Clinical trial NCT02761057
Conditions: Locally Advanced Papillary Renal Cell Carcinoma Metastatic Papillary Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v7 Stage IV Renal Cell Cancer AJCC v7 Type 1 Papillary Renal Cell Carcinoma Type 2 Papillary Renal Cell Carcinoma Unresectable Renal Cell Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2016-07-25; Completion date: 2023-10-19
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well cabozantinib s-malate, crizotinib, savolitinib, or sunitinib malate work in treating patients with kidney cancer that has spread from where it started to nearby tissue or lymph nodes or to other places in the body. Cabozantinib s-malate, crizotinib, savolitinib, and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving cabozantinib s-malate, crizotinib, or savolitinib will work better in treating patients with kidney cancer compared to sunitinib malate.

Detailed description:
PRIMARY OBJECTIVE:

I. To compare progression-free survival (PFS) in patients with metastatic papillary renal cell carcinoma (mPRCC) treated with sunitinib malate (sunitinib) to PFS in patients with mPRCC treated with MET kinase inhibitors.

SECONDARY OBJECTIVES:

I. To compare Response Evaluation Criteria in Solid Tumors (RECIST) response rate (RR; defined as the combined rate of confirmed and unconfirmed partial response \[PR\] and confirmed and unconfirmed complete response \[CR\]) in patients with mPRCC treated with sunitinib to RR in patients treated with putative MET inhibitors.

II. To compare overall survival (OS) in patients with mPRCC treated with sunitinib to OS in patients with mPRCC treated with putative MET inhibitors.

III. To compare the safety profile of sunitinib and putative MET inhibitors in patients with mPRCC.

TRANSLATIONAL OBJECTIVES:

I. To evaluate the prognostic and predictive value of MET mutations, MET copy number or other markers of MET signaling in patients with mPRCC treated with putative MET inhibitors.

II. To estimate the frequency of high oncometabolite levels in formalin-fixed, paraffin-embedded (FFPE) tissues of patients with advanced papillary renal cell carcinoma by liquid chromatography-mass spectrometry (LC-MS/MS) and estimate progression free survival for those with and without high oncometabolite levels being treated.

III. To correlate the mutational signature suggestive of a homologous recombination defect with high oncometabolite levels in patients with papillary renal cell carcinoma pRCC.

OUTLINE: Patients are randomized to 1 of 4 treatment arms. As of 12/5/18, patients will only be randomized to Arm I or Arm II.

ARM I: Patients receive sunitinib malate orally (PO) once daily (QD) on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.

ARM II: Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.

ARM III (CLOSED TO ACCRUAL 12/5/18): Patients receive crizotinib PO twice daily (BID) on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.

ARM IV (CLOSED TO ACCRUAL 12/5/18): Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.

After completion of study treatment, patients are followed up for 3 years.

Arms: arm 1: Patients receive sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. arm 2: Patients receive cabozantinib s-malate PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. arm 3: Patients receive crizotinib PO BID on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up. arm 4: Patients receive savolitinib PO QD on days 1-42. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT at screening and on study, undergo bone scan as clinically indicated, and undergo collection of plasma and serum samples at screening, on study, and during follow up.
Interventions: intervention 1: Biospecimen Collection intervention 2: Bone Scan intervention 3: Cabozantinib S-malate intervention 4: Computed Tomography intervention 5: Crizotinib intervention 6: Savolitinib intervention 7: Sunitinib Malate
Intervention descriptions: intervention 1: Undergo collection of plasma and serum samples intervention 2: Undergo bone scan intervention 3: Given PO intervention 4: Undergo CT intervention 5: Given PO intervention 6: Given PO intervention 7: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
Version Date:  September 15, 2020
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS
FROM:
Veronica Garcia, M.S., Protocol Coordinator II (E-mail:  vgarcia@swog.org) 
RE:
S1500, “A Randomized, Phase II Efficacy Assessment of Multiple MET Kinase Inhibitors 
(Cabozantinib [NSC #761968], Crizotinib [NSC #749005], Savolitinib [NSC #785348], and 
Sunitinib [NSC #736511]) in Metastatic Papillary Renal Carcinoma (PAPMET)” Study Chairs:  
Drs. S. K. Pal and P. N. Lara, Jr.
REVISION #14 
Study Chair: Sumanta K. Pal, M.D.
Phone number: 626/256-4673
E-mail: S1500question@swog.org  
Protocol Changes
(√) Other: Addition of Translational Medicine Sub-study
Sites using the CIRB as their IRB of record: The protocol and/or informed consent form changes have 
been approved by the CIRB and must be activated within 30 days of the CIRB posting of this notice
Sites not using the NCI CIRB: Per CTMB Guidelines, the protocol updates and/or informed consent 
changes must be approved by local IRBs within 90 days of distribution of this notice  
REVISION #14 
The above-referenced study has been updated as follows: 
1.
The Version date of the protocol and model consent were updated.  No other changes were 
made to the model consent form. 
2.
Title Page:  Dr. Brian Shuch’s contact information was updated on the title page.
3.
The Table of Contents was updated. 
4.
Section 1.3:  Two translational medicine objectives were added to include the objectives of the 
“Identification and Characterization of Oncometabolite-Induced DNA Repair Defects in Sporadic 
Papillary Kidney Cancer” TM sub-study.  
5.
Appendix 18.0:  The appendix was updated to include the TM study “Identification and 
Characterization of Oncometabolite-Induced DNA Repair Defects in Sporadic Papillary Kidney 
Cancer” as Appendix 18.4.  Subsequent sections were re-numbered.
6.
Appendix 18.4:  The TM sub-study “Identification and Characterization of Oncometabolite-
Induced DNA Repair Defects in Sporadic Papillary Kidney Cancer” was added. 
cc: 
PROTOCOL AND INFORMATION OFFICE
Naomi Balzer – Haas, M.D. (ECOG/ACRIN)
Mark Stein, M.D. (ECOG/ACRIN)
 
Daniel J. George, M.D. (Alliance)
Daniel Heng, M.D., M.P.H., F.R.C.P.C (CCTG)


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PRIVILEGED COMMUNICATION
Activation Date 4/5/16
FOR INVESTIGATIONAL USE ONLY
SWOG
TITLE
A Randomized, Phase II Efficacy Assessment of Multiple MET Kinase Inhibitors (Cabozantinib [NSC 
#761968], Crizotinib [NSC #749005], Savolitinib [NSC #785348], and Sunitinib [NSC #736511]) in 
Metastatic Papillary Renal Carcinoma (PAPMET)
NCT#02761057
STUDY CHAIRS: 
AGENTS: 
Principal Investigator:
NCI Supplied Agents (IND # 129330):
Sumanta K. Pal, M.D. (Medical Oncology) 
Cabozantinib (NSC #761968)
City of Hope Medical Center
Crizotinib (NSC #749005) 
Department of Medical Oncology 
Savolitinib (NSC #785348) 
1500 E. Duarte Road
Sunitinib Malate (NSC #736511) 
Duarte, CA 91010
Phone:  626/256-4673
FAX:  626/301-8233
E-mail:  S1500question@swog.org  
TRANSLATIONAL STUDY CO-CHAIR:
Primo N. Lara, Jr., M.D. (Medical Oncology)
Brian Shuch, M.D. (Urology)
UC Davis Cancer Center
Institute of Urologic Oncology
4501 X Street
Wasserman Bldg
Sacramento, CA 95817
300 Stein Plaza, Ste 368
Phone:  916/734-3771
Los Angeles, CA 90095
FAX: 916/734-7946
Phone:  310/206-8183
E-mail: S1500question@swog.org  
FAX:  310/794-3512
E-mail: bshuch@mednet.ucla.edu
ECOG/ACRIN STUDY CHAIR:
Naomi Balzer- Haas, M.D.
ECOG/ACRIN TRANSLATIONAL STUDY CO-CHAIR: 
Abramson Cancer Center
Mark Stein, M.D. (Translational Medicine)
3400 Spruce Street
Rutgers Cancer Institute of New Jersey
Perelman Center for Advanced Medicine
195 Little Albany Street
South Pavilion 7th Floor
New Brunswick, NJ 08903-2681 
Philadelphia, PA 19104
Phone:  732/235-6031
Phone:  215/662-7615
FAX:  732/235-6797
FAX:  215/349-8550
E-mail: mark.stein@rutgers.edu  
E-mail: Naomi.Haas@uphs.upenn.edu  
ALLIANCE STUDY CHAIR:
BIOSTATISTICIANS:
Daniel J. George, M.D.
Cathy M. Tangen, Dr.P.H. (Biostatistics)
Duke University Medical Center
Melissa Plets, M.S.
Box 102002
SWOG Statistics and Data Management Center
Durham, NC 27710
Fred Hutchinson Cancer Research Center
Phone:  919/668-8650
1100 Fairview Avenue North, M3-C102
FAX:  919/660-0178
P.O. Box 19024
E-mail:  daniel.george@duke.edu  
Seattle, WA 98109-1024
Phone:  206/ 667-4623
FAX: 206/667-4408 
E-mail: ctangen@fredhutch.org  
E-mail: mplets@fredhutch.org  


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CCTG STUDY CHAMPION: 
Daniel Heng, M.D. M.P.H. F.R.C.P.C.
Tom Baker Cancer Centre
ABC45, 1331-29 Street N.W.
Calgary, Alberta, Canada, T2N 4N2 
Phone: 403/521-3166
Fax: 403/283-1651
E-mail: daniel.heng@albertahealthservices.ca  
PARTICIPANTS 
ALLIANCE/Alliance for Clinical Trials in Oncology
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group
NRG/NRG Oncology
SWOG/SWOG 
CCTG/Canadian Cancer Trials Group


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TABLE OF CONTENTS
TITLE
.........................................................................................................................................................1
PARTICIPANTS............................................................................................................................................2
TABLE OF CONTENTS ...............................................................................................................................3
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION.......................5
SCHEMA.......................................................................................................................................................6
1.0
OBJECTIVES ..................................................................................................................................7
1.1
Primary Objective.............................................................................................................................7
1.2
Secondary Objectives ......................................................................................................................7
1.3
Translational Objectives...................................................................................................................7
2.0
BACKGROUND...............................................................................................................................7
3.0
DRUG INFORMATION ..................................................................................................................13
3.1
Cabozantinib s-malate (XL-184, EXEL-7184, EXEL-02977184, Cometriq®) (NSC #761968) (IND 
#129330) ........................................................................................................................................13
3.2
Crizotinib (Xalkori®, PF-02341066) (NSC # 749005) (IND #129330) ............................................21
3.3
Savolitinib (AZD6094, Volitinib) (NSC #785348) (IND #129330) ..................................................28
3.4
Sunitinib Malate (Sutent; SU011248 L-Malate salt; SU010398; PHA-290940AD; SU011248) 
(NSC 736511) (IND #129330) .......................................................................................................33
3.5
Drug Ordering, Accountability and Returns ...................................................................................41
3.6
Drug Information Useful Links and Contacts .................................................................................42
4.0
STAGING CRITERIA.....................................................................................................................42
5.0
ELIGIBILITY CRITERIA ................................................................................................................42
5.1
Disease Related Criteria ................................................................................................................42
5.2
Prior/Concurrent Therapy Criteria..................................................................................................43
5.3
Clinical/Laboratory Criteria.............................................................................................................45
5.4
Specimen Submission Criteria.......................................................................................................46
5.5
Regulatory Criteria .........................................................................................................................46
6.0
STRATIFICATION FACTORS.......................................................................................................47
7.0
TREATMENT PLAN ......................................................................................................................47
7.1
Pre-Medication ...............................................................................................................................47
7.2
Treatment.......................................................................................................................................47
7.3
Administration through G-tube .......................................................................................................48
7.4
Drug Compliance Documentation ..................................................................................................48
7.5
Full CDUS Reporting Requirement................................................................................................48
7.6
Criteria for Removal from Protocol Treatment ...............................................................................48
7.7
Discontinuation of Treatment .........................................................................................................49
7.8
Follow-Up Period............................................................................................................................49
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS..............................................49
8.1
NCI Common Terminology Criteria for Adverse Events ................................................................49
8.2
Dose Modifications.........................................................................................................................49
8.3
Dose Modifications for Hypertension .............................................................................................51
8.4
Dose modifications for QTc prolongation in patients receiving savolitinib.....................................54
8.5
Dose Modifications Contacts .........................................................................................................55
8.6
Adverse Event Reporting ...............................................................................................................55
9.0
STUDY CALENDAR......................................................................................................................56
9.1
Arm A .............................................................................................................................................56
10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS .....................................................59
10.1
Measurability of Lesions.................................................................................................................59
10.2
Objective Status at Each Disease Evaluation................................................................................59
10.3
Best Response...............................................................................................................................61
10.4
Performance Status .......................................................................................................................62
10.5
Time to Death.................................................................................................................................62
10.6
Progression-Free Survival..............................................................................................................62
11.0
STATISTICAL CONSIDERATIONS..............................................................................................63
11.1
Accrual Goal...................................................................................................................................63


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11.2
Analysis of Primary Endpoint .........................................................................................................63
11.3
Secondary Endpoints.....................................................................................................................64
11.4
TM Aims: ........................................................................................................................................64
11.5
Data and Safety Monitoring Committee Oversight ........................................................................65
12.0
DISCIPLINE REVIEW....................................................................................................................66
13.0
REGISTRATION GUIDELINES.....................................................................................................66
13.1
Registration Timing ........................................................................................................................66
13.2
Investigator/Site Registration .........................................................................................................66
13.3
OPEN Registration Requirements .................................................................................................69
13.4
Registration Procedures.................................................................................................................70
13.5
Exceptions to SWOG registration policies will not be permitted....................................................71
14.0
DATA SUBMISSION SCHEDULE ................................................................................................71
14.1
Data Submission Requirement ......................................................................................................71
14.2
Master Forms .................................................................................................................................71
14.3
Data Submission Procedures ........................................................................................................71
14.4
Data Submission Overview and Timepoints ..................................................................................72
15.0
SPECIAL INSTRUCTIONS............................................................................................................74
15.1
Translational Study: Next generation sequencing (Optional for patient) .......................................74
15.2
Plasma, Buffy Coat, and Serum Blood Specimen Banking (Optional for patient) .........................75
15.3
SHIPPING SAMPLES:...................................................................................................................76
16.0
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................78
16.1
Adverse Event Reporting Requirements........................................................................................80
17.0
BIBLIOGRAPHY............................................................................................................................85
18.0
APPENDIX.....................................................................................................................................87
18.1a
Intake Calendar: S1500 Arm 1 Sunitinib........................................................................................88
18.1b
Intake Calendar: S1500 Arm 2 Cabozantinib ................................................................................89
18.1c
Intake Calendar: S1500 Arm 3 Crizotinib.......................................................................................90
18.1d
Intake Calendar: S1500 Arm 4 Savolitinib .....................................................................................91
18.2
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 ......................................92
18.3a
Cabozantinib Patient Drug Information Handout and Wallet Card ................................................97
18.3b
Crizotinib Patient Drug Information Handout and Wallet Card ......................................................99
18.3c
Savolitinib Patient Drug Information Handout and Wallet Card...................................................101
18.3d
Sunitinib Patient Drug Information Handout and Wallet Card......................................................103
18.4
Identification and Characterization of Oncometabolite-Induced DNA Repair Defects in Sporadic 
Papillary Kidney Cancer...............................................................................................................105
18.5
Specimen Banking and Translational Medicine Material Instructions for SWOG Biospecimen 
Bank (BB).....................................................................................................................................114


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION
For regulatory requirements:
For patient enrollments:
For study data submission:
Regulatory documentation must 
be submitted to the CTSU via
the Regulatory Submission 
Portal: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
at 866-651-2878 to receive 
further information and support.  
Contact the CTSU Regulatory
Help Desk at 866-651-2878 for 
regulatory assistance.
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Please see the 
data submission section of the 
protocol for further instructions. 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Via the SWOG 
website (www.swog.org).
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.  
For patient eligibility or data submission questions contact the SWOG Data Operations Center by 
phone or email:
206/652-2267
guquestion@crab.org 
For treatment or toxicity related questions contact the Study Chair by phone or email: (Dr. Sumanta 
K. Pal at 626/256-4673)
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org.


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SCHEMA
Metastatic Type I or II Papillary
Renal Cell Carcinoma
RANDOMIZATION (1:1:1:1)
Arm 1  
 
Arm 2  
 
Arm 3*  
Arm 4* 
   Sunitinib 
 
Cabozantinib 
 
  Crizotinib
  Savolitinib 
Treatment until Progression
Follow Up
For a Maximum of
3 Years Post Randomization
* As of 12/05/18, patients will no longer be randomized to crizotinib or savolitinib based on 
findings from an interim analysis evaluating futility.  


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1.0
OBJECTIVES
In the current study, we will explore the hypothesis that inhibitors of MET kinase signaling will 
delay tumor growth in patients with metastatic papillary renal cell carcinoma (mPRCC) to a 
greater extent than standard of practice therapies such as the VEGFR inhibitor sunitinib.
1.1
Primary Objective
To compare progression-free survival (PFS) in patients with mPRCC treated with 
sunitinib to PFS in patients with mPRCC treated with MET kinase inhibitors.
1.2
Secondary Objectives 
a.
To compare RECIST response rate (RR; defined as the combined rate of 
confirmed and unconfirmed PR and confirmed and unconfirmed CR) in patients 
with mPRCC treated with sunitinib to RR in patients treated with putative MET 
inhibitors.
b.
To compare overall survival (OS) in patients with mPRCC treated with sunitinib to 
OS in patients with mPRCC treated with putative MET inhibitors.
c. 
To compare the safety profile of sunitinib and putative MET inhibitors in patients 
with mPRCC.
1.3
Translational Objectives
a.
To evaluate the prognostic and predictive value of MET mutations, MET copy 
number or other markers of MET signaling in patients with mPRCC treated with 
putative MET inhibitors.
b.
To estimate the frequency of high oncometabolite levels in formalin-fixed, 
paraffin-embedded (FFPE) tissues of patients with advanced papillary renal cell 
carcinoma by liquid chromatography–mass spectrometry (LC-MS/MS) and 
estimate progression free survival for those with and without high oncometabolite 
levels being treated.  
  
c.
To correlate the mutational signature suggestive of a homologous recombination 
defect with high oncometabolite levels in patients with papillary renal cell 
carcinoma pRCC.    
2.0
BACKGROUND
Overview of Papillary Renal Cell Carcinoma
Papillary renal cell carcinoma (pRCC) is the most prevalent form of non-clear cell renal cell 
carcinoma (RCC); there are between 6,000 – 9,000 cases per year and they represent about 10-
15% of all cases of RCC.  Males exceed females by approximately three-fold.  (1,2)  Most 
pRCCs are unilateral but pRCC is the most common multifocal or bilateral renal tumor.  (3)
PRCC has been subdivided histologically into two distinct classes (type I and type II); as 
discussed subsequently, there appear also to be molecular features that distinguish them.  A
familial or hereditary form of pRCC has been described in type I patients that is characterized by 
development of multiple, bilateral papillary renal tumors and associated with heterozygous 
germline mutation in the MET proto-oncogene on chromosome 7q31.  Somatic mutations in the 
MET gene have also been identified in up to 13% of papillary renal cell carcinomas.  (4)
The Role of MET in Papillary Renal Cell Carcinoma


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Recently, a great deal of attention has been focused on the status of MET signaling in pRCC.  
Over a decade ago, Sweeney et al. reported an analysis of MET expression in a series of 51 
patients with pRCC. (5) Cytoplasmic expression of MET was seen in 80% of the tumors 
assessed, while membrane expression of MET was seen in 56%. A trend towards poorer
survival with increased MET expression was noted in this series. A more recent tissue 
microarray based study including a total of 330 human RCC specimens suggested that MET 
expression was highest in papillary and sarcomatoid subtypes of RCC (compared to clear cell,
although both clear and non-clear cell RCC expressed higher MET levels than adjacent kidney 
parenchyma) and, similarly, that increased MET expression was associated with poorer survival. 
(6) 
In what is perhaps the most detailed assessment of MET aberrations to date, Albiges et al. 
assessed a series of 220 frozen tissues derived from patients with sporadic pRCC in the French
RCC Network.  (7) Gene expression was assessed in 98 of these specimens, and ultimately 
suggested high MET expression level across all patients with pRCC.  Notably, assessment of 
copy number pointed to the importance of MET in both type I and type II pRCC; specifically, 81% 
to patients with type I pRCC had copy number alterations, as compared to 46% in type II pRCC.  
Somatic mutations of the MET gene were identified in 11/51 (21.6%) of type I pRCC samples 
examined.
A preliminary report from the TCGA Kidney Renal Papillary Working Group described the 
comprehensive molecular characterization of 161 primary pRCC (75 type I, 60 type II and 26
unclassified).  In addition to MET somatic (9.3%) and germline (1.9%) mutations, two in-frame 
translocations involving the MET gene (fusion partners BAIAP2L1 and C8orf34) were described.  
An alternate MET RNA splicing isoform that codes for a shortened stable form of MET protein 
was also observed.  This new splice variant may represent a mechanism of ligand-independent 
MET activation.  These MET alterations were mutually exclusive and occurred predominantly in 
Type I pRCC tumor samples.  The previously recognized correlation between increased MET 
copy number and elevated MET expression was confirmed.  The study highlighted the diverse 
alterations leading to MET activation in pRCC and raised the question of molecular genotype and 
response to MET inhibitors. 
Current Treatment Standards for Advanced Papillary Renal Cell Carcinoma
There is no FDA-approved standard of care for the treatment of either subtype of mPRCC.  
Several efforts have been made to characterize the activity of vascular endothelial growth factor 
(VEGF)-directed therapies in this setting (Table 1).  A single-institution retrospective analysis 
suggested a low response rate (RR) with sunitinib, but an appreciable progression-free survival 
(PFS) of 11.9 months.  (8) Subsequent prospective studies have suggested a more modest PFS 
in association with sunitinib – for instance, Ravaud et al. reported a PFS of 6.6 months and 5.5 
months in a series of 61 patients with type I and type II mPRCC, respectively.  (9) Tannir et al.
examined a smaller series of mPRCC patients (n=27), with a sobering PFS of 2.7 months.  (10) 
Table 1. Studies evaluating sunitinib in mPRCC.
Agent 
N 
Source 
Key Descriptors/Findings
Sunitinib 
53 
Choueiri et al.
(J Clin Oncol 
2008) 
•
Retrospective analysis
• 
Histology: 
Papillary/Chromophobe 
• 
41 pts with papillary 
• 
Median PFS of 7.6 mos in 
papillary 
•
RR of 5% in papillary


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Sunitinib 
57 
Tannir et al. 
(Eur Urol 2012) 
•
Histology: Non-clear cell
• 
27 pts with papillary
• 
Median PFS 1.6 mos in 
papillary 
•
RR 0% in papillary
Sunitinib 
61 
Ravaud et al.
(Ann Oncol
2012)
(SUPAP) 
•
Histology: Papillary
• 
RR 13%/11% in Type 1/2
• 
PFS 6.6/5.5 mos in Type 1/2
Approximately 20% of patients enrolled on the pivotal Phase III assessment of temsirolimus, a 
mammalian target of rapamycin (mTOR) inhibitor, did possess non-clear cell histology.  (11) 
Consistent with findings for the overall study population, subset analyses from this study 
suggested that patients with non-clear cell histology derived greater benefit with respect to OS.  
(12) Other than this, scant prospective data are available to document the activity of mTOR 
inhibitors in mPRCC.  One Phase II study reported by Koh et al. included 29 patients, with an 
associated RR and PFS of 7% and 5.2 months, respectively.  (13)
Some comparative data can be gained from the RECORD-3 trial, which compared the sequence 
of sunitinib and everolimus and vice versa. (14)  Among patients with non-clear cell disease 
(n=64), first-line PFS with sunitinib in non-clear cell patients appeared to be slightly higher (7.23 
months versus 5.09 months; HR 1.54, 95%CI 0.86-2.75).  In the recently reported ESPN study, a 
heterogeneous mix of patients with non-clear cell disease was randomized to receive either 
sunitinib or everolimus.  (15)  In this study, median PFS with 1st-line sunitinib was 6.1 months as 
compared to 4.1 months with everolimus (P=0.25).
Given these data, moving forward, sunitinib is considered the preferred comparator in studies 
assessing novel targeted agents in pRCC.  It is for this reason that we have proposed a 
randomized, Phase II design, with individual comparisons of experimental agents to sunitinib.
A Potential Role for MET Inhibitors in Papillary Renal Cell Carcinoma
As noted, there is no standard of care for treating mPRCC – the bulk of data accumulated thus far
is from retrospective analyses or from small prospective Phase II trials evaluating either 
VEGF/VEGFR-directed therapies or mTOR inhibitors.  Because of the discouraging results noted 
in many of these efforts, investigators have been pursuing therapeutic avenues that better reflect 
the biology of the disease.  For instance, targeting MET signaling in type I mPRCC is a rational 
strategy based on increased MET expression and frequently observed aberrations in MET.  In 
one series of 51 patients with pRCC, cytoplasmic and membrane expression of MET was noted 
in 80% and 56% of specimens, respectively, and was associated with poor prognosis. (16)  In a 
larger series of RCC patients (n=330), MET expression was significantly higher in patients with 
pRCC, and was again associated with poorer survival. (17)
There are multiple MET inhibitors currently in clinical development by different pharmaceutical
companies and it is not clear which of these is the most efficacious.  The current trial would 
explore type I (MET-specific) and type II (multi-kinase) small molecule MET inhibitors that are at 
varying stages of clinical development.  While the approach of separate Phase II evaluations 
could be considered, having a randomized Phase II trial incorporating the full spectrum of 
therapies with a common comparator arm would allow for more efficient evaluation of these 
agents.  Careful inferences could be made about comparative efficacy and toxicity and facilitate 
selection of appropriate agents for subsequent monotherapy Phase III testing or combination 
therapy.  Given the rather small proportion of patients with mPRCC (roughly 10-15% of the 
mRCC population), the “umbrella” platform design proposed herein is considered to be optimal. 


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Choueiri et al. recently reported a Phase II assessment of the multikinase inhibitor foretinib in 
patients with pRCC. (18)  Foretinib has substantial activity against MET, as well as VEGFR,
RON, AXL and Tie-2. (19)  Among 57 evaluable patients, RR was 13.5% and median PFS was 
9.3 months. The RR was significantly higher in patients bearing germline mutations in MET (5 of
10, or 50%) as compared to those without (5 of 57, or 9%).  Notably, the mutations were relatively
infrequent.
Dr. Pal, the Study Chair of the current proposal, was one of several investigators involved with a 
Phase I study evaluating cabozantinib in metastatic clear cell RCC. (20)  This dual inhibitor of 
VEGFR2 and MET displayed significant activity in a heavily-pretreated patient population – 
amongst 25 patients, 17 patients (64%) had received 2 or more prior lines of therapy.  The overall 
RR was 28%, with a median PFS of 14.7 months.  Although this study included patients with clear 
cell disease, the high activity demonstrated in this experience suggests a potential synergy 
between targeting VEGF and MET simultaneously.  Several other putative MET inhibitors are 
currently in clinical development; their status in overall clinical development and in pRCC is noted 
in Table 2. 
Table 2. Current status of MET and HGF inhibitors. 
Manufacturer
Compound
Status
Status in pRCC
•  
Amgen
AMG-337
Phase I, II (Gastric)
• No data available
Astra-Zeneca
Savolitinib 
(HMPL-504)
Phase I/II (PRCC)
• Preclinical in vitro activity-
pRCC cell lines, Schuller 
et al; CCR 2015
Eisai
Golvatinib 
(E7050)
Phase III (Melanoma)
Phase I/II 
(Hepatocellular)
• No data available
EMD-Serono
EMD1214063
Phase I
• No data available 
Exelixis
Cabozantinib 
(XL184)
Approved (Medullary 
thyroid cancer)
Phase III METEOR trial
in RCC
• Activity in ACHN pRCC
cell line*
Novartis
INCB28060
Phase I
• No data available
Lilly
LY2801653
Phase I
• No data available
Pfizer 
Crizotinib
Phase III (NSCLC) 
• Approved for ALK+ 
NSCLC
• Activity in ACHN pRCC 
cell line* 
• Multi-histology Phase II 
(including mPRCC) 
underway 
(NCT01524926)
Sanofi-
Aventis
SAR155844
Phase I  
• No data available
Janssen
J&J38877605
Phase I
• No data available
GSK
Foretinib
Phase II
• Phase II data in pRCC 
available (Choueiri et al. J 
Clin Oncol 2010)
Mirati
MGCD265 
Phase II
• No data available


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Deciphera
Altiranib
Phase I 
• No data available
Abbvie 
ABT700
Phase I
• No data available
Pieris
PRS110
Preclinical
• No data available
Aveo
Ficlatuzumab
Phase I
• No data available
Amgen
Rilotumumab
Phase III (Gastric)
• No data available
Takeda
TAK-701
Phase I
• No data available
Source: http://www.clinicaltrials.gov and *Jeremy Jones, PhD (City of Hope).
As noted, the preponderance of agents have little data to date in pRCC.  However, Jeremy 
Jones, Ph.D. (City of Hope) has performed some preliminary assessments of cytotoxicity in the 
RENCA (clear cell) and ACHN (papillary) cell line using sunitinib, cabozantinib and crizotinib:
Figure 1 Cytotoxicity with cabozantinib and crizotinib in ACHN and RENCA cell lines.
At physiologic concentrations, it appears that both cabozantinib and crizotinib exhibit significant 
cytotoxicity in the ACHN cell line.  Interestingly, the activity of cabozantinib (which is currently 
being explored in a Phase III study in clear cell mRCC) appears to be higher in the papillary 
model examined as compared to the clear cell model (RENCA).  Dr. Jones is currently working to 
develop xenografts bearing ACHN tumors for further examination of these compounds.
Schuller and colleagues reported on the anti-tumor efficacy and pharmacodynamics of a type I 
(specific) MET inhibitor Savolitinib against two patient xenograft derived pRCC cell line models
with MET amplification.  Savolitinib induced tumor regressions in vivo in both cell lines at clinically 
relevant concentrations.  The investigators also demonstrated inhibition of MET activation (pMET) 
and activation of apoptotic signaling in tumors that regressed.  Savolitinib was superior to 
sunitinib, which had limited anti-tumor activity in these two pRCC models.
As these experiments demonstrate, MET inhibition holds promise as a therapeutic strategy for 
mPRCC.  Furthermore, there is no shortage of MET inhibitors available for clinical examination.  
As previously noted, an independent examination of these MET inhibitors in pRCC would be
highly inefficient, requiring high number of patients derived from a relatively small population.  
Furthermore, if multiple agents showed activity, it would be challenging to decide upon the
optimal treatment without randomized data – again requiring substantial numbers of patients and 
extensive resources.
Inclusion of Women and Minorities


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This study was designed to include women and minorities but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.


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DOMESTIC PLANNED ENROLLMENT REPORT
Racial 
Categories
Ethnic Categories
Total
Not Hispanic or Latino
Hispanic or Latino
Female
Male
Female
Male
American 
Indian/
Alaska Native
0
2
0
0
2
Asian
2
2
0
1
5
Native 
Hawaiian or 
Other Pacific 
Islander
0
0
0
0
0
Black or 
African 
American
7
14
2
2
25
White
46
86
5
11
148
More Than 
One Race
0
0
0
0
0
Total
55
104
7
14
180
3.0
DRUG INFORMATION
Investigator Brochures
For information regarding Investigator Brochures, please refer to SWOG Policy 15.
For this study cabozantinib, crizotinib, savolitinib and sunitinib are considered investigational and 
are being provided under an IND held by the National Cancer Institute.  Investigator Brochure 
Availability:  The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) application.  Access 
to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an “active” account status, a “current” password, and active person 
registration status.  Questions about IB access may be directed to the PMB IB coordinator via 
email (ibcoordinator@mail.nih.gov). 
3.1
Cabozantinib s-malate (XL-184, EXEL-7184, EXEL-02977184, Cometriq®)
(NSC 
#761968) (IND #129330) 
a. 
PHARMACOLOGY
Mechanism of Action: XL-184 (cabozantinib) inhibits several receptor tyrosine 
kinases (RTKs).  Activated RTKs stimulate various
intracellular
signaling 
pathways that lead to cell survival and/or proliferation, tumor growth, angiogenesis
and metastasis.  Cabozantinib inhibits the following RTKs; RET; met proto-
oncogene encoding hepatocyte growth factor (c-MET); vascular endothelial
growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3; stem cell factor 
receptor (c-Kit); tropomyosin receptor kinase B (trkB); fms-like tyrosine kinase 3
(Flt-3); AXL; ROS1, RON and TIE-2.
b.
PHARMACOKINETICS 
1.
Absorption: 
Following oral administration, the median time to peak 
plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose.  Area 


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under the concentration-time curve (AUC) indicated that daily
administration of 140 mg cabozantinib for 19 days resulted in 4-fold to 5-
fold mean
cabozantinib accumulation compared to single-dose 
administration. Steady-state concentrations of the drug were achieved in
15 days.  In healthy individuals, administration of a single 140 mg oral 
dose of the drug followed by a high-fat meal increased the peak plasma 
concentration and AUC of cabozantinib by 41 and 57%, respectively, 
compared to fasted conditions.
2.
Distribution: Cabozantinib is highly bound to plasma proteins (>99.7%). 
The oral volume of distribution (V/F) is approximately 349 L.
3.
Metabolism: Cabozantinib is metabolized in the liver by cytochrome P-
450 (CYP) isoenzyme 3A4. In vitro studies showed that cabozantinib 
malate is a substrate of CYP3A4, is an inducer of CYP1A1 mRNA, a 
mixed-type 
inhibitor 
of 
both 
CYP2C9
and 
CYP2C19 
and 
a 
noncompetitive inhibitor of CYP2C8. 
However when a single-dose 
rosiglitazone was coadministered with cabozantinib at steady state, the 
plasma exposure (Cmax and AUC) of rosiglitazone (a CYP2C8 
substrate) was unaffected. Inhibition of CYP2C9 had minimal effects on 
cabozantinib metabolite formation (i.e., less than a 20% reduction).  In 
vitro studies showed that cabozantinib malate is an inhibitor of P-
glycoprotein (P-gp) transport activities and may increase the plasma 
levels of P-gp substrates.  The XL184 N-oxide metabolite forms via 
CYP3A4 isoenzymes. In vitro studies showed that inhibition of CYP3A4 
reduced the formation of the XL184 N-oxide metabolite by more than 
80%.  Inhibition of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C19, 2D6,
and 2E1 had no effect on cabozantinib metabolite formation.
4.
Elimination:  Healthy individuals were administered a single dose of
radiolabeled cabozantinib, approximately 81% of the total administered 
radioactivity was recovered (54% in feces and 27% in urine) within 48
days. The total body cabozantinib clearance is estimated to be 4.4 L/hr 
at steady state. The study did not identify clinically relevant differences 
in cabozantinib clearance based on gender, age, race or the presence of 
mild to moderate renal impairment (CrCl 30 mL/min or greater).  The 
elimination half-life of cabozantinib is approximately 55 hours.
c. 
ADVERSE EFFECTS 
1.
Adverse Effects:   
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This 
subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification.  Frequency is provided based on 
3219 patients. Below is the CAEPR for XL184 (Cabozantinib).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 


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listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.
Version 2.4., December 17, 20181
Adverse Events with Possible 
Relationship to XL184 (Cabozantinib)
(CTCAE 5.0 Term)
[n= 3219]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM 
DISORDERS
Anemia
ENDOCRINE DISORDERS
Hypothyroidism
Hypothyroidism (Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain (Gr 3)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 3)
Dry mouth
Dry mouth (Gr 2)
Dyspepsia
Dyspepsia (Gr 2)
Gastrointestinal 
fistula2
Gastrointestinal 
hemorrhage3
Gastrointestinal 
perforation4
Mucositis oral
Mucositis oral (Gr 3)
Nausea
Nausea (Gr 3)
Oral pain
Oral pain (Gr 2)
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS
Edema limbs
Fatigue
Fatigue (Gr 3)
INFECTIONS AND INFESTATIONS
Infection5
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS
Wound 
complication
INVESTIGATIONS
Alanine 
aminotransferas
e increased
Alanine 
aminotransferase 
increased (Gr 3)
Aspartate 
aminotransferas
e increased
Aspartate 
aminotransferase
increased (Gr 3)
Lipase 
increased
Lipase increased (Gr 
4)


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Adverse Events with Possible 
Relationship to XL184 (Cabozantinib)
(CTCAE 5.0 Term)
[n= 3219]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Platelet count 
decreased
Platelet count 
decreased 
(Gr 3)
Weight loss
Weight loss (Gr 3)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 3)
Dehydration
Hypocalcemia
Hypokalemia
Hypomagnesem
ia
Hypophosphate
mia
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS
Arthralgia
Generalized 
muscle 
weakness
Muscle cramp
Osteonecrosis of
jaw
Pain in extremity
NERVOUS SYSTEM DISORDERS
Dizziness
Dysgeusia
Dysgeusia (Gr 2)
Headache
Intracranial 
hemorrhage 
Ischemia 
cerebrovascular
Reversible
posterior
leukoencephalop
athy syndrome
Stroke
Transient 
ischemic attacks
RENAL AND URINARY DISORDERS
Hematuria
Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS
Cough
Dyspnea
Pneumothorax6


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Adverse Events with Possible 
Relationship to XL184 (Cabozantinib)
(CTCAE 5.0 Term)
[n= 3219]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Respiratory 
fistula7
Respiratory 
hemorrhage8
Voice alteration
Voice alteration (Gr 3)
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS
Alopecia
Dry skin
Dry skin (Gr 2)
Hair color 
changes
Hair color changes (Gr 
1)
Palmar-plantar
erythrodysesthesia 
syndrome
Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 3)
Rash maculo-
papular
Rash maculo-papular 
(Gr 3)
VASCULAR DISORDERS
Hypertension
Hypertension (Gr 3)
Thromboembolic
event9
1This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be
obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail.
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal 
fistula, Esophageal fistula, Enterovesical fistula, Gastric fistula,
Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the 
GASTROINTESTINAL DISORDERS SOC.
3Gastrointestinal 
hemorrhage 
includes 
Anal 
hemorrhage, 
Cecal 
hemorrhage, Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal 
hemorrhage, 
Ileal 
hemorrhage, 
Intra-abdominal
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage 
under the GASTROINTESTINAL DISORDERS SOC.
4Gastrointestinal perforation includes Colonic perforation, Duodenal
perforation, Esophageal perforation, Gastric perforation, Ileal perforation, 
Jejunal perforation, Rectal perforation, and Small intestinal perforation 
under the GASTROINTESTINAL DISORDERS SOC.


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5Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.
6Pneumothorax has been observed at a higher than expected frequency 
(15-20%) in a study treating patients with relapsed Ewing sarcoma and 
osteosarcoma all of whom had pulmonary metastases.
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, 
Laryngeal fistula, Pharyngeal fistula, Pulmonary fistula, and Tracheal 
fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC.
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, 
Epistaxis, Hemoptysis, Laryngeal hemorrhage, Mediastinal hemorrhage, 
Pharyngeal 
hemorrhage, 
and 
Pleural 
hemorrhage 
under
the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC.
9Thromboembolic event includes pulmonary embolism which may be life-
threatening.
Adverse events reported on XL184 (Cabozantinib) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that XL184 (Cabozantinib) caused the 
adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS
-
Blood and 
lymphatic system disorders -
Other (pancytopenia);
Disseminated 
intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic 
uremic syndrome
CARDIAC DISORDERS
-
Atrial fibrillation; Atrioventricular block
complete; Cardiac arrest; Cardiac disorders -
Other
(hypokinetic 
cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular 
systolic 
dysfunction; 
Myocardial 
infarction; 
Myocarditis; 
Sinus 
bradycardia; Sinus tachycardia; Supraventricular tachycardia
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune 
thyroiditis); Endocrine disorders - Other (thyroiditis); Endocrine disorders 
- Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other 
(corneal epithelium defect)
GASTROINTESTINAL DISORDERS
-
Abdominal distension; Anal 
fissure; Anal mucositis; Anal pain; Anal ulcer; Cheilitis; Colitis; Colonic 
obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; 
Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (glossitis); Gastrointestinal disorders -
Other 
(pneumoperitoneum); 
Gastrointestinal 
pain; 
Gingival 
pain; 
Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; 
Rectal ulcer; Toothache
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Chills; Death NOS; Edema face; Fever; Gait disturbance; General 
disorders and administration site conditions - Other (general physical
health deterioration);
General disorders and 
administration site
conditions - Other (implant site inflammation); Hypothermia; Malaise; 
Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death NOS


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HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; 
Hepatic 
failure;
Hepatobiliary 
disorders 
-
Other 
(cholelithiasis); 
Hepatobiliary disorders -
Other (hepatic cirrhosis); Hepatobiliary 
disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other 
(hepatitis toxic); Hepatobiliary disorders - Other (hepatorenal syndrome); 
Portal vein thrombosis
IMMUNE
SYSTEM DISORDERS
-
Allergic reaction; Anaphylaxis; 
Autoimmune disorder
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; 
Injury, poisoning and procedural complications - Other (post procedural 
hemorrhage); Injury, poisoning and procedural complications - Other 
(tendon injury); Wound dehiscence; Wrist fracture
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin 
increased; Blood lactate dehydrogenase increased; CPK increased; 
Cardiac troponin I increased; Creatinine increased; Ejection fraction 
decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Investigations - Other (D-dimer); Investigations - Other (urine 
ketone body present); Lymphocyte count decreased; Neutrophil count 
decreased; Serum amylase increased; Thyroid stimulating hormone 
increased; White blood cell decreased
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; 
Hyperglycemia; 
Hypernatremia; 
Hyperuricemia; 
Hypoalbuminemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to
thrive); Metabolism and nutrition disorders - Other (hypoproteinemia)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS -
Back pain; Buttock pain; Chest wall pain; Flank pain; Muscle weakness 
lower limb; Musculoskeletal and connective tissue disorder - Other
(muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; 
Rhabdomyolysis
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (lip and/or oral cavity cancer); Tumor 
hemorrhage; Tumor pain
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; 
Concentration 
impairment; 
Dysarthria; 
Dysesthesia; 
Dysphasia; 
Encephalopathy;
Lethargy; Memory impairment; Nervous system 
disorders - Other (hemiparesis); Nervous system disorders - Other (vocal 
cord paralysis); Peripheral motor neuropathy; Peripheral sensory 
neuropathy; 
Presyncope; 
Seizure;
Somnolence; 
Spinal 
cord 
compression; Syncope
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; 
Hallucinations; Insomnia; Psychiatric disorders - Other (mental status 
changes)
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic
kidney disease;
Glucosuria; Renal and urinary disorders -
Other 
(hemorrhage urinary tract); Urinary tract obstruction
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; 
Reproductive 
system 
and 
breast 
disorders 
-
Other 
(scrotal 
ulcer/erythema/edema); 
Scrotal 
pain; 
Vaginal 
fistula; 
Vaginal 
inflammation; Vaginal perforation
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Allergic rhinitis; Aspiration; Atelectasis; 
Hoarseness; 
Hypoxia; 
Laryngeal 
edema; 
Oropharyngeal 
pain; 
Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; 
Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and


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mediastinal disorders - Other (nasal septum perforation); Respiratory, 
thoracic and mediastinal disorders - Other (pneumomediastinum); 
Respiratory, thoracic and mediastinal disorders - Other (rales); Sore 
throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema 
multiforme; Nail changes; Pain of skin; Pruritus; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (pain, sloughing of skin and 
erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); 
Skin hypopigmentation; Skin ulceration
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena 
cava syndrome; Vascular disorders - Other (bleeding varicose vein);
Vasculitis
Note: XL184 (Cabozantinib) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
2.
Pregnancy and Lactation: 
Pregnancy Category D. Cabozantinib can 
cause fetal harm if administered to a pregnant woman.  In animal 
reproduction studies, exposure below the recommended human dose 
were found to be embryolethal and resulted in increased incidences of 
skeletal and visceral variations and malformations.
Lactation studies have not yet been performed with cabozantinib malate. 
It is unknown whether cabozatinib malate or its metabolites are excreted 
in human milk. The potential benefits of drug treatment against potential 
risks need to weighed before prescribing this drug during breastfeeding.  
The manufacturer recommends discontinuing nursing or discontinuing 
drug, depending upon the importance of the drug to the mother. As 
many drugs are excreted in human milk and there is a potential for 
adverse effects in the nursing infant. 
3.
Drug Interactions: 
CYP450 isozymes:  Cabozantinib is a substrate of CYP3A4, potential 
inhibitor of P-glycoprotein transport activity, substrate of drug transporter
MRP2, highly protein bound and may interfere with other agents or 
patients that have a history of QT prolongation.  Due to potential drug 
interactions, a complete patient medication list including cabozantinib, 
should be screened prior to initiation of and during treatment with 
cabozanitinib.   See Appendix 18.2. 
d. 
DOSING & ADMINISTRATION
1.
See Section 7.0 Treatment Plan. 
e.
HOW SUPPLIED
1.
Cabozantinib is supplied by Exelixis and will be distributed by DCTD/NCI.
2.
Cabozantinib is available in 20 mg and 60 mg tablets. The tablets are 
yellow film-coated containing cabozantinib malate equivalent to 20 mg and
60 mg of cabozantanib. The 20 mg tablets have a round shape and the 60 
mg tablets have an oval shape, and they are packaged as 30 per bottle. 
Inactive ingredients include:  microcrystalline cellulose, lactose anhydrous, 


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hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium 
stearate, 
and 
opadry 
yellow 
film 
coating 
(HPMC 
2910/hypromellose 6 cp, titanium dioxide, tracetin, iron oxide yellow).
f.
STORAGE, PREPARATION & STABILITY
1.
Store intact bottles at controlled room temperature, 20° to 25°C (68° F to
77°F); temperature excursions are permitted between 15°C and 30° (59°F 
to 86°F) [see USP Controlled Room Temperature].
If a storage temperature excursion is identified, promptly return XL184 
(Cabozantinib) to 20° to 25°C (68° to 77°F) and quarantine the 
supplies. Provide 
a 
detailed 
report 
of 
the 
excursion 
(including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
2.
Sites and subjects are advised to dispense cabozantinib in its original 
container.  Cabozantinib tablets can be dispensed in a pill cup with an 
expiration date not to exceed 24 hours. It can also be repackaged in a 
HDPE prescription bottle with expiration date not to exceed 7 days.  
Labeling should be done in accordance to the law and contain the 
statement “CAUTION:  NEW DRUG – LIMITED BY FEDERAL LAW TO 
INVESTIGATIONAL USE”.
3.
Stability:  Stability testing of the intact bottles is on-going.
3.2
Crizotinib (Xalkori®, PF-02341066) (NSC # 749005) (IND #129330) 
a.
PHARMACOLOGY
Mechanism of Action:  Crizotinib is an inhibitor of receptor tyrosine kinases 
including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-
ros), and Recepteur d'Origine Nantais (RON). Translocations can affect the ALK
gene resulting in the expression of oncogenic fusion proteins. The formation of 
ALK fusion proteins results in activation and dysregulation of the gene's 
expression and signaling which can contribute to increased cell proliferation and 
survival in tumors expressing these proteins. 
Crizotinib demonstrated 
concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in
cell-based assays using tumor cell lines and demonstrated antitumor activity in 
mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion 
proteins or c-Met.
b. 
PHARMACOKINETICS
1.
Absorption: Crizotinib levels peak in 4-6 hours.  High-fat meals decrease 
AUCinf and Cmax by 14%.  Crizotinib may be administered with or without 
food.
2.
Distribution: Approximately 91% protein bound in healthy subjects.
3.
Metabolism: Predominantly metabolized by CYP3A4/5.  Crizotinib is also 
a P-glycoprotein substrate.
4.
Elimination:  Crizotinib is eliminated in both the feces and urine.  Single
dose crizotinib has a half-life of approximately 42 hours.  Multiple dosing 
results in autoinhibition and decreased mean apparent clearance.


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c.
ADVERSE EFFECTS  
1.
Adverse Effects: The Comprehensive Adverse Events and Potential 
Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive 
list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
2058 patients. Below is the CAEPR for crizotinib (PF-02341066).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required.
Version 2.3, October 30, 20181
 Adverse Events with Possible 
Relationship to Crizotinib (PF-02341066)
(CTCAE 5.0 Term)
[n= 2058]
Specific Protocol 
Exceptions to 
Expedited
Reporting 
(SPEER)  
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 2)
Febrile 
neutropenia
CARDIAC DISORDERS
Heart failure
Sinus 
bradycardia
ENDOCRINE DISORDERS
Testosterone 
deficiency
EYE DISORDERS
Eye disorders -
Other (vision 
disorders)2
Eye disorders -
Other (vision 
disorders)2 (Gr 2)
Periorbital edema
Periorbital edema 
(Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal 
pain
Abdominal pain (Gr 
2)
Colonic 
perforation


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 Adverse Events with Possible 
Relationship to Crizotinib (PF-02341066)
(CTCAE 5.0 Term)
[n= 2058]
Specific Protocol 
Exceptions to 
Expedited
Reporting 
(SPEER)  
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 2)
Dyspepsia
Esophageal 
ulcer
Esophagitis
Mucositis oral
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS
Edema face
Edema face (Gr 2)
Edema limbs
Edema limbs (Gr 2)
Fatigue
Fatigue (Gr 2)
Generalized edema
Generalized edema 
(Gr 2)
Localized edema
Localized edema (Gr 
2)
HEPATOBILIARY DISORDERS
Hepatic failure
Hepatobiliary 
disorders - 
Other 
(hepatotoxicity)
INFECTIONS AND INFESTATIONS
Upper 
respiratory 
infection
INVESTIGATIONS
Alanine 
aminotransfer
ase increased
Alanine 
aminotransferase 
increased (Gr 2)
Alkaline 
phosphatase 
increased
Aspartate 
aminotransfer
ase increased
Aspartate 
aminotransferase 
increased (Gr 2)
Blood bilirubin 
increased
Creatinine 
increased
Electrocardiogr


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 Adverse Events with Possible 
Relationship to Crizotinib (PF-02341066)
(CTCAE 5.0 Term)
[n= 2058]
Specific Protocol 
Exceptions to 
Expedited
Reporting 
(SPEER)  
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
am QT 
corrected 
interval 
prolonged
Lymphocyte
count 
decreased
Neutrophil count 
decreased
Neutrophil count 
decreased (Gr 2)
White blood 
cell
decreased
White blood cell 
decreased (Gr 2)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 2)
MUSCULOSKELETAL AND CONNECTIVE 
TISSUE DISORDERS
Muscle cramp
NERVOUS SYSTEM DISORDERS
Dizziness
Dizziness (Gr 2)
Dysgeusia
Dysgeusia (Gr 2)
Headache
Nervous 
system 
disorders - 
Other 
(neuropathy)3
Nervous system 
disorders - Other 
(neuropathy)3 (Gr 2)
Syncope
RENAL AND URINARY DISORDERS
Renal and 
urinary 
disorders - 
Other (renal 
cyst)
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS
Pneumonitis
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS
Rash4
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision. 
The current version can be obtained by contacting 


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pio@ctep.nci.nih.gov.
Your name, the name of the investigator, the 
protocol and the agent should be included in the e-mail.
2 Vision disorders may include the following: Chromatopsia, Diplopia, 
Halo vision, Photophobia, Photopsia, Vision blurred, Visual acuity 
reduced, Visual brightness, Visual impairment, Vitreous floaters, and 
Visual perseveration.
3 Neuropathy
may include the following:  Acute polyneuropathy, 
Amyotrophy, Areflexia, Autoimmune neuropathy, Autonomic failure 
syndrome, 
Autonomic 
neuropathy, 
Axonal 
neuropathy, 
Biopsy 
peripheral nerve abnormal, Burning feet syndrome, Burning sensation, 
Decreased 
vibratory 
sense, 
Demyelinating 
polyneuropathy, 
Dysesthesia, 
Electromyogram 
abnormal, 
Formication, 
Gait 
disturbance, 
Genital 
hypoesthesia, 
Guillain-Barre 
syndrome, 
Hyperesthesia,
Hypoesthesia, Hyporeflexia,
Hypotonia, Ischemic 
neuropathy,
Loss 
of 
proprioception,
Miller 
Fisher 
syndrome, 
Mononeuritis, Mononeuropathy, Mononeuropathy multiplex, Motor 
dysfunction, Multifocal motor neuropathy, Muscle atrophy, Muscular 
weakness, Myelopathy, Nerve conduction studies abnormal, Nerve 
degeneration, 
Neuralgia, 
Neuritis, 
Neuromuscular 
toxicity, 
Neuromyopathy, Neuropathy peripheral, Neuropathy vitamin B6 
deficiency, Neurotoxicity, Paresthesia, Peripheral motor neuropathy, 
Peripheral nerve lesion, Peripheral nerve palsy, Peripheral nervous 
system function test abnormal, Peripheral sensorimotor neuropathy, 
Peripheral sensory neuropathy, Peroneal muscular atrophy, Peroneal
nerve palsy, Phrenic nerve paralysis, Polyneuropathy, Polyneuropathy 
chronic, Polyneuropathy idiopathic progressive, Radiation neuropathy, 
Sensorimotor disorder,
Sensory disturbance, Sensory loss,
Skin 
burning sensation, Temperature perception test decreased, Tinel’s 
sign, Toxic neuropathy, and Ulnar neuritis.
4 Treatment-related rash may include erythematous rash, rash maculo-
papular, and pruritus.
Adverse events reported on crizotinib (PF-02341066) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that crizotinib (PF-02341066) caused the 
adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS -
Blood and 
lymphatic 
system 
disorders 
-
Other 
(basophilia); 
Disseminated 
intravascular coagulation; Eosinophilia; Leukocytosis
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain -
cardiac; Myocarditis; Pericardial effusion; Supraventricular tachycardia
EYE DISORDERS - Cataract; Optic nerve disorder; Papilledema
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Gastric ulcer; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(gastrointestinal amyloidosis); Ileus
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS -
Fever; General disorders and administration site conditions - Other 
(failure to thrive); Malaise; Non-cardiac chest pain
HEPATOBILIARY DISORDERS
-
Hepatobiliary disorders -
Other
(cholestasis); Hepatobiliary disorders - Other (hepatitis)
IMMUNE SYSTEM DISORDERS - Autoimmune disorder
INFECTIONS AND INFESTATIONS - Abdominal infection; Infections 
and infestations - Other (peridiverticular abscess); Kidney infection; Lung 
infection; Sepsis; Skin infection; Urinary tract infection


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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, 
poisoning and procedural complications - Other (traumatic lung injury); 
Spinal fracture; Wound complication
INVESTIGATIONS - Blood lactate dehydrogenase increased; CPK 
increased; GGT increased; Investigations - Other (monocyte count 
increased); Investigations - Other (platelet count increased); Platelet 
count decreased
METABOLISM
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperglycemia; Hyperkalemia; Hypermagnesemia; Hypertriglyceridemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypokalemia; 
Hyponatremia; 
Hypophosphatemia; Metabolism
and nutrition disorders - Other 
(hypoproteinemia)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthralgia; Musculoskeletal and connective tissue disorder - Other
(myopathy); Myalgia; Pain in extremity
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL
CYSTS AND POLYPS) - Treatment related secondary malignancy; 
Tumor hemorrhage
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia 
cerebrovascular; Pyramidal tract syndrome; Seizure; Stroke
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - 
Pregnancy loss
PSYCHIATRIC DISORDERS - Confusion; Delirium; Euphoria
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; 
Renal calculi; Urinary retention
RESPIRATORY,
THORACIC AND MEDIASTINAL DISORDERS - 
Bronchopulmonary hemorrhage; Dyspnea; Pleural effusion; Respiratory 
failure; Respiratory, thoracic and mediastinal disorders - Other 
(pneumomediastinum); Respiratory, thoracic and mediastinal disorders - 
Other (respiratory distress)
SKIN AND
SUBCUTANEOUS TISSUE DISORDERS -
Skin and 
subcutaneous tissue disorders - Other (drug eruption)
VASCULAR 
DISORDERS 
- 
Hematoma; 
Hypotension; 
Phlebitis; 
Thromboembolic event; Vasculitis
Note: Crizotinib (PF-02341066) in combination with other agents 
could cause an exacerbation of any adverse event currently known 
to be caused by the other agent, or the combination may result in 
events never previously associated with either agent.
2.
Pregnancy and Lactation: Pregnancy Category D.  Crizotinib can cause 
fetal harm when administered to a pregnant woman based on its
mechanism of action. Advise women of childbearing potential to avoid 
becoming pregnant while receiving crizotinib.  It is not known if crizotinib
is excreted in human milk.


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3.
Drug Interactions:  Crizotinib is primarily metabolized by CYP 3A4/5 with 
minor contributions from CYP2C8, CYP2C19, and CYP2D6. 
Avoid 
concomitant use of strong CYP3A inhibitors and inducers.  Use of potent 
CYP3A inducers should be avoided for at least 12 days prior to the first
dose of crizotinib.  Use of strong CYP3A inhibitors should be avoided for 
at least 7 days prior to the first dose of crizotinib.  Exercise caution with 
concomitant use of moderate CYP3A inhibitors.  Crizotinib moderately 
inhibits CYP3A4 in a time-dependent fashion.  Use caution with patients 
who receive CYP3A4 substrates with a narrow therapeutic index.  
Crizotinib is an inhibitor of
CYP2B6 in vitro. Use caution with 
coadministered drugs that are predominantly metabolized by CYP2B6.
Studies demonstrate that crizotinib is a substrate of P-gp and a weak 
BCRP inhibitor, however the potential to cause drug-drug interactions at 
therapeutic doses is low.  Crizotinib inhibited P-gp, OCT1, and OCT2 in 
vitro 
at 
clinically 
relevant 
concentrations. 
 
Use 
caution 
with 
coadministration of P-gp, OCT1, and OCT2 substrates.
Due to potential drug interactions, a complete patient medication list, 
including crizotinib, should be screened prior to initiation of and during 
treatment with crizotinib. See Appendix 18.2.
d.
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan. 
e.
HOW SUPPLIED
1.
Crizotinib is supplied by Pfizer and will be distributed by DCTD/NCI.
2.
Crizotinib is supplied as 200 mg (size 1, white opaque body and pink 
opaque cap, with “Pfizer” on the cap and “CRZ 200” on the body) and 
250 mg (size 0, pink opaque body and cap, with “Pfizer” on the cap and 
“CRZ 250 on the body) hard gelatin capsules.  Each bottle contains 60 
capsules.
Excipients include colloidal silicon dioxide, microcrystalline cellulose, 
anhydrous dibasic calcium phosphate, sodium starch glycolate, 
magnesium stearate, and hard gelatin capsule shells as inactive 
ingredients. The pink opaque capsule shell components contain gelatin,
titanium dioxide, and red iron oxide. The white opaque capsule shell 
components contain gelatin, and titanium dioxide. The printing ink
contains shellac, propylene glycol, strong ammonia solution, potassium 
hydroxide, and black iron oxide.
f.
STORAGE, PREPARATION & STABILITY
1.
Store at room temperature 20° to 25° C (68°F - 77°F), excursions 
permitted between 15 to 30°C (59 to 85°F).
If a storage temperature excursion is identified, promptly return crizotinib 
to between 15 and 30°C and quarantine the supplies.  Provide a detailed 
report of the excursion (including documentation of temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability.
2.
Stability: Shelf life is consistent with commercially-labeled product.


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3.3
Savolitinib (AZD6094, Volitinib) (NSC #785348) (IND #129330)
a.
PHARMACOLOGY
Mechanism of Action:  AZD6094 is a potent and selective small molecule cMet 
kinase inhibitor, with IC50 of 3 to 5 nM for cMet kinase inhibition at enzyme and 
anti-tumour cell levels.  Consistent with its potent enzyme and cell activity, 
AZD6094 was found to inhibit cell growth in vitro against tumours with cMet 
amplification in the absence of HGF-stimulation with IC50s generally below 10 
nM. It also potently inhibited HGF-stimulated cell proliferation against tumours
with cMet overexpression or carrying a HGF/cMet autocrine loop.  In human
xenograft mice models, AZD6094 demonstrated excellent anti-tumour activity 
against cMet gene amplified gastric and lung tumours following once daily 
treatment.  In tumours with both cMet and epidermal growth factor receptor 
(EGFR) overexpression, it was found that combination of AZD6094 with erlotinib, 
an EGFR inhibitor, was more effective than either agent alone. 
b.
PHARMACOKINETICS 
Preliminary pharmacokinetic (PK) data are included from Study D5081C00001. 
Preliminary single and multiple dose PK data are available following dosing with
100 mg, 20 0mg, 400 mg, 600 mg and 800 mg. Following administration of single
doses, exposure was typified by absorption with a Tmax of approximately 1.0-2.7 
hours followed by an elimination phase. The terminal half-life (t1/2) ranged from 
3.6-6.8 hours, consistent with achieving steady state by Day 3 of treatment. The 
dose-normalized exposure (Cmax and AUC) of AZD6094 after single doses, 
indicated that exposure may not be dose-proportional over the range of 100 to 
800 mg but the moderate variability observed may have influenced this 
conclusion. The oral clearance (CL/F) ranged from 27-48 L/h and volume of 
distribution (Vz/F) ranged from 219-322 L.
Following multiple doses, Tmax occurred at a range of 1.3-2.7 hours, which is
similar to that observed after a single dose followed by elimination which was 
generally consistent with the early elimination after single doses. There appeared 
to be no trend for accumulation of AZD6094; RAC values were approximately 1, 
and consistent with a relatively short t1/2. Overall the multiple dose PK was 
consistent with the single dose data. The AUCss exposure on Day 21 indicated 
that exposure may not be dose-proportional over the range of 100 to 800 mg but 
the moderate variability observed may have influenced this conclusion.  
The main metabolites M2
and M3 were rapidly formed following oral 
administration of the parent drug resulting in a Tmax range from 1.2-3.8hr. The 
relationship between dose and Cmax and AUC displayed nonlinear traits, which 
was supportive of observations made with the parent compound. Plasma profiles 
after multiple dosing were similar for each individual after single and multiple 
dosing, such that subjects with low M2 or M3 levels on day 1 also showed low 
levels at steady state. The mean T1/2 for M2 and M3 was in a similar range and 
was variable within cohorts, ranging from 5.5 –16.1hr. 
c.
ADVERSE EFFECTS  
1.
The Comprehensive Adverse Events and Potential Risks list (CAEPR)
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a


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separate column and is identified with bold and italicized text. This 
subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements'. 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf for further clarification. Frequency is provided based on 
259 patients. Below is the CAEPR for AZD6094 (savolitinib; volitinib). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if
expedited reporting is required.
Version 2.4, April 2, 20201
 Adverse Events with Possible 
Relationship to Savolitinib (AZD6094) 
(CTCAE 5.0 Term)
[n= 381]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM 
DISORDERS
Anemia
Anemia (Gr 2)
GASTROINTESTINAL DISORDERS
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 2)
Nausea
Nausea (Gr 2)
Vomiting
Vomiting (Gr 2)
GENERAL DISORDERS AND 
ADMINISTRATION SITE CONDITIONS
Edema limbs
Edema limbs (Gr 2)
Fatigue
Fatigue (Gr 2)
Fever
Fever (Gr 2)
HEPATOBILIARY DISORDERS
Hepatobiliary 
disorders - Other 
(hepatotoxicity)2
IMMUNE SYSTEM DISORDERS
Allergic reaction
INVESTIGATIONS
Alanine 
aminotransferase 
increased
Alanine 
aminotransferase 
increased (Gr 2)
Alkaline 
phosphatase 
increased
Aspartate 
aminotransferase 
increased
Aspartate 
aminotransferase 
increased (Gr 2)
Blood bilirubin 
increased


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 Adverse Events with Possible 
Relationship to Savolitinib (AZD6094) 
(CTCAE 5.0 Term)
[n= 381]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Creatinine 
increased
Electrocardiogram 
QT corrected 
interval prolonged
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 2)
Hypoalbuminemia
Hypoalbuminemia (Gr 
2)
RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS
Cough
SKIN AND SUBCUTANEOUS TISSUE 
DISORDERS
Stevens-Johnson 
syndrome
1This table will be updated as the toxicity profile of the agent is revised. 
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail.
2Hepatoxicity may manifest as increased liver enzymes (e.g., Alanine 
aminotransferase increased, Aspartate aminotransferase
increased, 
Alkaline phosphatase increased, Blood bilirubin increased), hepatic 
function abnormal, and drug-induced liver injury (DILI).  
Adverse events reported on savolitinib (AZD6094) trials, but for 
which there is insufficient evidence to suggest that there was a 
reasonable possibility that savolitinib (AZD6094) caused the 
adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated 
intravascular coagulation; Febrile neutropenia
CARDIAC DISORDERS - Heart failure
ENDOCRINE DISORDERS - Adrenal insufficiency
EYE DISORDERS - Blurred vision; Eye disorders - Other (diplopia)
GASTROINTESTINAL 
DISORDERS 
- 
Abdominal 
pain; 
Ascites; 
Dyspepsia; Gastritis; Gastrointestinal disorders - Other (abdominal 
incarcerated hernia); Gastrointestinal disorders - Other (GI [anastomotic] 
perforation); Ileus; Mucositis oral; Small intestinal obstruction; Upper 
gastrointestinal hemorrhage
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Death NOS; Edema face; Generalized edema; Non-cardiac chest pain; 
Pain 
HEPATOBILIARY DISORDERS - Hepatic pain; Hepatobiliary disorders - 
Other (hepatic
encephalopathy); Hepatobiliary disorders - Other 


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(hepatomegaly); 
Hepatobiliary 
disorders 
- 
Other 
(cholestasis); 
Hepatobiliary disorders - Other (hepatic lesion)
INFECTIONS 
AND 
INFESTATIONS 
- 
Abdominal 
infection; 
Conjunctivitis; Fungemia; Lung infection; Sepsis; Upper respiratory 
infection; Urinary tract infection
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, 
poisoning and procedural complications - Other (craniocerebral injury)
INVESTIGATIONS - GGT increased; Lymphocyte count decreased; 
Neutrophil count decreased; Platelet count decreased
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; Hypoglycemia; 
Hypokalemia; Hyponatremia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Back pain; Flank pain; Myalgia
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified
(incl cysts and polyps) - Other (malignant neoplasm progression)
NERVOUS SYSTEM DISORDERS - Dizziness; Dysgeusia; Headache; 
Spinal cord compression
PSYCHIATRIC DISORDERS - Confusion
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic 
kidney 
disease; 
Renal 
and 
urinary 
disorders 
- 
Other 
(urine 
albumin/creatinine ratio increased)
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Genital 
edema
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchopulmonary hemorrhage; Dyspnea; Hypoxia; Pleural effusion; 
Pneumonitis
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Photosensitivity; 
Pruritus; Rash maculo-papular
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; 
Thromboembolic event
Note: Savolitinib (AZD6094) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be 
caused by the other agent, or the combination may result in events never 
previously associated with either agent.
2.
Pregnancy and Lactation: Females of childbearing potential should use 
reliable methods of contraception from the time of screening until 3 
months after discontinuing study treatment.
Acceptable methods of contraception include abstinence, tubal ligation, 
combined oral, transdermal or intra-vaginal hormonal contraceptives, 
medroxyprogesterone injections (e.g. Depo-provera), copper-banded 
intra-uterine devices, hormone impregnated intra-uterine systems and 
vasectomised partners.  All methods of contraception (with the exception 
of total abstinence) should be used in combination with the use of a 
condom by their male sexual partner for intercourse.
Male patients must use a condom during sexual intercourse with all 
sexual partners including a pregnant female partner during the study and 
for 4 weeks after discontinuing study treatment. However, where a 
sexual partner of a male participant is a woman of childbearing potential 
who is not using effective contraception, men must use a condom during 
sexual intercourse during the study and for 6 months after discontinuing 
study treatment.


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Male patients should avoid procreation during the trial and for 6 months
after discontinuing study treatment.  
Male patients should refrain from donating sperm from the start of dosing 
until 6 months after discontinuing study treatment.
3.
Potential Drug Interactions:  According to in vitro studies, savolitinib 
(AZD6094) is primarily metabolized by CYP 3A4/5 and 1A2 and some 
NADPH-independent non-CYP enzymes. Avoid administration of strong 
CYP 3A4/5 and 1A2 inducers and inhibitors within 2 weeks of starting 
and during savolitinib (AZD6094) study treatment. Savolitinib (AZD6094)
is not a P-glycoprotein (P-gp) substrate. 
In vitro, savolitinib (AZD6094) and its metabolites weakly and reversibly
inhibited CYP450 1A2, 2C8, 2C9, 2D6 and 3A4/5 isoforms and UGT1A1. 
A drug interaction with substrates of CYP2C8/9 and/or CYP3A4/5 or
UGT1A1 may occur when savolitinib (AZD6094) is dosed at the 
maximum tolerated dose. Use caution in patients who are taking 
concomitant medications whose clearance is exclusively dependent on 
CYP2C8, CYP2C9, CYP3A4/5 or UGT1A1 because exposure of the 
concomitant medication may be increased. Since there is limited clinical 
experience with this agent, patients on concomitant drugs with narrow 
therapeutic ranges, such as warfarin, should be monitored closely.
Studies indicate that savolitinib (AZD6094) has little induction potential 
for major CYP isoforms.
In vitro studies demonstrate that savolitinib (AZD6094) and its major 
metabolite inhibit a number of drug transporters to varying degrees. The 
manufacturer cautions that when administered at clinically relevant
doses, savolitinib (AZD6094) has the potential to inhibit P-gp, BCRP 
(breast cancer resistance protein), OATP1B1, MATE1 and MATE2K. 
Therefore, co-administration of substrates that are dependent on these 
drug transporter systems should be used with caution. The potential for 
drug-drug interaction is considered unlikely when co-administering
substrates of OATP1B3, OAT1, OAT3 or OCT2
d.
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan. 
e.
HOW SUPPLIED
Astra Zeneca supplies and CTEP, NCI, DCTD distributes savolitinib ((AZD6094)
as coated tablets. Bottles are secured with a child-resistant closure; induction-
sealed membranes provide tamper evidence. Savolitinib (AZD6094) tablets are 
supplied in 24-count HDPE bottles containing desiccant in the following strength 
and description: 
•
200 mg yellow, plain, oval (7.25 x 14.5 mm)
Savolitinib (AZD6094) tablets consist of drug
substance, microcrystalline 
cellulose, mannitol, hydroxypropyl cellulose, and magnesium stearate. The film 
coating consists of hydroxypropyl methylcellulose, titanium dioxide, polyethylene 
glycol 400, black iron oxide, yellow iron oxide and red iron oxide. 


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f.
STORAGE AND STABILITY
1.
Store the AZD6094 tablets at controlled room temperature (20°-25°C). 
Brief excursions are permitted between 15°C and 30°C.
2.
Stability studies are ongoing. The manufacturer does not have stability
information to support repackaging tablets. Dispense in the original 
container.
If a storage temperature excursion is identified, promptly return AZD6094 
to controlled room temperature and quarantine the supplies.  Provide a
detailed report of the excursion (including documentation of temperature 
monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
3.4
Sunitinib Malate (Sutent; SU011248 L-Malate salt; SU010398; PHA-290940AD; 
SU011248) (NSC 736511) (IND #129330)
a.
PHARMACOLOGY
Mechanism of Action:  Sunitinib inhibits several receptor tyrosine kinases (RTKs), 
including platelet-derived growth factor receptors (PDGFRα and PDGFRβ), 
vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), 
stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony 
stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived 
neurotrophic factor receptor
(RET). RTKs are involved in tumor growth, 
angiogenesis and metastasis. 
b.
PHARMACOKINETICS
1.
Absorption: Maximum plasma concentrations (Cmax) of sunitinib are 
between 6 and 12 hours (Tmax) following oral administration. 
In the 
dosing range of 25-100 mg, the area under the plasma concentration-
time curve (AUC) and Cmax increase proportionately with dose.  Food has 
no effect on the bioavailability of sunitinib.
2.
Distribution: Binding of sunitinib and its primary active metabolite to
human plasma protein in vitro was 95% and 90%, respectively, with no 
concentration dependence in the range of 100 – 4000 ng/mL. The
volume of distribution (Vd/F) is 2230 L.
3.
Metabolism: Sunitinib is metabolized primarily by the cytochrome P450 
enzyme, CYP3A4, to produce its primary active metabolite, which is 
further metabolized
by CYP3A4. The primary active metabolite 
comprises 23 to 37% of the total exposure.
4.
Elimination:  Elimination is primarily via feces. In a human mass balance 
study of [14C] sunitinib, 61% of the dose was eliminated in feces, with 
renal elimination accounting for 16% of the administered dose. Sunitinib 
and its primary active metabolite were the major drug-related compounds 
identified in plasma, urine, and feces, representing 91.5%, 86.4% and 
73.8% of radioactivity in pooled samples, respectively. Minor metabolites 
were identified in urine and feces but generally not found in plasma. 
Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-
patient variability of 40%. Following administration of a single oral dose 
in healthy volunteers, the terminal half-lives of sunitinib and its primary 
active metabolite are approximately 40 to 60 hours and 80 to 110 hours, 


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respectively. With repeated daily administration, sunitinib accumulates 3- 
to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-
state concentrations of sunitinib and its primary active metabolite are 
achieved within 10 to 14 days. By Day 14, combined plasma 
concentrations of sunitinib and its active metabolite ranged from 62.9 – 
101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or 
the primary active metabolite were observed with repeated daily
administration or with repeated cycles in the dosing regimens tested.
c.
ADVERSE EFFECTS  
1. 
Adverse Effects: The Comprehensive Adverse Events and Potential 
Risks list (CAEPR) provides a single list of reported and/or potential 
adverse events (AE) associated with
an agent using a uniform 
presentation of events by body system. In addition to the comprehensive 
list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  for further clarification. Frequency is provided based on 
7115 patients. Below is the CAEPR for Sunitinib malate (SU011248 L-
malate).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade 
noted in parentheses next to the AE in the SPEER.  If this CAEPR is part 
of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.
Version 2.14, February 15, 20191
Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anemia
Anemia (Gr 3)
Hemolytic uremic 
syndrome
Thrombotic 
thrombocytopenic 
purpura
CARDIAC DISORDERS
Cardiac disorders 
- Other 
(cardiomyopathy)
Heart failure
Left ventricular 
systolic 
dysfunction


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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Myocardial 
infarction
ENDOCRINE DISORDERS
Endocrine 
disorders - Other 
(thyroiditis)
Hyperthyroidism
Hypothyroidism
Hypothyroidism (Gr 2)
EYE DISORDERS
Eye disorders -
Other (macular 
edema)
Eye disorders - Other 
(macular edema) (Gr 2)
Papilledema
Papilledema (Gr 2)
Vision decreased Vision decreased (Gr 2)
GASTROINTESTINAL DISORDERS
Abdominal 
distension
Abdominal distension (Gr 
2)
Abdominal pain
Abdominal pain (Gr 3)
Anal mucositis
Anal mucositis (Gr 2)
Constipation
Constipation (Gr 2)
Diarrhea
Diarrhea (Gr 3)
Dry mouth
Dry mouth (Gr 2)
Dyspepsia
Dyspepsia (Gr 2)
Esophagitis
Flatulence
Flatulence (Gr 2)
Gastritis
Gastritis (Gr 2)
Gastroesophag
eal reflux 
disease
Gastrointestinal 
perforation2
Mucositis oral
Mucositis oral (Gr 3)
Nausea
Nausea (Gr 3)
Oral pain
Oral pain (Gr 2)
Pancreatitis
Rectal mucositis
Rectal mucositis (Gr 2)
Small intestinal 
mucositis
Small intestinal mucositis
(Gr 2)
Vomiting
Vomiting (Gr 3)
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS
Chills
Chills (Gr 2)
Edema limbs
Edema limbs (Gr 2)
Fatigue
Fatigue (Gr 3)
Fever
Fever (Gr 2) 


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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Flu like 
symptoms
Non-cardiac 
chest pain
Non-cardiac chest pain 
(Gr 2)
HEPATOBILIARY DISORDERS
Cholecystitis
Hepatic failure
IMMUNE SYSTEM DISORDERS
Allergic reaction3
INFECTIONS AND INFESTATIONS
Infections and 
infestations - 
Other (necrotizing 
fasciitis)
INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS
Wound 
complication
INVESTIGATIONS
Alanine 
aminotransfera
se increased
Alanine aminotransferase 
increased (Gr 3)
Alkaline 
phosphatase 
increased
Alkaline phosphatase 
increased (Gr 2)
Aspartate 
aminotransfera
se increased
Aspartate 
aminotransferase 
increased (Gr 3)
Blood bilirubin 
increased
Blood bilirubin increased 
(Gr 2)
CPK increased
Creatinine 
increased
Creatinine increased (Gr 
3)
Electrocardiogra
m QT corrected
interval prolonged
Lipase 
increased
Lipase increased (Gr 4)
Lymphocyte 
count 
decreased
Lymphocyte count 
decreased (Gr 2)
Neutrophil 
count 
decreased
Neutrophil count 
decreased (Gr 4)
Platelet count 
decreased
Platelet count decreased 
(Gr 4)
Serum amylase 
Serum amylase increased 


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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
increased
(Gr 2)
Weight loss
Weight loss (Gr 2)
White blood 
cell decreased
White blood cell 
decreased (Gr 3)
METABOLISM AND NUTRITION DISORDERS
Anorexia
Anorexia (Gr 3)
Dehydration
Dehydration (Gr 3)
Hyperuricemia
Hyperuricemia (Gr 2)
Hypoalbumine
mia
Hypoalbuminemia (Gr 2)
Hypocalcemia
Hypoglycemia
Hypophosphate
mia
Hypophosphatemia (Gr 2)
Tumor lysis 
syndrome
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS
Arthralgia
Arthralgia (Gr 2)
Back pain
Back pain (Gr 2)
Musculoskeletal 
and connective 
tissue disorder - 
Other (fistula 
formation)
Myalgia
Myalgia (Gr 2)
Osteonecrosis of 
jaw
Pain in 
extremity
Pain in extremity (Gr 2)
Rhabdomyolysis
NEOPLASMS BENIGN, MALIGNANT AND 
UNSPECIFIED (INCL CYSTS AND POLYPS)
Leukemia 
secondary to 
oncology 
chemotherapy
Myelodysplastic 
syndrome
NERVOUS SYSTEM DISORDERS
Dizziness
Dysgeusia
Dysgeusia (Gr 2)
Headache
Headache (Gr 3)
Leukoencephalop
athy
Nervous system 


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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
disorders - Other 
(cerebral
infarction)
Paresthesia
Reversible 
posterior 
leukoencephalop
athy syndrome
Transient 
ischemic attacks
PSYCHIATRIC DISORDERS
Depression
Insomnia
Insomnia (Gr 2)
RENAL AND URINARY DISORDERS
Acute kidney 
injury
Nephrotic 
syndrome
Proteinuria
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS
Cough
Cough (Gr 2)
Dyspnea
Dyspnea (Gr 3)
Epistaxis
Epistaxis (Gr 2)
Laryngeal mucositis
Laryngeal mucositis (Gr 
2)
Pharyngeal mucositis
Pharyngeal mucositis (Gr 
2)
Tracheal mucositis
Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Alopecia
Alopecia (Gr 2)
Dry skin
Dry skin (Gr 2)
Erythema 
multiforme
Hair color 
changes
Hair color changes (Gr 2)
Palmar-plantar 
erythrodysesthesia 
syndrome
Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 3)
Pruritus
Rash maculo-
papular
Rash maculo-papular (Gr 
3)
Skin and 
subcutaneous 
tissue disorders - 
Other (pyoderma 
gangrenosum)


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Adverse Events with Possible 
Relationship to Sunitinib malate (SU011248 L-
malate)
(CTCAE 5.0 Term)
[n= 7115]
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%)
Less Likely 
(<=20%)
Rare but 
Serious (<3%)
Skin 
hypopigmentati
on
Skin hypopigmentation 
(Gr 2)
Stevens-Johnson 
syndrome
Toxic epidermal 
necrolysis
VASCULAR DISORDERS
Hypertension
Hypertension (Gr 3)
Thromboembolic 
event
Vascular 
disorders - 
Other 
(hemorrhage)4
1This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail.
2Gastrointestinal perforation includes Colonic perforation, Duodenal 
perforation, Esophageal perforation, Gastric perforation, Ileal perforation, 
Jejunal perforation, Rectal perforation, and Small intestinal perforation 
under the GASTROINTESTINAL DISORDERS SOC.
3Allergic reactions observed include anaphylaxis and angioedema.
4The majority of hemorrhage events were mild.  Major events, defined as 
symptomatic bleeding in a critical area or organ (e.g., eye, GI tract, GU 
system, respiratory tract, nervous system [including fatal intracranial 
hemorrhage, and cerebrovascular accident], and tumor site) have been 
reported.
Adverse events reported on Sunitinib malate (SU011248 L-malate) 
trials, but for which there is insufficient evidence to suggest that 
there was a reasonable possibility that Sunitinib malate (SU011248 
L-malate) caused the adverse event:
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Pericardial 
effusion
GASTROINTESTINAL 
DISORDERS 
- 
Ascites; 
Dysphagia; 
Gastrointestinal disorders - Other (enteritis); Hemorrhoids; Ileus; Small 
intestinal obstruction


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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Pain 
INVESTIGATIONS - GGT increased; INR increased
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypokalemia; Hyponatremia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Bone pain
NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Peripheral 
sensory neuropathy; Seizure; Spinal cord compression; Syncope
PSYCHIATRIC DISORDERS - Anxiety; Confusion
RENAL AND URINARY DISORDERS - Hematuria; Urinary retention
REPRODUCTIVE 
SYSTEM 
AND 
BREAST 
DISORDERS 
- 
Hematosalpinx
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Pharyngolaryngeal pain; Pleural effusion; Pneumothorax
VASCULAR DISORDERS - Flushing; Hypotension
Note: Sunitinib malate (SU011248 L-malate) in combination with other 
agents could cause an exacerbation of any adverse event currently
known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent.
2.
Pregnancy and Lactation:  Pregnancy Category D.  Sunitinib can cause 
fetal harm when administered to a pregnant woman. As angiogenesis is 
a critical component of embryonic and fetal development, inhibition of 
angiogenesis following administration of Sunitinib should be expected to 
result in adverse effects on pregnancy. In animal reproductive studies in 
rats and rabbits, sunitinib was teratogenic, embryotoxic and fetotoxic. 
Sunitinib and its metabolites are excreted in rat milk. It is not known 
whether this drug or its primary active metabolite are excreted in human 
milk. Because many drugs are excreted in human milk and because of 
the potential for serious adverse reactions in nursing infants from
sunitinib, a decision should be made whether to discontinue nursing or to
discontinue the drug taking into account the importance of the drug to the 
mother.
3.
Drug Interactions: Sunitinib is metabolized primarily by liver enzymes, 
particularly CYP3A4. 
Due to potential drug interactions, a complete 
patient medication list, including sunitinib, should be screened prior to 
initiation of and during treatment with sunitinib. See Appendix 18.2. 
d. 
DOSING & ADMINISTRATION
See Section 7.0 Treatment Plan. 
e.
HOW SUPPLIED
Sunitinib malate capsules are supplied by Pfizer, Inc. and distributed by the 
Pharmaceutical 
Management 
Branch, 
CTEP/DCTD/NCI.  
Capsules 
are 
packaged in 28-count bottles with mannitol, croscarmellose sodium, povidone (K-
25) and magnesium stearate as inactive ingredients in the following strengths:
•
12.5 mg hard gelatin capsule (size 4) with orange cap and orange body, 
printed with white ink "Pfizer" on the cap and "STN 12.5 mg" on the body.


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•
25 mg hard gelatin capsule (size 3) with caramel cap and orange body, 
printed with white ink "Pfizer" on the cap and "STN 25 mg" on the body.
•
50 mg hard gelatin capsule (size 2) with caramel top and caramel body,
printed with white ink "Pfizer" on the cap and "STN 50 mg" on the body.
Orange gelatin capsule shells contain titanium dioxide, and red iron oxide. 
Caramel gelatin capsule shells contain titanium dioxide, red iron oxide, yellow iron 
oxide and black iron oxide. White printing ink contains shellac, propylene glycol,
sodium hydroxide, povidone and titanium dioxide.
f.
STORAGE AND STABILITY
1.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
If a storage temperature excursion is identified, promptly return sunitinib 
malate to between 15 and 30°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability.
2.
Stability:  Shelf life is consistent with commercially-labeled product. 
3.5
Drug Ordering, Accountability and Returns
Agent ordering: NCI-supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. The CTEP-
assigned protocol number S1500 must be used for ordering all CTEP-supplied 
investigational agents. The eligible participating investigators at each participating 
institution must be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment Form, and 
Financial Disclosure Form (FDF). If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered under 
the name of one lead participating investigator at that institution. Submit agent requests 
through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP
requires the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an “active” account status, a “current” password, and active 
person registration status. For questions about drug orders, transfers, returns, or 
accountability, call or email PMB any time. Refer to the PMB’s website for specific 
policies and guidelines related to agent management.  
a.
Starter supply is not allowed. Patient must be first assigned to a treatment arm 
before ordering agent
b.
Agent Accountability
1. 
The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record Form (DARF) available 
on the CTEP forms page. Store and maintain separate NCI Investigational 
Agent Accountability Records for each agent, strength, formulation and 
ordering investigator on this protocol.
2.
Electronic logs are allowed as long as a print version of the log process
is the exact same appearance as the current NCI DARF.
c.
Drug Returns


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1.
All unused drug supplies should be recovered to the PMB.  When it is 
necessary to return study drug (e.g., sealed vials remaining when expired 
vials are recalled by the PMB), investigators should return the study drug to 
the PMB using the NCI Return Agent Form available on the NCI home 
page (http://ctep.cancer.gov).
2.
Drug expiration: Indicate drug expiration date on the DARF under 
Manufacturer and Lot # or follow institutional procedures. Use the drug 
lots with shorter expiration date first.
d.
Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between
8:30 am and 4:30 pm Eastern Time. 
3.6
Drug Information Useful Links and Contacts
Useful Links and Contacts
•
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/
•
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov
•
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm
•
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP
•
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/
•
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov
•
IB Coordinator: IBCoordinator@mail.nih.gov
PMB email: PMBAfterHours@mail.nih.gov
•
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET)
4.0
STAGING CRITERIA
This section is not applicable to this study. 
5.0
ELIGIBILITY CRITERIA
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration. Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations Center in 
Seattle at guquestion@crab.org or 206/652-2267 prior to registration.
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 2 weeks later would be considered Day 14.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14, 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day.
5.1
Disease Related Criteria 
a.
Patients must have histologically or cytologically confirmed papillary histology 
renal cell carcinoma which is metastatic or locally advanced disease not 
amenable to surgical resection.  (NOTE: A designation of type I or type II should 
be made by the local pathologist if possible.)  Mixed histologies containing type I 


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or type II will be allowed provided that they contain ≥ 50% of the papillary 
component.
b.
Patients must also have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (see Section 10.1).  
Disease X-rays, scans or physical examinations used for tumor measurement 
must have been completed within 28 days prior to registration.  If there is clinical 
suspicion for bone metastases at the time of enrollment (at the discretion of the 
investigator), bone scan should be performed at baseline (within 42 days prior to 
registration).  All disease must be assessed and documented on the Baseline 
Tumor Assessment Form.
c.
Patients with a history of treated brain metastases who are asymptomatic and 
have not received steroid therapy in the 14 days prior to registration are eligible.  
Anti-seizure medications are allowed provided they are non-enzyme inducing 
(e.g. topiramate, levatiracetam, gabapentin).
d.
Patients must not have cavitating pulmonary lesions.  Patients must not have 
tumor invading the GI tract or evidence of endotracheal or endobronchial tumor 
within 28 days prior to registration.
5.2
Prior/Concurrent Therapy Criteria
a.
Patients may have received prior surgery.  At least 28 days must have elapsed 
since surgery and patient must have recovered from any adverse effects of 
surgery.
b.
Patients may have received up to one prior systemic therapy for advanced or 
metastatic renal cell carcinoma with the exception of another VEGF inhibitor 
FDA-approved for advanced RCC (i.e., pazopanib, bevacizumab, sorafenib or 
axitinib).  If a patient develops metastatic disease within six months of 
discontinuation of adjuvant therapy, this will constitute one prior systemic therapy 
for advanced or metastatic RCC. If a patient develops metastatic disease and 
more than six months has elapsed since discontinuation of adjuvant therapy, this 
will not constitute prior systemic therapy for advanced or metastatic RCC.  
Patients may have also received prior immunotherapy. Patients must not have 
received a MET/HGF inhibitor or sunitinib as prior therapy.  At least 14 days must 
have elapsed since completion of prior systemic therapy.  Patients must have 
recovered from all associated toxicities at the time of registration.
c.
Patients may have received prior radiation therapy, but must have measurable 
disease outside the radiation port.  At least 14 days must have elapsed since 
completion of prior radiation therapy. Patients must have recovered from all 
associated toxicities at the time of registration.
d. 
Patients must not be taking, nor plan to take while on protocol treatment, strong
CYP3A4 inhibitors (e.g. boceprevir, cobicistat, danoprevir, elvitegravir/RIT, 
fluvoxamine, indinavir, itraconazole, ketoconazole, lopinavir/RIT, nefazodone, 
nelfinavir, posaconazole, ritonavir, telaprevir, telithromycin, tipravavir/RIT, or
voriconazole,); strong CYP3A4 inducers (e.g. avasimibe, phenytoin, rifampin, 
rifabutin); potent inhibitors of CYP1A2 (e.g. ciprofloxacin); and/or drugs known to 
be CYP3A4 substrates with a narrow therapeutic range (e.g., diergotamine, 
ergotamine) within 14 days prior to randomization.  (Moderate inhibitors or 
inducers of isoenzyme CYP3A4 should be avoided, but if necessary can be used 
with caution (see Section 18.2).


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e.
Patients must not be receiving or planning to receive any other investigational 
agents.


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5.3
Clinical/Laboratory Criteria
a.
Patients must have a complete physical examination and medical history within 
28 days prior to registration.
b.
Patients must have a Zubrod performance status of 0 - 1 (see Section 10.4).
c.
Patients must have adequate hematologic function as documented by a WBC ≥ 
2,000/mcL, an ANC ≥ 1,000/mcL, and a platelet count ≥ 75,000/mcL.  These 
tests must be obtained within 28 days prior to registration.
d.
Patients must have adequate hepatic function as evidenced by serum bilirubin ≤
1.5 x institutional upper limits of normal (ULN).  Serum transaminase (SGOT/AST 
and SGPT/ALT) must be ≤ 2.5 x the institutional ULN unless the liver is involved 
with the tumor, in which case serum transaminase (SGOT/SGPT) must be ≤5 x 
the institutional ULN.  These tests must be obtained within 28 days prior to 
registration.
e.
Serum creatinine must be ≤ 2 x the institutional ULN OR creatinine clearance 
(either measured or calculated) must be > 30 mL/min and obtained within 28 
days prior to registration. 
f.
Patients must not have any clinical evidence of congestive heart failure (CHF) 
(specifically, New York Heart Association [NYHA] Class III [moderate] or Class IV 
[severe]) at the time of registration. Baseline echocardiogram within 28 days of 
registration must demonstrate an EF ≥ 50%.  Due to the potential cardiac toxicity 
of the agents utilized in this protocol, patients must have QTc interval < 500 msec 
on prestudy EKG and no known history of congenital long QT syndrome. Patients 
must not have experienced unstable angina pectoris, clinically significant cardiac 
arrhythmias, or stroke (TIA or other ischemic event) within 3 months prior to 
registration and not have experienced myocardial infarction or thromboembolic 
event requiring anticoagulation within 6 months of registration.  Prestudy EKG 
must be obtained within 28 days prior to registration.
g.
Baseline urinalysis should show urine protein < 3+ and must be obtained within 
28 days prior to registration.  If urine protein is 3+ or greater, then urine protein 
by 24 hour collection must show less than 3 grams of protein.
h.
Patients must not have inadequately controlled hypertension.  Patients must 
have documented blood pressures of SBP < 150 and DBP < 90 within 14 days of 
starting randomization. Blood pressure medications (any number) are permitted.
i.
Patients must be able to take oral medications (i.e., swallow pills whole).  
Patients must not have gastrointestinal tract disease resulting in an inability to 
take oral medication or a requirement for IV alimentation, prior surgical 
procedures that could in the opinion of the treating investigator affect absorption, 
or active peptic ulcer disease.  Patients with intractable nausea or vomiting are 
not eligible.
j.
Patients must not have had any clinically-significant GI bleeding within 6 months 
prior to registration and patients must not have a GI disorder which (at the 
discretion of the investigator) bears a high risk of perforation or fistula.  Examples 
of this include (but are not limited to) Crohn’s disease or tumor with transmural 
extension through the gastrointestinal lining.


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k.
Patients must not have had hemoptysis of ≥ 0.5 teaspoon (2.5 ml) of red blood 
within 3 months prior registration.
l.
Patients must not demonstrate any other signs indicative of pulmonary 
hemorrhage within 3 months prior to registration.
m.
Patient’s baseline imaging must not indicate the presence of tumor invading or 
encasing any major blood vessels.
n.
Patients must not have any unresolved wounds from previous surgery.
o.
Albumin, 
alkaline 
phosphatase, 
bicarbonate, 
BUN, 
chloride, 
glucose, 
phosphorus, and total protein must be assessed within 28 days of registration.
p.
No other prior malignancy is allowed except for the following: adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 3 
years. Men receiving active surveillance for prostate cancer may also be 
enrolled.
q.
Due to the unknown effects of the study drugs, patients must not be pregnant or 
nursing. Women/men of reproductive potential must have agreed to use an 
effective contraceptive method while receiving study drug and for three months 
after last dose of study drug. A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months. In addition to routine contraceptive methods, "effective contraception" 
also includes heterosexual celibacy and surgery intended to prevent pregnancy 
(or with a side-effect of pregnancy prevention) defined as a hysterectomy, 
bilateral oophorectomy or bilateral tubal ligation.  However, if at any point a 
previously celibate patient chooses to become heterosexually active during the 
time period for use of contraceptive measures outlined in the protocol, he/she is 
responsible for beginning contraceptive measures.
r.
HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with cabozantinib, crizotinib, 
savolitinib or sunitinib.  In addition these patients are at increased risk of lethal 
infections when treated with marrow suppressive therapy.  Appropriate studies 
will be undertaken in patients receiving combination antiretroviral therapy when 
indicated.
s.
Patients must be ≥18 years of age.
5.4
Specimen Submission Criteria
a.
Patients must have tissue available and be willing to submit for independent
pathologic review in order to classify type I versus type II papillary disease (see 
Section 12.0).
b. 
Patients must be offered the opportunity to participate in specimen banking for 
future translational medicine studies (see Section 15.0).
5.5
Regulatory Criteria
a.
Patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines.


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b.
As a part of the OPEN registration process (see Section 13.2) for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system.
6.0
STRATIFICATION FACTORS
Patients will be randomized in a 1:1:1:1 allocation using a dynamic balancing algorithm (20) with 
stratification based on:
a. 
Predominant pRCC histologic subtype: type I versus type II versus Not Otherwise 
Specified (NOS).
b.
Prior treatment (see Section 5.2b):  0 vs. 1 line of systemic therapy.
7.0
TREATMENT PLAN
For treatment or dose modification questions, please contact Dr. Sumanta K. Pal or Dr. Primo 
Lara at S1500question@swog.org.  For dosing principles or questions, please consult the SWOG 
Policy #38 "Dosing Principles for Patients on Clinical Trials" at 
https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf. 
7.1
Pre-Medication
No pre-medications are required for sunitinib, crizotinib, savolitinib or cabozantinib.
7.2
Treatment
Patients will be randomized to either Arm 1: sunitinib, Arm 2:  cabozantinib, Arm 3:  
crizotinib or Arm 4: savolitinib. NOTE:  All treatments are administered in the outpatient 
setting.   As of 12/5/18, patients will only be randomized to Arm 1: sunitinib or Arm 
2: cabozantinib.
It is recommended that the patient be provided with the Patient Drug Information Handout 
and Wallet Card (see Section 18.3a-d).
a.
Treatment schedule for Arm 1: sunitinib.
AGENT
DOSE
ROUTE
DAYS
INTERVAL
DURATION
Sunitinib* 
50 mg 
Oral 
1-42 
Daily on Days 1-28 
See Section 7.6
 
 
 
Hold Days 29-42
* Sunitinib can be taken with or without food.
b.
Treatment schedule for Arm 2: cabozantinib.
AGENT
DOSE
ROUTE
DAYS  
INTERVAL
DURATION
Cabozantinib* 60 mg
Oral  
1-42
Daily
See Section 7.6
* Cabozantinib must be taken on an empty stomach (i.e., patient must not eat 
within 2 hours before or 1 hour after each dose). Cabozantinib must not be 
crushed or chewed.  Do not take a missed dose within 12 hours of the next 
dose.  Avoid grapefruit, grapefruit juice, and Seville oranges.


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c.
Treatment schedule for Arm 3:  crizotinib (Treatment arm closed to accrual 
12/5/18).
AGENT
DOSE
ROUTE
DAYS  
INTERVAL
DURATION
Crizotinib* 250 mg
Oral 
1-42
Twice daily
See Section 7.6
per dose
(500 mg total
* 
 daily dose)
* Crizotinib can be taken with or without food.
d.
Treatment schedule for Arm 4:  savolitinib (Treatment arm closed to accrual 
12/5/18).
AGENT
DOSE
ROUTE
DAYS  INTERVAL
DURATION
Savolitinib* 600 mg 
Oral  
1-42
Daily 
See Section 7.6
* Savolitinib must be taken with food (specifically, within 1 hour after the start of 
a meal).  Tablet must be swallowed whole with water.
NOTE:  A cycle of therapy is defined as 42 days.  There will be no pause between 
cycles.  Patients will be evaluated for response/progression every 12 weeks and 
will continue on therapy until progression or other reason for removal from 
treatment (see Section 7.7).
7.3
Administration through G-tube  
Administration of the study medications through a G-tube is not allowed.
7.4
Drug Compliance Documentation
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 18.1). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at 
the end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart. 
Note that the Intake Calendar is provided only as a tool for tracking patient compliance.  
Sites may utilize institutional pill diaries or other source documentation in place of the 
Intake Calendar at the discretion of the treating physician.
7.5
Full CDUS Reporting Requirement
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4, the S1500 Treatment Form, and 
the S1500 Adverse Event Form).  A cycle is defined as 42 days.
7.6
Criteria for Removal from Protocol Treatment
a.
Progression of disease or symptomatic deterioration (as defined in Section 10.2).
b.
Unacceptable toxicity.
c.
Delay in planned treatment for any reason > 4 weeks.
d.
Pregnancy.


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e.
The patient may withdraw from the study at any time for any reason.
7.7
Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice.
7.8
Follow-Up Period
All patients will be followed until death or 3 years after randomization, whichever occurs 
first
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS
8.1
NCI Common Terminology Criteria for Adverse Events
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
a.
Serious Adverse Event (SAE) reporting 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 
downloaded from the CTEP home page (https://ctep.cancer.gov). All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
b.
Routine toxicity reporting 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting. A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov). All appropriate treatment areas should have access to 
a copy of the CTCAE Version 4.0.
8.2
Dose Modifications
Dose reduction guidelines for hematologic and non-hematologic toxicities are shown in 
the table below.  If ≥Grade 3 toxicity that is expected to be manageable and reversible 
with a dose reduction occurs, treatment should be held until toxicity resolves to ≤ Grade 
1.  Study drug should be permanently discontinued in any patient with ≥Grade 3 
hematologic or non-hematologic toxicity lasting ≥7 days that does not resolve to ≤Grade 
1 within 2 weeks.
Dose modifications for hematologic and non-hematologic toxicities
NCI CTCAE v4.03 Toxicity Grade
Action
Grade 0, 1, or 2
None
Grade 3 or 4 
Expected manageable/reversible with dose 
reduction
Holda
     Toxicity remains Grade ≥ 3 for >7 days
Discontinue study drug
     Toxicity lasts ≥ 7 days and resolves to ≤ Grade 
1
Reduce one dose level


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Dose modifications for hematologic and non-hematologic toxicities
NCI CTCAE v4.03 Toxicity Grade
Action
Grade 0, 1, or 2
None
Recurrence of Grade 3  
Holda
     Toxicity remains Grade ≥ 3 for >7 days
Discontinue study drug
Toxicity lasts ≥ 7 days and resolves to ≤ Grade 
1
Reduce one dose level or 
discontinue study druga
Recurrence of Grade 4  
Discontinue study drug
Grade 3 or 4 (new or recurrent)
Not expected to be manageable/reversible with 
dose reduction
Discontinue study drug
a Study drug should be held until toxicity resolves to ≤ Grade 1.  Study drug should be 
discontinued in any patient with ≥Grade 3 hematologic or non-hematologic toxicity 
lasting ≥7 days that does not resolve to ≤Grade 1 within 2 weeks.
Dose modifications are drug specific. Notably, no dose re-escalation is permitted, even in 
the context of resolving toxicities that initially warranted dose reduction.  Dose 
modifications of sunitinib should be conducted using the following dose levels.
Sunitinib dose level modification*
Dose level
Sunitinib PO daily dose
Starting Dose
50 mg QD
-1 Dose Level
37.5 mg QD
-2 Dose Level
25 mg QD
*Of note, patients who receive a dose reduction on sunitinib should still be maintained on 
the conventional 4 week on, 2 week off dosing regimen. 
Notably, patients should be carefully monitored for clinical signs and symptoms of CHF 
while on sunitinib.
Dose modifications of cabozantinib should be conducted using the following dose levels: 
Cabozantinib dose level modification
Dose level
Cabozantinib PO daily dose
Starting Dose
60 mg QD
-1 Dose Level
40 mg QD
-2 Dose Level
20 mg QD


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Dose modifications of crizotinib should be conducted using the following dose levels: 
Crizotinib dose level modification
Dose level
Crizotinib PO daily dose
Starting Dose
250 mg BID
-1 Dose Level
200 mg BID
-2 Dose Level
250 mg QD
Dose modifications of savolitinib should be conducted using the following dose levels: 
Savolitinib dose level modification
Dose level
Savolitinib PO daily dose
Starting Dose
600 mg QD
-1 Dose Level
400 mg QD
-2 Dose Level
200 mg QD
Notably, G-CSF is not recommended for neutropenia.
8.3
Dose Modifications for Hypertension
Increases in blood pressure (BP) and cases of hypertension have been associated with 
many drugs acting on the VEGF pathway. The proposed mechanism for this increase is 
through inhibition of VEGF-induced peripheral vasodilation.
Recommended Hypertension Monitoring and Management
(BP in mmHg)
Grade
(CTCAE v4)
Antihypertensive
Therapy
Blood Pressure 
Monitoring
Dose 
Modification
Grade 1
Pre-hypertension
Systolic 120-139
Diastolic 80-90 
Standard
No change
Grade 2- Moderate
Systolic 140-159 
Diastolic 90-99 
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, including 
CTCAE v4 
Step 1) Initiate LA DHP 
CCB treatment and if 
needed, after 24-48 hr
Rx, increase dose in 
stepwise fashion every 
24-48 hours until BP is 
controlled or at max 
dose of Rx
Step 2) If BP still not 
controlled, add another 
antihypertensive Rx, a 
BB, ACE1, ARB, or 
ABB; increase dose of 
this drug as described 
in Step 1
BP should be 
monitored as 
recommended by 
the treating 
physician 
No change 
except as 
described in Step 
4


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Grade
(CTCAE v4)
Antihypertensive
Therapy
Blood Pressure 
Monitoring
Dose 
Modification
Step 3) If BP still not 
controlled, add 3rd drug 
from the list of 
antihypertensives in 
Step 2; increase dose 
of this drug as 
described in Step 1 
Step 4) If BP still not 
controlled, consider 
either 1 dose reduction 
of study drug or 
stopping study drug.
NOTE: Stopping or 
reducing the dose of 
study drug is expected 
to cause a decrease in 
BP The treating 
physician should 
monitor the patient for 
hypotension and adjust 
the number and dose of 
antihypertensive 
medication(s)
accordingly.
Grade
(CTCAE v4)
Antihypertensive
Therapy
Blood Pressure 
Monitoring
Dose 
Modification
Grade 3 Severe 
Systolic >160
Diastolic >100 
Protocol-specific 
guidance 
supersedes any 
other management 
guidelines, including  
CTCAE v4
HOLD study drug until 
systolic BP <159 and 
diastolic BP <99.  
BP management is 
identical to that for 
Grade 2 (see Steps 1-4 
above) with 2 major 
exceptions: 
1)  If systolic BP >180 
or diastolic BP >110 
and the patient is 
symptomatic: optimal 
management with 
intensive IV support 
in ICU; STOP study 
drug and notify 
hospital staff that 
stopping study drug 
may result in a 
decrease in BP
and 
2) If systolic BP >180 
BP should be 
monitored as 
recommended by 
the treating 
physician unless 
the patient is 
symptomatic 
with  
systolic BP >180 
or diastolic BP 
>110 in which 
case, monitoring 
should be 
intensive.
HOLD study drug 
until systolic BP 
<159 and 
diastolic BP 
<99.
In most 
circumstances, if  
BP cannot be 
controlled after an 
optimal trial of 
anti-hypertensive 
medications, 
consider either 1 
dose reduction of 
study drug or 
stopping study 
drug. 
HOWEVER,
if the patient 
requires 
hospitalization 
for management 
of symptomatic


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Grade
(CTCAE v4)
Antihypertensive
Therapy
Blood Pressure 
Monitoring
Dose 
Modification
or diastolic BP >110 
and the patient is 
asymptomatic,
2 new anti-
hypertensives must 
be given together in 
Step 1 (and dose
escalated 
appropriately as in 
Step 1).
NOTE: Stopping or 
reducing the dose of 
study drug is expected 
to cause a decrease in 
BP The treating 
physician should 
monitor the patient for 
hypotension and adjust 
the number and dose of 
antihypertensive 
medication(s)  
Accordingly
systolic BP >180 
or diastolic BP 
>110, 
permanently 
discontinue study 
drug or if BP is 
controlled, re-
start study drug at 
1 lower dose level 
after consultation 
with the Study 
Chair
Grade
(CTCAE v4)
Antihypertensive
Therapy
Blood Pressure 
Monitoring
Dose Modification
Grade 4
Life-threatening 
consequences of 
hypertension
Optimal management 
with intensive IV 
support in ICU; STOP 
study drug and notify 
hospital staff that 
stopping study drug 
may result in a 
decrease in BP
Intensive
Permanently 
discontinue study 
drug or if BP is 
controlled, re-
start study drug at 
1 lower dose level 
after consultation 
with the Study 
Chair
Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta 
blockers (BB), angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor 
blockers (ARB), alpha beta blocker (ABB)
• If patients require a delay of >2 weeks for management of hypertension, 
discontinue protocol therapy
• If patients require >2 dose reductions, discontinue protocol therapy
• Patients may have up to 2 drugs for management of hypertension prior to any dose 
reduction in study drug
• 24-48 hours should elapse between modifications of anti-hypertensive therapy
Hypertension should be graded using CTCAE v4.


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8.4
Dose modifications for QTc prolongation in patients receiving savolitinib
D
r
u
g
Drugs that prolong QT interval
GUIDANCE 
REGARDING 
POTENTIAL 
INTERACTIONS 
WITH 
CONCOMITANT 
MEDICATIONS KNOWN TO PROLONG QT INTERVAL 
The drugs listed in this section are taken from information provided by the Arizona Center 
for Education and Research on Therapeutics website: https://www.crediblemeds.org. The 
website categorizes drugs based on the risk of inducing Torsades de Pointes (TdP).  
During screening the drugs that patients are currently prescribed should be checked 
opposite the ArizonaCert website above.
Drugs with a known risk of Torsades de Pointes
The following drugs prolong the QT interval and are clearly associated with a known risk of 
TdP, even when taken as recommended. These drugs must have been discontinued prior 
to the start of administration of study treatment in accordance with guidance provided in 
the table below and should not be co-administered with savolitinib and for a period of one 
week after discontinuing study treatment. The list of drugs may not be exhaustive and is 
subject to change as new information becomes available. As such investigators are 
recommended to search the website to provide the most up to date information.
Dose modifications for savolitinib-related QTc prolongation 
NCI CTCAE Toxicity Grade
Action
Grade 0, 1, or 2
None
Grade 3
Hold dosing and follow algorithm bellow
•
Patients with QTcF prolongation to >500 
msec on at least two separate ECGs 
•
If the toxicity does not resolve to QTcF < 
481msec within 21 days
•
Consult with cardiologist to 
validate ECG finding. Ensure 
cardiac surveillance and take 
actions in accordance with 
clinical standards. Regular 
ECGs performed until 
resolution to QTcF < 481 
msec. Restart drug at one 
reduced dose level. 
•
Discontinue study drug and 
consult with a cardiologist to 
validate ECG finding and 
further management as 
clinically indicated.  
Grade 4 
•
QTcF >= 501 or >60 msec change from 
baseline and Torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia
•
Discontinue study drug and 
consult with a cardiologist to 
validate ECG finding and 
further management as 
clinically indicated


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Drugs with a known risk of TdP
Drug name
Withdrawal period prior 
to study treatment start
Anagrelide, ciprofloxacin, clarithromycin, cocaine, droperidol,
erythromycin, 
levofloxacin, 
ondansetron, 
papaverine
hydrochloride, procainamide, sulpiride, sultopride, terfenadine,
terlipressin
2 days
Cilostazol, Cisapride, disopyramide, dofetilide, domperidone,
flecainide, gatifloxacin, grepafloxacin, ibutilide, moxifloxacin,
oxaliplatin, propofol, quinidine, roxithromycin, sevoflurane,
sotalol, sparfloxacin, thioridazine
7 days
Azithromycin bepridil, citalopram, chlorpromazine, dronedarone,
escitalopram, 
fluconazole, 
halofantrine, 
haloperidol,
levomepromazine, levosulpiride, mesoridazine
14 days
Donepezil, terodiline
3 weeks
Levomethadyl, methadone, pimozide
4 weeks
Arsenic trioxide*, Ibogaine
6 weeks
Pentamidine
8 weeks
Astemizole, Probucol, vandetanib
4 months
Amiodarone, chloroquine
1 year
*  Estimated value as pharmacokinetics of arsenic trioxide has not been studied
8.5
Dose Modifications Contacts
For treatment or dose modification questions, please contact Dr. Sumanta K. Pal or Dr. 
Primo Lara at S1500question@swog.org.
8.6
Adverse Event Reporting
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements.


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9.0
STUDY CALENDAR
9.1
Arm A
REQUIRED STUDIES
BASE-
LINE
Cycle 1
Cycle 2
Cycle 3 +
W 
1 
W 
2 
W 
3 
W
4 
W
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10
W 
11
W 
12
W 
13
W 
14
W 
15
W 
16
W 
17
W 
18
FU 
Prior to 
Prog**
FU After 
Prog**
PHYSICAL
History & Physical exam£
X 
X 
X 
X 
X 
X q 6 wks
X 
X 
Weight & Performance Status£
X 
X 
X 
X 
X 
X q 6 wks
X 
Disease Assessment
X 
X q 12 wks
Toxicity Notation£
X 
X 
X 
X q 6 wks
Blood Pressure Monitoring≠
X 
X 
X 
X 
X 
X 
X q 6 wks
LABORATORY
CBC w/diff, plts£
X
X
X
X
X
X q 6 wks
X
Serum chemistry ϖ£Ω
X 
X 
X 
X 
X 
X q 6 wks
X 
TSH, free T3 and T4¿ 
X 
X 
X 
X 
X q 6 wks
Urinalysis  ۞
X
X
X
X
X
X q 6 wks
Pregnancy test (if applicable) ȸ
X
TREATMENT Δ
ARM 1:  Sunitinib
X
X
X
X
X
X
X
X
X
X
X
X
ARM 2:  Cabozantinib
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ARM 3:  Crizotinib
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ARM 4:  Savolitinib
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Calendar continued on next page.  Click here for footnotes.


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Cal 9.1 (contd.)
REQUIRED STUDIES
Cycle 1
Cycle 2
Cycle 3+
FU 
Prior to 
Prog**
FU After 
Prog**
BASE-
LINE
W
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10
W 
11
W 
12
W 
13
W 
14
W 
15
W 
16
W 
17
W 
18
X-RAYS AND SCANS
CT of chest, abdomen & pelvis
X 
X q 12 wks
Bone scan
X¥ 
X¥ 
q 12 wks
EKG and Echocardiogram∑
X
X
X
X
X
X
X
X
X
X
X
SAMPLES €
1 H&E slide (Mandatory for 
independent pathology review)
X 
Tissue block or 12 unstained slides
X 
Plasma & buffy coat
X 
X 
X 
X Ђ
X Ђ
Serum
X 
X 
X 
X Ђ
X Ђ
NOTE: Forms are found on the protocol abstract page of the SWOG website (www.swog.org). Forms submission guidelines are found in Section 14.0.
Click here for footnotes. 


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FOOTNOTES:
≠
See Section 8.3 regarding blood pressure monitoring.
ϖ Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium.  If prestudy labs are obtained > 14 days prior to beginning Cycle 1, they must be repeated.
ΩPatients randomized to Arm 4: savolitinib must have liver function tests monitored weekly for the first two months and then monthly thereafter since liver 
damage is a known side effect. Laboratory monitoring may be conducted remotely if chosen by the patient/investigator.
Δ For treatment plan and doses, see Section 7.2. Treatment and follow-up continues until progression or patient is removed from protocol treatment per Section 
7.6. 
¥ If there is clinical suspicion for bone metastases at the time of enrollment (at the discretion of the investigator), bone scan should be performed at baseline. If 
bone metastases are detected, a bone scan should be conducted at the time of each radiologic evaluation.  
€ For description of correlative studies, see Section 15.0. 
£ For the first two cycles (i.e., 12 weeks), patients will be followed on Days 1 and 22 in clinic.  For the third cycle and beyond, patients will be followed-up on day 
1 of each cycle. Please report AEs from all assessments within a single cycle at the end of that cycle.
** All patients will be followed until death or 3 years after registration, whichever occurs first.  If patient is removed from protocol treatment for reasons other than 
progression, patient will continue to be followed at same intervals as if on treatment.  Once disease progresses, follow-up is at the discretion of the treating 
investigator.
¿ TSH, free T3 and T4 must be collected each cycle for patients randomized to Arms 1 (Sunitinib) and 2 (Cabozantinib) prior to study drug administration.
۞ Urinalysis (UA) must be collected each cycle for patients randomized to Arms 1 (Sunitinib) and 2 (Cabozantinib) prior to study drug administration.  If urine 
protein on urinalysis is ≥ 3+, then perform 24-hour urine protein.  Interrupt sunitinib and cabozantinib if 24-hour urine protein is ≥ 3 grams.  Discontinue sunitinib 
or cabozantinib for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions.
Ђ Collect at the time of removal from protocol treatment (recurrence or other reason, whichever occurs first).
ȸ It is at the discretion of the treating investigator to determine whether to and when to perform pregnancy testing if applicable.
∑QTcF evaluation will be done based on triplicate 12-lead EKGs during the screening period. For patients randomized to savolitinib only, triplicate EKG must 
be performed every week in the first cycle, on Day 1 of every cycle thereafter, and at the end of treatment.  Twelve-lead EKGs (triplicate) will be obtained after 
the patient has been rested in a supine position for at least 5 minutes. The investigator or designated physician will review the 12-lead EKGs. EKGs will be 
recorded at 25 mm/sec. All EKGs should be assessed by the investigator to determine whether they are clinically significantly abnormal vs. not clinically 
significantly abnormal. If the treating investigator feels there is a clinically significant abnormal finding, the investigator will record it as an adverse event (AE).  
The original EKG traces must be stored in the patient medical record as source data. A 28-day follow-up assessment will be required if an on-treatment 
assessment was abnormal at the time of discontinuation of study therapy, to confirm reversibility of the abnormality.


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10.0
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS
10.1
Measurability of Lesions
a.
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below.
1.
Lesions that can be accurately measured in at least one dimension by ≥ 
1.0 cm with CT or MRI scans or ≥ 1.0 cm with calipers by clinical exam. 
All tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters).
2.
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm).
b.
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed.
c.
Notes on measurability
1.
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible. 
2.
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT.
3.
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement.
4.
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts.
5.
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded.
10.2
Objective Status at Each Disease Evaluation
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 


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including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease.
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the 
“target” areas. Therefore, in these studies it is not acceptable to image only the “target” 
areas of the body in follow-up scans. For study-specific imaging requirements, see the 
Study Calendar in Section 9.0.  
a.
Complete Response (CR):  Complete disappearance of all target and non-
target lesions (with the exception of lymph nodes mentioned below).  No new 
lesions.  No disease related symptoms.   Any lymph nodes (whether target or 
non-target) must have reduction in short axis to < 1.0 cm.  All disease must be 
assessed using the same technique as baseline.
b.
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline.
c.
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline.
d.
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).   Appearance of any new 
lesion/site.  Death due to disease without prior documentation of progression and 
without symptomatic deterioration (see Section 10.2e).
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
1.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of progression based on a new lesion.
2.
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 
of disease to be considered progressive disease.  In such a case, the 
date of progressive disease will be the date of the initial abnormal FDG-
PET.
e.
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation.


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f.
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used.
g.
Objective status notes:
1.
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).
2.
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds.
3.
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.
4.
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed. 
5.
For bone disease documented on bone scan only, increased uptake 
does not constitute unequivocal progression. However, increase in the 
soft tissue component of a lesion as measured by CT or MRI would 
constitute progression.
6.
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion.
7.
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate.
10.3
Best Response
This is calculated from the sequence of objective statuses.
a.
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration.
b.
PR: Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR.


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c.
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR.
d.
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.
e.
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above.
f.
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.  
g.
Symptomatic deterioration: Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.  
h.
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies.
10.4
Performance Status
Patients will be graded according to the Zubrod Performance Status Scale.
POINT
DESCRIPTION
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 
housework, office work.  
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.  
3 
Capable of 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.
10.5
Time to Death
Time of death is calculated from date of registration to date of death due to any cause.  
Patients last known to be alive are censored at date of last contact.
10.6
Progression-Free Survival
Progression-free survival is calculated from date of registration to date of first 
documentation of progression or symptomatic deterioration (as defined above), or death 
due to any cause.  Patients last known to be alive without report of progression are 
censored at date of last contact.


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11.0
STATISTICAL CONSIDERATIONS
11.1
Accrual Goal
Accrual Rate: 7 pts/month.
Total Expected Accrual:  Minimum 86 eligible
Maximum 164 eligible (180 total)
Note:  As of 12/05/18, patients will no longer be randomized to either the crizotinib or 
savolitinib arm due to a planned interim futility analysis.  Updated accrual goals are as 
follows:
Accrual rate: 7 pts/month
Total expected accrual: 41 eligible/45 total patients per arm for the sunitinib and 
cabozantinib arms for a maximum of 148 
  
The cabozantinib has not yet had an interim analysis.  It will be conducted when the 
requisite number of PFS events have occurred.
11.2
Analysis of Primary Endpoint
With a total of 164 eligible patients (41 patients per arm) with pRCC accrued over a span 
of 2 years (with 1 year of follow-up), we will have 85% power to detect a 75% 
improvement in median PFS (1-sided α=0.10) in any one of the 3 treatment arms relative 
to sunitinib. This makes the assumption of PFS with sunitinib of approximately 6 months, 
and an expected PFS on the experimental arm of approximately 10.5 months (HR=1.75).  
Assuming that 10% will be ineligible, an additional 16 patients will likely be accrued, thus 
totaling 180 patients in order to reach 164 eligible patients. A proportional hazards model 
will be used to evaluate each pair wise treatment comparison of PFS, adjusting for the 
two stratification factors as covariates in the model. If accrual is efficient, we will consider 
an amendment to decrease alpha to 0.05 prior to the one futility analysis.
Although accrual of type I patients is preferable, this study design does not require 
minimum number of type I patients per arm.  For all subset analyses of papillary type, the 
independent pathology review categorization will be used.
A futility analysis for each MET inhibitor treatment arm versus sunitinib comparison will 
be conducted after 15 PFS events are observed in each treatment group (e.g., half of the 
intended cohort).
Interim*
Final
# of events
(under Ha)
Expected time
# of events
(under Ha)
Expected 
time
Standard
20/sunitinib
20 months
37/sunitinib
3 years
Experimental
15/arm
20 months
31/arm
3 years
* 50% of expected events on the experimental arms assuming 10.5 month median PFS
If the PFS HR (sunitinib vs. met inhibitor) is < 1 corresponding to worse progression-free 
survival for the respective met inhibitor arm, that particular met inhibitor arm will be 
recommended for closure to further accrual. The other met inhibitor arms that do not 
satisfy the futility criteria would continue to full accrual. The study will continue to enroll 
patients during the interim analysis phase. The sunitinib arm will continue to accrue as 
long as at least one of the MET inhibitor arms is still accruing.


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Results of the first futility analysis after events were reached for savolitinib and 
crizotinib suggest futility of these arms based on the aforementioned criteria.  
Thus, randomization to these arms was terminated on 12/05/18. Randomization to 
sunitinib and cabozantinib continues thereafter. 
11.3
Secondary Endpoints
Survival curves will be estimated by the Kaplan-Meier method, and a log-rank test will be 
used to compare OS between treatment arms.  Assuming a median survival of 15 months 
for the sunitinib arm, two years of follow-up after accrual is completed (one year beyond 
the time of the PFS primary analysis) and a one-sided alpha=0.10 and 41 patients per 
arm, there will be 0.83 statistical power to detect a difference in median survival of 15
months versus 27 months (comparable to a HR=1.80) between the control group and 
each MET inhibitor.
The chi-square test will be used to compare response rate between the control arm of 
sunitinib and the MET inhibitor treatment arms.  With 41 patients per arm with 
measurable disease, and assuming a 7% response rate in the sunitinib arm, there will be 
80% statistical power to detect a 7% versus 27% response rate on a MET inhibitor arm, 
assuming a one-sided alpha=0.10.
11.4
TM Aims:
a.
Met Mutation and Activity
Preliminary analysis of the TCGA patients with papillary RCC have a 9% MET 
mutation rate (includes germline and somatic mutation) and 2% rate of high level 
MET amplification. Additionally, a significant number of patients, approximately 
20% have overexpression of MET as detected by RNAseq in the setting of low 
copy number gain. We hypothesize that patients with MET mutations, high level 
level MET amplification or high levels of MET expression in the setting of low 
copy number amplification, will have a higher response to putative MET inhibitors 
as compared to patients treated with sunitinib.    This hypothesis is based in part 
on data from the aforementioned study of foretinib (Choueiri et al. J Clin Oncol 
2011), where RR was significantly higher in patients bearing germline mutations 
in MET (5 of 10, or 50%) as compared to those without (5 of 57, or 9%). In this 
study the overall RR was 13%.
Given patient heterogeneity and the multiple potential mechanisms for increased 
Met activity and the relatively low rate of germline mutations in MET or MET 
amplification, we likely will perform a pooled analysis amongst patients with 
mPRCC treated with putative MET inhibitors in the current study (n=123, 
assuming 3 arms with MET-directed therapy and 41 eligible patients per arm) to 
determine if increased MET activity is correlated with PFS and RECIST
response.  In total, approximately 30% of patients are anticipated to bear 
germline or somatic MET mutations, increase in MET copy number or increased 
Met expression.  We would expect better PFS in that group.  If we assume the 
70% group has a median PFS of 6 months and those with a mutation, or an 
increase in MET copy number or MET expression (30% group) has a median 
PFS of 10 months (HR=1.67), then we will have 81% statistical power to detect 
this difference using a two-sided alpha=0.05.
However, this does not indicate a predictive response to treatment – only 
prognostic.  Ideally, we would compare the hazard ratio between the MET 
inhibitor vs. sunitinib in those with versus without the mutation (i.e., the 


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interaction).  As can be seen by the following table, the cell counts are low for 
this interaction, but there is moderate power for large interactions.
Combined 
Met Inhibitor Arms
Sunitinib
N 
Estimated 
Median PFS
N 
Estimated 
Median 
PFS
MET mutation/expression 
(30%)
37
18 mo.
12
6 mo
No 
mutation/expression 
(70%)
86
6 mo.
29
6 mo.
Total (n=123)
123
41
As illustrated in the above table, if the MET mutation status has no impact on 
prognosis so those receiving sunitinib have a median PFS of 6 months in either 
group, and among those randomized to a MET inhibitor arm, median PFS is 
three times longer in those with a MET mutation/increased expression, then there 
will be 81% statistical power to identify this interaction using a two-sided 
alpha=0.05.
RECIST response rate (confirmed and unconfirmed PR and CR) based on MET 
mutation/expression level will be compared using the chi-square test.  In 
exploratory analyses we will also assess whether one of the three subtypes 1) 
mutation; 2) copy number alteration; or 3) increased Met expression has a more 
favorable response to MET inhibitor drugs.
b.
Assessment of Type I and Type II Renal Papillary Cancer
Those with inadequate tissue submitted or for whom the independent review is 
unable to designate type, will not be included in this analysis.  Ideally, we would 
test the interaction of type I/II categorization with the treatment comparison of 
met inhibitors compared to sunitinib.  However, since we only expect that 
approximately 15% of patients on S1500 will have type I papillary disease, we 
would only expect about 6 type I patients and 32 type II patients in the sunitinib 
arm, thereby providing very little statistical power for evaluating the interaction.
We have chosen to pool the three met inhibitor arms (n=123) and we will 
evaluate the response to these treatments by type I vs. II status.  We will 
primarily look at RECIST response, but we will also look at PFS.  We expect 
approximately 18 patients in the combined met inhibitor arms will be type I and 
n=95 will be type II, and we'll assume 10 are not able to be categorized.  If we 
assume that there will be a 10% CR + PR rate among those with type II disease 
and 30% RECIST response rate for type I disease, then by using a one-sided 
alpha=0.05 there will be 39% statistical power to detect this difference.  If the 
response rate difference is 10% vs. 40% between the type II versus I groups 
respectively, there will be 76% statistical power.  Similarly, if the 6 month PFS 
rate is 20% for those with type II disease and 50% for those with type I disease, 
there will also be 76% power to detect this difference.
We will also describe the response rate and PFS estimates for type I and II for 
the sunitinib arm along with 95% confidence intervals.
11.5
Data and Safety Monitoring Committee Oversight
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 


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non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet 
at the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study.
12.0
DISCIPLINE REVIEW
Independent pathologic assessment will be conducted for this study to determine: (1) type I vs 
type II pRCC histologic subtype for those patients deemed subtype NOS by the local pathologist, 
(2) confirmation of local pathologist subtype assignment of type I vs. type II. This independent 
pathologic assessment will be conducted in a retrospective fashion (i.e., pathologic subtype type I 
or type II assignment is NOT necessary prior to consent, registration or enrollment). We expect 
local pathologists to designate 6% of randomized patients as type I, 42% type II and 52% NOS 
(i.e. not able to definitively assign type I or type II). Disagreement with the local site pathologists 
will not make the patient ineligible. However, failure to submit specimen for independent 
pathologic assessment will deem the patient ineligible.
Type I or type II designations will be arbitrated by a group of expert pathologists. Electronic 
images of the slides will be transmitted to the expert pathologists. 
Sites must submit one Hematoxilyn-eosin (H&E)-stained slide and local pathology report 
from initial diagnosis. If H&E slide is not available, submit an unstained slide. This slide must be 
submitted within 3 months after registration via standard mail to the SWOG Biospecimen Bank, 
Lab #201. Specimens should be wrapped in sufficient packing to prevent breakage during 
transport. See Section 15.3 for shipping instructions. 
Tumor material must be reviewed by a local pathologist to ensure sufficient tumor cells are 
present in the sample. The local pathologist must review prior to enrolling patient noting that the 
tumor volume is at least 0.2mm3 and the tumor tissue contains at least 20% viable tumor cells.
13.0
REGISTRATION GUIDELINES
13.1
Registration Timing
Patients must be registered prior to initiation of treatment (no more than ten working days 
prior to planned start of treatment).
13.2
Investigator/Site Registration
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet to CTEP.
a.
CTEP Investigator Registration Procedures
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored clinical trials to 
register and to renew their registration annually.  To register, all individuals must 
obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) (i.e., clinical site staff requiring write access to 


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OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements 
per registration type are outlined in the table below.
Documentation Required
IVR
NPIVR
AP
A
FDA Form 1572


Financial Disclosure Form



NCI Biosketch (education, training, 
employment, license, and 
certification)



HSP/GCP training



Agent Shipment Form (if applicable)

CV (optional)



An active CTEP-IAM user account and appropriate RCR registration is required 
to access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 
IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following:
•
Added to a site roster
•
Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN
•
Act as the site-protocol PI on the IRB approval
•
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks 
Log (DTL).
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm
>.  For questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >.
b.
CTSU Registration Procedures
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
1.
IRB Approval:
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria 
including but not limited to: the following:
•
An active Federal Wide Assurance (FWA) number
•
An active roster affiliation with the Lead Network or
a 
participating organization
•
A valid IRB approval
•
Compliance with all protocol specific requirements.


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In addition, the site-protocol Principal Investigator (PI) must meet the 
following criteria:
•
Active registration status
•
The IRB number of the site IRB of record listed on their Form 
FDA 1572
•
An active status on a participating roster at the registering site.
Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval 
documentation to the CTSU Regulatory Office. For sites using the CIRB, 
IRB approval information is received from the CIRB and applied to the 
RSS in an automated process. Signatory Institutions must submit a 
Study Specific Worksheet for Local Context (SSW) to the CIRB via IRB 
Manager to indicate their intent to open the study locally.  The CIRB’s 
approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in the study.
2.
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the S1500 protocol 
page located on the CTSU members’ website.
•
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password
•
Click on the Protocols tab in the upper left of your screen
•
Either enter the protocol # in the search field at the top of the 
protocol tree, or
•
Click on the By Lead Organization folder to expand
•
Click on the SWOG link to expand, then select trial protocol # 
S1500
•
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.
3.
Requirements for S1500 Site Registration: 
•
IRB approval (For sites not participating via the NCI CIRB; local 
IRB documentation, an IRB-signed CTSU IRB Certification Form, 
Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted). 
4.
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office via 
the Regulatory Submission Portal, where they will be entered and 
tracked in the CTSU RSS.
Regulatory Submission Portal:  www.ctsu.org (members’ area) → 
Regulatory Tab → Regulatory Submission


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When applicable, original documents should be mailed to:
CTSU Regulatory Office
1818 Market Street, Suite 3000
Philadelphia, PA 19103
Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 866-651-2878 in order 
to receive further instruction and support.
5.
Checking Your Site’s Registration Status:
You can verify your site registration status on the members’ section of 
the CTSU website.  
•
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password
•
Click on the Regulatory tab at the top of your screen
•
Click on the Site Registration tab
•
Enter your 5-character CTEP Institution Code and click on Go
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks.
13.3
OPEN Registration Requirements
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data.
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM
account (check at < 
https://ctepcore.nci.nih.gov/iam >) and a ‘Registrar’ role on either the LPO or participating 
organization roster.  Registrars must hold a minimum of an AP registration type.  If a DTL 
is required for the study, the registrar(s) must also be assigned the OPEN Registrar task 
on the DTL.
All site staff will use OPEN to enroll patients to this study.  It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database.  OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org.  To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval.  If a DTL is required 
for the study, the IVR or NPIVR must also be assigned the appropriate OPEN-related 
tasks on the DTL.
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions:


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a.
Institution CTEP ID
b.
Protocol Number
c.
Registration Step
d.
Treating Investigator
e.
Credit Investigator
f.
Patient Initials
g.
Patient’s Date of Birth
h.
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.)
i.
Country of Residence
j.
ZIP Code
k.
Gender (select one):
•
Female Gender
•
Male Gender
l.
Ethnicity (select one):
•
Hispanic or Latino
•
Not Hispanic or Latino
•
Unknown
m.
Method of Payment (select one):
•
Private Insurance
•
Medicare
•
Medicare and Private Insurance
•
Medicaid
•
Medicaid and Medicare
•
Military or Veterans Sponsored NOS
•
Military Sponsored (Including Champus & Tricare)
•
Veterans Sponsored
•
Self Pay (No Insurance)
•
No Means of Payment (No Insurance)
•
Other
•
Unknown
n.
Race (select all that apply):
•
American Indian or Alaska Native
•
Asian
•
Black or African American
•
Native Hawaiian or other Pacific Islander
•
White
•
Unknown
13.4
Registration Procedures
a.
All site staff will use OPEN to enroll patients to this study. OPEN is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient in the Rave database. OPEN can be accessed 
at https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 


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website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench.
b.
Prior to accessing OPEN site staff should verify the following:
•
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff 
should refer to Section 5.0 to verify eligibility.
•
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).
13.5
Exceptions to SWOG registration policies will not be permitted.
a.
Patients must meet all eligibility requirements.
b.
Institutions must be identified as approved for registration.
c.
Registrations may not be cancelled.
d.
Late registrations (after initiation of treatment) will not be accepted.
14.0
DATA SUBMISSION SCHEDULE
14.1 
Data Submission Requirement
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible
14.2 
Master Forms
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details.
14.3
Data Submission Procedures
a.
Data collection for this study will be done exclusively through the Medidata 
Rave® clinical data management system. Access to the trial in Rave is granted 
through the iMedidata application to all persons with the appropriate roles 
assigned in Regulatory Support System (RSS). To access Rave via iMedidata, 
you 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, 
Read-Only, Site Investigator) on either the LPO or participating organization 
roster at the enrolling site. To hold the Rave CRA role or CRA Lab Admin role, 
the user must hold a minimum of an AP registration type.  To hold the Rave Site 
Investigator role, the individual must be registered as an NPIVR or IVR.  
Associates can hold read-only roles in Rave.  If the study has a DTL, individuals 
requiring write access to Rave must also be assigned the appropriate Rave tasks 
on the DTL.  
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 


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(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen.
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website 
under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk 
at 888/823-5923 or by e-mail at ctsucontact@westat.com. 
b.
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on 
Workbenches, then CRA Workbench to access the home page for the CRA 
Workbench and follow the link to Rave® provided in the left-hand navigation 
panel.
To access the CRA Workbench the following must be done (in order):
1.
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number,
2.
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed,
3.
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to view data for that 
institution.
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).
For difficulties with the CRA Workbench, please email 
technicalquestion@crab.org. 
c.
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table.
14.4
Data Submission Overview and Timepoints  
a.
WITHIN 7 DAYS OF REGISTRATION:
Submit the following:
S1500 Advanced Renal Carcinoma Onstudy Form
Baseline Abnormalities Form
Baseline Tumor Assessment Form


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Pathology Report from Nephrectomy or Diagnostic Biopsy/Surgery (Pathology 
report should indicate a diagnosis of PRCC and indicate subtype)
Submit radiology reports from all scans performed to assess disease at baseline. 
b.
WITHIN 60 DAYS AFTER REGISTRATION: 
Submit specimens as outlined in Section 15.0.
c.
WITHIN 90 DAYS AFTER REGISTRATION: 
Submit specimens as outlined in Section 12.0.
d.
WITHIN 14 DAYS AFTER EACH TREATMENT CYCLE: 
Submit the following:
S1500 Treatment Form
S1500 Adverse Event Form
e. 
IMMEDIATELY PRIOR TO CYCLES 1-3: 
Submit specimens as outlined in Section 15.0. 
f.
WITHIN 28 DAYS AFTER EACH RESPONSE ASSESSMENT:
Submit the following:
Follow Up Tumor Assessment Form
Relevant radiology reports (corresponding to disease assessment).
g.
WITHIN 28 DAYS OF DISCONTINUATION OF TREATMENT:
Submit the following:
Off Treatment Notice
Final S1500 Treatment Form
Final S1500 Adverse Event Form
Submit specimens as outlined in Section 15.0. 
h.
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
Submit the following:
Follow Up Tumor Assessment Form 
Radiology reports documenting progression and Off Treatment Notice (if the 
patient was still on protocol treatment).


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Follow-Up Form (if the patient was off protocol treatment) documenting date, site 
and method for determining progression/relapse.
Submit specimens as outlined in Section 15.0. 
i.
IF PATIENT IS OFF PROTOCOL TREATMENT, EVERY 3 MONTHS FOR UP 
TO 3 YEARS FROM RANDOMIZATION
Submit the following:
Follow Up Form
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported). 
j.
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
Submit the Notice of Death and a final S1500 Treatment Summary Form, S1500
Adverse Event Summary Form, and Follow Up Tumor Assessment Form (if the
patient was still on protocol treatment) or Follow-Up Form (if the patient was off 
protocol treatment) documenting death information.
15.0
SPECIAL INSTRUCTIONS
The specimens outlined in this section are optional for the patient.  See Section 12.0 for details 
regarding MANDATORY specimen submission.
15.1
Translational Study: Next generation sequencing (Optional for patient)
a.
If the patient consents, the following must be submitted to the SWOG 
Biospecimen Bank, Lab #201:
1.
Tissue block (preferred) or at least 12 (4-5 micron) unstained slides (20 
slides are strongly recommended).
` 
2.
Local pathology report
b.
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.  When submitting tissue to the SWOG Biospecimen Bank, 
be prepared to provide answers to the following questions in the SWOG 
specimen Tracking System:
•
Protocol #:
•
Patient #:
•
Patient Initials #:
•
Time point:
•
Collection Date:
•
Specimen Type:
•
Surgery Path #:
•
Block #:


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c.
Tissue Specifications
Most optimally, core needle biopsies should be obtained.  Cytology smear 
specimens are not sufficient for the molecular studies proposed. However, fine 
needle aspirates with good cellularity are acceptable if the paraffin-embedded 
cell blocks are available. Specimens containing less than 80% nucleated cells 
require greater total volume and may not be suitable to assay. The key sample 
consideration is to submit a total mass of cells that is sufficient to extract the 
amount of DNA necessary for analysis.  Bone biopsies are not allowed.
d.
Specimen Use
The SWOG Biospecimen Bank will forward tumor blocks and whole blood to Yale 
School of Medicine. Translational research efforts will include next-generation 
DNA sequencing, SNP array for copy number analysis, and gene expression. 
With patient's consent, any remaining tissue will be banked in the SWOG 
Repository, Lab #201, for future exploratory analysis. Specimen banking is 
optional for the patient.
15.2
Plasma, Buffy Coat, and Serum Blood Specimen Banking (Optional for patient)
If the patient consents, plasma and buffy coat and serum specimens must be submitted 
at the timepoints listed below.  Collection instructions and submission instructions are 
outlined below.  Plasma, buffy coat and serum specimens for banking and future 
translational medicine studies will be submitted to the SWOG Biospecimen Bank – Solid 
Tissue, Myeloma and Lymphoma Division, Lab #201.  
a.
Plasma and Buffy Coat
Blood specimens (two purple top EDTA tubes for plasma and buffy coats) will be 
collected after registration, but prior to Cycle 1 treatment; at the beginning of 
Cycles 2 and 3; and at the time of removal from protocol treatment (regardless of 
timepoint).  These specimens must be shipped within 28 days after obtaining to 
Lab #201. These specimens will be banked until funding is obtained to perform 
translational medicine studies which will include assessing molecular biomarkers 
relevant to MET kinase signaling (such as plasma HGF levels) and other 
pathways implicated in the pathogenesis of renal carcinoma and investigating 
their potential predictive and prognostic value.
b.
Plasma, Buffy Coat, and Processing Instructions:
1.
Blood samples should be collected using standard venipuncture 
technique.
2.
Cryovials must be labeled with SWOG patient number, patient’s initials, 
and date and time of specimen collection and specimen type.
3.
Collect ~6 mL whole blood in each of two (2) purple top tubes (EDTA 
tubes).
4.
Immediately invert tube (gently) 8-10 times.  This reduces the possibility 
of clot formation.
5.
Centrifuge sample at 800 x g for 10 minutes (~1500-2000 rpm, 
determined by centrifuge rotor size).


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6.
Immediately after centrifuging, transfer plasma in 1 mL aliquots to 
labeled cryovials.
7.
Pipette slowly to avoid disturbing the buffy coat layer.
8.
Leave a small amount of plasma (~.5 cm) above the buffy coat layer in 
each tube.
9.
After removing plasma from both tubes, transfer buffy coat to labeled 
cryovials.
•
The buffy layer is the off-white layer between the plasma and the 
red blood cells.
•
Pipette slowly in a circular motion to obtain as many buffy coat 
cells as possible.
•
Contamination of the buffy coat with red blood cells is expected 
and not a concern.
10.
Immediately freeze vials on dry ice or in a -80°C freezer. Store frozen 
plasma vials in a -70°C to -80°C freezer until ready to ship.  If a -70°C to 
-80°C freezer is not available, a -20°C would be sufficient.
c.
Serum
10 mL of venous blood will be collected in a SST red/grey marble top tube 
immediately prior to Cycles 1-3 and at the time the patient is removed from 
protocol treatment. These specimens must be shipped within 28 days after 
obtaining to Lab #201.  These specimens will be banked until funding is 
obtained to perform translational medicine studies which may include 
evaluation of changes in serum cytokines induced by MET signaling inhibition.
d.
Serum Specimen Collection Instructions:
1.
Draw peripheral blood into SST red/grey marble top vacutainer
2.
Allow blood to clot for 20 minutes, then centrifuge at 25°C, 1500xg 
(2700-3000 rpm) for 15 minutes
3.
Four Cryovials must be labeled with the SWOG patient number, patient’s 
initials, and date and time of specimen collection and specimen type. 
4.
Immediately after centrifuging, transfer serum in 1-2 mL aliquots to four 
labeled cryovials.
5.
If you are using plastic vacutainer tubes, samples can be directly frozen 
at -70°C (preferred) or at -20°C until shipped.
e.
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies.
15.3
SHIPPING SAMPLES:
a.
SWOG Specimen Tracking System (STS)
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the 
online system via the CRA Workbench. To access the CRA Workbench, go to 
the SWOG Web site (http://swog.org) and logon to the Members Area. After you 


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have logged on using your SWOG roster ID number and password, click on the 
CRA Workbench link to access the home page for CRA Workbench website. 
First time non- SWOG users must refer to start-up instructions located at 
https://gill.crab.org/SpecTrack/.
A copy of the Shipment Packing List produced by the online Specimen Tracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag. The Specimen Submission Form is NOT 
required when the online system is used.
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS.
To report technical problems with Specimen Tracking, such as database errors 
or connectivity issues, please send an email to technicalquestion@crab.org. For 
procedural help with logging and shipping specimens, there is an introduction to 
the system on the Specimen Tracking main page
(http://dnet.crab.org/SpecTrack/Documents/Instructions.pdf); or contact the Data 
Operations Center at 206/652-2267 to be routed to the Data Coordinator for 
further assistance.
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of plasma, serum and tissue specimens for SWOG Biospecimen 
Bank submission is identified as follows:
Lab #201: SWOG Biospecimen Bank – Solid Tissue, Myeloma and Lymphoma 
Division
Contact:
SWOG Biospecimen Bank
Phone: 614/722-2865
Email:
bpcbank@nationwidechildrens.org  
Plasma, buffy coats, and serum must be shipped on dry ice by overnight courier 
Monday through Wednesday.
b.
Shipping guidelines for formalin-fixed paraffin embedded (FFPE) tumor tissue 
specimens:
1.
Specimens must be packaged to comply with IATA standards 
(www.iata.org). 
2.
Blocks and/or slides will be shipped in a padded envelope and should 
not be shipped in the same chamber as frozen specimens.  If frozen and 
FFPE specimens are to be shipped together, they must be shipped in a 
dual-chambered shipper.
3.
When shipping slides, place them in a plastic slide holder and stabilize 
by placing cotton or soft paper under the lid.  Tape the lid so that it does 
not pop open during shipment (one piece of tape is sufficient).
4.
Wrap any slide cartridge(s) in bubble wrap and mail in a padded 
envelope if available.
c.
Shipping guidelines for frozen specimens:
1.
Specimens must be packaged to comply with IATA standards 
(www.iata.org). 


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2.
First, place the specimen in a leak-proof biohazard envelope. Include an 
absorbent material. Next, place the biohazard envelope containing the 
specimen in a puncture and pressure resistant envelope (e.g. Tyvek 
envelope). 
3.
Place the packaged specimen(s) in an appropriate shipping container 
(composed of an inner styrofoam and outer cardboard layer). Place a 
layer of dry ice in the bottom of the shipping container, then set the 
specimen on top of the dry ice. Cover the specimen with dry ice until the 
shipping container is full.
4.
Include required paperwork (e.g. SpecTrack-generated packing list(s)) in 
the shipment.
5.
Close the shipping container and tape shut.  Do not completely seal the 
container. Complete a dry ice label.  Attach an "Exempt Human 
Specimen" label and the dry ice label to the side of the shipping 
container.
6.
Attach a shipping label to the top of the shipping container. 
7.
Batch shipments are permitted and must have specimens from 5 or 
fewer patients per shipping container.  Batches should be shipped at 
least quarterly to avoid sites storing specimens in freezers long term.
16.0
ETHICAL AND REGULATORY CONSIDERATIONS
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice:
Informed Consent
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations.
Institutional Review
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46).
Drug Accountability
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
Publication and Industry Contact
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 


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Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator" 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study:
1.
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2.
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"):
a.
NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol.
b.
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own Agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party 
Data 
solely 
for 
development, 
regulatory 
approval, 
and 
commercialization of its own Agent.
3.
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164.
4.
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them.
5.
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial.
6.
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's 


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confidential and proprietary data, in addition to the Collaborator(s)'s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also 
be forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/media presentation should be sent to:
E-mail: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information.
Monitoring
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to CTEP on 
a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are due 
January 31, April 30, July 31, and October 31.  Instructions for submitting data using the CDUS 
can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).
Note: As this study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.
Confidentiality
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained.
16.1
Adverse Event Reporting Requirements
a.
Purpose
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. 
b.
Reporting method
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office
electronically via the CTEP-AERS Web-based application located at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 


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c.
When to report an event in an expedited manner
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event, as specified in Table 16.1. 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system.
d.
Other recipients of adverse event reports
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required.
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures.
e.
Expedited reporting for investigational agents
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided
in Table 16.1. If there is any question about the reportability of an adverse event 
or if on-line CTEP-AERS cannot be used, please telephone or email the SAE 
Specialist at the Operations Office, 210/614-8808 or adr@swog.org, before 
preparing the report.


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Table 16.1:
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agents/Intervention1  Cabozantinib, Crizotinib, Savolitinib, or Sunitinib Malate.
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:  
1)
Death
2)
A life-threatening adverse event 
3)
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours 
4)
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
5)
A congenital anomaly/birth defect. 
6)
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.
Hospitalization
Grade 1 
Timeframes
Grade 2 
Timeframes
Grade 3 Timeframes
Grade 4 & 5 
Timeframes
Resulting in 
Hospitalization 
≥ 24 hrs
10 Calendar Days
24-Hour 5 
Calendar 
Days
Not resulting in
Hospitalization 
≥ 24 hrs
Not required
10 Calendar Days
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR.   
Expedited AE reporting timelines are defined as:
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report.
o
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE.
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for:
•
All Grade 4, and Grade 5 AEs
Expedited 10 calendar day reports for:
1. Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
•
Grade 3 adverse events
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f.
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent 
under a CTEP IND:
•
Group-specific instructions
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In 
the Operations Offices in order to complete the evaluation of the 
event.  If requested, the supporting data should be sent within 5 
calendar days by fax to 210-614-0006.  Supporting clinical data 
submitted should include:
•
Printed copy of the first page of the CTEP-AERS Report.
•
Copies of clinical sourced documentation of the event.
•
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death.
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS
1.
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm.
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event.
•
Leukemia secondary to oncology chemotherapy (e.g., 
Acute Myelocytic Leukemia [AML])
•
Myelodysplastic syndrome (MDS)
•
Treatment-related secondary malignancy
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting
mechanisms outlined in each protocol.
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified.
For more information see:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf. 
2.
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  A copy of the 
report and the following supporting documentation must also be 
submitted to SWOG Operations Office within 30 days by fax to 210-614-
0006 or mail to the address below:


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•
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis
•
(if available) a copy of the cytogenetics report  
SWOG
ATTN: SAE Program
4201 Medical Drive, Suite 250
San Antonio, Texas 78229
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial.
h.
Reporting Pregnancy, Fetal Death, and Death Neonatal
1.
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report.
2.
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence 
of respiration, heartbeat, or definite movement of a voluntary muscle 
after expulsion from the uterus, without possibility of resuscitation”
should be reported expeditiously as Grade 4 “pregnancy, puerperium 
and perinatal conditions – Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.  
3.
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the
General disorders and administration SOC.
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated.
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  The 
potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report.
The Pregnancy Information Form is available at: 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm  


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17.0
BIBLIOGRAPHY
1
Keegan KA, Schupp CW, Chamie K, et al.
Histopathology of surgically treated renal cell 
carcinoma: survival differences by subtype and stage. J Urol, 188:391-7, 2012. PMID: 22698625
2
Margulis V, Tamboli P, Matin SF, et al. Analysis of clinicopathologic predictors of oncologic 
outcome provides insight into the natural history of surgically managed papillary renal cell 
carcinoma. Cancer, 112:1480-8, 2008. PMID: 18240184
3
Reuter VE. The pathology of renal epithelial neoplasms. Semin Oncol, 33:534-43, 2006. PMID: 
17045082
4
Schmidt L, Junker K, Nakaigawa N, et al. Novel mutations of the MET proto-oncogene in papillary 
renal carcinomas. Oncogene, 18:2343-50, 1999. PMID: 10327054
5
Sweeney P, El-Naggar AK, Lin SH, et al. Biological significance of c-met over expression in 
papillary renal cell carcinoma. J Urol, 168:51-5, 2002. PMID: 12050491
6
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, 24:343-9, 2013. PMID: 23022995
7
Albiges L, Guegan J, Le Formal A, et al. MET is a potential target across all Papillary Renal Cell 
Carcinomas. Result from a large molecular study of pRCC with CGHa and matching Gene 
Expression array. Clinical Cancer Research, 20(13):3411-21, 2014. PMID: 24658158
8
Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary 
and chromophobe renal cell carcinoma. J Clin Oncol, 26:127-31, 2008. PMID:18165647
9
Ravaud A, Oudard S, Fromont MD, et al. First line treatment sunitinib in type I and II papillary 
renal cell carcinoma (PRCC): a phase II study (SUPAP) by the French Genito-Urinary Group 
(GETUG) and the Group of Early Phase
Trials (GEP). Ann Oncol, 26(6):1123-8 doi 
10.1093/annonc/mdv149, 2015. PMID: 25802238
10
Tannir NM, Plimack E, Ng C, Tamboli P, Bekele NB, Xiao L, Smith L, Lim Z, Pagliaro L, Araujo J, 
Aparicio A, Matin S, Wood CG, Jonasch E: A phase 2 trial of sunitinib in patients with advanced 
non-clear cell renal cell carcinoma. Eur Urol 62:1013-9, 2012.
11
Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for Advanced 
Renal-Cell Carcinoma. N Engl J Med, 356:2271-81, 2007. PMID: 17538086
12
Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on 
outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol, 
26:202-9, 2009. PMID: 19229667
13
Koh Y, Lim HY, Ahn JH, et al. Phase II trial of everolimus for the treatment of nonclear-cell renal 
cell carcinoma. Ann Oncol, 24:1026-31, 2013. PMID: 23180114
14
Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line 
everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in 
patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol, 32(25):2765-72, doi:
10:1200/JCO, 2013. PMID: 25049330
15
Tannir NM, Jonasch E, Altinmakas E, et al. Everolimus versus sunitinib prospective evaluation in 
metastatic non-clear cell renal cell carcinoma (The ESPN Trial): A multicenter randomized phase 
2 trial. ASCO Meeting Abstracts, 32:4505, 2014.


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Bellon SF, Kaplan-Lefko P, Yang Y, et al. c-Met inhibitors with novel binding mode show activity 
against several hereditary papillary renal cell carcinoma-related mutations. J Biol Chem, 
283:2675-83, 2008.  PMID: 18055465
17
Qian F, Engst S, Yamaguchi K, et al. Inhibition of tumor cell growth, invasion, and metastasis by 
EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. 
Cancer Res, 69:8009-16, 2009. PMID: 19808973
18
Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, 
Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas 
NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, 
Srinivasan R: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in 
patients with papillary renal cell carcinoma. J Clin Oncol 31:181-6, 2013.
19
Qian F, Engst S, Yamaguchi K, et al. Inhibition of tumor cell growth, invasion, and metastasis by 
EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. 
Cancer Res, 69:8009-16, 2009. PMID: 19808973
20
Choueiri TK, Pal SK, McDermott DF, et al. Efficacy of cabozantinib (XL184) in patients (pts) with 
metastatic, refractory renal cell carcinoma (RCC). ASCO Meeting Abstracts, 30:4504, 2012.


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18.0
APPENDIX
18.1
Intake Calendars
a.
Intake Calendar: Arm 1 Sunitinib
b.
Intake Calendar: Arm 2 Cabozantinib
d.
Intake Calendar: Arm 3 Crizotinib
e.
Intake Calendar: Arm 4 Savolitinib
18.2
Examples of Clinically Relevant Drug Interactions:  Substrates, Inducers and Inhibitors of 
the Isoenzyme CYP3A4
18.3
Patient Drug Information Handouts and Wallet Cards
a.
Cabozantinib
b.
Crizotinib
c.
Savolitinib
d.
Sunitinib
18.4
Identification and Characterization of Oncometabolite-Induced DNA Repair Defects in 
Sporadic Papillary Kidney Cancer
18.5
Specimen Banking and Translational Medicine Material Instructions for SWOG 
Biospecimen Bank (BB)


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18.1a
Intake Calendar: S1500 Arm 1 Sunitinib
Cycle: ________    Start Date: ____________ Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat  
Instructions for the participant:  Sunitinib is taken once a day. This is a 42 day cycle calendar on which you are to 
put the date in the box on the calendar and record the dose and time you take sunitinib (or the reason a dose was 
not taken). Take medication as directed by study doctor. Swallow sunitinib whole. Sunitinib may be taken with or 
without food. You must not drink grapefruit juice or eat grapefruit or Seville oranges during your treatment with 
sunitinib. You will take sunitinib every day for four weeks and then not take it for the next two weeks. If you develop 
any side effects from the drug, mark this on the calendar on the day you note the effect.
Storage:  Sunitinib should be stored at room temperature (not to exceed 25ºC/77ºF) in their original container.
Site Personnel:  Site personnel must ensure that patients clearly understand the guidelines for self-medication.  
Patients should be given a sufficient supply to last until their next study visit.  Unused drug and/or empty bottles 
should be returned to the site at the next study visit.
If you have questions contact: ____________________
Telephone: _____________________
Research Staff Comments:
Number of pills taken:________
Number of pills returned: ________
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
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AM:_____
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AM:_____
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AM:_____
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AM:_____
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AM:_____
PM: _____
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PM: _____
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PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
Patient Signature: 
 
 


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18.1b
Intake Calendar: S1500 Arm 2 Cabozantinib
Cycle: ________    Start Date: ____________  Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat  
Instructions for the participant:  Cabozantinib is taken once a day. This is a 42 day cycle calendar on which you 
are to put the date in the box on the calendar and record the dose and time you take cabozantinib (or the reason a 
dose was not taken). Take medication as directed by study doctor. Swallow cabozantinib whole. Cabozantinib must 
be taken on an empty stomach (do not eat within the 2 hours before you take it and for 1 hour after). If you miss a 
pill, take it as soon as you remember EXCEPT if your next scheduled dose is in less than 12 hours. In that case, just 
take the next pill at your regular time. Cabozantinib is taken continuously. There are no scheduled times when you 
stop taking it and then begin again. You must not drink grapefruit juice or eat grapefruit or Seville oranges during 
your treatment with cabozantinib. If you develop any side effects from the capsules, mark this on the calendar. 
Storage:  Cabozantinib should be stored at room temperature (not to exceed 25ºC/77ºF) in their original container.
Site Personnel:  Site personnel must ensure that patients clearly understand the guidelines for self-medication.  
Patients should be given a sufficient supply to last until their next study visit.  Unused drug and/or empty bottles 
should be returned to the site at the next study visit.
If you have questions contact: ____________________
Telephone: _____________________
Research Staff Comments:
Number of pills taken:________
Number of pills returned: ________
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
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PM: _____
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AM:_____
PM: _____
AM:_____
PM: _____
Patient Signature: 
 
 
 


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18.1c
Intake Calendar: S1500 Arm 3 Crizotinib
Cycle: ________    Start Date: ____________ Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat  
Instructions for the participant:  Crizotinib is a pill you take twice a day. This is a 42 day cycle calendar on which 
you are to put the date in the box on the calendar and record the dose and time you take each crizotinib capsule (or 
the reason a dose was not taken). Take medication as directed by study doctor. Swallow crizotinib capsules whole. 
Crizotinib may be taken with or without food. Crizotinib is taken continuously. There are no scheduled times when 
you stop taking crizotinib and then begin again. If you develop any side effects from the capsules, mark this on the
calendar on the day you note the effect.
Storage:  Crizotinib tablets should be stored at room temperature (not to exceed 25ºC/77ºF) in their original 
container for light protection. Keep the medication in the bottles provided and do not transfer it to any other 
container. Protect from moisture.
Site Personnel:  Site personnel must ensure that patients clearly understand the guidelines for self-medication.  
Patients should be given a sufficient supply to last until their next study visit.  Unused drug and/or empty bottles 
should be returned to the site at the next study visit.
If you have questions contact: ____________________
Telephone: _____________________
Research Staff Comments:
Number of pills taken:________
Number of pills returned: ________
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
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PM: _____
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PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
Patient Signature: 
 
 
 


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18.1d
Intake Calendar: S1500 Arm 4 Savolitinib
Cycle: ________    Start Date: ____________ Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat  
Instructions for the participant:  Savolitinib is taken daily. This is a 42 day cycle calendar on which you are to put 
the date in the box on the calendar and record the dose and time you take savolitinib (or the reason not taken). 
Take medication as directed by study doctor. Swallow savolitinib whole. Savolitinib must be taken with food
(specifically within 1 hour after the start of a meal). You must not drink grapefruit juice or eat grapefruit or Seville 
oranges during your treatment with savolitinib. Savolitinib is taken continuously. There are no scheduled times when 
you stop taking savolitinib and then begin again. If you develop any side effects from the medication, mark this on 
the calendar on the day you note the effect.
Storage: Savolitinib should be stored at room temperature (not to exceed 25ºC/77ºF) in their original container. 
Site Personnel:  Site personnel must ensure that patients clearly understand the guidelines for self-medication.  
Patients should be given a sufficient supply to last until their next study visit.  Unused drug and/or empty bottles 
should be returned to the site at the next study visit.
If you have questions contact: ____________________
Telephone: _____________________
Research Staff Comments:
Number of pills taken:________
Number of pills returned: ________
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
PM: _____
AM:_____
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AM:_____
PM: _____
AM:_____
PM: _____
Patient Signature: 
 
 
 


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18.2
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.
CYP2D6
SUBSTRATES
Amitriptyline (hydroxylation)
Amphetamine
Betaxolol
Bisoprolol
Brofaromine
Buturolol
Bupropion
Captopril
Carvedilol
Cevimeline
Chlorpheniramine
Chlorpromazine
Cinnarizine
Clomipramine (hydroxylation)
Clozapine (minor pathway)
Codeine (hydroxylation, o-demelhylation)
Cyclobenzaprine (hydroxylation)
Cyclophosphamide
Debrisoquin
Delavirdine
Desipramine
Dexfenfluramine
Dextromethorphan (o-demethylation)
Dihydrocodeine
Diphenhydramine
Dolasetron
Donepezil
Doxepin
Encainide
Fenlluramine
Flecainide
Fluosetine (minor pathway)
Fluphenazine
Haiofantrine
Haioperidol (minor pathway)
Hydrocodone
Hydrocortisone
Hydroxyamphetamine
lmipramine (hydroxylation)
Labetalol
Loratadine
Maprotiline
m-Chlorophenylpiperazine (m-CPP)
Meperidine
Methadone
Methamphetamine
Metoclopramide
Metoprolol
Mexitetine
Mianserin
Mirtazapine (hydroxylation)
Molindone
Morphine
Nortriptyline (hydroxylation)
Olanzapine (minor, hydroxymethylation)
Ondansetron
Orphenadrine
Oxycodone
Papaverine
Paroxetine (minor pathway)
Penbutolol
Pentazocine
Perhexiline
Perphenazine
Phenformin
Pindolol
Promethazine
Propafenone
Propranolol
Quetiapine
Remoxipride
Risperidone
Ritonavir (minor)
Ropivacaine
Selegiline
Sertindole
Sertratine (minor pathway)
Sparteine
Tamoxifen
Thioridazine
Tiagabine
Timolol
Tolterodine
Tramadol
Trazodone
Trimipramine
Tropisetron
Venlafaxine (o-desmethylation)
Yohimbine


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INHIBITORS
Amiodarone
Celecoxib
Chloroquine
Chlorpromazine
Cimelidine
Citalopram
Clomipramine
Codeine
Deiavirdine
Desipramine
Dextropropoxyphene
Diitiazem
Doxorubicin
Entacapone (high dose)
Fluoxetine
Fluphenazine
Fluvoxamine
Haloperidol
Labetalol
Lobeline
Lomustine
Methadone
Mibefradil
Moclobemide
Nortluoxeline
Paroxetine
Perphenazine
Propafenone
Quinacrine
Quinidine
Ranitidine
Risperidone (weak)
Ritonavir
Sertindole
Sertraline (weak)
Thioridazine
Vaiprolc acid
Venlafaxine (weak)
Vinblastine
Vincristine
Vinorelbine
Yohimbine
CYP3A3/4
Substrates
Acetaminophen
Aifentanil
Alosetron
Alprazolam
Amiodarone
Amitriptyline (minor)
Amlodipine
Anastrozole
Androsterone
Antipyrine
Astemizole
Atorvastatin
Benzphetamine
Bepridil
Bexarotene
Bromazepam
Bromocriptine
Budesonide
Bupropion (minor)
Buspirone
Busutfan
Caffeine
Cannabinoids
Carbamazepine
Cevimeline
Cerivastatin
Diergotamine
Digitoxin
Diltiazem
Disopyramide
Chlorpromazine
Cimetidine
Cisapride
Citałopram
Clarithromycin
Clindamycin
Clomipramine
Clonazepam
Clozapine
Cocaine
Codeine (demethylation)
Cortisol
Cortisone
Cyclobenzaprine (demethylation)
Cyclophosphamide
Cyclosporine
Dapsone
Dehydroepiandrostendione
Delavirdine
Desmethyldiazepam
Dexamethasone
Dextromethorphan (minor, N-demethylation) 
Diazepam (minor; hydroxylation, N-
demethylation)
Nefazodone
Nelfinavir
Nevirapine
Nicardipine


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Docetaxel
Dolasetron
Donepezil
Doxorubicin
Doxycycline
Dronabinol
Enalapril
Ergotamine
Erylhromycin
Estradiol
Ethinyl estradiol
Ethosuximide
Etoposide
Exemestene
Dofetilide (minor)
Felodipine
Fentanyl
Fexotenadine
Finaxteride
Fluoxetine
Flutamide
Glyburide
Granisetron
Halofantrine
Hydrocortixone
Hydroxyarginine
lfosfamide
lmipramine
lndinavir
lsradipine
ltraconazole
Ketoconazole
Lansoprazole (minor)
Letrozole
Levobupivicaine
Lidocaine
Loratadine
Losartan
Lovastatin
Methadone
Mibefradil
Miconazole
Midazolam
Mifepristone
Mirtazapine (N-demethylation)
Montelukast
Navelbine
Toremifene
Trazodone
Tretinoin
Triazolam
Troglitazone
Troleandomycin
Venlafaxine (N-demethylation)
Verapamil
Vinblastine
Nifedipine
Niludipine
Nimodipine
Nisoldipine
Nitrendipine
Omeprazole (sulfonation)
Ondansetron
Oral contraceptives
Orphenadrine
Paclitaxel
Pantoprazole
Pimozide
Pioglitazone
Pravastatin
Prednisone
Progesterone
Proguanil
Propafenone
Quercetin
Quetiapine
Quinidine
Quinine
Repaglinide
Retinoic acid
Rifampin
Risperidone
Ritonavir
Salmeterol
Saquinavir
Sertindole
Sertraline
Sibutramine
Sildenafil citrate
Simvastatin
Sirolimus
Sufentanil
Tacrolimus
Tamoxifen
Temazepam
Teniposide
Terfenadine
Testosterone
Tetrahydrocannabinol
Theophylline
Tiagabine
Tolterodine
Vincristine
Warfarin (R-warfarin)
Yohimbine
Zaleplon (minor pathway)
Zatoestron
Zileuton
Ziprasidone
Zolpidem


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Zonisamide
INDUCERS
Avasimibe
Carbamazepine
Dexamethasone
Ethosuximide
Glucocorticoids
Griseofulvin
Nafcillin
Nelfinavir
Nevirapine
Oxcarbazepine
Phenobarbital
Phenylbutazone
Phenytoin
Primidone
Progesterone
Rifabutin
Rifampin
Rofecoxib (mild)
St John’s wort
Sulfadimidine
Sulfinpyrazone
Troglitazone
INHIBITORS
Amiodarone
Anastrozole
Azithromycin
Boceprevir
Cannabinoids
Cimetidine
Clarithromycin
Clotrimazole
Cobicistat
Cyclosporine
Danoprevir
Danazol
Delavirdine
Dexamethasone
Diethyldithiocarbamate
Diltiazem
Dirithromycin
Disulfiram
Elvitegravir/RIT
Entacapone (high dose)
Erythromycin
Ethinyl estradiol
Fluconazole (weak)
Fluoxetine
Fluvoxamine
Gestodene
Grapefruit juice
lndinavir
lsoniazid
ltraconazole 
Ketoconazole
Lopinavir/RIT
Metronidazole
Mibefradil
Miconazole (moderate)
Nefazodone
Nelfinavir
Nevirapine
Norfloxacin
Norfluoxetine
Omeprazole (weak)
Oxiconazole
Paroxetine (weak)
Posaconazole
Propoxyphene
Quinidine
Quinine
Quinupristin and dalfopristin
Ranitidine
Ritonavir
Saquinavir
Sertindole
Sertraline
Telaprevir
Telithromycin
Tipranavir/RIT
Troglitazone
Troleandomycin
Valproic acid (weak)
Verapamil
Voriconazole
Zafirlukast
Zileuton


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CYP1A2
INHIBITORS
Ciprofloxacin
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 
2000: 1364-1371)


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18.3a
Cabozantinib Patient Drug Information Handout and Wallet Card
Information for Patients, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, XL184 (cabozantinib).  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient. 
These are the things that you as a healthcare provider need to know:
XL184(cabozantinib) interacts with a certain specific enzyme in your liver, a certain 
transport protein that helps move drugs in and out of cells, and the heart’s electrical 
activity (QTc prolongation).
•
The enzyme in question is CYP 3A4.  XL184 (cabozantinib) is metabolized by 
CYP3A4 and may be affected by other drugs that inhibit or induce this enzyme.
•
The protein in question are P-glycoprotein (P-gp) and MRP2.  XL184 (cabozantinib) 
is an inhibitor of P-gp and may be affected by other drugs that are “substrates.” 
XL184 is also a substrate of MRP2 and may be affected by other drugs that are 
“inhibitor” or “inducers” of MRP2. 
•
XL184 (cabozantinib) may affect the heart’s electrical activity causing QTc 
prolongation. The study doctor may be concerned about QTc prolongation and any 
other medicine that is associated with greater risk for having QTc prolongation.  
To the patient: Take this paper with you to your medical appointments and keep 
the attached information card in your wallet.  
XL184 (cabozantinib) may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking 
before you enroll onto this clinical trial.  It is also very important to tell your doctors if you 
stop taking any regular medicines, or if you start taking a new medicine while you take 
part in this study.  When you talk about your current medications with your doctors, 
include medicine you buy without a prescription (over-the-counter remedy), or any herbal 
supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an 
updated medication list with you.
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking 
part in a clinical trial. 
These are the things that you and they need to know: 
XL184 (cabozantinib) must be used very carefully with other medicines that use certain 
liver enzyme, transport proteins to be effective or to be cleared from your system 
or that may affect your heart’s electrical activity.  Before you enroll onto the clinical 
trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of 
CYP3A4, substrate of P-gp, or any medicine associated with greater risk for having 
QTc prolongation.”
•
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects. 


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


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18.3b
Crizotinib Patient Drug Information Handout and Wallet Card
Information for Patients, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, crizotinib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.
These are the things that you as a healthcare provider need to know:
Crizotinib interacts with a certain specific enzyme in your liver and a certain transport 
protein that helps move drugs in and out of cells.
•
The enzymes in question are CYP 3A4/5, 2C8, 2C19, 2B6 and 2D6.  Crizotinib is 
primarily metabolized by CYP3A4, with minor contributions from CYP2C8, 2C19, and 
2D6 and may be affected by other drugs that inhibit or induce these enzymes. 
Crizotinib is an inhibitor of CYP 3A4 and 2B6 and may affect the metabolism of other 
drugs.
•
The protein in question are P-glycoprotein (P-gp), OCT1 and OCT2.  Crizotinib is 
an inhibitor of P-gp and may be affected by other drugs that are “substrates.”
To the patient: Take this paper with you to your medical appointments and keep 
the attached information card in your wallet.  
Crizotinib may interact with other drugs which can cause side effects. For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll
onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, include medicine you 
buy without a prescription (over-the-counter remedy), or any herbal supplements such as 
St. John’s Wort.  It is helpful to bring your medication bottles or an updated medication 
list with you.
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking 
part in a clinical trial.
These are the things that you and they need to know: 
Crizotinib must be used very carefully with other medicines that use certain liver 
enzyme, transport proteins to be effective.  Before you enroll onto the clinical trial, 
your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors or 
substrates of CYP 3A4/5,2C8, 2C19, 2D6, 2B6, P-gp, OCT1 and OCT2.”
•
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.
•
Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or 
discontinuing any medicine.  
•
Your study doctor’s name is _____________________________________ and he or 
she can be contacted at _____________________________________.


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STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the experimental 
study drug crizotinib.  This clinical trial is sponsored by 
the NCI.  Crizotinib may interact with drugs that are 
processed by your liver or use certain transport 
proteins in your body.  Because of this, it is very
important to:
Tell your doctors if you stop taking any medicines or if 
you start taking any new medicines.
Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or 
pharmacists) that you are taking part in a clinical trial.
Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal 
supplement.
Crizotinib must be used very carefully with other 
medicines that interact with CYP 3A4/5, C2C8, 2C19,
2D6 and 2B6 enzymes, or transporter proteins (P-
gp), OCT1 and OCT2.

Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines and herbal 
supplements that are considered “strong 
inducers/inhibitors or substrates of CYP 3A4/5, 
2C8, 2C19, 2D6, 2B6, P-gp, OCT1 and OCT2.”

Before prescribing new medicines, your regular 
health care providers should go to a frequently-
updated medical reference for a list of drugs to 
avoid, or contact your study doctor.  

Your study doctor’s name is 
_____________________________ and can be 


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18.3c
Savolitinib Patient Drug Information Handout and Wallet Card
Information for Patients, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug savolitinib (AZD6094). This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient. 
These are the things that you as a healthcare provider need to know:
Savolitinib (AZD6094) interacts with certain specific enzymes in the liver and certain 
transport proteins that help move drugs in and out of cells.
•
The enzymes in question are CYP 3A4, 3A5, 1A2, 2C8, 2C9, and 2D6.
Savolitinib (AZD6094) is primarily metabolized by CYP 3A4/5 and 1A2 and some 
NADPH-independent non-CYP enzymes and may be affected by other drugs that 
strongly inhibit or induce CYP3A4/5 and CYP1A2.  Savolitinib (AZD6094) inhibits 
CYP 3A4, 3A5, 1A2, 2C8, 2C9, 2D6 and UGT1A1 and may affect other drugs 
that are substrates of these enzymes.  
•
Savolitinib (AZD6094) inhibits P-gp, BCRP, OATP1B1, MATE1 and MATE2K 
transporters and this may affect transport of other drugs that is dependent on any 
of these transport proteins.
•
Since there is limited clinical experience with this agent, patients on concomitant 
drugs with narrow therapeutic ranges, such as warfarin, should be monitored 
closely.
September 2017
To the patient: Take this paper with you to your medical appointments and keep 
the attached information card in your wallet.  
Savolitinib (AZD6094) may interact with other drugs which can cause side effects. For 
this reason, it is very important to tell your study doctors of any medicines you are taking 
before you enroll onto this clinical trial.  It is also very important to tell your doctors if you 
stop taking any regular medicines, or if you start taking a new medicine while you take 
part in this study.  When you talk about your current medications with your doctors, 
include medicine you buy without a prescription (over-the-counter remedy), or any herbal 
supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an 
updated medication list with you.
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking 
part in a clinical trial. 
These are the things that you and they need to know: 
Savolitinib (AZD6094) must be used very carefully with other medicines that need certain 
liver enzymes and transport proteins to be effective or to be cleared from your system.  
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered 
“strong inducers/inhibitors of CYP 3A4, 3A5 and 1A2.” Savolitinib (AZD6094) inhibits 
enzymes CYP 3A4, 3A5, 1A2, 2C8, 2C9, 2D6 and transport proteins P-glycoprotein (P-
gp), BCRP (breast cancer resistance protein), OATP1B1, MATE1 and MATE2K. These 
characteristics may change how other medicine works in your body.


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
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects. 

Avoid ingesting grapefruit juice, grapefruit and Seville oranges while taking savolitinib 
(AZD6094).

You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges.

Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is 

_____________________________________ and he or she can be contacted at
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the 
experimental study drug savolitinib (AZD6094).  This 
clinical trial is sponsored by the NCI.  savolitinib 
(AZD6094) may interact with drugs that are processed 
by your liver, or use certain transport proteins in your 
body.  Because of this, it is very important to:
Tell your doctors if you stop taking any medicines or 
if you start taking any new medicines. 
Tell all of your health care providers (doctors, 
physician assistants, nurse practitioners, or pharmacists) 
that you are taking part in a clinical trial.
Check with your doctor or pharmacist whenever you 
need to use an over-the-counter medicine or herbal
supplement.
Avoid ingesting grapefruit, grapefruit juice and Seville 
oranges.
You may need to be monitored more frequently if you 
are taking any drugs that have narrow therapeutic ranges, 
such as warfarin.
savolitinib (AZD6094) interacts with CYP 1A2, 3A4/5, 
2C8, 2C9, 2D6 and transport proteins, P-gp, BCRP, 
OATP1B1, MATE1 and MATE2K, and must be used very 
carefully with other medicines that interact with these 
enzymes and proteins. 
Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review 
any medicines and herbal supplements that are considered 
“strong inducers/inhibitors of CYP 3A4/5, 1A2.” 
savolitinib (AZD6094) inhibits CYP 3A4/5, 1A2, 2C8, 
2C9, 2D6 and transporters, P-gp, BCRP, OATP1B1, 
MATE1 and MATE2K. It may change how other medicine 
works in your body. 
Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your study 
doctor.  
Your study doctor’s name is 
_____________________________ and can be contacted 
at _________________________________.


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18.3d
Sunitinib Patient Drug Information Handout and Wallet Card
Information for Patients, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, sunitinib.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.
These are the things that you as a healthcare provider need to know:
Sunitinib interacts with a certain specific enzyme in your liver.
•
The enzyme in question is CYP 3A4.  Sunitinib is metabolized by CYP3A4 and may 
be affected by other drugs that inhibit or induce this enzyme.
To the patient: Take this paper with you to your medical appointments and keep 
the attached information card in your wallet.  
Sunitinib may interact with other drugs which can cause side effects.  For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll 
onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, include medicine you 
buy without a prescription (over-the-counter remedy), or any herbal supplements such as 
St. John’s Wort.  It is helpful to bring your medication bottles or an updated medication 
list with you.
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking 
part in a clinical trial.
These are the things that you and they need to know: 
Sunitinib must be used very carefully with other medicines that use certain liver enzyme.  
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered 
“strong inducers/inhibitors of CYP3A4.”
•
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.
•
Do not drink or eat grapefruit/juice or Seville oranges.
•
Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or 
discontinuing any medicine.  
•
Your study doctor’s name is _____________________________________ and he or 
she can be contacted at _____________________________________.


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STUDY DRUG INFORMATION WALLET CARD  
You are enrolled on a clinical trial using the experimental 
study drug sunitinib.  This clinical trial is sponsored by the 
NCI.  Sunitinib may interact with drugs that are processed by
your liver.  Because of this, it is very important to:
Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines.
Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial.
Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement.
Avoid ingesting grapefruit, grapefruit juice and Seville 
oranges.
Sunitinib must be used very carefully with other medicines 
that interact with CYP3A4 enzyme.
Before you enroll onto the clinical trial, your study doctor 
will work with your regular health care providers to review 
any medicines and herbal supplements that are considered 
“strong inducers/inhibitors CYP3A4.”
Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical 
reference for a list of drugs to avoid, or contact your study 
doctor.  
Your study doctor’s name is 
_____________________________ and can be contacted 
at _________________________________.


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18.4
Identification and Characterization of Oncometabolite-Induced DNA Repair Defects in 
Sporadic Papillary Kidney Cancer  
a.
Objectives:  
1.
To estimate the frequency of high oncometabolite levels in formalin-fixed, 
paraffin-embedded (FFPE) tissues of patients with advanced papillary 
renal cell carcinoma by liquid chromatography–mass spectrometry (LC-
MS/MS) and estimate progression free survival for those with and 
without high oncometabolite levels being treated.
  
2.
To correlate the mutational signature suggestive of a homologous 
recombination defect with high oncometabolite levels in patients with 
papillary renal cell carcinoma pRCC.    
b.
Brief justification:  
Papillary renal cell carcinoma (pRCC), although a rare disease, is the second 
most common form of kidney cancer and there no effective treatment options for 
patients with metastatic disease. Prior SWOG studies S0317 and S1107 have 
proven disappointing while the ongoing S1500 protocol had 2 arms closed for 
futility while two arms continue to accrue patients.  Accrual is expected to be 
completed on S1500 in late fall 2019.  Comprehensive genomic sequencing 
projects have greatly advanced our understanding of pRCC. (1)It is now 
established that both hereditary and sporadic RCCs harbor alterations in key 
tricarboxylic acid (TCA) genes, including the fumarate hydratase (FH) and 
Succinate Dehydrogenase (SDH) complex genes. Germline loss of FH leads to 
an aggressive kidney cancer syndrome known as Hereditary Leiomyomatosis 
and Renal Cell Carcinoma (HLRCC) where individuals are at risk to develop a 
lethal form of RCC often appearing similar to type 2 pRCC. (2) SDH mutations 
are associated with a second form of inherited RCC, referred to as SDH-RCC.
(3) HLRCC- and SDH-RCC-associated tumors produce extremely high levels of 
fumarate and succinate, respectively, which drive tumorigenesis via the inhibition 
of αketoglutarate (αKG)-dependent dioxygenases. (4) It was recently discovered 
that the (S) enantiomer of 2HG (S-2HG) is produced in subsets of sporadic renal 
tumors, which also potently inhibits 
αKG-dependent dioxygenases.
(5,6) 
Collectively, these “oncometabolites” represent novel therapeutic targets. 
The homologous recombination (HR) pathway is responsible for double strand 
DNA repair. Our team recently discovered that oncometabolites induce HR 
defects which render tumor cells exquisitely sensitive to poly(ADP)-ribose 
(PARP) inhibitors.
(7) We initially reported this finding in isocitrate 
dehydrogenase-1 and -2 mutant cancers, and we recently extended our findings 
to HLRCC- and SDHRCC-associated tumors.
(8) Furthermore, our new 
preliminary data suggests that subsets of sporadic pRCCs exhibit a similar 
phenotype, which forms the basis for this proposal. Our findings reveal a novel 
pathway by which tumors acquire an HR-defective phenotype, in the absence of 
BRCA1/2 mutations, often referred to as BRCAness. Our discovery is now being 
directly translated into an ongoing phase II trial with IDH1/2mutant tumors with 
PARP-inhibitor, olaparib. We have already observed efficacy signals in several 
patients including an IDH1-mutant chondrosarcoma and an IDH-1 mutant glioma, 
suggesting our findings are clinically relevant. 
Based on these findings and that some forms of sporadic pRCC can have a 
similar metabolic HLRCC phenotype, we hypothesize that subsets of advanced 
pRCC exhibit oncometabolite-induced BRCAness, which can be exploited with 
PARP inhibitors. We will validate that these tumors have prespecified levels 


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consistent with known HLRCC samples.  The S1107 and S1500 trials have 
enrolled large subsets of patients with metastatic pRCC, an orphan disease 
where translation of preclinical science to the bedside is hindered by lack of 
available samples. Therefore, samples from this trial are an ideal cohort to test
the hypothesis that there are a subset of patients with massively elevated levels 
of oncometabolites (Aim 1). We will utilize a novel methodology recently 
developed by our team (accepted to Scientific Reports) that will allow us to 
qualify 
the 
oncometabolite 
levels 
in 
archival formalin- 
fixed, 
paraffin 
embedded 
(FFPE) 
specimens. We previously demonstrated 
that a subset of pRCC submitted to the 
TCGA 
has 
a 
mutational 
signature 
suggestive of a defect in homologous 
recombination. 
In 
parallel, 
we 
will 
determine 
whether 
high 
levels 
of 
oncometabolites suggestive of the HLRCC 
phenotype can be linked to the mutational 
signatures suggestive of a defect in 
homologous recombination (Aim 2).  
The potential impact of our translational 
medicine proposal is that it will provide 
further insight into how common the 
oncometabolite-induced, HR defect is in 
sporadic pRCC and set the foundation to 
design 
rational, 
biologically 
targeted 
clinical trials focused on exploiting this 
unique biology. This proposal will also 
leverage the strength of a recently
established, 
cross-disciplinary 
collaboration between the laboratories of 
Drs. Shuch, Bindra and Li. Lead PI Dr. 
Shuch is a surgeon-scientist and an early-
stage investigator (ESI) at the UCLA School of Medicine, with a major interest in 
the genetic characterization and clinical management of RCC (9, 10, 11, 12, 13, 
14, 15, 16 17) Co-PI Dr. Bindra is a physician-scientist and clinical trialist at 
Yale, who is focused on developing novel synthetic lethal strategies to target 
solid tumors. (18, 19, 20, 21, 22) 
Finally, co-PI Dr. Li is an expert in 
metabolomics at the Karmanos Cancer Institute. (23, 24, 25, 26, 27, 28, 29, 30, 
31, 32, 33, 34)  
c.
Eligibility:  
Subjects with metastatic papillary kidney cancer treated on S1500 who submitted 
tissue. 
d.
Clinical Endpoint to be used in analyses:  
Although not the primary focus of the project, patients with high oncometabolite 
levels will be compared to those without high levels in terms of progression-free 
survival. 
e.
Experimental 
approach, 
validated 
assays 
employed 
and expertise of PI:  
  
Fig. 1. Fumarate and succinate levels in 
normal kidney and RCC tissues vs HLRCC 
and SDH tumors 
Fig. 2 Fumarate levels from sporadic papillary cancers at 
UCLA (U) and Yale (Y) (frozen samples).  Some of the 
specimens have >5-10mmol concentrations.


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Aim 1: Estimate the frequency of high oncometabolite levels in formalin-
fixed, paraffin-embedded (FFPE) tissues of advanced pRCC by LC-MS/MS. 
The central hypothesis of Aim1 is that a significant subset of pRCC produces
high levels of oncometabolites.  We have previously demonstrated that massive
elevations of fumarate, succinate, or 2-HG can induce a BRCAness phenotype, 
seen in IDH1/2-mutant, HRLCC kidney cancer, and SDH-associated tumors.  
Our
hypothesis
is 
supported by: 
(a) 
previous 
reports 
of 
elevated 
S-
2HG in cases 
of 
sporadic 
RCC 
(~10% 
of cases),5,6
(b) 
our 
preliminary 
data showing 
abnormally 
high fumarate 
and/or 
succinate 
levels 
in 
sporadic RCC
cases 
(Fig.2), 
and c) the fact 
that 
some 
sporadic pRCC 
are 
in 
fact 
unidentified 
HLRCC cases or are HLRCC-like (despite having no germline FH mutation). 
Here, we will determine oncometabolite levels in a large cohort of pRCC FFPE 
specimens from two SWOG trials.  We will quantitate oncometabolites (including 
succinate, fumarate, total total 2-HG, and R- and S-2HG enantiomers) in pRCC 
FFPE specimens by using a multiplex LC-MS/MS platform that has been 
established in the Li laboratory and has been accepted for publication (Scientific 
Reports). (35) In brief, FFPE tissue will be deparaffinizated and aliquots of tissue 
homogenate will be subjected to LC-MS/MS analysis of succinate, fumarate, and 
2-HG. (36, 37, 38) No LC-MS/MS methods have been published for profiling 
oncometabolites in FFPE tissue, however the Li laboratory has successfully 
developed and validated a multiplex LC-MS/MS platform that allows 
simultaneous determination of succinate, fumarate, total 2-HG, and R- and S-
2HG
enantiomers in FFPE tissues. The lower quality control (LQC) 
concentrations for this assay based on spike-in experiments are 0.06, 0.2, and 
0.006 μM of succinate, fumarate and 2-HG spiked in FFPE. The succinate/ 
alpha-keto-glutarate and fumarate/alpha-keto-glutarate ratios can also be used to 
accurately measure of the true concentration of oncometabolites for FFPE tissue. 
Normal kidney tissue FFPE specimens (not from SWOG trials) will be included 
as negative controls as we have demonstrated that fumarate levels are generally 
less than 25 uM in frozen tissue and less than the lower limit of 0.2 uM in the 
FFPE specimens. HLRCC, SDH-RCC, and IDH1/2 mutant glioma tissues with 
known oncometabolites will be used as positive controls. While 99% of fumarate 
is lost with fixation, to date all confirmed HLRCC kidney specimens run with 
FFPE assay (n=12) have detectable levels of fumarate at concentrations 
exceeding 1.5 umol/g of tissue) (Figure 3).  
Figure 3:  FFPE samples from HLRCC kidney cancers 
(high) and matched tumor/normal cases from sporadic 
renal tumors (less than lower limit of quantification)


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Aim 2: Correlate the mutational signature suggestive of a homologous 
recombination defect with high oncometabolite levels in patients with 
papillary renal cell carcinoma pRCC.    
Exome sequencing is ongoing as part of an already approved TM study with 
BIQSFP funding in SWOG S1500. A clinical pipeline with strict mutational calls
has been applied to interrogate clinically relevant cancer genes including MET, 
the integrated biomarker of the trial. To evaluate alterations across the entire 
exome, BAM files will be reprocessed and exome mutation calls performed with 
Mutect2. (39) Interrogation of mutations that could lead to the oncometabolite 
and HRD phenotype will be performed for germline and somatic alterations. 
Critical TCA genes (n= 32, from Gene set enrichment analysis (GSEA) set, 
M3985) will be analyzed since if these metabolic enzymes were altered, there 
may be an upregulation of structurally similar oncometabolites. While FH, the 
SDH genes, and IDH1/2, have been well-characterized, there is emerging data 
that other genes if altered, can lead to metabolic dysregulation and cancer. (40, 
41, 42) Similarly, a HR gene set (n=28, from GSEA set M11675) will be analyzed 
to see if other alteration could lead to double-strand DNA damage. Any 
alterations in both gene sets will be confirmed in the TCGA pRCC dataset. 
Different mutational processes such as exogenous or endogenous mutagen 
exposure may generate somatic single-nucleotide variants (sSNVs) with a unique 
nucleotide context pattern (signatures). Since nucleotides are paired, there are 
only six possible base substitutions (C>A, C>G, C>T, T>A, T>C, and T>G). 
Additional information on the adjacent 5’ and 3’ base to the sSNV can be useful 
to distinguish a particular mutational signature. Beyond sSNV patterns, signature 
3 (Figure 4) is associated with high number of large insertion/deletions with 
microhomologous 
sequences 
flanking breakpoints due to an 
“alternative (or salvage)” DNA 
repair 
process: 
nonhomologous end joining.  
To identify signatures in the
mutation 
spectra, 
post-
processing of the variant call 
files (VCF) will be 
performed. We will use a
robust, 
objective 
regression 
method 
(least 
absolute 
shrinkage 
and 
selection 
operator- LASSO) to identify 
operative mutational signature 
from 30 established signatures 
downloaded 
from 
COSMIC.
(43) This methodology has 


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been performed in our prior work with pRCC approximately 25% of TCGA 
samples had a suggestive signature of a defect in HR (Figure 5). (44) The 
oncometabolite and DNA mutational profile from aims 1 will be correlated with 
the mutational signature 3. 
f.
Statistical Plan:  
Statistical Analyses will be conducted in conjunction with the SWOG Statistical 
Center under the direction of Dr. Catherine Tangen’s team. 
  
Based on submission rates for S1500 and the trial accrual goal of 148 (currently 
at 132), we anticipate receiving adequate tissue specimens for at least n=120 
patients. We have not had any issues with this assay so expect all cases with 
available tissue to be successfully run. S1107 has residual tissue at City of Hope 
that can be used from 16 subjects once proper MUA agreements have been 
executed.  With both cohorts we would have a total sample size of ~136 patients 
with metastatic pRCC that have FFPE tissue available for this project.  Used 
tissue from S1107 and the current TM project for S1500 will not be returned to
Nationwide for banking.   
Aim 1 will evaluate oncometabolites in FFPE specimens from S1500 and S1107
patients. Based on the published data, 7-12% of pRCC should behave like 
HLRCC kidney cancer. 
Elevations in tumors with Krebs Cycle defects have massive elevation of 
metabolites by a factor of 50100X. Much of the fumarate is lost with formalin 
fixation, therefore only samples with very high levels will be identified (the 
presence/absence) with very high levels for the fumarate or alpha-keto-glutarate 
ratio (figure 3). We will determine the frequency of cases with HLRCC-like levels 
of oncometabolites. With a sample size of 136 patients, we will be able to 
estimate the proportion with high oncometabolite levels to within at least +/-9% 
(95% confidence interval).  If 12% have high oncometabolite levels, we’d expect 
16 patients in this group and 120 without high levels.  Descriptive Kaplan-Meier 
curves of progression-free survival will be generated, stratified by presence or 
absence of high oncometabolite levels.  
Aim 2 will correlate the mutational landscape with oncometabolite-induced DNA 
repair defects in pRCC.  Specifically, we will correlate mutational signature 3 
(present vs. absent) using established COSMIC signature. We will compare the 
having measurable oncometabolites with by LC-MS/MS to the mutational 
signature. Based on our prior work with TCGA data, we estimate that 25% of the 
patients will have a signature 3 (i.e., n=34), leaving 102 without the signature.  A 
generalized chi-square will be used to evaluate the association between positive 
mutational panel status and high oncometabolite levels.  
g.
Data analysis performed by:  
Assays developed by Drs. Shuch, Bindra, and Li will be employed for 
oncometabolite and DDR detection as shown above. Evaluation of the exome 
sequencing will be performed by Dr. Shuch and members of Dr. Paul Boutros’ 
computational biology laboratory. Members of the Boutros lab are experts at 
deconvoluting mutational signatures and will perform that particular analysis 
similar to what was performed with whole genome samples from the Cancer 
Genome Atlas pRCC cohort. (16)  These data will be shared with the SWOG 
Statistical Center where estimation and correlations will be performed. 


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h.
Who will be performing testing?  
Brian Shuch, MD (UCLA)
Ranjit Bindra, MD PhD 
(Yale) 
Jing Li, PhD (Karmanos) 
UCLA School of Medicine 
Factor Health Science Bld. 
Room 12-956 
700 Tiverton Avenue, 
Los Angeles, CA 90095 
Yale School of Medicine 
789 Howard Avenue,  
New Haven CT 06460 
Karmanos Cancer Institute 
Wayne State University  
School of Medicine 
4100 John R, 
HWCRC/Room 523 
Detroit, MI 48201 


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Shim EH, Sudarshan S: Another small molecule in the oncometabolite mix: L-2Hydroxyglutarate 
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Shim EH, Livi CB, Rakheja D, et al: L-2-Hydroxyglutarate: an epigenetic modifier and putative 
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Giles RH, Choueiri TK, Heng DY, et al: Recommendations for the Management of Rare Kidney 
Cancers. Eur Urol 72:974-983, 2017.
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Shuch B, Hahn AW, Agarwal N: Current Treatment Landscape of Advanced Papillary Renal 
Cancer. J Clin Oncol 35:2981-2983, 2017.
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Li S, Shuch BM, Gerstein MB: Whole-genome analysis of papillary kidney cancer finds significant 
noncoding alterations. PLoS Genet 13:e1006685, 2017. 


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17
Shuch BM, Lam JS, Belldegrun AS, et al: Prognostic factors in renal cell carcinoma. Semin Oncol 
33:563-75, 2006.
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Sulkowski PL, Corso CD, Robinson ND, et al: 2-Hydroxyglutarate produced by neomorphic IDH 
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Goglia AG, Delsite R, Luz AN, et al: Identification of novel radiosensitizers in a high-throughput, 
cell-based screen for DSB repair inhibitors. Mol Cancer Ther 14:326-42, 2015.
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King AR, Corso CD, Chen EM, et al: Local DNA Repair Inhibition for Sustained Radiosensitization 
of High-Grade Gliomas. Mol Cancer Ther 16:1456-1469, 2017.
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Surovtseva YV, Jairam V, Salem AF, et al: Characterization of Cardiac Glycoside Natural 
Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double 
Immunofluorescence Assay. J Am Chem Soc 138:3844-55, 2016. 
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addacha W, Koyen AE, Bastien AJ, et al: SAMHD1 Promotes DNA End Resection to Facilitate 
DNA Repair by Homologous Recombination. Cell Rep 20:1921-1935, 2017.
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Wiegand R, Wu J, Sha X, et al: Validation and implementation of a liquid chromatography/tandem 
mass spectrometry assay to quantitate aminoflavone (NSC 686288) in human plasma. J 
Chromatogr B Analyt Technol Biomed Life Sci 877:1460-4, 2009.
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Wiegand R, Wu J, Sha X, et al: Simultaneous determination of ABT-888, a poly (ADP-ribose) 
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spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:333-9, 2010.
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Wiegand R, Wu J, Shields AF, et al: Simultaneous determination of 1-(2'-deoxy2'-fluoro-beta-D-
arabinofuranosyl) uracil (FAU) and 1-(2'-deoxy-2'-fluoro-beta-Darabinofuranosyl) 5-methyluracil 
(FMAU) in human plasma by liquid chromatography/tandem mass spectrometry. J Chromatogr B 
Analyt Technol Biomed Life Sci 891-892:64-70, 2012.
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Wu J, Wiegand R, LoRusso P, et al: A stable isotope-labeled internal standard is essential for 
correcting for the interindividual variability in the recovery of lapatinib from cancer patient plasma 
in quantitative LC-MS/MS analysis. J Chromatogr B Analyt Technol Biomed Life Sci 941:100-8,
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Li J, Kim S, Sha X, et al: Complex disease-, gene-, and drug-drug interactions: impacts of renal 
function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics. Clin Cancer Res 
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Shaw J, Wiegand R, Wu J, et al: A liquid chromatography with tandem mass spectrometry 
method for simultaneous determination of UTL-5g and its metabolites in human plasma. J 
Chromatogr B Analyt Technol Biomed Life Sci 991:92-8, 2015.
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Wu J, Zhang Y, Wiegand R, et al: Quantitative analysis of intracellular nucleoside triphosphates 
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31
LoRusso PM, Li J, Burger A, et al: Phase I Safety, Pharmacokinetic, and Pharmacodynamic 
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with Irinotecan in Patients with Advanced Solid Tumors. Clin Cancer Res 22:3227-37, 2016.
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Li J, Wu J, Bao X, et al: Quantitative and Mechanistic Understanding of AZD1775 Penetration 
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Approach. Clin Cancer Res 23:7454-7466, 2017. 
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Bao X, Wu J, Shuch B, et al: Quantitative Profiling of Oncometabolites in Frozen and Formalin-
Fixed Paraffin-Embedded Tissue Specimens by Liquid Chromatography Coupled with Tandem 
Mass Spectrometry. Scientific Reports, 2019. (Accepted)
36
Struys EA, Jansen EE, Verhoeven NM, et al: Measurement of urinary D- and L-2hydroxyglutarate 
enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after 
derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50:1391-5, 2004  
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18.5
Specimen Banking and Translational Medicine Material Instructions for SWOG 
Biospecimen Bank (BB)
FFPE for Independent Pathology Review, NGS Analysis, and Banking
For each patient, the SWOG BB will receive either 1 FFPE tissue block or 12-20 
unstained charged slides with 1 H&E stained slide from the pre-study biopsy.  Upon 
receipt, the Bank will accession, barcode, and bank FFPE tissue blocks or slides at 
ambient temperature until distribution. 
The Bank will cut a slide and H&E stain (4-5 µm) from the specimens received as FFPE 
blocks, and scan the H&E slide up to 2 times per case at 40X magnification for 
Independent Pathology Review in batches of 20 cases.  Independent pathology review 
will be conducted with the Bank’s Virtual Imaging for Pathology, Education & Research 
(VIPER) application; the Bank will create an electronic pathology data form. 
At each quarter of enrollment (n=41), the Bank will receive a case list for distribution from 
the SWOG Statistics and Data Management Center, and then will prepare and distribute 
the FFPE tissue block (when available) or up to 20 unstained slides and a copy of the 
corresponding pathology report to Yale School of Medicine for next-generation 
sequencing (NGS) analysis at the address below:
Brian Shuch, MD/Urology Laboratory
Yale School of Medicine
Brady Memorial Laboratory
310 Cedar Street, BML 246
New Haven, CT 06510
After NGS analysis, residual FFPE specimens will be returned in batches to the SWOG 
Biospecimen Bank to store for future research. 
Additionally, the SWOG BB will receive frozen, processed plasma, buffy coat, and serum 
aliquots from up to 4 time points per patient: pre-study, Weeks 7 and 13, and at follow-up 
after progression. Upon receipt, the Bank will accession and barcode the frozen cryovials 
of plasma, buffy coat, and serum to store in a -80°C freezer for future TM studies (TBD). 
For NGS analysis, one aliquot of the buffy coat from one time point (preferably pre-study 
time point) per patient as the reference genomic sequence will be sent to Yale School of 
Medicine with the tissue samples.