinib 
Approved 
Phase III: vs. 
everolimus 
MET, 
VEGFRs, 
AXL, RET 
7.4 
After TKI 
progression, 
ccRCC 
21 
ccRCC, clear cell renal cell carcinoma 
 
 
 
By treating based on molecular alterations instead of pathology, we will be applying rational 
treatment assignment to less-prevalent forms of RCC such as papillary and chromophobic 
types. Non-clear cell RCCs are under-studied, and effective treatment options for this population 
are lacking. 
 
The successful accomplishment of this proposal has the potential to yield treatment algorithms 
for rational treatment selection that assign the optimal treatment to the optimal patient, using 
FDA-approved agents and assigning them based on individual tumor markers. This treatment 
optimization would benefit patients directly by improving outcome as well as by decreasing ex- 
posure to toxic yet ineffective agents. Administering the molecular targeted agent(s) most likely 
to be effective for each patient has the additional benefit of also decreasing their economic 


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health burden. Successful proof of our concept has the promise for application to other solid tu- 
mors. 
 
 
 
2 
OBJECTIVES 
 
2.1 
Primary 
Biomarker-guided selection of molecular-targeted agents for the treatment of RCC 
(Figure 3) 
 
 
Assess efficiency of algorithm-based allocation to treatment in first-line and second-line 
treatment of metastatic renal cell carcinoma, using progression free survival as the pri- 
mary endpoint 
o Molecularly characterize initial metastatic biopsy to choose a first-line targeted 
agent 
o Upon tumor progression, obtain a second metastatic biopsy to determine ac- 
quired resistance and adaption in molecular alterations and select the appropri- 
ate second-line agent for treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. Biomarker-guided treatment selection 
 
 
Prospectively compare RECIST 1.1 with MASS criteria and 3D segmentation and quanti- 
fication on follow-up scans to assess which criteria or parameter performs better in iden- 
tifying progressive disease. 
o We hypothesize that the degree of enhancement on pre-treatment imaging could 
prospectively predict response to antiangiogenic therapy and PFS 


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o We hypothesize that degree of response on the first post-therapy scan by MASS cri- 
teria and 3D quantification could identify early response assessment of an antiangi- 
ogenic effect, which could serve as a biomarker to prospectively predict PFS 
 
3 
PATIENT ELIGIBILITY 
 
3.1 
Inclusion Criteria 
 
 
Pathologically confirmed renal cell carcinoma. 
 
 
No prior systemic and/or investigative therapy of any kind. 
 
o Patients with primary tumor in place are strongly encouraged to undergo 
nephrectomy prior to initiation of study agent. 
 
o Prior palliative radiotherapy to metastatic lesion(s) is permitted. Patient must 
have adequately recovered from the acute toxicities of this treatment. 
 
o All major surgery of any type and/or radiotherapy must be completed at least 4 
weeks prior to registration. 
 
 
Must have progressive metastatic disease 
 
 
ECOG performance status ≤2 
 
 
Women of childbearing potential and male patients must use acceptable methods of 
contraception; tubal ligation, vasectomy, barrier contraceptive with spermicide while on 
study and for 3 months after the last dose of study therapy. Oral, implantable, or injecta- 
ble contraceptives may be affected by cytochrome P450 interactions, and are therefore 
not considered effective for this study. 
 
 
Age ≥18 years 
 
 
Required Initial Laboratory Values: 
 
o 
o 
Granulocytes 
Platelet Count 
≥1,500/µL 
≥100,000/µL 
o 
o 
Hemoglobin 
AST/ALT 
≥9 g/dL 
≤2.5 x upper limit of normal (ULN) 
o 
o 
o 
Alk. Phos. 
Serum bilirubin 
Amylase/Lipase 
≤2.5 ULN 
≤1.5 x ULN 
within normal range 
o 
o 
Urinalysis 
Pregnancy test for women 
≤1+ protein 
Negative 
o 
o 
o 
Serum creatinine 
Electrocardiogram (ECG) 
Echocardiogram 
≤1.5 x ULN 
no active ischemia 
ejection fraction ≥40% 
o Pulmonary function tests 


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o Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglyce- 
rides ≤2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, 
the patient can only be included after initiation of appropriate lipid lowering medi- 
cation. 
 
 
No clinical symptoms of hypothyroidism 
 
Signed informed consent prior to the performance of any study-specific procedures 
 
3.2 
Exclusion Criteria 
 
 
Ongoing hemoptysis, or cerebrovascular accident within 12 months prior to study entry, 
or peripheral vascular disease with claudication occurring upon walking less than one 
city block, or history of clinically significant bleeding. 
 
 
Deep venous thrombosis or pulmonary embolus within 12 months prior to study entry 
and no ongoing need for full-dose oral or parenteral anticoagulation. For maintenance of 
catheter patency daily prophylactic aspirin or low-dose coumadin (1-2 mg) is allowed. 
 
 
Evidence of current central nervous system (CNS) metastases. All patients must under- 
go a CT scan of the brain (with contrast, if possible) within 42 days prior to registration. 
Any imaging abnormality indicative of active CNS metastases will exclude the patient 
from the study. 
 
 
Significant cardiovascular disease defined as congestive heart failure (New York Heart 
Association Class II, II or IV) angina pectoris requiring nitrate therapy, or recent myocar- 
dial infarction (within the preceding 6 months prior to study entry). 
 
 
Uncontrolled hypertension (defined as blood pressure of ≥160 mmHg systolic and/or ≥90 
mmHg diastolic on medication). Document over 48 hours with minimum of 3 readings. 
 
 
Ongoing requirement for systemic corticosteroid therapy (except replacement therapy for 
adrenal insufficiency) or other immunosuppressants are not permitted. Topical and/or in- 
haled steroids are allowed. 
 
 
Uncontrolled psychiatric disorder. 
 
 
Delayed healing of wounds, ulcers, and/or bone fractures. 
 
 
―Currently active‖ second malignancy other than non-melanoma skin cancers. Patients 
are not considered to have a ―currently active‖ malignancy if they have completed anti- 
cancer therapy and are considered by their physician to be a less than 30% risk of re- 
lapse. 
 
 
Pregnant or nursing. Because there is an unknown but potential risk for adverse events 
in nursing infants secondary to treatment of the mother, breastfeeding should be discon- 
tinued if the mother is treated. 
 
 
Other concurrent severe and/or uncontrolled medical disease which could compromise 
participation in the study (i.e., uncontrolled diabetes, severe infection, severe malnutri- 
tion, ventricular arrhythmias, chronic liver or renal disease, active upper GI tract ulcera- 
tion). 
 
 
A known history of HIV seropositivity. 
 
 
Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of oral molecular targeted agents (e.g., ulcerative disease, uncon- 
trolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). 


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4 
STUDY DESIGN 
 
4.1 
DETERMINATION OF MOLECULAR ALTERATIONS 
We will assess biopsy samples using a targeted panel sensitive to the known pathways listed in 
Table 1 (see also Appendix E). All patients will undergo molecular alterations testing. Then, 
based on the results, we will select the most appropriate drug for first-line therapy of RCC. Once 
each patient’s disease progresses, we will use their second biopsies to determine which mark- 
ers are present in the evolved tumor and assign second-line treatment accordingly. 
 
Molecular profiling of tumor samples will follow two lines of assessment: genomics (next- 
generation sequencing [NGS]) and proteomics (selected reaction monitoring [SRM]) mass spec- 
trometry analyses. A targeted genomic and proteomic panel actionable in RCC will be used to 
determine molecular alterations in metastatic biopsy samples (Table 2). 
 
Table 2. Panel of actionable alterations 
 
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4.1.1 First-Line Molecular Targeted Agents 
 
The tyrosine kinases cause the phosphorylation of tyrosine residues that initiate cellular signal- 
ing pathways to promote cell survival, proliferation and angiogenesis. There are three small mo- 
lecule inhibitors of tyrosine kinases that have been Food and Drug Administration approved for 
use in metastatic RCC based on clinical evidence of efficacy in several recent trials: sorafenib, 
sunitinib, and pazopanib. 
The mTOR pathway can be activated in tumor cells by a variety of mechanisms, including those 
that enhance the PI3K/Akt signaling pathway (e.g., PTEN loss or activated receptor TK signal- 


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ing). In RCC, activation of PI3K signaling, regardless of mechanism, might sensitize tumors to 
mTOR inhibitors. mTOR inhibitors have direct antitumor activity by arresting cells in the G1 
phase of the cell cycle and increasing apoptosis, as well as enhancing the transcriptional activity 
of HIF. In addition, mTOR inhibitors suppress HIF transcription levels in tumor cells, thus reduc- 
ing VEGF expression and tumor angiogenesis through a VHL-independent mechanism.22 In en- 
dothelial cells, vascular smooth muscle cells, and pericytes, VEGFR signaling activates mTOR 
kinase.22 Treatment with mTOR inhibitors has been shown to reduce VEGF-stimulated endo- 
thelial cell proliferation and migration. An important difference from targeting the VEGFR signal- 
ing pathway directly appears to be that mTOR inhibition appears to have increased activity 
against the more mature vasculature of the tumor (Figure 4). 
 
4.1.1.1   Tyrosine Kinase Inhibitors 
Sorafenib is a Raf kinase inhibitor. Activation of the ras oncogene signaling pathway is consi- 
dered to be an important mechanism by which human cancer develops. Raf kinase is a down- 
stream effector protein in the Ras signal transduction pathway. Ras regulates several pathways 
which synergistically induce cellular transformation, including the Raf/Mek/extracellular signal- 
regulated kinase (ERK) cascade and the rac and rho pathways.15,23 In particular, Ras activates 
the Raf/Mek pathway by first localizing Raf to the plasma membrane, where Raf initiates a mito- 
genic kinase cascade. Activated Raf phosphorylates and activates Mek, which in turn phospho- 
rylates and activates ERK. Activated ERK then translocates from the cytoplasm into the nucleus 
and modulates gene expression via the phosphorylation of transcription factors. Thus activation 
of Raf kinase, via activation of Ras, is thought to play an important role in carcinogenesis. B- 
Raf, a serine/threonine kinase, has been shown to be activated in RCC. Sorafenib inhibits the 
receptor tyrosine kinases (RTK) VEGFR2, VEGFR3, FLT-3, c-Kit, and PDGFR as well as the 
non-receptor serine threonine kinases BRAF and CRAF. The BRAF and CRAF kinases are 
members of the Raf/Mek/ERK signaling cascade, which is involved in survival and proliferation 
of tumor cells and is a therapeutic cancer target. Additionally, sorafenib down regulates the ex- 
pression of activated (phosphorylated) STAT3 which also has implications regarding the expan- 
sion of T regulatory (suppressor) cells that could reduce anti-tumoral immune surveillance. The 
recommended dose of sorafenib is 400 mg orally twice daily. 
Sunitinib and Pazopanib Tumor VEGF expression has been associated clinically with disease 
prognosis in many different types of malignancies, including RCC. VEGF expression is elevated 
by diverse stimuli that include proto-oncogene activation and hypoxia, the latter frequently aris- 
ing in solid tumors because of inadequate perfusion. In addition to its angiogenic role, VEGF 
also has a profound permeabilizing effect on the vasculature which may also contribute to tumor 
progression. A leaky tumor endothelium enhances nutrient catabolite exchange and represents 
less of a barrier to tumor cell intravasation during metastasis. Two high-affinity receptors for 
VEGF with associated tyrosine kinase activity have been identified on human vascular endothe- 
lium; VEGFR1/Flt-1 and VEGFR2/kinase insert domain-containing receptor (KDR). Although the 
relative contributions of KDR and Flt-1 signaling in mediating tumor progression have not been 
elucidated, a number of studies suggest that KDR performs a predominant role. In addition to 
VEGF receptor signaling, increasing evidence implicates PDGF receptor signaling in tumor an- 
giogenesis. Recent preclinical evidence suggests that inhibition of PDGFR signaling augments 
the antitumor and anti-angiogenesis effects of VEGFR inhibitors. In addition, PDGF signaling is 
implicated in the autocrine growth of tumor cells, and in the recruitment and regulation of tumor 
fibroblasts. 
Sunitinib inhibits the RTK VEGFR2, PDGFR, FLT-3, and c-Kit. Sunitinib also down-regulates 
the expression of p-STAT3, similar to sorafenib, and inhibits T regulatory cells and myeloid- 
derived suppressor cells. The latter would be expected to enhance anti-tumoral immune surveil- 


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Figure 4. mTOR pathway 
4.1.1.3   Tyrosine kinase inhibitor 
Axitinib binds to VEGFR1-3 and inhibits them, thereby preventing the formation
vessels.20,27 It has highly specific action against VEGFR (and not other receptors
targeted by other tyrosine kinase inhibitors). This specificity means that axitinib c
tered at a slightly lower dose and has fewer adverse reactions. A dose of 5 mg g
is the recommended dose; patients able to tolerate it can be given up to 10 mg p 
Cabozatinib inhibits the tyrosine kinases MET, VEGF receptors, AXL, and RET
are up-regulated in RCC as a consequence of VHL inactivation, and high expres
associated with poor prognosis.28,29 Increased expression of MET and AXL has a
cated in the development of resistance to VEGFR inhibitors in preclinical models
cers, including RCC.21 A dose of 60 mg orally, once daily, is the recommended d 
 
lance. A dose of 50 mg given orally once per day for 4 weeks on with a 2-week rest is the rec- 
ommended dose.16,24 
Pazopanib has a broad spectrum of kinase inhibition, including VEGFR1-3, PDGFR-α and -β, 
and c-Kit. A dose of 800 mg given orally once per day is the recommended dose.18,25 
 
4.1.1.2   mTOR pathway inhibitor 
Temsirolimus is an analogue of rapamycin that inhibits the mTOR pathway (Figure 4) by bind- 
ing to ubiquitous intracellular protein termed FK506-binding protein-12 (FKBP12); this complex 
then binds to mTOR to inhibit cell growth by disrupting G-to-S phase progression along the 
S6K1 pathway and to inhibit cell proliferation by inhibiting mTOR-dependent protein translation 
along the 4E-BP1 pathway.26 These two inhibitory actions result in decreased tumor growth and 
increased cell apoptosis associated with suppression of the mTOR/Hif-1α/VEGF pathway.17 A 
dose of 25 µg once weekly is the recommended dose.17,26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of new blood 
, such as c-KIT, 
an be adminis- 
iven twice daily 
er dose.27 
MET and AXL 
sion of each is 
lso been impli- 
of several can- 
ose.30 
 
 
 
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4.1.1.4   mTOR pathway inhibitor 
Everolimus is, like temsirolimus, an analogue of rapamycin (Figure 3). Everolimus works along 
three pathways of action.19 (1) It inhibits cell growth and proliferation by reducing expression of 
proteins (such as Hif and VHL) that regulate the cell cycle. (2) It inhibits cell metabolism by de- 
creasing the activity of cell nutrient transporters via the PI3K-Akt-TSC1/2 pathway, thus reduc- 
ing the ability of cells to take up nutrients. (3) It reduces angiogenesis by inhibiting the growth of 
proliferation factors and preventing the release of VEGF and other angiogenic factors. A dose of 
10 mg given orally once daily is the recommended dose.19,31 
 
4.1.2 Gene Mutation Detection and mRNA Expression Profiling Using NGS 
 
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4.1.3 Proteomics 
 
Our targeted proteomics approach (SRM or multiple SRM [MRM]) is a non-scanning mass spec- 
trometry technology that can quantify both proteins and their post-translational modifications, 
such as phosphorylation. This technique enables the direct measurement of peptides derived 
from intact proteins without the need for antibodies or other affinity reagents;32,33 several groups 
have used this approach to target cellular signaling molecules and their regulation by phospho- 
rylation to understand signaling networks. Our Center for Clinical Proteomics has significant ex- 
perience designing SRMs for signaling molecules in fresh/frozen tissues and in biofluids. We 
are already using this technique with LMD cancer cells to couple quantitative protein measure- 
ments and activation profiles with morphology on the same patient specimens as above. 
Though our team has experience with these assays, we have been working with Expression 
Pathology, Inc. to develop assays to signaling molecules within archival, FFPE tissues from the 
patients as they have patented methods for working with fixed tissues. This approach will be 
used to complement the studies described above, adding quantitative data to the morphological 
information and providing assays for particular proteins and activation sites when immunological 
reagents are not available for key markers. 
Our SRM-based targeted strategy utilizes morphologic analysis (from LMD), quantitative pro- 
teomics, and high target specificity to discern the state of activation of signal transduction path- 
ways in tumor cells and companionate tissues. Sequence and phospho-specific assays are de- 
signed in silico and directed against putative sites of activation of a signaling protein. The 
unique LMD system we have developed uses conventional hematoxylin-eosin staining and a 
nonglass coverslip to ensure high-quality morphological assessment for selecting diagnostic 
cells from tissue sections cut from formalin-fixed, paraffin-embedded patient tissues. Stained 


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tissues mounted without coverslips often exhibit degraded morphology, which prevents accurate 
dissection of the desired cells. In addition, although a general region of a tumor can be dis- 
sected using approaches other than LMD, image-oriented, cell-specific correlations cannot be 
made from such dissections. In addition, digital images of target cells are captured during our 
LMD process; they are then annotated and stored for later correlation with SRM measurements. 
Our newly developed technique enables the selection of immunofluorescently labeled cells us- 
ing fluorescent optics and the coverslip system to couple subcellular marker expression with ac- 
curate marker quantification or with downstream signaling patterns. 
 
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4.2 
First-Line Therapy 
 
It is hypothesized that a more effective treatment protocol can be obtained and applied to pa- 
tients based on molecular alterations and the use of known targeted agents that inhibit the TK- 
dependent pathways or the mTOR-dependent pathways. A molecular targeted agent for each 
patient will be selected based on their molecular alteration profile; patients will receive that mo- 
lecular targeted agent and undergo radiographic evaluation according to RECIST criteria to de- 
termine response. The radiographic staging evaluation will be performed at baseline; restaging 
images will be obtained after two 6-week periods of sunitinib treatment or after two 8-week pe- 
riods for temsirolimus, sorafenib, or pazopanib treatment, then every 12 weeks thereafter in all 
patients (Figure 5, Table 3). 
 
 
 
 
Figure 5. Selection of first-line targeted therapy in patients with metastatic RCC based on molecular alterations. 
 
Table 3. Algorithm for individualized first-line therapy 


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Drug, Mechanism 
Reference 
First-line treatment 
Pazopanib 
18 
VEGFR1–3 
PDGFR 
Kit 
Sunitinib 
16 
VEGFR1–3 
Predominantly VEGFR2 (KDR) 
PDGFR 
Kit 
Flt3 
RET 
STAT3 
Sorafenib 
15 
VEGFR1–3 
PDGFR 
Kit 
Flt3 
RET 
B-Raf, C-Raf 
Temsirolimus 
17 
mTOR 
B-Raf and C-Raf, signal transduction protein kinases of the Raf kinase family; Flt, Fms-like tyrosine ki- 
nase; Kit, a stem cell signaling pathway; mTOR, mammalian target of rapamycin; PDGFR, platelet- 
derived growth factor receptor; RET, rearranged during transfection (an oncogene); STAT, signal trans- 
ducer and activator of transcription; VEGFR, vascular endothelial growth factor receptor 
 
Similar testing will be performed on biopsies obtained after disease progression. Samples will 
undergo molecular analysis to determine molecular alterations and adaptations conferring 
treatment resistance. Depending on the molecular alterations found, patients will be assigned 
second-line therapy with everolimus, axitinib, or cabozatinib. 
 
4.3 
Second-Line Therapy 
 
Upon radiographic progression after first-line therapy, we will obtain a second metastatic biopsy 
and, based on molecular alterations second-line therapy with the next molecular targeted agent 
(everolimus, axitinib, or cabozatinib) will be selected. This will allow us to determine the appro- 
priate second-line treatment based on the mechanisms of acquired resistance and adaptation. 
Based on RECIST criteria to determine response, radiographic evaluation will be performed af- 
ter two 8-week periods of treatment and every 12 weeks thereafter in all patients (Figure 6, Ta- 
ble 4). 


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Figure 6. Selection of second-line targeted therapy in patients with metastatic RCC based on molecular alterations. 
 
Table 4. Algorithm for individualized second-line therapy 
 
Drug, Mechanism 
Reference 
Axitinib 
19 
VEGFR1–3 
PDGFR 
Kit 
Everolimus 
20 
mTOR 
Cabozatinib 
21 
MET 
VEGFRs 
AXL 
RET 
Second-Line Molecular Targeted Agents 
 
4.4 
Dosing 
 
See Appendix E for dosing regimen, modifications, concomitant medications, and drug supply. 
 
4.5 
Definition of End of Study 
 
Upon progression after second-line therapy, each patient will undergo a third metastatic biopsy. 
Molecular analysis of the current biopsy will be compared to the previous molecular profiles to 
determine the acquired resistance and adaptation pathways. This has the potential for further 
discovery of new therapeutic agents and further use of existing molecular targeted agents. 
 
 
5 
VISIT SCHEDULE AND ASSESSMENTS 
 
5.1 
Study Flow 
 
5.1.1 Schedule of Assessments (See Appendix D) 
 
Evaluations during the entire study will consist of the following: 
• 
Complete history including histologic confirmation of RCC and disease staging. 
• 
Physical examination including vital signs, height, weight. 
• 
ECOG Performance Status. 


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•       Imaging and diagnostic studies. 
•       Hematology, coagulation, and chemistry studies. 
•       Urinalysis. 
•       Fasting triglycerides and cholesterol. 
•       β-HCG (females of childbearing potential). 
 
These assessments should be performed within ±3 days of the scheduled day of assessment. 
Every effort should be made to ensure that the protocol required tests and procedures are com- 
pleted as described. However, it is anticipated that from time to time there may be circums- 
tances, outside of the control of the investigator that may make it unfeasible to perform the test. 
In these cases, the investigator will take all steps necessary to ensure the safety and well-being 
of the patient. When a protocol-required test cannot be performed the investigator will document 
the reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. 
 
5.1.2   Screening 
 
The screening assessments will be performed within 28 days prior to receiving study medica- 
tion: 
 
• 
Signed informed consent 
• 
Vital signs 
• 
Concomitant medications assessment 
• 
Medical History: Includes histologic confirmation of malignancy, and best response(s), 
if applicable. Patient information will be entered into the Memorial Sloan-Kettering 
Cancer Center prognostic model (refer to J Clin Oncol, July 1999). 
• 
Physical Examination: Includes height, weight. A full neurologic examination (mental 
status, cranial nerves, motor, reflexes, sensory, gait, cerebella) will be performed at 
baseline only. 
• 
ECOG Performance Status: Refer to ECOG Performance Status Criteria. 
• 
Hematology Profile: Includes CBC with differential and platelets. 
• 
Coagulation Profile: Includes PT, INR, and PTT. 
• 
Chemistry Profile: Includes total protein, uric acid, BUN, creatinine, LDH with isoen- 
zymes, AST, ALT, alkaline phosphatase with isoenzymes, phosphorus, magnesium, 
total bilirubin, calcium, albumin, and glucose. 
• 
Electrolytes: sodium, potassium, chloride, and bicarbonate. 
• 
TSH level. 
• 
Amylase/lipase. 
• 
Miscellaneous Tests: VEGF, IL-6, TNF-α, C-reactive protein, sedimentation rate 
• 
Fasting triglycerides and cholesterol. 
• 
Cardiac Profile: Includes EKG and echocardiogram. 
• 
Pulmonary Profile: Includes spirometry with DLCO. 
• 
Pregnancy screening test: Includes beta-HCG pregnancy test within 7 days of the first 
treatment for females of childbearing potential 
• 
Urinalysis: Includes routine measurements. A microscopic analysis will be conducted 
pretreatment. Subsequent microscopic analyses will be done only if clinically indicated. 
• 
Imaging and Diagnostic Studies: CT of the chest and abdomen with IV contrast in ar- 
terial phase or CT of the abdomen and pelvis with IV contrast in portal venous phase. 
 
5.1.3   Treatment Period 


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All study visits beyond screening, including study drug administration and safety laboratory 
evaluations must be obtained within ±3 days of the day specified in the protocol schedule. 
 
• 
Hematology Profile: CBC, differential, and platelets will be obtained weekly for the first 
6-8 weeks, then every 2 weeks. 
 
• 
Chemistry Profile: Total protein, uric acid, BUN, creatinine, LDH with isoenzymes, 
AST, ALT, alkaline phosphatase with isoenzymes, phosphorus, magnesium, total bili- 
rubin, calcium, albumin, and glucose will be obtained weekly for the first 6-8 weeks, 
then every 2 weeks. 
 
• 
Electrolytes: sodium, potassium, chloride, and bicarbonate will be obtained weekly for 
the first 6-8 weeks, then every 2 weeks. 
 
• 
Amylase/lipase will be obtained every 4 weeks. 
 
• 
VEGF, IL-6, TNF-α, C-reactive protein, and sedimentation rate will be obtained at each 
restaging. 
 
• 
Fasting triglycerides and cholesterol will be obtained every 4 weeks. 
 
• 
TSH level will be obtained every 6-8 weeks. 
 
• 
Urinalysis will be obtained every 4 weeks. 
 
• 
Cardiac and pulmonary function tests as clinically indicated. 
 
• 
Tumor restaging will be performed every 8 weeks (twice) for patients receiving temsi- 
rolimus, sorafenib, pazopanib, axitinib, everolimus, or cabozatinib and every 6 weeks 
(twice) for those receiving sunitinib and every 12 weeks thereafter. 
 
• 
Interim history and exam with performance status and weight will be recorded every 2 
weeks for the first 4 weeks, then every 4 weeks thereafter. 
 
• 
Information regarding drug dosages, laboratory examinations and treatment related 
toxicities will be recorded before each treatment cycle is given. 
 
• 
Since all of the drugs in this trial are standard of care, there may be instances when 
subjects will receive their treatment at other infusion centers as well as their standard 
blood draws due to insurance network provider determinations, cost, etc. Dr. Amato 
will work closely with referring physicians and infusion centers. The lab results and 
clinic/infusion notes will be obtained and reviewed by Dr. Amato. All subjects will still 
come to the cancer center for restaging study visits. 
 
Evaluations 30 (±3) Days after Last Dose of Study Therapy or Withdrawal from The Study 
 
• 
Interim history and physical examination. 
• 
Adverse event assessment. 
• 
Hematology Profile: CBC with differential, platelet count. 
• 
Coagulation Profile: PT, INR, and PTT. 
• 
Chemistry Profile: Total protein, uric acid, BUN, creatinine, LDH with isoenzymes, 
AST, ALT, alkaline phosphatase with isoenzymes, phosphorus, magnesium, total bili- 
rubin, calcium, albumin, and glucose. 
• 
Electrolytes: sodium, potassium, chloride, and bicarbonate. 
• 
TSH level. 
• 
Fasting triglycerides and cholesterol. 
• 
Amylase/lipase. 
• 
Urinalysis. 


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• 
Vital Signs, ECOG performance status. 
 
5.2 
Tumor Assessment 
 
Disease assessments must be performed as scheduled according to the study schedule. As- 
sessment may be performed more often as clinically indicated. Tumor response and progres- 
sion will be defined according to RECIST 1.1 criteria (See Appendix C). 
 
In addition to the RECIST 1.1 evaluation for response assessment on each of the scans, MASS 
criteria would also be used to assign response category without affecting the treatment algo- 
rithm . Additionally a novel 3D quantification of enhancing tumor and necrotic tumor volume and 
percentage would be assessed on a separate 3D workstation for target lesions and the res- 
ponses on the above 2 criteria would be compared to the findings on 3D volumetry. 
 
Type of assessment 
Criteria 
Size based 
RECIST 1.1 
Size, Density, Enhancement, Morphology and 
Structure (Qualitative and semi-quantitative) 
MASS criteria 
MASS plus 3D volumetry (Qualitative and 
Quantitative) 
3D Segmentation and Quantification of 
enhancing tumor and necrotic tumor vo- 
lumes and density 
 
5.2.1   Safety 
 
Safety will be assessed by monitoring vital signs, clinical laboratory tests, physical examinations 
and the incidence and severity of adverse events (graded according to CTCAE v 4.0.). Investi- 
gators must document their review of laboratory reports by initialing and dating each report, as 
well as addressing the clinical significance (for significant abnormalities). 
 
6         REMOVAL FROM STUDY 
 
It will be documented whether or not each patient completed the clinical study. Reasons for dis- 
continuation will be recorded as follows: 
 
6.1      Off-Treatment 
May occur due to one or more of the following (note: patients off-treatment should con- 
tinue to be followed for all protocol assessments): 
 
Adverse event(s) 
 
Abnormal laboratory value(s) 
 
Disease progression (compared to baseline assessment) 
 
Investigator decision 
 
Non-compliance with protocol 
 
6.2      Off-Study 
May occur due to one or more of the following: 
 
Death 
 
Lost to follow-up 


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 
Withdrawal of consent 
 
Completion of protocol study period 
 
Administrative study closure 
 
 
 
7         SAFETY MONITORING AND REPORTING 
 
The investigator will monitor each patient for clinical and laboratory evidence of adverse events 
on a routine basis throughout the study following the NCI Common Terminology Criteria for Ad- 
verse Events (CTCAE), Version 4.0. A link to the electronic version of the CTCAE can be found 
in Appendix A. The investigator will assess and record any adverse event (serious and non- 
serious) in detail on the adverse event form including the date of onset, description, severity, 
time course, duration, outcome and relationship to the study drug from the time the patient signs 
the informed consent until 4 weeks after the patient has stopped study treatment. 
 
7.1      Adverse Events 
 
All adverse events (AEs) should be treated appropriately. Such treatment may include interrup- 
tion or discontinuation of study drug, starting or stopping concomitant treatments, changes in 
the frequency or nature of assessments, hospitalization, or any other medically required inter- 
vention. 
 
Information about common side effects already known about the study drug can be found in Ap- 
pendix E and package inserts. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed. 
 
7.2      Adverse Event Definition 
 
An AE is defined as any unintended or undesirable, noxious, or pathological change, compared 
to pre-existing conditions, experienced by a patient during a clinical study or the follow-up pe- 
riod, regardless of relationship to study drug. AEs include: 
    Suspected adverse drug reactions. 
    Reactions from drug overdose, abuse, withdrawal, sensitivity, or toxicity. 
 
Significant changes or abnormalities, when compared to baseline, in structure (sign), 
function (symptom), clinical laboratory results, or physiological testing. This includes any 
worsening of a pre-existing condition temporally associated with the use of study drug. 
 
Other medical events, regardless of their relationship to the study drug, such as injury, 
surgery, accidents, extensions of symptomatology, or apparently unrelated illnesses. 
 
7.3      Evaluating Adverse Events 
 
Each AE will be evaluated to determine: 
    the severity grade (mild, moderate, severe) or (grade 1-4) 
    its relationship to the study drug(s) (suspected/not suspected) 
    its duration (start and end dates or if continuing at final exam) 
 
action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
    outcome 
    whether it constitutes a serious adverse event (SAE) 


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7.3.1   Determination of Severity 
 
The severity of AEs will be assessed according to CTCAE, Version 4.0. If the AE is not defined 
in the CTCAE, the Investigator will determine the severity of an adverse event based on the fol- 
lowing definitions: 
 
Mild (Grade 1): The AE is noticeable to the patient but does not interfere with routine 
activity. The AE does not require discontinuing administration or reducing the dose of the 
study drug. 
 
Moderate (Grade 2): The AE interferes with routine activity but responds to symptomatic 
therapy or rest. The AE may require reducing the dose but not discontinuing administration 
of the study drug. 
 
Severe (Grade 3): The AE significantly limits the patient’s ability to perform routine activities 
despite symptomatic therapy. In addition, the AE leads to discontinuing administration or 
reducing the dose of the study drug. 
    Life-Threatening (Grade 4): The AE requires discontinuing administration of the study drug. 
The patient is at immediate risk of death. 
 
 
7.3.2   Determination of Relatedness 
 
The Investigator will determine the relatedness of an adverse event with the study drug based 
on the following definitions: 
 
Not Related 
This category applies to those adverse events which, after careful medical consideration, are 
felt to be due to extraneous causes (disease, environment, etc.) that are not related to the ad- 
ministration of study drug. 
 
Probably Not Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are 
clearly felt unlikely to be related to the administration of the study drug. The relationship of an 
adverse event to the study drug can be considered probably not related if: 
    It does not follow a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
    It does not follow a known response pattern to the suspected drug. 
    It does not reappear or worsen when the drug is readministered. 
 
Possibly Related (must have first two bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are 
felt unlikely to be related to the administration of the study drug, but the possibility cannot be 
ruled out with certainty. The relationship of an adverse event to the study drug can be consi- 
dered possibly related if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could readily have been a result of the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
    It follows a known response pattern to the suspected drug. 


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Probably Related (must have first three bullets below) 
This category applies to those adverse events which, after careful medical consideration, are 
felt with a high degree of certainty to be related to the administration of the study drug. The rela- 
tionship of an adverse event to the study drug can be considered probably related if: 
    It follows a reasonable temporal sequence from administration of the drug. 
    It could not be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the patient. 
    It disappears or decreases upon cessation of drug or reduction in dose.* 
    It follows a known response pattern to the suspected drug. 
 
Definitely Related (must have first three bullets below) 
This category applies to those adverse events, which, after careful medical consideration, are 
felt to be related to the administration of the drug. The relationship of an adverse event to the 
study drug can be considered definitely related if: 
 
It follows a reasonable temporal sequence from administration of the drug or drug levels 
have been established in body fluids or tissues. 
    It could not be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors or other modes of therapy administered to the patient. 
 
It disappears or decreases upon cessation of drug or reduction in dose and, if applicable, 
appears upon rechallenge.* 
    It follows a known response pattern to the suspected drug. 
 
*There are exceptions when an adverse event does not disappear upon discontinuation of the 
drug, yet drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug eruptions. 
 
7.4      Serious Adverse Events 
 
Information about all serious adverse events (SAEs) will be collected and recorded. A SAE is an 
undesirable sign, symptom or medical condition which: 
    is fatal or life-threatening 
    results in persistent or significant disability/incapacity 
    constitutes a congenital anomaly/birth defect 
 
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
  routine treatment or monitoring of the studied indication, not associated with any deteri- 
oration in condition (specify what this includes) 
  elective or pre-planned treatment for a pre-existing condition that is unrelated to the indi- 
cation under study and has not worsened since the start of study drug 
  treatment on an emergency outpatient basis for an event not fulfilling any of the definitions 
of a SAE given above and not resulting in hospital admission 
  social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
 
is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
 
7.5      Reporting 
 
The principal investigator has the obligation to report all serious adverse events to the IRB and 
DSMB according to their  respective requirements. 


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Serious Adverse Events (SAE) that are determined by the PI to be unexpected + related will be 
submitted to the DSMB within 7 calendar days of the determination by telephone or fax; written 
report no later than 15 calendar days of the determination.  Deaths should be reported to the 
IRB within 24 hours of investigator knowledge.  Any unexpected, serious, related adverse expe- 
riences should be reported to the IRB within 7 calendar days of investigator knowledge. 
 
Any pregnancy that occurs during study participation should be reported. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details of 
birth, and the presence or absence of any birth defects, congenital abnormalities or maternal 
and newborn complications. 
 
7.6      Unanticipated Problem Reporting 
 
The Principal Investigator (PI) must notify the IRB of unexpected problems that might arise dur- 
ing the study within 7 calendar days. The PI is must make a judgment call regarding the expec- 
tedness and causality of the problem. Examples include: 
 
any adverse event which in the opinion of the PI is both unexpected and related and places 
patients or others at risk of harm 
    Protocol deviation that harmed patients or placed patients in increased risk of harm 
    Unanticipated adverse device effect 
    A breach of confidentiality 
 
Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a 
research protocol 
    Information that indicates a change to the risks or potential benefits of the research 
 
 
 
8         DATA AND PROTOCOL MANAGEMENT 
 
8.1      Protocol Compliance 
 
Written informed consent must be obtained from the patient prior to study specific screening 
tests or procedures. Results of all baseline evaluations which assure that all inclusion and ex- 
clusion criteria have been satisfied, must be reviewed by the Investigator prior to enrollment of 
that patient. The investigator and/or research coordinator must see each patient prior to drug 
administration. All required interim and pre-treatment data should be available and the investi- 
gator must have made a designation as to tumor response and toxicity grade. The Principal In- 
vestigator will be the final arbitrator of response or toxicity should a difference of opinion exist. 
 
8.2      Data Collection 
 
Investigators or their designee must enter the data required by the protocol onto Case Report 
Forms (CRFs). A brief explanation for required but missing data should be recorded as a com- 
ment. The Principal Investigator is ultimately responsible for assuring that data entered into the 
CRFs are accurate, authentic/original, attributable, complete, consistent, legible, timely (con- 
temporaneous), enduring and available when required. 
 
Entries made in the CRF must be either verifiable against source documents, or have been di- 
rectly entered into the CRF, in which case the entry in the CRF will be considered as the source 
data. Any corrections to entries made in the CRFs or source documents must be dated, initialed 


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and explained (if necessary) and should not obscure the original entry. The Investigator will sign 
the CRFs to indicate that, to his/her knowledge, they are complete and accurate. 
 
8.3 
Database Management 
 
The data manager will review the CRF data entered by study staff for completeness and accu- 
racy. Data queries stating the nature of the problem and requesting clarification will be created 
for discrepancies and missing values and sent to the study coordinator. The study coordinator 
will respond promptly to queries and make any necessary changes to the CRFs. 
 
8.4 
Site Monitoring 
 
To ensure that the protocol and Good Clinical Practices (GCP) are being followed and that 
study data are accurate, complete and reliable, the trial will be monitored by a Data Safety 
Monitoring Board (DSMB), Medical Monitor and CRA monitoring as specified in the Data Safety 
Monitoring Plan (DSMP) for the study and the DSMB’s charter. 
 
Through ongoing monitoring the designee will periodically check the patient data recorded in the 
CRFs against source documents, to ensure accuracy, completeness, and adherence to the pro- 
tocol, regulatory compliance, and the maintenance of comprehensive clinical records. The study 
coordinator will provide access to source documents to perform this verification. 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design 
 
 
This will be a prospective, one-arm, proof of concept study designed to evaluate the efficacy of 
algorithm-based allocation (based on genomic/proteomic profile) of first-line therapy in RCC. 
 
After eligibility review, patients will receive one of the four first-line therapy agents based on 
their tumor’s genomic/proteomic profile. Upon disease progression, patients will then receive 
one of two second-line agents based on their tumor’s genomic/proteomic profile. 
 
Because this is a proof-of-concept study, the sample size is based on feasibility of accrual. The 
clinic should be able to recruit 100 patients within a reasonable timeframe for the study. Number 
of patients receiving each drug will vary based on the frequency of molecular alterations in the 
population. Therefore, groups will not be compared with one another – our research goal is to 
determine whether the PFS for each drug is improved over the PFS reported in FDA approval 
trials for each drug when they are assigned based on molecular analysis. 
 
9.2 
Analysis of Primary Endpoint 
 
 
The primary endpoint will be progression-free survival (PFS) on both first-line and second-line 
therapy. The PFS is defined as the time elapsed between treatment initiation and tumor pro- 
gression or death from any cause, with censoring of patients who are lost to follow-up. The me- 
dian PFS will be determined for each drug in both first-line and second-line therapy, and survival 
curves will be plotted using the Kaplan-Meier method. PFS will be reported as median and 95% 
confidence interval. 
 
Analysis of the secondary endpoint, exploratory endpoints, and subgroup will be carried out us- 
ing appropriate statistical methods and descriptive statistics. 


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9.3      Interim Analysis and Monitoring 
The data will be reviewed by the expert committee after 50% of the patients are enrolled. The 
committee will review safety and efficacy data. Ineffective treatment arms, if any, will be 
dropped. 
 
10       ETHICAL CONSIDERATIONS 
 
10.1    Ethical Compliance 
 
The study will be conducted in accordance with legal and regulatory (21 CFR 50, 56, 312 as 
applicable) requirements, as well as the general principles set forth in the Guidelines for GCP 
(ICH 1996) and the Declaration of Helsinki (World Medical Association 1996 and 2008). 
 
The principal investigator is responsible for ensuring that all participating staff members are 
adequately trained and competent to perform his/her assigned tasks. 
 
10.2    IRB Review 
 
Before implementing this study, the protocol, the proposed informed consent form, and other 
required information, must be reviewed and approved by a properly constituted Institutional Re- 
view Board (IRB). Any amendments to the protocol, other than administrative ones, must be re- 
viewed and approved by this committee before implementation. If an immediate change to the 
protocol is implemented for safety reasons by the investigator, the IRB must be informed imme- 
diately. The study must be reviewed and approved at least annually as well. 
 
10.3    Recruitment 
 
Upon obtaining approval form external agencies and internal review committees, we will begin 
recruitment for the clinical trial. Based on our previous experience with the regulatory review 
process, we estimate that this will be completed in approximately 4-6 months. Once approved, 
patients with RCC seen at the UT Memorial Hermann Cancer Center will be accrued; we esti- 
mate that accrual to the first-line molecular-targeted agent will be completed in approximately 18 
months. Upon radiographic progression, patients will undergo a second metastatic biopsy to 
determine the molecular tumor profile and initiate a second-line molecular targeted agent. 
Our recruitment plan for enrolling the 100 patients follows a multi-step approach: 
    Houston recruitment: 
o We will accrue patients from our direct clinic population: 
 
The University of Texas Health Science Center at Houston; 
 
Memorial Hermann Cancer Center – Texas Medical Center; 
 
Memorial Hermann Cancer Center – Southwest; 
 
Memorial Hermann Cancer Center – Northeast. 
 
We have referral relationships with local oncology faculty at primary care clin- 
ics. 
 
We have referral relationships with local medical oncologists. 
 
We employ a Nurse Navigator and Physician Liaison who work with local 
providers to increase referrals. 
 
Our referral area is extremely broad. Memorial Hermann pulls from the great- 
er Houston area. Based on the strength of its reputation, The University of 
Texas pulls from the entire state of Texas as well as from surrounding states. 
    Statewide recruitment: 


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o We have strong referral relationships for consults with medical oncologists in several 
areas of Texas: 
 
Austin 
 
Abilene 
 
Dallas-Fort Worth 
 
The Rio Grande Valley (McAllen-Harlingen-Brownsville) 
 
East Texas (Beaumont-Port Arthur-Lake Charles, LA) 
    Regional recruitment: 
o We have strong referral relationships for consults with medical oncologists in Louisi- 
ana, Arkansas, Oklahoma, and Colorado 
    National recruitment: 
o The Kidney Cancer Association (http://www.kidneycancer.org/) has an online clinical 
trial matching service for patients that reaches an international audience. We plan to 
register our trial with the association. 
o The   National   Institutes   of   Health’s   clinical   trials   registry,   ClinicalTrials.gov 
(http://clinicaltrials.gov/), is a large worldwide registry. All US human clinical trials are 
required to register on the site, which is searchable by the public. The World Health 
Organization 
has 
a 
similar 
clinical 
trials 
registry 
(http://apps.who.int/trialsearch/Default.aspx). 
o Dr. Amato has more than 30 years of experience as a treating physician and re- 
searcher. As such, he has a broad acquaintance within the urology and oncology 
communities. This results in a number of referrals each month from fellow urologists 
around the world. 
 
10.4    Informed Consent 
 
The Investigator will be responsible for obtaining consent, documented on the Informed Consent 
Form (ICF) signed and dated by each patient or his/her legally authorized representative, prior 
to his/her participation in the study, in accordance with ICH GCP guidelines. The ICF will be 
written in non-technical language. The patient should read and be given as much time as they 
need to consider their participation before signing and dating it. 
 
The investigator or study staff designee must explain to each patient the nature of the study, its 
purpose, the procedures involved, the expected duration, the potential risks and benefits in- 
volved and any discomfort it may entail. Each patient must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and that withdrawal 
of consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
 
Participation in the study and date of informed consent should be documented appropriately in 
the patient’s files. The original ICF will be maintained in the research files and a copy must be 
maintained in the institution’s medical records. The patient or his/her legally authorized repre- 
sentative will also be given a copy of the signed consent form. 
 
10.5    Confidentiality 
 
All records identifying the patient will be kept confidential and, to the extent permitted by the ap- 
plicable laws and/or regulations, will not be made publicly available. Patient names will not be 
supplied to third parties. A unique study accession number will be assigned to each patient on 
study and will be used on the CRFs. Identifiable data on any document (e.g., pathologist report) 


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must be redacted before a copy of the document is supplied to third parties. The study coordina- 
tor will maintain a list to enable patients’ records to be identified for verification purposes. 
 
Study data stored electronically will be stored in zone 100, on password-protected, encrypted 
computers. Paper study data will be maintained by the study coordinator in the locked research 
offices. 
 
10.6    Publication of Study Results 
 
The investigator will assure that the key elements of this protocol will be posted in a publicly ac- 
cessible database such as  www.ClinicalTrials.gov. In addition, upon study completion and finali- 
zation of the study report the results of this study will be submitted for publication in scientific 
journals and/or scientific meetings. If the results of the study are published, the patient’s identity 
will remain confidential. 
 
10.7    Retention of Documents 
 
To enable evaluations and/or audits from regulatory authorities or sponsors, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient information 
to link records, e.g., CRFs and hospital records), all original signed informed consent docu- 
ments, copies of all CRFs, safety reporting forms, source documents, detailed records of treat- 
ment disposition, and adequate documentation of relevant correspondence in a secure storage 
facility. 
 
Essential documents (written and electronic) should be retained for at least three (3) years after 
the completion of the study. The records should be retained by the investigator according to lo- 
cal regulations or as specified in the Clinical Study Agreement (CSA), whichever is 
longer. 


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11 
REFERENCES 
 
1. 
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antiangiogenic therapy outcome in renal cell carcinoma. Pharmacogenomics 
2012;13:1621 
2. 
De Mattos-Arruda L, Rodon J. Pilot studies for personalized cancer medicine: focusing 
on the patient for treatment selection. Oncologist 2013;18:1180 
3. 
Brufau BP, Cerqueda CS, Villalba LB, et al. Metastatic renal cell carcinoma: radiologic 
findings and assessment of response to targeted antiangiogenic therapy by using multi- 
detector CT. Radiographics 2013;33(6):1691 
4. 
Katabathina VS, Lassau N, Pedrosa I, et al. Evaluation of treatment response in patients 
with metastatic renal cell carcinoma: role of state-of-the-art cross-sectional imaging. Curr 
Urol Rep 2012;13(1):70 
5. 
Shinagare AB, Krajewski KM, Jagannathan JP, et al. Genitourinary imaging: part 2, role 
of imaging in medical management of advanced renal cell carcinoma. AJR Am J Roent- 
genol 2012;199(5):W554 
6. 
Kang HC, Tan KS, Keefe SM, et al. MRI assessment of early tumor response in metas- 
tatic renal cell carcinoma patients treated with sorafenib. AJR Am J Roentgenol 
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7. 
Yaghmai V, Miller FH, Rezai P, et al. Response to treatment series: part 2, tumor re- 
sponse assessment--using new and conventional criteria. AJR Am J Roentgenol 
2011;197(1):18 
8. 
Smith AD, Shah SN, Rini BI, et al. Morphology, attenuation, size, and structure (MASS) 
criteria: assessing response and predicting clinical outcome in metastatic renal cell car- 
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9. 
Smith AD, Lieber ML, Shah SN. Assessing tumor response and detecting recurrence in 
metastatic renal cell carcinoma on targeted therapy: importance of size and attenuation 
on contrast-enhanced CT. AJR Am J Roentgenol 2010;194(1):157 
10. 
Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor 
suppressor gene. Science 1993;260:1317 
11. 
Clifford SC, Prowse AH, Affara NA, et al. Inactivation of the von Hippel-Lindau (VHL) 
tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell 
carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. 
Genes Chromosomes Cancer 1998;22:200 
12. 
de Paulsen N, Brychzy A, Fournier MC, et al. Role of transforming growth factor-alpha in 
von Hippel-Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible 
mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl 
Acad Sci USA 2001;98:1387 
13. 
Patel PH, Chadalavada RS, Chaganti RS, et al. Targeting von Hippel-Lindau pathway in 
renal cell carcinoma. Clin Cancer Res 2006;12:7215 
14. 
O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine 
kinase signaling and activates Akt. Cancer Res 2006;66:1500 
15. 
Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral 
antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases 
involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099 
16. 
Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and 
platelet-derived growth factor receptor beta in preclinical models of human small cell 
lung cancer. Mol Cancer Ther 2003;2:471-8. 
17. 
Wan X, Shen N, Mendoza A, et al. CCI-779 inhibits rhabdomyosarcoma xenograft 
growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif- 
1alpha/VEGF signaling. Neoplasia 2006;8:394-401 


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18. 
Hurwitz H, Dowlati A, Savage S, et al: Safety, tolerability and pharmacokinetics of oral 
administration of GW786034 in pts with solid tumors. J Clin Oncol 23:195s, 2005 (suppl; 
abstr 3012) 
19. 
Lane HA, Wood JM, McSheehy PM, et al. mTOR inhibitor RAD001 (everolimus) has 
antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin 
Cancer Res 2009;15:1612 
20. 
Rini BI, Rixe O, Bukowski RM, et al. AG-013736, a multi-target tyrosine kinase receptor 
inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, 
metastatic renal cell cancer (RCC). J Clin Oncol 2005; 23: Abstr 4509. 
21. 
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced 
renal-cell carcinoma. N Engl J Med 2015;373(19):1814 
22. 
Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for 
cancer therapy. J Clin Oncol 2009;27: 2278 
23. 
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, 
Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, 
Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM. Sorafenib for treatment of renal 
cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in 
renal cancer global evaluation trial. J Clin Oncol. 2009 Jul 10;27(20):3312-8. 
24. 
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, 
Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA. Sunitinib versus 
interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356(2):115-24 
25. 
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, 
Gladkov OA, Kavina A, Zarbá JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, 
Hawkins RE. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of 
a randomized phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8. 
26. 
Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Sridhara R, 
Pazdur R. FDA approval summary: temsirolimus as treatment for advanced renal cell 
carcinoma. Oncologist. 2010;15(4):428-35. 
27. 
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, 
Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, 
Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative 
effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a 
randomised phase 3 trial. Lancet. 2011;378(9807):1931-9. Erratum in: Lancet. 2012 Nov 
24;380(9856):1818. 
28. 
Rankin EB, Fuh KC, Castellini L, et al. Direct regulation of GAS6/AXL signaling by HIF 
promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA 
2014;111:13373 
29. 
Gibney GT, Aziz SA, Camp RL, et al. c-Met is a prognostic marker and potential 
therapeutic target in clear cell renal cell carcinoma. Ann Oncol 2013;24:343 
30. 
Cabozatinib package insert, available at: 
http://www.exelixis.com/sites/default/files/pdf/COMETRIQ%20Prescribing%20Informatio 
n.pdf 
31. 
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, 
Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, 
Ravaud A; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell 
carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 
2008;372(9637):449-56. 
32. 
Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring 
assays for major plasma proteins. Mol Cell Proteomics 2006;5:573 
33. 
Miyazawa M, Yasuda M, Fujita M, Kajiwara H, Hirabayashi K, Takekoshi S, Hirasawa T, 
Murakami M, Ogane N, Kiguchi K, Ishiwata I, Mikami M, Osamura RY. Therapeutic 


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strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell 
adenocarcinoma. Pathol Int. 2009 Jan;59(1):19-27 


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12       APPENDIX A: NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
 
Safety  and  tolerability  will  be  assessed  according  to  Version  4.0  of  the  National  Cancer 
Institute’s Common Terminology Criteria for Adverse Events (CTCAE). An electronic version 
may be found at:  http://ctep.cancer.gov/reporting/ctc.html. 


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13 
APPENDIX B: ECOG PERFORMANCE STATUS 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 
5 
Dead 


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14 
APPENDIX C: RECIST 1.1 GUIDELINES 
 
Tumor response and progression will be defined according to RECIST 1.1 criteria. Electronic 
guidelines may be found at:  http://www.eortc.be/recist/documents/RECISTGuidelines.pdf. 


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15 
APPENDIX D: SCHEDULE OF ASSESSMENTS 
 
 
First-line Temsirolimus/Sorafinib/Pazopanib   Schedule of Assessments (8 week cycle) until progression 
Visit Name 
Pre-treat 
Cycle 1 
Subsequent Cycles 
Visit Day 
-28 to -1 
1 
8 
15 
22 
29 
36 
43 
50 
1 
8 
15 
22 
29 
36 
43 
50 
Informed consent 
X 
Documentation of histologic di- 
agnosis and extent of cancer 
X 
Inclusion/Exclusion criteria 
X 
History & Physical exam with 
height, weight, complete neuro- 
X 
logical exam 
Interim physical exam                                                                       X                    X                                           X                                           X 
ECOG Performance status                      X                                     X                    X                                           X                                           X 
Concomitant Med Assessments               X                                                                                                          X 
Study drug dosages, AE’s, drug 
toxicities                                                                                                                                                                 X 
CBC with diff, platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile 
X 
Electrolyte panel                                      X              X         X         X         X         X         X         X         X         X                    X                    X                    X 
Comprehensive metabolic panel              X              X         X         X         X         X         X         X         X         X                    X                    X                    X 
Amylase/Lipase                                        X                                                            X                                           X                                           X 
Fasting triglycerides and choles- 
terol                                                          X                                                            X                                           X                                           X 
Tumor markers 
 
X 
X 
Beta HCG (for females) 
-7 to -1 
TSH                                                          X                                                                                                          X 
Urinalysis 
X 
X 
 X 
X 
MRI or CT Brain (if indicated) 
X 
 
X1 
CT Chest with RECIST tumor 
measurements                                         X                                                                                                          X1 
MRI or CT Abdomen and Pelvis 
with  RECIST measurements                   X                                                                                                          X1 
Bone Scan if indicated                             X                                                                                                          X1 
Spirometry with DLCO                             X 
12 Lead EKG 
X 
Echocardiogram 
X 
As Indicated During Treatment 
Molecular Tumor Profiling 
X 
After Documentation of Progression of Disease 
Biopsy of Metastatic Tissue 
X 
1. 
Tumor assessments will be every 8 weeks for two cycles then every 12 weeks. This will fall just prior to D1 in Cycle 2, Cycles 3, 6, and every 3rd cycle thereafter. 
This will fall mid-cycle during Cycles 4, 7, and every 3rd cycle thereafter. There are no scans during Cycles 5, 8, and every 3rd cycle thereafter. 


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First-line Sunitinib Schedule of Assessments (6 week cycle) until progression 
Visit Name 
Pre-treat 
Cycle 1 
Cycles 2, 4, 6, etc. 
Cycles 3, 5, 7, etc. 
Visit Day 
-28 to -1 
1 
8 
15 
22 
29 
36 
1 
8 
15 
22 
29 
36 
1 
8 
15 
22 
29 
36 
Informed consent 
X 
Documentation of histologic 
diagnosis and extent of cancer 
X 
Inclusion/Exclusion criteria 
X 
History & Physical exam with 
height, weight, complete neuro- 
X 
logical exam 
Interim physical exam 
X 
X 
X 
X 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
X 
X 
X 
Concomitant Med Assess- 
ments 
X 
X 
X 
Study drug dosages, AE’s, 
drug toxicities 
X 
X 
CBC with diff, platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile 
X 
Electrolyte panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic 
panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase/Lipase 
X 
X 
X 
X 
X 
Fasting triglycerides and cho- 
lesterol 
X 
X 
X 
X 
X 
Tumor markers 
X 
X 
X 
Beta HCG (for females) 
-7 to -1 
TSH 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
MRI or CT Brain (if indicated) 
X 
X2 
X 
CT Chest with RECIST tumor 
measurements 
X 
X2 
X 
MRI or CT Abdomen and Pel- 
vis with RECIST measure- 
ments 
X 
X2 
X 
Bone Scan if indicated 
X 
X2 
X 
Spirometry with DLCO 
X 
12 Lead EKG 
X 
Echocardiogram 
X 
As Indicated During Treatment 
Molecular Tumor Profiling 
X 
After Documentation of Progression of Disease 
Biopsy of Metastatic Tissue 
X 
2. Tumor assessment only on Cycle 2. 


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X
X
X 
X 
X 
X 
X 
X 
X 
 
 
 
Second-Line Axitinib/Everolimus/Carbozatinib (8 week cycle) until progression 
 
Visit Name 
Cycle 1 
Subsequent Cycles 
Post Tx 
or EOS 
Visit Day 
1 
8 
15 
22 
29 
36 
43 
50 
1 
8 
15 
22 
29 
36 
43 
50 
30 day 
± 3d 
Interim history & physical exam         X                X                X                                   X                                   X                                       X 
ECOG Performance status                X                X                X                                   X                                   X                                       X 
Concomitant Med Assessments         X                                                                        X 
Study drug dosages, AE’s, drug 
toxicities 
CBC with diff, platelets                       X      X       X      X      X      X      X      X       X                X                X                X                    X 
Coagulation profile                                                                                                                                                                                                                           X 
Electrolyte panel                                X      X       X      X      X      X      X      X       X                X                X                X                    X 
Comprehensive metabolic panel        X      X       X      X      X      X      X      X       X                X                X                X                    X 
Amylase/Lipase                                  X                                   X                                   X                                   X                                       X 
Fasting triglycerides and choles- 
terol 
Tumor markers                                                                                                                               X 
Beta HCG (for females) 
TSH                                                    X                                   X                                   X                                   X                                       X 
Urinalysis                                           X                                   X                                   X                                   X                                       X 
MRI or CT Brain                                                                                                                            X1 
CT Chest with RECIST tumor 
measurements                                                                                                                                  1 
MRI or CT Abdomen and Pelvis 
with  RECIST measurements                                                                                                           1 
Bone Scan if indicated                                                                                                                   X1 
Spirometry with DLCO 
12 Lead EKG 
Echocardiogram 
As Indicated During Treatment 
Molecular Tumor Profiling 
After Documentation of Progression of Disease 
Biopsy of Metastatic Tissue 
1. 
Tumor assessments will be every 8 weeks for two cycles then every 12 weeks. This will fall just prior to D1 in Cycles 2, 3, 6, and every 3rd cycle thereafter. 
This will fall mid-cycle during Cycles 4, 7, and every 3rd cycle thereafter. There are no scans during Cycles 5, 8, and every 3rd cycle thereafter. 


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16 
APPENDIX E: DRUG INFORMATION 
 
16.1 
Everolimus 
 
The side effects most commonly reported at a frequency >20% includes the following: 
 
Peripheral edema (13%-39%) 
 
Dermatologic: acne (10%-22%) and rash (5%-59%) 
 
Gastrointestinal: decrease in appetite (6%-30%), diarrhea (14%-50%), nausea (16%-29%), 
vomiting (15%-29%), and stomatitis (44%-78%) 
 
Neurologic: asthenia (13%-33%) 
 
Renal: increased serum creatinine (19%-50%) 
 
Respiratory: cough (20%-30%) and dyspnea (20%-24%), 
 
Other: fatigue (14%-45%) and fever (15%-31%) 
 
The most common laboratory abnormalities include the following: 
 
Endocrine: hypercholesterolemia (66%-85%), hypertriglyceridemia (27%-73%), and hyper- 
glycemia (all grades, 14%-75%) 
 
Hematologic: anemia (all grades, 41%-86%), lymphopenia (all grades, 20%-54%), and 
thrombocytopenia (all grades, 19%-54%) 
 
Hepatic: increased levels of alkaline phosphatase (32%-74%), ALT/SGPT (18%-51%), and 
AST/SGOT (23%-69%) 
 
Grade 3 or 4 adverse effects include anemia (6.6%) and lymphopenia (1%-16%). Serious adverse 
effects include hemorrhage (3%), leukopenia (37%-58%) , infectious disease (37%-50%), hemolytic 
uremic syndrome, renal failure (3%), interstitial lung disease, pleural effusion (7%), pneumonia (6%), 
and non-infectious pneumonitis (1%-19%). See everolimus drug label for more information. 
 
16.2 
Sunitinib 
 
The most common adverse events occurring at ≥20% frequency are as follows: 
 
Dermatologic: discoloration of skin, yellow (25%), dry skin (23%), and rash (29%) 
 
Gastrointestinal: abdominal pain (30%), constipation (23%), diarrhea (66%), indigestion 
(34%), inflammatory disease of mucous membrane (47%), loss of appetite (48%), nausea 
(58%), vomiting (39%), and taste sense altered (47%) 
 
Musculoskeletal: pain in limb (40%) 
 
Neurologic: asthenia (26%) 
 
Renal: increased uric acid level (46%) 
 
Respiratory: cough (27%) 
 
Other: fatigue (62%) 
 
The most common laboratory abnormalities include the following: 
 
Hematologic: anemia (79%), bleeding (37%), leukopenia (78%), lymphocytopenia (68%), 
neutropenic disorder (77%) 
 
Hypothyroidism (16%) 
 
Serious adverse effects include hypertension (34%), left ventricular cardiac dysfunction (27%), pro- 
longed QT interval, Torsades de pointes (<0.1%), severe hypothyroidism, increased serum lipase 
level (56%), pancreatitis (1%), thrombocytopenia (68%), hepatotoxicity, pulmonary embolism (2%), 
radiation recall syndrome, and pneumonitis. See sunitinib drug label for more information. 
 
16.3 
Sorafenib 


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The most common adverse effects include occurring at >20% frequency are as follows: 
 
Dermatologic: acral erythema, alopecia (27%), and rash (up to 35%) 
 
Endocrine metabolic: hypophosphatemia (35%-45%) and hypothyroidism 
 
Gastrointestinal: decrease in appetite, diarrhea (43%-68%), increased serum lipase level 
(40%-41%), loss of appetite (16%-29%), nausea (21%-24%), increase serum amylase level 
(30%-34%) 
 
Other adverse effects include fatigue (37%-46%) 
 
The most common grade 3 or 4 laboratory abnormalities include lymphocytopenia (23%), increased 
ALT/SGPT level, and increased AST/SGOT level. 
Congestive heart failure occurred in 1.9% of patients. Other grade 3 or 4 adverse effects included 
hypertension (3%-10%), hemorrhage (15.3%), and infectious disease (>10%). Rare cases of 
squamous cell carcinoma, GI perforation, transaminitis, cerebral hemorrhage, QT prolongation, and 
interstitial lung disease have also been reported. See sorafenib drug label for more information. 
 
16.4 
Temsirolimus 
 
The most common (incidence ≥30%) adverse reactions observed with temsirolimus are rash (47%), 
asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most 
common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyper- 
lipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum 
creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated 
AST (38%), and leukopenia (32%). 
 
Most common grade 3/4 adverse reactions and laboratory abnormalities included asthenia (11%), 
dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased 
(16%), phosphorus decreased (18%), and triglycerides increased (44%). 
 
Pleural effusion, hemodynamically significant pericardial effusions requiring intervention, convul- 
sions, rhabdomyolysis, Stevens-Johnson Syndrome, complex regional pain syndrome, and extrava- 
sations have been reported during postmarketing use. 
 
 
16.5 
Pazopanib 
 
The most common adverse effects include occurring at >20% frequency are as follows: 
 
Hypertension (all grades, 40%) 
 
Hair color change (38%) 
 
Gastrointestinal: decrease in appetite (40%), diarrhea (52%), loss of appetite (22%), nausea 
(26%), and vomiting (21%) 
 
Musculoskeletal pain (23%) and myalgia (23%) 
 
The most common laboratory abnormalities include the following: 
 
Increased glucose level (41%) 
 
Hematologic: leukopenia (37%), neutropenia (34%), and thrombocytopenia (32%) 
 
Hepatic: increased levels of alkaline phosphatase (32%), ALT/SGPT (all grades, 53%), 
AST/SGOT (all grades, 53%), and bilirubin (36%) 
 
Lymphocytopenia (all grades, 31%) 
 
Serious adverse effects include myocardial infarction (2%), prolonged QT interval (2%), hypothyroid- 
ism (4%-7%), hemorrhage (13%), thrombocytopenia, grade 3 or 4 increases in ALT, AST, and biliru- 


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bin levels, infectious disease, lymphocytopenia, cerebrovascular accident, transient ischemic attack, 
pneumothorax, and pulmonary embolism. See pazopanib drug label for more information. 
 
16.6 
Axitinib 
 
The most common adverse effects include occurring at >20% frequency are as follows: 
 
Hypertension (all grades, 40%) 
 
Hand-foot syndrome (27%) 
 
Decreased weight (all grades, 25%) 
 
Gastrointestinal: constipation (all grades, 20%), diarrhea (all grades, 55%), loss of appetite 
(all grades, 34%), nausea (all grades, 32%), vomiting (all grades, 24%) 
 
Asthenia (all grades, 21%) 
 
Other: dysphonia (31%) and fatigue (all grades, 39%) 
 
The most common laboratory abnormalities include the following: 
 
Hepatic: increased ALT/SGPT level (all grades, 22%; grade 3, <1%) 
 
Serious adverse effects include hypertensive crisis (<1%), GI fistula (1%), arterial thrombosis (1%- 
2%), DVT (1%), hemorrhage (grade 3 or 4, 1%), venous thrombosis (grade 3 or 4, 3%), transient 
ischemic attack (1%), and pulmonary embolism (2%). 
 
16.7 
Cabozatinib 
 
The most commonly reported adverse drug reactions (≥25%) are diarrhea, stomatitis, palmar-plantar 
erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral 
pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. 
 
The most common laboratory abnormalities (≥25%) are increased AST, increased ALT, lymphope- 
nia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophospha- 
temia, and hyperbilirubinemia. 
 
Serious side effects include hand-foot syndrome (42%-50%), impaired wound healing (2%), gas- 
trointestinal fistula (1%-1.2%), gastrointestinal perforation (0.9%-3%), pancreatitis (<1%), Tracho- 
esophageal fistula (4%), anemia, Grade 3 or 4 (5%), arterial thromboembolism (0.9%-2%), bleeding, 
Grade 3 or higher (2.1%-3%), lymphocytopenia, Grade 3 or 4 (16%), neutropenia, Grade 3 or 4 
(3%), venous thromboembolism (6%-7.3%), cholestatic hepatitis (<1%), aseptic necrosis of bone of 
jaw (≤1%),posterior reversible encephalopathy syndrome (<1%), seizure (<1%),  and pulmonary 
embolism (3.9%). 
 
 
16.8 
How Supplied 
 
16.8.1 Everolimus 
 
Everolimus is supplied as white to slightly yellow, elongated tablets with a beveled edge and no 
score of 2.5 mg, 5 mg, 7.5 mg, and 10 mg strengths. The 2.5 mg tab is engraved with ―LCL‖ on one 
side and ―NVR‖ on the other. The 5 mg tablet is engraved with ―5‖ on one side and ―NVR‖. The 7.5 
mg tablet is engraved with ―7P5‖ on one side and ―NVR‖ on the other. The 10 mg tab is engraved 
with ―UHE‖ on one side and ―NVR‖ on the other. Everolimus will be supplied according to local prac- 
tice. 
 
16.8.2 Sunitinib 
 
Sunitinib is supplied as hard gelatin capsules in either 12.5 mg, 25 mg, or 50 mg strength. The 12.5 
mg and 25 mg capsules consist of a caramel-colored top orange body, printed with white ink "Pfizer" 
on the cap and either "STN 12.5 MG" or "STN25 MG" on the body. The 50 mg capsule consists of a 


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caramel top and caramel body, printed with white ink "Pfizer" on the cap and "STN50 MG" on the 
body. Sunitinib will be supplied according to local practice. 
 
 
16.8.3 Sorafenib 
 
Sorafenib is supplied as tablets containing sorafenib tosylate (274 mg) equivalent to 200 mg of sora- 
fenib. The tablet is round, biconvex, red film-coated tablets, debossed with the ―Bayer cross‖ on one 
side and ―200‖ on the other side. Sunitinib will be supplied according to local practice. 
 
16.8.4 Temsirolimus 
 
Temsirolimus is supplied as a 25 mg/mL injection with a 1.8 mL diluent designed for injection. The 
recommended initial dose of the drug is 25 mg infused over a 30-60 minute period once a week. 
Treat until disease progression or unacceptable toxicity.Temsirolimus injection vial contents must 
first be diluted with the enclosed diluent before diluting the resultant solution with 250 mL of 0.9% 
sodium chloride injection. Patients should receive prophylactic intravenous diphenhydramine 25 to 
50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose. Temsiroli- 
mus will be supplied according to local practice. 
 
16.8.5 Pazopanib 
 
Pazopanib is supplied as tablet containing 216.7 mg of pazopanib hydrochloride equivalent to 
200 mg of pazopanib. The tablet 200 mg tablet is modified capsule-shaped, gray, film-coated with 
―GS JT‖ debossed on one side. Pazopanib will be supplied according to local practice. 
 
 
16.8.6 Axitinib 
 
Axitinib is supplied as red, film-coated 1 mg and 5 mg tablets. The 1 mg tablet is oval-shaped and 
debossed with ―Pfizer‖ on one side and ―1 XNB‖ on the other side. The 5 mg tablet is triangular- 
shaped, debossed with ―Pfizer‖ on one side and ―5 XNB‖ on the other side. Axitinib will be supplied 
according to local practice. 
 
16.8.7 Cabozatinib 
 
Cabozantinib tablets are supplied as 60mg, 40mg, and 20mg yellow, film-coated tablets. The 60-mg 
tablets are oval shaped with no score, debossed with ―XL‖ on one side and ―60‖ on the other side of 
the tablet. The 40 mg tablets are triangle shaped with no score, debossed with ―XL‖ on one 
side and ―40‖ on the other side of the tablet. The 20 mg tablets are round shaped with no score, de- 
bossed with ―XL‖ on one side and ―20‖ on the other side of the tablet. Cabozatinib is supplied ac- 
cording to local practice. 
 
16.9 
Storage 
 
16.9.1 Everolimus 
 
Everolimus tablets should be stored at 25°C (77°F); excursions permitted between 15°C–30°C 
(59°F–86°F). Tablets should be stored in the original container, protected from light and moisture. 
Follow special handling and disposal procedures for anticancer pharmaceuticals. 
 
16.9.2 Sunitinib 
 
Sunitinib may be light-sensitive; capsules will be stored in the bottles in which they are received to 
protect the compound from light. Sunitinib capsules should be stored at 25°C (77°F); excursions 
permitted to 15°C-30°C (59°F-86°F). 
 
16.9.3 Sorafenib 


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Sorafenib tablets will be stored in a dry place at 25°C (77°F); excursions permitted to 15°C–30°C 
(59°F–86°F). 
 
16.9.4 Temsirolimus 
 
Temsirolimus must be stored under refrigeration at 2°–8°C (36°–46°F) and protected from light. Dur- 
ing handling and preparation of admixtures, temsirolimus should be protected from excessive room 
light and sunlight. Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
 
16.9.5 Pazopanib 
 
Pazopanib tablets will be stored at room temperature between 20°C and 25°C (68°F to 77°F); ex- 
cursions permitted to 15°C-30°C (59°F-86°F). 
 
16.9.6 Axitinib 
 
Axitinib tablets will be stored at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F- 
86°F). 
 
16.9.7 Cabozatinib 
 
Cabozatinib is stored at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 
30°C (59°F to 86°F). 
 
16.10  Monitoring of Toxicities 
 
Any AE/SAE not listed in the CTCAE version 4.0 will be graded as follows: 
Severity of Event 
Grade 
Definition 
1 
Mild: Symptoms which do not interfere with patient’s daily activities 
2 
Moderate: Symptoms which may interfere with patient’s daily activities 
3 
Severe: Events which interrupt patient’s usual daily activities 
4 
Life-threatening or disabling 
5 
Death 
Medically significant adverse events considered related to the study treatment will be followed until 
resolved or considered stable. 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is related 
and of sufficient severity to require the subject’s removal from treatment or from the study. A subject 
may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable ad- 
verse event. If either of these situations arises, the subject should be strongly encouraged to under- 
go medical supervision until symptoms cease or the condition becomes stable. 
 
 
16.10.1 
Management of stomatitis/oral mucositis/mouth ulcers 
 
Stomatitis/oral mucositis/mouth ulcers due to everolimus should be treated using local supportive 
care. Please note that investigators in earlier trials have described the oral toxicities associated with 
the everolimus as mouth ulcers, rather than mucositis or stomatitis. If your examination reveals 
mouth ulcers rather than a more general inflammation of the mouth, please classified the adverse 
event as such. Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth 
ulcers: 
1.  For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouthwash or 
salt water (0.9%) mouthwash several times a day until resolution. 
2.  For more severe toxicity (grade 2 in which case patients have pain but are able to maintain 
adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral 
alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local 


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anesthetics such as benzocaine, butyl amino benzoate, tetracaine hydrochloride, menthol, or 
phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kena- 
log in orabase). 
3.  Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers. It is preferable to avoid these agents. 
4.  Antifungal agents should be avoided unless a fungal infection is diagnosed. In particular, sys- 
temic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) should be 
avoided in all patients due to their strong inhibition of the everolimus metabolism, thereby 
leading to higher everolimus exposures. Therefore, topical antifungal agents are preferred if 
an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided un- 
less a viral infection is diagnosed. 
 
Note: stomatitis/oral mucositis should be appropriately graded using the functional grading given on 
the NCI-CTC for adverse events, version 4.0. 
 
16.10.2 
Management of nausea/vomiting 
 
Investigators should manage anemia as medically indicated per local standards. 
 
16.10.3 
Management of anemia 
 
Investigators should manage anemia as medically indicated per local standards. 
 
16.10.4 
Management of diarrhea 
 
Appearance of diarrhea attributed to therapy-related toxicity may be treated with loperamide or per 
local standards. 
 
16.10.5 
Management of Hypertension 
 
Severity 
Action 
A: symptomatic sustained SBP ≥160 and <170 
mmHg, or DBP ≥90 and <110 mmHg, or clini- 
cally significant decrease in tech DBP of ≥20 
mg of mercury. 
Step 1. Continue steady medication at the 
same dose. Step 2. Adjust current dose of or 
initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medications 
during next 2 weeks as indicated to achieve 
well-controlled blood pressure. If blood pres- 
sure is not well-controlled within 2 weeks, fol- 
low step 1 in scenario B. 
B: Symptomatic, or SBP ≥170 mg of mercury 
or DBP ≥110 mg of mercury, or failure to 
achieve well-controlled blood pressure within 2 
weeks in scenario A. 
Step 1. Interrupt study medication. Step 2. Ad- 
just current or initiate new antihypertensive 
medications. Step 3. Titrate antihypertensive 
medications during next 2 weeks as indicated 
to achieve well-controlled BP. Step 4. Restart 
study medication at the same dose or lower 
dose at discretion of investigator once BP is 
well-controlled. Dose adjustment for discontin- 
uation of antihypertensive medications may be 
necessary during scheduled to week off- 
treatment.. 


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C: Two or more symptomatic episodes of 
hypertension despite modification of antihyper- 
tensive medications and production of study 
medication dose. 
Discontinuation of study medication and fol- 
low-up per protocol. 
 
Well-controlled blood pressure defined as meaning SBP <160 mmHg and meaning DBP <90 mmHg. 
 
16.10.6 
Management of Fatigue (lethargy, malaise, asthenia) 
 
Severity 
Action 
Grades 1 and 2 
Continue study medication at same dose; 
monitor as clinically indicated. 
Grades 3 and 4 
Step 1. Interrupt study medication until toxicity 
reduced to ≤grade 2. Step 2. Restart study 
medication at the same dose or lower dose at 
discretion of investigator. 
 
16.10.7 
Management of infections 
 
Tyrosine kinase and mTOR inhibitors have immunosuppressive properties and may predispose pa- 
tients to infections, especially infections with opportunistic pathogens. Localized and systemic infec- 
tions, including pneumonia, other bacterial infections and invasive fungal infections, such as asper- 
gillosis or candidiasis, have been reported. Some of these infections have been severe (e.g., leading 
to respiratory failure) and occasionally have had a fatal outcome. Investigator will monitor close for 
symptoms and signs of infection, and institute treatment promptly. If a diagnosis of invasive systemic 
fungal infection is made, therapy will be stopped and permanently discontinued and the patient 
treated with appropriate antifungal therapy. 
 
16.10.8 
Management of noninfectious pneumonitis 
 
Both asymptomatic radiological changes (grade 1 = radiological long changes only) and symptomat- 
ic noninfectious pneumonitis (grade 2 = not interfering with activities of daily living; grade 3 = inter- 
fering with activities of daily living and oxygen indicated) have been noted in patients receiving eve- 
rolimus and sorafenib therapy. If noninfectious pneumonitis develops, consultation with a pulmonol- 
ogist is recommended. Record the non-infectious pneumonitis on the adverse event eCRF. If inves- 
tigator finds that noninfectious pneumonitis associated with therapy, dose modification will be made 
and corticosteroid initiated as appropriate per local standards. 
 
16.10.9 
Management of thyroid dysfunction 
 
Baseline laboratory measurement of thyroid function will be obtained prior to therapy initiation. Pa- 
tients will be observed closely for signs and symptoms of thyroid dysfunction. Routine thyroid func- 
tion test will be conducted at each appointment. Treatment will follow standard medical practice. 
 
16.10.10 Hemorrhage/bleeding/coagulopathy 
 
Severity 
Action 
Grade 1 
Continue study medication at same dose; 
monitor as clinically indicated. 
Grade 2 
Step 1. Interrupt study medication until the ad- 
verse event resolves to ≤Grade 1. Step 2. 
Restart medication with lower dose; monitor as 


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clinically indicated. 
 
Grade 3 or 4, or recurrent ≥Grade 2 event after 
dose interruptions/reduction 
Discontinuation of study medication and fol- 
low-up per protocol. Note: if abnormality is not 
clearly associated with clinical consequences, 
contact the Novartis medical monitor to dis- 
cuss the potential for continuation of study 
treatment. If agreed, subject may restart medi- 
cation at lower dose. 
 
 
 
16.10.11 Venous thrombosis 
 
Severity 
Action 
Grade 2 
Continue study medication with same dose; 
monitor as clinically indicated. 
Grade 3 or asymptomatic Grade 4 
Step 1. Interrupt study medication at same 
goes during the period of full-dose anticoagu- 
lant and if all of the following criteria are met: 
the subject must have been treated with an 
anticoagulant (enoxaparin preferred, but war- 
farin may be used) for at least 1 week. No 
Grade 3 or 4 hemorrhagic events have oc- 
curred while on anticoagulant should treat- 
ment. Subject should be monitored as clinical- 
ly indicated during anticoagulant should treat- 
ment and after resuming study medication. 
Symptomatic Grade 4 
Discontinuation of study medication and fol- 
low-up per protocol. 
 
 
 
16.10.12 Arterial thrombosis 
 
Severity 
Action 
 
Any Grade 
Discontinuation of study medication and fol- 
low-up per protocol 
 
 
 
 
 
16.11  Management of Everolimus-specific toxicities 
 
Management of hyperlipidemia and hyperglycemia 
 
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. 
Lead tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 hypercholesterole- 
mia (>300 milligrams per deciliter or 7.75 mmol/L) or grade 2 hypertriglyceridemia (greater than 2.5 
times ULN) will be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., 


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atorvastatin, pravastatin) or appropriate lipid-lowering medication, in addition to diet. Patients will be 
closely monitored. 
 
Grade 3 hyperglycemia has been observed in patients perceiving the everolimus therapy. Based on 
this finding, it is suggested that optimal glucose control be achieved before starting a patient on eve- 
rolimus and should be monitored during everolimus therapy. 
 
 
16.12  Management of sunitinib-specific toxicities 
The following sunitinib-related toxicities are graded according to NCI common terminology criteria for 
adverse events version 4.0. 
Left ventricular dysfunction 
 
Severity 
Action 
Grade 1 
Continue at the same dose level 
Grade 2 
Continue at the same dose level. If a sympto- 
matic decrease of left and trick alert ejection 
fraction by absolute value of 20% and to less 
than the lower limit of normal. And or non- 
urgent and trick alert for rocks is more dys- 
rhythmia requiring intervention: step 1. enter 
route study medication until toxicity reduced to 
less than grade 1. Step 2. Restart treatment 
with lower dose; monitor as clinically indicated. 
Grade 3 
Step 1. Interrupt study medication until toxicity 
reduced to less than grade 1. Step 2. Restart 
medication with lower dose: monitor as clini- 
cally indicated. 
Grade 4 
Discontinuation of study medication and fol- 
low-up per protocol. 
In the presence of clinical manifestations of congestive heart failure, discontinuation of sunitinib is 
recommended. 
 
Hand-foot syndrome 
 
Severity 
Action 
Grades 1 and 2 
Continue study medication at same does; 
monitor as clinically indicated. 
Grade 3 
Step 1. Interrupt study medication and till tox- 
icity reduced to ≤Grade 1. Step 2. Restart 
study medication at lower dose or discontinue 
at discretion of investigator. 
Grade 4 
Step 1. Interrupt study medication until toxicity 
reduced to ≤Grade 2. Step 2. Restart study 
medication at lower dose or discontinue at dis- 
cretion of investigator.  
 
 
 
Management of Abnormal Laboratory Results: 
All clinically important abnormal laboratory tests occurring during the study will be repeated at ap- 
propriate intervals until they return either to baseline or to a level deemed acceptable by the investi- 
gator and the medical monitor, or until a diagnosis that explains them is made. The criteria for de- 
termining whether or not an abnormal laboratory test result should be reported as an adverse event 
are as follows: 
1.  Test results is associated with accompanying symptoms, and/or 


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2.  Test result requires additional diagnostic testing or medical/surgical intervention (merely re- 
peating an abnormal test, in the absence of any of the above conditions, does not meet crite- 
ria for reporting and an AE), and/or 
 
3.  Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or 
 
4.  Test result leads to any of the outcomes included in the definition of a serious adverse event, 
and/or 
 
5.  Test result is considered to be an adverse event by the investigator or sponsor 
 
Any abnormal test result that is determined to be an error does not require reporting as an adverse 
event, even if it did meet one of the above conditions except for condition #4. Clinically significant 
laboratory results must be recorded in the patient’s CRF. 
 
16.13  Follow-up for toxicities 
 
Patients whose study medication is temporarily interrupted or discontinued due to an adverse event 
or abnormal laboratory value, should be followed at least once per week for 4 weeks, and subse- 
quently at 2-week intervals, until resolution, stabilization of the event, or until the initiation of another 
anticancer therapy (second-line or initiation of a post-study third-line anticancer therapy), whichever 
comes first. 
 
If the patient requires a dose delay of >21 days for everolimus due to an adverse event or abnormal 
laboratory value, from the intended day of the next scheduled dose, the patient should be discontin- 
ued from the specific line of treatment (first-line and/or second-line). 
 
If the patient requires a dose delay of >21 days for sunitinib or if the delay coincides with the 2-week 
arrest and is >28 days (14 days of rest and 14 additional), the patient should be discontinued from 
the specific line of treatment (first-line and/or second-line). 
 
For unexpected events that are not related to study medication toxicity (i.e., elective surgeries, per- 
sonal reasons), up to a maximum of 14 days is acceptable for a dose delay from therapy. 
 
16.14  Dose interruption for surgery or surgical procedures 
 
Temporary interruption of therapy is recommended in patients undergoing major surgical proce- 
dures. The decision to resume therapy following major surgical intervention should be based on clin- 
ical judgment of adequate wound healing. 
 
16.15  Other concomitant medications 
 
Patients must be instructed not to take any additional medications (over the counter or other prod- 
ucts, including nutritional supplements) during the study without prior consultation with approval from 
the investigator. All medications taken within 35 days of starting study treatment must be reported on 
the concomitant medication/significations non-drug therapy prior to start of study drug eCRF. The 
investigator or designee will continue collecting information on the initiation of additional anticancer 
therapies until the data cutoff date for the final analysis. All new anticancer therapies after the last 
dose of study treatment will be recorded in the appropriate eCRF. 
 
The investigator should instruct the patient to notify the study center about any new medications he 
or she takes after the start of the study treatment. All medications (other than study treatment) and 
significant non-drug therapies (including physical therapy and blood transfusions) administered after 
the patient starts treatment in the first-line and during the second-line. Must be listed on the conco- 
mitant dedications/significant non-drug hairpiece after start of study drug eCRF. 


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Investigational or commercial anticancer agents other than those included in this trial, are not al- 
lowed during the study. The initiation of any non-protocol specific anti-tumor treatment or surgery is 
considered an indication of disease progression and must be recorded appropriately. Patients would 
then only be followed for survival. 
 
Everolimus, sunitinib, pazopanib, axitinib, and cabozatinib are metabolized primarily by the cytoch- 
rome P450 isoenzyme CYP3A4, to produce its primary active metabolite. Drugs or substances 
known to be strong inhibitors, strong inducers, or substrates of the isoenzyme CYP3A4 should be 
avoided unless use of the drug is essential and no substitute is available. For a complete list of 
drugs which are substrates for CYP3A4, please refer to this website: 
http://medicine.iupui.edu/flockhart/clinlist.htm. 
 
A strong inhibitor is one that causes a >5-fold increase in the plasma AUC values or >80% decrease 
in clearance. A moderate inhibitor is one that causes a >2-fold increase in plasma AUC values or 
50%-80% decrease in clearance. A weak inhibitor is one that causes a >1.25-fold increase in plas- 
ma AUC values or 20%-50% decrease in clearance. (Distinction is not always categorical as interac- 
tion can vary according to conditions.) 
 
16.15.1 
Everolimus 
 
Strong inhibitors should not be co-administered with everolimus. Drugs or substances known to be 
inhibitors, inducers, or substrates of the isoenzyme CYP3A4 should be avoided unless use of the 
drug is essential and no substitute is available. 
 
The following concomitant treatment are not allowed during the study: 
 
 
Co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole ritonavir), 
and strong inducers (e.g., rifampin, rifabutin). 
 
Seville orange, grapefruit, and their juices affect cytochrome P450 and PgP activity. 
 
Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, calcium chan- 
nel blockers, benzodiazepines) and strong inducers (e.g., carbamazepine, Phenobarbital, and phe- 
nytoin) should also be avoided if possible or otherwise subject to caution (e.g., increased frequency 
of safety monitoring) and dose adjustment. 
 
If patients have to co-administer strong inducers of CYP3A4, start the dose at 10 mg daily and if well 
tolerated for the first 2 weeks of treatment, escalate as tolerated by 5 mg dose every 2 weeks to a 
maximum dose of 20 mg daily. If patient does not tolerate higher doses, reduction to highest tole- 
rated dose is recommended. If the strong inducer is discontinued, the everolimus dose should be 
returned to the dose used prior to initiation of the strong CYP3A4 inducer. 
 
If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, the everolimus dose 
should be reduced to 5 mg daily. Further dose reduction to 5 mg every other day may be required to 
manage adverse reactions. 
 
16.15.2 
Sunitinib 
 
Strong inhibitors of CYP3A4 may increase sunitinib plasma concentrations and should be avoided 
unless there is an overriding clinical need. In particular, ketoconazole should be avoided if possible, 
since a clinical interaction study of sunitinib indicated that up to a 2-fold increase in plasma levels of 
sunitinib was induced by ketoconazole. Selection of an alternate concomitant medication with no or 
minimal enzyme inhibition potential is recommended. A dose reduction to a minimum of 37.5 mg dai- 
ly should be considered if sunitinib must be co-administered with a strong CYP3A4 inhibitor. 
 
Inducers of CYP3A4 may decrease sunitinib plasma concentrations and should be avoided. For ex- 
ample, St. John’s wort may decrease the plasma concentrations unpredictably and should not be 
taken concomitantly. Selection of an alternate concomitant medication with no or minimal enzyme 
induction potential is recommended. 


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In addition, concomitant treatment with the following drugs with dysrhythimic potential (i.e., terfena- 
dine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, and 
indapamide) is not recommended. 
 
16.15.3 
Sorafenib 
 
Avoid rifampin as it is a strong CYP3A4 inducer. Co-administration with sorafenib resulted in 37% 
decrease in the mean AUC of sorafenib. Avoid concomitant use of strong CYP3A4 inducers (such 
as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. John’s wort), 
when possible, because these drugs can decrease the systemic exposure to sorafenib. Strong inhi- 
bitors of CYP3A4 and P-glycoprotein, did not alter the mean AUC of sorafenib. 
 
The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility. 
However, omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 
days, did not result in a clinically meaningful change in sorafenib single dose exposure. No dose ad- 
justment for sorafenib is necessary. 
 
 
16.15.4 
Temsirolimus 
 
Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, 
ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of 
temsirolimus, respectively. If alternatives cannot be used, dose modifications of temsirolimus are 
recommended. 
 
Avoid St. John's Wort which may decrease temsirolimus plasma concentrations, and grapefruit juice 
which may increase plasma concentrations of the major metabolite of temsirolimus. 
 
The combination of temsirolimus and sunitinib resulted in dose-limiting toxicity (grade 3/4 erythe- 
matous maculopapular rash, and gout/cellulitis requiring hospitalization). 
 
16.15.5 
Pazopanib 
 
In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is 
mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. So, co- 
administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) in- 
creases pazopanib concentrations and should be avoided. Alternate therapy that does not inhibit 
CYP3A4 should be considered. If co-administration of a strong CYP3A4 inhibitor is warranted, re- 
duce pazopanib dose to 400 mg. 
 
Grapefruit or grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase 
plasma concentrations of pazopanib. 
 
 
CYP3A4 inducers CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentra- 
tions. Consider an alternate concomitant medication with no or minimal enzyme induction potential. 
Pazopanib should not be used if chronic use of strong CYP3A4 inducers cannot be avoided. The 
concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentra- 
tions and should be avoided. Consider an alternate concomitant medication with no or minimal en- 
zyme induction potential. Pazopanib should not be used in patients who cannot avoid chronic use of 
strong CYP3A4 inducers. 
 
Concomitant administration of pazopanib with esomeprazole, a proton pump inhibitor (PPI), de- 
creased the exposure of pazopanib by approximately 40% (AUC and Cmax). As a result, concomi- 
tant use of pazopanib with drugs that raise gastric pH should be avoided. If such drugs are needed, 
short-acting antacids should be considered in place of PPIs and H2-receptor antagonists. Separate 
antacid and pazopanib dosing by several hours to avoid a reduction in pazopanib exposure. 


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16.15.6 
Axitinib 
 
Concomitant administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma 
AUC. Co-administration of axitinib with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or 
grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection 
of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a 
strong CYP3A4/5 inhibitor must be co-administered, the dose should be reduced to half the normal 
dose as this dose reduction is predicted to adjust the axitinib area under the plasma concentration 
vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be in- 
creased or decreased based on individual safety and tolerability. 
 
Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axiti- 
nib Co-administration of axitinib with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, 
phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be 
avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is 
recommended. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and 
nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. 
 
 
16.15.7 
Cabozatinib 
Concomitant use of a strong CYP3A4 inhibitors such as grapefruit juice, indinavir, itraconazole, or 
ketoconazole should be avoided. Ketoconazole (400 mg daily for 27 days) increased single-dose 
plasma cabozantinib exposure (AUC0-inf) by 38%. If concomitant administration cannot be avoided, 
reduce cabozatinib dose by 40mg daily. Resume dose that was used prior to initiating the CYP3A4 
inhibitor 2 to 3 days after discontinuation of inhibitor. 
 
Concomitant  use of a strong CYP3A4 inducer such as rifampin, phenytoin, carbamazepine, pheno- 
barbital, rifabutin, rifapentine, and St. John’s Wort should be avoided.  Rifampin (600 mg daily for 31 
days) decreased single-dose plasma cabozantinib exposure (AUC0-inf) by 77%. If concomitant ad- 
ministration cannot be avoided, increase cabozantinib dose by 40mg daily as tolerated with a maxi- 
mum dose of 180mg/day.  Resume the dose that was used prior to initiating the CYP3A4 inducer 2- 
3 days after discontinuation of inducer. 
 
 
Concomitant  use with gastric pH modifying agents such as proton pump inhibitor (PPI) esomepra- 
zole (40 mg daily for 6 days) did not have a clinically-significant effect on plasma cabozantinib expo- 
sure (AUC). 
 
16.16  STUDY MEDICATION COMPLIANCE 
 
Compliance will be assessed by the investigator or designee at each visit using pill counts for both 
everolimus and sunitinib. This information should be captured in the source document at each visit. 
 
Patients will be requested to bring their unused medication, including empty packaging, to 
the clinic at each visit. 
 
All doses taken by the patient and all dose changes during the study must be recorded on 
the Dosage Administration Record eCRF. 
 
The investigator or designee must keep documentation (overall drug accountability log for 
the study as well as individual study drug accountability records for each patient). of tablets 
administered, tablets used, dose changes, dates dispensed, and intervals between visits. 
 
Drug accountability will be monitored by the field monitor during site visits and at the comple- 
tion of the study. 


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16.17  References 
1. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and 
antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with can- 
cer. J Clin Oncol 2006;24(1):25-35. 
2. Robert C, Soria JC, Spatz A, Le Cesne A, Malka D, Pautier P, et al. Cutaneous side-effects of ki- 
nase inhibitors and blocking antibodies. Lancet Oncol 2005;6(7):491-500. 
3. Mendel DB, Laird AD, Xin X, Li G, Schreck R, Carver J, et al. Development of a preclinical phar- 
macokinetic/pharmacodynamic relationship for the angiogenesis inhibitor SU11248, a selective inhi- 
bitor of VEGF and PDGF receptor tyrosine kinases in clinical development. Proc Am Soc Clin Oncol 
2002;21:94. 
4. Everolimus (Afinitor) prescribing information; revised February 2014 
5. Axitinib (Inlyta) prescribing information; issued September 2013 
6. Sunitinib (Sutent) prescribing information 
7. Pazopanib (Votrient) prescribing information 
8. Sorafenib (Nexavar) prescribing information 
9. Cabozantinib (Cabometyx) prescribing information; issued April 2016 
10. Micromedex 2.0; Accessed 1 June 2014 


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17 
APPENDIX F: OBTAINING BIOPSY TISSUE FOR MOLECULAR DIAGNOSITCS 
 
Biopsy tissue samples are processed by flash freezing in liquid nitrogen (LN2) and embedding the 
sample in OCT medium for subsequent frozen tissue sectioning. Embedding in OCT embedding 
compound followed by flash freezing at -80°C not only preserves DNA, RNA, and protein integrity, 
but also enables sectioning of the frozen tissue. The advantage of this method is that the frozen 
OCT containing the specimen can be placed into a cryo-microtome chuck and sectioned. Frozen 
sections can be mounted on microscope slides and stained to characterize the tissue sample, de- 
termine the ratio of tumor to healthy tissure, and, if need be, microdissected to isolate specific cell 
populations. Expediting the processing is essential in order to ensure tissue integrity, which is the 
primary goal of the fresh/frozen tissue study. Tissue processing should be done immediately by a 
trained technician after biopsy is collected. 
 
Procedures to be followed: 
 
1.  The biopsy sample will be obtained by the interventional radiology and handed to a research 
coordinator. 
2.  The OCT compound is poured into a small plastic tray, the tissue sample is submerged in the 
compound, and the tray is placed on dry ice for freezing. After hardening of the OCT, the Di- 
vision of Oncology research coordinator will, if possible, transport OCT-embedded tissue 
immediately to CompanionDx for molecular analysis. If the tissue needs to be held at 
UTHealth for any reason (e.g., off-hours), the tissue will be held at -20°C no longer than 
overnight and transported on dry ice to the Division of Oncology’s -80°C freezer at IMM the 
next day and delivered to CompanionDx at the earliest opportunity. 
3.  Samples will be de-identified and given a barcode for tracking. 
4.  At CompanionDx, OCT-embedded tissues will be sectioned using the following prodecure: 
a) 
Clean work area and cryostat before beginning, wearing clean, sterile gloves. 
b) 
Clear all tissue debris from cyrostat with pressurized air and a vacuum and then wipe 
inside surfaces with 100% ethanol. 
c) 
Clean all instruments (forceps, brushes, pencils, etc) with 100% ethanol. 
d) 
Change blade on cyrostat between each block or at least between each different pa- 
tient or surgical pathology case number. If using nondisposable blades, clean careful- 
ly with 100% ethanol or RNA Zap, followed by a rinse with RNase-free water. 
e) 
Similar to sectioning paraffin sections place a chuck in stage and advance to fresh 
blade. Adjust the thickness dial to 5 microns. Shave blocks’ face until full representa- 
tion of tissue appears in shavings. Tease fine sections away from block with cold, 
fine-tipped paintbrush. Invert slide over section and allow section to melt to slide. Dip 
section 5 times in room temperatures acetone; briefly air dry, then replace slide in 
cryostat. Store cut slides either in cryostat or on dry ice until permanent storage. 
5.  Storing cut slides: Cut frozen sections should be stored in slide boxes wrapped air-tight in 
parafilm at -80°C for long-term storage and at -20°C for short-term storage (overnight). 
6.  After the completion of molecular analysis, tissues will be returned to the Division of Oncolo- 
gy lab for storage, in case molecular analysis needs to run a second time on that tissue 
block. Storage will be at -80°C.